CA2244256C - Antipruritic - Google Patents

Abstract

This invention provides an antipruritic comprising an opiate .kappa. receptor agonist as an effective component, a new morphinan quaternary ammonium salt derivative and a new morphinan-N-oxide derivative which are useful in treating pruritus complicated with some diseases.

Description

E _~».: r AIL!'', ~-t~ T"i s!~ /~~ti!' '~a ~AN~LATION
._ DESCRIPTION
ANTIPRURITIC
Technical Field The present invention relates to an opiate K receptor agonist and an antipruritic comprising it which are useful for the treatment of pruritus caused by various diseases.
Background Art Pruritus is an indication that is peculiar to skin, and is observed in a variety of dermatoses with inflammation. Pruritus may be provoked by some internal diseases .(malignant tumors, diabetes mellitus, hepatic diseases, renal failure, hemodialysis, gout, thyroid diseases, blood diseases, and iron deficiency), pregnancy, and vermination. In some cases, drugs and psychogenic causes may also provoke pruritus.
Since pruritus is a subjective, it is difficult to evaluate it quantitatively and objectively. The mechanism that induces pruritus has not yet been completely clarified.
Now, among the stimulants that are known to induce _ .,..
r s l pruritus included are histamine, substance P, bradykinin, proteinases, prostaglandins, and opiate peptides. It is considered that pruritus is provoked by reaction of these pruritic stimulants to multistimuli-reacting nerve terminals existing at the border area between the epidermis and dermis (pruritic receptors), and by transfer of the resulting impulse to tractus spinothalamicus, thalamus, and cortex cerebri in that order ("The approach to the therapy for pruritus cutaneous", by Yoshiki Miyachi, p.22, 1996, Sentan Igakusya).
Pruritus is a symptom in which patients experience significant discomfort, and in severe cases may cause significant disturbance of normal life. In the therapy for pruritus, primarily the treatment of dermatitis or an underlying disease that induces pruritus is necessary, and particularly in cases of dermatoses, simultaneous therapy for pruritus itself is necessary, because excoriation by a patient causes aggravation of symptoms.
Excoriation is the most exacerbating factor of dermatitis, because excoriation injures the skin resulting in defect of barrier function, and erosion by physical or chemical stimuli and bacterial infection may easily occur.

r' ,.
f Also, since the epidermis becomes thin and fragile and nerves are sensitized, pruritus readily occurs. As a result, a vicious cycle of repeated excoriation begins.
For example, although the period of excoriation resulting from pruritus during sleep is only 0.1~ in healthy cases, the average period of excoriation by patients with severe atopic dermatitis amounts to 24%. If an average period of sleep is assumed to be 8 hours, the period of excoriation will reach about 2 hours. It is clear that the excoriation during sleep exacerbates atopic dermatitis and becomes a factor in the occurrence of atpoic exanthema ("NIKKEI MEDICAL", JULY 10, 1996, p13).
Thus the therapy for pruritus itself may be a radical treatment, particularly in cases of dermatosis with significant pruritus.
Examples of dermatoses generally subjected to therapy for such pruritus include atopic dermatitis, nervous dermatitis, contact dermatitis, seborrheic dermatitis, autosensitization dermatitis, caterpillar dermatitis, asteatosis, senile pruritus cutaneuos, insect sting, photosensitive dermatosis, urticaria, prurigo, herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies, and I
i acne vulgaris; and examples of visceral diseases complicated with pruritus and being particular problems include malignant tumors, diabetes mellitus, hepatic diseases, renal failure, hemodialysis, and pregnancy.
Examples of drugs generally used for therapy for such pruritus include oral drugs, e.g. antihistamines, and antiallergic drugs; and dermatologic preparations, e.g.
antihistamines, adrenocortical steroid dermatologic preparations, nonsteroidal anti-inflammatory drugs, camphor, menthol, phenol, salicylic acid, tar, crotamiton, capsaicin, and humectants (urea, Hirudoid, and petrolatum). However, oral drugs have some problems, e.g.
a long lag time before presenting effects, and adverse events such as suppressive effects on the central nervous system (sleepiness and malaise) and impairment of the gastrointestinal system. Dermatologic preparations also have some problems, e.g. insufficient antipruritic effect, while topical steroids particularly cause some problems of adverse events such as decreased adrenocortical function caused by protracted administration and the rebound phenomenon.
With regard to the relationship between opiates and pruritus, it has been clear that opiates have function not only as analgesics but also as chemical mediators of pruritus. It was first reported that endogenous opiate peptides such as ~i-endorphin and enkephalin induced pruritus (B. FjellerActa, Dermato-Venereol. , 6~ (suppl.
97), 1-34,1981). It has been shown that morphine or opiate compounds induced pruritus as an adverse event when administered epidurally or intrathecally (J.H. Jaffe and W.R. Martin, Goodman and Gilman's Pharmacological Basis of Theraputics, Macmil-lan, New York, 1985). On the other hand, it has been also shown that pruritus which induced by morphine administered intrathecally was suppressed by naloxone, a morphine antagonist (J. Bernstein et al., J.
Invest. Dermatol. , 78, 82-83, 1982), and severe pruritus induced by increasing concentration of endogenous opiate peptides in cases of cholestasia with hepathopathy was suppressed by nalmefene (J. R. Thornton and M.S. Losowsky, Br. Med. J., 297, 1501-1504, 1988). Generally, opiate agonists induce pruritus, whereas opiate antagonists are antipruritic. Recently, it has become evident that the serum concentration of (3-endorphin in children with atopic dermatitis is significantly higher than that of healthy .iir r i )~

children. And it was reported that opiate antagonists were effective in pruritus induced by atopic dermatitis (S. Georgala et al., J. Dermatol. Sci., 8, 125-128, 1994):
Thus, it has been generally recognized that opiate agonists induce pruritus and opiate antagonists have a possibility as antipruritic. However, opiate antagonists do not have a practical use as an antipruritic at the present stage.
An object of this invention is to provide an opiate Fe receptor agonist and an antipruritic comprising it that solves the above problems and which has a significantly prompt and potent antipruritic activity.
Disclosure of Invention The present invention provides an opiate R receptor agonist and an antipruritic comprising it as an effective component.
Brief Description of the Drawings Fig. 1 shows the results of an eleventh embodiment.
Best Mode for Carrying Out the Invention It is known that there are u, b, and x opiate receptors, and endogenous opiate peptides each selectively _ _ 7 _ stimulating corresponding receptors have been discovered.
In other words, (3-endorphin and enkephalin are identified as u, and b receptor agonists, respectively, and dynorphin has been identified as an endogenous opiate peptide acting as a specific K receptor agonist. The effect of action of Fc receptor agonists including dynorphin on pruritus has not been clear, this invention, however, makes it clear for the first time.
Although the K receptor agonists of this invention may not have any chemical structural specificity regarding agonistic action on opiate K receptors,' the agonists preferably have higher specificity for R receptors than and b receptors. More particularly, morphinan derivatives or their pharmacologically acceptable salts with an added acid having an opiate K receptor agonistic activity are exemplified. Among these compounds are opiate R receptor agonists or their pharmacologically acceptable salt with an added acid represented by the general formula (I):

R,~ N ~ Rs_ ~B.Rs ..,' R6 A
R~

( I) _ g -wherein --- is a double bond, or a single bond; R1 is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, allyl, furan-2-ylalkyl having 1 to 5 carbon atoms, or thiophene-2-ylalkyl having 1 to 5 carbon atoms; R~ is hydrogen,,hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, or -NR9R1°; R9 is hydrogen or alkyl having 1 to 5 carbon atoms; R'-° is hydrogen, alkyl having 1 to 5 carbon atoms, or -C (=O) -R'-l; R11 is hydrogen, phenyl, or alkyl having 1 to 5 carbon atoms; R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; A is -XC(=Y)-, -XC(=Y)Z-, -X-, or -XSOz- (wherein X, Y, and Z are NR4, S, or O
independently; and R~ is hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms; and in the formula R4 may be the same or different); B is a valence bond, a straight or branched alkylene having 1 to 14 carbon atoms (wherein the alkylene CA 02244256 1998-09-O1' ,r .
_ g _ may have at least one substituent selected from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, and phenoxy, and one to three methylene groups may be replaced with carbonyl groups), a straight or branched acyclic unsaturated hydrocarbon having 2 to 14 carbon atoms with 1 to 3 double bonds and/or triple bonds (wherein the acyclic unsaturated hydrocarbon may have at least one substituent selected from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, vitro, cyano, trifluoromethyl, or phenoxy, and one to three methylene groups may be replaced with carbonyl groups), or a straight or branched, saturated or unsaturated hydrocarbon having 1 to 14 carbon atoms with one to five thioether, ether and/or amino linkages (wherein the hetero atom does not bond to A directly, and one to three methylene groups may be replaced with carbonyl groups) and Rsis hydrogen or an organic group having any one of the following fundamental structures:

I , I i N ~ N~ w ~ N
I i i I i i U C~J
I n I [ n I ~ n:N.a.s T:CH,N.S,O
(CH2)I ~ ~ = 0 - 5 (CHZ)mW /(CH2)n m , n ~ ~
T T m+n55 wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having_1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy; Rsis hydrogen; R' is hydrogen,, hydroxy, alkoxy having 1 to 5 carbon atoms, and alkanoyloxy having 1 to 5 carbon atoms, or R6 and R' are -O-, -CHZ-, -S-together; Rg is hydrogen, alkyl having 1 to S carbon atoms or alkanoyl having 1 to 5 carbon atoms; and the general formula (I) comprises (+), (-), and (~) isomers. And an opiate Fc receptor agonist represented by the general formula ( I I ) R
R ~~ . ~ s I. O
~R
,, O N A
/ I Ra Rs (II) wherein --- is a double bond, or a single bonds R1 is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, or allyl; RZ is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; Rais hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms A is alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C=C-1 and RS is an organic group having any one of the following fundamental structures:
/ / I , I /
a n:o.s la I I I /
(CH~~ ~ I -- 0-5 O
(CH~m~T/(CH2)n m. n >_ 0 m+n55 wherein the organic group may have at least one substituent selected from the Group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylendioxy~ R6 is alkyl having 1 to 5 carbon atoms and allyl~ X- denotes an anion to form a pharmacologically acceptable salty and the general formula (II) comprises (+), (-), and (~) isomers. And an opiate K receptor agonist or its pharmacologically acceptable salt with an added acid represented by the general formula (III):
Rz R~~N :' o ~ R
l~~~N~A~
.~~ 'R. 4 ~Ra (III) wherein --- is a double bond, or a single bonds R'- is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, or allyl; Rz is hydrogen, hydroxy, vitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, or alkyl having 1 to 5 carbon atoms R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms R4 is hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms; A is alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C=C-;
and RS is an organic group having any one of the following fundamental structures:
I
I , I , , ~
I o ~ I o ~ i T : CH, O
(CHZh n I = o--5 (CH~m~ /(CH~n m~~ n ~5 -- T
wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to S carbon atoms, hydroxy, ' - 14 -fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy; and the general formula (III) comprises (+), (-), and (~) isomers.
A compound to treat pruritus as an opiate K receptor agonist or its pharmacologically acceptable salt with an added acid other than morphinan derivatives is represented by the general formula (IV):
R O _ N~Ar p,r - \ / X or \
CHa Y ~ Z
' (LV) wherein R denotes two hydrogens, or -O-CHZCHaCH2-~ X and Y
are hydrogen or chlorine Z is O or S~ and the general formula (IV) comprises (+) , (-) , and (~) isomers. And an opiate K receptor agonist or its pharmacologically acceptable salt with an added acid represented by the general formula (V):
Z
~N ~ Y
(V) O ~X

wherein X is hydrogen, chlorine, or trifluoromethyl; Y is hydrogen or chlorine Z is CHz, -OCHzCH20-, or NCOzCHs: and the general formula (Vj comprises (+) , (-) , and (~) isomers. And an opiate x receptor agonist or its pharmacologically acceptable salt with an added acid represented by the general formula (VI):
O
Z
X
Y I / N
(VI) wherein X and Y are hydrogen or chlorine: Z is CHz, O, or S: and the general formula (VI) comprises (+), (-), and (~) isomers. And an opiate x receptor agonist or its pharmacologically acceptable salt with an added acid represented by the general formula (VII):
i I X
w o / I
~N N ~ Y

(VII) wherein X and Y are hydrogen or chlorine; and the general formula (VII) comprises (+). (-), and (~) isomers. One type or several types of opiate x receptor agonists may be used as effective components.
Examples of dermatoses complicated with pruritus as the subject for treatment include atopic dermatitis, nervous dermatitis, contact dermatitis, seborrheic dermatitis, autosensitization dermatitis, caterpillar dermatitis, asteatosis, senile pruritus cutaneous, insect sting, photosensitive dermatosis, urticaria, prurigo, herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies, and acne vulgaris. Typical examples of visceral diseases complicated with pruritus as the subject include malignant tumors, diabetes mellitus, hepatic diseases, renal failure, hemodialysis, and pregnancy. In addition, it can be applied to pruritus being a complication of ophthalmic diseases or otorhinolaryngologic diseases.
Of the compounds belonging to the K receptor agonists of this invention represented by general formula (I), R1 preferably is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, aryl, furan-2-yl-alkyl having 1 to 5 carbon atoms, or thiophene-2-yl-alkyl having 1 to 5 carbon atoms; and particularly methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, aryl, benzyl, phenetyl, furan-2-yl-methyl, or thiophene-2-yl-methyl is preferred.
R2 preferably is hydrogen, hydroxy, vitro, acetoxy, methoxy, methyl, ethyl, propyl, amino, dimethylamino, acetylamino, or benzoylamino; and further hydrogen, hydroxy, vitro, acetoxy, methoxy, methyl ar dimethylamino is preferred. Particularly, hydrogen, hydroxy, acetoxy or methoxy is more preferred.
R3preferably is a hydrogen, hydroxy, acetoxy or methoxy, and particularly hydroxy, acetoxy or methoxy is preferred.
"A" preferably represents, in concrete terms, -NR4C (=O) -~ -NR4C (=S) w -NR4C (=O) O-, -NR4C (=O) NR4-, -NR4C (=S ) NR4-, -NR4C (=O) S-, -OC (=O) -, -OC (=O) O-, -SC (=O) -, -NR4-, -O-, -NR4SOz-, or -OSOZ-; and particularly -NR4C (=O) -, -NR4C (=S ) -, -NR4C (=O) O-, -NR4C (=O) NR4-, -NR4C (=S ) NR4-, or -NR4SOz- .is preferred. Or preferred is -XC (=Y) - (where X
stands for NR4, S, or O, Y for O and R4 for hydogen or alkyl having 1 to 5 carbon atoms), -XC(=Y)Z-, -X-, or -XSOz- (where X stands for NR9, Y for O or S, Z for NR4 or O, and R4 for hydrogen or alkyl having 1 to 5 carbon atoms) . Further preferred is -XC (=Y) - or -XC (=Y) Z- (where X stands for NR4, Y for O, Z for O, and R4 for alkyl having 1 to 5 carbon atoms). Of them, -XC(=Y)- (where X stands for NR4, Y for O, and R4 for alkyl having 1 to 5 carbon atoms) is more preferred.
R4 is preferably hydrogen, or straight or branched alkyl having 1 to 5 carbon atoms and particularly straight or branched alkyl having 1 to 5 carbon atoms is preferred. Of them, methyl, ethyl, propyl, butyl or isobutyl is more preferred.
"B" is preferably - (CHz) n- (n=0-10) , - (CHI) n-C (=O) -(n=1-4) , -CH=CH- (CHI) n- (n=0-4) , -C°C- (CH2) n- (n=0-4) , -CHz-O-, -CHz-S-, - ( CHz ) z-O-CHz-, or -CH=CH-CH=CH- ( CHz ) n-(n=0-4) . Particularly, - (CHZ) n- (n=1-3) , -CH=CH- (CHZ) n=
(n=0-4) , -C=C- (CHZ) n- (n=0-4) , -CHz-O- or -CHz-S- can be cited as preferred examples. Of them, straight-chained alkylene having 1 to 3 carbon atoms, -CH=CH-, -C°C-, -CH20-or -CHZS- is more preferred. Particularly -CH=CH- or -C-C-is preferred. (Of course, these preferred examples include those which have their components substituted by various substituents as described above, or replaced with such substituents.) RS is preferably hyrogen or organic group having any one of the following basic skeletons:
Q
Q:N,O,S
(CH2)I ~ T:CH,N,S,O
l \ 1=0-5 (CH~m~(CNz)n m , n ~ 0 T m+n~5 (where the organic group may have its component substituted by at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to carbon atoms, hydroxy, fluorine, chlorine, bromine,' iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy);
and, of the compounds cited above with regard to R5, hydrogen, phenyl, thienyl or furanyl (these organic groups may have their component substituted by at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy) is more preferred.
More specifically, what is preferred may include hydrogen, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, perfluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-trichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3,4-methylenedioxyphenyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, cyclopentyl and cyclohexyl, but it should not be limited to above.
R6 and R7 are preferably -O-, -CHz- or -S- together, particularly their being -O- together is preferred.
R$ is preferably hydrogen, alkyl having 1 to 5 carbon atoms, or alkanoyl having 1 to 5 carbons; and, of the compounds cited above, hydrogen, methyl, ethyl or propyl can be cited as preferred examples. Particularly, hydrogen is preferred.
These K receptor agonists represented by general formula (I) can be prepared by the method disclosed in Japanese Patent No. 2525552.
Further, the compounds represented by general formula (II) are new morphinan derivatives from quaternary ammonium salts, and opiate K receptor agnoists: In that formula, R1 is preferably alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbons, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, or allyl; and particularly methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopenthylmethyl, cyclopentenylmethyl, cyclohexynylmethyl, benzyl, phenetyl, trans-2-butenyl, 2-methyl-2-butenyl, or allyl is preferred. More preferred is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, benzyl, phenetyl or allyl.
R2 is preferably hydrogen, hydroxy, vitro, acetoxy, methoxy, methyl, ethyl or propyl; and particularly hydrogen, hydroxy, acetoxy or methoxy is preferred.
R' is preferably hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbons, or alkoxy having 1 to 5 carbon atoms; and particularly hydroxy, acetoxy or methoxy is preferred.
R4 is preferably hydrogen, straight or branched alkyl having 1 to 5 carbon atoms, or a11y1 having 6 to 12 carbon atoms and particularly straight or branched alkyl having 1 to 5 carbon atoms, or, of them, methyl, ethyl, propyl, isopropyl, butyl or isobutyl is preferred.
"A" is preferably alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C=C-~ and, of them, -CH=CH- or -C=C-is more preferred.
RS is preferably an organic group having any one of the following basic skeletons:
I I Q : o,s (CHZ)~ ~~ T : CH, O
I ~// \\' I-0-5 ~T (Ct"{2)m~(CH2)n m. n ~ 0 T m+nSs (where the organic group may have its component substituted by at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having I to carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy); and particularly phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chloraphenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4--difluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluromethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 3-furanyl, 2-furanyl, 3-thienyl, 2-thienyl, cyclopentyl, or cyclohexyl is preferred, but what is preferred should not be limited to them.
R6 is preferably alkyl having 1 to 5 carbon atoms or allyl; particularly methyl is preferred.
The pharmacologically acceptable, ion-supplementing salt X- may preferably include iodide ions, bromide ions, chloride ions, methanesulfonate and the like, but of course it should not be limited to them.
Concrete examples of the compounds as represented by general formula (II) are shown in Table 1. The compounds represented by general formula (II) comprise (+), (-) and (~) isomers.

