CA2263441A1 - Naphtholactams and lactones as bone morphogenetic protein active agents - Google Patents

Naphtholactams and lactones as bone morphogenetic protein active agents Download PDF

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CA2263441A1
CA2263441A1 CA002263441A CA2263441A CA2263441A1 CA 2263441 A1 CA2263441 A1 CA 2263441A1 CA 002263441 A CA002263441 A CA 002263441A CA 2263441 A CA2263441 A CA 2263441A CA 2263441 A1 CA2263441 A1 CA 2263441A1
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alkyl
carbamoyl
mono
group
optionally
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Masaki Ogino
Masatoshi Hazama
Kohei Notoya
Shogo Marui
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Takeda Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C07D209/64—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with an oxygen atom in position 1
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/58—[b]- or [c]-condensed
    • C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
    • C07D209/66—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with oxygen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Abstract

A compound of formula (I) wherein Q is an optionally substituted carbon atom or N(O)p wherein p is 0 or 1; Y is an optionally substituted methylene group, S(O)q wherein q is an integer of 0 to 2, or an optionally substituted imino group; Z1 is a C1-3 alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain; Z2 is an optionally substituted C1-3 alkylene group; Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and R2 is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group; the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group; or R1 and R2 taken together with adjacent -c=c- form a ring; and ring A
is a benzene ring which may be substituted in addition to R1 and R2; or a salt thereof.

Description

WO 98l07?OS PCT/JP97102858 DESCRIPTION
Fused cyclic compound, Their Production and Us TECHNICAL FIELD
This invention relates to fused cyclic compounds having very satisfactory bone morphogenetic protein (BMP) like and/or neurotrophic factor [for example, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and filial cell line-derived neurotrophic factor (GDNF)] -like activity or enhancing activity of BMF and/or neurotrophic factor activity, to a technology for producing the compound, and to relevant pharmaceutical compositions.
BACKGROUND ART
Bone morphogenetic proteins (BMPs) are the family of proteins isolated from demineralized bone and known to be able to induce ectopic bone formation. As such, BMP is of value as a bone formation promoting agent for bone fracture healing and bone remodeling [A. E. Wang, Trends Biotechnol., 11, 379-383, I993].
Furthermore, since it directly promotes osteoblast differentiation, BMP is supposed to be playing the role of a coupling factor in bone remodeling and is, therefore, considered to be closely associated with bone metabolism. It has also been reported that the BMP content of bone matrix in aged animals has been considerably depressed [M. L. Urist, Bone and Mineral Research, 6 (ed by W. A. Peck), 57-112, Elsevier, l989], indicating that BMP is closely related to the maintenance of bone mass. This finding suggests that BMP may be a promising drug for the treatment of various diseases of bone, such as osteoporosis.
However, HMP usually exists only in trace amounts in the organisms, and sources of its supply were limited.
Moreover, as it is a protein, the routes of SU65TiT1JTE SHEET (RULE 26) administration are restricted, and therefore the spectrum of diseases which can be treated is quite limited.
It has also been reported that BMP has neurotrophic factor-like activity [V. M. Paralkar et al., J. Cell Biol., 119, I721-1728, 1992J. Also known is an intense expression of the BMP gene in the brain tissue [E. Ozkaynak et al., Biochem. Biophys. Res.
Commun., 179, 116-123, 1991]. It has also been suggested that BMP is playing an important rule in the formation of the neural tube during embryonic development [K. Basler et al., Cell, 73, 687-702, 1993]. It is, therefore, believed that BMP is closely involved in the differentiation or functional maintenance of nerve cells.
Neurotrophic factor (NTF) is a family of proteins playing important roles in the maintenance of neuron and functional expression of neurons and includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF}, neurotrophin-3 (NT-3), and glial cell line-derived neurotrophin factor (GDNF}, among others. NGF
in the peripheral nervous system promotes the differentiation and maturation of the neural crest sympathetic ganglion and dorsal root ganglion cells [A.
M. Davies & R. M. Lindsay, Dev. Biol., ~1, 62-72, l985; R. Levi-Montalcini, EMBO J., ~, 1145-1154, 1987]
and in the central nervous system acts on the cholinergic neurons of septa (forebrain basal ganglia) [H. Gnahn et al, Dev. Brain Res., 9_, 45-52, 1983; H.
Hatanaka & H. Tsukui, Dev. Brain Res., ~, 47-56, 1986;
F. Hefti, J. Neurosci., 6, 2155-21b2, 1986]. NGF is necessary for the maintenance of nerve function even after completion of differentiation of neurons. BDNF
in the peripheral nervous system acts on the dorsal root ganglion and nodular ganglion cells but does not act on sympathetic ganglion cells [R. M. Lindsay & H.
SUBSTITUTE SHEET (RULE ~fi) Rohrer, Dev. Biol., 112, 30-48, 1985; R. M. Lindsay et al., Dev. Biol., 112, 3l9-328, 19B5; A. M. Davies et al., J. Neurosci., 6_, 1897-1904, 1986]. In the central nervous system, BDNF acts on the cholinergic neurons and GAGA (y-aminobutyric acid)-nergic neurons of septa and the dopaminergic neurons of midbrain [R. F.
Alderson et al., Neuron, 5, 297-306, 1990; C. Hyman et al., Nature, ,~50, 230-232, 1991; B. Knusel et al., Proc. Natl. Acad. Sci. USA, 88, 961-965, 1991]. The activites of NT-3 on the peripheral nervous system are similar to that of NGF and BDNF, however NT-3 characteristically acts strongly on neural placodes-derived sensory neurons (P. Ernfors et al., Proc. Natl.
Acad. Sci. USA, 87, 5454-5458, 1990; A. Rosenthal et al., Neuron, 4, 767-773, 1990J. In the central nervous system, however, there is not known a nerve cell responsive to NT-3.
GDNF promotes the survival and morphelogical differentiation of dopaminergic neurons and increases their high affinity dopamine uptake [L-F. H. Lin et al., Science, 2 0, 1l30-1132 (1993)].
In Alzheimer type dementia, the degeneration and exfoliation of cholinergic neurons of the forebrain basal ganglia inclusive of septa and an extensive lesion and exfoliation of cerebrocortical neurons have been observed. The NGF and neurotrophic factors discovered more recently are considered among candidate therapeutic drugs for this disease (F. Hefti & W. J.
Weiner, Annu. Neurol., 20, 275-281, 1986].
Furthermore, in Parkinson's disease which is a syndrome involving the degeneration and exfoliation of dopaminergic neurons of midbrain, BDNF and GDNF as ~ neurotrophic factors for the associated neurons have been considered to be a promising therapeutic drugs.
However, since those neurotrophic factors are proteins, their applicability is limited.
SUBSTITUTE SHEET (RULE 2fiy As compounds in the lactose series which are of use as synthetic intermediates for the fused cyclic compound (IJ of the present invention, the following compounds have been disclosed.
(1) Helioxanthin, which has the following formula [R. S. Burden et al., J. Chem. Soc. (C), 693-701, 1969) (2) Compounds of the following formulas Cl Me0 Me Me O Me [Arch. Pharmacol., Q28_ (9), 640-644g 199S) (3) Compounds of the following formulas Me0 / / Me0 \ \ ~ o ~ \ \
Me0 ~' ~ Me0 OMe OMe i Me0'~ ~ ~OMe Me0 ~ ~~OMe OMe OMe [Indian J. Chem., Sect. B: Org. Chem. Include. Med.
Chem., 338 (9), 839-846, 1994j SUBSTiTLITE SHEET (RULE Z6) (4) Compounds of the following formulas Me Me /~ /
Me0/\ ~ ~ Me0 OMe / Me Me0 OMe OMe [Indian J. Chem. Sect. B: 31B (7], 401-406, 1992]
(S) Compounds of the following formulas OAc O
Me0 / / , Me0 Me ~H
MeO~~
Me0 Me OMe \ ~i CChem. Pharm. Hull., ~ (1), 31-7, 1984j (6) Compounds of the following formulas R r p a ~etrohelioxanthin helioxanthin (J. Chem. Soc. ~, (11), 2091-2094, 1971]
(7) Compounds of the following formula SUBSTITUTE SHEET (RULE 26) W O 98l07705 OMe PCTlJP97102858 / /

1e0 OH /
\ i ' H 0 ~. ~~
HU
HOJ
to ~ ~ I ~~ ~ / I
Ate 0 ~ \ ~ ~O~ \ o H0~ OMe ~ I I OMe / _ \ ~ ~ I

H 0~
[Phytochemistry, ,2~ (9), 2991-2993, 1990) (8) Compounds of the following formulas w w w w w w 2a o I ~ ~ o o~p ~~v o p ~ o Lo i ~ i \! ~ \ ~ J
OMe OAc OH
25 (Journal of Natural Products, 43 (4), 482-486, 19B0) (9) A compound of the following formula [J. Chem. Soc. ~, (5), 693-701, 1969) However, none of the above publications disclosing those lactone compounds (1) through (9) mention or even suggest the excellent activities of the fused cyclic SUBSTtTIJTE SHEET tRULE 26) WO 98l07705 PCTIJP97102858 compounds of the present invention as cell differentiation inducing factors, such as bone morphogenetic protein (BMP) or neurotrophic factor (NTF], or activity of enhancing the cell differentiation inducing factor.

The foregoing suggests that compounds which enhance the activities of BMP can enhance the activities of BMP in vivo, whether endogenous or exogenous, and as such would be of value as a therapeutic agent for the above-mentioned diseases of bone. The substances reported to date as having such enhancing effects on BMP activities are retinoic acid, vitamin D3, estrogen, and glucocorticoids [V. Rosen R. S. Thies, Trends Genet., 8_, 97-102, 1992; Y. Takuwa et al., Biochem. Biophys. Res. Commun., Q74, 96-101, 1991]. However, it is known that when administered, those substances promote bone resorption and/or cause such adverse reactions as hypercalcemia and ovarian cancer, and are thus not fully satisfactory as therapeutic drugs for diseases of bone.

Meanwhile, any compound capable of enhancing NTF

activity should be able to enhance the activities of NTF in vivo, whether endogenous or exogenous, and be of value as a therapeutic drug for dementia and peripheral nervous disorders. As compounds enhancing activities of NGF, sabeluzole (4-(2-benzothiazolylmethylamino)-a,-(p-fluorophenoxy)methyl]-1-(piperidine)ethanol) has been reported [New Current, 4, 26, 14, 1993]. However, its mechanism of action is not known and because such adverse reactions as headache, dizziness, and fatigue have been reported in clinical trials, this compound is not necessarily a suitable therapeutic drug for nerve . diseases. Aside from the above, 5R57746A

[Neuroscience, 55, 629, 1993), T-588 [JP Kokai H4-95070j, and MS430 [J. UOEN, ~, 131, 1995] are also claimed have NGF-like activity. SR57746A and T-58B are SUHS'i~TtJTE SHEET (RULE 26) WO 98l07705 PCT/JP97102858 currently under clinical investigation in Alzheimer's disease but their efficacy in humans has not been established. As to MS430, its activity is suspected to be insufficient. As compounds up-regulating endogenous NGF, steroids, catechols, and cytokines have been reported (Experimental Neurology, 124, 36-42, 1993).
However, some of those compounds are neurotoxic or have pharmacologically unfavorable actions that compromise immunological potency or cause hypercalcemia, IO accelerated bone resorption, etc. and because no clear line of demarcation can be drawn in the state of the art between the NGF secretion inducing effect and the adverse effect on tissues other than the nervous system, those compounds are not fully satisfactory for clinical application.
Furthermore, since cell differentiation inducing factors represented by BMP and neurotrophic factors are proteins, their administration to the living body is limited. Thus, compounds which enhance the cell differentiation inducing factors, whether endogenous or exogenous, are preferably of low molecular weight.
Assuming that a compound itself has cell differen-tiation inducing activity which is typically possessed by BMP and neurotrophic factors, it is considered that, if its molecular weight is low, the compound can be used with greater advantage than BMP and neurotrophic factors for application to the living body as a drug for promoting bone formation and bone remodeling or a therapeutic drug for dementia and peripheral nerve diseases.
As low molecular-weight compounds known to promote the proliferation and differentiation of osteoblasts, ipriflavone [K. Notoya et al., J. Bone Miner. Res., 395-400, 1994), vitamin K2 (Y. Akedo et al., Biochem.
Biophys. Res. Commun., 1 7, 814-820, 1992), etc. are known but none of those known substances have ectopic SUBST1?'UTE SHEET (RULE 26) WO 981077U5 PCTlJP97102858 osteoinductive activity like BMP.
As compounds having neurotrophic factor-like activities such as neurite sprouting activity and ~ promotion of the survival of neurons lactacystin (S.
Omura et al., J. Antibiot., 40, 113-117, 1991J, retionic acid (M. Minana et al., Prod. Natl. Acad. Sci.
USA, 87, 4335-4339, 1990], staurosporine (T. B. Shea et al., J. Neurosci. Res., 33, 398-407, 1990], K252a (G.
D. Borasio et al., Neuroscience Letters, 108, 207-212, 1990], and MS818 (A. Awaya et al., Biol. Pharm. Bull., 16, 248-253, 1993], among others, are known. It is reported that above-mentioned SR57746A and MS430 have not only enhancing activity but also neurotrophic factor-like activity by themselves, too. However, as to SR57746A, among them, its efficacy in humans has not been established as pointed out above, while the other compounds are not fully satisfactory for clinical application, either, in terms of the levels of activity and toxicological risk. Therefore, there has been a real need for development of a compound having satisfactory BMP or neurotrophic activity or the corresponding agonist activity from among compounds structurally different from the above known substances.
In view of the above state of the art and for the purpose of developing a low-molecular-weight drug substance having BMP- or neurotrophic factor-like activity or the specific enhancing effect on the differentiation of osteoblasts and neurons and promotion of the survival of neurons, the inventors of the present invention explored for low molecular compounds which would exhibit cell differentiation inducing factors activity or enhancing effect on these ' factors. As a consequence, the inventors succeeded for the first time in the creation of a novel compound of - 35 the following formula (I], inclusive of its salt.
SUBSTTTUTE SHEET (RULE 2fi) WO 98I07705 PCTlJP97102858 ~1 1 A I ~ \Y
R \ i .... R2 Ar Z2 [I]
wherein Q is an optionally substituted carbon atom or N(0)p wherein p is 0 or 1;
Y is an optionally substituted methylene group, S(0)q 10 wherein q is an integer of 0 to 2, or an optionally substituted imino group;
Z1 is a C,_i alkylene group which may have an oxo group or a thioxo group;
ZZ is an optionally substituted C1_3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and RZ is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group;
the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkvxy group; or R1 and RZtaken together with adjacent -c=c- form a ring; and rind A is a benzene ring which may have a substituent in addition to R1 and RZ; or a salt thereof. The inventors further found that the above compound [I] and its salt have unexpectedly high BMP-like activity, neurotrophic factor-like activity or the corresponding enhancing activity and are well qualified as medicines.
The present invention has been developed on the basis of the above finding.
DISCLOSURE OF INVENTION
The present invention, therefore, is directed to:
1. A compound of the formula:
SUHSTtTUTE SHEET (RULE 26~

ZI
\ Y' Z
. ...
wherein Q is an optionally substituted carbon atom or N(0)p wherein p is 0 or 1;
Y is an optionally substituted methylene group, S(0)q wherein q is an integer -of 0 to 2, or an optionally substituted imino group;
Z1 is a C1_~ alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain;
ZZ is an optionally substituted Ci_3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and Rz is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group;
the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group; or RI and RZtaken together with adjacent -c=c- form a ring; and ring A is a benzene ring which may be substituted in addition to R1 and RZ; or a salt thereof, 2. A compound as described in the above item 1, wherein Q is (A) CR4 wherein R4 is (1) a hydrogen atom, (2) a halogen atom, (3) a C,_,6 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C,_~
alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C~_~
SUBST1TLJTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 alkyl optionally having 1 to 3 halogen atoms, {vi) a C3_~ cycloalkyl, (vii) a C1_6 alkoxy which may be substituted with amino, mono- or di-C~_6 alkylamino or C,_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x} an amino, {xi) a mono-C1_6 alkylamino, (xii) a di-Ci_6 alkylamino, (xiii} a C1_6 alkyl-carbonyl, (xiv) a C1_6 alkyl-carbonyloxy, (xv) a C1_6 alkyl-carbonyloxy-C1_3 alkyl, (xvi} a carboxyl, (xvii) a C1_6 alkoxy-carbonyl, {xviii) a mono-C1_6 alkylamino-carbonyl, (xix) a di-C1_~
alkylamino-carbonyl, (xx) a carbamoyl, {xxi) a mono-C,_~
alkyl-carbamoyl, (xxii} a di-C1_6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1_6 alkylsulfonyl, (xxv) a C~_ to aryl, ( xxvi ) a C6_lfl aryloxy, ( xxvii ) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, {xxix) mono-C1_6 alkylthio-carbamoyl, ( xxx ) di-C1_6 alkylthio-carbamoyi , ( xxxi } C6_lo aryl-carbamoyl and {xxxii) C6_lo aryl-thiocarbamoyl, or (4) a hydroxyl group which may be substituted with a C1_16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1_3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3_6 cycloalkyl, (vii) a C~_~
alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C,_6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C,_6 alkylamino) (xii) a di-C1_~ alkylamino, (xiii) a C1_6 alkyl-carbonyl, SUBSTiTLJTE SHEET (RUL~ 26) {xiv) a C,_6 alkyl-carbonyloxy, (xv) a C,_6 alkyl-carbonyloxy-Ci_~ alkyl, (xvi) a carboxyl, {xvii) a Ci_6 alkoxy-carbonyl, (xviii) a mono-Ci_~ alkylamino-carbonyl, (xix) a di-C,_6 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-Ci_6 alkyl-carbamoyl, (xxii) a di-C1_6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1_6 alkylsulfonyl, (xxv) a C6_lo aryl, (xxvi) a C6_lo aryloxy, (xxvii) a S- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-CS_6 alkylthio-carbamoyl, (xxx) di-C1_6 alkylthio-carbamoyl, (xxxi) C6_ to aryl-carbamoyl and ( xxxii ) C6_lo aryl-thiocarbamoyl;
or (B) N(O)p wherein p is 0 or 1;
Y is (1) a group of the formula:
jC\Rs R9, wherein R9 and R9~ may be the same or different and each is (i) a hydrogen, (ii) a C1_6 alkyl which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (iii) a C,_6 alkoxy optionally having 1 to 3 halogen atoms, (iv) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (v) a hydroxyl, (vi) a cyano, (vii) a C1_6 alkyl-carbonyl, (viii) a C,_6 alkyl-carbonyloxy, (ix) a formylamino, (x) an amino, (xi) a mono-Ci_6 alkylamino, (xii) a di-C,_b alkylamino, (xiii) a carboxyl, (xiv) a C1_6 alkoxy-carbonyl, or (xv) a C1_,, alkyl-carbonylamino;
(2) a group of the formula:
jC=R10 wherein R1~ is ( i ) SUBSTITUTE SHEET (RULE 26) Rs %CvRs, in which R9 and R'~ are as defined above, (ii) =NR9 in which R9 is as defined above, (iii) 0 or (iv) S;
(3) =S(0) q wherein q is an integer of 0 to 2; or ( 4 ) =NRS wherein R5 is ( i ) a hydrogen, ( ii ) a C,_,6 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1_3 alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C1_6 alkyl optionally having 1 to 3 halogen atoms( (f) a C3_6 cycloalkyl, {g) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_s alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, {i) a hydroxyl, (j} an amino, ( k ) a mono-C1_6 alkylamino, ( 1 ) a di-C1_6 alkylamino, {m) a C1_6 alkyl-carbonyl, (n) a C1_6 alkyl-carbonyloxy, (o} a C1_6 alkyl-carbonyloxy-C1_~ alkyl, {p) a carboxyl, (q) a C1:6 alkoxy-carbonyl, (r) a mono-C1_s alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t} a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, (w) a sulfo, (x) a C1_6 alkylsulfonyl, {y) a C6_lo aryl, ( z ) a C6_io aryloxy, ( as ) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, {bb) thiocarbamoyl, (cc) mono-C1_6 alkylthio-carbamoyl, (dd) di-C,_~ alkylthio-carbamoyl, {ee) C~_io aryl-carbamoyl and (ff) C6_lo aryl-thiocarbamoyl, (iii) -(C=0)-R' wherein R' is a hydrogen or a Ci_,6 acyclic or cyclic hydrocarbon group which may have 1 to S substituents selected from the group consisting of (a) a halogen, SUBSTITUTE SHEET (RULE 26) i5 (b) a C1_3 alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C~_6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3_6 cycloalkyl, (g) a CI_6 alkoxy which may be ' substituted with amino, mono- or di-C1_6 alkylamino or S CI_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1_6 alkylamino, {1) a di-C1_6 alkylamino, (m) 5- or 6-membered cyclic amino optionally having hydroxyl ox oxo, (n) -NHCOOR6 wherein R6 is a C1_I6 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of {n-1) a halogen, (n-2) a C1_3 alkylenedioxy, (n-3) a vitro, {n-4) a cyano, (n-5) a C1_6 alkyl optionally having 1 to 3 halogen atoms, ( n-6 ) a C3_6 cycloalkyl, { n-7 ) a Cj_6 alkoxy which may be substituted with amino, mono- or di-C~_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (n-8) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (n-9) a hydroxyl, (n-10) an amino, (n-11) a mono-Cj_6 alkylamino, {n-12) a di-C1_6 alkylamino, (n-13) a C1_6 alkyl-carbonyl, (n-14) a C1_6 alkyl-carbonyloxy, (n-15) a C1_6 alkyl-carbonyloxy-C1_3 alkyl, (n-16) a carboxyl, ( n-17 ) a C1_6 alkoxy-carbonyl, ( n-18 ) a mono-C1_s alkylamino-carbonyl, (n-19) a di-C,_6 alkylamino-carbonyl, (n-20) a carbamoyl, (n-21) a mono-C1_6 alkyl-carbamoyl, (n-22) a di-C1_6 alkyl-carbamoyl, (n-23) a sulfo, (n-24 j a C1_6 alkylsulfonyl, {n-25 ) a C6_,o aryl, (n-26) a C6_,o aryloxy, (n-27) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected ( from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (n-28) thiocarbamoyl, {n-29) mono-C1_6 alkylthio-carbamoyl, ( n-30 ) di-C1_6 alkylthio-SUBSTITUTE SHEF?' (RULE Z6) WO 98/07705 PCTlJP97102858 is carbamoyl , ( n-31 ) C6_~o aryl-carbamoyl and ( n-32 ) C~_~o aryl-thiocarbamoyl, (o) -NHCONHR6 wherein R6 is as defined above, (p) -NHCOR6 wherein R6 is as defined above, (q) -NHSOZR6 wherein R6 is as defined above, (r) a C1_6 alkyl-carbonyl, (s) a C1_6 alkyl-carbonyloxy, (t) a C1_6 alkyl-carbonyloxy-C1_3 alkyl , ( a ) a carboxyl ( ( v ) a C1_6 alkoxy-carbonyl, (w) a mono-C1_6 alkylamino-carbonyl, (x) a di-C1_6 alkylamino-carbonyl, (y) a carbamoyl, (z) a mono-C1_6 alkyl-carbamoyl, (aa) a di-C,_ 6 alkyl-carbamoyl, (bb) a sulfo, (cc) a C1_6 alkylsulfonyl, (dd) a C6_lo aryl, (ee) a C6_lo aryloxy, (ff) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (gg) C_11 aralkyloxy-carbonyl, (hh) thiocarbamoyl, (ii) mono-C1_6 alkylthio-carbamoyl, ( j j ) di-C1_6 alkylthio-carbamoyl, ( kk) C6_lo aryl-carbamoyl and ( 11 ) C6_lo aryl-thiocarbamoyl, (iv) -SOZ-R' wherein R' is as defined above, (v) -SO-R' wherein R' is as defined above, ( vi ) - ( C=0 ) NRB-R' wherein R' is as def fined above, Re is hydrogen or C1_6 alkyl or (vii) -(C=O)0-R'wherein R' is as defined above;
Zlis a C1_3 alkylene group which may have an oxo or thioxo group;
Z2 is a C1_3 alkylene group which may contain oxygen or sulfur within the carbon chain as an ether or thioether and may have a substituent selected from the group consisting of (a) a halogen, (b) a C~_s alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (f) a C~_6 cycloalkyl, (g) a C1_~ alkoxy which may be substituted with amino, mono-or di-C1_6 alkylamino or C,_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C,_~, SUBSTITUTE 51-iEET (RULE Z6) WO 98l07705 PCTlJP97f02858 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, {j) an amino, (k) a mono-C1_6 alkylamino, (1) a di-C1_6 alkylamino, {m} a C1_6 alkyl-carbonyl, (n) a C,_ 6 alkyl-carbonyloxy, ( o ) a C1_6 alkyl-carbonyloxy-C,_3 alkyl, (p) a carboxyl, (q) a C1_6 alkoxy-carbonyl, (r) a ' mono-C1_6 alkyl amino-carbonyl, {s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, (w) a sulfo, (x) a C1_6 alkylsulfonyl, (y} a C6_lo aryl, (z) a C6_,o aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1_6 alkylthio-carbamoyl, (dd) di-C1_6 alkyithio-carbamoyl, ( ee ) Cb_lo aryl-carbamoyl and ( f f ) C~_lo aryl-thiocarbamoyl;
Ar is (1) a 3- to 14- membered monocyclic or fused polycyclic nonaromatic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1_3 alkylenedioxy, (iii) a vitro, (iv) a cyano, (v) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (vi) a Cz_6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a C2_6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3_6 cycloalkyl, {ix) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_s alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (xi} a hydroxyl, (xii) an amino, (xiii) a mono-C1_~ alkylamino, (xiv) a di-C1_6 alkylamino, (xv) 5- or 6- membered cyclic amino, (xvi) -NHCOOR~ wherein R~ is as defined above, (xvii) -NHCONHR6 wherein R' is as defined above, (xviii} -NHCORG wherein RG is as SUHSTjTUTE SHEET tRULE Z6) WO 98I07705 PCTlJP97102858 defined above, {xix) -NHSOzRb wherein R6 is as defined above, (xx) a C~_6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a Cl_6 alkoxy-carbonyl, (xxiii} a carbamoyl, (xxiv) a mono-C1_6 alkyl-carbamoyl, (xxv} a di-C,_~
alkyl-carbamoyl, (xxvi) a C6_loaryl-carbamoyl, (xxvii) a sulfo, (xxviii) a C1_6 alkylsulfonyl, (xxvix) a C5_lo aryl ( ( xxx ) a C6_lo aryloxy, ( xxxi ) C_16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1_6 alkylthio-carbamoyl, (xxxiv) di-C1_6 alkylthio-carbamoyl, (xxxv) C6_~o aryl-carbamoyl and ( xxxvi ) C6_lo aryl-thiocarbamoyl , (2} a 6- to 14-membered monocyclic or fused polycyclic aromatic hydrocarbon group, which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1_3 alkylenedioxy, {iii) a nitro, (iv) a cyano, (v) a C1_6 alkyl optionally having 1 to 3 halogen atoms, {vi) a CZ_6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a CZ_6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3_6 cycloalkyl, (ix) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (xi}
a hydroxyl, (xii} an amino, (xiii) a mono-C1_6 alkylamino, (xiv) a di-C1_6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) -NHCOOR6 wherein Rb is as defined above, (xvii} -NHCONHR6 wherein R6 is as defined above, (xviii) -NHCOR6 wherein R6 is as defined above, (xix} -NHSOzRb wherein R6 is as defined above, (xx) a C1_6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1_~ alkoxy-carbonyl, (xxiii) a carbamoyl, {xxiv) a mono-C1_b alkyl-carbamoyl, (xxv) a di-C1_~ alkyl-carbamoyl, (xxvi) a C6_loaryl-carbamoyl, {xxvii) a sulfo, (xxviii) a C1_6 alkylsulfonyl, (xxvix) a C~,_,o aryl, (xxx) a C~_lo aryloxy, (xxxi) C_16 araikyloxy, SUBSTITUTE SH EE'f' (RULE 26) WO 98I07705 PCTlJP97J02858 (xxxii) thiocarbamoyl, (xxxiii) mono-C~_6 alkylthio-carbamoyl, (xxxiv) di-C1_6 alkylthio-carbamoyl, (xxxv) C6_lo aryl-carbamoyl and ( xxxvi ) C6_io aryl-thiocarbamoyl , (3} 5- to 10- membered monocyclic nonaromatic heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen, an oxygen and a sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, which may have 1 to 5 substituents selected from the group consisting of {i) a halogen, (ii) a C1_3 alkylenedioxy, (iii) a vitro, {iv) a cyano, (v) a Ci_6 alkyl optionally having 1 to 3 halogen atoms, (vi) a Cz_6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a C2_6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3_6 cycloalkyl, ( ix) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1_6 alkylamino, {xiv} a di-C1_s alkylamino, {xv) 5- or 6- membered cyclic amino, (xvi) -NHCOOR6 wherein R6 is as defined above, {xvii) -NHCONHR6 wherein R6 is as defined above, (xviii) -NHCOR~
wherein R6 is as defined above, (xix) -NHSOZR6 wherein R6 is as defined above, (xx) a C1_6 alkyl-carbonyl, (xxi) a carboxyl group, (xxii} a C1_6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mono-C,_6 alkyl-carbamoyl, (xxv) a di-C1_6 alkyl-carbamoyl, (xxvi} a C6_io aryl-carbamoyl, (xxvii) a sulfo, (xxviii} a C1_6 alkylsulfonyl, (xxix) a C6_lo aryl, (xxx) a C~_io aryloxy, _ (xxxi) C_16 aralkyloxy, (xxxii} thiocarbamoyl, {xxxiii) mono-C,_6 alkylthio-carbamoyl, (xxxiv) di-C!_~ alkylthio-carbamoyl, (xxxv) C6_io aryl-carbamoyl and {xxxvi) C6_,o aryl-thiocarbamoyl, or (4) 5- to 10- membered SUBSTITUTE SHEET tRULE 26) monocyclic aromatic heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused 5 with a benzene ring, which may have 1 to 5 substituents selected from a group consisting of (i) a halogen, (ii) a C1_3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (vi}
a C2_6 alkenyl optionally having 1 to 3 halogen atoms, 10 (vii) a C2_6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3_6 CYCloalkyl, (ix) a Ci_6 alkoxy which may be substituted with amino, mono- or di-Ci_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1_s alkylthio optionally 15 having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1_6 alkylamino, (xiv) a di-C1_6 alkylamino, {xv) 5- or 6- membered cyclic amino, {xvi) -NHCOOR6 wherein R6 is as defined above, (xvii) -NHCONHR6 wherein R6 is as defined above, (xviii} -NHCOR~
20 wherein R6 is as defined above, (xix) -NH50zR6 wherein R6 is as defined above, (xx) a C1_6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1_6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mono-C1_6 alkyl-carbamoyl, (xxv} a di-C1_6 alkyl-carbamoyl, (xxvi) a C6_io aryl-carbamoyl, (xxvii) a sulfo, {xxviii) a C1_6 alkylsulfonyl, (xxix) a C6-to aryl. (xxx) a C6_lo aryloxy, ( xxxi ) C_16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1_6 alkylthio-carbamoyl, (xxxiv) di-C1_6 alkylthio-carbamoyl, (xxxv) Cs-to aryl-carbamoyl and ( xxxvi ) C6_lo aryl-thiocarbamoyl ;
one of R1 and RZ is (1) a hydrogen, (2) a halogen, (3}
a hydroxyl, (4) a C1_6 alkyl which may have 1 to 5 substituents selected from the group consisting of (a}
a halogen, {b) a C1_~ alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1_6 alkyl optionally having 1 to 3 halogen SUBST1TLJTE SH EE's (RULE 2fi) atoms, {f) a C~_6 cycloalkyl, (g) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or Ci_6 alkoxycarbonyl, and optionally having 1 to 3 ' halogen atoms, {h) a C1_~ alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, {k) a ' mono-Ci_6 alkyl amino, { 1 ) a di-Ci_~ alkyl amino, (m) a C,_,, alkyl-carbonyl, (n) a Cs_6 alkyl-carbonyloxy, (o) a Ci_5 alkyl-carbonyloxy-C1_3 alkyl, (p) a carboxyl, (q) a C1_~
alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carbonyl, (s) a di-Ci_6 alkylamino-carbonyl, (t) a carbamoyl, {u) a mono-C~_6 alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, {w) a sulfo, (x) a C1_6 alkylsulfonyl, (y) a Cb-to aryl, ( z ) a C6_lo aryloxy, ( as ) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1_~
alkylthio-carbamoyl, (dd) di-C1_b alkylthio-carbamoyl, ( ee ) C6_lo aryl-carbamoyl and ( f f ) C6_lo aryl-thiocarbamoyl, or (5) a C1_balkoxy group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1_3 alkylenedioxy, (c} a vitro, (d) a cyano, (e) a C1_6 alkyl optionally having 1 to 3 halogen atoms, {f) a C3_6 cycloalkyl, (g) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, {i) a hydroxyl, {j) an amino, ( k ) a mono-C1_~ alkyl amino, ( 1 ) a di-C1_~
alkylamino, (m) a C1_6 alkyl-carbonyl, {n) a C,_~ alkyl-carbonyloxy, (o) a C1_6 alkyl-carbonyloxy-Ci_3 alkyl, (p) a carboxyl, (q) a C1_6 alkoxy-carbonyl, (r) a mono-C1_~
- alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, {v) a SUBSTITUTE SHEET tRULE 26) di-C~_6 alkyl-carbamoyl, {w) a sulfo, (x) a C~_6 alkylsulfonyl, (y) a C6_lo aryl, (z) a C6_,o aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1_6 alkylthio-carbamoyl, (dd) di-C1_6 alkylthio-carbamoyl, (ee) C6_lo aryl-carbamoyl and ( f f ) C6_~o aryl-thiocarbamoyl ;
the other is (1) a halogen, (2} a hydroxyl, (3) a C1_6 alkyl which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b} a C1_3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C
alkyl optionally having 1 to 3 halogen atoms, (f) a C~_5 cycloalkyl, (g) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_s alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k} a mono-C1_6 alkylamino, (1) a di-C1_6 alkyl amino, (m) a C,_r, alkyl-carbonyl , ( n ) a C1_6 alkyl-carbonyloxy, ( o ) a C1_,) alkyl-carbonyloxy-C1_3 alkyl, (p) a carboxyl, (q} a C1_s alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carhonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, (w} a sulfo, (x} a C1_6 alkylsulfonyl, (y} a C6-to aryl, ( z ) a C6_lo aryloxy, ( as ) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1_~
alkylthio-carbamoyl, (dd) di-C1_6 alkylthio-carbamoyl, (ee) C6_lo aryl-carbamoyl and (ff) C~_lo aryl-thiocarbamoyl, or (4) a C1_~ alkoxy group which may have SUHST1TUTE SHEET (RULE 26) WO 98l07705 PCTlJP97102858 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C~_3 alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3_6 cycloalkyl, (g) a C1_6 alkoxy optionally having 1 to 3 halogen atoms, (h) a C,_~
alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k} a mono-C1_6 alkylamino, (1) a di-C1_6 alkyl amino, (m) a C1_6 alkyl-carbonyl, (n) a C,_ 6 alkyl-carbonyloxy, (o) a C1_6 alkyl-carbonyloxy-C1_3 alkyl, (p) a carboxyl, (q) a C1_s alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_b alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, (w) a sulfo, (x) a C1_6 alkylsulfonyl, (y) a C6_lo aryl, (z) a C6_lo aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, {cc) mono-C1_6 alkylthio-carbamoyl,~ (dd) di-C1_6 alkylthio-carbamoyl, (ee) C6_to aryl-carbamoyl and (ff) C6_lo aryl-thiocarbamoyl; or R1 and RZ taken together, to form the ring with adjacent -C=C-, are (1) a C1_6 alkylene group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1_~ alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C1_6 alkyl optionally which may be substituted with amino, mono- or di-C~_6 alkylamino or C1_6 alkoxycarbonyl, and having 1 to 3 halogen atoms, (f) a C5_6 cycloalkyl, (g) a C,_~ alkoxy optionally having 1 to 3 halogen atoms, (h) a C,_~
alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1_~ alkylamino, (1) a di-Ci_6 alkylamino, (m) a C,_6 alkyl-carbonyl, (n) a C,_ SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 6 alkyl-carbonyioxy, (o) a C1_6 alkyl-carbonyloxy-C~_3 alkyl, (p) a carboxyl, {q) a C,_6 alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-s carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, (w) a sulfo, _ ( x ) a C1_6 aikylsulfonyl, (y) a C6_lo aryl, ( z ) a C6_lo aryloxy, (aa} a S- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1_6 alkylthio-carbamoyl, (dd) di-C1_6 alkylthio-carbamoyl, ( ee ) C6_lo aryl-carbamoyl and ( f f ) C6_lo aryl-thiocarbamoyl, (2) a C1_6 alkylenedioxy group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1_3 alkylenedioxy, (c) a nitro, (d) a cyano, (e} a C1_6 alkyl optionally having 1 to 3 halogen atoms, (f) a C~_6 cycloalkyl, {g) a C1_6 alkoxy which may be substituted with amino, mono-or di-C1_6 alkyl amino or C1_6 alkoxycarbonyl ( and optionally having 1 to 3 halogen atoms, (h) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k} a mono-C1_6 alkylamino, (1) a di-C1_6 alkylamino, (m) a C1_6 alkyl-carbonyl, (n) a C,_ 6 alkyl-carbonyloxy, (o) a C1_6 alkyl-carbonyloxy-C1_3 alkyl, (p) a carboxyl, (q) a C1_6 alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, (w) a sulfo, (x) a C1_~ alkylsulfonyl, (y) a C6_lo aryl, (z) a C~_io aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a SUBSTITUTE SHEET (RULE ~6) benzene ring, (bb) thiocarbamoyl, (cc) mono-C,_~
alkylthio-carbamoyl, (dd) di-C1_6 alkylthio-carbamoyl, ( ee ) C6_,o aryl-carbamoyl and ( f f ) C6_lo aryl-thiocarbamoyl, or {3) a C1_6 alkyleneoxy group which may 5 have 1 to 5 substituents selected from the group ' consisting of (a) a halogen, (b) a C1_3 alkylenedioxy, (c) a nitro, (d) a cyano, {e) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3_6 cycloalkyl, (g) a C1_6 alkoxy which may be substituted with amino, mono-10 or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having I to 3 halogen atoms, (h) a C,_6 alkylthio optionally having 1 to 3 halogen atoms, (i} a hydroxyl, (j) an amino, (k) a mono-C1_6 alkylamino, (1) a di-C1_6 alkylamino, (m) a C1_6 alkyl-carbonyl, (n) a C~_ 15 6 alkyl-carbonyloxy, (o) a C1_6 alkyl-carbonyloxy-C,_3 alkyl, (p) a carboxyl, (q) a C1_6 alkoxy-carbonyl, (r) a mono-C1_b alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, (w) a sulfo, 20 {x) a C1_6 alkylsulfonyl, (y) a C6_lo aryl, (z) a C6_io aryloxy, {aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a 25 benzene ring, (bb) thiocarbamoyl, (cc) mono-Ci_s alkylthio-carbamoyl, (dd) di-C1_6 alkylthio-carbamoyl, {ee) C6_lo aryl-carbamoyl and ( ff ) C6_lo aryl-thiocarbamoyl; and ring A is a benzene ring which may have 1 or 2 substituents selected from the group consisting of (1) a hydrogen, (2) a halogen, {3) a C,_~6 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C~_3 alkylenedioxy, (iii) a nitro, (iv) a cyano, SUBSTITUTE SHEET (RULE Z6) WO 981077Q5 PCTlJP97l02858 (v) a C,_6 alkyl optionally having 1 to 3 halogen atoms, ( vi ) a C3_~ cycioalkyl , ( vii ) a C,_6 alkoxy which may be substituted with amino, mono- or di-C~_6 alkylamino or C,_6 alkoxycarbonyl, and optionally having 1 to 3 5 halogen atoms, (viii) a C,_6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi} a mono-C1_6 alkylamino, (xii) a di-C~_6 alkylamino, ( xiii ) a C,_6 alkyl-carbonyl, ( xiv ) a Ci_6 alkyl-carbonyloxy, (xv) a C1_6 alkyl-carbonyloxy-C1_s alkyl, 10 (xvi) a carboxyl, (xvii) a C~_6 alkoxy-carbonyl, (xviii) a mono-C1_6 alkyl amino-carbonyl, ( xix) a di-C1_s alkylamino-carbonyl, (xx) a carbamoyl, (xxi} a mono-C~_6 alkyl-carbamoyl, (xxii) a di-C1_6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1_6 alkylsulfonyl, (xxv) a C6_ 15 to aryl , ( xxvi } a C6_io aryloxy, ( xxvii ) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) 20 thiocarbamoyl, (xxix} mono-C1_6 alkylthio-carbamoyl, ( xxx ) di-C 1_6 alkylthio-carbamoyl , ( xxxi ) C6_,o aryl-carbamoyl and (xxxii) C6_lo aryl-thiocarbamoyl, 3. A compound of the formula:
Q~ (CH2)m-X-(CHZ)~
R1 \ L / Y
RZ Ar Z2 wherein Q is (1) CR'wherein R'' is (i) a hydrogen atom, (ii) a halogen atom, (iii) an optionally substituted hydrocarbon group or (iv) an optionally substituted hydroxyl group, or (2) N(0)p wherein p is 0 or 1;
X is C=0 or C=S;
SUBSTITUTE SHEET (RULE Z6~

Y is {1) CHZ, (2) S(O)q wherein q is an integer of 0 to 2, or (3) NRS wherein RS is (i) a hydrogen atom, (ii) an optionally substituted hydrocarbon group or (iii) an - acyl group;
m and n each represents 0 or 1, Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and RZ is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group;
the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group; or R1 and RZtaken together with adjacent -c=c- form a ring; and ring A is a benzene ring which may be substituted in addition to R1 and RZ;
4. A compound as described in the above item 3 wherein Q is (A) CR'wherein R' is (1) a hydrogen atom, (2) a halogen atom, (3) a C1_16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i} a halogen, (ii} a C1_3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3_6 cycloalkyl, (vii} a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, {viii) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (ix} a hydroxyl, (x) an amino, (xi) a mono-C1_6 alkylamino, (xii) a di-C1_6 alkylamino, (xiii} a C1_6 alkyl-carbonyl, (xiv) a C1_6 alkyl-carbonyloxy, (xv) a C1_6 alkyl-carbonyloxy-C1_~ alkyl, (xvi) a carboxyl, (xvii) a C1_6 alkoxy-carbonyl, (xviii) a mono-C1_~ alkylamino-carbonyl, (xix) a di-C1_~
SUBSTITUTE SHEEN' (RULE Z6) alkylamino-carbonyl, (xx) a carbamoyl, (xxi} a mono-C,_r, alkyl-carbamoyl, (xxii) a di-C1_6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a Ci_6 alkylsulfonyl, (xxv) a C~_ to aryl, ( xxvi ) a C6_lo aryloxy, ( xxvii) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-C1_6 alkylthio-carbamoyl, ( xxx ) di-C1_6 alkylthio-carbamoyl , ( xxxi ) C6_lo aryl-carbamoyl and (xxxii) C6_lo aryl-thiocarbamoyl, or (4) a hydroxyl group which may be substituted with a C_16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1_3 alkylenedioxy, (iii) a nitro, {iv) a cyano, (v) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3_6 cycloalkyl, (vii) a C1_b alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, {xi) a mono-C1_6 alkylamino, ( xii ) a di-C1_6 alkyl amino, ( xiii ) a C1_6 alkyl-carbonyl , { xiv } a C1_6 alkyl-carbvnyioxy, ( xv ) a C1_6 alkyl-carbonyloxy-C1_3 alkyl, (xvi) a carboxyl, (xvii} a C1_s alkoxy-carbonyl, (xviii} a mono-C1_6 alkylamino-carbonyl, (xix} a di-C1_~ alkylamino-carbonyl, (xx} a carbamoyl, (xxi) a mono-C1_6 alkyl-carbamoyl, (xxii) a di-C1_6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1_6 alkylsulfonyl, (xxv) a C~_to aryl, (xxvi) a C~_lo aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, SUBSTITUTE SHE~'t' (RULE 26~

(xxviii) thiocarbamoyl, (xxix) mono-Ci_6 alkylthio-carbamoyl, (xxx) di-C1_6 alkylthio-carbamoyl, (xxxi) C~_ ~o aryl-carbamoyl and ( xxxii } C6_~o aryl-thiocarbamoyl;
' ~ or (B) N(0)p wherein p is 0 or 1;
Y is (1) CHZ, (2) S{0)q wherein q is an integer of 0 to 2, or (3) NRS wherein RS is (i) a hydrogen, (ii) a C,_,~
acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1_3 alkylenedioxy, (c) a nitro, (d} a cyano, (e) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3_6 cycloalkyl, (g) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, ( k ) a mono-C1_6 alkylamino, ( 1 ) a di-C1_6 alkylamino, (m) a C1_6 alkyl-carbonyl, (n) a C1_6 alkyl-carbonyloxy, (o) a C1_6 alkyl-carbonyloxy-C1_~ alkyl, {p) a carboxyl, (q) a C1_6 alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, (v} a di-CI_6 alkyl-carbamoyl, (w) a suifo, (x) a C1_~
alkylsulfonyl, {y) a C6_lo aryl, (z) a C6_lo aryloxy, {aa}
a S- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C,_6 alkylthio-carbamoyl, (dd}
di-C,_6 alkylthio-carbamoyl, (ee) C6_lo aryl-carbamoyl and (ff) C~_lo aryl-thiocarbamoyl, (iii) -(C=0}-R' wherein R' is a hydrogen or a C1_16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C,_3 alkyienedioxy, (c) a nitro, (d} a cyano, (e) SUBSTITUTE SHEET (RULE ~6) WO 98I07705 PCTlJP97/02858 a Ci_~ alkyl optionally having 1 to 3 halogen atoms, (f) a C3_~ cycloalkyl, (g) a C~_6 alkoxy optionally having 1 to 3 halogen atoms, (h) a Cl_6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an 5 amino, ( k) a mono-C1_6 alkyl amino, ( 1 ) a di-C1_s alkylamino, (m) 5- or 6-membered cyclicamino optionally having carboxyl or oxo, {n) -NHCOOR6 wherein R6 is a C,_ 16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of 10 (n-1) a halogen, (n-2) a C1_3 alkylenedioxy, (n-3) a nitro, (n-4} a cyano, (n-5) a C1_6 alkyl optionally having 1 to 3 halogen atoms, {n-6) a C3_6 cycloalkyl, (n-7) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and 15 optionally having 1 to 3 halogen atoms, (n-8) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (n-9) a hydroxyl, (n-10) an amino, (n-11) a mono-C1_b alkylamino, (n-12) a di-C1_6 alkylamino, (n-13) a C1_6 alkyl-carbonyl, (n-14) a C1_6 alkyl-carbonyloxy, (n-15) 20 a C~_6 alkyl-carbonyloxy-C1_3 alkyl, (n-16) a carboxyl, (n-17) a C1_6 alkoxy-carbonyl, (n-18} a mono-Ci_6 alkylamino-carbonyl, (n-19) a di-C1_6 alkylamino-carbonyl, {n-20) a carbamoyl, {n-21) a mono-C1_6 alkyl-carbamoyl, (n-22) a di-C1_6 alkyl-carbamoyl, (n-23) a 25 sulfo, ( n-24 ) a C1_6 alkylsulfonyl, ( n-25 ) a C6_1 aryl, (n-26} a C~_lo aryloxy, (n-27} a S- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused 30 with a benzene ring, (n-28) thiocarbamoyl, (n-29) mono-C1_~ alkylthio-carbamoyl, ( n-30 ) di-C1_6 alkylthio-carbamoyl, ( n-31 ) C6_lo aryl-carbamoyl and ( n-32 ) C~_lo aryl-thiocarbamoyl, (o) -NHCONHR'' wherein RG is as defined above, (p) -NHCOR6 wherein R6 is as defined SUBSTITUTE SHEET (RULE 26) above, (q) -NH50~R5 wherein R6 is as defined above, (r}
a C1_~ alkyl-carbonyl, ( s ) a C1_6 alkyl-carbonyloxy, ( t ) a C1_6 alkyl-carbonyloxy-C1_3 alkyl, {u) a carboxyl, (v) a C1_6 alkoxy-carbonyl, (w} a mono-C~_6 alkylamino-carbonyl, (x) a di-C1_6 alkylamino-carbonyl, (y) a carbamoyl, {z) a mono-C1_b alkyl-carbamoyl, (aa) a di-C,_ alkyl-carbamoyl, C6_lo aryl-carbamoyl, (bb) a sulfo, (cc) a C1_6 alkylsulfonyl, (dd) a C6_lo aryl, (ee) a C6_lo aryloxy, (ff) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (gg) C_11 aralkyloxy-carbonyl, (hh) thiocarbamoyl, (ii) mono-C1_b alkylthio-carbamoyl, {jj) di-C1_6 alkylthio-carbamoyl, (kk} C6_lo aryl-carbamoyl and ( 11 ) C6_lfl aryl-thiocarbamoyl, ( iv) -SOZ-R' wherein R' is as defined above, (v) -SO-R' wherein R' is as de f fined above , ( vi ) - ( C=0 ) NRe-R' wherein R' i s as defined above, RB is hydrogen or C1_6 alkyl or (vii) -(C=0)0-R' wherein R' is as defined above, 5. A compound as described in the above item 3 wherein Q is CR4 wherein R~ is as defined in the above item 3, 6. A compound as described in the above item 3 wherein X is C=0, 7. A compound as described in the above item 3 wherein Y is NRS wherein RS is as described in the above item 3, 8. A compound as described in the above item 3 wherein Y is CHZ, 9. A compound as described in the above item 3 wherein SUBSTITUTE SH~~T (RULE 26) WO 98l07705 PCT/JP97102858 Ar is 3- to 14-membered aromatic group which may have 1 to 5 substituents selected from the group consisting of {i) a halogen, (ii) a C~_3 alkylenedioxy, (iii) a vitro, (iv} a cyano, (v) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (vi) a Cz_6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a Cz_6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3_6 cycloalkyl, (ix) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1_s alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mona-C,_6 alkylamino, (xiv) a di-C1_6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) -NHCOOR6 wherein R6 is a C1-is acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1_3 alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C1_6 alkyl optionally having I to 3 halogen atoms, ( f ) a C3_6 cycloalkyl, ( g) a C1_6 alkoxy optionally having i to 3 halogen atoms, (h) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (i} a hydroxyl, (j) an amino, (k) a mono-C1_6 alkylamino, (1) a di-C1_6 alkyl amino, (m) a C1_6 alkyl-carbonyl, (n) a C,_ alkyl-carbonyloxy, (o) a C1_b alkyl-carbonyloxy-C1_3 alkyl, (p) a carboxyl, (q) a C1_6 alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyl, (w) a sulfo, (x) a C1_6 alkylsulfonyl, (y) a C6_lo aryl, (z) a C5_,~
aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen, an oxygen and a sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTl.TP97I02858 thiocarbamoyl, (cc) mono-C1_6 alkylthio-carbamoyl, (dd) di-C,_6 alkylthio-carbamoyl, (ee) C6_lo aryl-carbamoyl and (ff) C6_lo aryl-thiocarbamoyl, (xvii) -NHCONHRG
- wherein R6 is as defined above, (xviii) -NHCORG wherein R6 is as defined above, (xix} -NHSO~R6 wherein R~ is as defined above, (xx) a C1_6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1_b alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mono-C1_6 alkyl-carbamoyl, (xxv) a di-C1_6 alkyl-carbamoyl, (xxvi) a C6_lo aryl-carbamoyl, IO (xxvii) a sulfo, (xxviii) a C1_6 alkylsulfonyl, (xxix) a Cs-to aryl , ( xxx ) a C6_lo aryloxy, ( xxxi ) C_16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1_6 alkylthio-carbamoyl, (xxxiv) di-C1_6 alkylthio-carbamoyl, (xxxv) C6_ to aryl-carbamoyl and ( xxxvi ) C6_,o aryl-thiocarbamoyl , 10. A compound as described in the above item 4 wherein Ar is a phenyl group which may have 1 to 5 substituents selected from the group consisting of {i) a halogen, (ii) a C1_3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C~_6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C2_6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a Cz_6 alkynyl optionally having 1 to 3 halogen atoms , { viii ) a C3_6 cycloalkyl , ( ix ) a C1_6 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, {x) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1_6 alkylamino, (xiv) a di-C1_6 alkylamino, (xv) S- or 6- membered cyclic amino, (xvi) -NHCOOR6 wherein R6 is a C,_,~
- acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1_3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C,_6 alkyl optionally having 1 to 3 SUBSTITUTE SHEET (RULE 26) halogen atoms, (f) a C3_6 cycloalkyl, (g) a C,_~ alkoxy optionally having 1 to 3 halogen atoms, (h) a C,_6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j} an amino, (k) a mono-C~_6 alkylamino, (1) a di-C1_6 alkyl amino, (m) a C1_~ alkyl-carbonyl, (n) a C,_ alkyl-carbonyloxy, (o) a C1_6 alkyl-carbonyloxy-Ci_~
alkyl, (p) a carboxyl, (q) a C1_6 alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carbonyl, ( s } a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1_6 alkyl-carbamoyl, (v) a di-Cj_6 alkyl-carbamoyl, (w) a sulfo, (x) a C1_6 alkylsulfonyl, (y) a C6_lo aryl, (z} a C6_lo aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen, an oxygen and a sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc} mono-C1_6 alkylthio-carbamoyl, (dd) di-C1_6 alkylthio-carbamoyl, (ee) C6_lo aryl-carbamoyl and (ff) C6_lo aryl-thiocarbamoyl, (xvii) -NHCONHR6 wherein R6 is as defined above, (xviii) -NHCOR6 wherein R6 is as defined above, (xix) -NHSOZR6 wherein Rb is as defined above, (xx) a C1_6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1_6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv} a mono-C1_6 alkyl-carbamoyl, (xxv) a di-C1_6 alkyl-carbamoyl, (xxvi} a C6_lo aryl-carbamoyl, (xxvii) a sulfo, (xxviii) a C1_6 alkylsulfonyl, (xxix) a Cb_~o aryl, ( xxx) a C6_lo aryloxy, ( xxxi ) C_16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono--C1_6 alkylthio-carbamoyl, (xxxiv} di-C1_6 alkylthio-carbamoyl, (xxxv) Cs_,o aryl-carbamoyl and ( xxxvi } C6_,o aryl-thiocarbamoyl , SUBST1TUTF SHEET (RULE Zfi) 11. A compound as described in the above item 4, wherein A I is R1 \
.... R 2 0 \
wherein R' is (1) a hydrogen atom, (2) a halogen atom, (3} a C,_ls acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a Cj_3 alkylenedioxy, {c) a nitro, (d) a cyano, (e) a C1_6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3_6 cycloalkyl, (g) a C1_6 alkoxy which may be substituted with amino, mono-or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1_6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, {j) an amino, (k) a mono-C1_6 alkylamino, (1}
a di-C~_6 alkylamino, (m) a C~_6 alkyl-carbonyl, (n) a C,_ 6 alkyl-carbonyloxy, ( o ) a C1_6 alkyl-carbonyloxy-C~_s alkyl, (p} a carboxyl, (q} a C1_6 alkoxy-carbonyl, (r) a mono-C1_6 alkylamino-carbonyl, (s) a di-C1_6 alkylamino-carbonyl, (t) a carbamoyl, (u} a mono-C1_6 alkyl-carbamoyl, (v) a di-C1_6 alkyl-carbamoyi, (w) a sulfo, {x} a C1_~ alkylsulfonyl, (y) a C6_io aryl, (z) a C~,_,a aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyciic group being optionally fused with a benzene ring, an optionally substituted hydrocarbon group, (bb) thiocarbamoyl, (cc) mono-C,_6 alkylthio-SUBSTITUTE 5liEET (RULE 26) WO 98l07705 PCT/JP97102858 carbamoyl, (dd) di-C~_~ alkylthio-carbamoyl, {ee) C6_lo aryl-carbamoyl and (ff) C6_lo aryl-thiocarbamoyl or (4) a hydroxyl group which may be substituted with a C,_,6 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, {ii) a C1_3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1_6 alkyl optionally having 1 to 3 halogen atoms, { vi ) a C3_6 cycloalkyl, ( vii ) a C,_5 alkoxy which may be substituted with amino, mono- or di-C1_6 alkylamino or C1_6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1_6 alkylthio optionally having I to 3 halogen atoms, (ix) a hydroxyl, {x) an amino, {xi) a mono-C1_6 alkylamino, (xii) a di-C1_6 alkylamino, (xiii) a C1_6 alkyl-carbonyl, ( xiv ) a C1_6 alkyl-carbonyloxy, ( xv ) a C1_6 alkyl-carbonyloxy-C1_3 alkyl, (xvi} a carboxyl, (xvii) a C1_s alkoxy-carbonyl, (xviii) a mono-C1_6 alkylamino-carbonyl, (xix) a di-C1_6 alkylamino-carbonyl, (xx) a carbamoyl, {xxi) a mono-C1_6 alkyl-carbamoyl, (xxii) a di-C1_6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv} a C1_6 alkylsulfonyl, (xxv) a C6_lo aryl, (xxvi) a C6_~o aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix} mono-C1_6 alkylthio-carbamoyl, (xxv) di-C1_6 alkylthio-carbamoyl, (xxvi) C6_ to aryl-carbamoyi and ( xxvii ) C6_,o aryl-thiocarbamoyl, I2. A compound as described in the above item 11 wherein R' is a hydrogen, 13. A compound as described in the above item 3 wherein Q is ( 1 ) CR'~ wherein RG~ is ( i ) a C1_6 alkyl group which SUBSTITUTE SHEET (RULE ~6) may be substituted with a di-C1_6 alkylamino group, (ii) a halogen atom, or (iii) a C1_6 alkoxy group, or (2) N;
X is C=0;
Y is NRS' wherein RS' is ( i ) a hydrogen, ( ii ) a C1_6 alkyl group which may be substituted with (a) a - morpholino, (b) a carboxyl, (c) a C1_6 alkoxy-carbonyl, or (d) a phenyl which may be substituted with C~_6 alkoxy, or (iii) COR'" wherein R'~ is (a) a hydrogen, (b) C1_6 alkyl which may be substituted with a carboxyl or a benzyloxycarbonyl, or a di-C1_6 alkylamino;
m and n each represents 0;
ZZ is (1) C=O, (2) CH2, (3) (CHz)Z, (4) (CHz)3, or (5) CH-OH;
Ar is (1) a phenyl group which may be substituted with (a) a halogen, (b) a C1_6 alkylenedioxy, (c) a Ci_6 alkoxy which may be substituted with (c-1) a halogen, (c-2) a di-C1_6 alkylamino or (c-3) a C1_6 alkoxy-carbonyl, (d) a C_11 aralkyloxy, (e) C1_6 alkyl which may be substituted with a halogen or (f) hydroxyl, (2) an optionally oxidized pyridyl group, or (3) a pyridinium group which may be substituted with C1_6 alkyl;
one of R1 and Rz is ( 1 ) a hydrogen, ( 2 ) a C,_6 alkyl , ( 3 ) a C1_6 alkoxy which may be substituted with (a) a C~_6 alkoxy-carbonyl, (b) a C_11 aralkyl or (c) a carboxyl, or (4) a hydroxyl;
the other is ( 1 ) a C1_6 alkyl, ( 2 ) a C1_6 alkoxy which may be substituted with (a) a C1_6 alkoxy-carbonyl or (b) a carboxyl, or (3) a hydroxyl; or R1 and RZ taken together with adjacent -c=c- form a C~_,) alkylenedioxy group, or a C1_6 alkyleneoxy group; or ring A is a benzene ring which may have a C1_6 alkoxy group, in addition to R' and R~, and a C1_6 alkoxy group on ring A and a C1_6 alkoxy group of R' may be taken SUBSTiTLJTE SHEET (RULE 26) WO 98l07705 PCTIJP97/02858 together form a C,_6 alkylenedioxy group;
14. A compound as described in the above item 13 wherein ' Q is CH or N;
X is C=0;
m and n each represents 0;
ZZ is CHZ; and R' and RZ taken together with adjacent -c=c- form a Ci_5 alkylenedioxy group, 15. A process for producing a compound of the formula:
W (CHZ)m-X\

wherein a11 symbols have the same meanings as defined in the above item 3, yr a salt thereof, which comprises subjecting a compound of the formula:
Q~ (CHZ)m-X\
R1 \ ' / 2 ~0 wherein a11 symbols have the same meaning as defined in the above item 3, or a salt thereof, to lactamization reaction, optionally followed by introducing a substituent RS into the resulting lactam, 16. A compound of the formula:
SUBSTiTLJT~ SHEET (RULE Zfi) WO 98l07705 PCT/JP97I02858 Q' (CH2)m-X\O
R1 \ /
R2 Ar Z2 ' 5 wherein all symbols have the same meaning as defined in the above item 3, or a salt thereof; provided that (1) when both of R' and Rz are methoxy groups, Q is CR4, X
is C=0, Zz is a methylene, and m is 0, Ar is not any of phenyl, 3,4,5-trimethoxyphenyl, 4,5-dimethoxy-2-methylphenyl and 1,3-benzodioxol-5-yl; that (2) when R~
is a hydroxyl or a methoxy, Q is CRS, X is C=0, Zz is a methylene, and m is 0, Ar is not 1,3-benzodioxol-5-yl;
and that (3? when R1 and RZ taken together represent a methylenedioxy which may be substituted with an oxygen atom, Q is CR4, X is C=0, ZZ is a methylene, and m is 0, Ar is not any of 1,3-benzodioxol-5-yl, 6-bromo-1,3-benzodioxol-S-yl, 7-hydroxyl-I,3-benzodioxol-5-yl, 7-acetoxy-1,3-benzodioxol-5-yl, and 7-methoxy-1,3-benzodioxol-5-yl, 17. A pharmaceutical composition comprising a compound of the above item 1, 18. A cell differentiation inducing factor composition comprising the compound of the above item i, 19. A composition of the above item 17 which enhances cell differentiation inducing factor, 20. A composition for treating or preventing neuropathy or bone and joint disease which comprises the compound of the above item 1, 21. A bone formation promoting composition comprising SUBSTITUTE SHEET (RULE 2C) the compound of the above item 1, 22. A cartilage disruption inhibitory composition comprising the compound of the above item 1, 23. A method of treating or preventing neuropathy or bone-and-joint disease which comprises administering to a mammal in need thereof an effective amount of a compound of the formula:

Z\

R 2 A r ~Z
wherein Q is an optionally substituted carbon atom or N(0)p wherein p is 0 or 1;
Y is an optionally substituted methylene group, S(0)q wherein q is an integer of 0 to 2, or an optionally substituted imino group;
Z1 is a C~_s alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain;
ZZ is an optionally substituted C1_3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and Rz is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group;
the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group; or R~ and Retaken together with adjacent -c=c- form a ring; and ring A is a benzene ring which may have a substituent SUBSTITUTE SHEET (RULE 26y WO 98!0770S PCTlJP97/02858 in addition to R' and R~; or a salt thereof, 24. Use of a compound of the formula:
/ Qw Z

\~
R2 Ar wherein Q is an optionally substituted carbon atom or N(0)p wherein p is 0 or 1;
Y is an optionally substituted methylene group, S(0)q wherein q is an integer of 0 to 2, or an optionally substituted imino group;
Z1 is a C1-~ alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain;
ZZ is an optionally substituted C1_3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and RZ is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group;
the~other is a halogen,atom, a hydroxyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group; or R' and RZ taken together form a ring; and ring A is a benzene ring which may have a substituent in addition to Ri and RZ; or a salt thereof, for the manufacture of a medicament for treating or preventing neuropathy or bone-and-joint disease, and 25. A compound as described in the above item 3, which is 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3,-SUBSTTTUTE SHEET tRULE 26) benzodioxolo[4,5-f]isoindol-7-one, 11-(1,3-Benzodioxol-5-yl)-7,8,9,10-tetrahydro-1,3,-benzodioxolo(4,5-g]isoquinolin-7-one, 4-(1,3-Benzodioxol-5-yl)-2,3-dihydro-5-methoxy-IH-benz[f]isoindol-1-one, 8,9-Dihydro-10-(4-trifluoromethylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 11-{1,3-Benzodioxol-5-yl)-9,10-dihydro-8H-isoindolo[5,6-f]bent[b]-1,4-dioxan-8-one, 10-{4-Fluorophenyi)-8,9,-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-6-methyl-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 10-{4-Fluorophenyl)-8,9-dihydro-6-methyl-7H-1,3-benzodioxolo[4,5-f]isoindol-7'-one, 8,9-Dihydro-6-methyl-10-(4-trifluoromethylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 10-(1,3-Benzodixol-5-yl)-8,9-dihydro-6-ethyl-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 4-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-methoxy-1H-benz(fjisoindol-1-one, 2,3-Dihydro-6-methoxy-4-(4-methoxypheny)-1H-benz[f]isoindol-1-one, 2,3-Dihydro-6-methoxy-4-(4-trifluoromethylphenyl)-1H-benz[f]isoindol-1-one, 4-(4-Fluorophenyl)-2,3-dihydro-6-methoxy-9-methyl-1H-benz[f]isoindol-1-one, 4-(4-Methoxyphenyl)-2,3-dihydro-6-methoxy-9-methyl-1H-benz[f]isoindol-1-one, 9-{4-Fluorophenyl)-1,2-dihydro-7-methoxy-3H-pyrrolo[3,4-b]quinolin-3-one, 1,2-Dihydro-7-methoxy-9-(4-methoxyphenyl)-3H-pyrrolo[3,4-b]quinolin-3-one, 3,4-Dihydro-7-methoxy-5-(4-methoxyphenyl)-benzo[b][1,7]naphthyridin-1(2H}-one, or a salt thereof.
SUBSTITUTE SHEET (RULE Z6) WO 98l07705 PCTIJP97l02858 Detailed description Referring to the above formulas, the "optionally substituted carbocyclic group or optionally substituted heterocyclic group" as mentioned for Ar may have any number of substituents in substitutable positions (pre-_ ferably 1 to 5 and more preferably 1 to 3 substituents}
and when two or more substitutions are involved, the substituent groups may be same or different and the mutually adjacent substituent groups may be bonded with each other to form a ring.
The ring that may be jointly formed by any two mutually adjacent substituent groups on Ar includes 3-through 10-membered carbocycles (preferably 5- or 6-membered carbocycles) such as, for example, benzene, C3_io cycloalkene (e. g. cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), and C3_ln cycloalkanes (e. g. cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.).
Preferred are 5- to 6-membered carbocycles such as benzene, cyclopentane, and cyclohexane. Among them, benzene ring is particularly preferred.
The above-mentioned "optionally substituted carbocyclic group" and "optionally substituted heterocyclic group" include, for example:
(1) 3- to 14-membered monocyclic or fused polycyclic nonaromatic hydrocarbon groups (preferably 5- or 6-mem-bered carbocyclic groups}, for example C3_~o cycloalkene (e. g. cyclobutene, cyclopentene, cyclohexene, cyclo-heptene, cyclooctene, etc.} and Cs_io cycloalkane (e. g.
cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.).
(2) 6- to 14-membered monocyclic or fused polycyclic aromatic hydrocarbon groups, for example C6_,4 aryl such as phenyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 1-anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2 phenanthryl, 3-phenanthryl, 4-phenanthryl, 9 SUBSTITUTE SHEET (RULE 26) phenanthryl, etc. Among them, preferred are phenyl, biphenyl, 1-naphthyl and 2-naphthyl, and phenyl is particularly preferred.
(3) 5- to 10-membered monocyclic nonaromatic heterocyclic groups each containing 1 or more (e.g. 1-4, preferably 1-3) hetero atoms of one or two kinds as selected from the group consisting of nitrogen, sulfur, and oxygen in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, preferably 5- or 5-membered nonaromatic heterocyclic groups, more specifically monovalent groups available upon elimination of one optiona2 hydrogen atom each from such rings as tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, and tetrahydroisoxazole rings, preferably from 6-membered nonaromatic heterocyclic rings each containing 1 or 2 nitrogen atoms in addition to carbon (e. g. tetra-hydropyridine, tetrahydropyrimidine, tetrahydropyridazine, piperidine, and piperazine rings, more preferably piperazine ring etc.).
(4) 5- to 10-membered monocyclic aromatic heterocyclic groups each containing one or more (for example, 1 to 4, preferably 1 to 3) hetero atoms of one or two kinds as selected from the group consisting of nitrogen, sulfur, and oxygen in addition to carbon atoms, said heterocyciic group being optionally fused with a SUBSTITUTE SHEET (RULE 2fi) benzene ring, specifically monovalent groups available upon elimination of any one hydrogen atom each from aromatic heterocyclic rings such as thiophene, - benzo[b)thiophene, benzo[b)furan, benzimidazole, S benzoxazole, benzothiazole, benzisothiazole, ' naphtho[2,3-b]thiophene, thianthrene, furan, iso-indolidine, xanthrene, phenoxathiin, pyrrole, imidazole, triazole, thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, 10 isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, p-carboline, phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazan, 15 phenoxazine, isochroman, etc. (preferably pyridine, thiophene, furan, etc., more preferably pyridine) or from the fused rings available on condensation of such rings (preferably said monocyclic heterocyclic rings) with one or more (preferably 1 or 2, more preferably 1) 20 aromatic rings (e. g. the aromatic hydrocarbons mentioned above, preferably benzene ring).
Particularly preferred, among the above items (1) to (4), are aromatic heterocyciic groups such as said "6- to 14-membered monocyclic and fused polycyclic 25 aromatic hydrocarbon groups" and "5- to 10-membered monocyclic aromatic heterocyclic groups each containing one or more (e. g. 1 to 4, preferably 1 to 3) hetero-atoms of one or two kinds as selected from the group consisting of nitrogen, sulfur, and oxygen in addition 30 to carbon atoms, said heterocyclic group being optionally fused with a benzene ring.
The substituent for the "optionally substituted carbocyclic group or optionally substituted heterocyclic group" as mentioned for Ar and R
35 includes, for example, (i) halogen (e. g. fluorine, chlorine, bromine, iodine), (ii) lower alkylenedioxy SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCTIJP97102858 (e.g. C1_3 alkylenedioxy such as methylenedioxy, ' ethylenedioxy, etc.), (iii) nitro, (iv) cyano, (v) lower alkyl that may be halogenated, (vi) lower alkenyl that may be halogenated, (vii) lower alkynyl that may be halogenated, (viii) lower cycloalkyl (e.g. C3_6 .
cyclaalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (ix) lower alkoxy that may be halogenated, (x) lower alkylthio that may be halogenated, (xi) hydroxyl, (xii) amino, {xiii) mono-lower alkylamino (e.g. mono-C1_6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xiv) di-lower alkylamino (e.g. di-C1_b alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (xv) 5- or 6-membered cycloamino (e. g. morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.), (xvi) acylamino, (xvii) lower aikylcarbonyl (e. g. C1_s alkyl-carbonyl such as acetyl, prvpionyl, etc.), (xviii) carboxyl, (xix) lower alkoxy-carbonyl (e. g. C1_5 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xx) carbamoyl, (xxi) mono-lower alkylcarbamoyl (e. g.
mono-C1_6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.), (xxii) di-lower alkylcarbamoyl (e. g. di-C1_6 alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (xxiii) aryl-carbamoyl (e. g.
C6-to aryl-carbamayl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxiv) sulfo, (xxv) lower alkylsulfonyl (e.g. C1_6 alkylsulfonyl such as ethylsulfonyl, ethylsulfonyl, etc.), (xxvi) aryl (e. g.
Cb-to aryl such as phenyl, naphthyl, etc.), (xxvii) aryloxy (e. g. C~_lo aryloxy such as phenyloxy, naphthyloxy, etc.), (xxviii) aralkyloxy (e.g. C~_1~
aralkyloxy such as benzyloxy etc.), (xxix) thiocarbamoyl, (xxx) mono-lower alkylthiocarbamoyl SUBSTITUTE SHEET (RULE 26f (e.g. mono-C1_~ alkylthio-carbamoyl such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (xxxi) di-Iower alkylthiocarbamoyl (e. g. di-C1_6 alkylthio-carbamoyl such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (xxxii) aryl-carbamoyl - {e.g. C6_lo aryl-carbamoyl such as phenyl-carbamoyl) and (xxxiii) aryl-thiocarbamoyl (e. g. C6_io aryl-thiocarbamoyl such as phenyl-thiocarbamoyl).
The "lower alkyl that may be halogenated" as men-tinned above includes lower alkyl {e. g. C1_6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) optionally having 1-3 halogen atoms (e. g. fluorine, chlorine, bromine, iodine}. Specifically, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifiuoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc. can be mentioned.
The "lower alkenyl that may be halogenated" and "lower alkynyl that may be halogenated", both mentioned above, include lower alkenyl {e.g. C2_6 aikenyl such as vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl, etc.) optionally having 1-3 halogen atoms {e.g. fluorine, chlorine, bromine, iodine) and lower alkynyl (e.g. CZ_6 alkynyl such as 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexyn-1-yl, etc.) optionally having 1-3 halogen atoms (e. g. fluorine, chlorine, bromine, iodine), respectively.
The above-mentioned "lower alkoxy that may be halogenated" includes lower alkoxy (e. g. C~_~ alkoxy such as rnethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.) optionally having 1-3 halogen atoms (e. g. fluorine, chlorine, SUBSTiTLffF SHEET (RULE 26~

bromine, iodine). Specifically, methoxy, ' difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc. can be mentioned.
The "lower alkoxy" of said "lower alkoxy that may be halogenated" may be substituted by amino, mono- or di-lower alkylamino (e. g. mono- or di-C1_6 alkylamino such as methylamino, dimethylamino, ethylamino, dimethylamino, etc.) or lower alkoxycarbonyl (e. g. C1_r, alkyl-oxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, etc.).
The above-mentioned "lower alkylthio that may be halogenated" includes lower alkylthio (e. g. C1_6 alkylthio such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc.) optionally having 1-3 halogen atoms {e. g. fluorine, chlorine, bromine, iodine). Specifically, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc. can be mentioned.
The above-mentioned "acylamino" includes -NHCOORr', -NHCONHR6, -NHCOR6, and -NHSOZR6 ( R6 represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group).
The preferred substituent for the "optionally substituted carbocyclic group or optionally substituted heterocyclic group" as mentioned for Ar includes halogen (particularly fluorine and chlorine), lower alkylenedioxy (particularly methylenedioxy), lower alkoxy that may be halogenated (methoxy in particular), and hydroxyl.
Particularly preferred are halogen (F and Cl in particular), lower alkylenedioxy (methylenedioxy in particular), and lower alkoxy (methoxy in particular}
SUHSTTTUTE SHEET (RULE 26) that may be halogenated.
Of those substituent groups, lower alkylenedioxy (methylenedioxy in particular) or lower alkoxy (methoxy . in particular) that may be halogenated is the most generally preferred.
. The "halogen" mentioned for R1, RZ, R' and Rr' includes fluorine, chlorine, bromine, and iodine.
The "hydrocarbon" of said "optionally substituted hydrocarbon" as mentioned for R', R4, RS and R6 means a group available upon elimination of one hydrogen atom from any of various hydrocarbon compounds, thus including acyclic and cyclic hydrocarbon groups such as alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl.
Preferred, among them, are C1_16 acylic (straight-chain or branched) hydrocarbon and C1_ls cyclic hydrocarbon.
The more preferable are:
a) alkyl groups [preferably lower alkyl (e.g. C~_6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.)], b) alkenyl groups [preferably lower alkenyl (e. g. CZ_~
alkenyl such as vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc)], c) alkynyl groups [preferably lower alkynyl (e. g. CI_~
alkynyl such as propargyl, ethynyl, butynyl, 1-hexynyl, etc.)], d) cycloalkyl groups [preferably lower cycloalkyl (e. g. C3_6 CyCloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl optionally fused to a benzene ring which, in turn, may have 1-3 lower alkoxy groups (e.g. C1_6 alkoxy such as methoxy)], e) aryl groups (e. g. C6_14 aryl such as phenyl, _ biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, [2-anthryl], 1-anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc., preferably phenyl), SUBSTITUTE SHEET (RULE 2fi) WO 98I07705 PCTJ.TP97102858 f) aralkyl groups [preferably lower aralkyl (e.g. C,_ ls aralkyl such as benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-5 phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc., more preferably benzyl)].
Most preferred are alkyl groups.
The "optionally substituted hydrocarbon" as men-tioned for R3, R4, R5, and R6 may have 1 to 5, 10 preferably 1 to 3, substituents in substitutable positions of the hydrocarbon group and where two or more substitutions are involved, the substituent groups may be the same or different.
The "substituent" for said "hydrocarbon that may 15 be substituted" includes (i} halogen (e. g. fluorine, chlorine, bromine, iodine), (ii} lower alkylenedioxy (e. g. C1_3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.}, (iii) nitro, (iv) cyano, (v) lower alkyl that may be halogenated, (vi) lower cyclo-20 alkyl (e. g. C3_6 cycloalkyl such as cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, etc.), (vii) lower alkoxy that may be halogenated, (viii) lower alkylthio that may be halogenated, (ix) hydroxyl, (x) amino, (xi) mono-lower alkylamino (e.g. mono-C1_6 alkylamino such as 25 methylamino, ethylamino, etc.), (xii) di-lower alkylamino (e.g. di-C1_6 alkylamino such as di-methylamino, diethylamino, etc.}, {xiii) lower alkyl-carbonyl (e. g. C1_6 alkyl-carbonyl such as acetyl, ethylcarbonyl, etc.), (xiv) lower alkyl-carbonyloxy 30 (e. g. C,_6 alkyl-carbonyloxy such as acetoxy, ethylcarbonyloxy, etc.), (xv) lower alkyl-carbonyloxy-C1_3 alkyl {e.g. C1_6 alkyl-carbonyloxy-C1_3 alkyl such as acetoxymethyl, ethylcarbonyloxymethyl, isopropylcarbonyloxymethyl, etc.), (xvi) carboxyl, 35 (xvii) lower alkoxy-carbonyl (e. g. C1_6 alkyl-SUBSTITUTE SHEET (RULE 2fiy oxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.}, (xviii) mono-lower alkylamino-carbonyl (e. g. mono-C1_6 alkylamino-carbonyl such as methylaminocarbonyl, ethyl-aminocarbonyl, etc.), {xix) di-lower alkylamino-carbonyl (di-C1_6 alkylamino-carbonyl such as dimethylaminocarbonyl, diethylaminocarbonyl, etc.}, (xx) carbamoyl, {xxi) mono-lower alkyl-carbamoyl {e. g.
mono-C1_6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.), (xxii) di-lower alkyl-carbamoyl (e. g. di-C1_6 alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.), {xxiii) sulfo, (xxiv) lower alkylsulfonyl (e.g. C1_6 alkanesulfonyl such as methanesulfonyl, ethanesulfonyl, etc.), (xxv) aryl (e. g. C6_lo aryl such as phenyl, naphthyl, etc.), (xxvi) aryloxy {e. g. C6_lo aryloxy such as phenyloxy, naphthyloxy, etc.), (xxvii) 5- to 7-membered heterocyclic group each containing 1-4 hetero-atoms selected from among nitrogen, oxygen, and sulfur in addition to carbon, said heterocyclic group being optionally fused with a benzene ring, (xxix) thiocarbamoyl, (xxx) mono-lower alkylthiocarbamoyl (e.g. mono-C~_6 alkylthio-carbamoyl such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (xxxi) di-lower alkylthiocarbamoyl (e. g. di-C1_6 alkylthio-carbamoyl such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (xxxii) aryl-carbamoyl (e.g. C6_io aryl-carbamoyl such as phenyl-carbamoyl) and (xxxiii) aryl-thiocarbamoyl (e. g. C6_lo aryl-thiocarbamayl such as phenyl-thiocarbamoyl).
The above-mentioned "lower alkyl that may be halo-genated", "lower alkoxy that may be halogenated~, and "lower alkylthio that may be halogenated" have the same - meaning of "lower alkyl that may be halogenated", "lower alkoxy that may be halogenated", and "lower SUBSTITUTE SHEET (RULE ~6) alkyithio that may be halogenated" as mentioned above -for the "substituent" of said "optionally substituted carbocyclic group or optionally substituted heterocyclic group".
The above-mentioned "aryl (preferably phenyl)" and "aryloxy (preferably phenyloxy)" may have substituent similar to those mentioned for the "substituent~ for said "carbocyclic group that may be substituted or "heterocyclic group that may be substituted".
The above-mentioned "5- to 7-membered heterocyclic group or said heterocyclic group being optionally fused with a benzene ring" includes 5- to 7-membered (preferably 5- or 6-membered) heterocyclic groups containing 1 to 3, preferably 1 or 2, hetero-atoms of preferably 1 or 2 kinds as selected from the group consisting of nitrogen, oxygen, and sulfur in addition to carbon. The specific examples of such groups includes 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazolidinyl, 2-, 3-, or 4-pyrazolidinyl, 3-, ~-, or 5-pyrazolyl, 2-, 4-, or 5-imidazolyl, piperidino, 2-, 3-, or 4-piperidyl, 1- or 2-piperazinyl, morpholino, 2-or 3-morpholinyl, 2- or 3-thienyl, 2-, 3-, or 4-pyridyl, 2- or 3-furyl, pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl, 3-pyridazinyl, 3-, 4-, or 5-isothiazolyl, 3-, 4- or 5-isoxazolyl, etc. These groups may respectively be fused to a benzene ring in any position. Furthermore, this "5- to 7-membered heterocyclic group or said heterocyclic group being optionally fused with a benzene ring" may have 1 to 3 substituents in any substitutable positions.
The substituent of the above "5- to 7-membered heterocyclic group or said heterocyclic group being optionally fused with a benzene ring" is the same substituent of the "optionally substituted carbocyclic group that may be substituted or heterocyclic group" as SUBSTITUTE SHEET (RULE Z6~

WO 98I07705 PCTlJP97102858 mentioned for Ar.
Preferred, among such substituent groups, are (i) halogen (e. g. fluorine, chlorine, bromine, iodine), (ii) lower alkylenedioxy (e. g. C,_3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (iii) nitro, (iv) cyano, (v) lower alkyl that may be halogenated, (vi) lower cycloalkyl (e.g. C3_6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (vii) lower alkoxy that may be halogenated, (viii) lower alkylthio that may be halogenated, (ix) hydroxyl, (x) amino, (xi) mono-lower alkylamino {e. g.
mono-C1_6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xii}
di-lower alkylamino (e.g. di-C~_6 alkylamino such as dimethylamino, diethylamino, dipropylamino, dibutyiamino, etc.), (xiii) 5- or 6-membered cycloamino (e. g. morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.), (xiv) lower alkylcarbonyl (e. g.
C1_6 alkyl-carbonyl such as acetyl, propionyl, etc.), (xv) carboxyl, (xvi) lower alkoxycarbonyl (e. g. C1_6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xvii) carbamoyl, (xviii) mono-lower alkylcarbamoyl {e. g. mono-C1_6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.), (xix) di-lower alkylcarbamoyl (e. g. di-C1_6 alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (xx) arylcarbamoyl {e. g. C6_~n aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxi) sulfo, (xxii) lower alkanesulfonyl (e.g. C1_6 alkanesulfonyl such as methanesulfonyl, ethanesulfonyl, etc.), (xxiii) aryl _ (e. g. C6_lo aryl such as phenyl, naphthyl, etc.), (xxiv}
aryloxy (e. g. C6_lo aryloxy such as phenyloxy, _ naphthylaxy, etc.), (xxv) thiocarbamoyl, (xxvi) mono-C1_6 alkylthio-carbamoyl, (xxvii) di-C~_6 alkylthio-SUBSTITUTE SHEET (RULE 26y carbamoyl , ( xxviii ) C6_~o aryl-carbamoyl and ( xxix ) C6_", _ aryl-thiocarbamoyl, among others.
The above-mentioned "lower alkyl that may be halo-genated", "lower alkoxy that may be halogenated", and ' "lower alkylthio that may be halogenated" have the same meaning of "lower alkyl that may be haloqenated", "lower alkoxy that may be substituted", and "lower alkylthio that may be substituted" as mentioned above for the "substituent" of said "carbocyclic group or optionally substituted heterocyclic group" as mentioned for Ar.
The "optionally substituted carbon atom" for Q
includes a group of the formula CR' (R' is as defined above).
Q is preferably CR'~ wherein R'~ is a hydrogen atom or a C1_6 alkyl group; or N{0)p wherein p is as defined above.
Ring A may have substituent groups, such as those mentioned for R' (R' is as defined above), in addition to R1 and R2.
The "optionally substituted methylene" as mentioned for Y includes (1) groups of the formula 2 5 ~ /R 9 ~C.,.Rs, wherein R9 and R9 may be the same or different and each represents (i) hydrogen, (ii) lower alkyl that may be , halogenated, (iii) lower alkoxy that may be halogenated, (iv) lower alkylthio that may be , halogenated, (v) hydroxyl, (vi) cyano, (vii) ' alkylcarbonyl (e. g. Ci_~ alkyl-carbonyl such as acetyl, propionyl, etc.), (viii) lower alkylcarbonyloxy (e.g.
C,_6 alkyl-carbonyloxy such as acetyloxy, propionyloxy, SUBST1TLJ'TE SiiEFi' (RULE 26) etc.), (ix) formylamino, (x) amino, (xi) mono-lower ' alkylamino (e.g. mono-C1_6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xii) di-lower alkylamino (e.g. di-5 Ct_6 alkylamino such as dimethylamino, diethylamino, _ dipropylamino, dibutylamino, etc.), (xiii} carboxyl, (xiv) lower alkoxy-carbonyl (e. g. C,_6 alkyloxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), or (xv) lower 10 alkyl-carbonylamino (e. g. C1_6 alkyl-carbonylamino such as acetylamino, propionylamino, etc.) wherein the "lower alkyl that may be halogenated", "lower alkoxy that may be halogenated", and "lower alkylthio that may be halogenated" include the same meaning of "lower 15 alkyl that may be halogenated", "lower alkoxy that may be halogenated", and "lower alkylthio that may be halogenated" as mentioned for the "substituent" for the "optionally substituted carbocyclic group or optionally substituted heterocyclic group" as mentioned 20 for Ar. R' and R' are the same or different and each preferably represents hydrogen, hydroxyl, cyano, C1_s alkoxy, amino, or mono-C1_6 alkylamino, more preferably represents hydrogen, hydroxyl, amino, or mono-C1_6 alkylamino, and most preferably represents hydrogen and (2) groups of the formula >C=R1~ wherein Rlo represents (i) _~/Rs ~R9~
wherein R' and R9~ are as def fined above, ( ii ) =NR' wherein R9 is as defined above, (iii) 0 or (iv) S.
_ The "imino that may be substituted" as mentioned for Y includes NRS (wherein RS is as defined above).
SUBSTITUTE SHEET (RULE 26) The "heterocyclic group" of the "optionally substituted heterocyclic group" as mentioned for RG
preferably includes 5- to 10-membered (monocyclic or bicyclic) heterocyclic groups each containing 1 or more (e.g. 1 to 4, preferably 1 to 3, and more preferably 1 or 2) hetero-atoms of preferably one or two kinds as selected from the group consisting of nitrogen, oxygen, and sulfur in addition to carbon, for example non-aromatic heterocyclic groups such as 1-, 2-, or 3-pyrrolidinyl, 2- or 4-imidazolidinyl, 2-, 3-, or 4-pyrazolidinyl, piperidino, 2-, 3-, or 4-piperidyl, f-or 2-piperazinyl, morpholinyl, thiomorpholinyl, 3- or 4-azepinyl, etc. (particularly saturated 5- through 7-membered cycloamino groups (e. g. 1- or 2-piperazinyl) are preferred) and aromatic heterocyclic groups such as 2- or 3-thienyl, 2-, 3-, or 4-pyridyl, 2- or 3-furyl, 4- or 8-quinolyl, 4-isoquinolyl, pyrazinyl, 2-pyrimidinyl, 3-pyrrolyl, 2-imidazolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isoxazolyl, 1-indolyl, 2-isoindolyl, etc. Among them, the aromatic heterocyclic groups and saturated 5- to 7-membered cycloamino groups are preferred. The more preferred are 5- or 6-membered aromatic heterocyclic groups each containing 1 to 3 hetero-atoms of preferably one or two kinds as selected from among nitrogen, oxygen, and sulfur in addition to carbon (e. g. 2- or 3-thienyl, 2- or 4-pyridyl, etc.) and saturated 5- to 7-membered cycloamino groups.
The "substituent" of said "optionally substituted heterocyclic" includes the same as the "substituent"
for the "optionally substituted hydrocarbon group" of R3, R4, R5, and R6.
The "acyl" as mentioned for RS includes -(C=0)-R', -SOz-R', -SO-R' , - ( C=0 ) NRB-R' , - ( C=0 ) 0-R' , - ( C=S ) O-R' , and -(C=S)NRB-R' (wherein R' is hydrogen or optionally substituted hydrocarbon and RB is hydrogen or lower alkyl (e. g. C,_6 alkyl such as methyl, ethyl, propyl, SUBSTITUTE SHEET (RULE 26~

WO 98l07705 PCTIJP97102858 isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. and preferably C1_3 alkyl such as methyl, ethyl, propyl, isopropyl, etc.)].
Among those groups , - ( C=0 ) -R', -SOZ-R', -SO-R', - ( C=0 ) NRB-R', and - ( C=0 ) 0-R' ( R' and Re are as de f fined above) are preferred and -(C=0}-R' (R' is as defined above) is more preferred.
The "hydrocarbon" of the "optionally substituted hydrocarbon" as mentioned above for R' is a group available upon elimination of one hydrogen atom from a hydrocarbon compound and includes acylic (straight-chain or branched) and cyclic hydrocarbon groups such as alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl. The specific list of such groups includes the same groups as those mentioned for the "hydrocarbon" of the "optionally substituted hydrocarbon" as mentioned for R3, R4, and R5. Among those groups, C1_16 acyclic or cyclic hydrocarbon groups are preferred and lower alkyl groups are particularly preferred.
The preferred substituent that may be present on the "hydrocarbon group" for R7 includes (i) halogen (e. g. fluorine, chlorine, bromine, iodine), (ii) lower alkylenedioxy (e.g. C1_3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (iii) nitro, (iv) cyano, (v) lower alkyl that may be halogenated, (vi) lower cycloalkyl (e.g. C3_b cycloalkyl such as cyclobutyl, cyclopentyl, cyclohexyl, etc.), {vii) lower alkoxy that may be halogenated, lower alkylthio that may be halogenated, {ix) hydroxyl, (x) amino, (xi) mono-lower alkylamino (e.g. C1_6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, . butylamino, etc.j, (xii) di-lower alkylamino (e.g. di-C1_6 alkylamino such as dimethylamino, diethylamino, . dipropylamino, dibutyiamino, etc.), (xiii) 5- or 6 membered cycloamino (e.g. morpholino, piperazin-1-yl, SUBSTiTLJTE SHEET (RULE 26~

WO 98I07705 PCTlJP97l02858 piperidino, pyrrolidin-I-yl, 2-pyrrolidon-1-yl, 2-pyridon-1-yl, etc.) optionally having hydroxyl or oxo, (xiv) acylamino, (xv) lower alkyl-carbonyl (e. g. C1_6 alkyl-carbonyl such as acetyl, propionyl, etc.), (xvi) lower alky-carbonyloxy (e. g. C1_6 alkyl-carbonyloxy such as methylcarbonyloxy, ethylcarbonyloxy, etc.), {xvii) lower alkyl-carbonyloxy-C1_3 alkyl (e. g. C1_6 alkyl-carbonyloxy-C1_3 alkyl such as methylcarbonyloxymethyl, ethylcarbonyloxymethyl, etc.), (xviii) carboxyl, (xix) 20 lower alkoxy-carbonyl (e. g. C1_6 alkyl-oxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.}, (xx) mono-lower alkylamino-carbonyl (e.g. mono-C1_6 alkylamino-carbonyl such as methylamino-carbonyl, ethylamino-carbonyl, etc.), (xxi) di-lower alkylamino-carbonyl (e. g. di-C1_6 alkylamino-carbonyl such as dimethylamino-carbonyl, diethylamino-carbonyl, etc.), (xxii) carbamoyl, (xxiii) mono-lower alkyl-carbamoyl (e.g. mono-C1_6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.), (xxiv) di-lower alkylcarbamoyl {e.g. di-C1_6 alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (xxv) arylcarbamoyl (e.g. C6_lo aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxvi) sulfo, (xxvii) lower alkylsulfonyl (e. g. C1_6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.), (xxviii) aryl (e. g. C6_lo aryl such as phenyl, naphthyl, etc.}, (xxix) aryloxy (e. g. C6_lo aryloxy such as phenyloxy, naphthyloxy, etc.), {xxx) 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being , optionally fused with a benzene ring, (xxxi) lower aralkyloxy-carbonyl (e. g. C_11 aralkyloxy-carbonyl such as benzyloxycarbonyl etc.}, (xxxii) thiocarbamoyl, (xxxiii) mono-lower alkylthio-carbamoyl (e. g. mono-C1_r, SUBSTITUTE SHEET (RULE 26) alkylthio-carbamoyl such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (xxxiv) di-lower alkylthio-carbamoyl (e.g. di-C1_6 alkylthio-carbamoyl such as dimethylthiocarbamoyl, diethyithiocarbamoyl, etc.) and (xxxv) arylthiocarbamoyl (e. g. C6_jo aryl-thiocarbamoyl such as phenylthiocarbamoyl etc.).
Preferred, among them, are halogen, di-lower alkylamino, carboxyl, and lower alkoxycarbonyl.
More preferred are di-lower alkylamino and carboxyl.
The above-mentioned "lower alkyl that may be halogenated", "lower alkoxy that may be halogenated", "lower alkylthio that may be halogenated", and "acylamino" are the same meaning as those mentioned for the "substituent" the "optionally substituted hydrocarbon group or optionally substituted heterocyclic group" as mentioned for Ar.
The "lower alkyl" of the "optionally substituted lower alkyl" as mentioned for R1 and RZ includes straight-chain or branched lower(C1_6)alkyl {e. g.
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.).
The "lower alkoxy" of the "optionally substituted lower alkoxy" as mentioned for R1 and Rz includes straight-chain or branched lower(C1_6)alkyloxy (e. g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc.).
The "substituent" of the above "optionally substituted lower alkyl" and "optionally substituted lower alkoxy are the same meaning as those mentioned for the "substituent" of the "optionally substituted hydrocarbon group" as mentioned for R3 R4, and R5.
Referring to various combinations of R' and RZ, the combination of any of hydrogen, halogen, hydroxyl, SUBSTITUTE SHEET (RULE 26) optionally substituted lower alkyl, and optionally ' substituted lower alkoxy for R' and any of hydrogen, halogen, hydroxyl, optionally substituted lower alkyl, and optionally substituted lower alkoxy for Rz are 5 preferred and the combination of methoxy for R1 and , hydrogen for Rz is generally useful.
Another preferable combinations of R1 and RZ are one of R1 and RZ is ( Z ) a hydrogen, ( 2 ) a C1_6 alkyl , ( 3 ) a C1_6 alkoxy which may be substituted with ( a } a C1_6 10 alkoxy-carbonyl, (b) a C_11 aralkyl or (c) a carboxyl, or (4) a hydroxyl;
the other is ( 1 ) a C1_6 alkyl , ( 2 ) a C1_6 alkoxy which may be substituted with (a) a C1_6 alkoxy-carbonyl or (b) a carboxyl, or (3) a hydroxyl.
15 Where R1 and RZ taken together form a ring with adjacent -C=C-, the preferred includes lower alkylene (e. g. C1_6 alkylene such as methylene, ethylene, propylene, trimethylene, tetramethyiene, etc.}, lower alkylenedioxy (e.g. C1_6 alkylenedioxy such as 20 methylenedioxy, ethylenedioxy, etc.} or lower alkyleneoxy (e.g. C1_6 alkyleneoxy, such as methyleneoxy, ethyleneoxy, etc.). Particularly preferred is lower alkylenedioxy (e. g. C1_s alkylenedioxy such as methylenedioxy, ethylenedioxy, 25 etc.), or lower alkyleneoxy (e. g. C1_6 alkyleneoxy, such as methyleneoxy, ethyleneoxy, etc.), especially lower alkylenedioxy, with methyienedioxy being particularly preferred.
The "substituent" of the ring formed by R1 and R', 30 taken together, are the same "substituent" the "optionally substituted hydrocarbon group" as mentioned for R', R4, and R5.
R' and R' may taken together form a ring with adjacent -C=C-.
35 The preferred includes lower alkylenedioxy (e. g.
SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97I02858 C3_6 alkylenedioxy such as methylenedioxy, ethylenedioxy, propylenedioxy, trimethylenedioxy, tetramethylenedioxy, etc.).
The "substituent" of the ring formed by R' and R', taken together, are the same "substituent" of the "optionally substituted hydrocarbon group" as mentioned for R3, R4, and R5.
The "optionally substituted hydroxyl" for R3 and R6 is either a hydroxyl group or a hydroxyl group having a group as said "optionally substituted hydrocarbon group" instead of its hydrogen atom. The "optionally substituted hydroxyl" is preferably a hydroxyl group or a hydroxyl group having said optionally substituted lower alkyl. Said "lower alkyl"
includes straight-chain or branched lower(C1_6)alkyl (e. g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the substituent of the "lower alkyl" includes the same groups as those mentioned for the substituent of the "optionally substituted hydrocarbon group" as def fined for R3, R' and RS .
Preferably, R' is Ci_6 alkoxy.
The "C1_3 alkylene" of the "C1_~ alkylene which may have an oxo or thioxo" as mentioned for Z1 is -CHZ-, ( CHZ ) Z-, or - ( CHZ ) 3- and may contain oxygen or sul fur within the carbon chain as an ether or thioether as it is the case with -CHZ-O-CHz-, -CHz-0-CHz-CHz-, -CHZ-S-CHz-, and -CHZ-S-CHZ-CHz- and the sulfur may be in the sulfoxide form or in the sulfone form.
More specifically, the "oxo- or thioxo-C,_~ alkyl-ene" includes groups of the following formula.
. - ( CH2 ) m-X- ( CH2 ) n-wherein X is C=0 or C=S; m and n each is 0 or 1.
In the above formula, X preferably is C=0 and m and n each is preferably equal to 0.
SUBSTiT~JTE SHEET (RULE Z6) WO 98I07705 PCTIJP97l02858 The "C1_j alkylene" of the "optionally substituted C~_3 alkylene" as mentioned for ZZ includes -CHz-, -(CHZ)2- or -{CH2)3- and may contain etherified oxygen or sulfur within the carbon chain as it is the case with -CHZ-O-CHz-, -CHZ-0-CHZ-CHZ-, -CHi-S-CHZ, or -CHZ-S-CHZ-CHZ- _ and the sulfur may be in the suifoxide form or in the sulfone form.
The "substituent" of said "optionally substituted C1_3 alkylene" includes the same groups as those men-tinned for the substituent of the "optionally substituted hydrocarbon group" mentioned for R', R', and R5.
The "Ci_3 alkylene" of the "optionally substituted C1_3 alkylene substituted" as mentioned for Zz may have an oxo or thioxo bond in a chemically feasible position.
Preferably ZZ is ( 1 ) C=O, ( 2 } CHz, ( 3 ) ( CHZ ) Z, { 4 ) ( CHZ ) 3 or ( 5 ) CH-OH .
Also preferably ZZ is -{CHZ)p- {where p represents an integer of 1 to 3} . More preferably ZZ is -CHZ-.
Among species of compound [I], the compounds in which Q is CR' {where R' is as defined above) are preferred.
Preferably, R' is hydrogen, halogen, optionally substituted hydrocarbon, or optionally substituted hydroxyl, more preferably, hydrogen, halogen, optionally substituted alkyl or hydroxyl optionally substituted by lower alkyl. The more preferred are hydrogen, halogen, lower alkyl, and hydroxyl optionally having lower alkyl as a substituent. Hydrogen is the most useful. , More preferably, Q is (1) CR'~ wherein R'~ is (i) a C,_6 alkyl which may be substituted with a di-C,_,, _ alkylamino, (ii) a halogen, or (iii) a C1_6 alkoxy, or (2) I~.
SUBSTITUTE SHEET RULE 2fi) WO 98l07705 PCTIJP97102858 Q is also preferably ( 1 ) CR~' wherein R4 is hydrogen, halogen, optionally substituted hydrocarbon, or optionally substituted hydroxyl, or (2) N(O)p wherein p is 0 or 1.
Q is also preferably CH or N.
X is preferably C=O.
Y is preferably CHZ or NR5 (where RS is as defined above) and more preferably NRS (where RS is as defined above).
Y is also preferably, NRS wherein R5~ is ( i ) hydrogen, (ii) C1_6 alkyl which may be substituted with (a) morpholino, (b) carboxyl, (c) C1_6 alkoxy-carbonyl, or (d) phenyl which may be substituted with C1_6 alkoxy, or ( iii ) COR'~ wherein R'~~ is ( a) hydrogen, ( b) C1_6 alkyl which may be substituted with carboxyl or benzyloxycarbonyl, or (c) di-C1_6 alkylamino.
RS is preferably hydrogen, alkyl that may be substituted, or acyl of the formula -{C=0)-R' (where R' is as defined above), with hydrogen being particularly preferred.
More preferred R5 is (i) hydrogen, (ii) C1_6 alkyl which may be substituted with (a) morpholino, {b) carboxyl, (c) C1_6 alkoxy-carbonyl, or {d) phenyl which may be substituted with C1_6 alkoxy, or { iii ) COR' wherein R'~ is { a ) hydrogen, ( b) C1_6 alkyl which may be substituted with carboxyl or benzyloxycarbonyl, or (c) di-C1_6 alkylamino.
Ar is preferably optionally substituted 3- to 14-membered aromatic group, preferably, optionally substituted aryl and more preferably optionally ( substituted phenyl.
The above-mentioned "optionally substituted 3- to 14-membered aromatic group", "optionally substituted - aryl" and "optionally substituted phenyl" include 3- to 14-membered aromatic group, aryl, or phenyl optionally SUBSTITUTE SHEET (RULE 2fi) WO 98I07705 PCTlJP97102858 t substituted with, for example, {i) halogen (e.g.
fluorine, chlorine, bromine, iodine), (ii) lower alkylenedioxy (e.g. C1_3 alkylenedioxy such as , methylenedioxy, ethylenedioxy, etc.), (iii) nitro, (iv) cyano, (v) lower alkyl that may be halogenated, (vi) lower aikenyl that may be halogenated, (vii) lower alkynyl that may be halogenated, (viii) Lower cycloalkyl (e. g. C3_6 CyClOalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (ix) lower alkoxy that may be halogenated, (x) lower alkylthio that may be halogenated, (xi) hydroxyl, (xii) amino, (xiii) mono-lower alkylamino (e. g. mono-Ci_6 alkylamino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (xiv) di-lower alkylamino (e.g. di-C1_6 alkylamino such as dimethylamino, diethyiamino, dipropylamino, dibutylamino, etc.), (xv) 5- or 6-membered cycloamino (e.g. morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-y1, etc.), (xvi) acylamino, (xvii) lower alkylcarbonyl (e. g. C1_6 alkyl-carbonyl such as acetyl, propionyl, etc.), (xviii) carboxyl, (xix) lower alkoxy-carbonyl (e. g. C1_6 alkyl-oxycarbonyl such as methoxycarbonyl, ethoxycarbonyi, propoxycarbonyl, butoxycarbonyl, etc.), (xx) carbamoyl, (xxi) mono-lower alkylcarbamoyl (e. g. mono-C1_6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.), (xxii) di-lower alkylcarbamoyl (e. g. di-C,_6 alkyl-carbamoyl such as dimethylcarbamoyl, diethylcarbamoyl, etc.), (xxiii) aryl-carbamoyl {e. g.
C6-to aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxiv) sulfo, (xxv) lower alkylsulfonyl (e.g. C1_6 alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, etc.), (xxvi) aryl (e. g.
C6-to aryl such as phenyl, naphthyl, etc.), (xxvii) aryloxy (e. g. C6_la aryloxy such as phenyloxy, SUBSTITUTE SHEET (RULE 26~

naphthyloxy, etc.), (xxix) thiocarbamoyl, (xxx) mono-- lower alkylthiocarbamoyl (e. g. mono-C,_6 alkylthio-carbamoyl such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (xxxi) di-lower 5 alkylthiocarbamoyl (e. g. di-C~_6 alkylthio-carbamoyl _ such as dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.), (xxxii) aryl-carbamoyl (e. g. C6_,o aryl-carbamoyl such as phenyl-carbamoyl) and (xxxiii) aryl-thiocarbamoyi (e.g. C6_io aryl-thiocarbamoyl such as 10 phenyl-thiocarbamoyl). The above-mentioned "lower alkyl that may be substituted", "lower alkoxy that may be halogenated", "lower alkylthio that may be halogenated", and "acylamino" are the same as those respectively mentioned for the "substituent" of the 15 "optionally substituted hydrocarbon group or optionally substituted heterocyclic group" as mentioned for Ar).
Preferred is phenyl substituted with halogen (fluorine or chlorine in particular), lower alkylenedioxy (methylenedioxy in particular), lower alkvxy (methoxy 20 in particular) that may be halogenated, or hydroxyl.
To be more sgecific, said "phenyl that may be substituted" includes groups of the following formulas.
25 ~ I A1 ~ ( A3 (A1) , A2 (A2) (wherein Ai, AZ, and A' are the same or different and each represents halogen (e. g. fluorine, chlorine, - 30 bromine, iodine), lower alkoxy that may be halogenated (e. g. methoxy, difluoromethoxy, trifluoromethoxy, ~ ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), or hydroxyl; or either A' 35 and Az or AZ and A', taken together, represent lower SUBSTtTLJTE SHEET (RULE Zfi) WO 98l07705 PCTIJP97102858 alkylenedioxy (e.g. C,_J alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.) A2 A (A3) [wherein AZ and A' are as defined above] or i0 A4 (A4) [wherein A4 is halogen (e. g. fluorine, chlorine, bromine, iodine), lower alkoxy that may be halogenated (e. g. methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), or hydroxyl) More preferred are groups of the formula i i or A2 (A3) A4 (A4) (wherein the all symbols have the same meanings as defined above).
Most useful is i OJ ' Ar is also preferably optionally substituted .
pyridyl group or optionally substituted pyridinium.
Substituents of the above-mentioned "optionally SUBSTTTUTE SHEET (RULE 26) WO 98l07705 PCT/JP97102858 substituted pyridyl group" and "optionally substituted pyridinium" are the same as the substituents of "optionally substituted 3- to 14-membered aromatic group" for Ar, as mentioned above.
Preferable example of Ar is (1) a phenyl group which may be substituted with (a) a halogen, (b) a C,_fi alkylenedioxy, (c) a C,_6 alkoxy which may be substituted with (c-1) a halogen (c-2) a di-C~_6 alkylamino, or (c-3) a C1_6 alkoxy-carbonyl, (d) a C~_i~
aralkyloxy, (e) C,_6 alkyl which may be substituted with a halogen, or (f) hydroxyl, (2) an optionally oxidized pyridyl group, or (3) a pyridinium group which may be substituted with C1_6 alkyl Preferably, Ri and RZ each is hydrogen, halogen, i5 hydroxyl, or lower alkoxy, or, taken together, represent lower alkylenedioxy.
Preferably, R' is hydrogen, halogen, lower alkyl, or hydroxyl optionally having lower alkyl as a substituent.
Each of m and n is equal to 0.
In the above formula (I], ring A as represented by the formula R1 \A

wherein a11 symbols have the same meanings as defined above is preferably a ring of the formula A

wherein a11 have the same meanings as defined above or SUBSTtTUTE SHEET (RULE 26) WO 98l07705 PCTIJP97/02858 a ring of the formula 0 _ ~0 wherein R' represents hydrogen, halogen, optionally substituted hydrocarbon group (preferably, lower alkyl), or hydroxyl optionally having lower alkyl as a substituent.
Particularly preferred is the ring of the formula 0 ~ ~ o r Me0 Moreover, in formula (I), the ring represented by the formula ~Y
i wherein a11 symbols have the same meanings as defined above, is preferably a ring of the formula (CHZ)m-X- (CH2)n Y

wherein all symbols have the same meanings as defined above.
More preferred is a ring of the following formula.
SUBSTITUTE SHEET (RULE 26) ' /Y

wherein Y and ZZ are as defined above.
Particularly preferred is a ring of the following formula.