Table 1 . 0 1\1 : O R t / _ O _.~' C H a ~ C
1 / O s Rs OH
Q Rl R2 R3 Q R1 R2 R3 _O _ H H . S H H H
_ H

_ _ _ __ _ __ _ _ _O _ _CH __ _ _ _ H __ _ 3 H H S CH H

_ _ _ _ _ _ _ _O _ CH _ _ _ _ CH _ _ _ _ 3 H _ H 3 Fi H S

_ _ _ _ _ _ _ O _ _ _ _ _ _ _ F3 _ __ H _ CH3 _ I-i CFi3 _ H S

O __F____H _H _ _F H__ _H__ __ __ __ __,S.__ O _ __H _F____H __S _H__ F _H__ __ __ _ __ __ __H _H _F____ __S _H___ H__ _F
__ __ __ ___ __O __C1:__H____H__ S _C1_ H H
_ _ _ _ _ __ _ O H _ _CI H S H CI __ _ _- __ _ H
_ __ - H___ _ CI __S___H__ H__ _CI__ O H _ _ __ _ __ __ __ _ Br H H S _B~ H__ _H__ _ __ _ _ _ _ __ __ _ - H B= H __S-__H B= _H__ O __ _ _ _ _ _ __ __ _ _ _ _ H H B= . __S _H__ H _B=
O _ _ _ _ _ _O _ _CF3H H S CF H H
_ 3 _ _ _ _ _ _ _O _ _H _ _ _ _ _ CF _ _ _ _ _CF H _ H 3 H
_ 3 S

_ _ _ _ _ _ _ _O _ _H _ _ _ _ _ _ _ _ _ _ _H CF _ H H CF

_ _ _ _ _ _ __O __CN _ _ _ _ _ _ _ _ H _ _ CN H _ H S H

__ _ _ __ _ _ _ __O __H _ ___ __ ___ CN ___ _ _ CN H S H H

_ _ _ __ _ __ _ O H __ _ _ __ H __ H ClY S H CN

' - 26 -Continuation of Table 1 ~3 off R~
-_~ .~~N ~ ' Q
p CH3 R
l 2 R

off . H H

__O _H _H _H -_S _H _- _-_ _CH_3__ _H ~ _ _ _ _ H
_ O _H _H _H S _ _CH__ _ _ _ _CH_3 CH3 _ 3 H -_ -_O H H _H _ _ _ H _ Fi _ _F__ _H __ S _ _ _ O _H _ _H ~ _ H _ CH_ CH3 __O _ _F__ __ S - -.F 3 H--_ =H=___H -F-== --S _ H H-_ __O CI _ -_H_ - _H_ -_ _ -H _ __S _ -H-_ __~__ _H __ _H __~__ _ CI-_-F _ _ _O _ _CI _ _ _ _ H -_ _ -_ H _ _ S_ _H - Cl_-_ _O _B= H C _ __ H
_ _ _H _H _ _ B r _ H__ O _ _ _ S - _ Br__ _ _o _H _B=__ _ _ -H_ _ H
_ _ _H _H _ S_- _H__ CI_ _ __O _H _ __ l _ CF_3_- -_ _ _H _B=__ -' _ H _H H
__O _CF3__ _H S _ - _ _ _H _CF3_ _H _ _ CF_3 ~_ _ _H _CF3 --S _ H Br H
_O _H _ _H - _ - _ _ _ _H _H -_S _ CN_ -H-_ -_ _O _CN_ _ CN - _ _ H
_ _H _CN_ _ _ _ H H _ _ _O _ H S _ - _ _ H - _ _ CN
_ _O - _ I-I _ _ S CF_3 _ _O - _ _ , _ H
O S- _ - -- _ _ S H
_ _ _ S _ - CN_ S -I-I

Continuation of Table 1 O
/ Q.
-.;

OH

Continuation of Table 1 ON ; O
.,. N / Q
- -. ~ CH3 v O
OH
Q~ R1 R2 R3 Q~ R1 R2 R3 O H H H S _H _H__ _H__ __ __ __ _ _ _ CF_i3_ _ H
_ CH _ H __ Fi _ O 3 H S _ _ _ _ _ _ _ H _ _ H
_ _ _ CFi H _ - CH_ -_ H 3 _ 3 _ O S

_ _ _ _ _ _ E3 _ _ CH_ _ _ _ _ CH3 _ _ H 3 _ H _ ~ _ _ _ O H S

_ __F____H _H __S -F H__ _H
__ __ _ - _ __O __H _F____H __S -H-_ _F _H__ _ _ __ _ _ __O __H _H _F___ _=S='_I-i___H__ F __ _ __ __ __ -_ __C1___H _H - Cl__ _H__ _H
__ s ' _ _ _ __O __H _CI___H S- H__ Cl _H__ _ _ __ _ ' _ . _ _ __H _H _C1_ _ H__ H__ _CI__ _,_ __ S - -_ _ _ __B=___H _H - Br _H__ _ __ __ S -' -_ __O __H _B=___H _ H _ Br H__ _ __ __ S _ - _ _ _ _ _ _ __O __H _H _B=__ S H H Br _ _ __ _ - -_ _ _ _ _C~__H _H S CF3 H H '_ _ _ ' _ _ _ __H _C~J__H___ _ _ _ _ _C~ _H _H
_ _ _ _ _ _ __H _CN _H _-S____H__ _C~_~_H.__ __ _ ___ O H H C N S H H CN

Continuation of Table 1 R

~N.
'\

l C3HSCH2 OH OAc CH3 CH2CHCH2 OH_ OH_ CH3 _ _ _ _ _ _ OC _ _ CH2CHCH2 OH OAc CH3 C3HSCH2 _ _ H CH3 _ _ -_ _ _ _ _ CH2CHCH2 OH- OCH_3CH3 C3HSCH2 _ _ _ CH3 _ -OH _ H

_ _ _ _ _ CH?CHCH2 OAc- OH-_ CH3_-C3HSCH2 _ OH CH3 OAc _ _ OAc __ CH2CHCH2 OAc OAc CH3 C3HSCH2 _ _ _ _ OAc CH3 _ _ OC _ _ CH2CHCH2 OAc OCH_3CH3 C3HSCH2 _ H CH3 -OAc 3 ~

_ _ _ _ _ CH2CHCH2 OCH3 OH__ CH3 C3HSCH2 _ _ CH3 _-OAc _ H

_ _ _ __ CH2CHCH2 OCH3 OAc CH3 C3H5CH2 OCH3 OH CH3 _ _ _ OAc _ _ CH2CHCH2 OCH_ OCH_3CH3 C3HSCH2 OCH3 CH3 _3 a _ _ _ _ OC _ _ CH2CHCH2~ ' _ C2H5 C3HSCH2 OCH3 H CH3 OH_ _ 3 _ OH

_ _ _ _ _ CH2CHCH2 OH_ OH_ n-C3H7_ C3F35CH2 OCFi _ CH3 _ _ 3 _ Fi _ _ _ _ CH2CHCH2 _ OH_ i-C3H7 C3HSCH2 _ OH C2H5 OH _ _ OH

_ _ _ n-C3H7 CH2CHCH2 _ OH_ n-C4L-i9_ C3HSCI~2 _ _ OH OH _ OH _ _ _ _ i-C3H7 CH2CHCH2 _ OH i-C4H9_ C3HSCH2 _ _ OH _ _ _ OH OH

_ _ _ _ n-C4Fi9 CH2CFiCH2 _ OAc C2F35 C3HSCH2 _ _ OH OH
OFi _ _ OH i C4H9 _ OH__ _ CH3__ C3HSCH2 _ _ PhCH2CH2 OEi__ _ OH r __ CH3_ _ _ OH P CH3_ hCH2CH2 OH_ OAc CH3 _ _ _ _ _ OH _ _ _ _ _ CH3 OH OAc CH3 PhCH2CH2 OH_ OCH3 CH3 _ _ _ _ _ _ _ 3 CH3 _ OAc OH CH3 _ _ _ OCH PhCH2CH _ _ CH OH _ _ _ _ _ _ _ _ _ OAc OAc CH3 _ _ _ _ OH CH3 PhCH2CH - 2 _ _ CH3 OAc _ _ _ _ OAc _ _ PhCH2CH2 OAc OCH_3CH3 _ _ _ CH3 _ _-CH3 OAc _ _ _ _ OCH _ _ PhCH2CH2 OCH3 OH_ CH3 _ _ _ 3 CH3 _ _ _ -CH3 OAc _ _ _ _ _ _ _ PhCH2CH2 OCH3 OAc CH3 _ OCH3 OH CH3 _ _ -_ _ _ _ OAc _ _ PhCH2CH2 OCH_ OCH_ CH3 _ _ OCH3 CH3 _ _3 _3 _ _ _ _ _ _ OCH _ _ PhCH2CH2 OH_ OH_ C2H5 _ _ OCH 3 CH3 _ _ _ _ _ _ _ _ _ PhCH2CH2 OH_ OH n-C3H7_ _ _ OH _ _ _ _ CH3 _ C2H5 r OH

_ _ _ _ _ _ PhCH2CH2 OH_ _ i-C3H7 _ _ _ _ OH n-C3H7 _ _ _ _ _ _ _ _ _ PhCH2CH2 OH_ OH_ n-C4H9_ _ _ _ OH i-C3 _ _ _ CH3 OH ~ H7 _ _ _ _ _ _ PhCH2Cf-i2OH OH i-C4H9_ _ _ _ _ OE-i n-C4Ei9 _ _ CH3 O~i _ _ _ _ _ _ PI1CE-I2Cf-i2_ OAc C?f-i5 _ _ _ _ OH i-C4E-I9 _ Cl-i3 OH OH

Continuation of Table 1 R

.,. /
~O
_ ..O R4 ~l Rl R2 R3 R4 RI R2 R3 R4 C3H5CH2 OH OAc CH3 CH2CHCH2 OH_ OH-- ~H3 _ _ _ -_ _ _ H _ _ CH2CHCH2 OH OAc CH3 C3H5CH2 _ 3 CH3 _ _ _ -OH OC

_ _ _ _ _ _ CHZCHCH2 OH-_ OCH3 CH3 C3H5CH2 _ _ CH3 _ __ OH _ _ H

C3H5CH2 _ __ __ _ OAc_ OH CH3_-_ OH CH3 CH2CHCH 2 -OAc _ _ _ __ CH2CHCH2 OAc_ OAc- CH3_-C3H5CH2 _ OAc CH3 _ OAc _ _ H __ CH2CHCH2 OAc OCH_3CH3_-C3H5CH2 _ 3 CH3 _ OAc OC

_ _ _ __ CH2CHCH2 _OCH3OH CH3 C3HSCH2 _ __ CH3 - _-OAc _ H

C3H5CH2 _ __ __ CH2CHCH2 _ OAc CH3 OCH3 OH CH3 OCH3 _ -_ _ _ _ _ CH2CHCH2 OCH_ OCF_33CH3 C3H5CH2 OCH3 OAc CH3 _3 _ _ _ _ H _ CH2CHCH2 _0H__OH_- C2H5 OC

C3HSCH2 _ _ _ CH2CFiCH2 OFi__OH__ n-C3H7_ OCH __ CH3 3 _ H

_ _ __ C2Fi5 CH2CHCH2 _0H__OH__ i-C3H7 C3~5CH2 _ OH
_ OH

_ __ __ n-C3H7 CH2CFiCH2 OH_ OH_ n-C4H9_ C3HSCF32 _ OH _ _ OH

C3HSCH2 _ _ _ i-C3H7 CH2CHCFi2 OH__ OH i-C4F-i9_ _ _ _ OH OFi C3HSCH2 __ __ n-C4H~ CH2CHCH2_ OH_ OAc C2H5_ _ OH Y
OH

_ __ __ i-C4H9 PhCH2~~I2__OH OF-i__CH3__ ~3HSCH2 _ OH _ OH

C~i3 __ __ CH3 PhCH2CH2 _ OAc CH3 _ OH _ OF-i_-OH _ _ _ _ _ _ _ _ _ PhCH2CH2 _0H_ OCH 3 CH3 _ _ OAc CH; _ _ -_ _ _ _ _ 3 _ _ PhCH2CH2_ _OAc_OH~- CH3-_ _ _ OCH CH3 ____ _ _ __ PhCH2CH2 _ O CH3 CH3 _ _ CH3 _ O Ac -O Ac OH Ac -_ _ _ _ _ _ _ _ PhCH2CH2 _ OCH3 CH3 _ _ OAc CH; _ OAc _ _ CH3 OAc _ _ _ _ OCH _ _ PhCH2CH2 _ OH-- CH3 _ _ 3 CH3 _ OCH3 _ -CH3 OAc _ _ _ _ _ _ _ PhCH2CH2 _ OAc CH3 _ OCH3 _ CH3 _ OCH3 _ -_ _ _ _ _ _ _ PhCH2CH2 _ OCH_ CH3 _ OCH3 OAc CH3 _ OCH_ _3 _ _ CH3 _3 _ _ _ _ OCH3 _ _ PhCH2CH2 _0H_ OH_ C2H5 _ OCH CH3 _ _ _ _ _ _ _ _ _ PhCH2CH2_ _0H__OH__ n-C3H7_ ~ _ OH C2H5 CH3 _ r OH

_ __ OH n-C3H7 PhCH2CH2 _0H__OH__ i-C3 ___ _ _ H7 ____ __ __ i-C3 PhCEi2CH2 _ O n-C4H9_ CI-I3 _ OI-i E-i7 _ O H
OH H _ _ _ _ _ _ _ _ _ _ n-C~H9 PhCE-i2CH2_ OH i-C~H9_ _ _ _ _ OH _ _ CE-i3 OH OH _ _ _ _ _ _ _ i-C4E-I9 PIKE-I2CH2OH OAc C2H5 _ _ _ CH3 OH .' OH

_ 3 1 _ Continuation of Table 1 ~H3 H

': N \/
O R4 ~ Ra OH
R1 R? R3 R4 R1 R2 R3 R4 H H H _ CH3 _ H __ __ Br __ Br ___ Br ~HS__ H __ __ - - _-_ Br ___ H
H

CH_3 H CH3___ F __ __ -_ ~ H ___ .H-___ __ _ CH3 __ H
F

__ CH3 H _ CH3___ __ __ __ - H __ CH3 __ F
H

H H CH3___ __ ___ CH3 H _-F
F

H CH3__ CH3 CH3 __ ___ ____ _ _ - 5 H ____ C2H5_ _ F
F

CH3_ _ _ ? _ _ _ F3 C2Fi NO _ _ H - _ _ n_C3H7 H H _ _ _ _ CH3 - _ -CH3 _ _ CH3 _ _ _ H

NO

H CH3_ H i-C3H7 _ _ _ _ _ _ _ _ - H _ 1~I0 H

_ H n=C4H9 _ _ CH3 3_ _ ___ CF _ _ _ _ _ H
H

_ CH3 H i=C4H_9 _ __ H__ ___ _ H
C

__ CH3 __ H __ __ H H __ ~__ O CH3 H CH3 _ - _ _ _ -__ _ NHS
~~
H

_ H____ ~~H3 __ _ CH3 __ . H __ - _ n-C3 Fi7 _ ~F3 -H-_ H _ _ O ~H3 O _ _ _ ~H3 CHI _ _ ~~3 ~-C~~I7 ~

~j-- d~I~3 ~-___ ~ _- _-_ _ _ ~H~ ~ C~3 - - n-~4FI9 - -~

'~5 CF~'3 n=~~i~ _ _ _ _ H - -- _ Ci_~== yC~f~9 _ _ ' ~ ~

- 6CI~3 W i=C3f~ _ _ _ _ H
H

H' ~5CH3 ~I n-C~4H9 _ _ - - _ _ _ _ _ _ _ -H
H

H-'_ ~I-___ __ __ 1-Cd.~I9= __ H'3 CH3 H

OH__ _ _ CH3__~ H__ _ _ H -_ H__ _ _ _ CH3_-_ __ __-_ OH H _ n-C3H7 ____ OH CH3 __ H _ _ __ - ____ _ i_C3H7 Cl H-___ H CH3 _- H _ _ _ _ _ _ n-C4H9 H__ Ci ___ CH3 __ H _ _ _ H_ H __ _ _ _ _ _ _ OCF3 H i-C4H9 H Cl = = CH' _ _ H _ _ Cl _ _ H3 _ _ _ Cl C

_ Ci _ _ - n=C3 _ Cl - E-I7 _ _ Cl _ _ -_ C~ - =C4E-I9 n -Br H-___ H- = CH3___ - - -H-- gc - ,'~ CH3___ H

__ ~____~~ -- ~H~

- 3z -Continuation of Table 1 H
O N : R1 .,.1 / ~ \ R2 ( - ~~ R4 /
/ ( Rs OH
Rl R2 R3 R4 R1 R2 R3 R4 Br Br ___ ___ _ ___ H____H___- __ B=
NHS ~H3=
B=
H

CH H H CH3 _ 3 H____ H____ __ F

_ __ ____ ___ __ __ CH H CH3 __ H 3 F____ H____ __ H

___ __ __ ___ _ H __ CH3 CH3 _ H _ F____ _ H
H

___ __ __ ___ _ H CH3 CH CH3 _ 3 ___ _ F

F
H

___ __ _ __ ____ H CH3 _ _ C2H5 ___ H ____ _ H
F____ F____ C2H5__ ___ __ ____ _ H
H CH3 H n-C3H7CH3 H
NO

___ __ ____ _ _ H CH3 H i-C3H7____ __ __ _ NO
H

H

___ __ ____ _ __ H CF33 H n-C4H9__ _ __ ___ NO
CFi3 H
H

___ __ ____ _ __ H 33 H i-C4H ____ CF 9 __ __ _ H
H
CF

_ ____ __ __ OC ___ H CH3 ____ H Fi __ 3 __ _ CF-i3 CF

H
H

_ ____ ___ _ __ OC H CF33 ___ F3 H __ 3 __ ___ CFi3 H
H

_ _ _ _ _ _ O~F-i3CH3 _ H _ _ _ _ H _ _ _ _ H
H

_ ~C~3 6CI~3 C~~____ _ ~___ ~____ CFA
n_~3F~fi _ ~C~3 ~ _ ~~5 ~_ _ _ _ _ _ ~_ _ _ _ ~F~
i=C~~7 6C~3 ~-___ n_~~~_~-__ ~____ CF~_-~-~.~g_ ~C~~ ~____ 1=C3F~..-~___ ~____ CF~_-~=C~Fi~-____ __ -'__ ~C~3 ~____ n_~4~I9H

F_3 H
OC

H--- ~5C ~i ~=C~F __ Fi -- I OC__F_3_ __ H

_ __ _ _ ___ (7H _ _ _ H
_ _ _ H
H _ C'H'~ OC__F_3_ T-~ CH3 _ H OH H CH3 ___ H____ _ H

___ ____ __ ___ ___ H____ n-C3H7_ H

__ ____ ____ ___ ___ Cl H H CH3 i-C3H7 H
H

___ ___ ____ ___ __ H Cl H CH3 _ ___ n-C4H9 CF

I-i ___ ____ ___ ___ ___ H H Cl CH3 _ _ ___ H

H
i-C4II9 ___ ___ ___ ___ H C1 Cl CH3 ___ ___ ___ _ H CI CL n-C3E-I7 ___ ___ ____ _ H CL CI n-C4 E-i9 __ ____ ____ _ B c I-I f-i _ _ C E-f _ 33 _ Continuation of Table 1 R

ON .
/ ~ OCH3 - ,.' N ~ I i ~ I

_C3HSCH2 OH OAc CH3 CH2CHCH2 OH OH CH3 _ _ _ _ _ _ _ _ _ _C3HSCH2 _ _ OC CH3 CH2CHCH2 _ OAc CFi3 _ _ _0H H OH

_C3HSCH2 _ _ _ _ _ _ CH2CHCH2 _ OCH3 CH3 OH _ CH3 OH_ _ H _ _ _ _ _ _ _ _CH2CHCH2 OAc_ OH__ CH3__ _C3HSCH2 _ _ CH3 OAc OH

_ __ _ __ CH2CHCH2 OAc OAc CH3 C3HSCH2 _ OAc CH3 _ OAc _G3H~GH?_ _ _OA~0~~3 GHi _ CH2CHCH2_OAc OCH3 CH3 _ _ _ _ _G~_H_5_GH2_QAc H G_H_3_ _ CH2CHCH OCH3 2 CH3 _ _ _ _ OH_ _ _ _ _ _~~_H_S~H2_ _pCH3Q_H_ ~_H_3 _CH2CHCH2 OCH3 OAc CH3 _ _ _ _ _ _ _C~_H_SGH2_ _OCH3QAc_ C_H-3 _ CH2CHCH2 OCH_ OCH_ CH3 _ _ _ _3 _3 _ _ _C3HSCH 2 CH3 H3 __ _CH2CHCH2 OH__ OH C2H5 _ _OCH3 _ O C

_C3HSCH 2 _ H H3 _ _ CH2CHCH2 OH_ _ n-C3H7_ _OCH3 _ _ _ OH_ C _ _ _ _CH 3 OH CH3 _ CH2CHCH2 OH_ OH_ i-C3H7 _ _ _ _ -OH _ _ _ _ _._ _ _ CH 3 OAc _ CH2CHCH2 OH OH n-C4H9 _ _ _ _ _0H CH3 _ _ _ _ _ _ _ _ _CH3 _ _ _0H OCH3 CH3 CH2CHCH2_ OH_ _ i-C4H
_ _ _ _ _ OH 9 _ _ _CH3_____ __OAc__ _ _ _ OH OH _ OH CH3 PhCH?CH2 CH3 __ __ _ __ __ __ _ CH3 _ _OAc OAc CH3 _ OH OAc CH3 _ _ _ PhCH2CH2 _ _ _ _ _ _ _ _ _CH3._ _ _OAcOCH CH3 _ _ OCH CH3 _ _ _ 3 PhCH2CH2 OFi 3 _ _ _ _ _ _ _ _ _ _CH3 _ _OCH3 OH CH3 _ OAc OH CH3 _ _ _ PhCH2CH2 ~
_ _ _ _ _ _ _ _ _ _CH3 _ _OCH3 OAc CH3 _ OAc OAc CH3 _ _ _ PhCH2CH2 _ _ _ _ _ _ _ _CH3 _ _OCH OCH CH3 _ OAc OCH CH3 _ _ _ 3 3 PhCFi2CH2 3 _ _CH3 _ _ _ _ OCH3 _ CH3 ~ OH OH C2H5 _ PhCH2CEI2 OH _ _ _ _ _CH3 _ _ _ n-C3H7 _ PhCH2CH2 OCH3 OAc CH3 _ _ _ _ _ _ _ _ _ OH OH

_CH3 _ _ _ i-C3H7 _PhCH?CH2 OCH_3OCH3 CH3 _ _ _ _ _ _ _ _ OH OH _ _ _ _ _ n-C4H9 _ PhCH2CH 2 OH C2H5 _CF-i3 _ OH _ OH _ _ OH ' _ _ _ ~

_ _ _ _ _ _ i-C4H9 3_ PhCH2CH2 OH_ OH n-C3H7_ _ _ _ _ _ _ _ CH OH OII _ _PhCH2CH2 OH__ OH__ i-C3 _ H7 _ PhCH2CH2 OH OH n-C4H9_ _ _ _ _ _ PhCH2CH2 OH OH i-C4H9 Continuation of Table 1 R

n .,, / ~ OCH3 I _ ...: N ~ I

~ I

C3H5CH2 OH OAc CH3 CH2CHCH2 OH OH CH3 _ _ _ _ _ _ _ OC _ _ _ OH OAc CH3 _ _ _ H CH3 CF32CHCH2 _ _ _ _ _ _ _ CH2CH~~i2_OH OCH_3CH3 _ _ _ _ CH3 _ _ _ C3H5CH2 OH H _ _ _ _ _ _ _ _ CH2CHCH? OAc OFi_ CH3 _ _ OH CH3 _ _ C3H5CH2 OAc _ _ _ _ _ _ CH2CHCH2 Ac OAc CH3 _ _ OAc CH3 O _ C3H5CH2 OAc _C3H~GH? _QA~ O~L~3 CHI _ CH2CHCH2_OAc OCH3 CH3 _ _ _ _ _C3H5_GH2 _Q_A_cH_ ~_H_3_ _ CH2CHCH 2 OH_ CH3 _ _ _ OCH3 _ _ _ _ _ _C3HSCH2 OCH3 OH CH3 _ CH2CHCH2 OCH3 OAc CH3 _ _ _ _ _ _C~HSCH2 _QCH3 _ CH3 _CH2CHCH2 OCH__3OCH__3CH3 O Ac __ __ _ _OC~I32 CH3 _CH2CHCH2 OH__ OH__ C2H5 _C3HSCH OCH3 __ _ _C3H5_C_H__2__OCH_3_H __ H3 _CH2CHCH2 OH__ OH__ n-C3H7_ C __ _CH3 ______0H__ OH CH3 _CH2CHCH2 OH__ OH__ i-C3H7 _ __ CH3 _ _ OH OAc CH3 _ CH2CHCH2 OH OH n-C4H9_ _ _ _ _ _ _ _ _ OCH _ _ _CH2CFiCH2_OH_ OH__ i-C4H_9_ _ _ _ 3 CH3 _CH3 ______0H __ CH3 _ _ CH3 PhCH2CH2 _ OH CH3 OAc _ _ OH_ _ _ _ OH _ _ _ _ _ _ _ OH OAc CH3 _ _ _ _ _ OAc CH3 PhCH2CH2 _ _ _ _ OAc _ _ _ _ OCH _ _ _ OH OCH_ CF-i3 _ _ _ _ _ 3 CH3 PhCH2CH2 _ _3 _ _ _ OAc _ _ _ _ _ _ _ OAc OH CH3 _ _ _ _ OCH3 OH CH3 PhCH2CH2 _ _ _ _ _ _ _ _ _ _ _ _ OAc OAc CH3 _ _ _ _ OCH3 OAc CH3 PhCH2CFi2 _ _ _ _ _ _ OCH _ _ _ OAc OCFi_3CH3 _ _ _ _ OCH 3 CH3 _ _ 3 PhCH2CH2 _ _ _ _ _ OCH3 OH CL I3 _ _ _ _ _ OH C2H5 _ PhC>:-i2CH2 _ _ _ OH _ _ _ _ _ _ n-C3H7 _ PhCH?CH2 OCH3 OAc CH3 _ _ _ _ _ _ OH _ _ OH

_ _ _ _ i-C3H7 _ OCH_3OCH_3CH3 _ _ _ _ _ _ OH _ PhCH2CH 2 _ OH

_ _ _ _ n-C4H9 _ PhCH2CH2 OH OH C2H5 _ _ _ _ _ _ OH _ _ _ _ OH _ _ _ _ _ _ i-C4F-i9 _PhCHZCH2 OH__ OH__ n-C3H7_ _ _ _ _ _ _ OH _ _ OH

_ PhCH2CH2 OH OH i-C3 _ _ _ H7 _ _ _PhCH?CH? OH__ OH__ n-C4H9_ _ PhCH2CH2 OH OH i-C4H9 Continuation of Table 1 ~Hs H
O N:.
\ R1 I \. ~ R 2 / 'O R4 I /
Rs OH
R1 R2 R3 R4 Rl R2 R3 R4 H H H CH3 H_ Br _ _ _ Br _ _ H__ H____ H____ _ H___ C2H5 Br__-_ Br____ C2H5___ CH H H CH3 F__-3 H____ H_-__ CH3__-__ __ ___ ___ __ H CH H CH3 F__-_ 3 H____ --H

__ ___ _ ___ _ H _ CH3 CH3 _ H F____ _-__ H__ H

__ __ _ ___ _ H CH3 CH CH3 _ 3 F____ F____ H
-__ __ __ __ _ Fi CH3 Fi C2H5 __ _ H
F____ F____ C2HS__ __ __ ___ _ H
H CH3 H n-C3Fi7 _ H____ __ NO

__ __ ___ _ __ H CFi3 H i-C3H7 _ NO__2__ H
_ __ H

__ __ __ _ _ H CH3 H n-C4F-i9_ NO_ _2_ _ _ _ H
Fi -_ _ _ _ i-C4H _ _ CH _ 9 _ H 3 H _ _ _ _ _ __ H
H
CF

OC __ __ _ _ H __ F-i __ _ H CH3 __ __ _ CFi3 I-I

H

_ OC ~-__~~___ _ FI- ~ H___ 3 H_.___ ~~~

__ __ __ OCH CH3 C2H5 H _ H
H H
~F3 _ ~I-- CSCI~3CSC ~fi~-__ _ _ ~___ ~___-~~~
n-~3I~7 ~I-- ~CH3 '~I-__~~F~~-- ~___ .~___-CFA--I=C3H'~l-~-I--6CH3 ~I-__n=~3~-I7--~-__ ~____ C~3--ri-~4T~9-=~CH3 ~-I--i=C3f~7"--T3-__ ~?-____-C~_3=-_ i=C~F-~3-H-- Z3CH3 H-- n=~4Hg- OC_F3 H
H__-_ _-H-- ~3C ~I- i=C~H H
H - 9 -_ 3 - - OC__F3_ H

_-_ _ _ __ __ OH __ _ _ H
_ H CH3 OC__F_3_ _ H~

__ __ __ ___ _ H____ _ H

__ ____ _ ___ ___ H____ n-C3H7_ H

_ ____ __ ___ ___ Cl H H CH3 OCF3 H
__ i-C3H7 _ H

__ ___ ___ ___ ___ H Cl H CH3 OCF3 CF_ _ _ n-C4H9 _ F-i _ _ _ _ _ _ _ _ _ CF-i3 _ H _ Cl _ H H

H
i-C4H9 _ _ _ _ _ _ _ _ Cl _ CH3 E3 ' C1 _ _ _ _ _ _ _ _ n-C3f-I7 I-i C1 CL

__ ___ __ _ H C1 C1 n-C4 E-iy _ _ _ _ _ B _ _ _ r _ E-i _ Ei C F-I3 ___ ~H~'__ H-- ~I ~c ~E-i3-__ , - 3~ -Continuation of Table 1 ~H3 H
R
0 , ~'-, .,' t ~ ~ R2 Ra OH

H H H CH3 II___ Br --_ Br -__ CH3_ _ __ ____ __ _ IH___ H H H C2H Br_-__ Br__-_ _ ____ ___ ___ F___ CH H H CH3 H_ 3 _ H_-__ -_ _ __ __ ___ H

_-H_--_ -_ ___ --H__ H___- _ _ H
CH3 _ H

F
___ __ H CH3 CH _ H___ 3 _ F
CH3 _--_ F
_ _ -__ __ _ C2H5 H
H CH3 __ F____ H F__-_ __ __ ___ _ NO__2_ H CH3 H n-C3H7 H
_ H_--_ __ __ __ __ _ H___ H CH3 H i-C3 I~IO__2__ _ __ __ _ ___ n-C4H9 H
H CF-i3 H _ _ _ _ NO_ _2_ _ --H

_ _ _ i=C4H9 _ _ CH _ 3 _ _ Fi _ _ _ _ -CF

H _ _ H CH3 _ OC _ _ CF_3___ H H
__ __ H

__ H ___ CH3 _ -H
H

H _ O~ CH3 _ _ L'LHS
H _ ~F3 H
H

_ OCH3 O~ CH3 _ H N _ _ _ II
H

n-C3H7 _ dCH3 _ CC'~I~S~-__ _ - ~____ ~ C~~
i-~~H7 ---'~-I_'6CH3 ~I-~-n=C'3~I7-~-__ ~____ ri-~4~39 ' -~i-- (5CH3 ~i-- i=C3Ft'r'-~-__ ~-__-_ C~_3=-_ yC~f~

~I-- .-6CH3W__ n=~4~I3-OCF3 H
H____ __ -__ ~I-- ~C W - H
H _ i=C~H OC__F_3_ 3 _ 9 H

__ _ _ _ _ H___ OH _ _ __ H
__ H CH3 OC__F_3_ _ ~

__ __ ___ ___ _ _ H___ H_ __ ____ _ __ H___ H_-__ n-C3 H7_ _ ____ __ CH3 H___ H
_ i-C3H7 _ __ ___ ___ __ H___ H Cl H CH3 OCF3 CF_3-_ n-C4H9_ __ ____ _ CH3 H
H H Cl OCF3 H
i-C4H9 _ _ _ _ CH3 _ _ _ _ H Cl C1 _ _ _ _ n-C3H7 _ _ _ _ H C( CL

_ _ _ _ n=C4_E-_I9_ _ _ _ _ _ _ _ CH3 Br _ _ _ _ f-I
E-i __ _ _ __ H B r E-i CE-I3 _~~ _ Continuation of Table 1 ~Hs R

yN:
I O _ ...: H
Oi ~l _C3HSCH2 _0H__ OAc CH3 CH2CHCH2 OH CH3 _ OH

__ _ __ __ _C3HSCH2 _0H OC CH3 CF32CHCH2 _ CF-i3 _ _ H OH
_ 3 OAc _ _ _ _ _ _ _ _C3HSCH2 _0H _ CH3 _ CH2CHCH2_ CFi3 _ _ H OIi _ _ _ _ _ _ _C3HSCH2 _OAc _ CH _CH2CHCH2 OAc CH3 _ OH 3 _ OH
-_ _ __ _ _ _ C3Fi5CH2 OAc OAc CH3 CH2CHCH2 OAc CH3 _ OAc _ _ _~3H5~1<i2 _Qp,~ Q~~~ ~~3 -CH2CHCH2 OAc CH3 _ _ =_ OCH

_ _ _ _~~_H_S_~H2_QAc _H_ ~_H_3_ CH2CHCH2 _ H3 _ _ _ _ C OCH3 _ _ OH
_ _ _ _ _ C3H5CH OCH3 OH__ 2 H2CHCH2 CH3 CH3 _ C CH3__ O Ac O

__ _~3HS~H2 _Q_C_H3OAc CH3 -CH2CHCH2 OCH H3 _ __ C 3 - OCH

_ _ _ _C3HSCF32 _OCH3 CH3 CH3__ _CH2CHCH2 _ C2HS
_ _ _ O _ ------ OH
OH

_C3HSCH2 _OCH3 H H3 CH2CHCH2 __ n-C3H7 C __ __ __ OH
OH

_ __ _ _CH 3 OH H3 _CH2CHCH2 __ i-C3H7 ___ _0H__ _ __ OH
C OH

_CH3 ,_-__ _0H__ OAc CH3__ _CH2CHCH2 __ n-C4H9 __ OH
OH

__ _ _CH3 _____ _0H OCH_3_CH3 _CFi2CHCH2__ i-C4H
_ __ OH 9 OH

_ __ _ _CH3 _____ _OAc OH CH3 PhCH2CH2 __ _ _ _ __ OH CH3 OH

_ __ _ _ CH3 _ _ _OAc OAc CH3 _ _ CH3 _ _ _ _ PhCH2CH2 OH
OAc _ _ _ _ _ _ _ _CH3 _____ _OAc OCH__3CH3 _ _ CH3 PhCFi2CFi2OI-i OCH

__ _ _ __ _CH3 _ _ _OCH3 OH CH3 _ __ CFi3 _ _ _ PhCFi2CH2 OAc OH

_ _ _ _ _ _ _ _CH3 _ _ _OCH3 OAc CH3 _ _ CH3 _ _ _ PhCH2CH2 OAc OAc _ _ _ _ _ _ _CFi3 _ _OCH_ OCH CH3 _ OAc CH3 _ _ _ _ _3 3 PhCH2CH2 OCF
-i _ _ _ _ _ _ _CH3 _ _ _0H OH C2HS _PhCH2CH2 _ CH3 _ _ _ _ _ OCH3 _ OI-i _ _ _ _ _CH3 _ _ _0H _ n-C3H7 H OCH3 H3 _ _ _ _ O _ PhCH2CH2OAc _ _ C

_ _ _ _CIi3 _ _0H _ i-C3H7 _ PhCH2CH2OCH H3 _ _ _ _ _ OH _ 3 _ OCH

C

_CH3_____ _0H_ _ n-C4H 9 _PhCH2CFi2__ C2EIS~
_ _ OH OH
OH

CF-I3 _ __ i-C4F-~9 _PhCH?CH2 __ n-C3H7 OII OLI _ __ OH
OH

__ __ _ _PhCF-i2CH2OH_ OH_ -C3H7 _ _ _ i _PUCH2CH2_OH__ OH__ n-C4E-I9 _ PhCH2CH2 OH OH -C~H9 i _ . _ 38 _ Continuation of Table 1 R

C l-_C3HSCH2 _0H__ OAc CH3 CH2CHCH2 OH OH CH3 _ __ _ __ _ __ _C3HSCH2 _0H__ OC CH3 CH2CHCH2 OH OAc CH3 _ H

_ __ _ __ __ _C3HSCH2 _0H _ CH3 _CH2CHCH2 OH OCH3 CH3 _ _ H _ __ __ __ _C3HSCH2 _OAc OH CH _CH2CHCH2_ OAc OH CH3 _ 3 _ _ _ __ _ _ _ C3HSCH OAc OAc CH3 2 OAc OAc CH3.
_CH2CHCIi2 _ _ _ _G3H~GH2 _QAG. p~F~3~j-~,~ _ CH2CHCH2_OAc OCH CFi3 _ _ _ 3 _ _ _ _ -G3H~G~2 _Qp,~ ~ Q~j~, _ CH2CHCH2 OCH3 _ CH3 _ _ _ _ OH
_ _ _ _ _ _ _ Q~~-I_5_G_H_2_QCH~ QH CH3_ _ CH2CHCH2 OCH3 OAc CH3 _ _ _ _ _ _ _ _Q~HSQF_i2 _QC_FI~QAc_ QF33 _CH2CHCH2 OCH OCH CH3 _ __ 3 3 __ __ _ _C3HSCH2 _OCH3 OCH 3 CH3 CH2CHCH2 OH OH 2H5 _ __ C

_C3H5CH _OCH_32 H3 _ __ __ n-C3H7 C H __ CH2CHCH2 OH OH
__ _ __ __ _ _CH 3 OH H3 CH2CHCH2 OH OH i-C3H7 _____ _0H__ _ __ C

_CH3 -____ _0H__ Ac CH3 _ __ __ n-C4H9 O __ CH2CHCH2 OH ~OH

_ __ __ _ -CH 3 OCH3_H3 CH2CHCH2 OH OH i-C4H
- _ _ _ _0H 9 _ _ C

_CH3 _ -- _OAc OH _ _ _ _ _ _ _ _ _ CH3 _ _ _ CF33 PhCH2CH2 OH OH

_ _ _ _ _ _ _ _ _CH3 _ _ _OAc OAc CH3 _ _ OAc CH3 _ _ _ _ PhCH2CFi2 OH

_ _ _ _ _ _ _CH3 _ _ _OAc OCH CH3 _ _ OCH CH3 _ _ _ 3 PhCH2CH2 OFi 3 _ _ _ _ _ _ _ _ _CH3 _ _ _OCH3 OH CH3 _ OAc _ CH3 _ _ _ PhCH2CFi2 OI-I

_ _ _ _ _ _ _ _ _CH3 _ _ _OCH3 OAc CH3 _ OAc OAc CH3 _ _ PhCH2CH2 _ _ _ _ _ _ _CH3 _ _ _OCH OCH CH3 _ OAc OCH CH3 _ _ _ 3 3 PhCH2CH2 3 _ _ _ _ _ _ _ _CH3 - _ _0H OH C2H5 _ OCH3 _ CFi3 _ _ _ _ PhCH2CH2 OH
_ _ _ _ _ _ _ _CH3 _ _ _0H _ n-C3H 7 _ PhCH2CH2CH3 OAc CH3 _ _ _ OH _ O

_ _ _ _ _ _CH3 _ _ _0H _ i-C3H7 _ PhCH2CH2 OCH OCH CH3 _ _ _ OH _ 3 3 _ _ _ _ _ _ _CH3 _ _ _0H _ n-C4H 9 _ PhCH2CH2OH _ C2H5 _ _ _ OH _ OH

CH _ _ _ i-C4H9 _PhCH2CH2 _ _ n-C3H7 OH _ _ _ _ 3 OH__ OH
OH

__ _ _ PhCH2CH2 OH O -C3 _ _ H H7 _ i _PhCH?CH2 OH__ _ n-C4H9 _ _ OH

__ _ PhCH2CH2 OH OH -C4H9 i .

The compounds of this invention represented by General formula (II) can be obtained, to put it specifically, by the following method.
Generally, as shown by Chart I, obtainment of the compounds can be achieved by the steps of treating tertiary amine at 17 position of the startir~g material represented by general formula (VIII) (where R1, R2, R3, R4, Rsand A represent the~same as defined in general formula (II)) with an alkylating agent such as halogenated alkyl and methanesulfonate ester, to convert it into a quaternary ammonium salt [Chart I]
a R6 Ra Rt~N :: R O R~~I~t :' O
' ~RS RsX X- ~~~ ~ ~Rs N A
..'O R4 A ~ .'O Ra or CHaSOaRs ~ I _ R' R
(VIII) (II) The starting material including tertiary amine at 17 position represented by general formula (VIII) can be produced by the method disclosed in Japanese Patent No.' 2525552.
There are many alkylating agents that can be used for converting the starting material as represented by general formula (STIII) into a quaternary ammonium salt. Methyl iodide, ethyl iodide, propyl iodide, butyl iodide, allyl iodide, methyl methanesulfonate and dimethyl sulfate are convenient because they react comparatively rapidly to produce quaternary ammonium salts. However, other alkylating agents such as methyl bromide, ethyl bromide, propyl bromide, butyl bromide, allyl bromide, methyl chloride, ethyl chloride, propyl chloride, butyl chloride and allyl chloride may be also used. As the solvent, ethylene chloride, chloroform, tetrahydrofuran, ethyl acetate, dimethylformamide, acetonitrile, methanol, ethanol, propanol, tertiary buthanol or acetone may be used alone or in combination to serve as the reaction solvent. The reaction temperature is preferably set at 0°C to the boiling point of solvent, or more preferably at room temperature to the boiling point of solvent; the period is preferably set at 1 to 14 days, or more preferably at 1 to 10 days and the reaction should proceed in a sealed tube or under a normal pressure. The aforementioned alkylating agent may be added by one equivalent with respect to one equivalent-of tertiary amine, or it may be further added, for example, 0.1-5.0 excess equivalents or more excess to amine. Further, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate or sodium carbonate may be added as a base. One equivalent with respect to one equivalent of tertiary amine, or additional 0.1-5.0 excess equivalents or more-excess of the base may be used.
Further, the compounds represented by general formula (III) are new morphinan N-oxide derivatives at 17 position, and opiate K receptor agnoists. In that formula, R1 is preferably alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl 1-~aving 5 to 7 carbons, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, or allyl; and particularly methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopenthylmethyl, cyclopentenylmethyl, cyclohexenylmethyl, benzyl, phenetyl, trans-2-butenyl, 2-methyl-2-butenyl, or allyl is preferred. More preferred is methyl, ethyl, propyl, butyl, isobutyl, Y s ~ Y

cyclopropylmethyl, benzyl, phenetyl or a11y1.
R2 is preferably hydrogen, hydroxy, nitro, acetoxy, methoxy, methyl, ethyl or propyl; and particularly hydrogen, hydroxy, acetoxy or methoxy is preferred.
R3 is preferably hydrogen, hydroxy, acetoxy or methoxy.
R4 is preferably hydrogen, straight or branched alkyl having 1 to 5 carbon atoms or phenyl; and particularly straight or branched alkyl having 1 to 5 carbon atoms is preferred. Of them, methyl, ethyl, propyl, isopropyl, butyl or isobutyl is more preferred.
is preferably alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C=C-; and of them -CH=CH- or -C=C- is more preferred.
RS is preferably an organic group having any one of the following basic skeletons:
O
I I
(CHZ)i !!''~~ T : CH, O
/// \\, I = 0-5 I (CKZ)m \ / (CI-12)n ftl, n >_ 0 T T m+nS5 (where the organic group may have its component.

substituted by at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, vitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy); and particularly phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,4--difluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromehylphenyl, 2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-furanyl, 3-furanyl, cyclopentyl, or cyclohexyl is preferred, but of course it should not be limited to them.
Concrete examples of the compounds as represented by general formula (III) are shown in Table 2. The compounds represented by general formula (III) comprise (+), (-) and (~) isomers.