/Y
CCH2)p wherein p is an integer of 1 to 3; Y is as defined above.
The preferred compounds, among species of compound [I), are compounds of the following formula.
/A I Q.~, CCHZ)m-X--(CIIZ)n~Y
R1 \
RZ Ar Z2 CI I]
wherein a11 symbols have the same meanings as defined above.
More preferred are the compounds of the following formulas.
Q CCH2)m-X
1 \ ~ / /~NR5 R 2 ZZ/ L I V]
R Ar . wherein all symbols have the same meanings as defined - above.
SU85Ti'TIJT~ SHEET (RULE 26) /A Qw (CH2)m-X-(CH2)n~
R1 \ ~ / Y
,2 ~ _ R Ar ~Z2 [V]

wherein a11 symbols have the same meanings as defined ' above.

R1 I j / ~ Y
R2 Ar [VI I]
wherein a11 symbols have the same meanings as defined above.
O

...., R 2 A r LX I I I
wherein a11 symbols have the same meanings as defined above.
A~ Q ~ m 0 R1 / ~ Z%N-R13 RZ A r '~ ._.
CX V I ~
wherein R" is hydrogen or optionally substituted lower alkyl; the other symbols have the same meanings as defined. The above "optionally substituted alkyl" has the same meaning as defined in R' and R2.
SUBSTITUTE SHEET (RULE Z6~

m o A ~ ~ IV H
R ~ ~ Z2~C H
i _ ' RZ Ar . ._.
s Cxx~
wherein ZZ' is optionally substituted C1_2 alkylene; the other symbols have the same meanings as defined above.
The "optionally substituted Ci_z alkylene" have the same substituents as defined in Z~.
m Q~ o Ai i 2' \ G
Z
R1 R2 Ar COZ R14 1 ~ ~~ ._.
[XXI I I]
wherein R1' is lower alkyl (e.g. C1-6 alkyl such as methyl, ethyl, propyl, etc.); G is hydrogen or the same group as the substituent of the substituted methylene mentioned above for Y; the other symbols have the same meanings as defined above.
Still more preferred are compounds of the following formula:

/ w \NR5 R1 \2 ~ CCH2)p ..... R
LV I
wherein ring B is a benzene ring that may be substituted wherein the substituent for this "benzene . ring that may be substituted" has the same meaning as those mentioned for the "substituent" of the "optionally substituted hydrocarbon group or optionally substituted heterocyclic group" as mentioned for Ar);
the other symbols have the same meanings as defined SUBSTITUTE SHEET (RULE 26) above. ' As the preferred species of compound {IIJ, Q is ( 1 ) CR4~ wherein R'~ is { i ) a C1_6 alkyl group which _ may be substituted with a di-C1_6 alkylamino group, (ii) a halogen atom, or {iii} a C1_6 alkoxy group, or (2) N; .
X is C=0;
Y is NRS~ wherein R5~ is ( i ) a hydrogen, ( ii ) a C,_5 alkyl group which may be substituted with (a} a morpholino, (b) a carboxyl, (c) a C1_6 alkoxy-carbonyl, or (d) a phenyl which may be substituted with C,_6 alkoxy, or (iii) COR'~ wherein R'~ is (a) a hydrogen, (b} C1_6 alkyl which may be substituted with a carboxyl or a benzyloxycarbonyl, or a di-CI_~ alkylamino;
m and n each represents 0;
ZZ is { 1 ) C=O, ( 2 ) CHz, ( 3 ) ( CHZ ) Z, ( 4 ) ( CHZ ) 3 , or { 5 }
CH-OH;
Ar is (1) a phenyl group which may be substituted with { a ) a halogen, ( b } a C1_6 alkylenedioxy, ( c ) a C1_6 alkoxy which may be substituted with (c-1) a halogen or ( c-2 ) a di-C1_6 alkyl amino, or ( c-3 } a C1_b alkoxy-carbonyl, (d) a C_11 aralkyloxy, (e) C1_6 alkyl which may be substituted with a halogen, or (f) hydroxyl, (2) an optionally oxidized pyridyl group, or (3) a pyridinium group which may be substituted with C,_6 alkyl;
one of R' and R2 is ( 1 ) a hydrogen, ( 2 ) a C1_6 alkyl, ( 3 }
a Cs_~ alkoxy which may be substituted with (a) a Ci_6 alkoxy-carbonyl, {b) a C_11 aralkyl or (c) a carboxyl, .
or (4} a hydroxyl.
the other is (1) a C,_6 alkyl, (2) a C1_6 alkoxy which may be substituted with (a) a C1_~ alkoxy-carbonyl or (b} a carboxyl, or (3) a hydroxyl;
R1 and RZ taken together with adjacent -c=c- form a C~_~, alkylenedioxy group, or a C1_6 alkyleneoxy group; or SUBSTITUTE SHEET (RULE Zfi) ring A is a benzene ring which may have a C1_6 alkoxy group, in addition to R1 and R2; and a C~_6 alkoxy group or ring A and a C~_6 alkoxy group of R1 may be taken together form C1_6 alkylenedioxy group.

More preferably, Q is CH or N;

X is C=0;

m and n each represents 0;

Zz is CHZ; and R' and R~ taken together form a C~_6 alkylenedioxy group.

As the preferred species of compound [I), the following compounds can be specifically mentioned.

10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3,-benzodioxoio[4,5-f]isoindol-7-one, 11-(1,3-Benzodiaxol-5-yl)-7,8,9,10-tetrahydro-1,3,-benzodioxolo[4,5-g]isoquinolin-7-one, 4-(1,3-Benzodioxol-5-yl)-2,3-dihydro-5-methoxy-1H-benz[f]isoindol-1-one, 8,9-Dihydro-10-(4-trifluoromethylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 11-(1,3-Benzodioxol-S-yl)-9,10-dihydro-8H-isoindolo[5,6-f]benz[b]-1,4-dioxan-8-one, 10-(4-Fluorophenyl)-8,9,-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 10-(1,3-Benzodioxol-S-yl)-8,9-dihydro-6-methyl-7H-1,3-benzodioxolo[4,5-f]isoindol-?-one, 10-(4-Fluorophenyl)-8,9-dihydro-6-methyl-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 8,9-Dihydro-6-methyl-10-(4-trifluoromethylphenyl)-7H-1,3-benzodioxolo[4,5-f)isoindol-7-one, 10-(1,3-Benzodixol-5-yI)-8,9-dihydro-6-ethyl-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 4-(1,3-Benzodioxol-S-yl)-2,3-dihydro-6-methoxy-1H-benz[f]isoindol-1-one, 2,3-Dihydro-6-methoxy-4-(4-methoxypheny)-1H-benz[f)isoindol-1-one, SUBSTITUTE SHEET (RULE 26) WO 98/07?OS PCT/JP97/02858 2,3-Dihydro-6-methoxy-4-(4-trifluoromethylphenyl)-1H-benz[fJisoindol-1-one, .
4-(4-Fluorophenyl)-2,3-dihydro-6-methoxy-9-methyl-1H-benz[f]isoindol-1-one, 4-(4-Methoxyphenyl)-2,3-dihydro-6-methoxy-9-methyl-1H-benz[f]isoindol-1-one, 9-(4-Fluorophenyl}-1,2-dihydro-7-methoxy-3H-pyrrolo[3,4-b]quinolin-3-one, 1,2-Dihydro-7-methoxy-9-(4-methoxyphenyl)-3H-pyrrolo(3,4-b)quinolin-~-one, 3,4-Dihydro-7-methoxy-5-(4-methoxyphenyl)-benzo(b][1,7]naphthyridin-1{2H)-one.
The preferred, among the above-mentioned compounds of formula [III), are the compounds in which Q is CH or N; X is C=O;
1 wA I
R

is R 1 '\

wherein R~ is hydrogen and Rz is methyl, or R1 and RZ
jointly form methylenedioxy; Ar is phenyl that may be substituted with hydroxyl, halogen (e. g. fluorine, chlorine, bromine, etc.), lower alkoxy (e. g. Ci-~) alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, ' isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, and hexyloxy}, and/or "_ methylenedioxy; ZZ is CH2, and m is equal to 0 (exclusive of Helioxanthin mentioned above. Compound [III], inclusive of its salt, like compound (I) and its salt, has cell differentiation inducing factor activity SUgSTiTUTE SHEET' {RULE 2fi) WO 98l07705 PCTlJP97I02858 or enhancing activity of the cell differentiation inducing factor.
A variety of synthetic processes may be used for the production of compound [I] of the invention 5 (hereinafter referred to briefly as compound [I]) and - its salt. Some representative reactions of compound [I] are presented below in Schemes 1-5.
In the explanation of the following processes, starting materials and reaction products way form a 10 salt thereof which does not inhibit the reaction.
Referring to compound [I] wherein Q is N(0)r (where p is equal to 0 or 1), the compound in which p is equal to 1 or a salt thereof can be provided by subjecting the corresponding compound in which p is 15 equal to 0 or a salt thereof or an intermediate thereof in a suitable production stage to a known chemical oxidation reaction [cf. Chemistry of the Heterocyclic N-Oxide, 22-60 (1971), Academic Press, London & New York or G. Jones (ed.), Quinolines Part 1, John Wiley &
20 Sons, Chapter I, pp. 61-62 (1977)] or an analogous reaction.
The compound of formula [I] wherein Q represents carbon that may be substituted, namely compound [VII], can be synthesized typically by the process shown below 25 in Schema 1.
SU85TtTLITE SHEET (RULE 26) WO 98I07705 PCTlJP97l02858 schema 1 R4 R4 ~Z ~y [X I7 wA I O H _ ~~A I 0 Z z/
-I- A r ~ N Step 1 R 1 ~ ~A r Step 2 R Rz [ I XJ ~ _ Rz N Hz ,.,[V I I I ] CX] ' Ra R4 I A% o Z %y Step 3' I Ai i Z /y Ri ~,Z R1 T
z Ar R z A r .~ R
[XI I] [VIIJ
Referring to compounds [VII]-[XII] in the above Schema 1, E represents hydrogen or halogen and the other symbols have the same meanings as defined above.
Compound [I] in which Q is N can be produced using an anthranil derivative of the following formula:
i \
R1 \A \ O
.... RZ ''fir [X.
wherein a11 symbols have the same meanings as defined above, instead of compound [X] in the above Schema 1 in a manner similar to that described the per se known technology (E. C. Taylor et al., Journal of Organic Chemistry, 32, 1899-1900, 1967).
Moreover, compound [I] can also be produced by .
subjecting compound of the following formula:
\ Q~ Z 1 R1 ~ j / j0 1' ~. Z 2 ..... RZ A' [I, ]
SUBSTITUTE SHEET (RULE 2fi~

wherein all symbols have the same meanings as defined above, to the reactions illustrated below in Schema 3-5.
Compound [I'] in which Q is a carbon atom that may be substituted can be produced using a compound of the formula:

\0 Z
[X I' wherein the respective symbols have the same meanings as defined above, instead of compound [XI) in Schema 1.
Comgound [XI] and compound [XI'] can be purchased from commercial sources or synthesized by using the per se known procedures for the synthesis of olefins, ketones, esters, amides, acid anhydrides, and imides (e. g. S. R. Sandler and W. Karo, Organic Functional Group Preparations I, 2nd ed., Academic Press, Chapter 2, pp. 39-81, Chapter 8, pp. 206-235. Chapter 10, pp.
2B9-31S, and Chapter 11, pp. 316-358 (19B3) and S. R.
Sandler and W. Karo, Organic Functional Group Preparations III, 2nd ed., Academic Press, Chapter 2, pp. 87-128 and Chapter 7, pp. 281-313 (1989)] in a suitable combination.
When the compound of formula [I') is an aryl-naphthalenelignan compound, it can also be produced by any of the per se known synthetic processes such as the processes described in R. S. Ward, Chemical Society Reviews, 11, 75-I25 (1982), R. S. Ward, Synthesis, 719-730 (1985), D. A. Whiting, Natural Product Reports, 2, 191-211 (1985) and Q, 499-S25 (1985), R. Stevenson et Y
' al . , ,lournal of Natural Products, ~2_ ( 2 ) , 367-37 S
(1989}, and other literature.
Compound [I'] in which Q is N, Z' is C=0, and Zi is methylene, namely compound [XIII], can be produced SU85TiTUTE SHEET (RULE 26y by, for example, the process illustrated below in -Schema 2.
Schema 2 ~) N C02 R11 ~ w N. OH
i ~ 1 1 ~ i i 0 H Step 5-T
~ 1 C 0 2 R Step 4 R 1 R2 Ar ~ R Ar '~ ._. ~ ._.
[X I V] [X V]

~A N 0 i i R2 A r ._.
I5 [XI I I]
Referring to compounds [XIII)-[XV) in the above Schema 2, R11 is lower alkyl (e. g. C1_b alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.; the other symbols have 20 the same meanings as defined above.
Compound [ Ii ) wherein Y is NRI~, wherein R13 is hydrogen or optionally substituted lower alkyl, and n=0, that is compound [XVI], can be produced by, for example, the process illustrated below in Schema 3.
25 Schema 3 Q m r~ ~A Q mC02R12 i i Z2.0 Step 6 Step 7 R R1 ~ ~ Z2 -OH
' R2 Ar ' R2 Ar ;, 30 ' [X V I I ]
[XV I I I ]
mC02 R12 iA Q 'n 0 13 ' R1 ~ ~ Z 2 -A Step $ R1 ~ ~ Z%N-R
' R2 A r ' RZ A r 3 5 .-- .-.
[X I X] [X V I ]
SUBSTITUTE SHEET (RULE 26~

WO 98I07705 PCTlJP97102858 Referring to compounds [XVI]-[XIX] in the above Schema 3, R'2 is lower alkyl; R1' is hydrogen or optionally substituted lower alkyl; A is a leaving group.
The "lower alkyl" as mentioned for R~z includes C,_,, alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
The "lower alkyl" of the "optionally substituted lower alkyl" as mentioned for R1' includes C,_6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
and the "substituent" for this "optionally substituted lower alkyl" includes the same groups as those mentioned for the "substituent" of the "optionally substituted hydrocarbon group" as mentioned for R', R', R5, and R6.
The compound of formula [II] wherein Y is NH, Z' is -ZZ~-CFiz-, wherein ZZ~ is optionally substituted C~_z alkylene, and n=0, that is compound [XX], can be produced by, for example, the process illustrated below in Schema 4.
Schema 4 JA\ ~ Jm 2 ~~ I ~) Q mC02R12 R 1 ~ ~ Z Z~ - A Step g ~ ~ , ' R2 A r R1 ~'~Z 2 -CN Step p ._. ' R 2 A r '', _ [XX I] " [XX I I]
m 0 ~N H
_ JA
R 1 ~ ~ Zz~C H Z
RZ A r '~, [XX]
Referring to compounds [XX]-[XXIIJ in the above Schema 4, a11 symbols have the same meanings as defined above.
SUBSTITUTE SHEET (RULE Z6?

WO 98I07705 PCTlJP97/02858 The "C,_z alkylene" of the "optionally substituted C,_z alkylene" as mentioned for Z2~ above is methylene or ethylene, and the "substituent" for this "optionally substituted C1_2 alkylene" includes the same groups as S those mentioned for the "substituent" of the "optionally substituted hydrocarbon group" as mentioned for R', R4, R5, and R6.
The compound of formula [II] wherein Y is substi-tuted methylene and n=0, that is compound [XXIII], 10 wherein R'4 is lower alkyl ( a , g . C1_6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.); G is hydrogen or the same group as the substituent of the substituted methylene mentioned above for Y; the other symbols have 15 the same meanings as defined above, can be produced by, for example, the process illustrated below in Schema 5.
~hema S
20 ~ ~ _ mC02R12 ~ Q C02R12 Rll ~ ~ ~2 _A G=CH2COZR14 ~ i ~ zm CXXV] R ~CO R1~
r R2 Ar ; R Ar 2 Step 11 ~'. (__ [XXIV] CX X V I J
m > ~ o' ( o Step 12 ~ A
i i Z2 R1 ~CO R14 ' RZ A r 2 CXX I I I
Referring to compounds [XXIII]-[XXVI] in the above Schema S, a11 symbols have the same meanings as defined above.
In this connection, the group COZR" may be eliminated by subjecting compound [XXIII] to decarboxylation reaction, and when G is a carboxylic SU85TtTUTE SHEET (RULE 26) WO 98I07705 PCTlJP97l02858 acid derivative, G can also be eliminated by this decarboxylation reaction.
The compound [I] in which Y is NR', wherein R~ is - optionally substituted C1_~ alkyl or optionally substituted C1_3 alkanoyl, can also be produced by subjecting the compound of general formula [I] wherein Y is NH or an intermediate thereof in a suitable production stage to a per se known alkylation or acylation reaction.
i0 The reactions involved in the above production Schemes 1 to 5 are now described in further detail.
Steps 1 to 3 can be carried out by the procedure reported by J. G. Smith et al. (Journal of Organic Chemistry, 53, 2942-29S3, 1988}.
In step 4, compound [XIV] is reduced to compound [xv].
This reaction can be carried out by, for example, a per se known method [S. R. Sandler and W. Karo, Organic Functional Group Preparations I, 2nd ed., Academic Press (1983}, Chapter 4 (pp. 111-114). If this reaction involves reduction of the quinoline ring, the reduced quinoline ring can be reoxidized by a per se known method [M. Antini et al., Heterocycles, 38, 103-111 (1994}).
The starting compound [XIV] for this reaction can be produced by, for example, a per se known method [G.
Jones (ed.}, Quinolines Part 1, John Wiley & Sons (1977}, Chapter 2 (pp. 93-318j].
Step 5 can be carried out in a per se known manner [M. Antini et al., Heterocycles, ~,, 103-111 (1994)].
Step 6 can be carried out by subjecting compound ~ [XVII] to alkaline hydrolysis and treating the resulting hydroxycarboxylate with a lower alkyl halide.
The base that can be used for this alkaline hydrolysis includes but is not limited to inorganic bases (e. g. lithium hydroxide, sodium hydroxide, SUBST1TUTF SH EEC' (RULE 26) potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, etc.). The amount of the base is generally equimolar through about 10 molar equivalents and preferably equimolar - about 3 molar equivalents with respect to compound [XVIII).
The lower alkyl halide may for example be methyl iodide, ethyl iodide, or ethyl bromide. The proportion of the lower alkyl halide is generally equimolar to about 100 molar equivalents and preferably 20-100 molar equivalents with respect to compound [XVIII].
This reaction can be carried out with advantage in a solvent. For this reaction, a solvent that does not interfere with the reaction is employed. Thus, the solvent can be selected from among hydrocarbons (e. g.
pentane, hexane, cyclohexane, benzene, etc.), lower alkanols (e. g. methanol, ethanol, propanol, etc.), ethers (e. g. diethyl ether, tetrahydrofuran, dioxane, etc.), amides (e. g. N,N-dimethylformamide, hexamethylphosphoric triamide, etc.), and ureas (e. g.
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine etc.).
Those solvents can be used each alone or, where necessary, as a mixture comprising two or more species in a suitable ratio, or even in admixture with water.
The proportion of the solvent is generally 1 to 100 milliliters and preferably 5 to 20 mL per gram of compound (XVIII). The reaction temperature is generally -20~C through the boiling point of the solvent used and preferably 25~C to 100~C. The reaction time is 10 minutes to 24 hours and preferably 20 minutes to 2 hours for each of the alkaline hydrolysis and the lower alkyl halide treatment.
In Step 7, the hydroxyl group of compound [XVIII) is converted to a leaving group. The leaving group , represented by A in compound [XIX] includes (1) halogen (e. g. chlorine, bromine, iodine, fluorine), (2) lower SUBSTjTt..ITE SHEET (RULE 26) alkanesulfonyloxy that may be substituted by 1 to 3 halogen atoms (e. g. C1_o alkylsulfonyloxy optionally substituted by 1 to 3 halogen atoms (e. g. chlorine, bromine, fluorine, etc.) such as methylsulfonyloxy, ethylsulfonyloxy, butylsulfonyloxy, - trifluoromethylsulfonyloxy, etc.), and (3) lower arylsulfonyloxy that may be substituted by 1 to 3 halogen atoms (e. g. C6_~o arylsulfonyloxy optionally substituted by 1 to 3 halogen atoms (e. g. chlorine, bromine, fluorine, etc.) such as benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy, mesitylenesulfanyloxy, etc.).
This reaction can be carried out in a per se known manner (S. R. Sandler and W. Karo, Organic Functional Group Preparations 1 (2nd ed.), Academic Press (1983), Chapter 6 (pp. 148-179) and Chapter 21 (pp. 630-633).
In step 8, compound [XIX] is reacted with ammonia or a monoalkylamine of the formula HZNR13 (where R13 is as defined above).
Ammonia as mentioned just above may be either aqueous ammonia, ammonia gas, or liquid ammonia.
The proportion of ammonia or monoalkylamine is generally equimolar through about 100 molar equivalents and preferably 2 to 10 molar equivalents with respect to compound (XIX].
This reaction can be carried out with advantage in a solvent which does not inhibit the reaction. Thus, the solvent that can be used includes hydrocarbons (e. g. pentane, hexane, cyclohexane, benzene, etc.), lower alkanols (e. g. methanol, ethanol, propanol, etc.), ethers (e. g. diethyl ether, tetrahydrofuran, dioxane, etc.), amides (e. g. N,N-dimethylformamide, hexamethylphosphoric triamide, etc.), and ureas (e. g.
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine etc.).
Those solvents can be used each alone or, where necessary, as a mixture of suitable proportions of two SUBSTITUTE SHEET (RULE 26~

or more species or even in admixture with water. The proportion of the solvent is generally 1 to 100 mL and preferably 5 to 20 mL per gram of compound [XIX]. The reaction temperature is generally -20~C through the boiling point of the solvent used and preferably 25~C
to 100~C.
The reaction time is generally 30 minutes to 24 hours and preferably 30 minutes to 12 hours.
In Step 9, compound [XXI] is reacted with a cyanide.
The starting compound [XXI] can be synthesized typically by the same procedure as shown for the production of compound [XIX] in Schema 3.
The cyanide that can be used includes the sodium salt, potassium salt, copper salt, silver salt, etc.
and the proportion of the cyanide is generally equimolar through about 100 molar equivalents and preferably 2 to 10 molar equivalents with respect to compound [XXI].
This reaction can be carried out with advantage in a solvent which does not inhibit the reaction. Thus, the solvent that can be used includes hydrocarbons (e. g. pentane, hexane, cyclohexane, benzene, etc.), lower alkanols (e. g. methanol, ethanol, propanol, etc.), ethers (e. g. diethyl ether, tetrahydrofuran, dioxane, etc.), amides (e. g. N,N-dimethylformamide, hexamethylphosphoric triamide, etc.), and areas (e. g.
1,3-dimethyl-3,4,5,5-tetrahydro-2(1H)-pyrirnidine etc.).
Those solvents can be used each alone or, where necessary, as a mixture of suitable proportions of two or more species or even in admixture with water. The proportion of the solvent is generally 1 to 100 milliliters and preferably 5 to 20 mL per gram of compound [XXI].
The reaction temperature is generally -20~C
through the boiling point of the solvent used and SUBST1'TUTE SHEET (RULE 26) preferably 25~C to 100~C. The reaction time is generally 30 minutes to 24 hours and preferably 1 to 12 hours.
In Step 10, the nitrite group of compound [XXII]
5 is reduced. This reduction reaction can be carried out - by a per se known method [e.g. S. R. Sandler and w.
Karo, organic Functional Group Preparations I" 2nd ed., Academic Press (1983), Chapter 13 {pp. 403-405)).
In Step 11, compound [XXIV] is condensed with 10 compound [XXV] in the presence of a base.
The relative proportions of the starting compounds [XXIV] and [XXV] for this reaction are dependent on the species of compounds, reaction conditions, etc.
However, compound [XXV] is used in a proportion of 15 generally 1 to 10 molar equivalents or preferably 1 to 2 molar equivalents for each mole of compound [XXiV].
The base that can be used includes alkyllithium reagents (e. g. methyllithium, n-butyllithium, s-butyl-lithium, t-butyllithium, etc., preferably n-20 butyllithium), inorganic bases (e. g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, sodium metal, etc.), and organic bases (e. g, sodium 25 methoxide, sodium ethoxide, triethylamine, pyridine, diethylisopropylamine, etc.). The proportion of the base is generally equimolar through about ZO molar equivalents and preferably equimolar to 2 molar equivalents with respect to compound [XXV].
30 This reaction can be conducted with advantage in a solvent selected from among, for example, lower alkanols (e. g. methanol, ethanol, propanol, isopropyl alcohol, etc.), hydrocarbons {e. g. pentane, hexane, cyclohexane, benzene, etc.), ethers (e. g. diethyl 35 ether, tetrahydrofuran, dioxane, etc.), amides {e. g.
N,N-dimethylformamide, hexamethylphosphoric triamide, SUBSTTTUTE SHEET tRULE zfi) etc.), halogenated hydrocarbons (e. g. dichloromethane, chloroform, etc.), sulfoxides (e. g. dimethyl suifoxide etc.), and ureas (e.g. 1,3-dimethyl-3,4,5,6-tetrahydro- -2(1H)-pirimidine etc.). Those solvents can be used each alone or, where necessary, as a mixture of suitable proportions of two or more species or even in admixture with water. The proportion of the solvent is generally 0.1 to 100 mL and preferably 5 to 20 mL per gram of compound [XXV].
The reaction temperature is generally -20~C
through the boiling point of the solvent used and preferably -5~C through the boiling point. The reaction time is generally 100 minutes to 24 hours and preferably 30 minutes to 5 hours.
In Step 12, compound [XXVI] is treated with a base to subject cyclization reaction.
The base that can be used includes alkyllithium reagents (e. g. methyllithium, n-butyllithium, s-butyl-lithium, t-butyllithium, etc., preferably n-butyllithium), lithium dialkylamides (e. g. lithium diisopropylamide, lithium hexamethyldisilazide, etc.), inorganic bases (e. g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, sodium metal, etc.), and organic bases (e. g. sodium methoxide, sodium ethoxide, triethylamine, pyridine, diethyl-isopropylamine, etc.). The proportion of the base is generally equimolar through about 10 molar equivalents and preferably equimolar to 2 molar equivalents with respect to compound [XXVI].
This reaction can be conducted with advantage in a solvent selected from among, for example, lower alkanols (e. q. methanol, ethanol, propanol, isopropyl alcohol, etc.), hydrocarbons (e. g. pentane, hexane, cyclohexane, benzene, etc.), ethers (e. g. diethyl SUBSTITUTE SHEET (RULE 2b) WO 98l07705 PCT/JP97/02858 ether, tetrahydrofuran, dioxane, etc.), amides (e. g.
N,N-dimethylformamide, hexamethylphosphoric triamide, etc.), halogenated hydrocarbons (e. g. dichloromethane, - chloroform, etc.), sulfoxides (e. g. dimethyl sulfoxide etc.), and ureas (e. g. 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pirimidine etc.). Those solvents can be used each alone or, where necessary, as a mixture of suitable proportions of two or more species or even in admixture with water. The proportion of the solvent is generally 0.1 to 100 mL and preferably 5 to 20 mL per gram of compound [XXV].
The reaction temperature is generally -20~C
through the boiling point of the solvent used and preferably -5~C through the boiling point. The reaction time is generally 10 minutes to 24 hours and preferably 30 minutes to 5 hours.
As shown in Scheme 5, compound [XXIII] may be subjected to decarboxylation. This decarboxylation can be carried out by a per se known procedure for hydrolysis of an ester (e.g. S. Patai (ed.), The Chemistry of Carboxylic Acids and Esters, Chapter I2 (pp. 589-622).
The compound of general formula [I] wherein Z1 is C=O, Zz is methylene, both of m and n are equal to 0, and Y is NR~', wherein Rl' is as defined above, can also be produced by partial reduction of the compound in which each of Z' and ZZ is C=0, both of m and n are equal to 0, and Y is NR13, wherein R1' is as defined above.
- 30 This partial reduction can be carried out by, for example, electrolytic reduction (e. g. the technique described in L. C. Craig, 3ournal of the American Chemical Society, Sue, 295-298, 1933), catalytic reduction (e.g. the method described in A. Dunet et al., Hulletin de la Societe Chimique de France, 17, 877-881, 1950), reduction with a metal hydride (e. g.
SUBSTITUTE SHEFt tRULE 26~

WO 98I07705 PCTlJP97l02858 the method described in E. Tagmann et al., Helvetica .
Chimica Acta, 37, 185-190, 1954), or reduction with zinc (e.g. the method described in ,1. H. Brewster and A. M. Fusco, Journal of Organic Chemistry, 28, 501-503, 1963).
The compound of general formula [I) wherein Y is alkylated or acylated nitrogen can also be produced by applying N-alkylation or N-acylation, in the per se known manner, to the compound of formula [I] wherein Y
is NH or an intermediate thereof in a suitable production stage.
In the production of the respective objective compounds by the processes shown in Schema 1 through Schema 5, where any substituent group on ring A, R', I5 Ar, Y, Z1, ZZ, Zz~, or G in [VII] through [XXV) contains a functional group such as hydroxyl, amino, mono-C1_6 alkylamino, ketone, carboxyl, or tetrazolyl, the func-tional group may be protected beforehand. As to the kinds of protective groups and methods for protection and deprotection that can be used, those groups and methods which are known per se can be successfully employed [T. W. Green and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley &
Sons, Inc., 199i).
The compound [I] or salt thus produced can be isolated and purified by the per se known procedure (e. g. redistribution, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc.).
The salt of compound [I] according to the present invention is preferably a pharmacologically acceptable salt. Thus, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids can be mentioned. The preferred salts with inorganic bases are salts with alkali metals SUBSTITUTE SHEET (RULE zfi1 (e. g. sodium salt, potassium salt, etc.), salts with alkaline earth metals (e. g. calcium salt, magnesium salt, etc.), aluminum salt, and ammonium salts. The preferred salts with organic bases are salts with trimethylamine, triethylamine, pyridine, picoline, . ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc.
The preferred salts with inorganic acids are salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
The preferred salts with organic acids are salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, malefic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
The preferred salts with basic amino acids are salts with arginine, lysine, ornithine, etc.
The preferred salts with acidic amino acids are salts with aspartic acid, glutamic acid, etc. When the objective compound produced is a free compound, it can be converted to a salt by the conventional procedure and when the objective compound obtained is in the form of a salt, it can be converted to the free compound.
The compound [I) or salt of the present invention may be a hydrated compound or anhydrous.
The compound [I) or salt of the invention can be isolated and purified by the per se known procedures such as solvent extraction, pH adjustment, redistribution, crystallization, recrystallization, chromatography, etc. While the starting compounds or salts for the compound [I] of the invention can also be isolated and purified by the same known procedures as above, the respective reaction mixtures containing them - 35 may be used as reactants for the next reactions.
In the event the compound [I] or salt of the SU85T1TUT~ SH~~T (RULE 2fi) WO 98I07705 PCTlJP97l02858 present invention includes optical isomers, .
stereoisomers, position isomers or rotamers, those isomers also fall within the scope of the invention and can respectively be isolated by the per se known 5 synthetic and/or fractionation techniques. For example, when the compound of the invention exists as ' optical isomers, the respective isomers falling within the scope of the invention can be separately provided.
Thus, optical isomers can be produced by per se 10 known techniques. Thus, the desired optical isomer can be provided by using an optically active synthetic intermediate or subjecting the racemic end product to routine optical resolution.
Optical resolution can be achieved by the per se 15 known alternative procedures such as fractional recrystallization, chromatography on a chiral column, and the diastereomer method, all described briefly below.
(1) Fractional recrystallization 20 This method comprises treating the racemic substrate with an optically active compound to give the corresponding salt, separating it by fractional recrystallization, and where necessary, neutralizing the same to recover the free optical isomer.
25 (2) Chiral column chromatography This is a method in which the racemic substrate or a salt thereof is fractionated on a chiral column.
Taking liquid chromatography as an example, the mixture of optical isomers is run on a chiral column, such as 30 ENANTIO-OVM (Tosoh Corporation), and elution is carried out with water, a buffer (e.g. phosphate buffer), or an organic solvent (e.g. ethanol, methanol, acetonitrile, etc.), or a mixture thereof, to thereby separate the desired optical isomer. Resolution by gas 35 chromatography can be carried out using CP-Chirasil-DeXCB (G. L. Science), for instance, as a chiral SUBSTITUTE SHEET (RULE 26) column.
(3) Diastereomer method This method comprises reacting the racemic substrate with an optically active reagent chemically to prepare a mixture of diastereomers, subjecting it to the routine fractionation treatment (e. g. fractional recrystallization, chromatography, etc.) to give the respective isomers, and cleaving the moiety corresponding to the optically active reagent off through chemical reaction such as hydrolysis. For example, when the compound of the invention contains a hydroxyl group or a primary or secondary amino group, diastereomers of its ester or amide can be obtained by subjecting said compound and an optically active I5 organic acid (e. g. MTPA [a-methoxy-a,-(tri-fluoromethyl)phenylacetic acid], (-)-menthoxyacetic acid, or the like) to condensation reaction. On the other hand, when the compound of the invention contains a carboxyl function, diastereomers of its amide or ester can be obtained by subjecting the compound and an optically active amine or alcohol to condensation reaction. The isolated diastereomers can be converted to optical isomers of the substrate compound by acid hydrolysis or alkaline hydrolysis.
The cell differentiation inducing factor relevant to the present invention includes a variety of factors which induce characteristic transductions in the process of differentiation from undifferentiated precursors of the osteoblasts, neurons, and other cells which are in charge of maintenance of vital functions in specific tissues, such as bone morphogenetic protein, neurotrophic factor, factors belonging to the TGF-J3 superfamily, such as transforming growth factor (TGF)-j3 and activins, factors belonging to the FGF
- 35 superfamily, such as basic fibroblast growth factor (bFGF) and acidic fibroblast growth factor (aFGF), SUBSTITUTE SHEET (RULE 26y WO 98107705 PCTIJP9?/02858 factors belonging to the neuropoietic cytokine family, such as leukemia inhibitory factor (LIF; also known as cholinergic differentiation factor, CDF), ciliary neurotrophic factor (CNTF), etc., interleukin (IL; this abbreviation applies hereinafter)-1; IL-2, IL-3, IL-5, IL-6 IL-7, IL-9, and IL-11, tumor necrosis factor - ' a{TNF-a.) interferon-y (INF-'y), etc. Preferred are bone morphogenetic protein and neurotrophic factor.
The bone morphogenetic protein includes factors of the BMP family, such as BMP-2, -4, -5, -6, -7, -8, -9, -10, -11, -12, etc., all of which are proteins which accelerate osteogenesis and chondrogenesis.
Particularly preferred are BMP-2, -4, -5, and -7. BMP
that can be used includes various homodimers of the respective factors mentioned above or heterodimers of all possible combinations of the factors.
The neurotrophic factor includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), etc. Preferred are factors of the NGF family.
The compound [I] or salt of the present invention can be safely administered as it is or in the form of a pharmaceutical composition prepared by using a pharma-cologically acceptable carrier. The composition includes a variety of dosage forms such as tablets (e. g. dragees, film-coated tablets, etc.), powders, granules, capsules (inclusive of soft capsules), syrup, emulsion, suspension, injection (e. g. subcutaneous, intradermal, intramuscular and other injections), suppositories, and controlled-release dosage forms as ' prepared by the established pharmaceutical procedures, and such dosage forms can be administered either orally or otherwise (e.g. topically, rectally, or intravenously). The proportion of compound [I] or its salt in a dosage form of the invention may range from 0.1 to 10Q weight $. The dosage depends on the SUBST1TUTF SHEET (RULE 2fi) recipient's characteristics, route of administration, ' diagnosis, and other factors. When the composition is used as a cell differentiation factor agent or agonist - in an adult patient (b. wt. 60 kg), for instance, the oral dose of about 0.1 to 500 mg, preferably about 1 to 100 mg, or more preferably about 5 to Z00 mg, as the active ingredient, can be administered once daily or in a few divided doses daily.
The injection can be prepared and used in the per se known manner. Thus, compound jI] or salt of the invention can be used independently or in combination with one or more other substances having cell differentiation factor activity, such as BMP and neurotrophic factor. The aqueous vehicle for such an injection includes physiological saline, isotonic solution, etc. and, where necessary, the vehicle can be used together with a suspending agent such as those mentioned hereinafter. The oily medium for an injection includes sesame oil, soybean oil, and other oils and these oils may be used together with a solubilizer such as those also mentioned hereinafter.
The prepared injection is generally dispensed and sealed in suitable ampules.
The pharmacologically acceptable carrier that can be used in the production of the pharmaceutical composition of the invention includes various organic and inorganic pharmaceutical carriers which are conventionally used in pharmaceutical production.
Thus, the excipient, lubricant, binder, disintegrator, etc. can be used for solid dosage forms and the solvent, solubilizer, suspending agent, isotonizing agent, buffer, local anesthetic, etc. can be used for ' liquid dosage forms. Where necessary, such other additives as the antiseptic, antioxidant, colorant, sweetener, adsorbent, wetting agent, etc. can also be used. The excipient includes but is not limited to SUHSTiTUTE SHEET (RULE 26~

WO 98l0??05 PCTlJP97102858 lactose, sucrose, D-mannitol, starches such as corn starch, crystalline cellulose, and light silicic anhydride. The lubricant includes but is not limited to magnesium stearate, calcium stearate, talc, and colloidal silica.
The binder includes but is not limited to crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, cane sugar, gelatin, methylceilulose, and carboxymethylcellulose sodium.
The disintegrator includes but is not limited to starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethylstarch sodium, and L-hydroxypropylcellulose.
The solvent includes but is not limited to water for injection, alcohol, propylene glycol, macrogols, sesame oil, and corn oil.
The solubilizer includes but is not limited to polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
The suspending agent includes but is not limited to surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzethonium chloride, glycerol monostearate, etc., and hydrophilic macromolecular substances such as polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.
The isotonizing agent includes but is not limited to glucose, D-sorbitol, sodium chloride, glycerin, and D-mannitol.
The buffer includes various buffer solutions such as phosphate, acetate, carbonate, citrate, and other SUBSTITUTE SN E~T (RULE 26) buffers.
The local anesthetic includes but is not limited to benzyl alcohol.
The antiseptic includes but is not limited to p-5 hydroxybenzoic esters, chlorobutanol, benzyl alcohol, ~ phenethyl alcohol, dehydroacetic acid, and sorbic acid.
The antioxidant includes but is not limited to sulfites and ascorbic acid.
The pharmaceutical composition of the invention, 10 which comprises compound [I] or a pharmacologically acceptable salt thereof, has satisfactory cell differentiation inducing factor activity or its enhancing activity and, as such, can be successfully used either as it is or in combination with other 15 active substances having cell differentiation inducing factor activity (e.g. BMP and neurotrophic factor) in the treatment or prevention of various nerve diseases [e. g. neurodegenerative lesions in cerebrovascular dementia, senile dementia, or Alzheimer's disease, 20 amyotrophic lateral sclerosis (Lou Gehrig's disease), diabetic peripheral neuropathy, etc.] or bone-and-joint diseases (e. g. bone fracture, osteoporosis, osteoarthritis, rheumatoid arthritis, etc.].
Specifically, as a therapeutic and prophylactic drug 25 for bone-and-joint diseases, the pharmaceutical composition of the invention can be used as a bone formation accelerator, a cartilage disruption inhibitor, a bone fracture healing accelerator, or a bone remodeling accelerator, for instance.
. 30 Furthermore, the physiological roles of BMP and neurotrophic factor remaining to be fully elucidated, there may be other diseases in which argumentation of BMP activity or neurotrophic factor activity should lead to improvements in morbidity. The enhancing ' 35 activity of cell differentiation factor of the present invention may be useful for the treatment or prevention SUBSTITUTE SH~~T (RUL~ Z6) of such diseases associated with BMP and/or r neurotrophic factor.
The enhancing activity of cell differentiation inducing factor of the present invention can be indicated in the above-mentioned diseases not only in man but also in other mammalian animals (e.g. the mouse, rat, rabbit, dog, cat, cattle, swine, etc.).
The pharmaceutical composition of the invention, which comprises compound (I] or a salt thereof, has a high toxicological threshold and a low risk for adverse reactions.
Because it has high activity to promote bone formation, the compound of the present invention can be incorporated in a bone remodeling matrix as a bone morphogenesis accelerator for bone repairing or in bone grafting. For example, the compound of the invention can be applied as attached to or incorporated in an artificial bone of a metal, ceramic material, or polymer material. The artificial bone is preferably provided with a porous surface so that, when it is implanted in the missing part of the host, the cell differentiation factor agonist of the invention will be released into the tissue. The compound of the invention can be attached to or incorporated in such a prosthesis by dispersing it in a suitable dispersion medium, binder or diluent (e. g. collagen, physiological saline, citric acid solution, acetic acid solution, hydroxyapartite, fibrin, or a mixture of them), coating or impregnating the prosthesis with the dispersion, and drying it. Such an artificial bone is implanted in the missing part of the host and securely immobilized there. The cementing agent for an artificial bone can '_ be prepared by mixing the compound of the present invention with a physiologically acceptable dispersion medium, binder, or diluent and optionally with other ingredients useful for bone remodeling (e. g. calcium).
SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCT/JP97102858 The artificial bone cement can also be used in such a manner that, in lieu of being applied to or incorporated in a prosthesis, it is filled in the gap between the implant and the missing part of the host.
The non-oral composition mentioned above can be put to use after osteoinductive proteins such as factors of the BMP family, have been deposited thereon or incorporated therein.
[Mode of Working the Invention]
The present invention is now described in further detail by way of the following reference examples, working examples, formulation examples, and test examples but a11 of these examples are merely illustrative and should by no means be construed as defining the scope of the invention. Thus, many changes and modifications may be made by those skilled in the art without departing from the spirit of the invention.
In the column chromatographic procedures in the following reference~and working examples, a11 elutions (eluents are shown in brackets) were carried out under thin-layer chromatographic (TLC) monitoring.
The TLC monitoring was carried out using Kieselgel 60Fzso (70-230 mesh, Merck) for TLC plates, the column chromatographic solvents as developers, and a UV
detector in combination with phosphomolybdate color reaction for detection. As the silica gel for column chromatography, Kieselgel 60 (70-230 mesh, Merck) was used. The NMR spectra represent proton NMR (~H-NMR) spectra, which were measured with Gemini 200 (Varian) using tetramethylsilane either as internal standard or as external standard and expressed in 8 (ppm). The infrared absorption spectra were recorded with IR-810 ' 35 spectrophotometer (Nippon Bunko Kogyo). The melting points were determined with the Yanagimoto micro-SUBST1T'UTE SHEET (RULE 2fi~

WO 98I07705 PCTlJP97102858 melting point meter MP-500D and the uncorrected values were tabulated. The term "room temperature" as used in the following reference and working examples means 0~-30~C and, in most cases, about 15~-25~C. In the drying -procedures, anhydrous magnesium sulfate or anhydrous sodium sulfate was used. All percents (%) are by weight unless otherwise indicated.
In the chemical formulas included in the following reference and working examples, Me stands for methyl, Ms for methanesulfonyl, Et for ethyl, and Ac for acetyl.
The other symbols or abbreviations used in the text have the following meanings.
s . singlet d . doublet dd . double doublet t . triplet m . multiplet br . broad J . coupling constant Hz . Hertz THF . tetrahydrofuran DMF . N,N-dimethylformamide DME . Dimethoxyethane CDC13: deuterochloroform NMR . proton nuclear magnetic resonance Reference Example 1 10-(3,4-Dihydroxyphenyl)-furo[3',4':6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)-one SUBSTITUTE SHEET (RULE 26) -OH
OH
Boron trichloride (1M dichloromethane solution:15m1) was added dropwise to a dichloromethane solution (50m1) of Helioxanthin (1.0 g) and stirred for 3 days at room temperature. To the solution was added methanol to stop the reaction and the reaction mixture was concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel 50g, eluent:ethyl acetate-hexane = 2:1) and triturated with methanol. Thus, the entitled compound (120mg) was obtained as powder.
m.p.:28B~C (decomp.}
NMR(DMSO-db)s: 5.21(lH,d,J=lSHz), 5.33(lH,d,J=lSHz), 6.00(lH,s), 6.01{lH,s), 6.68(lH,dd.J=2Hz,8Hz), 6.77(lH,d,J=2Hz), 6.79(lH,d,BHz), 7.51{lH,d,J=9Hz), 7.94(lH,d,J=9Hz), 8.55(lH,s), B.97(lH,s), 9.09(lH,s) IR(KBr): 3S10, 3230, 1715, 1625, 1450, 1275, 1245, 1075, 1060, 1030cm-1 Elemental Analysis for ClgHlzO6 ~ 0 . 3 Hz0 Calcd.: C:66.79, H:3.72 Found . C:66.98, H:4.04 Reference Example 2 10-(3,4-Dimethoxyphenyl)-furo(3',4':6,7)naphtho(1,2-d)-1,3-dioxol-7{9H)-one SUBSTtTLITE SHEET (RULE Z6) WO 98l07705 PCTlJP97I02858 0 ~ ~ -_ '--0 i OMe OMe To a DMF (2m1) solution of 10-(3,4-dihydro-phenyl)-furo[3',4':6,7)naphtho[1,2-d)-1,3-dioxol-7(9H)-one (120mg) as obtained in Reference Example 1 was added sodium hydride (60~ oily:36mg) under ice cooling, then methyl iodide{ 671) was added thereto after bubbling was stopped. The mixture was stirred for one hour at room temperature, and water was added thereto, then 1N hydrochloric acid was added thereto until the pH of the mixture became about 1. Then, the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The residue was purified by column chromatography(silica gel 10g, eluent:dichloromethane-ether = 9S:5). After recrystallized from THF-hexane, 53mg of the entitled compound was obtained.
m.p.:22i-223~C
NMR(CDC1~)s: 3.88(3H, s), 3.98{3H,s), 5.16(lH,d,J=l5Hz), 5.29(lH,d,J=lSHz), 5.94(2H, s), 6.86(lH,d,J=I.7Hz), 6.92(lH,dd,J=l.7Hz,8Hz), 6.97(lH,d,J=8Hz), 7.33(lH,d,J=9Hz), 7.73(lH,d,J=9Hz), 8.44(lH,s) IR(KBr): 1750, 1510, 145S, 1260, 1245, 1130, 106S, 1025 cm-~
Elemental Analysis for Cz,H160G
Calcd.: C:69.23, H:4.43 Found . C:69.21, H:4.53$
Reference Example 3 SU85TtTtJTF SHEET (RULE 26) WO 98I07705 PCT/JP97l02858 5,6-Dihydroxy-4-(3,4-dihydroxyphenyl)-naphtha[2,3-c]fran-1{3H)-one ~0 ' HO
OH
i H
OH
8,9-Dihydro-10-(2-oxo-1,3-benzodioxol-S-yl)-furo[1,2-d]-1,3-dioxol-2,7(9H)-dione(300mg)was synthesized by the ordinary method as described in T.L.Holmaes and R.Stevenson, Journal of the Chemical Society(C),2091-2094, 19?1. To the methanol (2m1) solution of 8,9-dihydro-10-(2-oxo-1,3-benzodioxol-5-yl}-furo(1,2-d)-1,3-dioxol-2,7(9H)-dione (300mg), was added 6N
hydrochloric acid (10m1), and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure, then the mixture was extracted with ethyl acetate. The extract was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 10g, eluent:ethyl acetate). Precipitation from chloroform-ethyl acetate gave the entitled compound (172mg).
m.p.. 160-165~C
NMR(DMSO-d6)8: 5.03{lH,d,J=lSHz), 5.17(lH,d,J=l5Hz), 6.59(lH,dd.J=2Hz,8Hz), 6.67(lH,d,J=2Hz}, 6.75(1H,J=8Hz), 7.29(lH,d,J=9Hz), 7.62(lH,d,J=9Hz), 8.05(lH,s), 8.34(l2H,s), 8.86(lH,s), 8,87(lH,s), 9.90{lH,s) IR(KBr): 3460, 3380, 1720, 1615, 1270, 1230, 1200, 1155cm ~
. 35 Reference Example 4 5,6-Dimethoxy-4-{3,4-dimethoxyphenyl)-naphtha[2,3-SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 c]fran-1(3H)-one n Me0 ._ l T 'OM a OMe To a DMF (6m1) solution of 5,6-dihydroxy-4-{3,4-dihydroxyphenyl)-naphtho[2,3-c]fran-1(3H)-one (300mg) as obtained in Reference Example 3, was added sodium hydride (60% oily:185mg) under ice cooling, then methyl iodide (290A ) was added after bubbling was stopped.
The mixture was stirred for one hour at room temperature, and water was added thereto, then 1N
hydrochloric acid was added until the pH of the mixture became about 3. Then the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The residue was purified by column chromatography(silica gel 10g, eluent:dichloromethane-ether = 95:5). After recrystallized from THF-hexane, 37mg of the entitled compound was obtained m.p.:207-209~C
NMR{DMSO-db)s: 3.27(3H, s), 3.87(3H, s), 3.97(3H, s), 4.01(3H, s), 5.06(lH,d,J=lSHz), 5.17(lH,d,J=lSHz), 6.86(lH,d.J=i.6Hz), 6.87(lH,dd,J=i.6Hz,9Hz), 6.94(lH,d,J=9Hz), 7.43(lH,d,J=9Hz), 7.89{lH,d,J=9Hz}, B.44(lH,s}
IR(KBr): 1750, 1510, 1270, 1240, 122S, 1130, 1070, 1020cm ~ .
Elemental Analysis for CZZHzo06 Calcd.: C:69.46%,H:5.30%
Found . C:69.14%,H:5.31%
Reference Example 5 SUBSTiTU'fF SHED {RULE 26) 10-(2-Naphthyl)-furo[3',4':6,7]naphtha[1,2-dj-1,3-.. dioxol-7(9H)-one t To a benzene solution (200m1) of helio alcohol (4.Og)was dropwise added n-BuLi (1.6M-hexane solution:36m1) at room temperature. The mixture was stirred for 2 hours at room temperature, then 2-cyanonaphthalene (3.9g:l.lequivalent)was dropwise added thereto. The mixture was stirred over night at room temperature, then water was added thereto, and the mixture was extracted with ether. The extract was washed with water and dried with magnesium sulfate, then concentrated under reduced pressure. The residue (orange, oily substance) was dissolved in toluene (250m1), then malefic anhydride (7.7g) and p-toluene sulfonic acid (catalitic amount) were added thereto.
The mixture was heated under reflux for 20 hours, then precipitates were removed by suction and the obtained filtrate was concentrated under reduced pressure. To the residue was added concentrated hydrochloric acid and heated under reflux for one hour. The mixture was cooled to room temperature, and the resultant yellow-brown precipitates were collected by suction. The precipitates were washed with water and recrystallized from tetrahydrofran and acid anhydride (about 3.4g) were obtained. To the DME (80m1) solution of NaHH4 was gradually added the acid anhydride. The mixture was _ 35 stirred for 30 minutes at 0~C, then the reaction mixture was added to diluted hydrochloric acid under SU85T1TUTE SHEET (RULE 26) ice cooling. The reaction mixture was extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent:chloroform) and the entitled compound (1.5g} was obtained. For elemental analysis and other analysis, some of the entitled compound was recrystallized from THF.
m.p.:224-226~C
NMR(CDCls)~: 5.13(1H, d, J=15.2H2}, 5.29(1H, d, J=15.2H2), 5.85(1H, d, J=1.4H2), 5.85(1H, d, J=1.4H2), 7.334(1H, d, J=B.BHz), 7.43(1H, dd, J=8.2H2, J=1.8H2), 7.57{2H, m), 7.75(1H, d, J=8.8H2}, 7.8-8.0{4H, m), 8.48(1H, s) Elemental Analysis for Gi~Hj4~4 Calcd.: C:77.96, H:3.98 Found . C:77.57, H:4.10 Reference Example 6 10-(3,4,5-Trimethoxyphenyl)furo(3'4':6,7]naphtho(1,2-d]-1,3-dioxol-7(9H)-one ' w W \~
i ~0 ~~ ~I
MeO~~Me OMe The entitled compound was obtained in a manner similar to that described in Reference Example 5.
m.p.:213-215~C
NMR(CDCIi)s: 3.85(6H, s), 3.96(3H, s), 5.25(2H, s), 5.95(2H, s), 6.56(2H, s), 7.33(1H, d, J=B.OHz), 7.73{1H, d, J=B.OHz), 8.44(1H, s) , Elemental Analysis for CZZHIaOT
Calcd. C:67.00$, H:4.60 SU85TiTUT~ SH~~T RULE Z6) WO 98I07705 PCTlJP97102858 Found: C:66.57, H:4.57$
- Reference Example 7 10-(4-Methoxyphenyl)-furo(3',4':6,7)naphtho[1,2-d)-1,3-- dioxol-7(9H)-one OMe The entitled compound was obtained in a manner similar to that described in Reference Example 5.
m.p.:217-2I9~C
NMR(CDC13)s: 3.90(3H, s}, 5.20(2H, s), 5.93(2H, s), 6.99(1H, d, J=8.8Hz), 7.28(1H, d, J=8.8Hz), 7.32(1H, d, J=8.6Hz), 7.72(1H, d, J=8.6Hz}, 8.43(1H, s) Elemental Analysis for CZOHI~Os'Q-5HZ0 Calcd.:C:70.58$, H:4.34 Found :C:70.52, H:4.38 Reference Example 8 IO-(4-Fluorophenyl)-furo[3',4':6,7)naphtho[I,2-d)-1,3-dioxol-7(9H)-one ' The entitled compound was obtained in a manner similar to that described in Reference Example 5.
- 35 m.p.:215-21B~C
NMR(CDC15)s: 5.18(2H, s), 5.92(2H, s), 7.15(2H, m), SUBSTZTLJTE SHEET tRULE 26) WO 98I07705 PCTlJP97102858 7.33(3H, m), 7.73(1H, d, J=8.8Hz), 8.45(1H, s) r Elemental Analysis for C19H1~04F
Calcd.: C:70.81, H:3.44 -Found . C:70.57$, H:3.65 Reference Example 9 10-Phenyl-furo[3',4':6,7)naphtho[1,2-d]-1,3-dioxol-7(9H)-one O
~-0 i I
I5 The entitled compound was obtained in a manner similar to that described in Reference Example 5.
m,p.:202-2Q4~C
NMR(CDC1~)&: 5.19(2H, s), 5.91(2H, s), 7.32(1H, d, J=8.4Hz), 7.37(2H, m), 7.44(3H, m), 7.72(IH, d, J=8.4Hz), 8.45(1H, s) Elemental Analysis far C19H1zOz Calcd.: C:74.99%, H:3.97 Found . C:74.47, H:3.95 Reference Example 10 10-~4-Chlorophenyl)-furo[3',4':6,7]naphtho[1,2-d)-1,3-dioxol-7(9H)-one The entitled compound was obtained in a manner similar to that described in Reference Example 5.
SUBSTITUTE SHEfT (RULE 26) WO 98l07705 PCT/JP97/02858 m.p.:225-227~C
NMR(CDC1~}6: 5.18(2H, s), 5.93(2H, s}, 7.33(3H, m), 7.44(2H, d, J=8.4H2), 7.73{1H, d, J=8.4H2), 8.45(1H, s) _ Elemental Analysis for C,9H1104CI ~ 0 . ZHZO
Calcd.: C:66.66, H:3.36 Found . C:66.59, H:3.14$
Reference Example 11 10-(4-Methylphenyl)-furo(3',4':6,7)naphtho[1,2-d)-1,3-dioxol-7(9H)-one Me The entitled compound was obtained in a manner similar to that described in Reference Example 5.
m.p.:208-210~C
NMR{CDC13)s: 1.45{3H, s), 5.19(2H, s), 7.25(4H, s), 7.32(IH, d, J=8.4H2), 7.72(1H, d, J=8.4H2), 8.43{1H, s}
Elemental Analysis for CzoH~40~
Calcd.: C:75.46, H:4.43 Found . C:75.17$, H:4.52 Reference Example 12 10-(1,3-Benzodioxol-5-yl)-1,3-dioxolo[4,5-f]furo(3,4-b]quinolin-7(9H)-one SUBSTITUTE SHEET (RULE 26) 1o8 N
1 \~
~-' 0 w To a suspension of and lithium aluminum Hydride (LAH) (2.0g) in THF (50 ml) was gradually added diethyl 8-(1,3-benzodivxol-5-yl)-1,3-dioxolo[4,5-f]quinoline-7,8-dicarboxylate (2.4g) which was synthesized by the ordinally method described in E.A.Fehnel,3ournal of organic Chemistry,vo1.31, 2899-2092, 1966 or W.Ried, et al.,Chemische Berichte,vol.B5,204-216, at 0~C. The mixture was stirred for 1 hour at room temperature. To the reaction mixture was added water to stop the reaction, then the insoluble solid was filtered off with Celite. The filtrate was extracted with ethyl acetate and the extract was washed with water and dried with magnesium sulfate. The solvent was removed by distillation and the obtained residue was dissolved in ethanol (100m1), and 10~ Fd-C (2.5g} was added thereto.
The mixture was stirred overnight at room temperature.
The.catalyst was filtered off, and the solvent was removed by distillation. The obtained residue was dissolved in chloroform (300m1) and manganese dioxide (20g} was added thereto, then the mixture was stirred for 3 hours at room temperature. The manganese dioxide was filtered off with Celite and the filtrate was ' concentrated under reduced pressure. The obtained crude crystals were washed with diisopropyl ether and the entitled compound (0.9g}was obtained. For elemental analysis, some of the entitle compound was recrystallized from THF.
m.p.:272-274~C
SUBSTITUTE SHEET (RULE 26~