Table 2 OH ~ OH
O R' ~N- : O . . R~
/ . .,.N / i N ~ O _ ...0 Ra ~ ~ O
~O R4 ~ ( Rs OH OH

H H H CH3 _ H __ _- __-__ . - _ H C2HS
- H _ H

~~~ _ __ __ _ _ _ H n-C3 H H H n-C3 - _ _ _ _ _ H7 H _ H i . ~3~I~I
_ - _ _ - ~I

i= ~ _ _ _ n-C4H9 H7 _ H
H H

_ _H _H _H _n-C4H9 _ - _ _ _ _ _ _ _ _ _ _ _ H9 y _ H _ H i- C4 H

E-3 H H i- C4H_ - -H-_ -H-_ _ '_ __ _9 -~~ ~3 ' _ -' _-~~3 _~ H ~~ _ ___ ~ F3 CH

_ _H _CH_3 _H _CH3 _ _ _ _ _ _ _ _ _ _ CH3 H Fi CH

H H CH3 CH3 ' _ _ _ _ '~21~~
'_ ___ - ~3 H _ =
- - H
-__CI~_~_ ~ ~F~S_ _ _ _ _ _ C1 __ __ _ H Fi ~

CI H H CH3 _ _ - -~-_ _ -_ .

_ _ ~~ _ H ~ ~i3-_ 3 H -_ -Cl CH3 _ _ _ _ _ -_ _ _ _ C2Fi5 H _ CI F-i H Cl H C2H5 - _ _ _ _ _ __ - _ _ - _ - _ _ Br H Ii CH~
__ _ -_ H H3 _ _ _ _ C _ __ _ CH3 _ H Br H
_-=Br H =CH3 __ _ _ ___ - ' ~ ~ _ _ $_ ~I3 B= CH3 __ _ - __ _ _ _ _ . -_ __ _ C2H5 _ _ - H Br Fi _ _ $r ~ ~ - _ _ _ _ __ ~~ ~' ~I H ~~
_ -H CH3 __ _- _- _-_ __ _ _ CH3 H F H

H F H ~H3 _ - __-_ _ __ -~__ _~__ - ~ ~H~
___ --___ __ - -H-_ _.F_=-.H-=
_ -_ ~ C2H5 , - H I-i CH3 _ __ -CF
___ _ 3 ~ C~ _ _ _ ___ _ _ _- CE-I3 ~ H CF3 H

H CF3 H _CH3 - _ __-_ _ _ - - H CF C~I3 H _ - -~F~_ _~H3 - _ _ _ _ _ - _ C2E-IS
CF3 _ E-I
E-i.

_ CF 3 H H C2H5 - _ _ ___ ___ -~_ _H__ -H ~3 -CN -H -~ =CH3___ _ -_ __ H CN_ E-I CE-i3 __H _CI~f _H _CH3 __ _ _ __-_ _ -- __ E-i _ C E-i _ H H CI~t CH 3 _ _ _ -___ _ _ H -~~- -~-(_- C2E-i5 _ -H C2~S

Continuation of Table 2 O R
z R~.N .:. O
..:.0 Ra ~O

Ri R2 R3 R4 Rl R2 R3 R4 O _ _ __ Ac __ _ ~ -aH OH CH3 C3H5CH2 OH O CH3 CF3~CI~CH~__ _ -.
C Of3 6Ac Cfi3 H

_ _ _ _ _ _ _ _ _ C~HSC~i'2 _ _ _ CH3 ~H2CFiCH2 _ OCH CH3 OH _ OH 3 ~

_ _ _ _ _ _ _ _ _ C3H5CH2 _ OH CH3 ~i-i2CH.CH2OAc _ CF-33 OAc OH

_ _ _ _ _ _ C3HSCf~ -OAc OAc CH3 CH2CHCH2 OAc OAc CH3 - -_ _ _ _ _ _ _ _ C3HSCH2 _ OC CH3 CH2CHCH2 OAc OCH CH3 _ _OAc H 3 _ 3 _ __ _ __ C3H5CH2 OAc _ CH3 CH2CF3CH2 OCH3 _ CFi3 _ OFi H
~

_ _ _ CH3 CH2CHCH2_ OCH3 _ CH3 C3HSCII2 _OCH3 OH~_ __ OAc __ _ C3H5CFi2 OCH3 _ - CH2CHCH2 OCH3 OCF33CH3 OAc CH3 C3H~GF~.. _O~'J33O~'J33CFi'~ C~~~~~I~ 6f~' df~' C~f~s _ - _-'_ _- -. _-C3HSCH2 OCH H CH3 CH2CFiCH2 OH OIT n-C3H7 _ _ _ _ CFI2.~CH~ 6I-~--6I~--i=~3I~~
C3HSCH2. _ OAc C2H5 _ OH

C~HS'C~2 - OAc n=C3fI7 CFt2~HCF3ZdFI---OH'--ri-~4FI9 - OH ---_ _ _ i- C~T'2'C'HCH~6Ft--OFt--i=
C3H5CH2 _ OAc C3H ~4H9 _ OH

C3HSCFI~ - 0~3 C2HS _ aFt' 6Ac CZ~-T
- OH - CA~2~iCHZ - - 5 -- - ' -_ _ _ _ _ _ C3HSCIi2 _ OCH3 n-C3F-i7 1~CHZCI~Z _ OH _ _ dL~' _ CH3- - OH- CH3 IShCI~CHZ-6~-- OAc CFI3-- OH - -- - -- - -- -_ _ _ _ ~hCf~C~I~-aft 6CH3 _ _ _ OAc _ - _ _ _ CH3 - C$~
__ OH -CH3 _-_ _ OCH3 _ _ _ _ OH C~I3 _ _ _ _OFi _ PhCH2CFi2 ~Ac _ _ CH3 _ _ _ _ CH 3 _ _ PhCH2CH2 OAc OAc CH3 OAc OH CH3 _ --_ _ _ _ _ _ _ _ PhCH2CH2 OAc OCH CH3 _ _ OAc CH3 3 CH3 OAc _ _ _ _ _ _ _ _ _ _ _ _ OCH3 CH3 PhCH2CH2 OCH3 _ CH3 CH3 OAc OH

_ _ _ _ _ _ CH3 - OI-~ CH3 PhCH2CH2_ OCFi3OAc CH3 - O~E~~ - _ _ - - _ _ _ _ _ _ _ _ PhCH2CH2 OCH OCH CH3 _ OCF33 OAc CH3 3 3 _ _ _ _ CH3- -OZ~ O~ CH3-- PhCH2CF-i2_ _ C2H5 -- 3 3 OH OFi - __ __ -__ _ _ _ PhCH2CH2 OFi OH n-C3H7 _ _ _ C2H5 _ _ _ _ OIH _ _ _ _0I _ CH3 _ _ I
_ _ _ _ _ CH3 OH _ n-C3H7 PhCH2CH2_ OH OH i-OH _ C3H7 _ _ _ _ _ _ _ i- PhCHZCH2_ OH _ n-C4F-I9 _ _ _ OI-i C3IH7 _ _ CH3 OI _ OH
I _ _ _ _ _ _ _ _ n=C4F-I9 PhCH2CH2 OH OH i-_ _ _ _ C4H9 CH3 _ _ OEi OH
_ _ _ _ _ i- ~C~? _ OAc CZ~
CH3 _ _ OE-i C4E-I _ - -OI 9 ~K
I

_ _ _ _ _ _ _ _ _ _ CH

3 OEi OAc C2H5 Continuation of Table 2 O R
R~~N :' 2 O
'''N ~ i .::0 Ra ~O

R1 R2 R4 R1 R2~ R3 R4 c_:~iti~ UH UAc CH3 L.t~LLtiLriLV ri V iris Cain ri _ _ _ _ _ _ _ _ C3HSCH2 _ _ OCH3 CH3 Cf~'l.C~C~I~6F~ 6Ac _ OH - C

C~~.~C~_ _O~ ~_ C~j ~H2GH~H2 _ _ OCFI CFi3 _ _ _ _ OH 3 -_ _ _ C3Fi5CH2 OAc OH CH3 CH2CHCFi2_ _ _ OAc _ _ _ _ _ _ _ _ _ _ C~E~~Cf~ _ OAc CL~3 CH2CHCH2 OAc OAc CH3 OAc _ _ _ _ _ _ _ C3~i5CH2 _ OC CFi3 CH2CHCFi2OAc OCI-ICH3 _ _OAc H 3 _ _ _ _ _ _ _ C3HSCH2 OAc _ CH3 CH2CHCH2 OCH3 _ CH3 _ OH _ H _ _ _ _ _ _ _ CFi2CHCH2OCH3 OAc CFi3 C3Fi5CH2 _OCH3 _ CH3 _ _ OH _ _ _ _ C3HSCH2 OCH3 OAc CH3 CH2CHCH2 OCFi3 OCH3 CH3 C3F~,5G~2__Q~3 0~3 CIA Cf~2~I~C~I~6f~' 6~' C~fiS
. . _- _- -. _- _-C3HSCH2 OCH CH3 CH2CFiCH2OFi OFi n-C3H7 _ _ _ _ CI3'2~TC~-I~6F~-- 6I-~--i=~'7.
C3HSCH2 _ OAc C2H5 _ OH

C~I~'~'Cf~'_Oj~ OAc n=C31~'~ CF32L'FIC~IZ~3F~ ~I~ ri-C-4A9 __ _ _ - -' "

C3HSCH2 OH _ i- CA'2~CF3Z~3F!'--OH---i=~4Fi9 OAc C3H

C~ E~~Cf~-- O-CT~3C2~5 CF~2~CHZ 6 F~ 6 C~
_ OH - - - Ac -F~"~"
- --_ _ OCH3 n-C3H7 _ _ _ CI~3---C3HSCH2 _ l3hCF~22~.'~~Z_ _ _ 6I~ 6I~
OH

CH'~'-_____0H__ OH-- CF~3- 1~CH2~~T2-6I~- 6Ac CFI3'__ - - -CIi3 OH _ _ ~hCI-~~1~2-_ 6CH3 CF~3---OAc _ _ CFi3 6f~

CH3 _ _ OCH3 CH3 PhCH2CH2 _ OH CH3 _ _ _ _0H _ OAc _ _ _ _ _ _ _ _ _ CH 3 OH CH3 PhCF-i2CH2_OAc OAc CH3 OAc _ f _ _ _ _ _ _ _ PhCH2CH2 OAc OCH CH3 _ _ _ OAc CF-~3 3 CH3 OAc _ _ _ _ _ _ _ _ _ _ _ _ OCH CH3 PhCH2CH2 OCH3 _ CF33 CH3 OAc 3 OH

_ _ _ _ _ _ _ _ _ _ OCI~~ _ C~3 PhCH2CH2 OCH3 OAc CH3 C~3 O~

_ _ _ _ _ _ _ _ _ _ _ OCH3 OAc CH3 PhCH2CH2 OCH OCH CH3 _ _ _ _ _ _ CF~3 -- - O~ CF~3 PhCH2CH2 _ _ C2H5 O~ 3 OH OII
3 _ _ _ CH3 _ _ _ _ _PhCH2CH2_OH OH n-C3E-~7 _ _ _ _ OH C2H5 _ _ _ _ _ _ _ _0H
_ _ CH 3 _ n-C3H7 PhCH2CH2_OE-I Of-I i-OPI OH _ _ C3EI7 _ _ _ _ _ _ _ i- PhCH2CH2 OE-I OH n-C4H9 _ _ _ _ _ C3H7 _ CH3 OH OH _ ' _ _ _ _ _ n-C4H9 _ OH _ i-_ _ _ OH -PhCH?CH2 _ C4Hy Cf-I3 _ OH
_ _ _ _0H
_ _ _ _ _ i- PliCH?'CPi?-SFr-- ~Ac CZ~-CF-I3 OF-i OF-i C4f-i -_____ _ _ _ I __ CE- O E-i O ~2I-i 3 Ac S

r Continuation of Table 2 O OH O
OH
O ~N_ ' O
N / I O R . ...N / O
.:O Ra Ra . / y / ...0 Ra I / Ry R2 ~ Rs - OH R
OH

__~___ _~____~____CIL3____ H H H CH3 H H H_ C2H5 --~__ ~__ _~__ _~L.__ ~-__ .~__ ~o._C3~7_ --H-- H__ _H__ n-C3H7 _ H H H i_ C3H7_ H H H i -C3H7 _ _ _-_Ji__ .~L__Ji__ ~-~d.LL9_ --~__ ~__ _~__ n=

_ _H _H _H_ _i= _C_4H9 H Ii Fi i- C4 _ _ F
_ i9 CH H 3 CH3 _ _ _ _ _ H _ _ _ _ _ _ _ ~ CH3 H H CH3 _ __~L__ _CH~ .~L___CIL~___ -_ _H _H _C_H_3__C_H_3_ H H CH CH3 _ 3 _ _ _ _ _ - CH3 H H C2H5 _ _ _ _ C'2H5 CHI H Fi _ __CI__ ._~____~____CI~ - CI H-_ - H CH3 ___ - _ -__ _ _ _ _ _H _C1 _H CH3 _ CI _ _ _ _ _ - _ H CH3 H

_H _H Cl _ _ -_ _C1 _H _ _ ' Cl H H C2H5 _ _ _ _H _C2H5 _ _ _ _ _ _ _ -_Br- H H CH3 _ _ _ _ _ CH3 -_ __ Br H H

_ H_ -Br _H __ --_ _ _CH3 -_ EI _H _Br____CH3 __~.__ ~__ _$_ C, __ _ ___ -Br_ H H C2H5 Br H I-i C2H5 __F___ _~____~-I____CH3 --F H__ _ H__ C
___ __ __H _F _H____CH3 H F H CH3 _ _ __ __ __ _ __ _ _H_ _H _F CE-i3 __ H __ CH3 _ _ H F

_ _H _ _~2H5 --~__ ~__ _~__ ~.H~'_ _ _ __ _H
__ - CF3 H . CH3 CF3 H H CF-I3 H

_ _ _CF3__H_ -C~ _ I-i CF3 _ CH3 _ _ _ _ _ _ _ -_ _ H _ --_ _H _~i _CF_3__CH3 _ H _ _ _ _ _ _ _ _ _ _ CF H3 C

_ _ _ _ _ CF3 H H C2H5 _ _ _ _ C2f-i5 CF3 I-I _ I-i __CCl _H____ _CH~____ --_ _ H
_ _ _H_ _CN _H H3 _ _ CI~1H CH3 _ _ ____ I-I

_ _ _ _ _ _ _ _H _H_ _CN _CI I 3 H H _ _ -CH3 _ _ _ _ t CI~

_ _ _ _ _ _ CN H H C2H5 ' _ _ _ _ C2E-IS
Cat H _ H

Continuation of Table 2 OH
~N. . O Ry N / I ~ Rz .~O R4 / Rs ( OH

H H CH3 _ Br H H__ CH3 __ __ ___ _~___ ~.___~.__ __ 5 H ___ H CH3 __ ~~ Br _ _ CH3 H CH3 ___ _ Br CF33 _ H
H

_ _ _ _ _ - H- B= B= ~H3 -_ H3 CH3 _ _ _ - _ H C _ _ _H ___ H _ CIi3 _~___ ~r__ ~_ ~~~__ ___ CH3 H CH3 _ __ F H____H__ CH3 -_ _ _ _ __ ___ F____Fi__CH3 __ ___ CH3 C2H5 _ H H

_ _ _ n-C3H7 ___ Fi F CH3 ___ CH 3 _ H H

_ _ _ _ _ _ _ H CH3 i- _ ~ _ ~ ~~~_ _ _ C3 _ _ ~ _ _ _ H7 _ _ H _ _ n-C4.H9 _ H F F C2H5 CH3 _ _ _ _ _ _ _ _ _ i= 2 H H__ CH3 --_ CH C4F I~IO _ _ _ _ _ __ 2 H CH3 OC __ _ _ NO
H H CH3 _ 3 ~ H

_ __ _ ___ __ __ _ OCH3 H _ _ _ N02 ~H3 __ CH3 H Ii H

_H ___ H -_CH3__ _ C~~= ~--___~_= C~=__ ___ CH3 H OCH3 ~H CH3 H_ _ _ H CH3 _ 3 _ _ _ _ CF_ 3 _ OCFi3_ _ _ _ H CF3 CH3 -_ _ _ C2H5 H ____ -_ H

_~___ bCf3~_ n-C~~7 - H-__ H Cue C2H5 _ _~___ ~CF~3-I~'- i= _~_.. ~_.._C~3_n-~3I~~__ - C3F~'-T

I~ - _ _ n-C~F~ H H CH3_i= C3 - b _ _ H7 _ _ Cf~'3I~ _ _ _ O _ i- _ _ H CF'3n-C4H9 _ H3 C4H9 _ _ _ _ _ _ _ _ H H _ C _ _ H _ CH3 i _ _ H____CF_3_-C4H9 _ _ _ OH _ H

_ ___ __ __ _ H H CF33 __ OH H CH3 F3 H ~ OC

___ ___ _ _ _ ~~F3___ ~H3 __ _ H __ _ _ H___ H

___ ___ __ __ 3 _ H H OC_ CH3 _ _ H H CH F3 CI

___ ____ __ __ _ OCF3 H__ C2H5 _ CL H CH3 H _ H

___ ___ __ __ __ OCF3 f-i___n-C3H7_ _ H C1 CFi3 _ F-I I-i _ ____ __ __ ___ OCF3 _ i- C3H7 ___ C1 CL CI-I3 __ H
H H

_ _ _H ___ Cj___Cl-- C2E-IS'_ _ ~___ 6C.~ _~___n=C.~~~

H Cl _ n-C3H7 ~I dC'F3~I i-~'~9 CI

_ ___ __ n-C4H9 ___ Cl CL
H

Continuation of Table 2 O OH
N :' O R y OH

H H - H CH3 _ B H H CH3 r _ _ _ _ _ _ _ _~___ ~.___ ~__ ~~ ~ H__ Br H CH3 __ _ _ CH3 H H CH3 E-i H____Br- CH3 -_ _ _ __ __ __- H Br ~H3 _ CH3 H CH3 _ Br H ' _H H _' _ _ _ --~-__~_ ~r C~FrS_-___ CH3 CH3 _= _ _ H CH3 C H3 _ F___H__-_H_-- CH3 -_ CH

___ _ _ __ H___ F____H__ CH3 __ _ CH3 _ C2H5 H H

___ __ __ n-C3 _ H F CH3_ _ CH3 H H7 H _ -H -_H _ _ i-C3Fi7 _ _~____~___ ~~~ -___ CH3 _ _ F3 _ ~
__ H CH3 __ n-C4H9 _ ~ F F C2H5_ H H _ _ -- --_ _ _ _ _ i= C4H _ NO_ H H CH3 -_ 3 _ 9 _2_ _ _ _ _ CH H -H _ _ _ _ _ _ _ H NO__2H CH3 --L _ _ CH3 _ OC
F

_ OCFi3 ___ __ - ___ _ N02 CH3_ _ H CH3 _ H -_ ~ H
_ F-i _H H _-_ ~CFi3CH3- ' C~~__ ~___ C~ _-___ _ ~
_-_ - O~H3 '_H _ _ H CF_ H CH3 _ ~I 3 _ _ 3_ _ -OC CI~3 _ -_ _ _ _ bCH3 _ _ H Fi CF3 CH3 _ _ _ C2H~ -__ __-_ -_ H
H

bC~ _ n=C~~I7 - H H Cue C2Fi5 _ -~ ' _~___ ~Cf~~ I~- i= C~I~'T ~___ ~____C~~= _ - 3F~~
n-~

_ H. _ _ n-~~F_~9 _ Fi CH3_ i= C3H7 _ bC~~ _ _ .H _ _ _ ~ _ _ - _ H OCH _ i- C4H9 _ H CF3 n-C4Fi9 _ H _ _ _ 3 _ _ H _ _ _ _ _ _ _ CH3 _ H_____ -C4H9 _ H _ i CF_3_ OH H H

__ __ __ __ _ F-i F-i_ CH3 --_ OH H CH3 OCF3 _ H

-- _ _ _ H_ ~~~ H ~H3 _ CH3 _ _ _ _ ~

Cl H H _ _ H _ H OC_ CH3 CH3 _ _ F_3 --_ _ _ - H OCF3 H C2H5 - CH3 - _ _ - - -H H Cl CH3 H_-_ OCF3 _Fi___n-C3H7_ ___ ___ ___ __ _ OCF3_H i- C3H7_ _ Cl Cl CH3 f-I ___ -H _ __- C2E-I5-_ __~__-~C.~ ~ n_~4~~
-- -_H CI___ CI n_C3F-I7 -~-__ dC~- ~ i-~4~9 ___ _ _ H C1 CI n-C4H~) Continuation of Table 2 O R

R~~N :' O
' OCH3 .' R v I /

/I

RI R2 R3 R4 RI R2 R3 R4~

~H5 CH2 _0H OAc CH3 c.:Hlc_a~~ai~vn vn L.n~
_ _ _ _ _ ~F-i2CH~H2_ _ ~H3 2 _ OAc OH

C3H5CH OH H CH3 _ 3 _ OC

_ _ _ _ _ ~H2CHCH2 OH OCF-i3_CH3 ~~HSCH2 _ _ _ ~H3 _ OH _ H

_ _ _ _ _ CH2CHCH2 OAc_ OHy CH3 C3HSCH2 _ _ CIi3 _ _ OAc OH

_ _ _ _ C~I3 ~CH2CFiCFi2OAc OAc CH3 C~~~Cf~2 _ OAc _ OAc _ _ OCH3_ _ CH2CHCH2 OAc OCF33_CF33 C3H5CH2_ _ CH3 OAc ~ _ _ _ _ CH2CHCH2 OCH3 OH CH3 C3H5CH _ H CH3 _ OAc _ _ _ _ _ CH2CF3CH2 OCFi3_ CH3 C3HSCH2 OCH3 _ CI-i3 OAc OH

_ _ _ _ _ CH2CFiCFi2OCH_3_OCH_3_CH3 C3HSCH2 OCH3 OAc CH3 _ - -C3H~.GI~2__O~I3 Q~J33CHI. ~H2CHC~i2 OH OH C2H5 _ _ _ _ _ _ _ C3H5CH2 OCH H CH3 CH2CHCH2 OH OH n-C3H7 _ _ _ _ CF(2~C~IZ _ __ i= '7 C3H5CH2 _ OAc C2H5 6H- 6K
_ OH

_ _ _ _ n-C3H7 C~~~~ ~~- O~- ri-~~g ~3HS~H2 _ OAc - -OH

_ _ _ i- C3H C~~~Z _ _ i- ~'~i9 C3H5CH2 _ _ OAc _ _ '-OH O~ 6~

CSI-~~'Cf3~'__ O CSI-~~- CF~~CHZ 6I~'-OAc C~A'_~_ OH - - _ _-_ _ OCH3n-C3H7 _ _ _ CF~'3 C3H5CH2 _ ~C~~~ _ _ -__ _ 6~ O1~
OH

CF~3.______0H__ OH__C~.__ ~.~Cf~~fi~-6f~- 6Ac Cf~'3 - ~ -CH3 OH OAc CH3 _ _ 6CH3 Cf-~'3 ~hCf~C$2 _ = _ 6f~
_ _ _ _ _ OCH _ _ PhCH2CH2 OAc OH CH3 _ _ _ _ 3 CH3 _ _ CIi3 OH _ _ _ _ _ _ _ _ PhCH2CH2 OAc OAc CH3 _ _ _ _ CH3 _ CH3 OAc OH

_ _ _ _ _ _ _ PhCH2CH 2 OCH3_CH3 _ _ _ OAc CH3 OAc CH3 OAc _ _ _ _ OCH _ _ PhCH2CH2 OCFi3OH CFi3 _ _ _ 3 CH3 _ CH3 OAc _ _ _ _ _ _ CI~3 PhCH?CH2 OCI33OAc CH3 _ _ O~I~ _ C~3 OIL

_ _ _ _ _ _ _ PhCH2CH2 OCH_3_OCH3_CH3 _ _ OCH3 OAc CI-i3 _ _ _ _ O~ CR-3 PhCH2CH2 OH OH C2H5 _ _ OC'T~ 3 _ _ CF~3 3 _ _ _ _ _ _ _ _ PhCH2CH2 OH OH n-C3~i7 _ _ _ OH C2H5 _ _ CH3 OH _ _ _ _ _ _ _ _ n-C3H7 PhCH2CH2 OH OH i- C3H7 _ _ _ _ _ _ CH3 OH OH _ _ _ _ _ _ i- C3Z-i7 PhCH2CH2_ OE-I OH n-C4E-~9 _ _ _ _ OH _ _ CH3 OH _ _ _ _ _ _ _ n-C4E-I9 PhCH2CH2 OH OH i- C4H9 _ _ _ _ OH
~H3 OE-I

_ _ _ _ _ i- C4H_9 ~C~~Z dK' OAc CZ~
_ _ _ _ OH -CH3 _ _0H _ _ _ _ _ _ _ ~f-I3 O E-I O ~2I-L5 . Ac Continuation of Table 2 O R

R~~N : O
j OCH3 . ..: .,.N I ~
_ .~ R4 /
/I

C~H5CH2 _0H OAc CH3 c.:ri%Law-tipvn vrm_ _ _ OC _ ~f~2CF~C~~_ 6Ac Cfi~
CH _ _ _ H 3 O~I

2 O H CH _ C3H5 3 _ _ _ _ _ C~I3 ~H2CHCH2 ~F-i O~H_3_CH3 ~Cfi2 _ _ _ _ C~~i OI-~ _ H

_ _ _ _ _ ~HZCFiCI~2dAc ~~i Cfi3 . _ _ CH3 _ _ _ C3H5CH2 OAc OFi _ _ _ _ OAc CI-~3 CH2CFiCFi2OAc OAc CH3 C~I~CI~ OAc - - _ ---_ _ OC __ CH2CFiCH2 OAc OCH_3_CFi3 C3HSCH2 - H CFi3 --OAc 3 _ _ _ _ _ CFi2CHCH2 OCH3 OH CH3 C3H5CH2 _ _ CH3 _ -OAc _ _ H

_ _ _ _ _ CFi2CHCH2 OCH3 OAc CH3 C3HSCF32 OCH3 _ CH3 --OH

_ _ _ __ CH2CHCH2 OCH3 OCH3 CH3 C3H5CH2 OCH3 OAc CH3 ' ' _ -_ C3H.~.GI~2__O~a OS''J33CIA Cf~C'~L~-I~6f~ _ C~f~
. .. -_ 6f-~ 5 -_ ~
_ ~ OCH H CH3 CH2CF3CH2 OH OFi n-C3H7 _ _ _ _ C~~~Z __ __ i=
C3H5CH2 _ OAc CZHS aI~ 6I~ ~31~~
_ .
OH

C~~~C~2 - OAc n=C3fi7 CH2~H~-IZ ~3~T-O~- ri-~'4H9 - OH- - - --_ _ _ i- CF~~~Z _ _ I=
C3H5CH2 _ OAc C3H _ _ ~~I9 _ ., ~~ ~~ ' -OH

C3I~'SCf~2--OH O~ C2H'S CF~2~C~IZ .- O CZ~_ _ - - dFi' Ac _ - - - _ _ _ OCH3 n-C3H7 _ _ _ CH'3 C3H5CH2 _ ~C~~'Z _ _ -__ _ O~ 6~
OH

CI~3-__: -OH-- OH-- CH'3- I~CI~C1~Z-6F~'--6Ac CFr3 _ - - -CH3 -____ -~H-- _ _ ~hC~~~Z- a~-- 6~ __ ~Ac _ C~~

CH3 OH OCF __ PhCH2~H2 OAc OH CFi3 i3 CH3 _ _ -_ _ _ _ _ _ _ _ _ PhCHZCH2 OAc OAc CH3 _ _ _ CH3 _ --CH3 OAc OH

_ _ _ _ _ _ CH3 PhCH2CH2 OAc OCH_3_CH3 _ _ OAc --CH3 OAc _ _ _ _ _ OCH3 _ _ PhCH?CH~. OCH3 OH CF33 _ _ CH3 _ CH3 OAc _ ~a:.; ---_--r.xr-t~t~r~r--r.rr.;
Lrm V~.ri.~Vri - Pf~Ci?CH~ QGu~ 1J ~,I~~
~.ri~ a~ -_ _ _ _ _ _ _ _ _ PhCH2CH2_ OCH_3_OCH_3_CH3 _ OCH3 OAc CH3 -_ _ _ _ _ 3 C~I3 PhCIi2CH2 OEi OH C2H5 _ OZ~ O~ __ _ CI~3 3 _ _ _ _ _ _ C2H5 PhCH2CF-I2_OH OH n-C3H7 _ _ _ _ _ CH3 _ Of-i _ _ 0(-i _ _ _ _ _ _ _ n-C3H7 PhCH2CH2 OF-i OH i-_ _ _ _ _ C3H7 CH3 OH OH _ _ _ _ _ _ _ _ i- PhCH2CF-I2OE-i OH n-C4H9 _ _ OL C3 -_ _ CH3 OEi I H7 _ _ _ _ _ _ _ _ n-C4H9 PhCHZCH2 OH OH i-_ _ OH C4H9 _ _ _ _ _ _ _ i- ~C~Z ~~ ~3Ac CZFi~"
_ _ OH C4f-i_9 -CH3 _ _ _0H _ ' _ _ _ _ _ CI-I3 OH ~Ac 2H5 C

Continuation of Table 2 O R
z ~N :~~ O
Ri ::O Ra / R
OH
4 Rl R2 R3 R4 H H H CH3 Br H H CH3.

_ _ _ __ ~__ ~~j - H-___B=___H___-CH3 __ .__ ~.__ ~~__ _ H____H____B= CH3 __ __-___ ~~_ ~__ ~~__ _ __ ~~- ~y_ _ _ _ _ _ ~ - _ _ _ _ _ _ -__ ~~- ~-_ C~~-IS-- - H-___F____H___-CH3 -_ _ H CH3 H n-C3H7 H H F CFi3 _ _ _ _ _ _ _ _ _ _ _H ___ CH3_ __ H _ ~ __ __ C~~ _ i- C3H7 __ _H___ CH3_ H__ n-_C4H9 _ H F_-__F__-C2H5 _ _ __ _ H CH3_ H i C4H_ 9 2 H H CH3 _ NO

_ _ _ _ _ _ _OC_H3 H H CH3 _ 2 _ CH3 _ _- _ _ _ NO _ H _ H

_ _ __ _ __ H _ OCH3 H CH3 ____ __ Nb2 ~H3 _ __ _ - H H
_ _ __ H ~CH3 CH3 = C~3=___ __ C~~'3 ' __ _ __ _H _ OCH OC_H_CH3 3 CF_3___H CH3 _ 3 __ _ H_'___ __ __ _H __ OCH3 H C2H5 H H CF3 CH3 __ _ ____ __ _ _H ___ OCH3 H n-C3H7 ____ H CF3 C2H5 H

__ ____ ____ __ _ _ H OCH3 H i- C3H7 _ I~ ~~~ n-C3I~fi _ _ H
_ _ H OCH3 _ n-C4H9 - - CFr3-i= ~3I37 _ _ _ -H- - - -H - --_ _ _ _ _ _ _ H O _ i- C4 _ _ _ n-C4H9 _ _ C_ H H _ _ CF3 F_i3 9 _ _ _ H H

_ _ _ _ _ _ _0H___ H _ _ _ _ _ _ i-C4H
__ H CFi3 _ _ _ CF 9 H _ 3 H

__ __ _ ____ _ _ _H _ OH H CH3 OC H ___ _ ~ F H CH3' _ __ __ __ _ _______ _H H OH CFi3 __ O~__F_3_H ~H3 _ I
_ _ H____ ___ __ __ __ __ _C1___ H H CH3 _ H____H OC_ CH3 __ F

__ __ _ _ _IH Cl F-I CH3 H OCF3 _ C2H5 _ H

___ __ __ __ ____ _____ F-i H Cl CH3 _ OCF3 H n-C3H7 H

_ _E-i___~1___~1___~~-i3___ - H-__-pCF'3'H____i=C3F-i7 _H ___ CI__ Cl__ C2H5 _~____ 6~~'3H____ii-~4E~~

_ _ C1 Ct H H OCF3 H i- C4H9 _ - _ _ n-C3 _ _ H7 H Ci n-C4H9 CI

,Continuation of Table 2 O R

~N-:~ O

.::0 Ra R
OH
4 R1 R2 R" R4 H H H CH3 Br H H CH3 ~
_ -- _ _ - H-___B=___H CHj ~~~ __- -_ C~i3- ~'_- ~-__ C~I~-- - H-___H____B= CH3 __- -_ __ C~~ ~ - ~~~'_ _ H____B=___B=__-CH__ __ ~~_ ~3__ _~_-_ r r __ __ _ _~.___ __ ___ CF.~"___ .-- ~~j-- - H____F____H____-CH3 ' _H CH3_ H __ n-C3H7 H H F CH3 ___ ____ ____ ____ __ _H CH3_ H __ i-C3H7 _ F____F CH3 ___ _ H____ ___ _ _H CH3_ H __ n-_C4H9 _ H F_____ C2H5__ ___' ~ _ F____ _H CH_3_H __ i C4H__9 2 H H_ CH3 NO _ __ _OC_H__3H H _ CH3__ __ 2 ___ CH3 __ NO H
_ H

____ __ _ _ H OCH3 H' CH3 _ __ N02 __ - ~ H F3 CH3 -H pCH3 _ _ - C~~' _ _ C~_ _ __ . CH3 _ _ _ _ _ _ ____ n _ __ __ ri___ ~

_H OCH3 OC_H_3__ ___ CF_3___H CH3 ___ CH3 H __ __ __ _H OCH3 H _ C2H5 _ F-i CF3 CH3 ___ _ H

_ ____ ____ __ _ _ H OCH3 H _ n- _ H CF3 C2F35 _ _ C3H7 H
_ _ _ _ _ _ _ _ H OCH3 H i- C3H7 _ _ _ _ n-C3H7 _ _ _ CF3 _ H _ _ Fi _ F3 O _ _ n-C4H9 . - _ CFI3-_i= ~3T~7 _ CH3 H _ ~-_ _ -_ -_ _ _ -_ -_ _ -_ -_ _ _ _H OC_H_3H i-C4H _ H CF3_ n-C4H9 __ 9 H __ __ __ ____ __ _ _ _0H___H H CH3 . _ H CF i-C4H
__ H 3 9 __ __ _ ____ _ _ H OH H CH3 OC H ___ _ _ __ __ __ _ ____ __ __ H OH CH3 __ OC__F_3_H _~H3 _H _ __ __ ___ _ __H____ _C1____ __ __ _ H____H OC__F_3_CH3 H H CH3 _ _H __ __ __ H OCF3 H___ C2H5 _ Cl H CH3 __ __ __ __ ____ _ _ H H CL CH3 _ OCF3 H n-C3E-I7 H

_ _L-i.___C1___Cl___ ~i3___ --H____~C~ H_____i=
C3F-i7 _ _H CI__ CI__ C2H5 --~____bC~
___ H CI CI n-C3H7 H OCF3 H i- C4H9 _ _ _ _ _ _ _ _ H CI _ n-C4H9 CI
, Continuation of Table 2 O R

R~~N
N
.:O R, I cF3 ' .

H5 H2 _ H Ac H3 _ __ __ __ _ __ C3HSCH2 OH OCH3 CH3 ~~i2~HC~'~6F~ 6Ac CHI

_ _ _ _ C~f~.~Cfi2-_OI-~'-fI-- C~I3 ~H2CHCH2 OH OCH CH3 _- - - -- 3 -_ _ _ _ _ __ C3HSCH2 OAc _ _ CH2CHCFi2OAc _ CH3 _ _ _ _ _ _ _ _ C~I~SC~ -O Ac OAc CI~3 CH2CHCH2 OAc OAc~ CFi3 _ _ _ _ _ C3HSCF32 _OAc OCH3 CH3 CH2CHCH2 OAc OCFi CF33 _ _ _ 3 _ _ _ _ C3HSCH2 OAc H CH3 CH2CHCFi2OCH3 _ CH3 OH ' _ _ _ _ _ _ _ C3Fi5CH2___OCH3 _ CH3 CF32CHCFi2OCH3 OAc _ _ __ __ C3HSCH2 OCH3 OAc - CH2CHCF32OCH3 OCH3 CFi3 C3~L~.GF32__Q~ 033 CHI. ~~2~~C~~ ~~ - C~~IS
_ _ _-_- -_ 6~

C3HSCH2 _OCH3 H CH3 CII2CFiCH2OF3 _ n-C3H7 _ _ OFi C3HSCFi2 _ _ _ CFi2~~-I~__ __ i=~'7 OH OAc -- 6F~ 6Fi~

_ C~~~'C~i2-_O~ OAc n=C3fi7 CA2ZFIC~i~~Ff' A- ri-C.4FI9 __ _ _ - - _ - _ C3HSCH2 OH _ i- CA'2~I~I~6H' 6Ft i=
OAc C3H ~41~9 C~H'SC~T2'_ OC~3 C2I~S CFI2~~.'Fi~QI~ OAc C~FIS