WO 98l07705 PCTlJP97102858 NMR(CDC1~)6: 5.30(1H, d, J=15.6Hz), 5.41(1H, d, J=15.6Hz), 6.05(2H, d, J=4.4Hz), 6.10(2H, d, J=4.2Hz), 6.86(2H, m), 6.95(1H, d, J=8.4Hz), 7.57(1H, d, - J=9.2Hz}, B.11(1H, d, J=9.2Hz) S Elemental Analysis for C~9HIINOs Calcd.: C:65.33$, H:3.17, N:4.01 Found . C:64.91, H:3.07, N:4.18 Reference Example 13 4-(1,3-Benzodioxol-5-yl)-5-methoxynaphtho[2,3-c}fran-1(3H)-one ~y~,~0 Me0 i , w~
By using 3-methoxybenzyl alcohol, the entitled compound was obtained in a manner similar to that described in Reference Example 5.
m.p.:216-219~C
NMR(CDC1~)s: 3.57(3H, s), 5.09(1H, d, J=15.OHz), 5.18(1H, d, J=15.0Hz), 6.05(2H, d, J=4.OHz), 6.69(1H, d, J=7.6Hz), 6.73(1H, s), 6.88(1H, d, J=7.6Hz), 6.93(1H, d, J=8.0Hz), 7.50(1H, t, J=8.OHz), 7.67(1H, d, J=8.4Hz), 8.44(1H, s) Elemental Analysis for CZflHi4~s Calcd.: C:71.85, H:4.22 Found . C:71.45, H:4.18 Reference Example 14 Methyl 9-(1,3-Henzodixol-5-yl}-8-methanesulfonyloxymethylnaphtho[1,2-d}-1,3-benzodioxole-7-carboxylate acid SUBST1'TLJTE SHEET (RULE 26) WO 9817705 PCTiJP97102858 COzMe i ~ ~0 M s .0 ~
l O ~/
To a DMF (10m1) solution of Helioxanthin (1g) was added 1N sodium hydroxide solution (2.9m1), the mixture was stirred at 60~C, for 30 minutes. The solvent was removed by distillation under reduced pressure, the residue was dissolved in DMF (10m1). To the mixture was added methyl iodide (5m1), the mixture was stirred at 60~C for 1 hour. The solvent was removed by distillation under reduced pressure and to the residue was added water. The mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was dissolved in THF (10m1), triethylamine (0.80m1) was added thereto. To the mixture was dropwise added methanesulfonylchloride (0.22m1) under ice cooling and stirred for 30 minutes. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure to give the entitled compound (1.25g). The crude compound as obtained was used for the following reactions without further purification.
NMR(CDCl~)8: 3.00(3H,s), 3.91(3H,s), ' 5.24(lH,d,J=lOHz}, 5.34(lH,d,J=IOHz), 5.91(IH,d,J=I.2Hz), 5.94(IH,d,J=l.2Hz), '.
6.09(lH,d,J=0.8Hz), 6.13(lH,d,J=0.8Hz), 6.73(lH,dd,J=l.6Hz,8Hz), 6.86(lH,d,J=l.6Hz), 6.98(lH,d,J=8Hz), ?.49(lH,d,J=9Hz), 7.81(lH,d,J=9Hz), 8.54(lH,s}
SU85TiTUTE SHEET (RULE Z6~

WO 98!077U5 PCTIJP97l02858 Reference Example 15 Methyl 9-(1,3-Benzodioxol-5-yl)-8-cyanomethyl-naphtho[1,2-d]-1,3-benzoxole-7-carboxylate - ~ ~ C02Me i i CN

To a DMF (lOmi) solution of methyl 9-(1,3-benzodixol-5-yl)-8-methanesulfonyloxymethyl-naphtho[1,2-d~-1,3-benzodioxole-7-carboxylate (1.25g) as obtained in Reference Example 14 was added sodium cyanide (0.28g) and stirred for 6 hours at room temperature. To the reaction mixture was added water and resultant precipitates were collected by suction.
The obtained precipitates were washed with water and dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was triturated with ethyl acetate and purified by column chromatography (silica gel 10g, eluent:dichloromethane). Then the residue was recrystallized from chloroform (3.5m1)-hexane (12m1) to give the entitled compound (0.23g}.
m.p.:200-202~C
NMR(CDC13)b: 3.91{lH,d,J=16H2}, 4.00(3H, s), 4.01(lH,d,J=l6Hz), 5.B4(lH,d,J=l.4Hz), 5.87(lH,d,J=l.4Hz), 6.05(lH,d,J=l.4Hz), 6.09(lH,d,J=l.4Hz), 6.75(lH,dd,J=l.6Hz,8Hz), 6.76(lH,d,J=l.6Hz), 6.90(IH,d,J=8H2), 7.26(IH,d,J=9H2), 7.57(lH,d,J=9H2), 8.60(lH,s) IR(KHr):2240, 1705, 1450, 1435, 1265, 1225, 1085cm-~
Elemental Analysis for CZZH1sN06 ~ 0 . 2H20 Calcd.: C:67.24$, H:3.95, N:3.56 SUBSTITUTE SHEET (RULE 2fi~

WO 98l07705 PCTiJP97l028S8 Found . C:67.23$, H:3.92, N:3.59 Reference Example 16 N-(3-Phenyl-2-propin-1-yl)-3-(6-bromobenzo[d)-1,3- _ benzodioxol-S-yl)-2-propenoylamide T ~
'~ '~~ ,NH
O
~-- O /
w To a thionyl chloride (2ml) was added 3-{6-bromobenzo[d]-1,3-benzodioxol-5-yl)-2-propenoic acid (461mg) which was synthesized from 6-bromopiperonal I5 mentioned in D. Brown and R. Stevenson, Journal of Chemical Society,vol. 30, 1759-1763, 1965 by using the known Wittig-Horner reaction, and heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to give a corresponding crude compound of acid chloride. Sodium hydrogen carbonate (429mg) was dissolved in water (5ml), and dichloromethane(3m1) solution of N-(3-phenyl}-3-propin-2-yl amine~hydrochloride (285mg) described in LeRoy H.
Klemm et al, Journal of Chemical Society, vol. 41, 2S71-2570, 1976, was added thereto under ice cooling.
After bubbling was stopped dichloromethane (3m1}
solution of above-mentioned acid chloride was dropwise added, and the mixture was stirred at room temperature for 1 hour. The product were extracted with dichloromethane and the extract was dried with magnesium sulfate, then concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate (20m1) - hexane (5m1) to give the entitled compound (483mg). .
NMR(CDC1~)S: 4.25(2H,m}, 5.87(lH,brs), 6.02(2H, s), 6.23(lH,d,J=l6Hz), 7.04{lH,s), 7.06(lH,s), 7.25-SUBSTITUTE SHEF'3' (RULE 26) PCTlJP97I02858 7.50(SH,m), 7.94(lH,d,J=l6Hz) Reference Example 17 Ethyl 3-~(9-(1,3-Benzodioxol-5-yl)-7-methoxycarbonyl-naphto[1,2-d]-1,3-benzodioxol-8-yl}-2-cyanopropionate 4 ~. ~ C02Me i / CN
C02 E t i I

O.
THF (1m1) solution of ethyl cyanoacetate (231) was added sodium hydride (60~ oily:llmg) and stirred for 5 minutes under ice cooling. To the reaction mixture was added methyl 9-(1,3-benzodioxol-S-yl)-8-methanesulfonyloxymethyl-naphtho[I,2-d]-1,3-benzodioxole-7-carbonxylate (0.1g) as obtained in Reference Example 14 and stirred for 2 hours, at room temperature. 1N hydrochloric acid was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel 10g, eluent:ethyl acetate-dichloromethane-hexane =
1:1:8) to give the entitled compound (l2mg).
NMR(CDC13)6: 1.25(3H,t,J=7Hz), 3.45-4.00(3H, m), 4.18(2H, quartet,J=7Hz), 5.81(lH,d,J=l.4Hz), 5.83(lH,d,J=I.4Hz), 6.06(lH,d,J=l.6Hz), 6.08(IH,d,J=l.6Hz), 6.60-6.70(lH,m), 6.80-6.95(2H, m), 7.23(lH,d,J=9Hz), 7.54(lH,d,J=8Hz), 8.58(lH,s) Reference Example 18 Methyl 9-(1,3-Henzodioxol-5-yl)-8-- methanesulfonyloxymethyl-1,3-dioxolo[4,5-f]quinoline-7-carboxylate SUBSTITUTE SHEET (RULE 2fi) WO 98/07705 PCTlJP97102858 ~ N\ C02Me , i ~ OMs ~.0 ~0 The entitled compound was obtained from 10-(1,3-benzodioxol-5-yl)-1,3-dioxolo[4,5-f]furo-[3,4-b]guinolin-7(9H)-one in a manner similar to that described in Reference Example 14.
NMR(CDC1~)8: 2.97(3H, s), 4.07(3H, s), 5.36(lH,d,J=lOHz), 5.42(lH,d,J=lOHz), 5.93(lH,d,J=l.6Hz), 5.96(lH,d,J=l.6Hz), 6.07(lH,d,J=2Hz), 6.10(lH,d,J=2Hz), 6.75-6.95(3H, m), 7.49(lH,d,J=9Hz), 7.90(lH,d,J=9Hz).
Reference Example 19 Dimethyl 6-Methoxy-9-(4-methoxyphenyl)-naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate (a) Dimethyl 6-Hydroxy-9-(4-methoxyphenyl)-naphtho[1,2-d]-1,3-dioxol-7,8-dicarboxylate OH
~ C02Me 0 1 ~ ~ C02Me I
OMe Ta a solution of benzene (200m1) solution of helio -alcohol (4.0g, 26.3mmo1} was dropwise added 1.6M n-butyl lithium (1.6M-hexane solution:37m1, 59mmol) at .
room temperature and stirred for 1.5 hours at room temperature. Then, a benzene solution (50m1) of p-methoxybenzonitrile (3.86g, 29.Ommo1) was dropwise ' added thereto at room temperature and stirred for 2 SUBSTITUTE SHEET (RULE 26) hours at room temperature. To the reaction mixture was added water and extracted with ether. The extract was washed with water, saturated sodium chloride solution and dried with magnesium sulfate, then the solvent was distilled off. To the residue was added toluene - (200m1), acetylenedicarbonic acid dimethylester (16.8g, 118mmo1), and p-toluenesulfonic acid~mono hydrate (lg, Smmol), and then heated under reflux for 12 hours. To the reaction mixture was added sodium hydrogencarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution and, dried with magnesium sulfate, then the solvent was distilled off to give the entitled compound (3.28g, 30$} as a colorless crystals.
m.p.:200-201~C (ether) NMR(CDC1~)&: 3.51{3H, s), 3.86(3H, s), 3.92(3H, s), 5.81(2H, s), 6.87(2H, d, J=9Hz), 7.00-7.30(3H, m), 8.14(IH, d, J=9Hz).
IR(KBr): 2948, 2896, 1739, 1652, 1521, 1444, 1332, 1290, 1224 cm-1.
Elemental Analysis for Cz2H18, Na Calcd.: C:64.39%, H:4.42, Found . C:64.27$, H:4.55.
(b) Dimethyl 6-Methoxy-9-(4-methoxyphenyl)-naphtho(1,2-d]-1,3-dioxole-7,8-dicarboxylate OMe C02Me 0 ~ ~ C02Me 3 0 ~--0 i I
- OMe To an acetone (200m1) solution of dimethyl 6-hydroxy-9-(4-methoxyphenyl)-naphtho[1,2-d]-1,3-dioxole-7,8-dicarbonic acid (3.0g, 7.31mmo1) was added methyl SUBSTjTtJTE SHEET (RULE Z6~

WO 98l07705 PCTIJP97102858 iodide (1.5m1, 24mmo1) and potassium carbonate (5.0g, , 36mmo1), and then heated under reflux for 2 hours. The solvent was distilled off and water was added to the residue and the mixture was extracted with ether. The extract was washed with water, saturated sodium chloride solution and dried with magnesium sulfate, then the solvent was distilled off to give the entitled compound (2.92g, 94~) as colorless crystals.
m.p.:166-167~C {ether) NMR(CDC13)8: 3.51(3H, 5}, 3.86(3H, s), 3.92(3H, s), 4.06(3H, s), 5.83(2H, s), 6.88(2H, d, J=9Hz), 7.15-7.30(3H, m), 7.88(1H, d, J=9Hz).
IR(KBr}: 29S0, l842, 1744, 1708, 1629, 1612, 1521, l438, 1345, 1270 cm 1.
Elemental Analysis for Cz3HzoOe Calcd.: C:65.09, H:4.75, Found . C:65.04, H:4.88.
Reference Example 20 Dimethyl 9-(1,3-Benzodioxol-5-yl)-6-(2-N,N-dimethylaminoethoxy)-naphtho[1,2-d)-i,3-dioxole-7,8-dicarboxylate {a) Dimethyl 9-{1,3-Benzodioxol-5-yl)-6-hydroxy-naphtho(1,2-d]-I,3-dioxole-7,8-dicarboxylate OH
j ~ ~ COZMe p ~ ~ COZMe -o The entitled compound was obtained in a manner similar to that described in Reference Example 19(a).
m.p.:222-223~C (THF-ether) NMR{cDCl,)s: 3.57(3H, s), 3.92(3H, s), 5.85(1H, d, , J=l.4Hz), 5.87(1H, d, J=l.4Hz), 6.00(1H, d, J=l.4Hz), 6.03(1H, d, J=l.4Hz), 6.60-6.703H, m), 7.25(lEi, d, SUBSTITUTE SHEET (RULE Z6) WO 98l07705 PCTIJP97102858 J=9Hz), 8.l4{1H, d, J=9Hz), 12.60(1H, s).
IR(KBr): 3001, 2952, 2895, 1729, 1654, 1448, 1226 cm-Elemental Analysis for CzzH16O9 Calcd.: C:62.27~k, H:3.80, Found . C:62.05, H:3.76.
{b) Dimethyl 9-(1,3-Benzodioxol-5-yl)-6-[2-{N,N-dimethylamino)ethoxy]-naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate M a 2 N~0 COZMe 0 ~ ~ C02Me ~0 The entitled compound was obtained in a manner similar to that described in Reference Example 19(b).
m.p.:129-I30~C (THF-ether) NMR(CDC13)s: 2.39(6H, s), 2.82{2H, t, J=5Hz), 3.57(3H, s), 3.91(3H, s), 4.24(2H, t, J=5Hz}, 5.87(1H, brs), 5.89(1H, brs), 6.01(1H, brs), 6.03(1H, brs), 6.68-6.75(3H, m), 7.28{1H, d, J=9Hz), 7.97(1H, d, J=9Hz).
IR(KBr): 2950, 2898, 2779, 1720, 1710, 1629, 148B, 1442, 1344, I235 cm-1.
Elemental Analysis for Cz6HzsN09 Calcd.: C:63.03, H:5.09, N:2.83 Found . C:62.79, H:5.07, N:2.82$.
Reference Example 21 Dimethyl 9-(1,3-Henzodioxol-5-yl)-7,8-dimethyl-6-(1-- hexyloxy)-naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97I02858 !'~ 0 .
COzMe 0 ~ ~ C02Me ~0 i 0,../
The entitled compound was obtained in a manner similar to that described in Reference Example 19(b).
m.p.:110-111~C (ethyl acetate-isopropyl ether) NMR(CDCIj)s: 0.93(3H, t, J=6.6Hz), 1.3o-1.60(6H, m), 1.89(2H, m), 3.57(3H, s), 3.91(3H, s), 4.11(2H, t, J=7Hz), 5.86( M, d, J=l.4Hz), 5.89(1H, d, J=l.4Hz), 6.00(1H, d, J=l.4Hz), 6.03(1H, d, J=l.4Hz), 6.70-6.85(3H, m), 7.26(1H, d, J=9Hz), 7.88(1H, d, J=9Hz).
IR(KBr): 2950, 1716, 1629, 1490, 1442, 1276, 1222 cm i Elemental Analysis for ClBHzgO9 Calcd.: C:66.13, H:5.55~s, Found . C:65.9Io, H:5.53.
Reference Example 22 Dimethyl 9-(1,3-Benzodioxol-5-yl)-6-methoxy-naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate OMe ~ ~ C02Me 0 ( ~ ~ CO Me i The entitled compound was obtained in a manner similar to that described in Reference Example 19(b).
m.p.:170-171~C (THF-ether) NMR(CDCl~)b: 3.58(3H, s), 3.93(3H, s), 4.06(3H, s), 5.87(1H, hrs), 5.90(1H, brs), 6.01(1H, brs), 6.04{1H, SUBSTtTLITE SHEET tRULE 26~

WO 98l07705 PCT/JP97102858 brs), 6.70-6.85(3H, m), 7.29(1H, d, J=9Hz), 7.88(1H, d, J=9Hz).
IR(KBr): 2949, 2891, 1739, 1442, 1218 cm-~.
- Elemental Analysis for C23Hisw Calcd.: C:63.020, H:4.14, Found . C:62.83, H:4.09.
Reference Example 23 Dimethyl 9-(1,3-Benzodioxol-5-yl}-6-(2-propyl)-naphtho[1,2-d]1,3-dioxole-7,8-dicarboxylate 0' P r C02Me COZMe i The entitled compound was obtained in a manner similar to that described in Reference Example 19(b).
m.p.:I55-156~C (THF-ether) NMR(CDC1~)s: 1.35(6H, dd, J=l.6Hz,6Hz), 3.57(3H, s), 3.91(3H, s), 4.41(1H, septet, J=6Hz), 5.85(IH, d, J=l.4Hz), 5.88(1H, d, J=l.4Hz), 6.00(1H, d, J=l.4Hz), 6.03(iH, d, J=i.4Hz), 6.70-6.85(3H, m}, 7.24(1H, d, J=9Hz}, 7.93(1H, d, J=9Hz).
IR(KBr): 2980, 2880, 1745, 1727, 1625, 1488, 1438, 1214 cm 1 .
Elemental Analysis for CZSHzZOg Calcd.: C:64.38, H:4.75, Found . C:64.16, H:4.69.
Reference Example 24 Dimethyl 9-(4-Fluorophenyl)-6-methoxy-naphtho(1,2-d]-1,3-dioxole-7,8-dicarboxylate (a) Dimethyl 9-(4-Fluorophenyl}-6-hydroxy-naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate SUBSTITUTE SHEET (RULE 26) OH
~COZMe i i COZMe F
The entitled compound was obtained in a manner similar to that described in Reference Example 19(a).
m,p.:223-224 (THF-ether.) NMR(CDC13)s: 3.51(3H, s), 3.92(3H, s), 5.81{2H, s), 6.95-7.10(2H, m}, 7.1S-7.30(3H, m}, 8.65(1H, d, J=9H2}.
IR(KBr): 2950, 2900, 1733, 1650, 1S20, l455, 1386, l226 cm-~.
Elemental Analysis for CZ1H150~F ~ 0 . 2H20 Calcd.: C:62.75$, H:3.B5~, Found . C:62.75, H:3.93.
(b) Dimethyl 9-(4-Fluorophenyl)-6-methoxy-naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate OM a ~ Co2Me 0 ~ ~ C02Me ~.-- 0 i I
F
The entitled compound was obtained in a manner similar to that described in Reference Example 19(b).
m.p.. 154-15S {THF-ether) NMR(CDC1~)8: 3.52(3H, s), 3.93(3H, s), 4.07(3H, s), 5.83(2H, s}, 6.95-7.10(2H, m), 7.15-7.30(3H, m}, 7.89(1H, d, J=9H2).
IR(KBr}: 2960, 2B90, 1795, 1735, 1640, l521, 1455, 137l, 1226 cm-i.
Elemental Analysis for CzZHI~O~F
Calcd.: C:64.08, H:4.16, SUBSTITUTE SHEET (RULE 2fi~

Found . C:63.80, H:4.14.
Reference Example 25 (a) 6-Methyl-4-(4-methylphenyl)-naphtho[2,3-c)furan-1,3-dione Me Me To a DME (200m1) solution of 3-(4-Methylphenyl)propiolic acid (10.0g) was gradually added WSC (1-ethyl-3-(3-dimethylaminopropyl)carbodiiimide hydrochloride) {9.0g) at -10~C and stirred at room temperature for overnight. The solvent was distilled off under reduced pressure and water was added thereto, then the mixture was extracted with chloroform. The extract was washed with water and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained crude crystal was washed with isopropyl ether to give the entitled compound (6.0 g).
NMR(CDC13)s: 2.51 (6H, s), 7.30 (2H, d, J = 8Hz), 7.40 (2H, d, J = 8Hz), 7.6-7.7 (ZH, m), 8.06 (1H, d, J =
9Hz), 8.49 (1H, s).
IR{KBr):3028, 2922, 1835, 1772 cm~.
(b) 6-Methyl-4-(4-methyiphenyl)-naphtho[2,3-c]furan-1(3H)-one Me M a SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCTlJP97102858 To a suspension of sodium boron hydride (2.0g) in DME (100 ml) was gradually added 6-methyl-4-(4-methylphenyl)-naphtho(2,3-c)furan-1,3-dione (6.0g) under ice cooling and stirred for 30 minutes. The =
S reaction mixture was added to the diluted hydrochloric acid under ice cooling and the mixture was extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with silica gel column chromatography (eluent:hexane-ethyl acetate = 3:1), recrystallized from THF to give the entitled compound (0.7g) as colorless crystals.
m.p.. 175-176~C (THF) I5 NMR(CDCls)s: 2.47 (3H, s), 2.49 (3H, s), S.25 (2H, s), 7.27 (2H, d, J = BHz), 7.38 (2H, d, J = 8H2), 7.44 (1H, dd, J =l.6Hz,9Hz), 7.S8 (1H, d, J = 1.6H2), 7.99 (1H, d, J = 8H2), 8.46 (1H, s).
IR(KBr): 3026, 2922, 1768, 1629, 151S cm-'.
Elemental Analysis for CZOHISOz' 0. 4H20 Calcd.: C:81.28, H:5.73, Found . C:8I.12~, H:5.63$.
(c) Methyl 3-(4-Methanesulfonyloxymethyl)-6-methyl-4-(4-methylphenyl)naphthalene-2-carboxylate COZMe i OMs Me M a The entitled compound was obtained in a manner similar to that described in Reference Example 14.
NMR(CDC1,)s: 2.40 (3H, s), 2.49 (3H, s), 2.90 (3H, s), 3.99{3H, s), 5.48 (2H, s), 7.15-7.60(5H, m), 7.86 (2H, d, J = BHz), 8.52 (1H, s).
SUBSTITUTE SHEET (RULE 26) Reference Example 26 ' 11-(1,3-Benzodioxol-5-yl)-9,10-dihydro-7H-1,3-benzodioxolo[5,4-ej(2]benzopyran-7-one (a) Methyl 2-{9-(1,3-Benzodioxol-5-yl)-7-methoxycarbonylnaphtho(1,2-d]-1,3-benzodioxol-8-yly acetate C02Me 0 ' ~ COZMe 'o To an acetic acid (50m1) solution of methyl 9-{1,3-benzodioxol-5-yl}-8-cyanomethylnaphtho[1,2-dj-1,3-benzodioxol-7-carboxyiate (3.0g) was added concentrated hydrochloric acid (25m1), and then heated under reflex for 6 hours. The mixture was cooled to room temperature and water was added thereto. The resultant precipitates were collected by suction and dissolved in THF (30m1), and then~an ether solution of diazomethane was added thereto under ice cooling. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified with column chromatography (silica gel 50g, eluent:ethyl acetate-hexane = 1:3) to give the entitled compound (328mg).
NMR(CDCli)6: 3.66(3H, s), 3.85(lH,d,J=l7Hz), 3.90(lH,d,J=l7Hz), 3.91(3H, s), 5.82(lH,brs), 5.82(lH,brs), 6.02(lH,d,J=l.4Hz), 6.05(lH,d,J=l.4Hz}, _ 30 6.69(lH,dd,J=l.4Hz,8Hz), 6.73(lH,d,J=l.4Hz), 6.82(lH,d,J=8Hz), 7.2i(lH,d,J=9Hz), 7.54(lH,d,J=9Hz), 8.55(lH,s).
(b} 9-(1,3-Benzodioxol-5-yl)-8-(2-hydroxyethyl)-7-hydroxymethylnaphtho[1,2-d]-1,3-dioxole SUBSTITtJT~ SH~~T (RULE 2fi) WO 98l07705 PCTIJP97/02858 off OH
~n ~ J _ 0~/
To a suspension of lithium aluminum hydride (LAH) (36mg) in THF (1m1) was added THF (2m1) solution of methyl 3-~9-(1,3-benzodioxol-5-yl)-7-methoxycarbonylnaphtho[1,2-d]-1,3-benzodioxol-8-yl) acetate (208mg) dropwise thereto under ice cooling and stirred at room temperature for 1 hour. To the mixture was added saturated sodium sulfate solution under ice cooling to stop the reaction. The reaction mixture was diluted with ethyl acetate, and washed with 1N
hydrochloric acid and saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with column chromatography {silica gel 20g, eluent:ethyl acetate-hexane = 2:1) to give the entitled compound (35mg).
NMR(CDC1~)6: 2.89(2H,t,J=6Hz), 3.57(2H,t,J=6Hz), 4.74(2H,s}, 5.74(2H, s), 6.00(lH,brs), 6.03(lH,brs), 6.64(lH,dd,J=0.9Hz,8Hz), 6.70(lH,d,J=0.9Hz), 6.80(lH,d,J=8Hz), 7.10(lH,d,J=9Hz), 7.34(lH,d,J=9Hz), 7.72(lH,s).
(c) 11-(1,3-Benzodioxol-5-yl)-9,10-dihydro-7H-1,3-benzodioxolo[5,4-a][2]benzopyran-7-one SUBSTITUTE SH~~T (RULE 26) WO 98107705 PCTIJP97l02858 \' To a chloroform (3m1) solution of 9-(1,3-benzodioxol-S-yl)-8-(2-hydroxyethyl)-7-hydroxymethylnaphtho[1,2-d]-1,3-dioxole (36mg) was added manganese dioxide (360mg) and stirred for 4 hours,at room temperature. The manganese dioxide was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the entitled compound (l6mg).
m.p.:263-266~C
NMR(CDCli)6: 2.80-2.90(2H, m), 4.45(2H,t,J=6Hz), 5.87(lH,d,J=1.4H2), 5.89(lH,d,J=l.4Hz), 6.04(lH,d,J=l.SHz), 6.07(lH,d,J=l.SHz), 6.70(lH,dd,J=l.6Hz,8Hz), 6.74(lH,d,J=l.6Hz), 6.88(lH,d,J=8Hz), 7.23(lH,d,J=9Hz}, 7.62(lH,d,J=9Hz}, 8.69(lH,s).
Elemental Analysis for Ci1H140s Calcd.: C:69.61, H:3.89 Found . C:69.46, H:3.77 Reference Example 27 Methyl 8-(3-Aminopropyl)-9-(1,3-benzodioxol-5-yl}-naphtho(1,2-d]-1,3-dioxole-7-carboxyiate (a) Methyl 9-(1,3-Benzodioxol-5-yl)-B-(2-methanesulfonyloxyethyl)-naphtho[1,2-d)-1,3-benzodioxole-7-carboxylate SUBSTITUTE SHEET (RULE 26) ~ C02Me OMs ~0 ~
I

0.~/
The entitled compound was obtained from 11-(1,3-benzodioxol-5-yl)-9,10-dihydro-7H-1,3-benzodioxolo[5,4-a][2]benzopyran-7-one as in a manner similar to that described in Reference Example 14.
NMR(CDC13)6: 2.91(3H, s), 3.20-3.45(2H, m), 3.96(3H, s), 4.29(2H,t,J=8Hz), 5.80(lH,d,J=1Hz), 5.82(lH,d,J=IHz), 6.04(lH,d,J=l.2Hz), 6.06(IH,d,J=l.2Hz), 6.65-6.75(2H,m}, 6.86(lH,d,J=8Hz}, 7.21(IH,d,J=9Hz), 7.51(lH,d,J=9Hz), 8.45(lH,s).
{b) Methyl 9-(1,3-Benzodioxol-5-yl)-8-{2-cyanoethyl)-naphtho(1,2-d]-1,3-benzodioxole-7-carboxylate ( w ~ C02Me 0~ ~ ~ ~'C N
C '0 The entitled compound was obtained from methyl 9-(1,3-benzodioxol-5-yl)-8-(2-methanesulfonyloxyethyl)-naphtho(1,2-d]-1,3-benzodioxole-7-carboxylate as in a manner similar to that described in Reference Example 15. -NMR(CDC1~)6: 2.50-2.60(2H, m), 3.10-3.35(2H, m), 3.97{3H,s), 5.81(lH,d,J=1Hz), 5.82(lH,d,J=1Hz), 6.06(lH,d,J=l.ZHz), 6.08(lH,d,J=l.2Hz), 6.65-6.75(2H,m), 6.87(lH,d,J=9Hz), 7.21(lH,d,J=9Hz), 7.52(lH,d,J=9Hz), 8.49(lH,s).
{c) Methyl 8-(3-Aminopropyl)-9-(1,3-benzodioxol-5-yl)-SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCTIJP97102858 naphtho(1,2-d]-1,3-dioxole-7-carboxylate C02Me i ~ NH2 S ~0 _ i \ l '0 J
To a DMF (1m1) solution of methyl 9-{1,3-benzodioxol-5-yl}-8-(2-cyanoethyl)-naphtho[1,2-d]-1,3-benzodioxole-7-carboxylate (2lmg) was added Raney nickel (about 200mg) and stirred for 6 hours under hydrogen atmosphere. The catalist was filtered off and the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified with column chromatography {silica gel lg, eluent:dichloromethane-methanol concentrated NH40H =
15:1:0.1) to give the entitled compound (llmg).
NMR{CDC1~)8: 1.45-1.70(2H, m), 2.50-2.70(2H, m), 2.75-2.95(ZH,m}, 3.94(3H, s), 5.79(lH,d,J=l.4Hz), 5.80(lH,d,J=l.4Hz), 6.03(lH,d,J=l.6Hz), 6.06(lH,d,J=l.6Hz), 6.69{lH,dd,J=l.6Hz,8Hz), 6.73(lH,d,J=I.6Hz), 6.84(lH,d,J=SHz), 7.I7{lH,d,J=9Hz), 7.48(lH,d,J=9Hz), 8.47(lH,s).
Reference Example 28 Methyl 8-Cyanomethyl-9-(4-fluorophenyl)-6-methylnaphtho(1,2-d]-1,3-dioxole-7-carboxylate (a) Dimethyl 9-(4-Fluorophenyl)-6-methylnaphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate SUBST1TUTF SHEET (RULE Z6y WO 98l07705 PCTlJP97l02858 Me COOMe 0 ~ ~ COOMe i _ I
F
To a THF (200m1) solution of 1-(1,3-benzodioxol-5-yl)-ethanol (8.2g) was dropwise added butyl lithium 1.6M (hexane solution, 66.7m1) at 0~C. The mixture was stirred for 1.5 hours and THF (30m1) solution of p-fluorobenzonitrile (6.9g) was dropwise added thereto and stirred for 1 hour at 0~C. To the reaction mixture was added water and the mixture was extracted with diethyl ether and dried with magnesium sulfate, then the solvent was distilled off under reduced pressure.
The obtained residue was dissolved in toluene (200m1), then dimethyl fumarate (14.4g) and trichloroacetic acid (2.45g) were added therein, and heated under reflux for 3 hours. After cooling, the solvent was distilled off under reduced pressure, and concentrated hydrochloric acid (75m1) was added thereto. The reaction mixture was heated under reflux for 1 hour, separated crystals were collected and washed with, methanol and ether to give the entitled compound (2.0g).
m.p.:160-162~C (AcOEt-isopropyl ether) NMR(CDC1~)s: 2.74(3H, s), 3.50(3H, s), 3.90(3H, s), 5.82(2H, s), 6.92-7.33(SH,m), 7.76(lH,d,J=9Hz) Elemental Analysis for CZZH~~F06 Calcd.: C:66.67%, H:3.95%, N:4.79%, Found . C:66.63%, H:4.25%, N:4.53%.
(b) 9-(4-Fluorophenyl)-8-hydroxymethyl-6 methylnaphtho(1,2-d)-1,3-dioxole-7-methanol SUBSTITUTE SHEET (RULE 2fi) OH
p ' ~ OH
S
To a suspension of Lithium aluminum hydride (0.32g) in THF (30m1) was-dropwise added a THF (30m1) solution of dimethyl 9-(4-fluorophenyl)-6-methylnaphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate {1.67g). After 1.5 hours, a saturated sodium sulfate solution was added thereto and insoluble materials were filtered off. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-isopropyl ether to give the entitled compound {1.3g} as colorless crystals.
m.p.:170-172~C
NMR(CDC1~)&: 2.43{lH,brs), 2.B0(3H,s), 2.96(lH,brs), 4.62(2H, s), 5.01(2H,s}, 5.73{2H,s}, 7.01-7.27(SH,m), 7.72(lH,d,J=9Hz).
IR(KBr) . 3275 cm 1 . Elemental Analysis for C2oH1~F04 Calcd.: C:70.58, H:5.03, Found . C:70.36, H:4.78$.
(c) 10-(4-Fluorophenyl)-6-methylfuro[3',4':6,7]-naphtho[1,2-d]-1,3-dioxole-7(9H)-one SUBSTiTLJTE SHEET (RULE 26) WO 98l07705 PCT/JP97/02858 M a .~ -o- ~ ,-s ~-.o F
To a chloroform (4Qm1) solution of 9-(4-fluorophenyl)-8-hydroxymethyl-6-methylnaphtho[1,2-d)-1,3-dioxole-7-methanol (880mg) was added manganese dioxide (8.8g) and stirred for 60 hours at room temperature. The insoluble substances were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate-hexane ) to give the entitled compound (93mg) as a pale-yellow crystals.
m.p.:197-199~C (AcOEt-isopropyl ether) NMR(CDC13}b: 3.13(3H, s), 5.06(2H,s}, 5.89(2H, s), 7.08-7.38(SH,m), 7.93(lH,d,J=9Hz).
Elemental Analysis for CZOH13F04' 0. 25 HZO
Calcd.: C:70.48%, H:3.99%, Found . C:70.76%, H:3.71%.
(d) Methyl 9-(4-Fluorophenyl}-8-methanesulfonyloxymethyl-6-methylnaphtho(1,2-d]-1,3-dioxole-7-carboxylate Me ~ ~ ~ COOMe 0~ Y ~~0 M s 1n The entitled compound was obtained in a manner SUBST1TLJTE SHEET (RULE ~fi) WO 98I07705 PCTlJP97/02858 similar to that described in Reference Example 14.
' NMR(CDCli)s: 2.66(3H, s), 2.82(3H, s), 4.01(3H, s}, 5.78(2H, s), 7.00-7.40(SH,m), 7.76(lH,d,J=9Hz).
s (e) Methyl 8-Cyanomethyl-9-(p-fluorvphenyl)-6-methylnaphtho[1,2-d]-1,3-dioxol-7-carboxylate COOMe i CN
15 The entitled compound was obtained in a manner similar to that described in Reference Example i5.
NMR(CDC13}6: 2.67(3H,s}, 3.50(2H,s}, 4.04(3H, s), 5.77(2H, s), 7.09-7.35(SH,m), 7.71(lH,d,J=9Hz) IR(KHr) . 2249, 1732 cm ~
Reference Example 29 8-Cyanomethyl-9-(4-fluorophenyl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid (a) Dimethyl 9-(p-Fluorophenyl)-naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate COOMe COOMe L.0 i _ 30 F
The entitled compound was obtained in a manner similar to that described in Reference Example 28(a).
m.p.:172-174~C (AcOEt-hexane) ' 35 NMR(CDC15)8: 3.59(3H, s), 3.94(3H, s), 5.85(2H, s), 6.98-7.12(2H,m), 7.24-7.35(2H, m), 7.29(lH,d,J=9Hz), SUBSTITUTE SHEET (RULE 2fi) 7.61(lH,d,J=9Hz), 8.56(lH,s).
IR(KBr): 1741, 1720, 145S, 1272, I261, 1216, 1160, 107 7 cm-1 .
Elemental Analysis far CZ,HISF~6 Calcd.: C:65.97, H:3.95, Found . C:65.96, H:3.84.
(h) 9-(4-Fluorophenyl)-8-hydroxymethylnaphtho[I,2-d]-1,3-dioxole-7-methanol OH
OH
The entitled compound was obtained in a manner similar to that described in Reference Example 28(b).
m.p.:206-208~C (THF) NMR(CDC13}8: 2.70-3.00(2H,m}, 4.57(2H,brs), 4.93(2H,brs), 5.76(2H, s), 7.04-7.34(SH,m), 7.45(lH,d,J=9Hz), 7.81(lH,s).
IR(KBr): 3332, 14S3, 1324, 1295, 1046, 1000 cm-'.
Elemental Analysis for C19H15FO4 Calcd.: C:69.93, H:4.63%, FOUrid . C:69.83%, H:4.61.
(c) 8-(tert-Butyldiphenylsilyloxymethyl)-9-(4-fluorophenyl)-naphtho[1,2-d]-1,3-dioxole-7-methanol SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCTI3P97t02858 ' /
~' ~ 0 i -C (CH3)3 ~o To a DMF (20m1) solution of 9-(4-Fluorophenyl)-8-hydroxymethylnaphtho(1,2-d]-1,3-dioxole-7-methanol (2.28g) were added imidazole (0.95g)~and tert-butylcholorodiphenylsilane (2.31g) and stirred for 1 hour at room temperature. To the reaction mixture was added water and resultant precipitates were collected by suction. The obtained precipitates were dissolved in ethyl acetate and washed with 1N hydrochloric acid, saturated sodium chloride solution, saturated sodium hydrogencarbonate solution, and saturated sodium chloride solution successively. The ethyl acetate solution was dried with magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified with silica gel column chromatography {eluent:ethyl acetate-hexane = 1:9) to give the entitled compound (1.48g, 83%} as colorless powder.
NMR(cDCl,)S: 1.06{9H,s), 3.45(lH,t,J=7Hz), 4.52(2H,d,J=7Hz), 4.94(2H,brs), 5.77(2H,s}, 7.00-7.55(l3H,m), 7.70-7.80(4H, m).
IR(KHr}: 3516, 1S04, 1448, 1322, 1068, Z048 1039 cm-~.
(d) 7-(tert-eutyldiphenylsilyloxymethyl)-9-(p-fluorophenyl)-naphtho(1,2-d]-1,3-dioxole-8-acetonitrile SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 0 i -C (CH3)3 cN
10 To a THF{30m1) solution of 8-{tert-Butyldiphenylsilyloxymethyl)-9-(4-fluorophenyl)-naphtho[1,2-d]-1,3-dioxole-7-methanol'(3.Og) were added triethylamine (1.48m1) and methanesulfonylchloride (0.49m1) and stirred for 30 minutes under ice cooling.
To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was dissolved in DMF (30m1) and sodium cytnide {0.52g) was added thereto and stirred overnight. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained crude crystals were recrystallized from diisopropyl ether to give the entitled compound (2.54g) as colorless crystals.
m.p.:147-149~C
NMR(CDCI~}&: 1.08(9H, s), 3.69(2H,brs), 4.96(2H,brs), 5.77(2H, s), 7.10-7.55(l2H,m), 7.57(lH,s), 7.65-7.75(4H,m). , IR(KBr): 2248, 145S, 1220, 1112, 1073 cm-~.
Elemental Analysis for C~H~ZFNO~Si Calcd.: C:75.36, H:5.62, N:2.44, Found . C:75.13$, H:5.57$, N:2.43.
SUBSTITUTE 5H~~T (RULE 26) WO 98I07705 PCTl3P97102858 (e) 9-(4-Fluorophenyl)-7-hydroxymethylnaphtho[1,2-d]-1,3-dioxole-8-acetonitrile OH
S CN

To a THF (10m1) solution of 7-(tert-butyldiphenylsilyloxymethyl)-9-(4-fluorophenyl)naphtho(1,2-d]-1,3-dioxole-8-acetonitrile (1.0g) was added tetrabutylammoniumfluoride {1 N THF
solution) (2.3m1) and stirred for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, and water was added to the residue.
Separated solid was collected and washed with methanol to give a crude crystals (481mg) of the entitled compound. Some of the crude crystals were recrystallized from ethyl acetate-hexane for analysis.
m.p.:190-193~C
NMR(CDC1~)8: 3.69(2H, s), 4.96(2H, s), 5.77(2H, s), 7.10-7.34{SH,m), 7.45(lH,d,J=B.4Hz), 7.B2(lH,s).
IR(KHr): 35S4, 2252, 1S05, 14S9, 1326, 1266, 1222, 1077 cm-1.
Elemental Analysis for CZOH~~FN03~O.1H20 Calcd.: C:71.25%, H:4.25, N:4.15%, Found . C:71.09%, H:4.22%, N:3.98%.
(f) 8-Cyanomethyl-9-(4-fluorophenyl)-naphtho[1,2-d]-1,3-dioxole-7-carboxylic acid SUBSTiTtJTE SHEET (RULE 26) WO 98I0??OS PCT/JP9?l02858 COON
w w CN

~.-0 -s To a mixture of acetone (5mi) and water (2m1) was dissolved 9-(4-fluorophenyl)-7-hydroxymethylnaphtho[1,2-d]-1,3-dioxole-8-acetonitrile (200mg), and potassium permanganate (400mg) was gradually added thereto. The mixture was stirred for 1 hour at room temperature and potassium permanganate (200mg) was gradually added thereto. The insoluble substances were filtered off and 1N hydrochloric acid was added to the filtrate. The resultant precipitates were collected by suction and recrystallized from methanol to give the entitled compound (23mg) as colorless crystals.
m.p.:230-233~C
NMR(cDCl,)s: 3.9e(zH,s), s.7s(zH,s), 7.1o-7.3s(sH,m), 7.SB(lH,d,J=8Hz), 8.69(lH,s).
IR(KBr): 2997, 2240, 1681, 1451, 1274, l230, i097 cm i Reference Example 30 Methyl 9-(1,3-Benzodioxol-s-yl)-8-cyanomethyl-6-methylnaphtho[1,2-d]-1,3-dioxole-7-carboxylate (a) Dimethyl 9-(1,3-Benzodioxol-s-yl)-6-methylnaphtho[1,2-d)-I,3-dioxole-7,8-dicarboxylate SUBSTITUTE SHEET (RULE 26?

WO 98I07705 PCTlJP97l02858 Me COOMe COOMe O
-' S ~-0 0,/
The entitled compound was obtained in a manner similar to that described in Reference Example 28(a).
m.p.:157-158~C (MeOH) NMR(CDC13)6: 2.73(3H, s), 3.56(3H,), 3.90(3H, s), 5.85(lH,d,J=l.4Hz), 5.89(lH,d,J=1.4H2), 6.00(lH,d,J=l.4Hz), 6.04(lH,d,J=l.4Hz), 6.72(lH,dd,J=l.6Hz,8Hz), 6.79(lH,d,J=8Hz), 6.80(IH,d,J=l.6Hz), 7.29(lH,d,J=9Hz), 7.74(IH,d,J=9Hz).
IR(KBr): 1726, 1488, 1438, 123S, 1205, 1035 cm-~.
Elemental Analysis for C23H18O8 Calcd.: C:65.40, H:4.30%, Found . C:65.21, H:4.20.
(b)~9-(1,3-Benzodioxol-5-yl)-8-hydroxymethyl-6-methylnaphtho[1,2-d]-1,3-dioxole-7-methanol a OH
' i ~ 0 H

~-0 w The entitled compound was obtained in a manner similar to that described in Reference Example 28(b).
m.p.:215-217~C (THF) NMR(CDC1~)b: 1.7D-2.00(2H, m), 2.80(2H, s), 4.69(2H,brs), 5.01(2H,brs), 5.7B(lH,d,J=l.4Hz)) 5.80(lH,d,J=l.4Hz), 6.02(lH,d,J=l.4Hz), SU85TiTLJTE SHEET (RULE 2fi) 6.06(lH,d,J=l.4Hz), 6.69(lH,dd,J=l.6Hz,8Hz), 6.74(lH,d,J=l.6Hz), 6.B4(lH,d,J=SHz}, 7.21(lH,d,J=9Hz), 7.72(lH,d,J=9Hz).
IR(KBr): 329B, 1492, 1434, 1291, 1070, 1Q39, 998 cm-~.
Elemental Analysis for CZ1H,806 Calcd.: C:68.85, H:4.95, Found . C:68.49$, H:4.93.
(c) 9-(1,3-Benzodioxol-5-yl)-8-(tert-butyldiphenylsilyloxymethyl)-6-methyinaphtho[1,2-d)-1,3-dioxole-7-methanol Me OS i -C (CH3)3 ~ off ' w The entitled compound was obtained in a manner similar to that described in Reference Example 29(c).
NMR(CDC13)s: 1.05(9H, s), 2.32(3H, s), 3.14(lH,brs), 4.53(2H, m), 5.05(2H, s), 5.77(lH,d,J=l.4Hz), 5.79(lH,d,J=l.4Hz), 6.00(lH,d,J=l.4Hz), 6.0S{lH,d,J=l.4Hz), 6.74-6.88(3H, m), 7.18(lH,d,J=9Hz), 7.28-7.52(6H, m), 7.59{lH,d,J=9Hz), 7.58-7.80{4H,m).
IR(KBr): 3340, 1488, 1436, 1230, 107Z, 104i cm~~.
(d) 9-(1,3-Benzodioxol-5-yl)-7-{tert-butyldiphenylsilyloxymethyl)-6-methylnaphtho[I,2-d)-1,3-dioxole-8-acetonitrile SUBSTITUTE SHEET (RULE 26~

Me ~ ~OS i -C (CH3)3 0 ~ ~ CN
~0 i i I

0~/
The entitled compound was obtained in a manner similar to that described in Reference Example 29(d).
m.p.:191-193~C (AcOEt) NMR(CDC13)s: 1.04(9H,s), 2.42(3H,s}, 3.58(lH,d,J=16H2), 3.70(lH,d,J=16H2), 5.02{2H,s}, 5.?8(lH,d,J=1.4H2), 5.80{lH,d,J=1.4H2), 6.04(lH,d,J=1.4H2), 6.07{lH,d,J=1.4H2), 6.68-6.80(2H,m), 6.88(lH,d,J=8H2), 7.20(lH,d,J=9H2), 7.28-7.52(6H,m), 7.62(lH,d,J=9H2), 7.64-7.70(4H, m).
IR(KBr): 2246, 1488, 1436, 1068, 1039 cm-1.
Elemental Analysis for Cj8H35FNO5Si Calcd.: C:75.29, H:5.83, N:2.25, Found . C:75.26, H:5.79, N:2.32.
(e) 9-(1,3-Benzodioxol-5-yl)-7-hydroxymethyl-6-methylnaphtho(1,2-d)-1,3-dioxole-8-acetonitrile a OH
0 ' i ~ CN
~0 - The entitled compound was obtained in a manner similar to that described in Reference Example 29(e).
NMR(CDC1~)s: 1.70(lH,m), 2.79(3H, s), 3.72{lH,d,J=17H2), 3.81(lH,d,J=17H2), 5.04(2H, m), SUBSTITUTE SHEET (RULE 26) 5.79(lH,d,J=l.4Hz), 5.82(lH,d,J=l.4Hz), 6.05(lH,d,J=l.4Hz), 6.08(lH,d,J=l.4Hz), 6.70-6.80(2H,m), 6.89(lH,d,J=8Hz), 7.24(lH,d,J=9H2), 7.72(lH,d,J=9Hz).
IR(KBr): 3280, 2249, 1489, 1437, 1229, 1067, 1040 cm-(f) Methyl 9-(1,3-Benzodioxol-5-yl)-8-cyanomethyl-6- ' methylnaphtho(1,2-d]-1,3-dioxole-7-carboxylate Me COOMe 0 ~ ~ CN
i I
w 9-(1,3-Benzodioxol-5-yl)-7-hydroxymethyl-6-methylnaphtho[1,2-d)-1,3-dioxol-8-acetonitrile (lBOmg) was dissolved in a mixture of acetone (5m1) and water (1.5m1) and 1N sodium hydroxide solution (0.48m1) was added thereto under ice cooling. To the mixture potassium permanganate (400mg) was added gradually and stirred for 2 hours under ice cooling, then stirred 1 hour at room temperature. The insoluble substance was filtered off, and 1N hydrochloric acid was added to the filtrate and the mixture was extracted with ethyl acetate. To the extract was added diazomethane (ether solution) and washed with 1N hydrochloric acid, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution, and saturated sodium chloride solution successively, and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with ;
silica gel column chromatography (eluent:ethyl acetate-hexane = 1:2) to give the entitled compound (l2mg).
NMR(CDC1~)8: 2.66(3H, s), 3.56(2H,5), 4.04(3H, s), SUBST1TUTE SHEET (RULE 26) WO 98I07705 PCTlJP97/02858 5.04(2H, m), 5.81(lH,d,J=l.4Hz), 5.83(lH,d,J=l.4Hz), - 6.04(lH,d,J=l.4Hz), 6.07(lH,d,J=l.4Hz), 6.70-6.80(2H,m), 6.88(lH,d,J=8Hz), 7.26(lH,d,J=9Hz), _ 7.78(lH,d,J=9Hz).
IR(XHr): 2251, 1728, 1489, 1439, 126Q, 1244, 1040 cm-i Reference Example 31 Methyl 8-Cyanomethyl-9-{4-fluorophenyl}-6-methylnaphtho[1,2-d]-1,3-dioxole-7-carboxylate (a) Dimethyl 9-(4-Fluoraphenyl)-6-methylnaphtho(1,2-d]-1,3-dioxole-7,8-dicarboxylate Me COOMe 0 ~ ~ COOMe ~-0 I
w F
The entitled compound was obtained in a manner similar to that described in Reference Example 28(a).
m.p.:160-162~C (AcOEt-isopropyl ether) NMR(CDC13)s: 2.74(3H, s), 3.50(3H, s), 3.90(3H, s), 5.82(2H,s}, 6.92-7.33(SH,m}, 7.76(lH,d,J=9Hz).
Elemental analysis for CizH11F06 Calcd.: C:66.67, H:3.95$, Found . C:65.63, H:4.25.
(b} 9-(4-Fluorophenyl)-8-hydroxymethyl-6-methylnaphtho[1,2-d]-1,3-dioxole-7-methanol SUBSTITUTE SHEET{RULE 26) WO 98l07705 14 2 PCTIJP97102858 Me .
OH
OH
10 The entitled compound was obtained in a manner similar to that described in Reference Example 28(b).
m.p.:170-172~C (AcOEt-isopropyl ether}
NMR(CDC13)s: 2.43(lH,brs), 2.80(3H,s), 2.96(lH,brs}, 4.62(2H, s), 5.01(2H, s), 5.73(2H, s), 7.01-7.27(SH,m), Z5 7.72(lH,d,J=9Hz).
IR(KBr): 3275 cm 1 Elemental analysis for CioH1~F04 Calcd.: C:70.58, H:5.03%, Found . C:70.36, H:4.78$.
20 (c) 10-(4-Fluorophenyl)-6-methylfuro[3',4':6,7]naphtho[1,2-d]-1,3-dioxol-7(9H)-one Ni a 0 i ~-0 J
The entitled compound was obtained in a manner similar to that described in Reference Example 26(c).
m.p.:197-199~C (AcOEt-isopropyl ether}
NMR(CDCl~)s: 3.13(3H, s), 5.06(2H,s}, 5.89(2H,s}, 7.08-7.38(5H,m), 7.93(lH,d,J=9Hz). ' Elemental analysis for CzoH,~F0,,~0.25HZ0 SUBSTITUTE SHEET (RULE Z6~

Calcd.: C:70.48$, H:3.99$, Found . C:70.76$, H:3.71$.
(d) Methyl 9-(4-Fluorophenyl)-8-methanesulfonyloxymethyl-6-methylnaphtho(1,2-d]-1,3-.' S dioxole-7-carboxylate Me ~ COOMe OMs ~--- 0 J..
The entitled compound was obtained in a manner similar to that described in Reference Example 14.
NMR(CDC13)s: 2.66(3H, s), 2.B2(3H,s}, 4.01(3H, s), 5.78(2H, s), 7.00-7.40(SH,m), 7.76(lH,d,J=9Hz).
(e) Methyl 8-Cyanomethyl-9-(4-fluorophenyl)-6-methylnaphtho[1,2-d}-1,3-dioxole-7-carboxylate Me COOMe 0 ~ ~ CN
~0 i ~J
The entitled compound was obtained in a manner similar to that described in Reference Example 15.
NMR(CDC1~)s: 2.67(3H, s), 3.50(2H, s), 4.04(3H, s), 5.77(2H, s), 7.09-7.35(SH,m), 7.71(lH,d,J=9Hz) IR(KBr) :2249, 1732 cm-'.
Reference Example 32 Methyl 8-Cyanomethyl-9-(4-methoxyphenyl)naphtho[1,2-d]-1,3-dioxole-?-carboxylate SUBSTITUTE SHEET (RULE 2fi) (a) Dimethyl 9-(4-Methoxyphenyl)naphtho(1,2-d]-1,3-dioxole-7,8-dicarboxylate , COOMe 0 ~ ~ COOMe ~.- 0 i I .
OMe The entitled compound was obtained in a manner similar to that described in Reference Example 28(a).
m.p.:219-221~C
NMR(CDC13)S: 3.60(3H,s}, 3.87(3H, s), 3.94(3H, s), 5.85(2H, s), 6.90(2H,d,J=9z), 7.20-7.31(3H, m), 7.60(lH,d,J=9Hz), 8.54(lH,s).
IR(KBr) :1723, 1454, 1271 cm-1.
(b) 8-Hydroxymethyl-9-(4-methoxyphenyl)naphtho[1,2-dj-1,3-dioxole-7-methanol ~ ~~ ~0 H
i ~ OH
.0 y ,E
Me The entitled compound was obtained in a manner similar to that described in Reference Example 28(b).
m.p.:181-183~C (AcOEt-isopropyl ether) NMR(CDC1~)8: 2.82(2H,brs), 3.89(3H, s), 4.60(2H, s), 4.93(2H,s}, 5.77(2H, s), 6.95(ZH,d,J=9Hz}, 7.15-7.27(3H,m), 7.44(lH,d,J=8Hz), 7.80(lH,s). ' IR(KBr): 3348, 2926, 1451, 1244 cm-~.
(c) 10-(4-Methoxyphenyl)furo(3',4':6,7jnaphtho(1,2-dj- , 1,3-dioxol-7(9H)-one SUBSTITUTE SHEET (RULE 26) . 'w w o '..' ~---o OMe The entitled compound was obtained in a manner similar to that described in Reference Example 26(c).
m.p.:216-218~C (CHC13) NMR(CDC13)s: 3.90(3H, s), 5.20(2H, s), 5.93(2H, s), 6.95-7.10(2H,m), 7.24-7.35(3H, m), 7.71(lH,d,,3=9Hz), 8.43(lH,s).
Elemental analysis for CZpH14~5 Calcd.: C:71.85, H:4.22, Found . C:71.66, H:4.11.
(d) Methyl 8-Methanesulfonyloxymethyl-9-(4-methoxyphenyl)naphtho(1,2-d]-1,3-dioxole-7-carboxylate ~ C00Me 0 ~ ~ OMs OMe The entitled compound was obtained in a manner similar to that described in Reference Example 14.
NMR(CDC11)S: 2.89(3H, s), 3.89(3H, s), 3.97(3H, s), 5.43(2H,5), 5.81(2H, s), 6.95(2H, d,3=9Hz), 7.18-7.30(3H,m), 7.55(lH,d,3=8Hz), 8.49(lH,s).
(e) Methyl 8-Cyanomethyl-9-(4-' methoxyphenyl)naphtho[1,2-d]-1,3-dioxole-7-carboxylate SUBSTITUTE SHE~~' (RULE 26) WO 98l07705 14 6 PCTIJP97102858 ~COOMe p ~ ~ CN
f Me The entitled compound was obtained in a manner similar to that described in Reference Example 15.
m.p.:163-166~C (CHC13) r~r~R(cDCl,)s: 3.91{3H,s}, 3.93(2H, s), 4.01{3H,s), 5.81(2H, s), 6.99(2H,d,J=8Hz), 7.13-7.30{3H,m), 7.57(lH,d,J=9Hz), 8.60(lH,s}.
Reference Example 33 Methyl 8-Cyanomethyl-9-(4-trifluoromethylphenyl)naphtho[1,2-d]-1,3-dioxole-7-carboxylate (a) Dimethyl 9-(4-trifluoromethylphenyl)naphtho[1,2-d]-1,3-dioxole-7,8-dicarboxylate ~ COOMe 0 ~ ~ COOMe i I
w The entitled compound was obtained in a manner similar to that described in Reference Example 28(a).
m.p.:i63-166~C (CHC13) NMR{CDC1,)s: 3.56{3H,s), 3.94{3H,s), 5.83(2H,s}, 7.30{lH,d,J=9Hz), 7.46{2H,d,J=8Hz), 7.60-7.6S{3H,m), 8.58{lH,s).
IR(KBr): 1732, 1456, 132S, 127Z cm~.
(b) 8-Hydroxymethyl-9-{4-trifluoromethylphenyl}naphtho[1,2-d]-1,3-dioxole-7-methanol SUBSTiTIJTE SHEE'~ (RULE 25~

~oH
o ~ i off ~-o ~

The entitled compound was obtained in a manner similar to that described in Reference Example 28(b).
m.p.:196-198~C (AcOEt-isopropyl ether) NMR(CDC13)s: 2.80-3.00(2H,brs), 4.52(2H, s), 4.94(2H, s), 5.74(2H, s), 7.21(lH,d,J=8Hz), 7.40-7.50(3H,m), 7.67(2H,d,J=8Hz), 7.84(lH,s).
IR(KBr): 3310, 14S3, 1323 cm-'.
Elemental analysis for CZpHiSF3O4 Calcd.: C:63.83, H:4.02, Found . C:63.92, H:4.01.
(c) 10-(4-Trifluoromethylphenyl)furo[3',4':6,7)naphtho[1,2-d)-1,3-dioxol-7(9H)-one O

The entitled compound was obtained in a manner similar to that described in Reference Example 26(c).
m.p.:235-237~C (CHC1~) NMR(cDCl,)s: 5.17(2Fi,s), 5.92(2H, s), 7.35(lH,d,J=9Hz), 7.46-7.54(2H, m), 7.70-7.78(3H, m), 8.99(lH,s).
IR(KBr): 1755, 1464, 1327, 1073 cm-'.
Elemental analysis for C~oH"F04 Calcd.: C:64.52$, H:2.98, SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCT/J1'97102858 Found . C:64.35, H:2.95.
(d) Methyl 8-Methanesulfonyloxymethyl-9-(4-trifluoromethylphenyl)naphtho[1,2-d)-1,3-dioxole-7- .
carboxylate ~ ~ COOMe 0 ~ ~ OMs The entitled compound was obtained in a manner similar to that described in Reference Example 14.
NMR{CDC13)s: 2.89(3H, s), 4.00(3H, s), 4.85{2H,5), 5.77(2H,s}, 7.20-7.80(6H, m), 8.51(lH,s).
(e) Methyl 8-Cyanomethyl-9-(4-trifluoromethylphenyl)naphtho[1,2-d]-1,3-dioxole-7-carboxylate COOMe 0 ~C N

The entitled compound was obtained in a manner similar to that described in Reference Example 15.
m.p.:180-181~C (CHC13}
NMR(CDCla)6: 3.88(2H, s), 4.02(3H, s), 5.79(2H,5), 7.28(lH,d,J=9Hz), 7.46(2H, d,3=8Hz), 7.6I(lH,d,J=9Hz), 7.74{2H,d,J=8Hz), 8.65(lH,s).
Elemental analysis for CZZH~4F~O4~ 0. 2HZ0 Calcd.: C:63.37$, H:3.48~r Found . C:63.43, H:3.47.
Example 1 SUBSTITUTE SHEET (RULE 26) 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzadioxolo[4,5-f]isoindol-7-one ~~ .~ ,~ ,NH

~0 Methyl 9-(1,3-benzodioxol-5-yl)-8 methanesulfonyloxymethyl-naphtho[1,2-d)-1,3 benzodioxole-7-methylcarboxylate (150mg), which was obtained in Reference Example 14, was dissolved in a mixture of THF (6 ml) and methanol (3 ml) and concentrated NH40H (1m1) was added thereto. The mixture was stirred overnight at room temperature, and the reaction mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel 5g, eluent:dichloromethane-methanol - 95:5j and recrystallized from THF to give the entitled compound (55mg).
m.p.:252-254~C
NMR(DMSO-db)s: 4.20(2H,brs), 5.95(lH,brs), 5.96(lH,brs), 6.07(lH,brs), 6.11(lH,brs), 6.86(lH,dd,J=l.5Hz,8Hz), 6.95(lH,d,J=,8H2), 7.00(lH,d,J=1.5H2), 7.42(lH,d,J=9H2), 7.84(lH,d,J=9H2), 8.29(lH,s), 8.60(lH,brs) IR(KBr): 1695, l630, 159Q, 143S, 1270, 1230, 1035cm-~
Elemental Analysis for CZOH1~N05 ~ 0. 5H20 Calcd.: C:67.41, H:3.96, N:3.93$
SUBSTITUTE SHEET (RULE 26~

Found . C:67.72, H:3.82, N:3.89 Example 2 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-8-methyl-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one.
W W \
NMe 0 ~
~-- 0 0 ~/
Methyl 9-(1,3-benzodioxol-5-yl)-8-methanesulfonyloxymethyl-naphtho[1,2-d]-1,3-benzodioxol-7-carboxylate (150mg), which was obtained in Reference Example 14 was dissolved in THF (6m1) and methylamine (40% methanol solution:lml) was added thereto. The mixture was stirred for 3 days at room temperature and the reaction mixture was concentrated under reduced pressure. To the obtained residue was added water and extracted with ethyl acetate. The obtained extract was-washed with saturated sodium chloride solution and dried magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel 5g, eluent:dichloromethane-ether = 4:1) and recrystallized from ethyl acetate-hexane to give the entitled compound (67mg).
m.p.:234-236~C
NMR(CDC13}S: 3.18(3H,s), 4.21(lH,d,J=l7Hz}, 4.30(lH,d,J=l7Hz), 5.91(lH,d,J=l.4Hz), 5.93(lH,d,J=l.4Hz}, 6.05(lH,d,J=l.4Hz}, 6.
08(lH,d,J=l.4Hz), 6.79-6.92(3H, m), 7.26(lH,d,J=9Hz), 7.66(lH,d,J=9Hz), 8.30(lH,s) IR(KBr): 1685, 1485, 1435, 1270, 1230, 1065, 1025cm-~
Elemental Analysis for Cz,H~5N05 ~ 0 . 2H20 Calcd.: C:69.11, H:4.25, N:3.84 SUBSTITUTE SHEET (RULE 26) WO 98l07705 15 1 PCT/JP97102858 Found . C:69.09, H:4.31, N:3.90 Example 3 10-(1,3-Benzodioxol-S-yl)-B,9-dihydro-8-(2-morpholinoethyl)-7H-1,3-benzodioxolo(4,5-f)isoindol-7-one hydrochloride ~ w W r, /~/ N
0 ~' ~ v ~ HC 1 --O

Methyl 9-(1,3-benzodioxol-5-yl)-8-methanesulfonyloxymethyl-naphtho[1,2-d]-1,3-benzodioxol-7-carboxylate (150mg), which was obtained in Reference Example 14, was dissolved in THF (6m1) and 2-{morpholino)-ethylamine (691) was added thereto.
The mixture was stirred for over night at room temperature, then 2-(morpholino)-ethylamine (691) was added thereto and stirred for 8 hours. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added water and extracted with ethyl acetate. The obtained extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel Sg, eluent:dichloromethane-methanol - 95:5) to give a free amine of the entitled compound. The free amine of the entitled compound was dissolved in a mixture of - methanol (1m1) and dichloromethane {lml.) and 4N
hydrogen chloride-ethyl acetate was added thereto. The reaction mixture was concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the entitled compound (115mg).
m.p.:260~C (decomp.) SUHSTtTUTE SHEET (RULE 26) WO 98l07705 15 2 pCTlJP97l02858 NMR(DMSO-dG)&: 3.00-3.80(8H, m), 3.85-4.05(4H,m}, 4.43 (2H,s), 5.96(lH,s), 5.97(lH,s), 6.08(lH,s), 6.15(lH,s), 6.88(lH,dd,J=l.4Hz,8Hz), 7.00{lH,d,J=8H2), 7.OI(lH,d,J=1.4H2), 7.46{lH,d,J=9H2), 7.87{lH,d,J=9H2), 8.35(lH,s), 9.95(lH,brs) IR(KSr): 3430, 168S, 167S, 1630, 1485, 14S5, 1435, 1270, I235, 1060cm-' Elemental Analysis for Cz6H24N3O6 ~ HC1 ~ 0 . 5H20 Calcd.: C:61.720, H:5.180, N:5.540 Found . C:61.58, H:5.42, N:5.450 Example 4 10-{1,3-Benzodioxol-5-yl)-8,9-dihydro-8-ethyl-7H-1,3-benzodioxolo[4,5-fJisoindol-7-one W \
N-Et 0 ~ _'' ~Y
0'%
10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-fJisoindol-7-one (200mg), which was obtained in Example 1 was dissolved in DMF {5m1) and sodium hydride (34.5mg) was added thereto under ice cooling. The mixture was stirred for 5 minutes at room temperature and ethyl iodide (0.14m1) was added thereto and stirred overnight. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added water and the resultant precipitates were collected by suction and dissolved in ethyl acetate. The obtained ethyl acetate solution was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel 5g, eluent:ethyl SUBSTITUTE SHEET (RULE 26) acetate-hexane = 4:1) and recrystallized from ethyl acetate/diisopropyl ether to give the entitled compound (113mg).
m.p.:210-212~C
S NMR(CDC13)8: 1,25(3H,t,J=7H2), 3.86(2H,d,J=7H2), 4.21(lH,d,J=17H2), 4.30(lH,d,J=17H2), ' 5.91(lH,d,J=1.4H2), 5.93(lH,d,J=1.4H2}, 6.05(lH,d,J=1.4H2), 6.08(lH,d,J=1.4H2), 6.79-6.86(2H,m), 6.91(lH,dd,J=lHz,8Hz), 7.26(lH,d,J=9H2), 7.66(lH,d,J=9H2), 8.30{lH,s) Elemental Analysis for CzzH1~N05 ~ 0. 2H20 Calcd.: C:70.39%, H:4.56%, N:3.73%
Found . C:70.07%, H:4.65%, M:3.66%
Example 5 10-{1,3-Benzodioxoi-5-yl)-8,9-dihydro-$-(isopropyl)-7H-1,3-benzoxolo[4,5-f]isoindol-7-one w N~M a 2 0 0 ~ ~ --~ M a ~-0 0 ~/
10-(1,3-Benzodioxol-5-yl)-$,9-dihydro-7H-1,3-benzodioxolo[4,5-f)isoindol-7-one (200mg}, which was obtained in Example 1 was dissolved in DMF {5m1) and sodium hydride {34.5mg) was added thereto under ice cooling. The mixture was stirred for 5 minutes at room temperature and isopropyl iodide {0.17m1} was added thereto and stirred overnight, then stirred for 8 hours at 60~C. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added water and the resultant precipitates were collected by suction and dissolved in dichloromethane. The obtained dichloramethane solution was dried with magnesium SUBST1TUTF SHEET (RULE 26~

sulfate and concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel Sg, eluent:ethyl acetate-hexane = 4:1) and recrystallized from ethyl acetate-s diisogropyl ether to give the entitled compound (27mg).
m.p.:2lB-220~C
NMR(CDC13)b: 1.26(6H,d,J=7Hz), 4.14(lH,d,J=l7Hz), 4.22(lH,d,J=l7Hz), 4,71(lH,m), 5.9I(lH,d,J=l.4Hz), 5.92(lH,d,J=l.4Hz), 6.07{lH,d,J=l.4Hz), 6.09{lH,d,J=l.4Hz), 6.80-6.87(2H, m), 6.92(lH,dd,J=lHz,7Hz,), 7.26{lH,d,J=9Hz), 7.66(lH,d,J=9Hz), 8.30{lH,s) Elemental Analysis for CZ3H1yN~5~0.2H20 Calcd.: C:70.29, H:4.98, N:3.56 Found . C:70.28, H:5.16', N:3.43 Example 6 Ethyl 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one-8-acetate [ ~ ~ N-CHZ C02 E t t 0 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one (400mg), which was obtained in Example 1 was dissolved in DMF (IOml) and added sodium hydride (50.6mg) under ice cooling. The mixture was stirred at room temperature and ethyl bromoacetate (0.14m1) was added thereto and stirred overnight. To the mixture was added ethyl bromoacetate (0.07m1) and stirred for 2 hours at 60~C. The reaction mixture was concentrated under reduced pressure. To the obtained residue was added water and the resultant SUBSTITUTE SHEET (RULE 2fi) precipitates were collected by suction and dissolved in dichloromethane. The obtained dichloromethane solution was dried with magnesium sulfate and concentrated under - reduced pressure. The obtained residue was purified with column chromatography (silica gel 5g, eluent:dichloromethane-ether = 9:1) to give the entitled compound (318mg).
m.p.:80-85~C
NMR(CDC13)b: 1,28(3H,t,J=7Hz), 4.20(2H,d,J=7Hz), 4.35(lH,d,J=l7Hz), 4.38(2H, s), 4.43(lH,d,J=l7Hz), 5.92(lH,d,J=l.4Hz), 5.93(lH,d,J=l.4Hz), 6.04(lH,d,J=l.4Hz), 6.07(lH,d,J=l.4Hz), 6.75-6.86(2H,m), 6.89(lH,dd,J=lHz,BHz), 7.27(lH,d,J=9Hz}, 7.67(lH,d,J=9Hz), 8.34(lH,s) Elemental Analysis for C24H~9N0~ ~ 0 . 5H20 Calcd.: C:65.16, H:4.56, N:3.17 Found . C:65.34, H:4.46, N:3.19 Example 7 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one-8-acetic acid \IV-CH2 C02 H
i ~0 Ethyl 10-(1,3-benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one-8-acetate (260mg), which was obtained in Example 6, was dissolved in a mixture of THF (3m1) and methanol (3m1) and 1N sodium hydroxide solution (1.2m1) was added thereto. The mixture was stirred for 3 hours at room temperature and the reaction mixture was concentrated under reduced pressure. To the obtained residue was added 1N
SUBSTITUTE SHEET (RULE Z6) WO 98/077d5 15 6 pCTIJP97102858 hydrochloric acid and the resultant precipitates were collected by suction and dissolved in dichloromethane.
The obtained dichloromethane solution was dried with magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the entitled compound (201mg).
m.p.:160-161~C
NMR(DMSO-db)s: 4.27(2H,brs), 4.35(lH,s), 5.96(lH,d,J=l.4Hz), 5.98(lH,d,J=l.4Hz), 6.06(lH,d,J=l.4Hz), 6.13(lH,d,J=1.4H2), 6.86(lH,dd,J=3.6Hz,8Hz), 6.97(lH,d,J=8Hz), 7.00(lH,d,J=l.6Hz), 7.44(lH,d,J=9Hz), 7.87{lH,d,J=9Hz), 8.34(lH,s) Elemental Analysis for CZZH15NO~ ~ HZO
Calcd.: C:62.430, H:4.05, N:3.31 Found . C:62.14, H:4.23, N:3.20 Example 8 8-Acetyl-5-bromo-10-phenyl-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one NAc N-(3-Phenyl-2-propin-1-yl}-3-(6-bromobenzo[d]-1,3-benzodioxol-5-yl)-2-propenoylamide (0.50g), which was obtained in Reference Example 16, was dissolved in acetic anhydride (200m1) and heated under reflux for 4 hours. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in p-cymene (25m1). To the mixture was added 10~ palladium-carbon {0.25g) and heated under reflux for 10 hours, The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCTIJP97102858 residue was washed with water and purified with column . chromatography (silica gel 40g, eluent:dichloromethane) to give the entitled compound (0.16g).
. NMR(CDC1~)b:2.71(3H,s), 4.64(2H, s), 5.89(2H, s), 7.20-- 5 7.35(2H, m), 7.40-7.64(3H, m), 7.64(lH,s), 8.89(lH,s) Example 9 B-Acetyl-10-phenyl-8,9-dihydro-7H-1,3-benzodioxolo{4,5-f]isoindol-7-one ~~ ~~N A c i ~-.._/
0~ 0 8-Acetyl-5-bromo-10-phenyl-8,9-dihydro-7H-1,3-benzodioxolo[4,5-fJisoindol-7-one {156mg), which was obtained in Example 8 was dissolved in DMF (60m1) and sodium acetate (I82mg) and 10~ palladium-carbon (80mg) was added thereto, then the mixture was stirred for 2 hours under hydrogen atmosphere. The catalysts were filtered off and the filtrate was concentrated under reduced pressure and the obtained residue was triturated with DMF. The obtained powder was washed with water and methanol to give the entitled compound (83mg).
m.p.:335~C (decomp.) NMR(DMSO-db)b: 2.70(3H, s), 4.65(2H, s), 5.89(2H, s), 7.30(lH,d,J=,8Hz), 7.30-7.40{2H,m), 7.40-7.50(3H, m), 7.72(lH,d,J=8Hz), 8.44(lH,brs) IR(KBr): 1725, 1685, 133S, 131S, 1295, 1280, 1265cm-~
Elemental Analysis for CZ~H~SN0,,0.2H20 Calcd.: G:75.28$, H:4.45, N:4.01$
Found . C:75.12$, H:4.45, N:4.17 - 35 Example 10 10-Phenyl-8,9-dihydro-7H-1,3-benzodioxolo(4,5-SUBSTITUTE SHEET (RULE 25~

WO 98l07705 15 8 PCT/JP97/02858 f]isoindol-7-one H

S
To an ethanol (60m1} solution of 8-acetyl-10 phenyl-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f)isoindoi 7-one (60mg}, which was obtained in Example 9, was added concentrated hydrochloric acid (1m1} and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gellg, eluent:dichloromethane-methanol = 95:S} and recrystallized from ethanol to give the entitled compound {32mg).
m.p.:290-292~C
NMR(DMSO-db)s: 4.17(2H,s}, 5.91(2H, s), 7.43(SH,s), 7.45(lH,d,J=,8Hz), 7.87(lH,d,J=8Hz), 8.33(lH,brs), 8.62(lH,brs) IR(KHr): 1695, 1630, 1455, 1290, 1265cm-1 Elemental Analysis for ClyH1~N03 Calcd.: C:75.24, H:4.32, N:4.62 Found . C:75.21, H:4.3I$, N:4.63$
Example 11 11-(1,3-Benzodioxol-5-yl)-7,B,9,10-tetrahydro-1,3-benzodioxolo(4,5-g]isoquinolin-7-one SUBST1TLJTE SHEET (RULE 26) WO 98/07705 15 9 PCT/JP97l02858 w ~N H
i 0~ ( ~0 - s I

~'l To the DMF (2m1) solution of Methyl 9-(1,3-benzodioxol-5-yl)-8-cyanomethyl-naphtho[1,2-d)-1,3-dioxole-7-carboxylate (100mg), which was obtained in Reference Example 15 was added Raney nickel {about 100mg) and stirred for 6 days under hydrogen atmosphere. The solvent was filtered off and the reaction mixture was concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel lg, eluent:dichloromethane-methanol = 9S:5) and recrystallized from chloroform to give the entitled compound (40mg).
m.p.:256-25B~C
NMR(CDC13)s: 2.82{2H,t,J=6Hz), 3.40-3.50{2H,m), 5.84(2H,brs), 6.03(iH,d,J=l.4Hz), 6.12(lH,m) 6.68(lH,dd,J=l.9Hz,8Hz), 6.75(lH,d,J=l.4Hz), 6.87(lH,d,J=8Hz), 7.19(lH,d,J=,9Hz), 7.60(lH,d,J=9Hz), 8.63{lH,brs) IR(KBr): 1660, 1625, 1480, 14S5, 1285, 1230, 1075cm~
Elemental Analysis for CZIHISN0s~0.2H20 Calcd.: C:69.11, H:4.25, N:3.84 Found . C:69.06, H:4.19, N:3.77 Example 12 - 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-cyclopenta[6.7)naphtho(1,2-d)-1,3-dioxol-7-one SUBSTITUTE SHEET (RULE 26) WO 98I07705 16 0 PCT~~97~02858 Ethyl 3-~9-(I,3-Benzodioxol-5-yl)-?-methoxycarbonyl-naphtho(1,2-d)-1,3-benzodioxol-8-yl}-2-cyano propionate (407mg), which was obtained in Reference Example 17, was dissolved in a mixture of THF
(5m1), and methanol (5m1) and 1N sodium hydroxide solution (3.5m1) was added thereto and stirred for 2 I5 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with ethyl acetate. 1N hydrochloric acid was added to the water layer to adjust the pH to about 2, and the mixture was extracted with ethyl acetate. The extract was dried with magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in acetic acid (4m1) and heated under reflux overnight.
The reaction mixture was concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel 50g, eluent:ethyl acetate-hexane = 1:4) and recrystallized from ethyl acetate to give the entitled compound (25mg}.
m.p.:235-237~C
NMR(CDC13)6: 2.65-2.75(2H, m), 2.90-3.15(2H, m), 5.91(lH,d,J=I.4Hz), 5.92(lH,d,J=l.4Hz), 6.05(lH,d.J=l.4Hz), 6.07(lH,d,J=l.4Hz), 6.75-6.85(2H,m), 6.89(lH,d,J=8Hz), 7.24(lH,d,J=9Hz), 7.67(lH,d,J=9Hz), 8.29(lH,s) Elemental Analysis for CZ,H~4Og Calcd.: C:72.83$, H:4.07 Found . C:72.51, H:4.00$
SUBST1TLJT~ S1-f EET tRULE 26) Example 13 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3-dioxolo[4,5-f]pyrrolo(3,4-b]quinolin-7-one ~ N
0 I ~ ~ NH
1-n I
w I
The entitled compound was obtained from methyl 9-{1,3-benzodioxol-5-yl)-8-methanesulfonyloxymethyl-1,3-dioxolo(4,5-f]quinoline-7-carboxylate, which was obtained in Reference Example' 18, in a manner similar to that described in Example 1.
m.p.:310~C (decomp.) NMR(CDC13)S: 4.36(lH,d J=l7Hz), 4.45(lH,d,J=l7Hz), 5.99(lH,brs), 6.01(lH,brs), 6.74(lH,m), 6.80-6.88(2H, m), 7.50(lH,d,J=9Hz), B.09(lH,d,J=9Hz}
Elemental Analysis for C19H12NZO5 ~ 0 . 5Hz0 Calcd.: C:64.19$, H:3.63a, N:7.88 Found . C:64.04$, H:3.77, N:7.87$
Example 14 10-(4-Methoxyphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7,9(8H)-dione H

OM a To a benzene (200m1) solution of helio alcohol (4.0g) was added dropwise n-BuLi (1.6M hexane solution:36m1) at room temperature. The mixture was SUHSTiTLJTE SHEET (RULE 26) stirred for 2 hours at room temperature and benzene (50m1) solution of p-methoxybenzonitrile (3.9g:l.lequivalent) was dropwise added thereto. The mixture was stirred overnight at room temperature and water was added thereto, then extracted with ether.
The organic layer was washed with water and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue (orange, oily substance) was dissolved in toluene (250m1) and maleimide {6.0g) and p-toluenesulfonic acid monohydrate (catalysis equivalent) were added thereto. The mixture was heated under reflux for 20 hours and the separated solid was filtered off. The filtrate was concentrated under reduced pressure. To the obtained residue was added concentrated hydrochloric acid and heated under reflux for 1 hour. The mixture was coated to the room temperature and the resultant yellow-brown solid was collected by suction. The yellow-brown solid was washed with water and recrystallized from THF to give the entitled compound {7.2g).
m.p.:311-313~C
NMR(CDC13)8: 3.89(3H,s), 5.90(2H,s}, 6.95(2H,d,J=8.8Hz), 7.30(2H, d, J=8.8Hz), 7.34(1H, d, J=8.4Hz), 7.67{1H, d, J=8.4Hz), 8.23{1H, s), 10.42{1H, brs) Elemental Analysis for CZOH1~N05 Calcd.: C:69.16, H:3.77, N:4.03 Found . C:69.07, H:4.15, N:4.00$
Example 15 10-(3,4,5-Trimethoxyphenyl)-7H-1,3-benzodioxalo[4,5-f]isoindol-7,9(8H)-dione SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 ~ ~ ~ ~ ~N H
i i ~ \0 ~.._ 0 _.
I
Me0 ~ OMe ~ OMe The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:318-322~C
NMR(CDC13)S: 3.84(5H, s), 3.97(3H, s), 5.92(2H, s), 6.59(2H, s), 7.38(1H, d, J=B.4Hz), 7.70(1H, d, J=8.4Hz}, 7.72(1H, brs}, 8.30(1H, s) Elemental Analysis for CzzH1~N07 Calcd.: C:64.86%, H:4.21, N:3.44%
Found . C:64.25%, H:4.21%, N:3.24%
Example 16 10-(1,3-Benzodioxol-5-yl)-7H-1,3-benzodioxolo[4,5-fJisoindol-7,9(8H)-dione w \N H
i ~ ~o ~--o i ~
0 ~./
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:320~C (decomp.)(THF) NMR(DMSO-db)s: 5.97(lH,brs), 5.99{lH,brs), 6.10(lH,brs), 6.06(lH,d,J=l.4Hz), 6.81{lH,dd,J=l.5Hz,8Hz}, 6.92(lH,d,J=8Hz), 6.95(lH,d,J=l.SHz), 7.57(lH,d,J=9Hz), 7.93(lH,d,J=9Hz), B.41(lH,s).
IR(KBr): 1745, 170S, 1440, 1285, 1225 cm-~.
Elemental Analysis for CzoH~,NO~
SUBSTITUTE SHEET (RULE 26) Calcd.: C:66.49, H:3.07, N:3.88 Found . C:66.71, H:3.20, N:3.72.
Example 17 4-{1,3-Benzodioxol-5-yl)-5-methoxy-1H-benz(f)isoindol-1,3(2H)-dione ~ \N H
i M a 0 '0 i 0 ~/
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:291-293~C (THF) NMR(DMSO-db)S: 3.48(3H, s), 6.06(lH,brs), 6.10(lH,brs), 6.64{lH,dd,J=l.4Hz,8Hz), 6.82(lH,d,J=l.4Hz), 6.89(lH,d,J=8Hz), 7.14(lH,d,J=8Hz), 7.68{lH,t,J=8Hz), 7.85(lH,d,J=8Hz), 8.40{lH,s}.
IR(KBr): 1756, 1714, Z538, 15Q5, 1472 cm '.
Elemental Analysis for CzoH1jN05 ~ 0. 4HZ0 Calcd.: C:67.76, H:3.92, N:3.95 Found . C:67.83$, H:4.07, N:3.94.
Example 18 4-(1,3-Benzodioxol-5-yl)-5,6-dimethoxy-1H-benz[f)isoindol-1,3(2H)-dione ~ ~ ~ N H
Me0 M a 0 '0 O~.J
The entitled compound was obtained in a manner SUBSTITUTE SHEET (RULE 2fi) WO 98l07705 PCT/JP97/02858 similar to that described in Example 14.
- m.p.:274-2?6~C (THF) NMR(DMSO-d~)s: 3.19(3H, s), 3.94{3H,s}, 6.05(lH,brs), . 6.09(lH,brs), 6.61{lH,brs), 6.71(lH,dd,J=l.6Hz,8Hz}, 6.85(lH,d,J=l.6Hz), 6.89(lH,d,J=8Hz), 7.72(lH,d,J=9Hz), - 8.08(lH,d,J=9Hz), 8.39{lH,s).
IR(KBr): 1760, 1710, 1515, 127S, 1225, 1060 cm-'.
Elemental Analysis for CZ1H15N06 Calcd.: C:66.840, H:4.01%, N:3.71%
Found . C:67.14%, H:3.72%, N:3.82%
Example 19 5,6-Dimethoxy-4-(4-methoxyphenyl)-1H-benz(fjisoindol-1,3(2H)-dione w w \N H
i i Ma0 Me0 i Me The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:288-290~C {THF) NMR(DM50-db)&: 3.08(3H, s), 3.83(3H, s), 3.93(3H, s), 6.92{lH,d,J=9Hz), 7.20(lH,d,J=9Hz), 7.73(lH,d,J=9Hz), 8.10(lH,d,J=9Hz), 8.40{lH,s), 11.24(lH,brs).
IR(KBr): 1762, 1714, 1520, 1280, l245, 1066 cm-'.
Elemental Analysis for CZ1H~~N05 Calcd.: C:69.41%, H:4.72$, N:3.85%
Found . C:69.32%, H:4.92%, N:3.82%.
Example 20 10-(4-Trifluoromethylphenyl)-7H-1,3-benzodioxolo[4,5-fjisoindol-7,9(8H)-dione SUBSTITUTE SHEET (RULE 2fi) W~ 98l07705 PCTlJP97102858 l66 w w \N H
i 0 ~ ~\0 ~--0 The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:304-306~C (AcOEt) NMR(CDC13)s: 5.89(2H, s), 7.39(lH,d,J=8Hz), 7.50(2H,d,J=8Hz), 7.70(2H,d,J=BHz), 7.72(lH,d,J=8Hz), 7.82(lH,brs), 8.34(lH,s).
IR(KBr): 1762, 1722, 1328, 1291, 1160, 1126, 1068 cm-i Elemental Analysis for CzoH~oNO~F3 ~ 0 . 2H20 Calcd.: C:61.77%, H:2.70, N:3.60 Found . C:61.73%, H:2.92, N:3.49.
Example 21 10-{4-Benzyloxyphenyl)-7H-1,3-benzodioxolo[4,5-f)isoindol-7,9(8H)-dione H
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:265-267~C (THF) NMR(CDC1~)S :5.14(2H, s), 5.90 (2H,s), 7.06(2H,d,J=8Hz), 7.30-7.50(8H, m), 7.68(lH,d,J=8Hz), 7.8B(lH,brs), 8.27(lH,s).
SUBSTITUTE SHEET (RULE 26) IR(KBr): 3288, 3261, 3093, 2927, 1733, 1714, 1S06 cm Elemental Analysis for CzsH2~N0s Calcd.: C:73.75, H:4.05%, N:3.31%
Found . C:73.23%, H:4.12%, N:3.08%.
Example 22 10-(4-Pyridyl)-7H-1,3-benzodioxolo(4,5-fJisoindole-7,9(8H)-dione ~N H
I i i 0 ~0 N
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:299-302~C (THF) NMR(CDC1~-one drop DMSO-dd)b: 5.89(2H, s), 7.34(2H,d,J=6Hz), 7.42(IH,d,J=6Hz), 7.72(lH,d,J=6Hz), 8.31(lH,s), 8.67(2H,d,J=6Hz), 10.77(lH,brs).
IR(KBr): 2900, 17S6, 17I4 cmi.
Elemental Analysis for CleH~oNzO~ ~ 0 . 3H20 Calcd.: C:66.67%, H:3.32%, N:8.64%
Found . C:66.79%, H:3.05%, N:8.54%.
Example 23 10-(3-Pyridyl)-7H-1,3-benzodioxolo[4,5-f)isoindol-7,9(8H)-dione The entitled compound was obtained in a manner ZH
SUBSTITUTE SHEET (RULE 26) similar to that described in Example 14.
m.p.:323-325~C (THF) NMR(DMSO-d~)b: 5.96(2H, s), 7.44(lH,m), 7.61(lH,d,J=8Hz), 7.85(lH,m), 7.98(lH,d,J=8Hz), 8.50(lH,s), 8.61(2H, m), 11.40(lH,brs).
IR(KBr): 2949, 1728 cml.
Elemental Analysis for ClBHioNzOa ~ 0 . 3Hz0 Calcd.: C:66.67%, H:3.32%, N:8.64%
Found . C:66.40%, H:3.08%, N:8.42%.
Example 24 10-(4-Benzyloxy-3-methoxyphenyl)-7H-1,3-benzoxolo(4,5-f]isoindol-7,9(8H)-dione W w \
0 ~ ~ ~ NH
'0 i I
0 Bn OMe The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:282-284~C (THF) NMR(DMSO-db)s: 3.72(3H, s), 5.13(2H, s), 5.97(2H,d,J=3Hz), 6.90(lH,dd,J=2Hz,8Hz), 7.04(2H, m), 7.40-7.60(6H, m), 7.93(lH,d,J=9Hz), 8.41{lH,s), 11.31(lH,brs).
IR(KBr): 3168, 3068, 2783, 1760, 1714 cm-~.
Elemental Analysis for Cz7HiqN06 Calcd.: C:71.52, H:4.22, N:3.09%
Found . C:71.75%, H:4.45%, N:3.00%.
Example 25 11-(1,3-Benzodioxol-5-yl)-8H-isoindolo[5,6-f]benz[b]-1,4-dioxan-8,10{9H)-dione SUBSTITUTE SHEET (RULE 26~

w \N H
i /
~0 ~I
O
0,,/
The entitled compound was obtained in a manner similar to that described in Example 14.
30 m.p.:346-349~C {THF) NMR{DMSO-db)s: 3.90(2H, m), 4.21(2H, m), 6.06(2H,d,J=7Hz), 6.67(lH,d,J=6Hz), 6.86{2H,m), 7.36(lH,d,J=8Hz), 7.79(lH,d,J=8Hz), 8.33(lH,s), 11.22(lH,brs).
IR{KBr): 3176, 3072, 2765, 1751, l704, 1606, 1585 cm-i Elemental Analysis for CzlHs3N06 Calcd.: C:67.20, H:3.49, N:3.73 Found: C:66.67, H:3.82, N:3.44.
Example 26 10-{4-Bromophenyi)-7H-1,3-benzodioxolo[4,5-f)isoindol-7,9{6H)-dione w w \N H
I i O ~0 ~.-0 I
Br - The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:324-327~C (THF) NMR{CDC1~-one drop DMSO-db)S: 5.92 (2H,s), 7.28(2H,d,J=9Hz), 7.37(lH,d,J9=Hz), 7.55(2H,d,J=9Hz), 7.71(lH,d,J=9Hz), 8.28{lH,s), 10.72(lH,brs).
SUBSTITUTE SHEET (RULE 2fi) PCTlJP97102858 IR(KSr): 3170, 3064, 28B5, 2759, 17S1, 1718 cm~~.
Elemental Analysis for C,9H~oBrNOr, Calcd.: C:57.60, H:2.54, N:3.54 Found . C:57.63, H:2.84~s, N:3.39.
Example 27 10-(4-Fluorophenyl)-7H-1,3-benzodioxolo(4,5-f)isoindol-7,9(8H)-dione H
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:269-271~C (THF) NMR(CDC13)s: 5.90(2H, s), 7.10-7.30(SH,m), 7.37(lH,d,J=8Hz), 7.70(lH,d,J=8Hz), 8.30(lH,s).
IR(KBr): 3182, 3074, 1760, 1716, 1540, 1509, 128? cm-Example 28 10-(1,3-Benzodioxol-5-yl)-6-methyl-7H-1,3-benzodioxolo(4,5-f)isoindol-7,9(8H)-dione ~ M a 0 ~N H
I i i '--0 i The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:310-313~C (ethanol) NMR(DMSO-db)&: 2.99(3H, s), 5.99-6.20(4H, m), 6.65-7.00(3H,m), 7.53(lH,d,J=9Hz), 7.93(lH,d,J=9Hz).
SUBSTiTLJT~ SHEET (RULE 26) IR(KBr):3172, 3062, 17S3, 1710, 1625, 1550, 1492, 1360, ' 1284 cm ' .
Elemental Analysis for Cz~H1~N06 ~ 0 . 2HZ0 Calcd.: C:66.56%, H:3.45, N:3.69%
Found . C:66.48%, H:3.72%, N:3.69%.
Example 29 IO-(4-Fluorophenyl)-6-methyl-7H-1,3-benzodioxolo[4,5-f)isoindol-7,9(8H)-dione Me p to ~N H
i ~0 ~-0 J

The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:302-3Q4~C (THE) 20 NMR(DMSO-d6)8: 3.00(3H, s), 5.91(2H, s), 7.10-7.40(SH,m), 7.55(lH,d,J=9Hz}, 7.95(lH,d,J=9Hz).
IR(KBr}: 3170, 3060, 1749, 1714, l625, 1513, 1362, 1274 cm-I.
Elemental Analysis for C2oH12NO4F
25 Calcd.: C:68.77%, H:3.46%, N:4.01%
Found . C:68.55%, H:3.59%, N:4.09.
Example 30 6-Methyl-10-(4-trifluoromethylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7,9(8H)-dione SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCTlJP97102858 Me 0 ~N H
i 0 v.0 ~0 ~J

The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:315-317~C (THF-ether) NMR(CDClj)s: 3.12(3H, s), 5.86(2H, s), 7.30-7.55(4H, m), 7.60-7.75(3H, m), 7.92(lH,d,J=9Hz).
IR(KBr): 3190, 30S0, 1753, 1714, 1620, 1550, 14S7, 1363, 1330, 1277 cm-'.
Elemental Analysis for CziHlzN0~F3 ~ 0 . 3Hz0 Calcd.: C:62.32, H:3.19$, N:3.46 Found . C:62.33, H:3.07, N:3.87.
Example 31 10-(4-Methoxyphenyl)-6-methyl-7H-1,3-benzodioxolo(4,5-f]isoindol-7,9(8H)-diane Me 0 w w \IV H
/
0 Y ~0 Me The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:3li-313~C (THF-ether) NMR(CDC1,)b: 3.09(3H, s), 3.90(3H, s), 5.88(2H, s), 6.96(2H,d,J=9Hz), 7.20-7.35(2H, m), 7.36(lH,d,J=9Hz), 7.66(lH,brs), 7.89(lH,d,J=9Hz).
IR(KBr): 3167, 3064, 1753, 1710, 1623, 1548, 1511, 1450, 1360, 1277 cm-~ .
SUBSTITUTE SHE~T (RULE 26) Elemental Analysis for Cz,H,5NO5Ø1HZ0 Calcd.: C:69.46, H:4.22, N:3.86 Found: C:69.40, H:4,44$, N:4.02$.
Example 32 10-(1,3-Benzodioxol-5-yl)-6-ethyl-7H-1,3 benzodioxolo[4,5-f]isoindol-7,9(8H)-dione E t p w W
~N H

i i The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:253-254~C (THF-ether) NMR(CDC13)6: 1.39(3H,t J=7Hz), 3.65(2H,q,J=7Hz), 5.91(lH,d,J=l.4Hz), 5.93(lH,d,J=l.4Hz), 6.04(lH,d,J=l.4Hz), 6.07(lH,d,J=l.4Hz), 6.75-6.90(3H,m), 7.37(lH,d,J=9Hz), 7.75(lH,brs}, 7.93(lH,d,J=9Hz).
IR(KHr): 3172, 3064, 2974, 17S4, 1708, 1625, 15S0, 1502, 1401, 1280 cm-'.
Example 33 10-(1,3-Benzodioxol-S-yl}-6-[2-(N,N-dimethylamino)ethyl]-7H-1,3-benzodioxolo[4,5-f]isoindol-7,9(8H)-dione SUBSTITUTE SHEET (RULE 26) WO 98I07705 1 ? 4 PCT/JP97102858 M a 2 h'~ 0 \ ~N H
i 0 n i The entitled compound was obtained in a manner similar to that described in Example 14.
NMR(CDCI3)6: 2.52(2H, m), 2.6S-2.85(2H,m),3.80-3.95(2H,m), S.85-6.10(4H, m), 6.50-6.95(3H, m), 7.05(lH,brs}, 7.38(lH,d,,7=9Hz), 8.00(lH,d,J=9Ha) Example 34 10-(4-Methylphenyl)-7H-1,3-benzodioxolo(4,5-f]isoindol-7,9(8H)-dione w w ~N H
i i i I
Me The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:297-299~C (THF-ethanol}
NMR(CDC1~)&: 2.46(3H, s), 5.90(2H, s), 7.26(4H,brs), ?.35(lH,d,J=9Hz), 7.68(IH,d,J=9Hz), 7.86(IH,brs), 8.28(lH,s).
IR(K8r): 3230, 3064, 1760, 1713, 1544, 1455, 12B7 cm-i Elemental Analysis far C2oH1~N04~ 0.2Hz0 Calcd.: C:71.72, H:4.03, N:4.18 Found . C:71.67, H:3.94$, N:4.17.
Example 35 SUBSTITUTE SHEET (RULE 26) 10-(3-Methylphenyl)-7H-1,3-benzodioxolo[4,5-f)isoindol-7,9(BH)-dione I w w ~N H
S
0 ~0 W.._- 0 I
w Me The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:261-264~C (THF) NMR(CDC13)b: 2.42(3H, s), 5.90(2H, s), 7.19(2H, m), 7.31(2H, m), 7.36(lH,d,J=8Hz}, 7.69(lH,d,J=8Hz), 7.87(lH,brs), 8.29(lH,s).
IR(KBr): 3190, 3064, 1756, 1716, 1629, Z538 cm-'.
Elemental Analysis for CTOH1~N0~~ 0. 2H20 Calcd.: C:71.72, H:4.03, N:4.18 Found . C:71.47, H:4.19$, N:4.03.
Example 36 10-{2-Methylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7,9(8H)-dione NH

~0 ~0 ~ ~M a The entitled compound was obtained in a manner similar to that described in Example 14.
- 30 m.p.:275-27B~C (THF) NMR(CDC13)b: 2.06(3H, s), 5.88(2H, s), 7.20-7.40(SH,m), 7.70(lH,d,J=8Hz), 7.81(lH,brs), 8.31(IH,s).
IR(KBr): 3I76, 3062, 2767, 1760, 1718, 1627 cm-'.
Elemental Analysis for CiQH~sN04 Calcd.: C:72.50$, H:3.95$, N:4.23$
Found . C:72.21$, H:4.14, N:4.08.
SUBSTITUTE SHEET (RULE 26) Example 37 4-(1,3-Benzodioxol-5-yl)-6-methoxy-1H-benz(f)isoindol-1,3(2H1-dione H
Me0 To a THF (50m1) solution of 2-bromo-5-methoxybenzaldehyde (10g) was added dropwise a THF
(30m1) solution of the Grignard reagent prepared from 5-Bromo-1,3-benzodioxole (11.2g) and Mg (1.6g). The mixture was stirred for 1 hour at room temperature and ammonium chloride solution was added therein, then extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then concentrated. The residue was purified with silica gel column (Hex/EA = 3/1) to give (2-bromo-5-methoxyphenyl)(1,3-benzodioxol-5-yl)methanol as an oily substance (15g). (2-bromo-5-methoxyphenyl)(1,3-benzodioxol-5-yl)methanol was dissolved in ether (300m1) and n-BuLi(1.6M/Hex . 64m1) was added dropwise at -78~C. The reaction mixture was stirred for 5 minutes at -78~C, then stirred for 1 hour at 0~C. To the mixture was added DMF (30m1) and stirred for 1 hour at room temperature. To the reaction mixture was added water and extracted with ether. The extract was washed with water and dried with magnesium sulfate then concentrated under reduced pressure. The obtained residue was dissolved in toluene (250m1) and maleimide (6g) and p-toluenesulfonic acid monohydrate (1.0g) were added thereto. The reaction mixture was refluxed for 20 hours and the separated solid was filtered off. The filtrate was concentrated under reduced pressure. To SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97/02858 the obtained residue was added concentrated hydrochloric acid and heated under reflux for 1 hour.
The mixture was cooled to room temperature and the resultant yellow-brown solid was collected by suction and washed with water, then recrystalized with THF to give the entitled compound (5.4g).
m.p.:307-310~C (THF) NMR(CDC13-one drop DMSO-db)s: 3.B4(3H,s), 6.30(2H, s), 6.92(2H, m), 7.04(lH,m), 7.23{lH,d,J=9Hz), 7.36(lH,d,3=9Hz), 7.46(lH,d,J=BHz), 8.32(lH,s), 10.57(lH,brs).
ZR(KBr): 3070, 2900, 2744, 1756, 1713 cm-~.
Elemental Analysis for CZOHi3NOs Calcd.: C:69.16, H:3.77, N:4.03 Found . C:68.88$, H:3.82, N:3.95.
Example 38 6-Methoxy-4-(4-methoxyphenyi)-1H-benz[f)isoindol-1,3(2H)-dione ~ \ \ \N H
Me0 i Me The entitled compound was obtained in a manner similar to that described in Example 37.
m.p.:290-292~C (THF) NMR(CDC1~-one drop DMSO-db)s: 3.76(3H, s), 3.92(3H, s), - 30 7.07(2H,d,J=9Hz), 7.14(lH,d,J=2Hz), 7.35(3H, m), 7.98(lH,d,J=9Hz), 8.25(lH,s), 10.23(lH,brs).
IR(KBr): 3I70, 3056, 2949, 2785, 1760, 1724, 1616, 1515 cm-1 .
Elemental Analysis for CZ~H~SNOL
Y 35 Calcd.: C:72.06, H:4.54, N:4.20 Found . C:71.79$, H:4.48, N:4.19$.
SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 Example 39 6-Methoxy-4-(4-methylphenyl}-1H-Benz[f]isoindol-1,3(2H)-dione H
Me0 Me The entitled compound was obtained in a manner similar to that described in Example 37.
m.p.:298-30I~C (THF) NMR(cDCl,)s: 2.49(3H, s), 3.76(3H, s), 7.13(lH,d,J=2Hz), 7.33(SH,m), 7.83(lH,brs), 7.99(lH,d,J=9Hz), 8.30(lH,s).
IR(KBr): 3167, 3064, 2773, 1760, 1714, 1616 cm-~.
Elemental Analysis for C2oH1sN~3 Calcd.: C:75.70, H:4.76, N:4.42 Found . C:75.36, H:4.88, N:4.32$.
Example 40 6-Methoxy-4-(4-trifluoromethylphenyl}-1H-benz[f]isoindol-1,3(2H)-dione Me ~F3 H
The entitled compound was obtained in a manner similar to that described in Example 37.
NMR(CDC13)b :3.76(3H, s), 6.96(lH,d,J=2Hz), 7.37(lH,d,J=2Hz,9Hz), 7.55(2H,d,J=8Hz), 7.83(2H,d,J=BHz), 7.85(lH,brs}, 8.03(lH,d,J=9Hz), 8.36(lH,s) SUBSTITUTE SHEET (RULE 2fi) Example 41 6-Methoxy-4-(4-trifluorvmethoxyphenyl)-1H-benz[f]isoindol-1,3(2H)-dione NH
Me0 0 G~3 The entitled compound was obtained in a manner similar to that described in Example 37.
m.p.:282-284~C (THF) NMR(CDC13}s: 3.77 (3H,s), 7.02(lH,d,J=2Hz}, IS 7.36{lH,dd,J=2Hz,9Hz), 7.44(4H, m), 7.80{lH,bs), 8.02(IH,d,J=9Hz), 8.34(lH,s).
IR(KHr):3174, 3068, 2775, 1762, 1733, 1616 cm-~.
Elemental Analysis for CzoHIZF3N04 Calcd.: C:62.02, H:3.12~s, N:3.62 Found . C:62.18$, H:3.23, N:3.69$.
Example 42 6-Benzyloxy-4-(4-methoxyphenyl)-IH-benz[f]isoindol-1,3(2H)-dione ~N H
Bno i w OMe The entitled compound was obtained in a manner similar to that described in Example 37.
m.p.:208-210~C (THF) NMR(CDC1~)8: 3.94{3H,s), 5.02{2H,5), 7.06(2H,d,J=9Hz), 7.34(9H, m), 7.76(lH,brs), 7.99(lH,d,J=9Hz), 8.2B(lH,s).
IR(KBr): 3066, 2836, 1766, 1714, l616, 1S15 cm-~.
SUBSTITUTE SHEET (RULE 2fi~

Elemental Analysis for CZ~H~9N0~
Calcd.: C:76.27, H:4.68, N:3.42 Found . C:75.64, H:4.6B~, N:3.47.
Example 43 4-(4-Fluorophenyl)-6-methoxy-1H-benz(f)isoindol-i,3(2H)-dione Me0 H
The entitled compound was obtained in a manner similar to that described in Example 37.
m.p.:281-284~C (THF}
NMR(CDC13)s: 3.77(3H, s), 7.05(1H, d, 3 = 2Hz), 7.20-7.40 (5H, m), 7.85 (1H, brs), 8.01 (1H, d, J = 9Hz), 8.32 (1H, s).
IR(KBr): 3178, 3072, 1?62, 1718, l610, 150B cm'.
Elemental Analysis for C19H12FN03 ~ 0 . 2HZ0 Calcd.: C:70.24, H:3.85, N:4.31 Found . C:70.25$, H:3.90, N:4.26.
Example 44 4-(4-Fluorophenyl)-6-methoxy-9-methyl-1H-benz[f]isoindol-1,3(2H}-dione Me n M a 0 H
The entitled compound was obtained in a manner similar to that described in Example 37.
m.p.:311-314~C (THF) SUBSTITUTE SHEET ~RUIE 26) NMR(CDCI~)b: 3.11 (3H, s}, 3.75 (3H, s}, 7.00 (1H, d, J = 3H2), 7.22 (2H, t, J.= 9H2), 7.34 {3H, m}, 8.21 {1H, d, J = 9H2}, 9.59 (1H, brs).
- IR{KBr): 3184, 3062, 2966, 1756, 1714, 1602 cm~~.
Elemental Analysis for CZOHi4FN03 0.2H20 Calcd.: C:70.87%, H:4.28%, N:4.13%
Found . C:70.64%, H:4.33, N:4.06%
Example 45 6-Methoxy-4-(4-methoxyphenyl)-9-methyl-1H-benz[f]isoindol-1,3(2H)-dione Me p ~N H
i i Me0 I
Me The entitled compound was obtained in a manner similar to that described in Example 37.
m.p.:282-284~C (THF) NMR(CDC13)b: 3.11 (3H, s}, 3.75 (3H, s), 3.92 (3H, s), 7.06 (2H, d, J = 9H2), 7.12 {1H, d, J = 3H2), 7.32 (3H, m}, 7.59 (1H, brs), 8.20 {1H, d, J = 9H2).
IR(KBr): 316S, 3055, 2839, 1747, 1710, 1616 cm-~.
Elemental Analysis for, CzIHi~N04 Calcd.: C:72.61%, H:4.93%, N:4.03%
Found . C:72.40%, H:4.92%, N:4.06%.
Example 46 6-Methoxy-10-(4-methoxyphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7,9(8H)-dione SUBSTITUTE 5HE~T tRULE 2fi) WO 98l07705 PCT/JP97/02858 OM a 0 ~N H
i /