__ OH - -- - -_ _ C3HSCH2 _ OCH3 n-C3H7 IShCF~2C'~~-6Ff 6~-- CF~'3---_ --_ OH

C~S_____ _0H__ ~H,__CH3-- pMCE~~2- aI~'- 6Ac CH'3-__ - -CFi3 ~ OH OAc CF-i3 ~hCF~'l~H~-._ 6CH3 Cf~'3 6F~ --_ _ _ _ _ CH3 _ _ _ OCH3 CH3 PhCF-i2~H2OAc OH _ _ _ _ _0H CFi3 _ _ _ _ _ _ _ _ _ CH 3 OH CH3 PhCH2CH2 OAc OAc CH3 OAc _ _ _ _ _ _ _ CH3 _ _ C~Ac CH3 PhCH2CH2 OAc OCH CH3 _ _ _ _OAc 3 _ _ _ _ _ _ _ _ CH3 OAc OCH CH3 PhCH2CH2 OCH3 _ _ 3 OF-I CF-i3 _ _ _ _ _ C~3 _ O~I~3 _ CFi3 PIiCH2CH2OCH3 OAc CH3 _ _ _ OIL
_ _ _ _ _ _ _ CF-i3 OCH3 OAc CH3 PhCH2CH2 OCH OCF- CH3 3 i3 _ _ _ _ CH'3------OC~ OC'F-CF~3- PhCH2CH? _ _ C2H5 CH3 _ _ _ _ PhCH2CH2 __ __ n-C3F-i7 _ _ _ _ _ C2I-iS OH OH
_ _ Of-i _OI-i _ _ _ CH3 _ OH _ n-C3H7 PhCF32CF-i2_ _ _ i-_ _ _ OH' OH _ C3H7 _ OE-I

CH3 _ _ i- PhCH2CE-i2_ _ _ n-C4f-i9 _ _ OH C3F-I7 OF-i _ OI-i OE-H

CH3 _ _ _ n-C4L~9 _ _ _ _ i-_ _ _ _ _ PhCH2CH2 OH _ C4H9 _ _OE-H OE-H OH
_ _ CH3 OE-I _ i- 1'liCFi?Cft2'Z7 ~7flcC?R5'-OE-I C4Ei H'-- -_ _ _ _ _ _ _ _ _ _ OAc C2E
CE-i3 OH ' I

-S

Continuation of Table 2 O R
Ry\N 2 ~~'N
R.

Rs Rl R2 ' R3 R4 R1 R2 R3 R4 L~iH~Caiz_UH UAc CH3 C:HZL:HC:HZUH UH C:H3 _ _ _ OC _ ~H2CH~F~i2_ _ _ _ C3HSCH2 OH H _ _ OAc CH3 3 CH3 C~H

_ _ _ _ _ _ __ _ _ C~ H~C~ _ _ _ CH3 CHZCHCFi2OFi OCH _ -_ _ _ _ _ _ _ _ _ C3HSCH2 _ _ CH3 CH2CHCFi2OAc _ _ OAc OH OH CH3 _ _ _ _ _ _ _ _ _ _ C3HSCA'Z _ OAc CH3 CF32CHCH2OAc OAc CF33 _ OAc _ _ _ _ _ _ C3HSCH2 _ OCH _ CH2CHCH2 OAc OCFI CH3 _ _OAc 3_ CFi3 3 _ _ _ _ _ _ C3HSCH2 OAc H CH3 CH2CHCH2 OCFi3 _ CH3 OH

_ _ _ _ _ _ _ _ C3HSCH2 _OCH3 _ CH3 CFi2CFiCH2OCF33 OAc CF33 _ OH

_ _ _ _ OAc 3 3 _ _ _ C3T-~SG~__O 0~3 CI~~_ ~H2CHCFi2_ _ C2H5 _ _ ~I-i OH
_ _ _ _ C3H5CH2 _OCH3_ H CH3 CF32CHCH2OH OH n-C3H7 _ ' C3HSCH2 OH - _ Cfl~C'~~~_ _ _ i= ~3~fi _ - df~ _ OAc CZHS ~f~

C3~'~'Cfi2--OH OAc n=C3~7 CF~2~CHZ 6F~' 6Ff' ri-~'4~I9 _ - - - --- -_ _ _ i- CF~'2~CHZ_ _ i= ~4~9 C3~i5CH2 _ OAc C3H _ _ _ 6Fi~ 6F~
OH

C~HSC~- _ 0~3 CZHS CF~2~IC;_iZ6FT' 6Ac CZI~
_ OH - - -_ -_ _ _ OCH3 n=C3H7 _ _ _ C~I~---C3HSCH2 _ ~hCf~2~Fi~_ 6H
_ 6H' OH

CH3'______0H__ OH__ ~.3__ ~IiCH2~~TZ6Fi 6Ac CH'3-__ - -- -CH3 OH OAc CH3 _ _ 6C~H Cf33 PhC~2~H~ dl=i 3 _ _ _ _ _ _ _ _ CI-i3 _ _ ~CH3 CH3 PhCH2CH2_OAc _ CH3 _ _ _ _0H _ OH
_ _ _ _ _ _ _ _ _ CH OAc OH 3 PhCH2CH2 OAc OAc CH3 _ _ _ _ _ _ _ _ _ _ _ _ _ _ OAc ~H3 PhCH2CH2 OAc OCH _ CH3 _ _OAc 3 CH3 _ _ _ _ _ _ _ _ _ _ CH3 OAc OCH CH3 PhCH2CFi2OCFi3 _ CH3 _ _ _ _ _ _ _ _ _ _ _ _ 0~3 _ CH3 PhCH2CH2 OCH3 OAc CH3 CH3 _ OH
_ _ _ _-_ _ _ _ _ _ _ CH3 OCF33 OAc CH3 PhCH2CH2 OCH OCH CH3 _ _ _ _ _ _ _ _ _ _ OZ~ O~ CH3-- . PhCH2CH2 _ _ C2H5 CH~~ 3 3 OI-i OEI

CH3 _ _ _ _ _ __ __ n-C3F37 _ _ _ _ _ C2H5 PhCH2CH2 OH OFH
_ _ OIi _0H _ _ _ CH 3 OH n-C3H7 _ _ _ _ i- C3H7 OH PhCI-I2CH2OH _ OH

_ _ _ _ _ i- _ _ _ _ n-C4f-i9 _ _ _ _ _ C3H7 PhCH2CH2_OH _ CI-i3 OI-i OH _ OF-I
_ CH3 _ _ _ n=C4E-iy PhCH2CII2OH _ i- C4E-I9 _ _ _ _ OE-i _ _ _0H Of-i _ _ CF-i3 OFi _ i- FliCH2~H?-OED OAc CZft~
_~ OH C4Ei -- ' -_ _ _ _ _ _ _ _ _ OAc I

' .
,.

Continuation of Table 2 O R

R~'N ;' O
.._ -.~ N \ ~ CH3 _O R4 _ _ __ Ac 3 _ ~a~.LLrmrir.~r~ ~~~
~~nynL vn v ._-~~ __ - _ C~2C~C~~ 6Ac HI _ 6~

_ _0H OC_H_3CH3 _ -C3HSCF32 _ _ _ _ ~H2CFiCI~2_ OCH3 CH3 OH

C~HSCH2 OH H CH3 _ -_ _ _ __ __ CH2CHCF32 OAc OH CFi3 C3Fi5CH2 _ OH CH3 _ __ --OAc C~~-~'~C~I2_ _ CH3 CH2CHCH2 OAc OAc CH3 - _ OAc _ --OA.c _ _ OCH3_ CII2CHCH2 OAc OCH3_CH3 C3HSCH2 _ CH3 _-OP,c _ -_ _ H _ CH2CHCH2 OCF33OH CH3 C3HSCH2 _ _ _ --OAc CH3 _ _ _ _ _ _ CH2CHCH2 OCH3 OAc CH3 C3HSCH2 OCF-i3 _ CH3 _ -OH _ _ _ _ _ CH3 CH2CHCH2 OCH_3_OCH_3_CH3 C3Fi5CFi2OCH3 OAc ._ C3F~G~2 G~3 O~3 CHI. CH2CHC~2 OH OH ~2H5 O _ _ _ _ _ _ _ _ _ H CH3 CH2CHCH2 OH OH n=C3H7 C3HSCH2 _ _ _ OCH _ _ _ _ _ _ C~~~ 6~ aI~ i= ~7 C3Fi5CH2 _ OAc C2H5 - -_ _ _ -OH

_ _ OAc n=C~fi~ CFl2'CHCHZ_ OFr-_ri-~4~I9 C~~-f~C~I2OH- - dF!' _ - _ _ _ _ i- C3H C~~~~ ~~ d~ 1- ~'~9 C3H5CH2 _ OAc - - ' _ -OH

C3HSCfi~ OH- OCH3C2.H5- CFI2~~I~ _ _ C~A
- - _ CSAc_~=
- 6I-~ ' ' -_ _ OCH3n-C3H7 _ 6~ aH 3 C3HSCH2 _ ~C~~~ -- ~ --_ CA
OH ' --CH3-__-_ _0H__ OH--CH3- ~tiCI~~2- _ 6Ac Cf-I

_ -' CH3 OH _ _ _ 6~ 6CH~_Cf~
OAc _ ~hC~~~ _ 3 CH3 _ . _ _ _ _ _ OCH3_ PhCH2CH2 OAc OH CH3 _ _ _ _ _ _ CH3 OH CH3 _ _ _ _ _ _ _ PhCH2CH2 OAc OAc- CH3_-_ _ _ OH CH3 _ _ CH3 OAc ~

_ _ _ _ _ C~I3 PhCH2CH2 OAc OCH3_CH3 _ _ _ OAc -CH3 Oflc _ _ _ _ OCFi3_ _ PhCH2C~I2 OCH3 OH CH3 _ _ _ CH3 __ --CH3 OAc C~3 ------0~~~ O~j--C~3 PhCH2CH2 OCH3 OAc CH3 - ---CH3 OCH3 OAc _ PhCT-i2CH2OCH_3_OCFi_3_CH3 _ -_ _ _ _ 3 CH3 PhCH2CH2 OH OH C2H5 _ _ 3 O~ _ _ CH3 O~

_ _ _ _ _ _ PhCH2CH2 OH OH n-C3H7 _ _ _ OH C2H5 _ _ CH3 OH _ _ _ _ _ _ _ _ n-C3Ii7 PhCF-i2CH2OIi OH i= C3H7 _ _ _ OH _ _ CH3 OH _ _ _ _ _ _ _ i- C3H7 PhCH2CH2 OH OH n-C4E-i9 _ _ _ OH _ -CH3 OEH _ _ _ _ _ _ _ _ n-C4Ei9 PhCH2CH2 OL-I OH i- C4Ei9 _ _ _ OEi - -CI-i3 OE-i CH3 '____-QH-- OH- i= C4H9 FtiCFI?~ft2-T3E~'-~3Ac ~H3 OH . bAc 1.2H5 Continuation of Table 2 - 57 -O

R1~N
.,,N H 3 _ .:O R, /..

HS H2 _ H _ H _ ~:HLC:HC_:ri~Vri t~ri ~.n~
_ _ _ Ac _ ~H2CHCH2 _ _ .-_ dAc -_ _ C3HSCH2 _0H C_H_3_CH3 ~H2CHCH2 _ OC-H3CH3 _ _ _ v CH3 _ C3F-i5~H2OH ~ OH

_ _ __ __ _ _ --C3HSCH2 _ H CH3 CH2CHCH2 OAc OH CH3 OAc v _ __ _-_ _ _ C~3 CH2C~ICH2 OAc OAc CFi3 C~~~C~I2 _ Ac _ --bAc _ _ CH3 __ CH2CF3CH2 OAc OCFi3_CH3 C3HSCH2 _ CFi3 - _ OAc _ _ _ _ _ CH2CHCH2 OCH3 OH CH3 C3HSCH _ CH3 - _ _ -OAc _ _ _ _ _ _ CH2CFiCH2 OCH3 OAc CH3 C3HSCH2 OCH3 _ CFi3 -_ H
v _ _ _ __ CH2CHCH2 OCH3 OCH3 CH3 C3Fi5CH 2 OCH3 Ac CH3 -- -C3F-L~.GLH2-._0~3 _ CHI. ~~2~~~~ ~~ 6~ ~~5 _ .C~3~_ _ _-v C3HSCH2 OCH3 CH3 CF32CFiCH2OH OH n-C3H7 _ -_ - = _ C~2CT~CHZ 6I~' OIL i= Z3T~7 C3 HS pH - Ac C2H5 -CH2 _ - -_ _ _ n-C3H7 CA~~~ _ _ n-~'~I9 C3HSCH2 _ Ac _ _ ' _ d~ OFf ~H

_ __ _ i- C3H C~~~ _ _ 4~ig C3HSCH2 _ _ _ _ i- C
OH Ac d~ O~ ' -C~ HSCf~ -bH Z''~~C2H'S CF~~~I~ df~ OAc CZF~S
- - - - - - -__ - --_ -OH =CH3n-C3H7 1~CH2C$~- dR---OIL' CI~3 C3HSCH2 _ " - -__ C~I3-_____CH__ H-- CI-~3- ~hCf~l~F~2-C3f~-6Ac C~I'3 - -CH3 -_ _OH - _ ~hCf~'2C~i~-_ 6C~3_CFI'3 _ _ _ _ _ A~ _ _ _ - CH3 6f'~
_ CH3 OH CF- _ _ PhCH2CFi2 OAc OH CH3 i3 CH3 _ _ -v _ _ _ _ _ _ _ _ PhCH2CH2 OAc OAc CH3 _ _ _ _ CH3 _ _-CH3 OAc H - --_ _ _ _ _ CH3 PhCHZCH2 OAc OCH_3_CH3 _ _ _ Ac CF33 bAc _ _ _ _ _ _ _ PhCH2CH2 OCH3 OH CH3 _ _ _ CH CH3 _ --CH3 OAc 3 "

C~3 - -C~.R~ _ C~3 phCF-i2CFi2OCH3 OAc CFi3 _ . _ _ _ -_ H

CH3 OCH3 Ac C~I3 PhCH2CH2 OCH3 OCH3 CH3 v _ -_ _ _ _ ~ CF-~3 PhCH2CFi 2 OH C2H5 _ _ :3 ~ OH _ CR'3 O~ _ _ _ _ _ _ _ _ _ PhCFi2CH2 OH OH n-C3H7 _ _ _ _ C2Fi5 _ _ CH3 _ H
OFi _ _ _ _ _ ___ n-C3H7 PhCH2CH2 OH OH i- C3 _ _ _ _ _ _ H7 CH3 OH H _ _ v _ _ _ _ _ _ i-C3Ii7 PhCH2CH2 OLI OH n-C4H9 _ _ _ _ -_ __ CH3 OL-i H

____ _ __ n-C4Ii9 PhCH2CH2 OE-i OH i- C4F-i9 CH3 __ vH -OH

_ _ _ _ _ i- C4H_9 FhCFI2L~I2-~3Fr--~Ac CZAR
_ _ _ _ _ -_____ _0H O_ CH __ H
3 _ CH3 O E-I Ac C2I-i5 The compounds of this invention represented by general formula (III) can be obtained, to put it specifically, by the following method.
Generally, as shown by Chart 2, obtainment of the compounds can be achieved by the steps of oxidizing tertiary amine at 17 position of the starting material represented by general formula (IX) (where R1, R2, R3, R4, RS and A represent the same as defined in general formula (III)) with an organic peroxide such as m-chloroperbenzoic acid, performic acid, peracetic acid, perbenzoic acid, trifluoro peracetate, permaleic acid and perphthalic acid, but the oxidants should not be limited to them.
[Chart 2]
R~ Rz ~ O Rz ~N :~ O s Organic peroxide or ~N :=
~R . ~Rs 1~~~ N A
_ .,,0 N A inorganic peroxide , Ra / I 'I ~~ (~~
R~ w R~
(I;C) (III) The starting material including tertiary amine'at 17 position represented by general formula (VIII) can be ' - 59 -produced by the method disclosed in Japanese Patent No.
2525552. There are many oxidizing agents that can be used for converting the starting material as represented by general formula (IX) into a tertiary amine N-oxide (III).
m-chloroperbenzoic acid is convenient because generally it reacts comparatively rapidly to produce an N-oxide.
However, other organic peroxides such as performic acid, peracetic acid, perbenzoic acid, trifluoro peracetate, permaleic acid and perphthalic acid maybe used. Or alternatively, the oxidizing agent may be generated in the reaction system: a tertiary amine is dissolved in, for example, formic acid, acetic acid or trifluoro acetate, and aqueous hydrogen peroxide with a concentration of 3-50~, or more preferably with a concentration of 30-50~ is added thereto. As a solvent, the halogen solvent such as methylene chloride, chloroform or 1,2-dichloroethane, the aromatic solvent such as benzene or toluene, the ether solvent such as diethylether or tetrahydroflan, the alcohol solvent such as methanol, ethanol, propanol or tertiary buthanol may be used as the reaction medium. Or alternatively, when the oxidizing agent is generated in the reaction system, the corresponding acid may be used as ' - 60 -the reaction medium as appropriate.
Instead of the organic peroxides described above, peroxides such as hydrogen peroxide may be used. Aqueous hydrogen peroxide alone may be used at a concentration of 3-50~, or it may be used in conjunction with a solvent like the one described above. Other usable oxidizing agents include ozone, tertiary butylhydroperoxide and cumene hydroperoxide.
Generally, the oxidizing agent may be used at 0°C to the boiling point of solvent, or more specifically at room temperature to the boiling point of solvent, for several minutes to three days, or more specifically for one to 24 hours. The aforementioned oxidizing agent may be added by one equivalent with respect to one equivalent of tertiary amine, or it may be further added, for example, 10-100 excess or more excess to amine. When excess peroxide (which is easily detected by the use of iodine/starch paper) is present on completion of the reaction, addition of an inorganic reducing agent such as sodium bisulfite or sodium sulfite, a metal catalyst such as 5$ platinum or palladium bound to carbon or alumina, or an organic reducing agent such as dimethylsulfide will ensure a ' ..

' - 61 -proper treatment.
Other oxidizing agents to be used for the production of tertiary amine oxide include ozone in a solvent (for example, in chloroform, methylene chloride, fluorene or methanol), ozone adsorbed onto silica gel, hydroperoxide such as tertiary butylhydroperoxide, as desired, in the presence of a catalyst such as a vanadium compound.
4~lhen cost is important, for example, when the product is manufactured in an industrial scale, the preferable reaction agent is 30-50~ aqueous hydrogen peroxide dissolved in tertiary buthanol. For example, when several kg of morphinan derivative (general formula (IX)) is allowed to react with 50~ aqueous hydrogen peroxide dissolved in boiling tertiary buthanol for two and a half hours, it can be oxidized into a morphinan-N-oxide derivative (general formula (III)).
Further, of the compounds represented by general formula (IV) of the Fc receptor agonist of this invention, preferred is trans-2-(3,4-dichlorophenyl)-N-methyl-N-[2-1-pyrrolidinyl) cyclohexyl] acetamide~ trans-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzo [b] thiophene-4-acetamide~ (5(3, 7(3, 8a) -3, 4-dichloro-N-methyl-N-[7- (1-r '_ pyrrolidinyl)-1-oxaspiro [4,5] dec-8-y1] benzeneacetamide;
(5(3, 7[3, 8a) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4, 5] dec-8-yl] benzo [b] furan-4-acetamide; or (5(3, 7(3, 8a) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4, 5] dec-8-y1] benzeneacetamide. The K receptor agonists as represented by general formula (IV) can be produced according to the method disclosed by J. Szmuszkovicz et al., J. Med. Chem., 25, 1125(1982); D.C. Horwell et al., U.S. Patent Appl. 558737 (1983); J. Szmuszkovicz et al., Eur. Patent Appl. EP126612 (1984); and P.R. Halfpenny, D.C. Horwell et al., J. Med. Chem., 33, 286 (1990).
Of the compounds represented by general formula (V) of the K receptor agonist of this invention, preferred is methyl 4-[(3,4-dichlorophenyl) acetyl]-3-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate; 1-[(4-trifluoromethylphenyl) acetyl]-2-[(1-pyrrolidinyl) methyl]
piperidine; or 1-[(3,4-dichlorophenyl) acetyl]-2-[(1-pyrrolidinyl) methyl] piperidine; 1-[(3,4-dichlorophenyl) acetyl]-4,4-ethylenedioxy-2-[(1-pyrrolidinyl) methyl]
piperidine. The ~c receptor agonists as represented by general formula (V) can be produced by the method provided by A. Naylor et a1_, J. Med. Chem., 36, 2'075 (1993); V.

t '~
' - 63 -Vecchietti et al., J. Med. Chem., 34, 397 (1991); ibid.
Eur. Patent Appl. EP232, 612 (1987), EP260,041 (1988), EP275,696 (1988); D.I.C. Scopes et al., J. Med. Chem., 35, 490 (1992).
Of the compounds represented by general formula (VI) of the K receptor agonists of this invention, 3-(1-pyrrolidinylmethyl)-4-[5,6-dichloro-1-indancarbonyl]-tetrahydro-1,4-thiazine is preferred. These K receptor agonists represented by general formula (VI) can be produced by the method disclosed in WO 94/05646.
Of the compounds represented by general formula (VII) of the K receptor agonists of this invention, 2-(3,4-dichlorophenyl)-N-methyl-N-[1-phenyl-2-(1-pyrrodinyl)ethyl] acetamide is preferred.
These K receptor agonists represented by general formula (VII) can be produced by the method disclosed by J.J.
Barlow et al., J. Med. Chem., 34, 3149(1991).
In the production of said K receptor agonists, the pharmacologically acceptable, acid-supplementing salt to be added to the compounds represented by formulae (I), (III), (IV), (V), (VI) and (VII) may preferably include inorganic salts such as hydrochloric acid salts, sulfates, nitrates, hydrobromic acid salts, hydriodic acid salts, phosphates, etc.; organic carbonate such as acetates, lactates, succinates, oxalates, glutarates, malates, tartrates, fumarates, mandelates, maleates, benzoates, phthalates, etc.; and organic sulfonates such as methane sulfonates, ethane sulfonates, benzene sulfonates, p-toluene sulfonates, camphor sulfonates, etc. 0f them, hydrochloric acid salts, hydrobromic acid salts, phosphates, tartrates, methane sulfonates and the like are preferred, but of course what is preferable is not limited to above.
These ~ receptor agonists may be refined sufficiently pure to be used as a medicinal preparation, and, after having passed the necessary safety test, as the neat state or as a composition to be combined with a publicly known or pharmacologically accepted carrier, vehicle, excipient or the like, can be administered orally or parenterally.
The oral preparation may occur as tablets and capsules, but, when used for the treatment of skin diseases, preferably may occur as topical preparations.
Preparation of the topical preparations may comprise the steps of combining a fat (preferably,.plant oil, animal t '.

oil, wax, fatty acid, fatty alcohol, mineral oil, turpentine oil, vaseline, etc.), a solvent (preferably, water, ethanol, glycerin, propylene glycol, isopropyl alcohol, ether, etc.), a preserving agent (preferably, paraoxybenzoic acid ester, benzoic acid, salicylic acid, sorbic acid, benzalkonium, benzethonium, propyleneglycol, chlorobuthanol, benzyl alcohol, ethanol, etc.), a stabilizer (preferably, tocopherol, butylhydroxyanisol, dibutylhydroxytoluene, sulfites, edetic acid disodium, etc.), an anionic surfactant (preferably, potassium soap, medical soap, zinc undecylenate, calcium stearate, magnesium stearate, aluminum monostearate, calcium linolate, sodium laurylsulfate, etc.), a non-ionic surfactant (preferably, glyceryl monostearate, sorbitan fatty acid partial esters, sugar fatty acid ester, stearic acid polyoxyl 40, macrogolic acids, lauromacrogol, polyoxyethylene160polyoxypropylene30glycol, polyoxyethylene hardened castor oil, polyoxyethylene sorbitan fatty acid partial esters, etc.), a cationic surfactant (preferably, benzalkonium chloride, benzethonium chloride, cetyl piridinium chloride, etc.), powders (preferably, zinc oxide, zinc powder in starch, kaolin, bismuth hyponitrite, titanium oxide, titanium dioxide, sulfur, anhydrous silicic acid, tarc, etc.), a preserving agent (preferably, paraoxybenzoic acid ester, sorbic acid, p-chloro-m-xylenol, Irgasan, hexachlorophene, etc.), an emulsifier (preferably, arabic gum powder, tragacanth powder, bentonite, carboxymethylcellulose sodium, methylcellulose, etc.), and a moisturizer (preferably, glycerin, propylene glycol, polyethylene glycol, 1,3-butylene glycol, sorbitol, polypyrrolidone carboxylic acid sodium, sodium lactate, sodium hyaluronate, chitin derivatives, urea, amino acids, sugar amino acid, etc.) to form a base, and of preparing it not only as an ointment, cream, emollient, lotion, patch, etc., but as a liquid preparation for topical use.
Further, the preparation may be made as a solution for topical ophthalmic use.
The content of K receptor agonist in a medicinal composition is not limited to any specific range, but the composition, to be used orally, should be prepared so that one ingestion may contain usually O.l~g-1000mg, and, to be used topically, should be prepared so that one application may give a dose of usually O.OOlng/m2 - lOmg/m2.

[Examples]
This invention will be described below in concrete terms by means of Examples. However, the following Examples are given just for illustration, and this invention should not be limited to those Examples in any sense.

17-cyclopropylmethyl-3,14(3-dihydroxy-4,Scc-epoxy-17-methyl-6(3- (N-methyl-traps-3- (3-furyl) acrylamido) morphinanium.idodide 1 CHI OH
~NO
~~~~ N
/ ~ . ~O CH3 ~ O
'O H