~.0 i w UMe To an ethanol (100m1) solution of dimethyl 6-methoxy-9-(4-methoxyphenyl)-naphtho[1,2-dJ-1,3-dioxole-7,8-dicarboxylate (2.33g, 5.04mmo1) was added 4N sodium hydroxide solution (100m1) and heated under reflux for 2 hours. Ethanol was distilled off under reduced pressure. Concentrated hydrochloric acid was added to the residue to adjust the pH of the mixture to about 1 and extracted with THF-ethyl acetate{1:1) twice. The organic layer was washed with saturated sodium chloride solution and dried with magnesium sulfate, then the solvent was distilled off under reduced pressure. The ZO obtained residue was heated for 10 minutes at 150~C to give crude crystals of 6-methoxy-10-(4-methoxyphenyl)-furo[3',4':6,7]naphtho(1,2-d]-1,3-dioxol-7,9-dione.
The obtained crude crystals of 6-methoxy-10-(4-methoxyphenyl)-furo[3',4':6,7]naphtho(1,2-dJ-1,3-dioxol-7,9-dione (1.79g} was dissolved in THF (30m1) and 25~ NH~OH (3m1) was added thereto and stirred for 2 minutes at room temperature. The solvent was distilled off and the residue was heated for 10 minutes at 200~C.
The above procedure was repeated 8 times and water was added thereto, then extracted with THF-ethyl acetate (1:1) twice. The organic layer was washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent was removed by distillation under reduced pressure to give the entitled compound(1.48g, 83g) as yellow crystals.
m.p.:265-266~C (ethanol ether) SUBSTITUTE SHEET (RULE Z6) WO 981077U5 PCTlJP97102858 NMR(CDCl,)s: 3.89(3H, s), 4.37(3H, s), 5.88(2H, s), 6.96(2H, d, J=8Hz), 7.2 07.30(3H, m), 7.81(1H, brs), 8.12(1H, d, J=9Hz).
IR{KBr): 3217, 3074, 1745, 1708, 1542, 1450, 133S, 1276 cm-'.
Elemental Analysis for CzIH~5N06 ~ 0 . 2HZ0 Calcd.: C:66.21, H:4.07, N:3.68 Found . C:66.36, H:4.04, N:3.73.
Example 47 10-(1,3-Benzodioxol-5-yl)-6-(2-N,N-dimethylaminoethoxy)-7H-1,3-benzodioxolo[4,5-f)isoindol-7,9(8H)-dione M a 2 N w/'~
~ ~ ~ NH
i i i 0~
The entitled compound was obtained in a manner similar to that described in Example 46.
m.p.:223-225~C (THF-ether) NMR(CDC13)s: 2.42(6H, s), 2.91(2H, t, J=5Hz), 4.70(2H, t, J=5Hz), 5.89(1H, bra), 5.91(1H, brs), 6.02(1H, d, J=l.4Hz), 6.06(1H, d, J=l.4Hz), 6.70-6.80(2H, m), 6.86(1H, d, J=8Hz), 7.29{1H, d, J=9Hz), 8.19(1H, d, J=9Hz).
IR(KBr): 2900, 1747, 1712, 1544, 1490, 1369, 1266, - 30 1228 cm-' , Elemental Analysis for Cz4HzoNzO~ ~ 0 . 5Hz0 Galcd.. C:63.02, H:4.63, N:6.12 Found . C:63.03, H:4.46, N:6.00.
Example 48 10-(1,3-Benxodioxol-5-yl)-6-(1-hexyloxy)-7H-1,3 benzodioxolo[4,5-f)isoindol-7,9(8H)-dione SUBST'iTUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 ~N H
i 0 ~0 0 _/
The entitled compound was obtained in a manner similar to that described in Example 46.
m.p.:222-223~C (ethyl acetate-isopropyl ether) NMR(CDCI3)6: 0.92(3H, brt), 1.3d-2.10(8H, m), 4.59(2H, t, J=7H2), 5.92(1H, brs), 5.93(1H, brs), 6.04(1H, brs), 6.07(1H, brs), 6.70-6.90(3H, m), 7.30(1H, d, J=9H2), 8.15(1H, d, J=9H2}.
IR(KHr): 3174, 3064, 2925, 1754, 1718, 1627, 1540, 1344 cm-1.
Elemental Analysis for CZ6HZ3NO~ ~ 0 . 2H20 Calcd.: C:67.15, H:5.07, N:3.01 Found . C:67.22, H:5.04%, N:3.14.
Example 49 10-(1,3-Benzodioxol-5-yl)-6-methoxy-7H-1,3-benzodioxolo[4,5-f}isoindol-7,9{8H)-dione OMe 0 ~'~ \~~N H

The entitled compound was obtained in a manner similar to that described in Example 46.
m.p.:263-265~C (ethyl acetate ether) NMR{CDC13)s: 4.37(3H, s), 5.90-5.93(2H, m), 6.00-6.OB(2H, m), 6.75-6.90{3H, m), 7.31(1H, d, J=9H2), SUBSTtTLJTE SHEET (RULE 2fi) WO 98107705 PCT/JP97l02858 8.12(1H, d, J=9Hz).
IR(KSr): 3200, l750, 1716, 1630, 1445, 13S9 cm-~.
Elemental Analysis for CZ,H1~N0~ ~ 0 . 2Hz0 _ Calcd.: C:63.B7~, H:3.42, N:3.55 Found . C:63.41, H:3.43$, N:3.54.
_ Example 50 10-(1,3-Benzodioxol-5-yl)-6-(2-propyloxy)-7H-1,3-benzodioxolo[4,5-fJisoindol-7,9(8H)-dione O~Pr ~ 0 'N H
0 ' ,0 0 '1 The entitled compound Was obtained in a manner similar to that described in Example 46.
m.p.:259-260~C (THF-ether) NMR(CDC13)b: 1.45(6H, d, J=6Hz), 5,27(1H, septet, J=6Hz), 5.91(1H, d, J=l.4Hz), 5.93(1H, d, J=l.4Hz), 6.03(1H, d, J=l.4Hz), 6.07(1H, d, J=l.4Hz), 6.70-6.90(3H, m), 7.29(1H, d, J=9Hz), 7.85(1H, brs), 8.17(1H, d, J=9Hz).
IR(KBr): 3207, 3068, ?979, 1754, 1710, 1625, 1544, 1461, 1371, 1228 cm '.
Elemental Analysis for CZ~H~N0~~0.5Hz0 Calcd.: C:65.03$, H:4.18, N:3.30 Found . C:64.91$, H:4.39, N:3.15.
Example 51 10-{4-Fluorophenyl)-6-methoxy-7H-1,3-benzodioxolo[4,5-fJisoindol-7,9(8H)-dione M
SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCT/JP97I02858 OMe H

The entitled compound was obtained in a manner similar to that described in Example 46.
m.p.:274-276~C (THF-ether) NMR(CDC13)8: 4.39(3H, s), 5.88(2H, s), 7.05-7.20(3H, m), 7.25-7.35(2H, m), 7.64(1H, brs), 8.14(1H, d, J=9Hz}.
IR(KBr): 3213, 3058, I753, 1716, 1621, 1544, 15i3, 1442, 1361, 1281 cm-1.
Elemental Analysis for CzflHIZNOSF
Calcd.: C:65.11, H:3.39, N:3.80 Found . C:64.90, H:3.450, N:3.68.
Example 52 10-Cyclohexyl-7H-1,3-benzodioxolo{4,5-f]isoindol-7,9(8H)-dione H
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:305-30B~C (THF) NMR(CDC13)6: 1.4-2.0 (8H, m), 2.45 (2H, m), 4.2S {1H, m), 6.2S (2H, s}, 7.35 (1H,. d, J = 8Hz}, 7.62 (1H, d, J
- 8Hz), 7.96 (1H, brs), 8.14 {1H, s).
IR(KBr): 3193, 293S, 2854, 1756, 1714 cm-~.
Elemental Analysis for C~9H,4NO4 ~ 0 . 2HZ0 SUBSTITUTE SHEFi' (RULE 26) WO 98l07705 PCTlJP97/02858 Calcd.: C:70.45$, H:4.48, N:4.32 Found . C:70.58, H:4.83, N:4.20.
Example 53 = B,9-Dihydro-10-(4-methoxyphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one w w ~N H
i lo Me 8,9-Dihydro-10-(4-methoxyphenyl)-7H-1,3-benzodioxolo{4,5-fJisoindol-T,9(8H)-dione (200mg) was dissolved in acetic acid (lOmi) and zinc powder (1.5g) was added thereto, then heated under reflux for 3 hours. The insoluble solid was filtered off and the solvent was distilled off. The obtained residue was dissolved in ethyl acetate, and the solution was washed with water and sodium hydrogen carbonate solution, then dried with magnesium sulfate. The mixture was concentrated under reduced pressure and the obtained residue was recrystallized from THF to give the entitled compound (107mg).

m.p.:266-269C

NMR(CDCl~)b: 3.90(3H, s), 4.30(2H, s}, 5.88(2H, s), 6.62(1H, brs), 6.98(2H, d, J=8.6H2), 7.27(1H, d, J=8.4H2), 7.28(2H, d, J=8.6H2), 7.68(1H, d, J=8.4H2), 8.34(1H, s}.

IR(KBr): 3290, 2898, 1710, 1662, 1635, 1508, 1463 cm Elemental Analysis for CzoH15N04 Calcd.: C:72.06, H:4.54, N:4.20 Found . C:71.40, H:4.73, N:4.14 Example 54 SUBSTITUTE SHEET tRULE 26) WO 98l07705 PCT/JP97l02858 B,9-Dihydro-ZO-(3,4,5-trimethoxyphenyl)-7H-1,3-benzodioxolo(4,5-f)isoindol-7-one O
NH
-.0 Me0' Y~OMe OMe The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:263-265~C
NMR(CDC13)8: 3.85(6H, s), 3.96(3H, s), 4.36(2H, s), 5.92(2H, s), 6.58(2H, s), 6.62(1H, brs), 7.29(1H, d, J=8.8Hz), 7.69(1H, d, (T=8.8Hz), 8.36(1H, s).
ZR(KBr): 3163, 3062, 2775, 1756, 1714, 16Z7, 1583 cm-i Elemental Analysis for Cz2H19NO6 Calcd.: C:67.17%,, H:4.870, N:3.56%
Found . C:66.72%, H:5.05%, N:3.29%
Example 55 4-(1,3-Benzodioxol-5-yl)-2,3-dihydro-5-methoxy-1H-benz[f)isoindol-1-one NH
Me The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:295-298~C (THF) NMR(DMSO-db)s: 3.49(3H, s), 4.10(2H,brs), 6.07(lH,brs), 5 U B ST1TLITE 5 H E ET ( R U LE 26 WO 98l07705 PCTlJP97/02858 6.08(lH,brs), 6.71(lH,dd,J=l.5Hz,8Hz), - 6.85(lH,d,J=1.5H2), 6.94(lH,d,J=8H2), 7.01(lH,d,J=SHz), 7.49(lH,t,J=8H2), 7.75(lH,d,J=8H2), 8.27(lH,s), -- 8.66(lH,brs).
IR(KBr): 1697, 1490, 1465, 1237, 1039 cm-~.
Elemental Analysis for CzoH15N04 ~ 0 . 2H20 Calcd.: C:71.29$, H:4.61, N:4.16 Found . C:71.09, H:4.84, N:4.20.
Example 56 4-(1,3-Benzodioxol-5-yi)-2,3-dihydro-5,6-dimethoxy-1H-bent[f]isoindol-1-one NH
Me0 Me0 i I

0,/
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:255-256~C (MeOH) NMR(CDC13)8: 3.32(3H, s), 3.99(3H, s), 4.17(lH,d,J=14H2), 4.27(lH,d,J=14H2}, 6.02(lH,d,J=1.4H2), 6.03(lH,d,J=1.4H2}, 6.14(lH,brs), 6.7g(lH,dd,J=l.6Hz,8Hz},, 6.80(lH,d,J=1.6H2}, 6.88(lH,d,J=BHz), 7.39(lH,d,J=9H2), 7.85(lH,d,J=9H2), 8.35(lH,s).
IR(KBr): 1695, 1485, 1265, 1230, 108S, 1030 cm-~.
Elemental Analysis for CZ~H1~N050.2Hz0 Calcd.: C:68.73, H:4.78$, N:3.82 Found . C:68.84, H:4.84, N:3.B5~.
Example 57 2,3-Dihydro-5,6-dimethoxy-4-(4-methoxyphenyl}-1H-benz(f]isoindol-1-one SUBSTITUTE SHEET (RULE 26~

l90 ~~ ~~ ~ N H
Me0 Me0 i I
Me The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:258-260~C (THF) NMR{DMSO-d6)8: 3.10(3H, s), 3.82(3H, s), 3.91(3H, s), 4.02(2H,brs), 6.97(lH,d,J=9Hz), 7.25(lH,d,J=9Hz), 7.56(lH,d,J=9Hz), 8.00(lH,d,J=9H2), 8.26(1H,5), 8.53(lH,brs).
IR(KBr): 1697, 1515, 1508, 1457, 1272, 1249, l093 cm-1 Elemental Analysis far CZ1H~9N0~ ~ 0 . 2H20 Calcd.: C:71.46, H:5.54, N:3.97 Found . C:71.52, H:5.46, N:3.950.
Example 58 8,9-Dihydro-10-(4-trifluoromethylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one O
~N H
i i _ i The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:315-3I7~C (THF) NMR(DMSO-d6)8: 4.21(2H,brs), 5.94(2H, s), 7.47(lH,d,J=9Hz), 7.69(2H,d,J=8Hz), 7.80(2H,d,J=BHz), 7.91(lH,d,J=9Hz), 8.39(lH,s), 8.64(lH,brs).
IR(KBr): I698, 1324, i274, I162, 1124, 1110, 1079, SUBSTITUTE SHEET (RULE 2~) 1070 cm~~ .
Elemental Analysis for CZpH~ZNO~F~
Calcd.: C:64.69, H:3.26, N:3.77 _ Found . C:64.8I~, H:3.50, N:3.74.
Example 59 10-(4-Benzyloxyphenyl)-8,9-dihydro-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one \ \
~ , _ ,N H

OBn The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:257-260~C (THF) NMR(CDC1~-one drop DMSO-db)S: 4.27 (2H, s), 5.l4 (2H, s), 5.89 (2H, s), 7.05 {2H, d, J = 9H2), 7.3-7.5 (9H, m), 7.68 (1H, d, J = 9H2), 8.30 (1H, s).
zR(KBr): 3290, 2883, I708, 1662, 1635 cm I.
Elemental Analysis for CZ6H19NO4 ~ 0 . 3H20 Calcd.: C:75.17, H:4.77, N:3.37 Found . C:74.98, (i:4.75$, N:3.28$.
Example 60 8,9-Dihydro-10-(4-pyridyl)-7H-1,3-benzodioxolo[4,5-f)isoindol-7-one ~ ~ \
'N H

N
The entitled compound was obtained in a manner SUBSTITUTE SHEET (RULE 26y WO 98l07705 PCT/JP97102858 similar to that described in Example 53.
m.p.:316-3l9~C (THF-MeOH) NMR(CDC1~)&: 4.30 (2H, s), 5.89 (2H, s), 6.58 (1H, b), 7.32 (3H, m), 7.72 (1H, d, J = 9Hz), B.41 (1H, s), B.71 (2H, d, J = 6Hz).
IR(KBr): 3082, 2904, 1683, 1635 cm-~.
Elemental Analysis for C,eHIZNzO~
Calcd.: C:?1.05$, H:3.97$, N:9.210 Found . C:70.76$, H:4.17$, N:8.97$.
Example 61 8,9-Dihydro-10-(3-pyridyl)-7H-1,3-benzodioxolo[4,5-f)isoindol-7-one I \ NH
~-o n ~,N
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:257-260~C (THF) NMR(CDC13-one drop DMSO-d6)8: 4.27 (2H, s), 5.19 (2H, s), 5.89 (2H, s), 7.05 (2H, d, J = 9Hz), 7.3-7.5 (9H, m), 7.6B (1H, d, J = 9Hz), 8.30 (1H, s).
IR(KBr): 3290, 2883, 1708, 1662, 1635 cm-'.
Elemental Analysis for CZ6H19N0~~0.3Hz0 Calcd.: C:75.17$, H:4.77$, N:3.37$
Found . C:74.98$, H:4.75$, N:3.28$.
Example 62 10-(4-Benzyloxy-3-methoxyphenyl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f)isoindol-7-one SUgSTZTLJT~ SHEET (RULE 26) WO 98I07705 PCTlJP97/02858 H

- 'Y ' 0 M a OBn The entitled compound was obtained manner in a similar to that described in Example 53.

m.p.:236-239C (THF) NMR(CDC13)s: 3.87 (3H, s), 4.25 l7Hz), (1H, d, J =

4.38 (1H, d, J = l7Hz), 5.23 (2H, s), 5.88 (2H, s), 6.65 (1H, brs), 6.88 (2H, m), - 8Hz), 6.98 (1H, d, J

7.3-7.5 (6H, m), 7.68 (1H, (1H, d, J = 8Hz), 8.3S s).

IR(KBr): 3176, 3064, 2893, 1695, cm-1.
1635, 1515 Elemental Analysis for CZ~HZ1NO5-0.2Hz0 Calcd.: C:73.19, H:Q.B7~, N:3.16 Found . C:72.92, H:5.13, N:3.11.

Example 63 11-(1,3-Benzodioxol-5-yl)-9,10-dihydro-8H-isoindolo[5,6-f]benz[b]-I,4-dioxan-8-one 'N H

~0 w~

The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:312-315~C (THF) NMR(CDC1~)s: 3.97 (2H, m), 4.22 (4H, m), 6.03 (2H, d, (1 = 4Hz}, 6.66 (1H, b), 6.74 (2H, m), 6.85 (1H, d, J =
8Hz), 7.16 (1H, d, J = 9Hz), 7.57 (1H, d, J = 9Hz), 8.28 (1H, s}.
SUBSTiTU'fF SHEE'3' tRUL~ 26) WO 98l07705 PCT/JP97I02858 IR(KHr): 3195, 3078, 2879, 1695, 1616 cm-'.
Elemental Analysis for Cz~Hi5N0s ~ 0 . 2H20 Calcd.: C:69.11, H:4,25, N:3.84 Found . C:69.10, H:4.20, N:3.72.
Example 64 10-(4-Bromophenyl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one \ \
~N H

~--0 i I
r The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:273-274~C (THF) NMR(CDC13)8: 4.2$ {2H, s), 5.89 {ZH, s), 6.S4 {1H, b), 7.24 (2H, d, J = 8H2), ?.28 (IH, d, J = 9H2), 7.S7 (2H, d, J = 8H2), 7.69 (1H, d, J = 9H2), 8.37 (1H, b).
IR(KBr): 3203, 308S, 2908, 1700, i635 cm-'.
Elemental Analysis for Cl9HszBrNO~
Calcd.: C:59.71, H:3.16, N:3.66 Found . C:59.77, H:3.44, N:3.47.
Example 65 10-{4-Fluorophenyl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one ~ ~ ~ ~N H
QY
~-o The entitled compound was obtained in a manner similar to that described in Example 53.
SU85TiTUTE SHEET jRULE 2fi) WO 98l07705 PCT/JP97/02858 m.p.:294-297~C (THF-ethanol) _ NMR(CDC1~}b: 4.28(2H, s), 5.88(2H, s}, 6.83(1H, brs}, 7.0S-7.20(5H, m), 7.68(1H, d, J=9Hz), 8.36(1H, s}.
_ IR(KBr): 3199, 3085, 2904, 1693, 1637, 1508, 1461, S 1272 cm'.
Elemental Analysis for C19H1zN03 ~ 0 . 2H20 Calcd.: C:70.24, H:3.85$, N:4.31$
Found . C:70.53$, H:3.72, N:4.31.
Example 66 10-(1,,3-Benzodioxol-5-yl)-8,9-dihydro-6-methyl-7H-I,3-benzodioxolo(4,5-f)isoindol-7-one Me 0 'N H

i w The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:292-Z93~C (ethanol) NMR(CDC13)&: 3.16(3H, s), 4.15(1H, d, J=l6Hz), 4.25(1H, d, J=l6Hz), 5.89(1H, d, J=I.4Hz), 5.91(1H, d, J=l.4Hz), 6.03(1H, d, J,=l.4Hz), 6.06(1H, d, J=l.4Hz), 6.70-6.95(4H, m), 7.28(1H, d, J=9Hz), 7.87(1H, d, J=9Hz).
IR(KBr): 3184, 3078, 2889, 1689, 1633, 1490, 1438, 1378, 1237 cm-~.
Elemental Analysis for Ci1H15N05 Calcd.: C:69.80, H:4.18, N:3.88$
Found . C:69.41, H:4.3I~, N:3.85.
Example 67 10-(9-Fluorophenyl)-8,9-dihydro-6-methyl-7H-1,3-benzodioxolo[4,5-f)isoindol-7-one SUBSTi'CLJTE SHEET (RULE 26) Me 0 ~N H

~..-0 ~J
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:293-295~C (THF-ethanol) NMR{CDC13)s: 3.17(3H, s), 4.16{2H, s), 5.85{2H, s), 6.44(1H, brs), 7.Q0-7.40{5H, m), 7.89(1H, d, J=9Hz).
IR(KBr): 3186, 3D80, 2891, 1683, 1634, 1508, 1459, 1291, 1218 cm 1.
Elemental Analysis for CZQH14N03F
Calcd.: C:71.64%, H:4.21%, N:4.18%
Found . C:71.36, H:4.07%, N:4.40%.
Example 68 8,9-Dihydro-6-methyl-10-{4-trifluoromethylphenyl)-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one ~'N H
i i ~.-0 I
w .

The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:303-305~C (ethyl acetate-isopropyl ether) NMR(CDC13)s: 3.18(3H, s), 4.15(2H, s), 5.85(2H, s), 6.48(1H, brs), 7.31(1H, d, J=9Hz), 7.46(2H, d, J=BHz), 7.69(2H, d, J=8Hz), 7.91(1H, d, 3=9Hz).
IR(KBr): 3210, 309D, 1591, 1620, 1470, 1328, 129S cm-SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCT/JP97I02858 Elemental Analysis for CilH~r,NO3F~
Calcd.: C:65.46$, H:3.66, N:3.63$
_- Found . C:65.37, H:3.65, N:3.69.
Example 69 8,9-Dihydro-10-(4-methoxyphenyl)-6-methyl-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one Me 0 ' ~, ~ ~N H
i i ~..--0 i w I
Me The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:295-296~C (THF-ether) NMR(CDC13)S: 3.16(3H, s), 3.89(3H, s), 4.17(2H, s), 5.86(2H, s), 6.37(1H, brs), 6.96(2H, d, J=9Hz), 7.20-7.35{3H, m), 7.86(1H, d, J=9Hz).
IR (KBr): 3201, 3082, 2871, 1687, 1633, 1511, 1461, 1378, 1243 cm-~.
Elemental Analysis for CZ1H1~N0~
Calcd.: C:72.61 , H:4.93 , N:4.03 Found . C:72.34, H:4.81, N:4.11%.
Example 70 10-(1,3-Benzodioxol-5-yl}-6-ethyl-8,9-dihydro-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one SUBSTITUTE SHEET (RULE 26~

WO 98l07705 PCTIJP97f02858 Et 0 ~N H
i i ~--0 The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:296-298~C (THF-ether) NMR(CDC13)8: 1.38(3H, t, J=7Hz), 3.77{2H, q, J=7Hz), 4.15(1H, d, J=l7Hz), 4.25(1H, d, J=l7Hz), 5.88(1H, m), 5.86(1H, m), 6.03(1H, d, J=l.4Hz), 6.05(1H, d, J=l.4Hz), 6.64{1H, brs), 6.?0-6,90{3H, m), 7.29(1H, d, J=9Hz), 7.92(1H, d, J=9Hz).
IR(K8r): 3197, 2887, 1685, 1631, 1614, 1457, 1236 cm-i Elemental Analysis for CzZH1~N05 Calcd.: C:70.39$, H:4.56, N:3.73 Found . C:74.02$, H:4.61, N:3.76.
Example 7I
10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-6-(2-N,N-dimethylaminoethyl)-7H-1,3-benzodioxolo{4,5-f)isoindol-7-one Me2N~ 0 NH
i~
o ..._. o i o..~
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:226-228~C (THF-ether) SUB5T1TU'i'E Sd-fE~T (RULE ~6) NMR(CDC1~)8: 2.47(6H, s), 2.71(2H, m), 3.97(2H, m), - 4.14(1H, d, J=l6Hz), 4.24(1H, d, J=l6Hz), 5.85-5.95(2H, m)) 6.03(1H, d, J=l.4Hz), 6.06(lII, d, J=l.4Hz), - 6.25(1H, brs), 6.70-6.90(3H, m), 7.30(1H, d, J=9Hz), 7.96{1H, d, J=9Hz).
IR(KBr): 3210, 2850, 168S, 1629, 1492, 1455, 1374, 1239 cm'.
Elemental Analysis for CZ4HZZNZOs ~ 0 . 4Hz0 Calcd.: C:67.44, H:5.42, N:6.65 .Found . C:67.63, H:5.37, N:6.72.
Example 72 8,9-Dihydro-10-{4-methylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one 2o M a H
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:284-286 (THF) NMR{CDC13)s: 2.45(3H, ,s), 4.28(2H, s), 5.88(2H, s), 7.06{1H, brs), 7.15-7.35(5H, m), 7.67(1H, d, J=9Hz), 8.34(1H, s).
IR(KBr): 3192, 3080, 2887, 1697, 1637, 1457, 1274 cm-Elemental Analysis for CZOH1sN03 ~ 0 . 3Hi0 Calcd.: C:74.43, H:4.87, N:4.34 Found . C:74.30, H:4.5B~, N:4.31.
Example 73 B,9-Dihydro-10-(3-methylphenyl)-7H-1,3-benzodioxolo(4,5-fjisoindal-7-one SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCT/3P97/02858 ~~ ~~ 'N H
i /
0 _ ~.--0 i I
Me The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:244-246~C (THF) NMR(CDC13}s: 2.41 (3H, s), 4.30 (2H, s}, 5.88 (2H, s), 6.92 (1H, brs), 7.2-7.4 (5H, m), 7.68 (1H, d, J = 9Hz), 8.35 (1H, s).
IR(KBr): 32i0, 3091, 2893, 1683, 1637, 1457 cm-'.
Elemental Analysis for CZOH15N03 Calcd.: C:75.70, H:4.76, N:4.41 Found . C:75.25, H:4.93, N:4.30.
Example 74 8,9-Dihydro-10-(2-methylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one ~N H
i r 2 5 'r-~ ~M a C/\
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:252-255~C (THF) NMR(CDC13)&: 4.04 (1H, d, J = l7Hz), 4.29 (1H, d, J =
l7Hz), 5.84 (2H, s}, b.78 (1H, brs), 7.2-7.4 (6H, m), 7.90 (1H, d, J = 8Hz), 8.36 (1H, s).
IR(KBr}: 3222, 3060, 2881, I695, 1635, 1461 cm-~.
Elemental Analysis for CzQHi5N0~
Calcd.: C:75.70$, H:4.76$, N:4.41 SUBSTITUTE SKEET (RULE fib) Found . C:75.10, H:4.85$, N:9.38$.
- Example 75 4-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-methoxy-1H-benz[f]isoindol-1-one - ( \ \ NH
i Me0 i I
0-../
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:259-252~C (CHCIi) NMR(CDC13)6: 3.B5 (3H, s), 4.33 (2H, s), 6.24 (2H, s), 6.S4 (1H, brs), 6.9-7.1 (3H, m), 7.20 (1H, d, J = 9Hz), 7.31 (IH, d, J = 9Hz), 7.45 (1H, m), 8.43 (1H, s).
IR(KBr): 3419, 305S, 2902, 1704, 1683 cm-1.
Elemental Analysis for CzoH15N04 ~ 0 . 2HZ0 Calcd.: C:71.29, H:4.61%, N:4.16 Found . C:71.27, H:4.660, N:4.28.
Example 76 2,3-Dihydro-6-methoxy-4-(4-methoxyphenyl)-1H-benz[f]isaindol-1-one H
Me0 OMe The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:290-29Z~C (THF) - 35 NMR(CDC1~-one drop DM50-db)S: 3.76 (3H, s), 3.9Z (3H, s), 7.07 (2H, d, J = 9Hz), 7.14 (1H, d, J = 2Hz), 7.35 SUBSTITUTE SHEET (RULE ~6) WO 98l07705 PCTIJP97/02858 (3H, m), 7.98 (1H, d, J = 9Hz), 8.25 (1H, s), 10.23 (1H, brs).
IR(KBr): 3170, 3066, 2949, 2785, 176D, 1724, 1616, Z515 cm-'.
Elemental Analysis for CZOH15N04 Calcd.: C:72.06, H:4.54, N:4.20 Found . C:71.79, H:4.48$, N:4.19.
Example 77 2,3-Dihydro-6-methoxy-4-(4-methylphenyl)-1H-benz[f]isoindol-1-one H
Me0 The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:298-301~C (THF) NMR(CDC13)8: 2.49 (3H, s), 3.76 (3H, s), 7.13 (1H, d, J = 2Hz), 7.33 (5H, m), 7.83 (1H, brs), ?.99 (1H, d, J
- 9Hz), 8.30 {1H, s).
IR(KBr): 3167, 3064, 2773, 176b, 1714, 1616 cm-'.
Elemental Analysis for C2oH~SN03 Calcd.: C:75.70, H:4.76, N:4.41 Found . C:75.36, H:4.88, N:4.32%.
Example 78 2,3-Dihydro-6-methoxy-4-(4-trifluoromethylphenyl)-1H-benz[f]isoindol-1-one SUBSTITUTE SHEET (RULE 26) NH
Me0 The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:219-221~C {THF) NMR(CDC13)s: 3.76 (3H, s), 4.32 (2H, s), 6.90 {1H, d, J = 3Hz), 7.2S (1H, dd, J = 3Hz,9Hz), 7.49 (1H, brs), 7.55 (2H, d, J = 8Hz), 7.83 (2H, d, J = 8Hz), 7.99 (1H, d, J = 9Hz}, 8.39 (1H, s).
IR(KBr): 3184, 3070, 2B89, 1695, 1623 cm-'.
Elemental Analysis for CioH14F3NOz Calcd.: C:67.23, H:3.95, N:3.92 Found . C:67.25, H:3.94, N:3.98$, Example 79 2,3-Dihydro-6-methoxy-4-{4-trifluoromethoxyphenyl)-1H-benz[fjisoindol-1-one ~ ~ NH
Me0 i C
w The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:277-280~C (THF}
NMR(CDC1~)b: 3.77 {3H, s), 4.33 (2H, s}, 6.93 (1H, d, J = 2Hz), 7.24 (1H, dd, J =2Hz,9Hz), 7.39 (1H, brs), 7.43 (4H, m), 7.98 {1H, d, J = 9Hz), 8.37 (1H, s).
IR(KBr): 3184, 3078, 2898, 1695, 1635, I506 cm ~.
Elemental Analysis for CZOH~4F~N0~
SUBSTtTtJTE SH~~T (RULE 26) Calcd.: C:64.39, H:3.78, N:3.75 Found . C:64.37, H:3.80, N:3.81.
Example 80 6-Benzyloxy-2,3-dihydro-4-(4-methoxyphenyl)-1H-benz(f]isoindol-1-one ~N H
Bn0 Me The entitles compound was obtained in a manner similar to that described in Example 53.
m.p.:213-216~C (THF) NMR(CDC13)8: 3.93(3H, s}, 4.32 (2H, s), 5.01 (2H, s), 7.08 (3H, m), 7.20-7.30 (9H, m), 7.97 (1H, d, J = 9Hz), 8.33 (1H, s).
IR(KBr) : 2837, 1695 cm-'.
Example 81 4-(4-Fluorophenyl}-2,3-dihydro-6-methoxy-1H-benz[f]isoindol-1-one Me0 H
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:282-2B4~C (THF) NMR(CDC1~)s: 3.76 (3H, s), 4.32 (2H, s}, 6.78 (1H, brs), 6.95 (1H, d, J = 2Hz), 7.26 (2H, m), 7.37 (3H, m}, 7.98 (1H, d, J = 9Hz}, 8.37 (1H, s}.
IR(KBr): 31B4, 306B, 1695, 1623, 150b cm-'.
SUBST1TUT~ SH~~T (RUL~ 26) Elemental Analysis for C~9H~4FNOZ
Calcd.: C:74.26%, H;4.59%, N:4.56%
Found . C:73.61%, H:4.90%, N:4.37%.
( Example 82 4-(4-Fluorophenyl)-2,3-dihydro-6-methoxy-9-methyl-1H-benz[fjisoindol-1-one Me ..
Me0 The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:236-238~C {THF) NMR(CDC13)s: 3.17 (3H, s), 3.75 (3H, s), 4.2l (2H, s), 6.61 {IH, brs), 6.91 {1H, d, J = 3Hz), 7.2-7.4 {5H, m), B.20 (1H, d, J = 9Hz).
IR(KBr): 3184, 3070, 2900, 1695, 1623 cm-1.
Elemental Analysis for CioHI6FNOZ
Calcd.: C:74.75%, H:5.02%, N:4.36%
Found . C:74.61%, H:5.09%, N:4.36%.
Example 83 2,3-Dihydro-6-methoxy-4-{4-methoxyphenyl)-9-methyl-1H-benz(f]isoindol-1-one me p 'N H
Me0 I
OMe The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:235-237~C (THF) SUBSTITUTE SHEET (RULE 26~

WO 98I07705 PCTlJP97f02858 NMR(CDC13}s: 3.17 (3H, s), 3.76 (3H, s), 3.91 (3H, s), 4.22 (2H, s), 6.24 (1H, brs), 7.00 (1H, d, J = 3Hz), 7.06 {2H, d, J = 9Hz), 7.27 (3H, m), 8.19 (1H, d, J =
9Hz).
IR(KBr): 3228, 2933, 2B85, 1673, 1621 cm-'.
Elemental Analysis for CZ1H19N0~
Calcd.: C:75.66, H:5.74, N:4.20 Found . C:75.52, H:5.74, N:4.22.
Example 84 8,9-Di.hydro-6-methoxy-1D-(4-methoxyphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one Ma 0 H
~- .
OMe The entitled compound was obtained in a manner similar to that described in Examgle 53.
m.p.:274-276~C (THF-ether) NMR(CDC13)s: 3.89(3H, s), 4.22(2H, s), 4.31(3H, s), 5.87(2H, s), 6.70(1H, brs), 6.96(2H, d, J=9Hz), 7.10-7.30(3H, m), 8.10(1H, d, J=9Hz}.
IR (KHr): 3210, 1685, 1612, 1513, 1457, 1369, 1290, 124S cm-t.
Elemental Analysis for CzIH~~N05 Calcd.: C:69.41, H:4.72, N:3.85 Found . C:69.17, H:4.62, N:3.81.
Example 85 10-(1,3-Benzodioxol-5-yl)-6-(2-N,N-dimethylaminoethoxy)-8,9-dihydro-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one SUBSTITUTE 5HE~T (RULE Zfi) WO 98l07705 PCT/JP97/02858 M a 2 N~0 - , \ ~ NH
i i - ~.- 0 I

0.../
The entitled compound was obtained in a manner IO similar to that described in Example 53.
m.p.:200-202~C (ethyl acetate ether) NMR(CDC13)s: 2.43(6H, s), 2.90(2H, brs), 4.22{2H, brs), 4.61(2H, brs), 5.89(1H, brs), 5.90(1H, brs), 6.03{1H, brs), 6.05(1H, brs), 6.7S-6.90(3H, m), 7.23(1H, d, J=9Hz), 8.20{1H, d, J=9Hz).
IR (KBr): 3190, 3090, 2900, 1691, 1630, 1460, 1240 cm-i Elemental Analysis for Cz4HzzNz~s ~ 0 . 5Hz0 Calcd.: C:63.02, H:4.63k N:6.12 Found . C:63.030, H:4.46, N:6.00.
Example 86 10-(1,3-Benzodioxol-5-yl}-6-{1-hexyloxy}-8,9-dihydro-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one NH

~0 The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:182-183~C (ethyl acetate ether) NMR(CDC1~)s: 0.91(3H, t, J=7Hz}, 1.30-1.70(6H, m), 1.94(2H, m), 4.16(1H, d, J=l7Hz), 4.26(1H, d, J=l7Hz), SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 4.52(2H, t, J=7Hz), 5.89(1H, d, J=l.4Hz), 5.90(1H, d, .
J=l.4Hz), 6.03(1H, d, J=l.4Hz), 6.05(1H, d, J=l,4Hz), 6.35(1H, brs), 6.70-6.90(3H, m), 7.22(iH, d, J=9Hz), 8.13(1H, d, J=9Hz).
IR (KHr): 3199, 3072, 2927, 1700, 1631, 161S, 1461, 1440, 1237 cm-~.
Elemental Analysis for CZ6HzsN06 ~ 0 . 2Hz0 Calcd.: C:69.23%, H:5.68%, N:3.11%
Found . C:69.34%, H:5.49%, N:3.20%.
Example B7 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-6-methoxy-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one OM a .0 ~ \~ ~~ N H

i I

0-~/
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:262-264~C (THF-ether) NMR(CDC13)s: 4.10-4.39(2H, m), 4.31(3H, s), 5.90(1H, d, J=l.BHz), 5.92(1H, d, J=l.BHz), 6.03(1H, d, J=l.2Hz), 6.06(1H, d, J=l.2Hz), 6.70(1H, brs), 6.70-6.90(3H, m), 7.23(1H, d, J=9Hz), 8.10(1H, d, J=9Hz).
IR (KBr): 3194, 308S, 2875, 168S, 1629, 1442, 1367, 1239 cm-1.
Elemental Analysis for CZ~HisN~b ~ 0 . 2HZ0 Calcd.: C:66.21%, H:4.07%, N:3.6B%
Found . C:65.95%, H:4.17%, N:3.56%.
Example 88 10-(1,3-Benzodioxol-5-yi)-B,9-dihydro-6-(2-propoxy)-7H- _ 1,3-benzodioxolo[4,5-f)isoindol-7-one SUBSTiTLITE SKEET (RULE 26) WO 98I07705 PCTlJP97I02858 0'Pr H
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:283-285~C (THF-ether) NMR(CDC1~)8: 1.41(6H, d, J=6H2), 4.16(1H, d, J=l7Hz), 4.26(1H, J=l7Hz), 5.26(1H, septet, J=6Hz), 5.89(1H, d, J=l.4Hz), 5.90(1H, d, J=l.4Hz), 6.03(1H, d, J=l.4Hz), 6.05(1H, d, J=l.4Hz), 6.49(1H, brs), 6.7S-6.90(3H, m), 7.20(1H, d, J=9Hz), 8.15(1H, d, J=9Hz).
IR(KBr): 3197, 3100, 1693, 1627, 1533, 1496, 1380, 1239 cm 1.
Elemental Analysis for Cz~Hi9N06 ~ 0 . 2H20 CalCd.: C:67.54, H:4.78, N:3.42 Found . C:67.43, H:4.83$, N:3.35.
Example 89 10-(4-Fluoraphenyl)-8,9-dihydro-6-methoxy-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one OM a 0 I ~ ~ NH

~-0 i ( 30 F
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:308-310~C (THF-ether) NMR(CDC1~)6: 4.19(2H, s), 4.33(3H, s), 5.87(2H, s), SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 6.13(1H, brs), 7.05-7.35(5H, m), 8.12(1H, d, J=9Hz}.
IR (KBr):3197, 30B4, I689, 1527, 16l7, 1508, 1444, 1372, 1291 cm-~.
Elemental Analysis for CZOH~4N0cF
Calcd.: C:68.37, H:4.02, N:3.99 Found . C:67.98, H:4.31, N:3.75. ' Example 90 10-(Cyclohexyl)-8,9-dihydro-6-methoxy-7H-I,3-benzodioxolo(4,5-f]isoindol-7-one NH

The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:244-246~C (THF) NMR(CDC13)8: 1.20-1.90 (10H, m), 4.20 (1H, m), 4.75 (2H, s), 6.16 (2H, s), 7.0S (1H, brs), 7.25 (1H, d, J =
9Hz), 7.61 (1H, d, J = 9Hz), 8.20 (1H, s).
IR(KBr): 3184, 3084, 2927, 2858, 1724, 1683, 1644 cm-i Elemental Analysis for C1gH19N03 Calcd.: C:69.71, H:6.47, N:4.28 Found . C:69.80, H:6.11, N:3.93.
Example 91 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-9-hydroxy-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one SUBSTiTLITE SHEET (RULE ~6) NH

'--0 i OH
I

To a suspension of 10-(1,3-benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo(4,5-f]isoindol-7,9(8H)-dione (1.00g) in DMF (l.DOm1) and methanol (50m1) was added,NaBH4 (0.31g), then stirred for 2 hours. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was purified with column chromatography (silica gel 100g, eluent:ethyl acetate) and recrystallized from THF to give the entitled compound (2lmg) as colorless crystals.
m.p.:227-232~C (AcOEt) Elemental Analysis for CZOH1~N06 ~ 0 . 7H20 NMR(DMSO-db)s: 5.75-6.15(6H, m), 6.80-7.05(3H, m), 7.43(lH,d,J=9H2), 7.83(lH,d,J=9H2), 8.22(lH,s), 8.95(lH,brs).
IR(KBr): 3215, 167S, 1490, 1293, 1234, 1060, 1041 cm-i Calcd.: C:63.90, H:3.86, N:3.73 Found . C:63.99, H:3.76, N:3.57.
Example 92 2,3-Dihydro-6-methyl-4-(4-methylphenyl)-1H-1,3-benzodioxolo(4,5-f]isoindol-1-one SUBSTITUTE SHEET (RULE 26) NH
Me Me The entitled compound was obtained in a manner similar to that described in Example Z.
m.p.:297-298~C (THF) NMR(CDC13)6: 2.45 (3H, s), 2.49 (3H, s), 4.34 (2H, s), 6.64 (1H, brs), 7.27 (2H, d, J = 8Hz), 7.36 (2H, d, J =
8Hz), 7.39 (1H, m), 7.52 (1H, m), 7.97 (1H, d, J =
8Hz), B.38 (1H, s).
IR(KBr): 3190, 3082, 2902, 170B, 1633 cm-1.
Elemental Analysis for CzoHI~NO~O.lHzO
Calcd.: C:83.05$, H:6.03, N:4.84%
Found . C:82.94, H:5.88$, N:4.88.
Example 93 10-(4-Cyanophenyl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f)isoindol-7-ane H
CN
To a DMF (2m1) solution of 10-(4-Bromophenyl)-8,9- ' dihydro-7H-1,3-benzodioxolo[4,5-fJisoindol-7-one (150mg) was added CuCN (60mg) and heated under reflux ~
for 9 hours. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then concentrated to give the entitled compound (64mg) SUBST1TUTF SHEET (RULE 26) WO 98l07705 PCT/3P97102858 m.p.:306-308~C (THF) - NMR(CDC13)&: 4.23 (2H, s.), 5.89 (2H, s), 7.31 (1H, d, J = 9Hz), 7.52 (2H, d, J = BHz), 7.71 (1H, d, J = 9Hz), -- 7.76 (2H, d, J = 8Hz), 7.85 (1H, brs), 8.36 (1H, s).
IR(KBr): 3261, 2B93, 22Z5, 1706, 1634 cm~l.
Elemental Analysis for CzoHlzNzO~ ~ 0 . 3Hz0 Calcd.: C:7I.85~, H:3.82$, N:8.38 Found . C:71.93, H:3.95, N:8.08.
Example 94 11-(1;3-Benzodioxol-5-yl)-8-pivaloyloxymethyl-7,8,9,10-tetrahydro-1,3-benzodioxolo[4,5-g]isoquinolon-?-one NCO
i i i 0~
The entitled compound was obtained in a manner similar to that described in Example 4.
m.p.:173-175~C (AcOEt-hexane) NMR(CDC11)b: 1.20(9H, s), 2.82(2H,t,J=7Hz), 3.61(2H,t,J=7Hz), 5.65(2H,s}, 5.84(lH,d,J=l.OHz), 5.85(lH,d,J=l.OHz), 6.03(lH,d,J=l.4Hz), 6.06(lH,d,J=l.4Hz), 6.G8(lH,dd,J=l.5Hz,8Hz), 6.75(lH,d,J=l.SHz), 6.86(lH,d,J=8H2), 7.19(lH,d,J=9H2), 7.60(lH,d,J=9Hz), 8.67(lH,s}.
IR(KBr): 1725, 1665, 1625, 1480, 1450, 1275, 1225, 112 0 cm-' .
Elemental Analysis for Cz~HzsNO~
Calcd.: C:68.20, H:5.30, N:2.95 Found . C:68.00, H:5.29$, N:2.83.

Example 95 Ethyl 11-(1,3-Benzodioxol-5-yl)-7,8,9,l0-tetrahydro-- 35 1,3-benzodioxolo[4,5-g]-isoquinolin-7-one-8-acetate SUBSTITUTE SHEET (RULE Z6) N~C02 E t ' ~--o The entitled compound was obtained in a manner similar to that described in Example 6.
m.p.:149-1S1~C (AcOEt-hexane) NMR(CDC1~)s: 1.29(3H,t,J=7Hz), 2.85-2.95(2H, m), 3.56{2H,t,J=6Hz), 4.22{2H,q,J=7Hz), 4.37(2H, s), 5.84(lH,d,J=l.4Hz), 5.85(lH,d,J=l.9Hz), 6.03(lH,d,J=l.2Hz), 6.06(lH,d,J=l.2Hz), 6.70(lH,dd,3=l.6Hz,BHz), 6.75(lH,d,J=l.6Hz), 6.88{lH,d,J=8Hz), 7.19(lH,d,J=9Hz), 7.59(lH,d,J=9Hz), 8.64(lH,s).
IR(KBr): 1740, 1655, 1625, 1480, 14S0, 1280, 1225, 119S cm-i.
Elemental Analysis for C25HZ1N0~
Calcd.: C:67.11, H:4.730, N:3.13 Found . C:66.83$, H:4.74, N:3.10.
Example 96 11-(1,3-Benzodioxol-5-yl)-7,8,9,10-tetrahydro-1,3 berizodioxolo[4,5-g)isoquinolin-7-ane-8-acetic acid I i! -The entitled compound was obtained in a manner similar to that described in Example 7.
m.p.:231-233~C (MeOH) Elemental Analysis for Cz~Hi~NO~ ~ 0. 7H20 SUBST1T1JTE SHEET (RULE 26) WO 9810770S PCTlJP97102858 Calcd.: C:63.95$, H:4.29, N:3.24 Found . C:63.84, H:,4.13, N:3.34.
NMR(CDC1~)8: 2.8S-2.95(2H, m), 3.58(2H,t,J=7Hz), 4.39(2H, s), 5.84(lH,d,J=l.4Hz), 5.86{lH,d,J=l.4Hz), 6.03(lH,d,J=l.4Hz), 6.06{lH,d,J=l.4Hz), 6.68(lH,dd,J=l.6Hz,8Hz), 6.73(lH,d,J=l.6Hz), 6.86{lH,d,J=8Hz), 7.19(lH,d,J=9Hz), 7.59(lH,d,J=9Hz), 8.62(lH,s).
IR(KBr): 3400, 1720, 1645, 1620, 1480, 1450, l275, 1Z25 cm 1.
Example 97 N,N-diethyl-11-{1,3-benzodioxol-5-yl)-7,8,9,10-tetrahydro-1,3-benzodioxolo[4,5-g]isoquinolin-7-one-8-acetoamide C0~1E t2 11-(1,3-Benzodioxol-5-yi)-7,8,9,10-tetrahydro-1.3-benzodioxolo(4,5-g]isoquinolin-7-one-8-acetic acid (220mg) and N-methylmorpholine (691) were dissolved in THF {2.5m1) and isobutyl chloroformate (821) was added dropwise thereto at -15~C. The mixture was stirred for 10 minutes and diethylamine {0.11m1) was added therein, then stirred for 15 minutes. The mixture was stirred for 1 hour at room temperature and water was added thereto. The mixture Was extracted with ethyl acetate.
The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the entitled compound (149mg) as pale-yelllow crystals.
m.p.:169-171~C (AcOEt) SU85T1TUTE SHEET (RULE 26) WO 98l07705 PCT/JP97I02858 Elemental Analysis for CZ~Hz~NZOGØ5HZ0 Calcd.: C:67.0?~, H:5.63, N:5.79$
Found . C:67.30, H:5.58, N:5.78$.
NMR(CDCI3)s:1.14(3H,t,J=7Hz), 1.28(3H,t,J=7Hz}, 2.B0-2.95(2H, m), 3.40(4H,q,J=7Hz), 3.6l{2H,t,J=6Hz), 3.39(lH,d,J=l6Hz), 3.47(lH,d,J=l6Hz), 5.84(lH,brs), 5.85(lH,brs), 6.03(lH,d,3=l.4Hz), 6.06(lH,d,J=l.4Hz), 6.70(lH,dd,J=l.4Hz,8Hz), 6.75(lH,d,J=l.4Hz}, 6.86{lH,d,J=8Hz), 7.18(lH,d,J=9Hz), 7.5$(lH,d,J=9Hz), 8.62(lH,s).
IR(KBr): 1645, 162Q, 1480, 1450, I280, 1225 cm-~.
Example 98 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-8-pivaloyl-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one To the DMF (50m1} solution of 10-(1,3-benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one {2.0g) was added sodium hydride (253mg) under ice cooling and stirred for I5 minutes at room temperature.
The reaction mixture was cooled with ice and pivaloylchloride (0.9m1) was added thereto, then stirred overnight at room temperature. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under reduced pressure. The obtained .
residue was purified with column chromatography and recrystallized from ethyl acetate to give the entitled compound (76mg) as a pale-yellow crystals.
m.p.:238-240~C (AcOEt}
SUBSTtTUTE SH~~T (RULE 26) NMR(CDC13)b: 1.46(9H, s), 4.69(lH,d,J=iBHz), ' 4.77(lH,d,J=l8Hz), 5.93(lH,d,J=l.4Hz}, 5.95(lH,d,J=l.4Hz), 6.04(lH,d,J=l.4Hz), -' 6.08(lH,d,J=l.4Hz), 6.79(lH,dd,J=l.2Hz,BHz), 6.81(lH,s), 6.86(lH,dd,J=l.2Hz,8Hz), 7.28(lH,d,J=9Hz), 7.69(lH,d,J=9Hz), 8.38(lH,s).
IR(KBr): 1715, 1670, 1625, 1270, 1225, l180, 1165, 1035 cm 1 .
Elemental Analysis for CZSHZ~N06 Calcd.: C: 69.60%, H:4.91%, N:3.25%
Found . C:69.34%, H:4.92%, N:3.21%.
Example 99 Benzyl 3-[10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1.3-benzodioxolo[4,5-f)isoindol-?-one-B-yl]carbonylpropionate 0 I ~ ~ N~C 0 2 B n ~.. n The entitled compound was obtained in a manner similar to that described in Example 98 m.p.:128-129~C (AcOEt-hexane) Elemental Analysis for C31HZ3N08~0.5Hz0 Calcd.: C:68.13%, H:4.43%, N:2.56%
Found . C:67.87%, H:4.32%, N:2.68%.
NMR(CDC1~)6: 2.80(2H,t,J=6Hz), 3.47(2H,t,J=6Hz), 5.14(2H, s), 5.94(lH,d,J=l.4Hz), 5.95(lH,d,J=l.4Hz), 6.04(lH,d,J=l.2Hz), 6,08(lH,d,J=l.2Hz}, 6.75-6.80(2H, m), 6.89(lH,d,J=9Hz), 7.25-7.40(SH,m), 7.70(lH,d,J=9Hz), 8.41(lH,s).
IR(KBr): 1729, 1695, 1347, 1272, 1235, 1164 cm-~.
Example 100 3-[10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-1,3-SUBSTITUTE SHEET (RULE 26) WO 98/07705 PCTlJP97102858 benzodioxolo[4,5-f)isoindol-7-one-8-yl)carbonylpropionic acid ~ \ ~ N~C02H
i i .0 i 0 ~/
To an ethyl acetate (2m1) solution of Benzyl 3-[10-(1,3-benzodioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one-8-yl]carbonyl-propionate (50mg) was added 10% palladium carbon (lOmg) and stirred overnight under hydrogen atmosphere. The catalysts were filtered off and the filtrate was concentrated under reduced pressure, then recrystallized from ethyl acetate-hexane to give the entitled compound (28mg) as colorless crystals.
m.p.:231-233~C
NMR(DMSO-db}6: 2.57(2H,t,J=6Hz), 3.25(2H,t,J=6Hz), 4.59(2H, s), 5.99(lH,d,J=l.OHz}, 6.01(lH,d,J=l.OHz), 6.09(lH,d,J=0.9Hz), 6,14(lH,d,J=0.9Hz), 6.88(lH,dd,J=l.6Hz,8Hz), 6.99(lH,d,J=8Hz), 7.01(1H,J=l.6Hz), 7.48(IH,d,J=9Hz), 7.94(lH,d,J=9Hz), 8.5'6(lH,s).
IR(KBr): 1733, 1631, 1490, 1347, 1272, 1232, 1064 cm-i Elemental Analysis for CZ4H1~N08 Calcd.: C:64.43%, H:3.83%, N:3.13%
Found . C:64.06%, H:4.03%, N:3.05%.
Example 101 8,9-Dihydro-10-(4-hydroxyphenyl)-7H-1,3-benzodioxolo[4,5-f)isoindol-7-one SUBSTITUTE SHEET (RULE Z6) NH
0 ~
~.-0 w H
The entitled compound was obtained in a manner similar to that described in Example 100.
m.p.:300~C (decomp.)('hHF) NMR(DMSO-db)s: 4.1B(2H,brs), 5.94(2H,brs), 6.81(2H,d,J=9H2), 7.22(2H,d,J=9H2), 7.42(lH,d,J=9H2), 7.84(2H,d,J=9H2}, 8.27(lH,s), 8.59(lH,brs), 9.50(lH,s).
IR(KHr): 1679, 151,3, 1459, 1297, 1276, 1245, 1070 cm-I .
Elemental Analysis for C19H1~N04 ~ 0 . 3H20 Calcd.: C:70.28, H:4.22, N:4.31 Found . C:70.47, H:4.32, N:4.21.
Example 102 8,9-Dihydro-10-(4-(2-dimethylaminoethoxy)phenyl)-7H
1,3-benzodioxolo[4,5-f]isoindol-7-one oxalate .0 'N H

y 1/2 (C02H)Z
~NMe2 To a DMF (4m1} solution of 8,9-dihydro-10-(4-hydroxyphenyl)-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one (175mg) was added 2-dimethylaminoethylcloride hydrochloride (95mg}, potassium carbonate (152mg) and sodium iodide (B.3mg) and stirred for 13 hours at 60~C.
To the reaction mixture was added water and extracted with ethyl acetate. The basic component was extracted with 1N hydrochloric acid and pH of the mixture was SUBSTtTtJTE SHEET (RULE 2fi) WO 98l07705 PCTIJP97/02858 adjusted to about 9 by 1N sodium hydroxide solution and then extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then concentrated under -reduced pressure. The obtained residue was suspended in THF and methanol (1m1) solution of oxalic .
acid~dihydrate (3.8mg). The reaction mixture was concentrated under reduced pressure and the obtained residue was dissolved in methanol. Methanol was distilled off under reduced pressure and the obtained powder was washed with THF to give the entitled compound (l4mg).
m.p.:209-210~C {THF) NMR(DMSO-db)b: 3.60(2H,t,J=7Hz), 4.18(2H,brs}, 4.34{2H,m), 5.92(2H,brs}, 7.a4{2H,d,J=8Hz), 7.39(2H,d,J=8Hz), 7.44(lH,d,J=9Hz), 7.87(2H,d,J=9Hz), 8.3I(lH,s), 8.61(lH,brs}.
IR(KBr}: I685, 1637, 1S11, l457, 1280, 1241, 1068 cm-i Example 103 8,9-Dihydro-10-(4-hydroxy-3-methoxyphenyl)-7H-1,3-benzodioxolo[4,5-fJisoindol-7-one w. ~ 'N H
~ ~

I
~OM a OH
To a solution of 10-(4-benzyloxy-3-methoxyphenyl}-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f)isoindol-7-one (3.0g) in THF (100m1) and DMF (30m1) was added 10~
palladium carbon (0.8g) and stirred for 2 hours under hydrogen atmosphere. The catalysts were filtered off with Celite and the filtrate was concentrated under reduced pressure to give the entitled compound (2.7g) SUBSTiTUfE SHEE'i' (RULE ~fi) as colorless crystals.
m.p.:280-282~C (THF) NMR(CDC13}8: 3.88 (3H, s), 4.25 (1H, d, J - l7Hz), 4.39 (1H, d, J = l7Hz), 5.90 (2H, d, J = l.4Hz}, 6.38 (1H, brs), 6.87 {2H, m), 6.99 (1H, d, J = 8Hz), 7.28 (1H, d, J = 9Hz), 7.6B (1H, d, J = 9Hz), 8.35 (IH, s).
IR(KBr): 3200, 3064, 2881, 1695, 1634, 151S cm-~.
Elemental Analysis for CzoH15N05 ~ 0 . 2Hz0 Calcd.: C:68.06, H:4.71, N:3.97 Found . C:67.87, H:5.04, N:3.58.
Example 104 Methyl [4-{8,9-Dihydro-7H-1,3-benzodioxolo(4,5 f]isoindol-7-on-10-yl)-3-methoxyphenoxy]acetate I ~ ~ ~N H
i t-0 i I
OMe O~C02Me To a DMF (20m1) solution of 8,9-dihydro-IO-(4-hydroxy-3-rnethoxyphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one (600mg) was added, potassium carbonate (360mg) and methylbromoacetate (250A ) and stirred overnight at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then the solvent was distilled off to give the entitled compound (290mg) as colorless crystals.
m.p.:198-200~C (THF) NMR(CDC1~)6: 3.86 (3H, s), 3.87 (3H, s), 4.24 (1H, d, J = l7Hz), 4.38 (1H, d, J = l7Hz), 4.79 (2H, s), 5.89 (2H, s), 6.42 {iH, b), 6.89 (3H, m), 7.29 (1H, d, J =
. 35 8Hz), 7.69 {1H, d, J = 8Hz), 8.36 (1H, s}.
IR(KBr): 3209, 2954, 2889, 1756, 1695, I515 cm-~.
SUBSTITUTE SHEET (RULE 26) WO 98107705 PCTlJP97/02858 Elemental Analysis for CZ~I-i~9N0~. 0 , 2Hz0 Calcd.: C:64.00, H:4.60, N:3.30 Found . C:64.26$, H:4.64, N:3.24.
Example 105 2,3-Dihydro-6-hydroxy-4-{4-methoxyphenyl)-1H-benz[f)isoindol-1-one H
HO
To a THF (20m1) and ethanol (30m1) solution of 6-benzyloxy-2,3-dihydro-4-(4-methoxyphenyl}-1H-benz[f)isoindol-1-one (0.8g) was added 10~ palladium carbon {0.2g) and stirred for 2 hours under hydrogen atmosphere. The catalysts were filtered off by Celite, and the filtrate was concentrated to give the entitled compound {480mg) as colorless crystals.
m.p.:249-251~C (THF}
NMR(CDC13}s: 3.89 (3H, s), 4.29 (2H, s), 7.0-7.4 (7H, m), 7.91 (1H, d, J = 9Hz), 8.27 (1H, s), 9.2S (IH, brs).
IR(KBr): 3215, 1683, 1616 cm-'.
Elemental Analysis for C19HISN0~
Calcd.: C:74.74, H:4.95$, N:4.59 Found . C:74.42$, H:5.03, N:4.59.
Example 106 6-Ethoxy-2,3-dihydro-4-(4-methoxyphenyl)-1H- ' Benz[f)isoindol-1-one SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97/02858 - H
Et0 - OMe To a THF (10m1) solution of 6-hydroxy-2,3-dihydro-4-(4-methoxyphenyl}-1H-benz[f]isoindol-1-one (80mg) and potassium carbonate (60mg) was added ethyliodide (150u1) and heated under reflux for overnight. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then concentrated under reduced pressure to give the entitled compound (6lmg) as colorless crystals.
m.p.:235-238~C (THF) NMR(CDC13)s: 1.40 (3H, t, J = 7Hz), 3.92 (3H, s), 3.97 (2H, q, J = 7Hz), 4.33 (2H, s}, 6.46 (1H, brs), 7.04 (1H, m), 7.07 (2H, d, J = 9Hz), 7.21 (1H, dd, J =
3Hz,9Hz), 7.32 (2H, d, J = 9Hz), 7.96 (1H, d, J = 9Hz), 8.33 (1H, s).
IR(KBr): 3209, 2979, 1695, 1616, 1506 cm-1.
Elemental Analysis for CZ1H19NO3 Calcd.: C:75.66, H:5.74, N:4.20 Found . C:75.23~,~H:5.83~, N:4.15.
Example 107 2,3-Dihydro-6-isopropoxy-4-(4-methoxyphenyl)-1H-benz[f]isoindol-1-one SUBSTITUTE SHEET (RULE 26~

WO 98I07705 PCTlJP97102858 H
' P r 0 OMe The entitled compound was obtained in a manner similar to that described in Example 106.
m.p.:212-215~C (THF) NMR(CDC1~)b: 1,31 (6H, d, J = 7Hz), 3.92 (3H, s), 4.39 (2H, s}, 4.50 (1H, m), 6.43 (1H, brs), 7.05 (1H, m), 7.07 (2H, d, J = 9Hz), 7.20 (1H, dd, J = 3Hz,9Hz), 7.32 (2H, d, J = 9Hz}, 7.96 (1H, d, J = 9Hz), 8.33 (IH, s).
iR(KHr): 3222, 2977, 1695, 1616, 1506 cm-'.
Elemental Analysis for CZZHz1N03 ~ 0 . 2HZ0 Calcd.: C:75.28%, H:6.15%, N:3.99%
Found . C:75.32%, H:6.33%, N:3.92%.
Example 108 Methyl [2,3-Dihydro-4-(4-methoxyphenyl)-1H-benz[f]isoindol-1-one-6-yl]oxyacetate \ 'N H
i M a 0 2 C~0 OMe The entitled compound was obtained in a manner similar to that described in Example I06.
m.p.:202-203~C (THF) NMR(CDC1~)s: 3.77 (3H, s), 3.93 (3H, s), 4.34 (2H, s), 4.59 (2H, s), 6.48 (1H, brs), 7.00 (1H, d, J = 3Hz), 7.08 (2H, d, J = 9Hz), 7.29 (3H, m), S.01 (1H, d, J =
9Hz), 8.3S (1H, s).
IR(KBr): 3178, 3076, 2956, I764, I683, 163I cm '.
SUBSTITUTE SHEET (RULE 2fi) WO 98I07705 PCT13P97l02858 Elemental Analysis for CzZH19NO5 _ Calcd.: C:70.02%, H:5.07%, N:3.71%
Found . C:69.54%, H:5.09%, N:3.72%.
. Example l09 S (2,3-Dihydro-4-(4-methoxyphenyl}-1H-bent[f]isoindol-1-one6-yl]oxyacetic acid ,0 'N H
H02 C~0 i Me To a THF (5m1) and methanol (1m1) solution of methyl [2,3-dihydro-4-(4-methoxyphenyl)-1H-benz[f]isoindol-1-on-6-yl]oxyacetate (90mg) was added 1N sodium hydroxide solution (3m1) and stirred for 2 hours at room temperature. To the reaction mixture was added diluted hydrogen chloride and extracted with ethyl acetate-THF. The extract was washed with water and dried with magnesium sulfate, then concentrated under reduced pressure to give the entitled compound (48mg} as colorless crystals.

m.p.:350-352C (THF}

NMR(DMSO-db)s: 3.86 (3H, s), 4.27 (2H, s), 4.64 (2H, s), 6.99 (1H, d, J = 2Hz), 7.11 (2H, d, J = SHz), 7.31 (1H, dd, J = 2Hz,9Hz), 7.40 (2H, d, J = 8Hz), 8.1S (1H, d, J = 9Hz), 8.26 (1H, s), 8.60 (1H, brs}.

IR(KBr): 3336, 2842, 1733, 1714, I616 cm~~.

Elemental Analysis for CiIHI~N05~0.5HZ0 Calcd.: C:67.74%, H:4.87%, N:3.76%

Found . C:67.50%, H:4.80%, N:3.75%.

' Example 110 12-(1,3-Benzodioxol-5-yl)-8,9,10,11-tetrahydro-7H-1,3-benzodioxolo[4,5-g][2]benzazepin-7-one SUBSTITUTE SHEET (RULE 2fi) w w NH
i i 0 - _ ~0 .../
Methyl 8-(3-Aminopropyl)-9-(1,3-benzodioxol-5-yl)-naphtho[1,2-d]-1,3-dioxol-7-carboxylate (l2mg) was dissolved in toluene (5m1), and heated under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified with column chromatography (silica gel lg, eluent:ethyl acetate-hexane = 2:1), then triturated with ether to give the entitled compound (3mg).
m.p.:245-248~C
NMR(CDC13)8: 1.86(2H, quintet,J=7Hz), 2.72(2H,t,J=7Hz), 3.18(2H, quartet,J=7Hz), 5.81(lH,d,J=l.4Hz), 5.83(lH,d,J=l.4Hz), 6.03(lH,d,J=l.4Hz), 6.06(lH,d,J=l.4Hz), 6.31{lH,brs), 6.69(lH,dd,J=l.5Hz,8Hz), 6.74(lH,d,J=l.SHz), 6.85{lH,d,J=8Hz), 7.18(lH,d,J=9H2), 7.53(lH,d,J=9Hz), 8.19(lH,s).
Example 111 8,9-Dihydro-10-(4-pyric~yl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one hydrochloride H
O
~n ~ HC 1 To a methanol (20m1) solution of 8,9-dihydro-10-(4-pyridyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one (120mg) was added 4N hydrogen chloride-ethyl acetate SUBSTITUTE SHEET (RULE 2fi~

WO 98/077U5 PCTlJP97102858 solution (4m1) and stirred for 30 minutes. The resultant precipitates were collected by suction and washed with ethyl acetate to give the entitled compound . (126mg).
m.p.:325-328~C
NMR(Dz0)6: 4.28 (2H, s), 5.95 (2H, s}, 7.30 (1H, m), 7.S5 (IH, m), 8.00 (1H, s), 8.13 (2H, m), 8.91 (2H, m).
IR(KBr): 3230, 3057, 2914, 1683, 1635 cm-1.
Elemental Analysis for C18H,3C1NZ03 ~ 0 . 3Hz0 Calcd.: C:62.35, A:3.97$, N:8.08 Found . C:62.23$, H:4.08, N:7.90.
Example I12 4-(B,9-Dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-on-10-yl)-1-methylpyridinium iodide H
~N~ I-Me To a methanol (10m1) solution of 8,9-dihydro-10-(4-pyridyl)-7H-I,3-benzodioxolo(4,5-f]isoindol-7-one {63mg) was added methyl iodide (3m1) and heated under reflux for 3 hours. The resultant precipitates were collected by suction and recrystallized from methanol-THF to give the entitled compound (5lmg) as yellow crystals.
m.p.:315-319~C
NMR(DMSO-d6)8: 4.36 (2H, s), 4.42 (3H, s), 6.03 (2H, s), 7.57 (1H, d, J = 9Hz), 8.00 (1H, d, J = 9Hz), 8.33 ' (2H, d, J = 7Hz), 8.53 (1H, s), 8.79 (1H, brs), 9.0S
(ZH, d, J = 7Hz).
IR{KBr): 3192, 3101, 1683, 1695 cm-~.
Elemental Analysis for C,qH,5IN20~ ~ 0 . 5Hi0 SUBSTITUTE SiiEE~' (RULE 2fiy WD 98I07705 PCTlJP97/02858 Calcd.: C:50.13%, H:3.54%, N:6.15%
Found . C:50.00%, H:3.69%, N:6.11%.
Example 113 8,9-Dihydro-10-(4-pyridyl)-7H-1,3-benzodioxolo[4,5- ' f)isoindol-7-one N-oxide NH

y To a dichloromethane (100m1} solution of 8,9-dihydro-10-(4-pyridyl)-7H-1,3-benzodioxolo[4,5-fjisoindol-7-one (200mg) was added MCFBA (350mg) and stirred for 2 hours at room temperature. To the reaction mixture was added water. The organic layer was taken and washed with sodium hydrogencarbonate solution and water. The mixture was dried with magnesium sulfate and concentrated to give the entitled compound (84mg).
m.p.:270-274~C
NMR(CDC13)&: 4.32 (2H, s), 5.95 (2H, s), 7.3-7.4 (3H, m), 7.71 (2H, m), 8.29 (ZH, d, J = 7H2), 8.37 (1H, s).
IR(KBr): 3416, 3107, 2902, 1695 cm~l.
Elemental Analys is f or C18H1zNx04 ~ 0 - 5H20 Calcd.: C:65.65%, H:3.98%, N:8.51%
Found . C:65.66%, H:4.29%, N:8.25%.
Example 114 1,2-Dihydro-7-methoxy-2-(4-methoxybenzyl)-9-(4-methoxyphenyl)-3H-pyrroio[3,4-bjquinolin-3-one SUSST1TLJTE SHEET (RULE Z6) WO 98l07705 PCTlJP97102858 Me0 ' S OMe OMe To 4-carbomethoxy-1-(4-methoxybenzyl)-2,3-dioxo-pyrrolidine (2.5g, 9.lmmol) was added 20% hydrochloric acid (150m1) and heated-under reflux for 30 minutes.

The mixture was cooled to room temperature and extracted three times with a mixed solvent of THF and ethyl acetate (1:2). The organic layer was washed with saturated sodium chloride solution and dried with magnesium sulfate, then the solvent was distilled off.

To the residue was added 2-amino-5-methoxyphenyl 4-methoxyphenyl ketone (670mg, 2.60mmo1), acetic acid (100m1), and concentrated sulfuric acid {0.5m1) and heated under reflux for 40 minutes. The solvent was distilled off. To the residue was added water and potassium carbonate solution, then extracted twice with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with magnesium sulfate, then the solvent was distilled off.

The. residue was purified with silica gel column chromatography {eluent:ethyl acetate) to give the entitled compound (987mg, 86%) as colorless crystals.

m.p.:191-192C (ethyl ether) NMR (CDC13)6: 3.77(6H, s), 3.91(3H, s), 4.19(2H, s), 4.82(2H, s), 6.81-7.35(9H, m), 7.42(1H, dd, J=3Hz, - 9Hz), 8.31{1H, d, J=9Hz) IR (KHr): 3001, 2912, 2839, 1700, 1623, 1513, 1463, 1289, 1243 cm ~.

Elemental Analysis for C2~H24Nx0,, ~ 0 . 2HZ0 Calcd.:C:73.02%, H:5.54$, N:6.31%

Found: C:72.99%, H:5.57%, N:6.30%.

SUBSTtT'UTE SHEET {RULE 26) WO 9S10??05 PCTlJP97/02858 Example 115 9-(4-Fluorophenyl)-1,2-dihydro-7-methoxy-2-(4- -methoxybenzyl)-3H-pyrrolo[3,4-b)quinolin-3-one Me0 Me The entitled compound was obtained in a manner similar to that described in Example 114.
m.p.:170-173~C (ethyl acetate-ether) NMR(CDC1~)F: 3.78(3H, s), 4.16(2H, s), 4.82(2H, s), 6.85{2H, d, J=7.8Hz), 6.95(1H, m), 7.20-7.50(7H, m), 8.34(1H, d, J=9Hz).
IR(KHr): 2929, 1700, 1612, I506, 1515, 1249, 1230 cm-i Elemental Analysis for CZ6H1yNz04F ~ 0 . 2Hz0 Calcd.: C:72.28$, H:4.990, N:6.48 Found . C:72.39, H:5.03, N:6.10.
Example 116 1,2-Dihydro-7-methoxy-2-(4-methoxybenzyl)-9-(4-trifluoromethylphenyl)-3H-pyrrolo[3,4-bJquinolin-3-one O
Me0 OMe The entitled compound was obtained in a manner similar to that described in Example 114.
m.p.:140-142~C (THF-ethyl acetate) NMR (200MHz, CDC1~) ppm: 3.78(3H, s), 4.15(2H, s), 4.82(2H, s), 6.80-6.90(3H, m), 7.20-7.30(2H, m), 7.40-SUBSTITUTE SHEET (RULE 26y 7.50(1H, m), 7.52(2H, d, J=9.2H2), 7.83(2H, d, J=B.OHz), 8.36(1H, d, J=9.2H2) Example 117 3,4-Dihydro-7-methoxy-2-(4-methoxybenzyl)-5-(4-trifluoromethylphenyl)-benzo(b](1,7]naphthyridin-1(2H)-one J
Me0 OMe The entitled compound was obtained in a manner similar to that described in Example 114 from 3,3-dimethoxy-1-(4-methoxybenzyl)-2-piperidone.
m.p.:234-236~C (THF) NMR(CDC1~)8: 2.77 (ZH, t, J = 6H2), 3.43 (2H, t, J =
6H2), 3.73 (3H, s), 3.78 (3H, s), 4.82 (2H, s), 6.59 (1H, d, J = 3H2), 6.85 (2H, d, J = 9H2), 7.32 (2H, d, J
- 9H2), 7.41 (3H, m), 7.82 (1H, d, J = 8H2), 8.35 (1H, d, J = 9H2).
IR(KBr): 2964, 2933, 2835, 1661, 1621 cm-'.
Elemental Analysis for CZeH23FN20~
Calcd.: C:68.29%, H:4.71%, N:5.69%
Found . C:68.46%, H:4.78%, N:5.57%.
Example llB
3,4-Dihydro-7-methoxy-2-(4-methoxybenzyl)-5-(4-methoxyphenyl)-benzo(b][1,7]naphthyridin-1(2H)-one SUBSTITUTE SHEET RULE 26) I ~ W , Me0 ~ OMe OMe The entitled compound was obtained in a manner similar to that described in Example 117.
m.p.:132-134~C (THF) NMR(CDC1~)s: 2.83 {2H, t, J = 6Hz), 3.41 (2H, t, J =
6Hz), 3.74 (3H, s), 3.78 (3H, s), 3.90 (3H, s), 4.82 (2H, s), 6.76 (1H, d, J = 3Hz), 6.85 {2H, d, J = 9Hz), ?.05 (2H, d, J = 9Hz), 7.18 (2H, d, J = 9Hz), 7.32 (2H, d, J = 9Hz), 7.36 (1H, dd, J = 3Hz,9Hz), 8.32 (1H, d, J
- 9Hz).
IR(KBr): 2958, 2935, 2837, 1662, 1616, 1515 cm-~.
Elemental Analysis for CZBH26N2~4 Calcd.: C:73.99, H:5.77, N:6.16 Found . C:73.52, H:5.71, N:6.14%.
Example 119 1,2-Dihydro-7-methoxy-9-(4-methoxyphenyl)-3H-pyrrolo[3,4-b]quinolin-3-one N U
NH
i i Me0 i wl OM a ' A mixture of 1,2-Dihydro-7-methoxy-2-{4- a methoxybenzyl)-9-(4-methoxyphenyl)-3H-pyrrolo(3,4-b]quinolin-3-one (500mg, 1.14mmo1), diammonium cerium (IV) nitrate (3.9g, 7.lmmol), acetonitrile (30m1), and water(30m1) was stirred for 40 minutes at room SUBSTITUTE SHEET RULE 26) temperature. The solvent was distilled off and water was added to the residue, The mixture was extracted twice with THF-ethyl acetate (1:1). The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate, then the solvent was distilled off to give the entitled compound (75mg} as colorless crystals.
m.p.:307~C (Decomp.)(methanol-ethyl acetate) NMR{DMSO-d6)8: 3.77(3H, s), 3.87(3H, s), 4.37(2H, s), 7.00-7.25(3H, m), 7.40-7.70(3H, m), 8.16(1H, d, J=9H2), 9.13(1H, s).
IR(KBr): 3186, 3101, 1716, 1687, 1608, 1S08, 1463, 1253, 1230 cm~l.
Elemental Analysis for C19H16Nz03~0.2H20 Calcd.: C:70.45$, H:5.10, N:8.65 Found . C:70.22, H:5.04, N:6.54.
Example 120 9-(4-Fluorophenyl)-1,2-dihydro-7-methoxy-3H-pyrrolo[3,4-b]quinolin-3-one zo _. n Me H
The entitled compound was obtained in a manner similar to that described in Example 119.
m.p.:284-286~C (ethanol-ethyl acetate) NMR(CDC1~)8: 3.79(3H, s), 4.42(2H, s), 6.96(1H, m), 7.10-7.60(4H, m), 7.96(1H, brs), 8.29(1H, d, J=9H2).
IR(KBr): 3Z80, 1733, 1625, 1506, 1463, 1232 cm-~.
Elemental Analysis for C~BH11NZO~F ~ 0. 2H20 Calcd.: C:66.34$, Ii:3.53$, N:8.60$
. 35 Found . C:66.70$, H:3.95, N:8.60$.
Example 121 SUBSTITUTE SHEET (RULE z6) 1,2-Dihydro-7-methoxy-9-(4-trifluoromethylphenyl)-3H-pyrrolo[3,4-b)quinolin-3-one __ O
H -Me The entitled compound was obtained in a manner similar to that described in Example 119.
m.p.:305~C (Decomp.)(THF-ethyl acetate) NMR(CDC13)b: 3.80(3H, s), 4.41(2H, s), 6.91(1H, m), 7.20-7.65(4H, m), 7.75-8.00(2H, m), 8.34(1H, d, J=9Hz).
IR(KBr): 3199, 1727, 1684, 1627, 1507, 1326, 1Z34 cm-i Elemental Analysis for CIgHI3NZOZF3 ~ 0. 4H10 Calcd.: C:62.43%, H:3.81%, N:7.66%
Found . C:61.98%, H:3.47%, N:7.55%.
Example 122 3,4-Dihydro-7-methoxy-5-(4-methoxyphenyl)-benzo[b][1,7]naphthyridine-1(2H)-one , ~ N N H
i Me0 i I
OMe The entitled compound was obtained in a manner similar to that described in Example 119.
m.p.:287-288~C
NMR(CDC1~)6: 2.95 (2H, d, J = 6Hz), 3.56 (2H, m), 3.74 (3H, s), 3.93 (3H, s), 6.77 (iH, d, J = 3Hz), 7.09 (2H, d, J - BHz), 7.23 (2H, d, J = BHz), 7.37 (1H, dd, J =
3Hz,9Hz), 7.73 (1H, brs), 8.30 (1H, d, J = 9Hz).
SUBSTITUTE SHEET {RULE 26) IR(KBr): 3257, 2995, 2952, 2873, 2831, 1695) 1662, l616 cm-1.
Elemental Analysis for CzoH~8Ni03 ~ 0 . 3H20 Calcd.: C:70.57, H:5.46, N:8.23 Found . C:70.44$, H:5.46, N:7.83.
Example 123 Methyl [8,9-Dihydro-10-(4-methoxyphenyl}-7H-1,3-benzodioxolo(4,5-f]isoindol-7,9-dion-8-yl]acetate 15 OMe ~~p2Me To a DMF (50m1} solution of 8,9-dihydro-10-(4-methoxyghenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7;9-dione (2.0g) was added sodium hydride (60o in oi1:0.3g) under ice cooling and stirred for 1 hour at room temperature. To the mixture was added methyl bromoacetate (0.65m1) and stirred for 1 hour at room temperature. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and dried with magnesium sulfate, then the solvent was distilled off under reduced pressure to give the entitled compound (1.8g) as yellow crystals.
m.p.:253-25S~C (THF-ethyl acetate) NMR(CDC13}S: 3.73 (3H, s), 3.89 (3H, s), 4.37 (2H, s), 5.91 (ZH, s}, 6.97 (2H, d, J = 9Hz), 7.32 (2H, d, J =
9Hz}, 7.35 (1H, d, J = BHz), 7.6B (1H, d, J = 8Hz), 8.30 (1H, s}.
IR(Ker): 2954, 2904, 1756, 1750, 1713, 1616, 1S13 cm-i Elemental Analysis for CZ~H1~N0~
Calcd.: C:65.87, H:4.09$, N:3.34 SUBST1TUTF S1-iEFT (RULE 26) Found . C:65.38, H:4.16, N:3.43.
Example 124 .
10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-8-(2-pyridyl)-7fi-1,3-benzodioxolo[4,5-f]isoindol-7-one -To a solution of 10-(1,3-Benzadioxol-5-yl)-8,9-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one (200 I5 mg), which was obtained in Example 1, in DMF (5 ml) were added 2-bromopyridine {0.11 ml), CuI (121 mg), and potassium carbonate (159 mg). The reaction mixture was stirred overnight at 120~C. To the reaction mixture was added concentrated NH40H, and resultant 20 precipitates were collected by suction. The precipitates were washed with methanol and ether, and then recrystallized from THF and ethanol to give the entitled compound (78 mg).
m.p.:305~C (decomp.) 25 NMR(DMSO-d6)8: 4.91(2H, s), 5.99(lH,d,J=l.OHz), 6.01(lH,d,J=l.OHz), 6.11(IH,d,J=l.OHz), 6.16(lH,d,J=l.OHz), 6.94(lH,dd,J=l.6Hz,$Hz), 7.03(lH,d,J=8Hz), 7.09(lH,d,J=l.6Hz), 7.15-7.Z3(lH, m), 7.47(lH,d,J=9Hz), 7.85-7.95(lH,m), 7.92(lH,d,J=9Hz), 30 8.40(lH,m), 8.50(lH,s), 8.59(lH,d,J=8Hz).
Example 125 4-{1,3-Benzodioxol-5-yl)-5,7-dimethoxy-1H-benz[f]isoindol-1,3{2H)-dione SUBSTt'fUTE SHEET (RULE 2fi) OMe -- OM a s The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:265-267~C
NMR(DMSO-db)S: 3.51(3H, s), 3.97(3H, s), 6.03(lH,brs), 6.05(lH,brs), 6.57(lH,d,J=2Hz), 6.69(lH,dd,J=l.6Hz,8Hz), 6.75(IH,d,J=l.6Hz), 6.87(lH,d,J=8Hz), 6.96(lH,d,J=2Hz), 7.59(lH,brs), 8.16(lH,s).
IR(KBr): 1756, 1718, 1610, 1361, i312, 1232, 1212 cm-i Elemental Analysis for CZ1H~SN06 ~ 0 . 4HZ0 Calcd.: C:65.59, H:4.14, N:3.64 Found . C:65.59, H:4.30$, N:3.59.
Example 126 4-(1,3-Benzodioxol-5-yl)-2,3-dihydro-5,7-dimethoxy-1H-benz(f]isoindol-1-one OMe C
The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:252-254~C (MeOH) _ 35 NMR(CDC1~)b: 3.52(3H, s), 3.95(3H, s), 6.03(lH,brs), 4.15(lH,d,J=l7Hz), 4.22(lH,d,J=l7Hz), 6.02(lH,brs), SUBSTITUTE SHEET (RULE 26) 6.03(lH,brs) 6.29(lH,brs), 6.54(lH,d,J=2Hz}, 6.68(lH,dd,J=l.BHz,BHz),.6.73(lH,d,J=l.BHz), ' 6.85(lH,d,J=8Hz), 6.93(lH,d,J=2Hz), 8.23{lH,s).
IR(KBr): 1697, 1617, 1486, 1230, I214, 1162 cm~.
Elemental Analysis for CZ~H1~N05 ~ 0 . 6Hz0 Calcd.: C:67.41, H:4.90, N:3.74 Found . C:67.31, H:4.79, N:3.52.
Example 127 9-(1,3-Benzodioxol-5-yl)-6H-1,3-benzodioxolo[5,6-f]isoindol-6,8(7H)-dione H
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:299-301~C (decomp.}(THF) NMR(CDC1~)s: 6.09(2H, m), 6.13(2H, m), 6.8I(2H,m), 6.98(lH,d,J=8Hz), 7.14{lH,s}, 7.34(lH,s), 8.08(IH,brs), 8.16(lH,s).
IR~(KBr): 3168, 2920, 2783, 1768, 1724 cm-1.
Elemental Analysis for CZOH11N06 Calcd.: C:66.49, H:3.07%, N:3.88 Found . C:65.96, H:3.33, N:3.55.
Example 128 9-(I,3-Benzodioxol-5-yl)-7,8-dihydro-6H-1,3-benzodioxolo[5,6-f]isoindol-6-one SUBSTITUTE SHEET (RULE 26) H
The entitled compound was obtained in a manner similar to that described in Example 53.
NMR(CDC1~)s: 4.31(2H, s), 6.07(2H, s), 6.08(2H, s), 6.53(lH,brs), 6.80(2H,m), 6.96(lH,d,J=8Hz}, 7.05(lH,s}, 7.3I(lH,s), 8.22(lH,s).
Example 129 11-{4-Fluorophenyl}-7,8,9,10-tetrahydro-6-methyl-1,3-benzodioxolo[4,5-g)isoquinolin-7-one H
The entitled compound was obtained in a manner similar to that described in Example 12 from methyl 8-cyanomethyl-9-(p-fluorophenyl)-6-methylnaphtho[i,2-dj-1,3-dioxol-7-carboxylate, which was obtained in Reference Example 28.
m.p.:237-240~C
NMR{CDC1~)b: 2.69(2H,t,J=6Hz), 3.08{3H,s), 3.28-' 3.38(2H,m), 5.77(2H,s), 6.16{lH,brs}, 7.04-7.27{SH,m}, 7.B8(lH,d,J=9Hz).
IR{KBr): 3202, 1659, 1507, 1447, 1285, l069 cm-~.
Example 130 11-{4-Fluorophenyl)-7,8,9,10-tetrahydro-1,3-benzodioxolo[4,5-gjisoquinolin-7-one SUBSTITUTE SHEET (RULE 3,fi~

H
The entitled compound was obtained in a manner similar to that described in Example 11, from 8-cyanomethyl-9-(g-fluorophenyl)-naphtho(1,2-d]-1,3-dioxol-7-carboxylic acid, which was obtained in Reference Example 29.
m.p.:2B5-286~C
NMR(CDC13)8: 2.78(2H,t,J=6Hz), 3.48(2H,dt,J=3Hz,6Hz), 5.80(2H, s), 6.16(lH,m), 7.05-7.30(5H, m), 7.61(lH,d,J=9Hz), 8.65(lH,s).
IR(RBr): 1672, l630, 1S05, l481, 1454, 1282, 1074 cm~
Example 13l 11-(1,3-Benzodioxol-5-yl)-7,8,9,10-tetrahydro-6-methyl-1,3-benzodioxolo(4,5-g]isoquinolin-7-one H
30 The entitled compound was obtained in a manner similar to that described in Example 11 from methyl 8-cyanomethyl-9-(1,3-benzodioxol-5-yl)-6-methylnaphtho[1,2-d]-1,3-dioxol-7-methylcarboxylate, which was obtained in Reference Example 30.
m.p.:239-241~C
NMR(CDCI~)b: 2.74(2H,t,J=6Hz), 3.30-3.40(2H, m), SUBSTITUTE SiiEET (RULE Z6) WO 98t07705 PCTIJP97102858 5.82(lH,d,J=l.4Hz), 5.83(lH,d,J=l.4Hz), 6.02(lH,d,J=l.4Hz), 6.06(lH,d,J=l.4Hz), 6.67(lH,dd,J=l.4Hz,8Hz), 6.72(lH,d,J=l.4Hz), 6.85(lH,d,J=8Hz), 7.21(lH,d,J=,9Hz), 7.87(lH,d,J=9Hz).
' 5 IR(KBr): 165S, 1489, 1437, 12$7, 1233, 1065, 1039 cm-f Example 132 ' 11-(4-Fluorophenyl)-8H-isoindolo(5,6-f)benz(b}-l,4-dioxan-8,10(9H}-dione is dH
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:274-276~C (THF) NMR(CDC13}s: 3.89(2H,m}, 4.23(2H,m), 7.09(2H,t,J=9Hz}, 7.26(3H, m), 7.60(lH,d,3=9Hz), 7.68(lH,brs), 8.25(lH,s).
IR(KBr): 3214, 1759, 1717, 1605, 1508 cm-1.
Elemental Analysis for CzoHizFN04 Calcd.: C:68.770, H:3.46%, N:4.01%
Found . C:68.56%, H:3.24$, N:3.75.
Example 133 11-(4-Fluorophenyl)-9,10-dihydro-8H-isoindolo[5,6-f}benz(b}-1,4-dioxan-8-one SUBSTtTLJTE SHEET tRULE Zfi) WO 98l07705 PCTIJP97102858 H
s The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.~:276-278~C (THE) NMR(CDC13)s: 3.91(2H, m), 4.17(2H, s), 4.23(2H, m), 6.96(lH,brs), 7.09(2H,t,J=9Hz), 7.21(3H, m), 7.59(lH,d,J=9Hz), 8.31(lH,s).
IR(KBr): 3196, 30B6, 2B90, 1'694, 1617, 1508 cm-1.
Elemental Analysis for CZOH~4FN03 Calcd.: C:71.64, H:4.21$, N:4.18 Found . C:71.08, H:4.60, N:3.84.
Example 134 10-(1,3-Benzodioxol-5-yl)-2,3-dihydro-7H-benzofuro-[6,7-f]isoindol-7,9{8H)-dione ~H
30 The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:>320~C (THE) .
NMR(DMSO-db)s: 3.26(2H,t,J=lOHz), 4.39(2H,t,J=lOHz), 6.09(2H,d,J=4Hz), 6.71(lH,d,J=9Hz), 6.86(lH,s), 6.88(lH,d,J=9Hz), 7.66(lH,d,J=8Hz), 7.78(lH,d,J=SHz), 8.37(lH,s), 11.30(lH,brs).
SUBSTITUTE SHEET (RULE 26) IR(KBr): 3194, 3071, 2B99, 1752, 1711 cm-'.
Elemental Analysis for CZ~H~jN05~0.3Hz0 Calcd.: C:69.04%, H:3.77%, N:3.83%
Found . C:68.82%, H:3.81%, N:4.01%.
Example 135 10-(1,3-Benzodioxol-5-yl)-2,3-dihydrobenzofuro-(6,7-' f)isaindol-7(9H)-one to The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:275-277~C {THF) NMR(CDC1~)s: 3.29(2H,t,J=9H2), 4.23(lH,d,J=l7Hz), 4.34(lH,d,J=l7Hz), 4.46(2H,t,J=9Hz), 6.05(2H,t,J=6Hz), 6.76(2H,m),6.87(iH,d,J=8Hz), 7.32(IH,brs), 7.43(lH,d,J=8Hz), 7.60(lH,d,J=8Hz), 8.35(1H,5).
IR(KHr): 3225, 289Z, 1698, 1489 cm-1.
Elemental Analysis for CZiHiSNOa ~ 0 . 2HZ0 ~ Calcd.: C:72.2$%,,H:4.45$, N;4.01%
Found . C:72.25$, H:4.47%, N:3.93%.
Example 136 10-(4-Fluorophenyl)-2,3-dihydro-7H-benzofuro-(6,7-f]isoindol-7,9(8H)-dione SUBSTITUTE SHEET tRULE Z6) WO 98I07705 PCTIJP9?I02858 dH
The entitled compound was obtained in a manner similar to that described in Example 14.
m.p.:>310~C (THF) NMR(CDC1~)8: 3.29{2H,t,J=9Hz), 4.42(2H,t,J=9Hz), 7.12(2H,t,J=9Hz), 7.27(2H, m), 7.56(lH,d,J=BHz), 7.63(lH,d,J=8Hz), 7.69(lH,brs), 8.32(lH,s).
IR(KBr): 3193, 30S2, 1767, 1721, 1S08 cm-'.
Elemental Analysis for CZOHizFN03 ~ 0 . 2HZ0 Calcd.: C:71.30, H:3.71, N:4.16 Found . C:70.93, H:4.09, N:3.82.
Example 137 10-(4-Fluorophenyl)-2,3-dihydrobenzofuro-[6,7-f]isoindol-7(9H)-one H
30 The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:302-305~C (THF) NMR(CDC1~)&: 3.29(2H,J=9Hz), 4.24(2H, s), 4.42(2H,t,J=9Hz), 6.42(lH,brs), 7.12(3H,t,J=9Hz), 7.29(2H,t,J=9Hz), 7.44(lH,d,J=8Hz), 7.62(lH,d,J=BHz), 8.38(lH,s).
SUBSTITUTE SHEET (RULE 26) WO 98l07705 PCTlJP97102858 IR(KBr): 3194, 30B5, 2894, 1713, 1694, 1508 cm-'.
Elemental Analysis far CioH~4FNOz ' Calcd.: C:75.23, H:4.42$, N:4.39 Found . C:74.78, H:4.40, N:4.34 ~ 5 Example 138 6,7-Diethoxy-4-(4-pyridyl)-1H-benz[f]isoindol-1,3(2H)-dione Et H
1~ E t 15 The entitled compound was obtained in a manner similar to that described in Example 46.
m.p.:210-213~C (CHC13, AcOEt).
NMR(DMSO-d6)s: 1.43(3H,t,J=7Hz), 1.58(3H,t,J=7Hz), 3.95(2H,q,J=7Hz), 4.29(2H,q,J=7Hz), 6.88(lH,s), ?.20-20 7.40(3H, m), 8.22(lH,s}, 8.82(2H, m).
Example 139 2,3-Dihydro-6,7-diethoxy-4-(4-pyridyl)-1H-benz[f]isoindol-1-one 25 E t H
Et The entitled compound was obtained in a manner similar to that described in Example 53.
m.p.:169-172~C (EtOH-Et20).
r NMR(DMSO-d~)b: 1.34(3H,t,J=7Hz), 1.46(3H,t,J=7Hz), 3.88(2H,q,J=7Hz}, 4.18(2H,q,J=7Hz), 4.21(2H, s), 6.74(lH,brs), 6.79(lH,s), 7.17(lH,s), 7.30(2H,brs), SUBSTTTUTE SHEET (RULE 26) 8.17(1H,5), 8.73(lH,brs).
Example 140 11-(4-Fluorophenyl)-7,8,9,10-tetrahydro-6-methyl-1,3-benzodioxolo(4,5-g]isoquinolin-7-one The entitled compound was obtained in a manner similar to that described in Example 11.
m.p.:237-240~C (decomp.){THF).
NMR(DMSO-d~)8: 2.69(2H,t,J=6Hz), 3.08(3H,5), 3.28-3.38(2H,m), 5.77(2H,5), 6.16(lH,brs), 7.04-7.27{SH,m), 7.88(IH,d,J=9Hz).
IR(KBr): 320D, 1659, 1507, 1287, 1069 cm-1.
Example 141 7,8,9,10-Tetrahydro-11-(4-methoxyphenyl)-1,3-benzodioxolo[4,5-g]isoquinolin-7-one z5 The entitled compound was obtained in a manner similar to that described in Example 11.
m.8.:245-247~C (CHC1~), NMR(DMSO-db)S: 2.80(2H,t,J=7Hz), 3.4?(2H,dt,J=2Hz,7Hz), 3.90(3H,5), 5.81(2H,5), -6.20(2H,brs), 6.96(2H,d,J=9Hz), 7.15-7.23(3H, m), SUBSTITUTE SHEET (RULE 2fi) WO 98I07705 PCTlJP97/02858 7.60(lH,d,J=9Hz), 8.63(lH,s).
IR(KBr): 2890, 1669, 924 cm'.
Example 142 7,8,9,10-Tetrahydro-11-(4-trifluoromethylphenyl)-I,3-benzodioxolo(4,5-gJisoquinolin-7-one H

to s The entitled compound was obtained in a manner similar to that described in Example 11.
m.p.:246-248~C
NMR(DMSO-db)s: 2.74(2H,t,J=6Hz),3.48(2H,dt,J=3Hz,6Hz), 5.78(2H, s), 6.22(lH,brs), 7.21(lH,d,J=8Hz), 7.40(2H,d,J=BHZ), 7.62(lH,d,J=8Hz), 7.68(2H,d,J=8Hz), 8.68(lH,s).
IR: 1672, 1456, 132.5, 1071 cml Example 143 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-8-methoxy-7H-1,3-benzodioxolo(4,5-f)isoindol-7-one Me To a solution of methyl 9-(1,3-benzodioxol-5-yl)-8-methanesulfonyloxymethylnaphtho(1,2-d)-1,3-dioxole-7-carboxylate (400 mg), which was obtained in reference example 14, in DMF (4 ml) were added Q-methylhydroxylamine hydrochloride (219 mg) and SUBSTITUTE SHEET (RULE 26) potassium carbonate (362 mg). The reaction mixture was stirred for 1 hour at room temperature and for 5 hours at 60~C. To the reaction mixture was added water.
The resultant precipitates were collected by suction and dissolved in ethyl acetate. The solution was washed with brine, dried over magnesium sulfate, and .
concentrated under reduced pressure. The residue was purified by column chromatography (silica ge1:30 g, eluent:ethyl acetate-hexane = 1:2) and then recrystallized from ethyl acetate to give the entitled compound (130 mg).
m.p.:214-216~C
NMR(DMSO-db)s: 3.95(3H, s), 4.42{lH,d,J=16H2), 4.49(lH,d,J=16H2), 5.92(lH,d,J=1.4H2}, 5.94(lH,d,J=1.4H2), 6.05(lH,d,J=1.4H2}, 6.08(lH,d,J=1.4H2}, 6.78-6.94(3H,m), 7.27(lH,d,J=9H2}, 7.65(IH,d,J=9H2), 8.33(lH,s}.
IR(KBr): 1713, 1489, 1458, 1439, 1273, 1235, 1063 cml Elemental analysis for CzlHisN06 Calcd.: C:66.84, H:4.01k N:3.71 Found . C:66.73, H:3.97, N:3.66.
Test Example 1 Induction of alkaline phosphatase {ALP) production in cultured murine osteoblasts The mouse-derived osteoblast cell line MC3T3-E1 cells in 10$ fetal calf serum (FCS)-a,-minimum essential medium (MEM) were seeded in a 96-well microtiter plate {8x10' cells/well). After 2 days when the growth had become confluent, the test substance diluted to various concentrations [Table 1) with the medium either -containing or not containing 3 ng/ml of BMP-4/7 heterodimer (described in Japanese Patent Publication {Kokai) No. H7-265083) was added and the micrvtiter plate was further incubated for 72 hours. After the plate was washed once with phosphate buffered saline, the substrate solution was added and the plate was SUBSTITUTE SHEET (RULE 2fi) further incubated at room temperature for 15 minutes.
The reaction was stopped by adding 0.05 N-sodium hydroxide and the absorbance at 405 nm was measured.
It was found that, as shown in Tables 1-6, the compound " 5 of the invention enhances BMP activity, that is to say the induction of ALP production by BMP and that, regardless of the presence or absence of BMP, the compound of the invention by itself shows high ALP
production inducing activity.
SUBS'~ITUTE SH~~~' (RULE 25) WO 98l07705 PCTlJP97/02858 [Table 1]

Induction of alkaline phosphatase (ALP) production in mouse osteobl ast cell lineMC3T3-E1 Example Concentration ALP activity (1000xA4oslSD) No of d m . co n ou (uM~ With BMP Without BMP

1 1 21838w 133lz.,~

O.I 515 1,., 224 9;

, 0.01 670124 227117 0 (blank control)253 4 641 3 2 1 52329,~ 172 6,, 0.1 58723,., 162118;, 0.01 414t29 112112 0 (blank control)341t23 74111 ,.

9 1 37839;, 199168 0.1 306148;, 166171 0.01 296t34 152t42 0 (blank control)213134 106124 10 1 169137 r 8013fi., 0.1 402t52,., 190133 0.01 348134 171151 0 (blank control)213134 106124 11 1 33513,~ 214119,;

0.1 630t25,., 327116 .

, 0.01 57134 , 0 (blank control)177110 761 3 12 1 78210,~ 362 3,.~

0.1 699140 3231I8 0.01 504178 236114 0 (blank control)542125 2131 7 13 1 705127',,, 341k10;, 0.1 603131 23517 0.01 4l4 8 I811 1 0 (blank control)374121 1391I0 14 1 615 7" 30719;
"

, 0.1 673128 297 5, 0.01 475116 223 ?"

0 (blank control)4S7116 195110 SUBSTITUTE SHEET (RULE ~6) [Table 2]

31 1 71441',, 24010~' ' 0. 1 429 4 16016 ;

0.01 31912 , 1l5 1 0 (blank control} 29510 87 3 53 1 453t65;, 31231"

( 0.1 77135,; 393t11 .

, 0.01 8I9155 , 0 (blank control} 49228 244 5 ' 55 1 12i154; 42227', 0.1 751t 8,., 261 9, 0.01 567t10 205 9 0 (blank control) 40628 149 3 58 1 1082t37. 66615:i 0.1 101837,, 65422 0.01 1005t29 602t65 0 {blank control) 709t 9 46811 59 1 117732,~ 482t22'., 0.1 152757" 60130,.

, 0.01 95649 278t17 0 {blank control) 399t56 182 3 60 1 1118t46'~~ 43024,, "

O.I 1746106 57439,., 0.01 121461 31415 0 {blank control) 762t51 202t 9 61 1 89021" 276t13'.

0.1 597t42 169 6~~

0.01 48819 147 6 0 {blank control) 464t16 155 3 62 1 166387,, 68313,.

, 0.1 81069 235 3 0.01 66740 17310 0 (blank control) 67852 171 9 63 1 113037,'., 68828.~

0.1 157524;, 599t26"

0.01 135576 46911 0 {blank control) 81735 211t 9 SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 [Table 3]

64 1 45321" 16910,, 0.1 64817;, 194 2.

0.01 69233 1B7 6"

0 (blank control) 42032 124t 3 65 1 354 9;, 2331~.,~

0.1 142755 , 450 6:, e 0.01 1513127 50114 0 (blank control} 795t163 182 2 66 1 80319 , 197 5.,~

0.1 1460t123,; 324 6,;

0.01 15871127 422110 0 (blank control) 78022 422t10 67 1 261 7:, 12S 3.f:.

0.1 312 9, 142 1 ' 0,01 42768 17711 0 (blank control} 244t10 108 4 68 1 34818,; 227 6;, 0.1 640 7* 35519;~

0.01 41922 189U2 0 (blank control) 152t 6 72 6 69 1 29821,, 185 7'., 0.1 59321* 309 4 .

, 0.01 671t48 , 383t12 0 (blank control) 152 6 72 6 70 1 59826, 385t27 0.1 30910;, 162 4"

0.01 199t13 9B 2 0 (blank control) 158 ? 83t 4 72 1 433t21" 178 8,., 0.1 1543t18,; 51021 ;

0.01 161050 , 0 (blank control) 74539 21412 73 1 80526,, 467 4,., 0.1 884t43* 538t14;
' 0.01 97410 59833 0 (blank control) 69537 46719 SUBSTi'tLJTE SHEET (RULE 26) [Table 4) 7 5 1 9 0 8112 313110'.' ', 0.1 1098145;, 294116"
"

0.0l 974154 297 7 0 (blank control) 451123 149 4 76 1 586139.; 293 9, O.I 914136,., 359124.

0.01 1049110 478135"

0 (blank control) 324 8 101 5 77 1 638t36; 356 8;, 0.1 886132;, 446t20"

0.01 711t32 347119 0 (blank control) 33429 135 2 78 1 617154,, 3S823~~
~

0. 1 555118., 3161 6.
' 0.01 247116 125 2'' 0 (blank control) 161t 7 791 2 79 1 586112;, 3061 3,..

0.1 66227 332t14:.

0.01 320143 136 5~

0 (blank control) 1611 7 791 2 80 1 379t80; 224 8"

0.1 201111 981 6 0.01 168 8 821 8 0 (blank control) 158 B 831 5 81 1 437130',., 175117,:

0.1 61161a, 232 2.
"

0.01 483t26 164112 0 (blank control) 216 3 671 2 82 1 393111, 177112',., 0.1 647134,., 264117;, 0.01 5?11 6 206124 0 (blank control) 201115 601 4 - .

83 1 352t16;, 200110;' 0.1 585130;, 264 4;

0.01 639157 248122 - 55 0 (blank control) 229119 7l1 4 SUBSTITUTE SHEET (RULE 26) [Table 5j 87 1 293124., 149 $,,,.
' 0 . 1 40034 153 12,., .
"

0.01 328 8 103 8 -0 (blank control) 174t 2 451 1 89 1 416t30, 109130., -0 . 1 382 t26,; 90110 0.01 232t14 471 6 0 {blank control) 151 3 371 3 0.1 368128* 135 6..

0.01 535119 166t 7 0 (blank control) 420132 124 3 91 1 4241 4,, 276 1,;

0.1 61228 326 3:
~

0.01 322111 119 4 0 (blank control) 158 7 83t 4 93 1 283 7.', II61 1;.;

0.1 64116,~ 200 6;, 0.01 675182 175110 0 (blank control) 486118 132t 3 94 1 1487127"' 493t12;, 0.1 925150., 274128,., ' 0.01 656127 196t 9 0 (blank control) 486118 153110 98 1 463t38* 1761 6.,~' 0.1 638t59,., 194t 9;, Q.01 617131 181 2 0 (blank control) 421136 151t 3 " .

99 1 907 9i, 529 9"

0.1 903330i, 539110i , 0.01 930 1 5611 6 0 (blank control) 703 1 4431 7 100 1 93725 539 7~
' 0 . 1 899131* 571 U5;, 0.01 932t22 579t30 -0 (blank control) 703136 443 7 SUBSTITUTE SHEET (RULE 26) WO 98I07705 PCTlJP97102858 [Table 6]

103 1 1473t55" 577t18;, 0.1 141321. 36115.;

0.01 92665~ 206 5 0 (blank control) 67852 171 9 104 1 848166i' 203 4'~

0.1 720126 184t 6 0.01 74844 172 1 0 (blank control) 696131 172t 9 , 105 1 368 8,., 28218;, 0.1 300130 1S3 6 0.01 182110 89 2 0 (blank control) 158t 8 83t 5 106 - - 1 589132" 243 6.."

0 . 1 40925;, 132 t 5;, 0.01 288113 100 4 0 (blank control) 215133 69 7 112 1 706139',., 442 8r, 0.1 588126;, 362112 0.01 464124 3031l7 0 (blank control) 423t16 284 7 113 1 72918;, 55321'., ' 0.1 613116* 47212B

0.01 568122 43018 0 {blank control) 520115 41015 119 1 1165t82, 63735;' ' 0.1 671172 291 7 .
"

0.01 395120 16310 0 (blank control) 334123 123t 4 *

124 1 680118 244 4~~.

0.1 558 3 193 4;~
' 0.01 461t29 164 3 0 (blank control) 478~44 142~ 2 '~. Statistically significant (p<0.05 vs. control; t-test) Test Example 2 Action on neurite extension in the rat pheochromocytoma cell line To a suspension of PC12 cells (rat pheochromocytoma cell line; 2000 cells/well) in 10~
FCS-Dulbecco's MEM was added NGF (2 ng/ml) as well as SUBSTITUTE SiiEET (RULE 26) the test substance of varying concentration and the mixture was seeded in a 96-well microtiter plate and incubated for 3 days. The medium was then discarded and the cells were stained with hematoxylin-eosin using '-a commercial kit (Difquick R, Kokusai Shiyaku K.K.)) The outgrowth of neurites was observed under the microscope and compared with the drug-free control involving addition of NGF (2 ng/ml) alone. The case in which a definite neurite out growth was observed was rated + and the case in which no definite difference from the control was found was rated -. As shown in [Table 7], the compound of the invention was found to have high nerve growth factor agonist activity.
[Table 7]
Neurite extending activity in the rat pheocromocytoma cell line Example of compound of NGF
1 I +
0.1 +
0.01 +
4 1 +
0.1 0.01 5 1 +
0.1 -0.01 -11 1 +

0.1 +

0.01 +

I2 1 +

0.1 +

0.01 -16 1 +

0.1 +

0.01 +

124 1 +

0.1 -0.01 -Formulation Example 1 SUBSTITUTE SHEET (RULE 26~

WO 98l07705 PCT/JP97102858 By mixing the following components (1)-(6) and compressing the mixture with a tablet machine, about 1,000 uncoated tablets measuring 6.5 mm in diameter and containing 5 mg of the compound of Example 1 per tab let can be manufactured. Then, by coating those tablets using the following components (7)-(9), film-coated tablets each measuring 6.6 mm in diameter can be provided.