17-cyclopropylmethyl-3, 14(3-dihydroxy-4, Scx-epoxy-6(3-(N-methyl-traps-3-(3-furyl) acrylamido) morphinan 2.06998 (4.3mmo1), ethyl acetate 60m1, methanol 6m1, and methyl iodide 1.3m1 were placed together in a container to be sealed, and, while being sealed, was stirred at 100°C for four days. To the reaction solution was added methanol t '.
.a 60m1; the precipitated solid was dissolved and concentrated; and to the resulting residue was added distilled water 400m1. This aqueous solution was washed with chloroform (100m1 x 7); the water phase was concentrated; the resulting residue was recrystallized from ethyl acetate-methanol; and the resulting crystal was dissolved in distilled water 500m1. This aqueous solution was washed with chloroform (100m1 x 3); the water phase was concentrated; the resulting residue was recrystallized three times from methanol; and the compound in the title 102mg was obtained.
mp 202.40-207.9°C(decomposition) NMR(500MHz, DMSO-d6) b 0.38 (1H, m) , 0. 60 (1H, m) , 0.70 (1H, m) , 0 . 78 ( 1H, m) , 1 . 23 ( 1 . 4H, m) , 1 . 32 ( 0 . 6H, m) , 1 . 40-1 . 62 ( 2H , m) , 1 . 73 ( 1H, m) . 1 . 97-2 . 22 ( 1H, m) , 2 . 63 ( 1H, m), 2.75(1H, m), 2.84-2.95(1H, m), 2.87(1.8H, s), 3.02-3.20(1H, m), 3.10(1.2H, s), 3.22-3.35(1H, m), 3.44-3.70(1.6H, m), 3.58(3H, s), 3.85 (2H, m), 4.18(0.4H, m), 4 . 8 0 ( 0 . 6H, d, J=7 . 8 Hz ) , 4 . 8 8 ( 0 . 4H, d, J=8 . 3Hz ) , 5.86(0.4H, br s), 5.93(0.6H, br s), 6.36(0.6H, d, J=15.6Hz), 6.63(0.6H, s), 6.71(1H, s), 6.77(0.4H, d, l J=8.3Hz), 6.84(0.6H, d, J=7.8Hz), 6.89 (0.4H, d, J=15 . 1Hz ) , 6 . 99 ( 0 . 4H, s ) , 7 . 23 ( 0 . 6H, d, J=15 . 6Hz ) , 7.36 (0.4H , d, J=15.1Hz) , 7.66 (0. 6H, s) , 7.72 (0.4H, s) , 7 . 92 ( 0 . 6H, s ) , 8 . 03 ( 0 . 4H, s ) , 9 . 33 ( 0 . 4H, s ) , 9 . 72 ( 0 . 6H, s) .
IR (KBr) v 3460, 1649, 1595, 1454, 1410, 1321, 1158, 1139, 596 cm i Mass(FAB) m/z 491 (M+H)+.
Elementary analysis CZ9H35N205I1Ø5H20:
calculated values: C, 55.51; H, 5.78; N, 4.46; I, 20.22 measured values: C, 55.50; H, 5,86; N, 4.45; I, 20.23 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-17-methyl-6(3-(N-methyl-3-methoxycinnamamido) morphinanium.iodide 2 ~ H3 OH
N. O
~ OCH3 N v ..O CH3 'O H

17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-6~3-(N-methyl-3-methoxycinnamamido) morphinan 2.0014g (3.9mmo1), tetrahydrofuran 40m1, and methyl iodide 1.3m1 were placed together in a container to be sealed, and, while being sealed, was stirred at 100°C for eight days.
To the reaction solution was added methanol 60m1; the precipitated solid was dissolved and concentrated and the resulting residue was dissolved by a mixture 120m1 of chloroform and methanol; and extracted by distilled water 200m1 x 3. The water phase was concentrated; and the resulting residue was recrystallized four times from methanol-distilled water, to give the compound 295mg in the title.
mp: 176.0-183.0°C (decomposition) NMR(600MHz, DMSO-d6) s 0 . 37 ( 1H, m) , 0 . 60 ( 1H, m) ,' 0 . 7 0 ( 1H, m) , 0 . 77 ( 1H, m) , 1 . 23 ( 1 . 4H, m) , 1 . 35 ( 0 . 6H, m) , 1 . 43-1 . 63 ( 2H, m) , 1 . 74 ( 1H, m) , 2 . 02-2 . 22 ( 1H, m) , 2 . 62 ( 1H , m) , 2 . 75 ( 1H, m) , 2 . 83-2.96(1H, m), 2.90(1.8H, s), 3.04-3.19(1H, m), 3. 15(1.2H, s), 3.23-3.35(1H, m), 3.50(0.6H, s), 3.53(0.4H, s), 3.59 (3H, s) , 3,. 68 (0. 6H, m) , 3.78 (1.8H, s) , 3.80 (1.2H, s) , r '_ 3.85(2H, m), 4.21(0.4H, m), 4.82(0.6H, d, J=7.9Hz), 4.89(0.4H, d, J=8.2Hz), 5.87(0.4H, br s), 5.94 (0.6H, br s) , 6.63 (0.6H, d, J=15.OHz) , 6.72 (0.8H, s) , 6.76 (0. 6H, d, J= 8.2Hz), 6.81(0.6H, d, J=8.2Hz), 6.92(0.6H, dd, J=8.2 and 2.lHz), 6.96(0. 4H, dd, J=8.2 and 2.lHz), 7.00(0.6H, m) , 7 . 0 9 ( 0 . 6H, d, J=7 . 6Hz ) , 7 . 17 ( 0 . 4H, d, J=15 . 3Hz ) , 7.24-7.30(2H, m), 7.33(0.4H, t, J=7.9Hz), 7.42(0.4H, d, J=15.3Hz), 9.35(0.4H, s), 9.63(0.6H, s).
IR (KBr) v 3410, 1642, 1595, 1491, 1460, 1410, 1321, 1274, 857, 7 9 3 cm 1.
Mass(FAB) m/z 531 (M+H)+ .
Elementary analysis C3aH39N205.I1Ø3H20:
calculated values: C, 57.89; H, 6.01; N, 4.22; I, 19.11 measured values: C, 57.80; H, 5,86; N, 4.22; I, 19.14 17-cyclopropylmethyl-4,5a-epoxy-3, 14[i-dihydroxy-6(3-[N-methyl-traps-3-(3-furyl) acrylamido] morphinan-N-oxide . .
i O OH
~N .:: O
N
.''O Me ~ O
'O
H

17-cyclopropylmethyl-4,5a-epoxy-3,14(3-dihydroxy-6(3-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan 600mg (1.26mmo1) was dissolved in tetrahydrofuran 30m1; and to this solution was added dropwise at 0°C for 15 minutes a solution which was obtained after m-chlorobenzoic acid 348mg had been added to tetrahydrofuran 8m1. On completion of the dropwise addition, the reaction solution was stirred at room temperature for about one hour and half, to which was added a mixture of chloroform/methanol (4:1), to dissolve precipitated solid in the reaction solution. The solution was concentrated the resulting residue was purified by column chromatography [filled with alkaline alumina 20g and chloroform/methanol (10:0 to 10:1)]; and the yield was recrystallized with ethyl acetate-methanol, to give the compound 473mg (yield being 76~) in the title.
mp: 238-239.8°C (decomposition) NMR ( 600MHz, CDC13) b 0.38(1H, m), 0.45(1H, m), 0.76(2H, m), 1.34(1H, m), W

1.46(1H, m), 1. 61(2H, m), 1.76(1H, m), 2.25(0.2H, m), 2.42(0.8H, m), 2.90-3.03(1H, m), 3.05(2.4H, s), 3.06-3.22 (4.6H, m) , 3.41 (2H, m) , 3.72 (0.8H, m) , 3.79 (1H, m) , 4 . 58 ( 0 . 2H, m) , 4 . 67 ( 0 . 8H, d, J=7 . OHz ) , 4 . 75 ( 0 . 2H, d, J=7.OHz), 6.3 5(0.8H, d, J=15.3Hz), 6.59(0.2H, d, J=8.2Hz), 6.61(0.2H, d, J=15.3Hz), 6.64(0.8H, d, J=8.2Hz), 6 . 68 ( 0 . 8H, s ) , 6 . 83 ( 0 . 2H, d, J=8 . 2Hz ) , 6 . 91 ( 0 . 8 H, d, J=8.2Hz), 7.32(0.8H, d, J=15.3Hz), 7.33(1H, s), 7.38(0.8H, s ) , 7 . ~ 4 3 ( 0 . 2H, s ) , 7 . 55 ( 0 . 2H, d, J=15 . 3Hz ) , 7 . 62 ( 0 . 2H, s), 9.49(1H, br s),12. 12(1H, br s).
IR (KBr) v 3420, 1653, 1605, 1504, 1408, 1321, 1160, 872 ciri 1.
Mass(FAB) m/z 493 (M+H)+.
Elementary analysis CZ$H32N206Ø2AcOEt:
calculated values: C, 67.80; H, 6.64; N, 5.49 measured values: C, 67.80; H, 6:6'7; N, 5.65 17-cyclopropylmethyl-4,5a-epoxy-3, 14(3-dihydroxy-6~i-(N-methyl-3-methoxycinnamamido) morphinan-N-oxide 4 l _ _ 74 -O OH
I
~Nl\'~ O
~;j-~.''O1~N / f ~ OCH~
tvt a OH
17-cyclopropylmethyl-4, 5cx-epoxy-3, 14(3-dihydroxy-6(3-(N-methyl-3-methoxycinnamamido) morphinan 405mg was dissolved in tetrahydrofuran 20m1; and to this solution was added dropwise at 0°C for ten minutes a solution which was obtained after m-chlorobenzoic acid 225mg had been added to tetrahydrofuran 5m1 for dissolution.. On completion of the dropwise addition, the reaction solution was stirred at room temperature for about 40 minutes the reaction solution was concentrated the residue was submitted to column chromatography based on the use of alkaline alumina 20g; and the yield was recrystallized with ethyl acetate/methanol, to give the compound 329mg (yield being 79~) in the title.
mp: 234-236.8°C (decomposition) NMR ( 600MHz, CDC13) b 0 . 35 ( 1H, m) , 0 . 42 ( 1H, m) , 0 . 74 ( 2H, m) , 1 . 34 ( 1H, m) , 1.45 (1H, m) , 1. 61 (2H, m) , 1.72 (1H, m) , 1.81 (2H, m) , 2.24(0.3H, m), 2.41(0.7H, m), 2.86 -2.97(1H, m), 2.97-3.14(2H, m), 3.06(2.1H, s), 3.15(0.9H, s), 3.32-3.44 (2H, m) , 3.70-3.80 (1.7H, m) , 3.83 (3H, s) , 4.62 (0.3H, m) , 4 . 70 ( 1H, d, J= 7 . 9Hz ) , 6 . 57-6 . 68 ( 0 . 7H, m) , 6 . 58 ( 0 . 3H, d, J=7.9Hz), 6.62(0.7H, d, J=8.2 Hz), 6.77(0.7H, dd, J=8.2 and 2.lHz), 6.82(0.3H, d, J=8.2Hz), 6.84(0.7H, d, J=8.2Hz), 6.86(1H, d, J=15.6Hz), 6.91(0.3H, dd, J=8.2 and 2 . 1Hz ) , 6 . 94 ( 0 . 7H, d, J=7 . 3Hz ) , 7 . 03 ( 0 . 3H, s ) , 7 . 11 ( 0 . 3H, d, J=7 . 6Hz ) , 7 . 15 ( 0 . 7H, t, J=7 . 9Hz ) , 7 . 2 9 ( 0 . 3H, t, J=7 . 9Hz ) , 7 . 4 0 ( 0 . 7H, d, J=15 . 6Hz ) , 7 . 62 ( 0 . 3H , d, J=15.3Hz), 9.00(1H, br s), 12.15(1H, br s).
IR (KBr) v 3420, 1647, 1593, 1495, 1408, 1321, 1160, 917, 855 cm i Mass(FAB) m/z 533 (M+H) +.
Elementary analysis C31H3sNz~sØ3H20:
calculated values: C, 69.20; H, 6.86; N, 5.21 measured values: C, 68.11; H, 6.87; N, 5.21 17-cyclopropylmethyl-4,5a-epoxy-3, 14[3-dihydroxy-6[3-[N-methyl-3-(4-trifluoromethylphenyl) propyolamido]
morphinan-N-oxide 5 r _ - 76 -O OH
:: O
l'~~ N \
~O Me S
17-cyclopropylmethyl-4, 5cc-epoxy-3, 14(3-dihydroxy-6[i-[N-methyl-3-(4-trifluoromethylphenyl) propyolamido]
morphinan 413mg was dissolved in tetrahydrofuran 20m1; and to this solution was added dropwise at 0°C for 15 minutes a solution which was obtained after m-chlorobenzoic acid 205mg had been added to tetrahydrofuran 5m1 for dissolution. On completion of the dropwise addition, the reaction solution was stirred at room temperature for ' about one hour; the reaction solution was concentrated the residue was submitted to column chromatography based on the use of alkaline alumina 20g; and the yield was recrystallized with ethyl acetate/methanol, filtered and dried in a vacuum, to give the compound 304mg (yield being 74$) in the title.
mp: 205-208°C (decomposition) NMR ( 600MHz, CDC13) b 0.37 (1H, m) , 0.44 (1H, m) , 0.76 (2H, m) , 1.35 (0.2H, m) , 1 . 47 ( 1 . 8H, m) , 1 . 62 (2H, m) , 1 .75 ( 0 . 2H, m) , 1 . 82 ( 0 . 8H, m) , r 2.27(0.2H, m), 2:42(0.8H, m), 2.92(0.8H, m), 2.99(0.2H, m), 3.02-3.12(2H, m), 3.05(2.4H, s), 3. 12-3.22(2H, m), 3.31(0.6H, s), 3.40(2H, m), 3.79(1H, m), 4.22(0.8H, m), 4 . 50 ( 0 . 2H, m) , 4 . 7 4 ( 0 . 8H, d, J=7 . 9Hz ) , 4 . 7 6 ( 0 . 2H, d, J=7.9Hz), 6.00-7.2 0(1H, br s), 6.56-6.64(1.8H, m), 6.83(0.2H, d, J=7.9Hz), 7.40(1.6H, d, J=7.9Hz), 7.55(1.6H, d, J=8.2Hz), 7.64(0.4H, d, J=8.5Hz), 7.66(0.4H, d, J= 8.5Hz), 12.22(1H, br s).
IR (KBr) v 3420, 2224, 1615, 1506, 1408, 1325, 1170, 1129, 1067 cm 1.
M ass(FAB) m/z 569 (M+H)+.
Elementary analysis C31H31N20sF3Ø2C6H12ØlAcOEt:
calculated values: C, 65.89; H, 5.80; N, 4.71; F, 9.59 measured values: C, 65.71; H, 5.86; N, 4.73; F, 9.52 17-cyclopropylmethyl-4,5a-epoxy-3, 14(3-dihydroxy-6(3-[N-methyl-3-(3-methylphenyl) propyolamido~ morphinan-N-oxide _6 O OH
~N''. ~ O
N
i ~ .''O Me ~ I ~ CH3 'O
H

t Fo r _ 78 _ 17-cyclopropylmethyl-4,5a-epoxy-3,14(3-dihydroxy-6[3-[N-methyl-3-(3-methylphenyl) propyolamido] morphinan 408mg was dissolved in tetrahydrofuran 20m1; and to this solution was added dropwise at 0°C for 15 minutes a solution which was obtained after m-chlorobenzoic acid 244mg had been added to tetrahydrofuran 5m1 for dissolution. On completion of the dropwise addition, the reaction solution was stirred at room temperature for about one hour; the reaction solution was concentrated;
the residue was submitted to column chromatography based on the use of alkaline alumina 20g; and the yield was recrystallized with ethyl acetate/methanol, filtered and dried in a vacuum, to give the compound 269mg (yield being 64~) in the title.
mp: 192.0-202.0°C (decomposition) NMR ( 600MHz, CDC13) b 0.37(1H, m), 0.44(1H, m), 0.75(2H, m), 1.35(0.3H, m), 1.40-1 .53 (1. 7H, m) , 1 .54-1 . 66 (2H, m) , 1 . 68-1 . 85 (2H, m) , 2.20-2.32 (0.3H, m) , 2.31 (2. 1H, s) , 2.36 (0.9H, s) , 2.36-2.45 (0.7H, m) , 2.86-3.00 (1H, m) , 3.00-3.22 (3H, m) , r s 3.03 (2.1H, s) , 3.31 (0.9H, s) , 3.34-3.46 (2H, m) , 3.77 (0.3H, m), 3.79(0.7H, m), 4.30(0.7H, m), 4.50(0.3H, m), 4.73(0.7H, d, J=8.2H z), 4. 75(0.3H, d, J=8.5Hz), 6.20-7 . 20 ( 1H, br s ) , 6 . 59 ( 0 . 3H, d, J=8 . 2Hz ) , 6 . 60 ( 0 . 7H, d, J=8.2Hz), 6.63(0.7H, d, J=8.2Hz), 6.82(0.3H, d, J=8.2Hz), 7 . 04 ( 0 . 7H, s ) , 7 . 0 8 ( 0 . 7H, d, J=6 . 1Hz ) , 7 . 13-7 . 2 0 ( 1 .
4H, m) , 7 . 2 3 ( 0 . 3H, d, J =7 . 6Hz ) , 7 . 2 6 ( 0 . 3H, t, J=7 . 3Hz ) , 7.35(0.3H, d, J=7.6Hz), 7.37(0.3H, s), 12.22(1H, br s).
IR (KBr) v 3410, 2218, 1622, 1489, 1439, 1408, 1377, 1321, 1125, 1033, 915, 6 9 0 ciri 1.
Mass(FAB) m/z 515 (M+H)+.
Elementary analysis C31H3~N205Ø5H20:
calculated values: C, 71.11; H, 6.74; N, 5.35 measured values: C, 71.16; H, 6.73; N, 5.37 - Assay of opioid activity by Guinea pig ileum assay.
Male Hartley guinea pigs were used. The guinea pig was killed with a blow, and the ileum excised; the lumen i ' .

of ileum was washed with a nutritious fluid; and only a piece of longitudinal muscle was stripped. This longitudinal muscle strip was suspended in a Magnus tube filled with Krebes-Henseleit solution (NaCl 135mM; KC1 4.8mM; CaCl~ 3.4mM; KHZP04 l.2mM; NaHC03 8.3mM; MgS04, 2.5mM; and glucose llmM) kept at 37°C,and gassed with a mixture of 5~ carbon dioxide and 95g oxygen. Electrical stimulation was delivered at a rate of O.lHz with 0.5ms pulses through ring-shaped platinum electrodes placed at upper and lower levels in a Magnus tube. Tissue contractions were recorded via an isometric transducer on a polygraph.
The test drug was cumulatively added until it inhibited over 50~ the contraction of specimen evoked by the electrical stimulation, in the presence or absence of naloxone as a ,u antagonist, or nor-BNI as a K antagonist, and IC50s were calculated for respective experimental conditions. From the difference in drug efficacy in the presence and absence of the antagonist, Ke values were calculated on the basis of following equations.
Ke = [Concentration of antagonist added]/(ICso ratio - 1) ICso ratio = ICso in the presence of antagonist/ICSO in the absence of antagonist Compounds 1, 2, 3, 4, 5 and 6 were used as the test drug. When the ratio of Ke (u) against Ke (zc) is calculated from the data shown in Table 3, Ke(u)/Ke(K) value ranges from 182 to ~, which indicates that the compounds of this invention are agonists selectively acting on a K receptor.