(I) Compound of Example 1 5 g {2) Lactose H2.5 g (3) Hydroxypropylcellulose 2.8 g (4) Magnesium stearate 0.4 g (5) Hydroxypropylmethylcellulose 2910 2.994 g (6) Corn starch 19.3 g (7) Macrogol 6000 0.6 g (8) Titanium dioxide 0.4 g (9) Iron sesquioxide 0.006 g Formulation Example 2 By suspending or dissolving the following components {1), {3), (4), (5), (6), (7), and (8) in purified water and coating a granular core material (2), shown below, with the suspension or solution, uncoated fine granules can be provided. Hy coating these fine granules using the following components 9}-( (11) and mixing the resulting coated granules with the following component (12), about 500 g of 1~ fine granules of the compound of Example 1 can be manufactured. The fine granules are dispensed in packets, 500 mg per packet.

(1) Compound of Example 1 5 g (2) Lactose-crystalline cellulose (granular) 330 g (3) D-mannitol 29 g (4) Low-substitution-degree hydroxypropyl-cellulose 20 g - (5) Talc 25 g (6) Hydroxypropylcellulose 50 g (7} Aspartame 3 g (8) Dipotassium glycyrrhizinate 3 g (9) Hydroxypropylmethylcellulose 2910 30 g (10) Titanium dioxide 3.5 g (11) Yellow iron sesquioxide 0.5 g (12) Light silicic anhydride 1 g SUBSTITUTE SHEFf (RULE 26) WO 98I07705 PCTlJP97/02858 INDUSTRIAL APPLICABILITY
The cell differentiation inducing composition or the cell differentiation factor activity enhancing composition comprising compound [I] or salt according to the present invention has high bone morphogenetic protein-like activity or enhances bone morphogenetic protein activity and, as such, acts on bone tissues to increase bone mass and bone strength. Therefore, the composition of the invention is of value for the treatment and prevention of bone diseases such as osteoporosis and for the acceleration of bone fracture healing and bone remodeling. Furthermore, this composition has neurotrophic factor-like activity or enhancing neurotrphoc factor activity and, as such, finds application in the treatment and prevention of various nerve diseases such as Alzheimer type dementia, senile dementia in general, motor neuronal diseases (e. g. amyatrophic lateral sclerosis) and diabetic peripheral neuropathy, among other diseases.
SUBSTITUTE SHEET (RULE 2b)

Claims (34)

259
1. A compound of the formula:
wherein Q is an optionally substituted carbon atom or N(O)p wherein p is 0 or 1;
Y is an optionally substituted methylene group, S(O)q wherein q is an integer of 0 to 2, or an optionally substituted imino group;
Z1 is a C1-3 alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain;
Z2 is an optionally substituted C1-3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and R2 is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group;
the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group; or R1 and R2 taken together with adjacent -c=c- form a ring; and ring A is a benzene ring which may be substituted in addition to R1 and R2; or a salt thereof.
2. A compound as claimed in Claim 1 wherein Q is (A) CR4 wherein R4 is (1) a hydrogen atom, (2) a halogen atom, (3) a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii} a vitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkylamino, (xiii) a C1-6 alkyl-carbonyl , (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6 alkoxy-carbonyl, (xviii) a mono-C1-6 alkyl amino-carbonyl, (xix) a di-C1-6 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-5 alkyl-carbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C4-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7- membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbarnoyl, (xxix) mono-C1-6 alkylthio-carbamoyl, xxx ) di-C1-6 alkylthio-carbamoyl,(xxxi) C6-10 aryl-carbamoyl and (xxxii) C6-10 aryl-thiocarbamoyl, or (4) a hydroxyl group which may be substituted with a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a vitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkylamino, (xiii) a C1-6 alkyl-carbonyl, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6 alkoxy-carbonyl, (xviii) a mono-C1-6 alkylamino-carbonyl, (xix) a di-C1-6 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-6 alkyl-carbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-C1-6 alkylthio-carbamoyl, (xxx) di-C1-6 alkylthio-carbamoyl, (xxxi) C6-10 aryl-carbamoyl and (xxxii) C6-10 aryl-thiocarbamoyl;
or (B) N(O)p wherein p is 0 or 1;
Y is (1) a group of the formula:

, wherein R9 and R9' may be the same or different and each is (i) a hydrogen, (ii) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (iii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (iv) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (v) a hydroxyl, (vi) a cyano, (vii) a C1-6 alkyl-carbonyl, (viii) a C1-6 alkyl-carbonyloxy, (ix) a formylamino, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkylamino, (xiii) a carboxyl, (xiv) a C1-6 alkoxy-carbonyl, or (xv) a C1-6 alkyl-carbonylamino;
(2) a group of the formula:

wherein R10 is (i) , in which R9 and R9' are as defined above, (ii) =NR9 in which R9 is as defined above, (iii) O or (iv) S;
(3) =S(O) q wherein q is an integer of 0 to 2; or ( 4 ) =NR5 wherein R5 is (i) a hydrogen, (ii) a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl , (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and {ff) C6-10 aryl-thiocarbamoyl, (iii) -(C=O)-R7 wherein R7 is a hydrogen or a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) 5- or 6-membered cyclic amino optionally having hydroxyl or oxo, (n) -NHCOOR6 wherein R6 is a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (n-1) a halogen, (n-2) a C1-3 alkylenedioxy, (n-3) a nitro, (n-4) a cyano, (n-5) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (n-6 ) a C3-6 cycloalkyl, (n-7 ) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (n-8) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (n-9) a hydroxyl, (n-10) an amino, (n-11) a mono-C1-6 alkylamino, (n-12) a di-C1-6 alkylamino, (n-13) a C1-6 alkyl-carbonyl, (n-14) a C1-6 alkyl-carbonyloxy, (n-15) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (n-16) a carboxyl, (n-17) a C1-6 alkoxy-carbonyl, (n-18) a mono-C1-6 alkylamino-carbonyl, (n-19) a di-C1-6 alkylamino-carbonyl, (n-20) a carbamoyl, (n-21) a mono-C1-6 alkyl-carbamoyl, (n-22) a di-C1-6 alkyl-carbamvyl, (n-23) a sulfo, (n-24) a C1-6 alkylsulfonyl, (n-25) a C6-10 aryl, (n-26) a C6-10 aryloxy, (n-27) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (n-28) thiocarbamoyl, (n-29) mono-C1-6 alkylthio-carbamoyl, (n-30) di-C1-6 alkylthio-carbamoyl, (n-31) C6-10 aryl-carbamoyl and (n-32) C6-10 aryl-thiocarbamoyl, (o) -NHCONHR6 wherein R6 is as defined above, (p) -NHCOR6 wherein R6 is as defined above, (q) -NHSO2R6 wherein R6 is as defined above, (r) a C1-6 alkyl-carbonyl, (s) a C1-6 alkyl-carbonyloxy, (t) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (u) a carboxyl, (v) a C1-6 alkoxy-carbonyl, (w) a mono-C1-6 alkylamino-carbonyl, (x) a di-C1-6 alkylamino-carbonyl, (y) a carbamoyl, (z) a mono-C1-6 alkyl-carbamoyl, (aa} a di-C1-6 alkyl-carbamoyl, (bb) a sulfo, (cc) a C1-6 alkylsulfonyl, (dd) a C6-10 aryl, (ee) a C6-10 aryloxy, (ff) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (gg) C7-11 aralkyloxy-carbonyl, (hh) thiocarbamoyl, (ii) mono-C1-6 alkylthio-carbamoyl, (jj) di-C1-6 alkylthio-carbamoyl, (kk) C6-10 aryl-carbamoyl and (11) C6-10 aryl-thiocarbamoyl, (iv) -S02-R7 wherein R7 is as defined above above, (v) -SO-R7 wherein R7 is as defined above, (vi) - (C=O) NR8-R7 wherein R7 is as defined above , R8 is hydrogen or C1-6 alkyl or (vii) -(C=O)O-R7 wherein R7 is as defined above;
Z1 is a C1-3 alkylene group which may have an oxo or thioxo group;
Z2 is a C1-3 alkylene group which may contain oxygen or sulfur within the carbon chain as an ether or thioether and may have a substituent selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkyl amino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl;
Ar is (1) a 3- to 14- membered monocyclic or fused polycyclic nonaromatic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C2-6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a C2-6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3-6 cycloalkyl, (ix) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1-6 alkylamino, (xiv) a di-C1-6 alkylamino, (xv) 5- or 6- membered cyclic amino, (xvi) -NHCOOR6 wherein R6 is as defined above, (xvii) -NHCONHR6 wherein R6 is as defined above, (xviii) -NHCOR6 wherein R6 is as defined above, (xix) -NHSO2R6 wherein R6 is as defined above, (xx) a C1-6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1-6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mano-C1-6 alkyl-carbamoyl, (xxv) a di-C1-6 alkyl-carbamoyl, {xxvi) a C6-10 aryl-carbamoyl, (xxvii) a sulfo, (xxviii) a C1-6 alkylsulfonyl, (xxvix) a C6-10 aryl, (xxx) a C6-10 aryloxy, (xxxi) C7-16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1-6 alkylthio-carbamoyl, (xxxiv) di-C1-6 alkylthio-carbamoyl, (xxxv) C6-10 aryl-carbamoyl and (xxxvi) C6-10 aryl-thiocarbamoyl, (2) a 6- to 14-membered monocyclic or fused polycyclic aromatic hydrocarbon group, which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi} a C2-6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a C2-6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3-6 cycloalkyl, (ix) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1-6 alkylamino, (xiv) a di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic camino, (xvi) -NHCOOR6 wherein R6 is as defined above, (xvii) -NHCONHR6 wherein R6 is as defined above, (xviii) -NHCOR6 wherein R6 is as defined above, (xix) -NHSO2R6 wherein R6 is as defined above, (xx) a C1-6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1-6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mono-C1-6 alkyl-carbamoyl, (xxv) a di-C1-6 alkyl-carbamoyl, (xxvi) a C6-10 aryl-carbamoyl, (xxvii) a sulfo, (xxviii) a C1-6 alkylsulfonyl, (xxvix) a C6-10 aryl , (xxx) a C6-10 aryloxy, (xxxi) C7-16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1-6 alkylthio-carbamoyl, (xxxiv) di-C1-6 alkylthio-carbamoyl, (xxxv) C6-10 aryl-carbamoyl and (xxxvi) C6-10 aryl-thiocarbamoyl, (3) 5- to 10- membered monocyclic nonaromatic heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen, an oxygen and a sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C2-6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a C2-6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3-6 cycloalkyl, (ix) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1-6 alkylamino, (xiv) a di-C1-6 alkylamino, (xv) 5- or 6- membered cyclic amino, (xvi) -NHCOOR6 wherein R6 is as defined above, (xvii) -NHCONHR6 wherein R6 is as defined above, (xviii) -NHCOR6 wherein R6 is as defined above, (xix) -NHSO2R6 wherein R6 is as defined above, (xx) a C1-6 alkyl-carbonyl, (xxi) a carboxyl group, (xxii) a C1-6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mono-C1-6 alkyl-carbamoyl, (xxv) a di-C1-6 alkyl-carbamoyl, (xxvi) a C6-10 aryl-carbamoyl, (xxvii) a sulfo, (xxviii) a C1-6 alkylsulfonyl, (xxix) a C6-10 aryl, (xxx) a C6-10 aryloxy, (xxxi) C7-16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1-6 alkylthio-carbamoyl, (xxxiv) di-C1-6 alkylthio-carbamoyl, (xxxv) C6-10 aryl-carbamoyl and (xxxvi) C6-10 aryl-thiocarbamoyl, or (4) 5- to 10- membered monocyclic aromatic heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, which may have 1 to 5 substituents selected from a group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C2-6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a C2-6 alkynyl optionally having 1 to 3 halogen atoms , (viii) a C3-6 cycloalkyl (ix) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1-6 alkylamino, (xiv) a di-C1-6 alkylamino, (xv) 5- or 6- membered cyclic amino, (xvi) -NHCOOR6 wherein R6 is as defined above, (xvii) -NHCONHR6 wherein R6 is as defined above, (xviii) -NHCOR6 wherein R6 is as defined above, (xix) -NHSO2R6 wherein R6 is as defined above, (xx) a C1-6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1-6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mono-C1-6 alkyl-carbamoyl, (xxv) a di-C1-6 alkyl-carbamoyl, (xxvi) a C6-10 aryl-carbamoyl, (xxvii) a sulfo, (xxviii) a C1-6 alkylsulfonyl, (xxix) a C6-10 aryl, (xxx) a C6-10 aryloxy, (xxxi) C7-16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1-6 alkylthio-carbamoyl, (xxxiv) di-C1-6 alkylthio-carbamoyl, (xxxv) C6-10 aryl-carbamoyl and (xxxvi) C6-10 aryl-thiocarbamoyl ;
one of R1 and R2 is (1) a hydrogen, (2) a halogen, (3) a hydroxyl, (4) a C1-6 alkyl which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (1) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (5) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl, or (5) a C1-6 alkoxy group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl (q) a C1-6 alkoxy-carbonyl , (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryioxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl;
the other is (1) a halogen, (2) a hydroxyl, (3) a C1-6 alkyl which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkyl amino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene rings (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl, or (4) a C1-6 alkoxy group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkyl amino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl; or R1 and R2 taken together, to form the ring with adjacent -C=C-, are (1) a C1-6 alkylene group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkyl amino, (m) a C1-6 alkyl-carbonyl,(n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl, (2) a C1-6 alkylenedioxy group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl, or (3) a C1-6 alkyleneoxy group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (1) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl; and ring A is a benzene ring which may have 1 or 2 substituents selected from the group consisting of (1) a hydrogen, (2) a halogen, (3) a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkylamino, (xiii) a C1-6 alkyl-carbonyl, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6 alkoxy-carbonyl, (xviii) a mono-C1-6 alkyl amino-carbonyl, (xix) a di-C1-6 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-6 alkyl-carbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7- membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-C1-6 alkylthio-carbamoyl, (xxx) di-C1-6 alkylthio-carbamoyl , (xxxi) C6-10 aryl-carbamoyl and (xxxii) C6-10 aryl-thiocarbamoyl.
3. A compound of the formula:
wherein Q is (1) CR4 wherein R4 is (i) a hydrogen atom, (ii) a halogen atom, (iii) an optionally substituted hydrocarbon group or (iv) an optionally substituted hydroxyl group, or (2) N(O)p wherein p is 0 or 1;
X is C=O or C=S ;
Y is (1) CH2, (2) S(O)q wherein q is an integer of 0 to 2, or (3) NR5 wherein R5 is (i) a hydrogen atom, (ii) an optionally substituted hydrocarbon group or (iii) an acyl group;
m and n each represents 0 or 1;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and R2 is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group;
the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group, or an optionally substituted lower alkoxy group; or R1 and R2 taken together with adjacent -c=c- form a ring; and ring A is a benzene ring which may be substituted in addition to R1 and R2.
4. A compound as claimed in Claim 3 wherein Q is (A) CR4 wherein R4 is (1) a hydrogen atom, (2) a halogen atom, (3) a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-6 alkylenedioxy, (iii) a vitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkylamino, (xiii) a C1-6 alkyl-carbonyl, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6 alkoxy-carbonyl, (xviii) a mono-C1-6 alkylamino-carbonyl, (xix) a di-C1-6 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-6 alkyl-carbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7- membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-C1-6 alkylthio-carbamoyl, (xxx) di-C1-6 alkylthio-carbamoyl, (xxxi) C6-10 aryl-carbamoyl and (xxxii) C6-10 aryl-thiocarbamoyl, or (4) a hydroxyl group which may be substituted with a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a vitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkylamino, (xiii) a C1-6 alkyl-carbonyl, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6 alkoxy-carbonyl, (xviii) a mono-C1-6 alkylamino-carbonyl, (xix) a di-C1-6 alkyiamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-6 alkyl-carbamoyl, (xxii) a di-C1-6, alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-C1-6 alkylthio-carbamoyl, (xxx) di-C1-6 alkylthio-carbamoyl, (xxxi) C6-10 aryl-carbamoyl and (xxxii) C6-10 aryl-thiocarbamoyl;
or (B) N(O)p wherein p is 0 or 1;
Y is (1) CH2, (2) S(O)q wherein q is an integer of 0 to 2, or (3) NRS wherein R5 is (i) a hydrogen, (ii) a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl, (iii) -(C=O)-R7 wherein R7 is a hydrogen or a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) 5- or 6-membered cyclicamino optionally having carboxyl or oxo, (n) -NHCOOR6 wherein R6 is a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (n-1) a halogen, (n-2) a C1-3 alkylenedioxy, (n-3) a nitro, (n-4) a cyano, (n-5) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (n-6) a C3-6 cycloalkyl, (n-7) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkyl amino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (n-8) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (n-9) a hydroxyl, (n-10) an amino, (n-11) a mono-C1-6 alkylamino, (n-12) a di-C1-6 alkylamino, (n-13) a C1-6 alkyl-carbonyl, (n-14) a C1-6 alkyl-carbonyloxy, (n-15) a C1-6 alkyl-carbonyloxy-C1-3 alkyl (n-16) a carboxyl (n-17) a C1-6 alkoxy-carbonyl, (n-18) a mono-C1-6 alkylamino-carbonyl, (n-19) a di-C1-6 alkylamino-carbonyl, (n-20) a carbamoyl, (n-21) a mono-C1-6 alkyl-carbamoyl, (n-22) a di-C1-6 alkyl-carbamoyl, (n-23) a sulfo, (n-24) a C1-6 alkylsulfonyl, (n-25) a C6-10 aryl, (n-26) a C6-10 aryloxy, (n-27) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (n-28) thiocarbamoyl, (n-29) mono-C1-6 alkylthio-carbamoyl, (n-30) di-C1-6 alkylthio-carbamoyl, (n-31 ) C6-10 aryl-carbamoyl and (n-32) C6-10 aryl-thiocarbamoyl, (o) -NHCONHR6 wherein R6 is as defined above, (p) -NHCOR6 wherein R6 is as defined above, (q) -NHSO2R6 wherein R6 is as defined above, (r) a C1-6 alkyl-carbonyl, (s) a C1-6 alkyl-carbonyloxy, (t) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (u) a carboxyl, (v) a C1-6 alkoxy-carbonyl, (w) a mono-C1-6 alkylamino-carbonyl, (x) a di-C1-6 alkylamino-carbonyl, (y) a carbamoyl, (z) a mono-C1-6 alkyl-carbamoyl, (aa) a di-C1-6 alkyl-carbamoyl, C6-10 aryl-carbamoyl, (bb) a sulfo, (cc) a C1-6 alkylsulfonyl, (dd) a C6-10 aryl, (ee) a C6-10 aryloxy, (ff) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (gg) C7-11 aralkyloxy-carbonyl, (hh) thiocarbamoyl, (ii) mono-C1-6 alkylthio-carbamoyl, (jj) di-C1-6 alkylthio-carbamoyl, (kk) C6-10 aryl-carbamoyl and (ll) C6-10 aryl-thiocarbamoyl, (iv) -SO2-R7 wherein R7 is as defined above, (v) -SO-R7 wherein R7 is as def fined above, (vi) -(C=O)NR8-R7 wherein R7 is as defined above, R8 is hydrogen or C1-6 alkyl or (vii) -(C=O)O-R7 wherein R7 is as defined above.
5. A compound as claimed in Claim 3 wherein Q is CR4 wherein R4 is as defined in Claim 3.
6. A compound as claimed in Claim 3 wherein X is C=O.
7. A compound as claimed in Claim 3 wherein Y is NR5 wherein R5 is as defined in Claim 3.
8. A compound as claimed in Claim 3 wherein Y is CH2.
9. A compound as claimed in Claim 3 wherein Ar is 3- to 14-membered aromatic group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a vitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi} a C2-6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a C2-6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3-6 cycloalkyl, (ix) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1-6 alkylamino, (xiv) a di-C1-6 alkylamino, (xv) 5- or 6-membered cyclic amino, (xvi) -NHCOOR6 wherein R6 is a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (1) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 aikoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen, an oxygen and a sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl, (xvii) -NHCONHR6 wherein R6 is as defined above, (xviii) -NHCOR6 wherein R6 is as defined above, (xix) -NHSO2R6 wherein R6 is as defined above, (xx) a C1-6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1-6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mono-C1-6 alkyl-carbamoyl, (xxv) a di-C1-6 alkyl-carbamoyl, (xxvi) a C6-10 aryl-carbamoyl, (xxvii) a sulfo, (xxviii) a C1-6 alkylsulfonyl, (xxix) a C6-10 aryl, ( xxx ) a C6-10 aryloxy, ( xxxi ) C7-16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1-6 alkylthio-carbamoyl, (xxxiv) di-C1-6 alkylthio-carbamoyl, (xxxv) C6-10 aryl-carbamoyl and (xxxvi) C6-10 aryl-thiocarbamoyl.
10. A compound as claimed in Claim 4 wherein Ar is a phenyl group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C2-6 alkenyl optionally having 1 to 3 halogen atoms, (vii) a C2-6 alkynyl optionally having 1 to 3 halogen atoms, (viii) a C3-6 cycloalkyl, (ix) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (x) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (xi) a hydroxyl, (xii) an amino, (xiii) a mono-C1-6 alkylamino, (xiv) a di-C1-6 alkylamino, (xv) 5- or 6- membered cyclic amino, (xvi) -NHCOOR6 wherein R6 is a C1-6 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a vitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkyl amino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from the group consisting of a nitrogen, an oxygen and a sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl, (xvii) -NHCONHR6 wherein R6 is as defined above, (xviii} -NHCOR6 wherein R6 is as defined above, (xix) -NHSO2R6 wherein R6 is as defined above, (xx) a C1-6 alkyl-carbonyl, (xxi) a carboxyl, (xxii) a C1-6 alkoxy-carbonyl, (xxiii) a carbamoyl, (xxiv) a mono-C1-6 alkyl-carbamoyl, (xxv) a di-C1-6 alkyl-carbamoyl, (xxvi) a C6-10 aryl-carbamoyl, (xxvii) a sulfo, (xxviii) a C1-6 alkylsulfonyl, (xxix) a C6-10 aryl, (xxx) a C6-10 aryloxy, (xxxi) C7-16 aralkyloxy, (xxxii) thiocarbamoyl, (xxxiii) mono-C1-6 alkylthio-carbamoyl, (xxxiv) di-C1-6 alkylthio-carbamoyl, (xxxv) C6-10 aryl-carbamoyl and (xxxvi) C6-10 aryl-thiocarbamoyl.
11. A compound as claimed in Claim 4, wherein is wherein R3 is (1) a hydrogen atom, (2) a halogen atom, (3) a C1-15 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono-or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, an optionally substituted hydrocarbon group, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthio-carbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl or (4) a hydroxyl group which may be substituted with a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylenedioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkylamino, (xiii) a C1-6 alkyl-carbonyl, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6 alkoxy-carbonyl, (xviii) a mono-C1-6 alkylamino-carbonyl, (xvix) a di-C1-6 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-6 alkyl-carbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-C1-6 alkylthio-carbamoyl, (xxx) di-C1-6 alkylthio-carbamoyl, (xxxi) C6-10 aryl-carbamoyl and (xxxii) C6-10 aryl-thiocarbamoyl.
12. A compound as claimed in Claim 11 wherein R3 is a hydrogen.
13. A compound as claimed in Claim 3, wherein Q is (l) CR4' wherein R4' is (i) a C1-6 alkyl group which may be substituted with a di-C1-6 alkylamino group, (ii) a halogen atom, or (iii) a C1-6 alkoxy group, or (2) N;
X is C=O;
Y is NR5' wherein R5' is (i) a hydrogen, (ii) a C1-6 alkyl group which may be substituted with (a) a morpholino, (b) a carboxyl, (c) a C1-6 alkoxy-carbonyl, ar (d) a phenyl which may be substituted with C1-6 alkoxy, or (iii) COR7~ wherein R7~ is (a) a hydrogen, (b) C1-6 alkyl which may be substituted with a carboxyl or a benzyloxycarbonyl, or a di-C1-6 alkylamino;
m and n each represents 0;
Z2 is (1) C=O, (2) CH2, (3) (CH2)2, (4) (CH2)3, or (5) CH-OH;
Ar is (1) a phenyl group which may be substituted with (a) a halogen, (b) a C1-6 alkylenedioxy, (c) a C1-6 alkoxy which may be substituted with (c-1) a halogen or (c-2) a di-C1-6 alkylamino or (c-3) a C1-6 alkoxy-carbonyl, (d) a C7-11 aralkyloxy, (e) C1-6 alkyl which may be substituted with a halogen or (f) hydroxyl, (2) an optionally oxidized pyridyl group, or (3) a pyridinium group which may be substituted with C1-6 alkyl;
one of R1 and R2 is (1) a hydrogen, (2) a C1-6 alkyl, (3) a C1-6 alkoxy which may be substituted with (a) a C1-6 alkoxy-carbonyl, (b) a C7-11 aralkyl or (c) a carboxyl, or (4) a hydroxyl;
the other is (1) a C1-6 alkyl, (2) a C1-6 alkoxy which may be substituted with (a) a C1-6 alkoxy-carbonyl or (b) a carboxyl, or (3) a hydroxyl; or R1 and R2 taken together with adjacent -c=c- form a C1-6 alkylenedioxy group, or a C1-6 alkyleneoxy group; or ring A is a benzene ring which may have a C1-6 alkoxy group, in addition to R1 and R2, and a C1-6 alkoxy group on ring A and a C1-6 alkoxy group of R1 may be taken together form a C1-6 alkylenedioxy group.
14. A compound as claimed in Claim 13 wherein Q is CH or N;
X is C=O;
m and n each represents 0;
Z2 is CH2; and R1 and R2 taken together with adjacent -c=c- form a C1-6 alkylenedioxy group.
15. A process for producing a compound of the formula:

wherein all symbols have the same meanings as defined in Claim 3, or a salt thereof, which comprises subjecting a compound of the formula:

wherein all symbols have the same meaning as defined in Claim 3, or a salt thereof, to lactamization reaction, optionally followed by introducing a substituent R5 into the resulting lactam.
16. A compound of the formula:

wherein all symbols have the same meaning as defined in Claim 3, or a salt thereof; provided that (1) when both of R1 and R2 are methoxy groups, Q is CR4, X is C=O, Z Z
is a methylene, and m is 0, Ar is not any of phenyl, 3,4,5-trimethoxyphenyl, 4,5-dimethoxy-2-methylphenyl and 1,3-benzodioxol-5-yl; that (2) when R1 is a hydroxyl or a methoxy, Q is CR4, X is C=O, Z1 is a methylene, and m is 0, Ar is not 1,3-benzodioxol-5-yl;
and that (3) when R1 and R2 taken together represent a methylenedioxy which may be substituted with an oxygen atom, Q is CR4, X is C=O, Z2 is a methylene, and m is 0, Ar is not any of 1,3-benzodioxol-5-yl, 6-bromo-1,3-benzodioxol-5-yl, 7-hydroxyl-1,3-benzodioxol-5-y1, 7-acetoxy-1,3-benzodioxvl-5-yl, and 7-methoxy-1,3-benzodioxol-5-yl.
17. A pharmaceutical composition comprising a compound of Claim 1.
18. A cell differentiation inducing factor composition comprising the compound of Claim 1.
19. A composition of Claim 17 which enhances cell differentiation inducing factor.
20. A composition for treating or preventing neuropathy or bone-and joint disease which comprises the compound of Claim 1.
21. A bone formation promoting composition comprising the compound of Claim 1.
22. A cartilage disruption inhibitory composition comprising the compound of Claim 1.
23. A method of treating or preventing neuropathy or bone-and-joint disease which comprises administering to a mammal in need thereof an effective amount of a compound of the formula:

wherein Q is an optionally substituted carbon atom or N(O)p wherein p is 0 or 1;
Y is an optionally substituted methylene group, S(O)q wherein q is an integer of 0 to 2, or an optionally substituted imino group;
Z1 is a C1-3 alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain;
Z2 is an optionally substituted C1-3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and R2 is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group;
the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group; or R1 and R2 taken together with adjacent -c=c- form a ring; and ring A is a benzene ring which may have a substituent in addition to R1 arid R2; or a salt thereof.
24. Use of a compound of the formula:

wherein Q is an optionally substituted carbon atom or N(O)p wherein p is 0 or 1;
Y is an optionally substituted methylene group, S(O)q wherein q is an integer of 0 to 2, or an optionally substituted imino group;
Z1 is a C1-3 alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain;
Z2 is an optionally substituted C1-3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
one of R1 and R2 is a hydrogen atom, a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group;
the other is a halogen atom, a hydroxyl group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group; or R1 and R2 taken together form a ring; and ring A is a benzene ring which may have a substituent in addition to R1 and R2; or a salt thereof, for the manufacture of a medicament for treating or preventing neuropathy or bone-and-joint disease.
25. A compound as claimed in Claim 3, which is 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-1H-1,3,-benzodioxolo[4,5-f)isoindol-7-one, 11-(1,3-Benzodioxol-5-yl)-7,8,9,10-tetrahydro-1,3,-benzodioxolo[4,5-g)isoquinolin-7-one, 4-(1,3-Benzodioxol-5-yl)-2,3-dihydro-5-methoxy-1H-bent[f]isoindol-1-one, 8,9-Dihydro-10-(4-trifluoromethyiphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 11-(1,3-Benzodioxol-5-yl)-9,10-dihydro-8H-isoindolo[5,6-f]benz(b]-1,4-dioxan-8-one, 10-(4-Fluorophenyl)-8,9,-dihydro-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-6-methyl-7H-1,3-benzodioxolo(4,5-f]isoindol-7-one, 10-(4-Fluorophenyl)-8,9-dihydro-6-methyl-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 8,9-Dihydro-6-methyl-10-(4-trifluoromethylphenyl)-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 10-(1,3-Benzodixol-5-yl)-8,9-dihydro-6-ethyl-7H-1,3-benzodioxolo[4,5-f]isoindol-7-one, 4-(1,3-Benzadioxol-5-yl)-2,3-dihydro-6-methoxy-1H-benz[f]isoindol-1-one, 2,3-Dihydro-6-methoxy-4-(4-methoxypheny)-1H-benz[f]isoindol-1-one, 2,3-Dihydro-6-methoxy-4-(4-trifluoromethylphenyl)-1H-benz(f]isoindol-1-one, 4-(4-Fluorophenyl)-2,3-dihydro-6-methoxy-9-methyl-1H-benz[f]isoindol-1-one, 4-(4-Methoxyphenyl)-2,3-dihydro-6-methoxy-9-methyl-1H-benz[f]isoindol-1-one, 9-(4-Fluorophenyl)-1,2-dihydro-?-methoxy-3H-pyrrolo[3,4-b]quinoiin-3-one, 1,2-Dihydro-7-methoxy-9-(4-methoxyphenyl)-3H-pyrrolo[3,4-b]quinolin-3-one, 3,4-Dihydro-7-methoxy-5-(4-methoxyphenyl)-benzo[bj[1,7]naphthyridin-1(2H)-one, or a salt thereof.
26. A compound of the formula:

wherein Q is an optionally substituted carbon atom or N(O)p wherein p is d or 1;
Y is an optionally substituted methylene group, S(O)q wherein a is an integer of 0 to 2, or an optionally substituted imino group;
Z1 is a C1-3 alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain;
Z2 is an optionally substituted C1-3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
R1 and R2 taken together with adjacent -c=c- form a ring which may be substituted; and ring A is a benzene ring which may be substituted in addition to R1 and R2; or a salt thereof.
27. A compound as claimed in claim 26, wherein is wherein R~ is (1) a hydrogen atom, (2) a halogen atom, (3) a C1-10 acyclic or cyclic hydrccarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-4 alkyl optionally having 1 to 3 halogen atoms, (f) a C1-6 cycloalkyl, (g) a C1-5 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-~ alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-caxbonyl, (n) a C1-10 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (s) a C1-6 alkoxy-carboxyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamayl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C5-10 aryl (z) a C5-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group hawing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene rigs, an optionally substituted hydrocarbon group, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthiocarbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 arylthiocarbamoyl, or (4) a hydroxyl group which may be substituted with a acyclic or cyclic hydrocarbon, group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylene dioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C1-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- cr di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-8 alkylamino, (xii) a C1-3 alkyl-carbonyl, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6alkoxy-carbonyl) (xviii) a mono-C1-6 alkylamino-carbonyl, (xvix) a di-C1-6 alkylamino-caxbonyl) (xx) a caybamoyl, (xxi) a mono-C1-6 alkyl-carbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzone ring, (xxviii) thiocarbamoyl, (xxix) mono-C1-6 alkylthio-carbamoyl, (xxx) di-C1-3 alkylthio-carbamoyl, (xxxi) C6-10 aryl-carbamoyl, and (xxxii) C6-10, aryl-thiocarbamoyl.
28. A compound as claimed in Clam 27 wherein R3 is a hydrogen.
29. A compound as claimed in Claim 26, wherein Q is CH or N;
Z' is C=O;
Z2 is CH2; and R1 and R2 taken together with adjacent -c=c- form a C1-6 alkylenedioxy group.
30. A compound of the Formula wherein is an optionally substituted methylene group, S(O)q wherein q is an integer of 0 to 2, or an optionally substituted imino group;
is a C1-3 alkylena group which may have an oxo group or a thioxo group and may contain etherified oxygan or sulfur within the carbon chain;
Z1 is an optionally substituted C1-3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; and ring A is a benzene tins whit may be substituted in addition to R1 and R2 ;
Q is (A) CR4 wherein R4 is (1) a hydrogen atom, (2) a halogen atom, (3) a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylen dioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-5 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkylamino, (xiii) a C1-6 alkyl-carbonyl, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6alkoxy-carbonyl, (xviii) a mono-C1-6 alkylamino-carbonyl (xvix) a di-C1-6 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-6 alkyl-carbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) triocarbamoyl, (xxix) mono-C1-5 alkylthio-carbamoyl, (xxx) di-C1-4 alkylthio-carbamoyl) (xxxi) C5-10 aryl-carbamoyl, and (xxxii) C6-10 aryl-thiocarbamoyl; or (4) a hydroxyl group which may be substituted with a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-~ alkylene dioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C1-6 cycloalkyl, (vii) a C1-6 alkoxy which tray be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amine, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-5 alkylamino, (xiii) a C1-4 alkyl-carbonyloxy, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6 alkoxy-carbonyl, (xviii) a mono-C1-6 alkylamino-carbonyl, (xvix) a di-C1-5 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-6 alkyl-caxbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-C1-5 alkylthio-carbamoyl, (xxx) di-C1-6 alkylthio-carbamoyl, (xxxi) C6-10 aryl-carbamoyl, and (xxxii) C5-10 aryl-thiocarcamoyl;

Y is =NR5 wherein R~ is (i) a hydrogen, (ii) a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C1-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1-6 alkylamino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl -carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a 1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (bb) thiocarbamoyl, (cc) mono-di-C1-6 alkylthio-carbamoyl, (dd) di-C1-5 alkylthio-carbamoyl, (ee) C6-1c aryl-carbamoyl and (ff) C6-10 aryl-thiocarbamoyl, (iii) -(C=O)-R7 wherein R7 is a hydrogen or a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-~ alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C1-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amine, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amine, (k) a mono-C1-6 alkyl amino, (l) a di-C1-5 alkylamino, (m) 5- or 6-membered cyclic amino optionally having hydroxyl or oxo, (n) -NHCOOR4 wherein R6 is a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected for the group consisting of (n-1) a halogen, (n-2) a C1-3 alkylenedioxy, (n-3) a nitro, (n-4) a cyano, (n-5) a C1-6 alkyl optionally having 1 to 3 halogen atoms;
(n-6) a C1-6 cycloalkyl, (n-7) a C1-6 alkoxy which may be substituted with amino) mono- or di-C1-6 alkylamino or alkoxycarbonyl, and optionally having to 3 halogen atoms, (n-8) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (n-9) a hydroxyl, (n10) an amino, (n-11) a mono-C1-6 alkylamino, (n-12) a di-C1-6 alkylamino, (n-13) a C1-6 alkyl-carbonyl, (n-14) a C1-6 alkyl-carbonyloxy, (n-15) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (n-16) a carboxyl, (n-17) a C1-6 alkoxy-carbonyl, (n-18) a mono-C1-6 alkylamino-carbonyl, (n-19) a di-C1-6 alkylamino-carbonyl, (n-20) a carbamoyl, (n-21) a mono-C1-6 alkyl-carbamoyl, (n-22) a di-C1-6 alkyl-carbamoyl, (n-23) a sulfo, (n-24) a C1-6 alkylsulfonyl, (n-25) a C6-10 aryl, (n-26) a C6-10 aryloxy, (n-27) a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (n-28) thiocarbamoyl, (n-29) mono-C1-6 alkylthio-carbamoyl, (n-30) di-C1-6 alkylthio-carbamoyl, (n-31) C6-10 aryl carbamoyl, and (n-32) C6-10 aryl-thiocarbamoyl, (o) -NHCONHR6 wherein R6 is as defined above, (p) -NHCOR6 wherein R6 is as defined above, (q) -NHSO2R6 wherein R6 is as defined above, (r) ~ a C1-6 alkyl-carbonyl, (s) a C1-6 alkyl-carbonyloxy, (t)~ a C1-3 alkyl-carbonyloxy-C1-3 alkyl, (u) a carboxyl, (v) a C1-6 alkoxy-carbonyl, (w) a mono-C1-6 alkylamino-carbonyl, (x) a di-C1-6 alkylamino-carbonyl, (y) a carbamoyl, (z) a mono-C1-6 alkyl-carbamoyl, (aa) a di-C1-6 alkyl-carbamoyl, (bb)~a sulfo, (cc)~a C1-6 alkylsulfonyl, (dd)~a C6-10 aryl , (ee)~a C6-10 aryloxy, (ff)~a 5- to 7-membered heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzen ring, (gg) C1-11 aralkyloxy-carbonyl, (hh) thiocarbamoyl, (ii) mono-C1-6 alkylthio-carbamoyl, (jj)~di-C1-6 alkylthio-carbamoyl, (kk)~C6-10 aryl-carbamoyl and (ll) C6-10 aryl-thiacarbamoyl, (iv) -SO2-R7 wherein R7 is as defined above, (v) -SO-R~ wherein R7 is as defined above, (vi) -(C=O) NR6-R7 wherein R7 is as defined above, hydrogen or C1-6 alkyl or (vii -(C=O) O-R7 wherein R7 is a defined above;

or a salt thereof.
31. A compound of the formula:

wherein Q is an optionally substituted carbon atom or N(O)p wherein p is 0 or 1;
Y is an optionally substituted methylene group, S (O) q wherein q is an integer of 0 to 2, or an optionally substituted imino group;
Z1 is a C1-3 alkylene group which may have an oxo group or a thioxo group and may contain etherified oxygen or sulfur within the carbon chain;
Z2 is an optionally substituted C1-3 alkylene group;
Ar is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
R1 and R2 taken together with adjacent -c=c- form a ring which may be substituted and ring A is a benzene ring which may be substituted in addition to R1 and R2; or a salt thereof.
32. A compound as claimed in Claim 31, wherein is wherein R3 is (1) a hydrogen atom, (2) a halogen atom, (3) a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (a) a halogen, (b) a C1-3 alkylenedioxy, (c) a nitro, (d) a cyano, (e) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (f) a C3-6 cycloalkyl, (g) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkyl amino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (h) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (i) a hydroxyl, (j) an amino, (k) a mono-C1- alkyl amino, (l) a di-C1-6 alkylamino, (m) a C1-6 alkyl-carbonyl, (n) a C1-6 alkyl-carbonyloxy, (o) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (p) a carboxyl, (q) a C1-6 alkoxy-carbonyl, (r) a mono-C1-6 alkylamino-carbonyl, (s) a di-C1-6 alkylamino-carbonyl, (t) a carbamoyl, (u) a mono-C1-6 alkyl-carbamoyl, (v) a di-C1-6 alkyl-carbamoyl, (w) a sulfo, (x) a C1-6 alkylsulfonyl, (Y) a C6-10 aryl, (z) a C6-10 aryloxy, (aa) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, an optionally substituted hydrocarbon group, (bb) thiocarbamoyl, (cc) mono-C1-6 alkylthiocarbamoyl, (dd) di-C1-6 alkylthio-carbamoyl, (ee) C6-10 aryl-carbamoyl and (ff) C6-10 arylthiocarbamoyl, or ~

(4) a hydroxyl group which may be substituted with a C1-16 acyclic or cyclic hydrocarbon group which may have 1 to 5 substituents selected from the group consisting of (i) a halogen, (ii) a C1-3 alkylene dioxy, (iii) a nitro, (iv) a cyano, (v) a C1-6 alkyl optionally having 1 to 3 halogen atoms, (vi) a C3-6 cycloalkyl, (vii) a C1-6 alkoxy which may be substituted with amino, mono- or di-C1-6 alkylamino or C1-6 alkoxycarbonyl, and optionally having 1 to 3 halogen atoms, (viii) a C1-6 alkylthio optionally having 1 to 3 halogen atoms, (ix) a hydroxyl, (x) an amino, (xi) a mono-C1-6 alkylamino, (xii) a di-C1-6 alkyl amino, (xiii) a C1-6 alkyl-carbonyl, (xiv) a C1-6 alkyl-carbonyloxy, (xv) a C1-6 alkyl-carbonyloxy-C1-3 alkyl, (xvi) a carboxyl, (xvii) a C1-6alkoxy-carbonyl, (xviii) a mono-C1-6 alkylamino-carbonyl, (xvix) a di-C1-6 alkylamino-carbonyl, (xx) a carbamoyl, (xxi) a mono-C1-6 alkyl-carbamoyl, (xxii) a di-C1-6 alkyl-carbamoyl, (xxiii) a sulfo, (xxiv) a C1-6 alkylsulfonyl, (xxv) a C6-10 aryl, (xxvi) a C6-10 aryloxy, (xxvii) a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, said heterocyclic group being optionally fused with a benzene ring, (xxviii) thiocarbamoyl, (xxix) mono-C1-6 alkylthio-carbamoyl, (xxx) di-C1-6 alkylthio-carbamoyl, (xxxi) C6-10 aryl-carbamoyl, and (xxxii) C6-10 aryl-thiocarbamoyl.
33. ~A compound as claimed in Claim 32 wherein R3 is a hydrogen.
34. A compound as claimed in Claim 31, wherein Q is CH or N;
Z' is C=O;
Z2 is CH2; and R1 and R2 taken together with adjacent -c=c- form a C1-6 alkyle-nedioxy group.
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Families Citing this family (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6391005B1 (en) 1998-03-30 2002-05-21 Agilent Technologies, Inc. Apparatus and method for penetration with shaft having a sensor for sensing penetration depth
TR200100642T2 (en) * 1998-08-25 2001-07-23 Yale University Prevention and treatment of helioxanthin and its analogs, hepatitis B virus and flavivirus.
JP2001002572A (en) * 1999-04-19 2001-01-09 Sankyo Co Ltd Neurotrophin action enhancer
ZA200300255B (en) * 2000-07-20 2004-09-28 Bristol Myers Squibb Pharma Co Tricyclic 2-pyridone compounds useful as HIV reverse transcriptase inhibitors.
US6596729B2 (en) 2000-07-20 2003-07-22 Bristol-Myers Squibb Company Tricyclic-2-pyridone compounds useful as HIV reverse transcriptase inhibitors
US8641644B2 (en) 2000-11-21 2014-02-04 Sanofi-Aventis Deutschland Gmbh Blood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means
GB0031302D0 (en) 2000-12-21 2001-01-31 Glaxo Group Ltd Napthalene derivatives
US7026484B2 (en) * 2001-02-23 2006-04-11 Ligand Pharmaceuticals Incorporated Tricyclic androgen receptor modulator compounds and methods
US7214690B2 (en) * 2001-02-23 2007-05-08 Ligand Pharmaceuticals Incorporated Tricyclic quinolinone and tricyclic quinoline androgen receptor modulator compounds and methods
US8337419B2 (en) 2002-04-19 2012-12-25 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US9226699B2 (en) 2002-04-19 2016-01-05 Sanofi-Aventis Deutschland Gmbh Body fluid sampling module with a continuous compression tissue interface surface
US7981056B2 (en) 2002-04-19 2011-07-19 Pelikan Technologies, Inc. Methods and apparatus for lancet actuation
EP1404233B1 (en) 2001-06-12 2009-12-02 Pelikan Technologies Inc. Self optimizing lancing device with adaptation means to temporal variations in cutaneous properties
US9795747B2 (en) 2010-06-02 2017-10-24 Sanofi-Aventis Deutschland Gmbh Methods and apparatus for lancet actuation
JP4149911B2 (en) 2001-06-12 2008-09-17 ペリカン テクノロジーズ インコーポレイテッド Electric lancet actuator
US7025774B2 (en) 2001-06-12 2006-04-11 Pelikan Technologies, Inc. Tissue penetration device
US9427532B2 (en) 2001-06-12 2016-08-30 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
EP1404235A4 (en) 2001-06-12 2008-08-20 Pelikan Technologies Inc Method and apparatus for lancet launching device integrated onto a blood-sampling cartridge
MXPA04002644A (en) 2001-10-05 2004-07-08 Cytos Biotechnology Ag Angiotensin peptide-carrier conjugates and uses thereof.
US7229458B2 (en) 2002-04-19 2007-06-12 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8221334B2 (en) 2002-04-19 2012-07-17 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US8784335B2 (en) 2002-04-19 2014-07-22 Sanofi-Aventis Deutschland Gmbh Body fluid sampling device with a capacitive sensor
US7901362B2 (en) 2002-04-19 2011-03-08 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US9314194B2 (en) 2002-04-19 2016-04-19 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US7892183B2 (en) 2002-04-19 2011-02-22 Pelikan Technologies, Inc. Method and apparatus for body fluid sampling and analyte sensing
US8372016B2 (en) 2002-04-19 2013-02-12 Sanofi-Aventis Deutschland Gmbh Method and apparatus for body fluid sampling and analyte sensing
US7976476B2 (en) 2002-04-19 2011-07-12 Pelikan Technologies, Inc. Device and method for variable speed lancet
US7331931B2 (en) 2002-04-19 2008-02-19 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7297122B2 (en) 2002-04-19 2007-11-20 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7674232B2 (en) 2002-04-19 2010-03-09 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8702624B2 (en) 2006-09-29 2014-04-22 Sanofi-Aventis Deutschland Gmbh Analyte measurement device with a single shot actuator
US7175642B2 (en) 2002-04-19 2007-02-13 Pelikan Technologies, Inc. Methods and apparatus for lancet actuation
US7909778B2 (en) 2002-04-19 2011-03-22 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8267870B2 (en) 2002-04-19 2012-09-18 Sanofi-Aventis Deutschland Gmbh Method and apparatus for body fluid sampling with hybrid actuation
US8360992B2 (en) 2002-04-19 2013-01-29 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US7232451B2 (en) 2002-04-19 2007-06-19 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US7491178B2 (en) 2002-04-19 2009-02-17 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US8579831B2 (en) 2002-04-19 2013-11-12 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US9248267B2 (en) 2002-04-19 2016-02-02 Sanofi-Aventis Deustchland Gmbh Tissue penetration device
US7226461B2 (en) 2002-04-19 2007-06-05 Pelikan Technologies, Inc. Method and apparatus for a multi-use body fluid sampling device with sterility barrier release
US7547287B2 (en) 2002-04-19 2009-06-16 Pelikan Technologies, Inc. Method and apparatus for penetrating tissue
US9795334B2 (en) 2002-04-19 2017-10-24 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
TWI293248B (en) * 2002-05-23 2008-02-11 Nat Health Research Institutes Anti-virus compounds
US8574895B2 (en) 2002-12-30 2013-11-05 Sanofi-Aventis Deutschland Gmbh Method and apparatus using optical techniques to measure analyte levels
ES2347248T3 (en) 2003-05-30 2010-10-27 Pelikan Technologies Inc. PROCEDURE AND APPLIANCE FOR FLUID INJECTION.
US7850621B2 (en) 2003-06-06 2010-12-14 Pelikan Technologies, Inc. Method and apparatus for body fluid sampling and analyte sensing
WO2006001797A1 (en) 2004-06-14 2006-01-05 Pelikan Technologies, Inc. Low pain penetrating
EP1671096A4 (en) 2003-09-29 2009-09-16 Pelikan Technologies Inc Method and apparatus for an improved sample capture device
WO2005037095A1 (en) 2003-10-14 2005-04-28 Pelikan Technologies, Inc. Method and apparatus for a variable user interface
US7822454B1 (en) 2005-01-03 2010-10-26 Pelikan Technologies, Inc. Fluid sampling device with improved analyte detecting member configuration
US8668656B2 (en) 2003-12-31 2014-03-11 Sanofi-Aventis Deutschland Gmbh Method and apparatus for improving fluidic flow and sample capture
KR20070011451A (en) * 2004-05-05 2007-01-24 예일 유니버시티 Novel antiviral helioxanthin analogs
EP1751546A2 (en) 2004-05-20 2007-02-14 Albatros Technologies GmbH &amp; Co. KG Printable hydrogel for biosensors
US9775553B2 (en) 2004-06-03 2017-10-03 Sanofi-Aventis Deutschland Gmbh Method and apparatus for a fluid sampling device
WO2005120365A1 (en) 2004-06-03 2005-12-22 Pelikan Technologies, Inc. Method and apparatus for a fluid sampling device
US20090054811A1 (en) * 2004-12-30 2009-02-26 Dirk Boecker Method and apparatus for analyte measurement test time
US8652831B2 (en) 2004-12-30 2014-02-18 Sanofi-Aventis Deutschland Gmbh Method and apparatus for analyte measurement test time
WO2009126900A1 (en) 2008-04-11 2009-10-15 Pelikan Technologies, Inc. Method and apparatus for analyte detecting device
US9492375B2 (en) * 2008-07-23 2016-11-15 Warsaw Orthopedic, Inc. Foam carrier for bone grafting
US8039433B2 (en) * 2008-08-19 2011-10-18 Warsaw Orthopedic, Inc. Osteogenic compositions containing a coloring agent
ES2622562T3 (en) 2008-12-09 2017-07-06 Pfizer Vaccines Llc IgE CH3 peptide vaccine
US9375169B2 (en) 2009-01-30 2016-06-28 Sanofi-Aventis Deutschland Gmbh Cam drive for managing disposable penetrating member actions with a single motor and motor and control system
GB0908394D0 (en) 2009-05-15 2009-06-24 Univ Leuven Kath Novel viral replication inhibitors
GB0913636D0 (en) 2009-08-05 2009-09-16 Univ Leuven Kath Novel viral replication inhibitors
US8965476B2 (en) 2010-04-16 2015-02-24 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
CA2800774A1 (en) 2010-06-07 2011-12-15 Pfizer Vaccines Llc Ige ch3 peptide vaccine
CA2817165A1 (en) 2010-11-15 2012-05-24 Patrick Chaltin Novel antiviral compounds
US10609505B1 (en) 2018-01-06 2020-03-31 Stillwater Designs And Audio, Inc. Method and apparatus for automated tuning of vehicle sound system
US10608596B1 (en) 2018-01-06 2020-03-31 Stillwater Designs And Audio, Inc. Anti-clipping protection in audio systems

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4942516B1 (en) * 1967-03-30 1974-11-15
US3558632A (en) * 1968-09-16 1971-01-26 American Home Prod 2-(benzonaphthyridin-2-yl acyl) benzonaphthyridines
US3649632A (en) * 1970-01-27 1972-03-14 American Home Prod 3 4-dihydroacridin-2-(1h)-one derivatives
US3691168A (en) * 1970-04-01 1972-09-12 American Home Prod 5-arylbenzo (b) (1,7) naphthyridine derivatives
DE2357253A1 (en) * 1973-11-16 1975-05-22 Thomae Gmbh Dr K Tetrahydro azepinoquinolines - with anorexigenic, hypolipaemic, hypoglycaemic, antidepressant and antiallergic activitys
ES431307A1 (en) * 1973-11-16 1976-09-01 Thomae Gmbh Dr K Tetrahydro-azepinoquinolines
ES8705837A1 (en) * 1985-01-10 1987-05-16 Tanabe Seiyaku Co Naphthalene derivatives, process for the preparation thereof and pharmaceutical composition containing same.
JPS62142170A (en) * 1985-12-13 1987-06-25 Takasago Corp Production of lignan lactone
JPS62142169A (en) * 1985-12-13 1987-06-25 Takasago Corp Production of lignan lactone
JPH07103020B2 (en) * 1986-03-06 1995-11-08 大正製薬株式会社 Anti-cancer drug
JPS63146845A (en) * 1986-07-01 1988-06-18 Tanabe Seiyaku Co Ltd Naphthalene derivative
JP2692742B2 (en) * 1988-11-30 1997-12-17 株式会社ツムラ New lignans
JPH02160248A (en) * 1988-12-14 1990-06-20 Toyobo Co Ltd Electrophotographic sensitive body
JPH02160583A (en) * 1988-12-14 1990-06-20 Toyobo Co Ltd Optical recording medium
US5003087A (en) * 1989-02-03 1991-03-26 Tanabe Seiyaku Co., Ltd. Process for preparing a naphthalene derivative and a synthetic intermediate thereof
JPH0381274A (en) * 1989-08-22 1991-04-05 Tanabe Seiyaku Co Ltd Production of naphthalene derivative and synthetic intermediate thereof
JP3099243B2 (en) * 1990-03-22 2000-10-16 武田薬品工業株式会社 Bone resorption inhibitor and naphthalene derivative
JPH04321681A (en) * 1991-02-25 1992-11-11 Kyowa Hakko Kogyo Co Ltd Compound es-242-7 and es-242-8
KR100252428B1 (en) * 1991-10-17 2000-04-15 시오노 요시히코 Lignan analog, production thereof, and hypolipidemic drug
US5482967A (en) * 1992-09-04 1996-01-09 Takeda Chemical Industries, Ltd. Condensed heterocyclic compounds, their production and use
DE69422450T2 (en) * 1993-06-29 2000-06-08 Takeda Chemical Industries Ltd Quinolines or quinazoline derivatives and their use in the manufacture of a medicament for the treatment of osteoporosis
WO1996025929A1 (en) * 1995-02-21 1996-08-29 Takeda Chemical Industries, Ltd. Use of helioxanthin as an enhancer of cell differentiation inducing factors

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