Table 3. Opiod activity of Compounds evaluated by guinea pig ileum assay IC50 (nM) Ke (nM) Naloxone nor-BNI

{100nM) (5nM) 1 1.94 16.67 0.03 2 6.71 98.2 0.54 3 1.06 - 0.02 4 4.09 28.7 0.09 1.55 29.5 0.19 6 11.3 75.1 0.89 Assay of opioid activity by mouse vas deferens assay Male ddY mice were used for the experiment. The vas deferens specimen removed from the animal was suspended in a Magnus tube filled with Krebes-Henseleit solution (NaCl 120.7nM; KC1 5.9mM; CaCl2 2.5mM; NaH2P04 l.2mM; NaHC03 15.5mM; and glucose 11.5mM) kept at 37°C, and gassed with a mixture of 5~ carbon dioxide and 95~ oxygen. Electrical stimulation was delivered at a rate of O.lHz with l.Oms pulses through ring-shaped platinum electrodes placed at upper and lower levels in a Magnus tube. Tissue contractions were recorded via an isometric transducer on a polygraph.
The test drug was cumulatively added until it inhibited over 50~ the contraction of specimen evoked by the electrical stimulation, in the presence or absence of naloxone as a ,u antagonist, or nor-BNI as a K antagonist, and ICsos were calculated for respective experimental conditions. From the difference in drug efficacy in the presence and absence of the antagonist, Ke values were calculated on the basis of following equations.
Ke = [Concentration of antagonist added]/(ICSQ ratio - 1) ICso ratio = ICso in the presence of antagonist/ICso in the absence of antagonist Compounds 1, 2, 3, 4, 5 and 6 were used as the test drug. When the ratio of Ke(u) against Ke(K), and Ke(b) against Ke(K) values are calculated using the value listed on Table 4, Ke(u)/Ke(K) value ranges from 18 to ~, and Ke (b) /Ke (ic) does from 15 to ~ respectively, which indicates that the compounds of this invention are agonists selectively acting on a Fc receptor.

Table 4. Opioid activity of Compounds by. rat vas deferens assay IC50 (nM) Ke (nM) Naloxone NTI nor-BNI

(30nM) (lOnM) (lOnM) 1 4.42 14. 18 11.23 0.17 2 5.9 100 25 0.45 3 2.14 30.48 - 0.040 4 1.80 50 11 0.67 0.59 5.9 5.0 0.33 6 4.6~ - 20 0.26 An opioid compound selectively acting on a K
receptor, (-) -17- (cycloprogylmethyl) -3, 14(3-dihydroxy-4, 5a-epoxy-6(3-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride 7, OH
~Nl\'~ O
HCI ~ ~/_°~~~-°O~1CH v/ ~O

_O H
Z
was dissolved in physiological saline, to give an aqueous solution with a concentration of 40fcg/ml. This aqueous solution was topically applied to three erupted lesions of urticaria, on the lower limb of a male adult at a dose of 0 . 2,ug/ cm2 .
As a result, itching whose intensity was evaluated as moderate (ranked as "++") before treatment was completely eradicated five minutes after the treatment (ranked as "-"). No itching state continued for about five hours.

An aqueous solution of Compound 7 was topically applied to the lesions on the skin surface of arm and leg of a female patient with atopic dermatitis which had caused severe itching (ranked as "+++"). The drug solution was applied on five spots with a volume of about 501 per lOcmz, which was equivalent to a topical dose of 0.2~.cg/cm2. As a comparison, indomethacin cream (having a drug concentration of 7.5mg/g) was applied at a dose of 75,ug/cmz in the same manner.
As shown in Table 5, the aqueous solution of Compound 7 eradicated itching completely from all the lesions to which it had been applied in five minutes after application. Thus it was confirmed that the compound 7 has a significant antipruritic activity. Further, no itching state continued at least three hours. On the other hand, the patient did not have complete relief from itching with treatment by indomethacin cream. Therefore, it was concluded that Compound 7 is more potent than indomethacin in terms of antipruritic activity in this condition.
Table 5 Antipruritic activities of a K receptor agonist (Compound 7) and indomethacin against itching due to atopic dermatitis Medicine used Intensity of itching ("+++,"
maximum intensity, and "-,"
no itching) Prior 5 minutes 10 minutes 3 hours to applicatiafter after after on applicationapplication application Aqueous solution+++ - - -of Compound Indomethacin +++ +++ + t cream It was tested whether K receptor agonists reduced the number of the scratching behavior induced by the subcutaneous administration of x receptor antagonist, non-BNI, into the rostral back of DDY mice. To be noteworthy in this connection, it was confirmed that, when a buffer adjusted to pH 4 - 6 was administered subcutaneously into the rostral back of mice instead of nor-BNI, the administration itself did not induce any scratching behavior toward the treated skin in the mouse.
An opioid compound selectively active to a K
receptor, that is, trans-2-(3,4-dichlorophenyl)-N-methyl -N-[2-(1-pyrrolidinyl) cyclohexyl] acetamide (to be referred to as U-50488H) was dissolved in physiological saline. This aqueous solution was administered intraperitoneally to mice at a dose of 1, 3 or IOmg/kg, and, 30 minutes after the administration, 0.1$ solution of nor-BNI was subcutaneously administered into the skin of rostral back at a volume of O.lml/10g (body weight) to induce scratching. Following the nor-BNI administration, the number of scratching behavior was counted over 60 minutes.
In another session, chlorophenylamine, an anti-_ 88 -histamine agent was dissolved in physiological saline, and this solution was administered intraperitoneally to mice at a dose of 0.3, 1.0 or 3.Omg/kg. Thirty minutes after the administration, nor-BNI was administered and the number of scratching behavior was counted as mentioned before. In a third session, to provide a control, a saline-treated group was implemented for which, following nor-BNI administration, the number of scratching behavior was counted over 60 minutes. The above sessions of experiment were performed on groups each of which comprises 10 animals.
As shown in Fig. 1, in the saline-treated group, a significant increase in the numbers of scratching behavior were observed as a result of nor-BNI administration, while, in the U-50488H treated group, the number of scratching behavior induced by nor-BNI treatment decreased significantly. This result suggests that the test substance has a significant antipruritic activity. On the other hand, in the chlorophenylamine-treated group, the number of scratching behavior was decreased, but the degree of it was less than that of U-50488H. These results indicate that, as far as antipruristic activity is concerned, U-50488H is more potent than chlorophenylamine.

Male ddY mice were purchased from Japan SLC when they were 4 weeks old, and used in the experiments when they became 5 weeks old after acclimation. The day before experiment, the mouse had hair on the rostral back skin clipped with a hair clipper. Each of test drug was dissolved in 10~ DMSO. Either of the test drug or solvent was administered subcutaneously into rostral back of the mouse, and 30 minutes later Compound 48/80 dissolved in saline was administered intradermally into the hair-clipped skin at a dose of about 50,u1 (100~g/site).
Immediately thereafter, the mouse was put into a cage for observation (10 x 7 x l6cm), and~the subsequent behavior of the mouse was recorded with a video camera under unmanned conditions. The video tape was replayed, and the number of the scratching of the Compound 48/80-treated site or its vicinity by hind paws was counted. Each experimental group comprised 8 to 10 animals.
Inhibition percent of scratching by the test compound was calculated by averaging the inhibition of scratching n behavior () of each mice, which is obtained on the basis of the following equation. The degree of inhibition was regarded as correlated with antipruritic potential of the test compound.
Inhibition of scratching behavior (~) - [1-(A - C/B - C)]
x 100 A = Average scratching count of the group which received a test drug B = Average scratching count of the group which-received solvent instead of a test drug C = Average scratching count of the group which received solvent instead of the pruritic agent The test compounds used included 17-cyclopropylmethyl-3, 14(3-dihydroxy-4,5a-epoxy-17-methyl-6(3-(N-methyl-3-methoxycinnamamido) morphinanium iodide 2; 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5a-epoxy-6(3-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan-N-oxide 3; 17-cyclopropylmethyl-3, 14(3-dihydroxy-4, 5cx-epoxy-6(3- [N-methyl-3-(4-trifluoromethylphenyl) propyolaniido] morphinan-N-oxide 5; 17-cyclopropylmethyl-3,14[3-dihydroxy-4,5cx-epoxy-6[i-[N-methyl-3-(3-methylphenyl) propyolamido] morphinan-N-oxide 6; 17-cyclopropylmethyl-3, 14[i-dihydroxy-4, 5cx-epoxy-6[i-[N-methyl-trans-3-(3-furyl) acrylamido] morphinan hydrochloride 7: 17-cyclopropylmethyl-3,14[3-dihydroxy-4,5a-epoxy-6(3-(N-methyl-3-methoxycinnamamido] morphinan tartrate 8; 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5cc-epoxy-6(3-[N-(1,4-dioxo-4-methoxy-traps-2-butenyl)-N-methyl] morphinan methanesulfonate 9; 17-cyclopropylmethyl-3, 14(3-dihydroxy--4, 5cx-epoxy-6(3- (N-methyl-3,4-dichlorophenylacetamido] morphinan hydrochloride 10; 17-cyclopropylmethyl-3,14(3-dihydroxy-4, 5cx-epoxy-6[3- (N-methylcinnamami do) morphinan hydrochloride 11; 17-cyclopropylmethyl-3,14(3-dihydroxy-4, 5cx-epoxy-6cx- (N-methyl-N' -benzylureido) morphinan tartrate 12; 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5cx-epoxy-6[3-(N-methylbenzyloxycarbamido) morphinan hydrochloride 13; 17-cyclopropylmethyl-3,14[3-dihydroxy-4,5a-epoxy-6(3-(benzyloxycarbamido) morphinan hydrochloride 14; 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5cx-epoxy-6a-(N-methylphenylmethanesulfonamido) morphinan hydrochloride 15; 17- (cyclopropylmethyl) -3, 14(3-dihydroxy-4, 5a-epoxy-6(3- [
N-methyl-traps-3-(4-bromo-2-thiofuryl) acrylamido]
morphinan hydrobromide 16; 17-cyclopropylmethyl-3,14(3-dihydroxy-4,5cc-epoxy-6(3-[N-methyl-3-(phenyl) propyolamido]
morphinan hydrochloride 17; 17-cyclopropylmethyl-3,14(3-dihydroxy-4, 5cx-epoxy-6[3- [N-methyl-3- (3-methylphenyl) propyolamido] morphinan hydrochloride 18; 17-cyclopropylmethyl-3, 14[i-dihydroxy-4, 5cc-epoxy-6(3- [N-methyl-3-(4-trifluoromethylphenyl) propyolamido] morphinan hydrochloride 19: 2-(3,4-dichlorophenyl)-N-methyl-N-[1-phenyl-2-(1-pyrrolidinyl) ethyl] acetamide hydrochloride 20; 3-(1-pyrrolidinylmethyl)-4-[5,6-dichloro-1-indancarbonyl]-tetrahydro-1,4-thiazine hydrochloride 21;
traps-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzo [b]
thiophene-4-acetaminde hydrochloride 22; and (5(3, 7[i, 8cx) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4, 5] dec-8-yl]
benzo [b] furan-4-acetamide hydrochloride 23.

OH OH
~Nl\'~ O ~N'\'~ O
HO C02H _ ~/j_ N i . ~ OCH3 /:-v_ 'N~OCHa ~ / ''O CH ~ CH3S03H ~ , ~O CH O
HO"COZH ' ~ ~ ~ a I a ~O ~OH
H

OH OH
~Nl~~~ O / CI " Nl\' j 1 O
i -,,O N ~ CI HCI =
HCI . .= CHa / I CHa .~ ~ v 'OH
OH
OH OH
~N . O ~N - O
w HO\/C02H _- . -~,O N H I ~ HCI = '°O ~N O
/ CHa / CHa HO COZH
OH OH

OH OH
~~S~O w ~N'~~~ O ~N
HCI = ~'O H ~ ~ / HCI / .I~O'CHa OH OH

OH OH
Nl\'~ O ~ Nl\'~ O
/J~vJ~_S
HSr / I '~O CH3 v I ~ HCI / I -~O CH3 \ I \
~OH Br ~OH /
~7 OH OH
N _: O ~ N~~~~ O
_ -., N \
HCI --~O ~ ~ CH HCI / O CH \ w CH3 ~ 3 3 OH \ OH / CFA
1~.
O
N S
/ O , C1 CI
HCI~CH \ CI CI / HCI N

O / ~ . ~ O /
-''N ~ S -~'N ~ O

The results are summarized in Table 6. The compounds used for the test exhibited an antipruritic activity at the dose used.
Table 6 .Antipruritic activities of various opioid K
receptor agonists Test preparation Dose (mg/kg) Inhibition (~) Compound 2 1.0 41 Compound 3 0.0057 64 Compound 5 0.016 55 Compound 6 ~ 0.005 45 Compound 7 0.005 58 Compound 8 0.01 72 Compound 9 1.8 52 Compound 10 0.46 14 Compound 11 0.0018 45 Compound 12 0.07 39 Compound 13 0.07 47 Compound 14 0.31 46 Compound 15 1.88 56 Compound 16 0.0046 14 Compound 17 0.0066 90 Compound 18 0.03 92 Compound 19 0.03 40 Compound 20 0.006 62 Compound 21 0.0003 23 Compound 22 1.2 70 Compound 23 0.0069 46 Industrial Applicability An antipruritic of this invention comprises an opiate K receptor agonist as an effective component, and is useful for dermatoses with pruritus such as atopic dermatitis, nervous dermatitis, contact dermatitis, seborrheic dermatitis, autosensitization dermatitis, caterpillar dermatitis, asteatosis, senile pruritus cutaneous, insect sting, photosensitive dermatosis, urticaria, prurigo, herpes, impetigo, eczema, tinea, lichen, psoriasis, scabies, and acne vulgaris; visceral diseases complicated with pruritus such as malignant tumors, diabetes mellitus, hepatic diseases, renal failure, hemodialysis, and pregnancy.

Claims (46)

CLAIMS:

1. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) a morphinan derivative or a pharmacologically acceptable acid addition salt thereof, in which the morphinan derivative is represented by the general formula (I):

wherein is a double bond, or a single bond; R1 is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aryl having 6 to 12 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, allyl, furan-2-ylalkyl having 1 to 5 carbon atoms, or thiophene-2-ylalkyl having 1 to 5 carbon atoms; R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkyl having 1 to 5 carbon atoms, or -NR9R10; R9 is hydrogen or alkyl having 1 to 5 carbon atoms; R10 is hydrogen, alkyl having 1 to 5 carbon atoms, or -C(=O)-R11-; R11 is hydrogen, phenyl, or alkyl having 1 to 5 carbon atoms; R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; A is -XC(=Y)-, -XC(=Y)Z-, -X-, or -XSO2- (wherein X, Y, and Z are NR4, S, or O
independently; and R4 is hydrogen, straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms; and in the formula R4 may be the same or different); B is a valence bond, straight or branched alkylene having 1 to 14 carbon atoms (wherein the alkylene may have at least one substituent selected from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, and phenoxy,tand one to three methylene groups may be replaced with carbonyl groups), straight or branched acyclic unsaturated hydrocarbon having 2 to 14 carbon atoms with 1 to 3 double bonds and/or triple bonds (wherein the acyclic unsaturated hydrocarbon may have at least one substituent selected. from the group consisting of alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl, and phenoxy, and one to three methylene groups may be replaced with carbonyl groups), or straight or branched, saturated or unsaturated hydrocarbon having 1 to 14 carbon atoms with one to five thioether, ether and/or amino linkages (wherein the hetero atom does not bond to A, directly, and one to three methylene groups may be replaced with carbonyl groups); R5 is hydrogen, or an organic group having any one of the following fundamental structures:
wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy hawing 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy; R6 is hydrogen; R7 is hydrogen, hydroxy, alkoxy having 1 to 5 carbon atoms, or alkanoyloxy having 1 to 5 carbon atoms, or R6 and R7 are -O-, -CH2- or -S-together; R8 is hydrogen, alkyl having 1 to 5 carbon atoms or alkanoyl having 1 to 5 carbon atoms, and the general formula (I) comprises (+), (-), and (~) isomers.

2. The antipruritic according to claim 1, wherein the morphinan derivative is represented by the general formula (I), wherein R1 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl, benzyl, or phenetyl; R2 and R3 are hydrogen, hydroxy, acetoxy, or methoxy independently;
A is -XC(=Y)- (wherein X is NR4, S or O: Y is O; and R4 is hydrogen or alkyl having 1 to 5 carbon atoms), -XC(=Y)Z-, -X-, or -XSO2-(wherein X is NR4; Y is O or S; Z is NR4 or O; R4 is hydrogen or alkyl having 1 to 5 carbon atoms); B
is a straight alkylene having 1 to 3 carbon atoms; R6 and R7 are -O- together; and R8 is hydrogen.

3. The antipruritic according to claim 2, wherein the morphinan derivative is represented by the general formula (I), wherein A is -XC(=Y) - or -XC(=Y)Z- (wherein X is NR4;
Y is O; Z is O; and R4 is alkyl having 1 to 5 carbon atoms).

4. The antipruritic according to claim 2, wherein the morphinan derivative is represented by the general formula (I), wherein R5 is hydrogen, or an organic group having any one of the following fundamental structures:

wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon, atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylendioxy.

5. The antipruritic according to claim 4, wherein the morphinan derivative is represented by the general formula (I), wherein A is -XC(=Y)- or -XC(=Y)Z- (wherein X is NR4;
Y is O: Z is O; and R4 is alkyl having 1 to 5 carbon atoms).

6. The antipruritic according to claim 1, wherein the morphinan derivative is represented by the general formula (I), wherein R1 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl, benzyl, or phenetyl; R2 and R3 are hydrogen, hydroxy, acetoxy, or methoxy independently;
A is -XC(=Y)- (wherein X is NR4; Y is O; and R4 is alkyl having 1 to 5 carbon atoms); B is -CH=CH-, -C=C-, -CH2O-, or -CH2S-; R6 and R7 are -O- together; and R8 is hydrogen.

7. The antipruritic according to claim 6, wherein the morphinan derivative is represented by the general formula (I), wherein R5 is hydrogen or an organic group having any one of the following fundamental structures:

wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 2 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylendioxy.

8. The antipruritic according to claim 6, wherein the morphinan derivative is represented by the general formula (I), wherein B is -CH=CH- or -C=C-.

9. The antipruritic according to claim 8, wherein the morphinan derivative is represented by the general formula (I), wherein R5 is hydrogen or an organic group having any one of the following fundamental structures:

wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylendioxy.

10. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) a morphinan quaternary ammonium salt derivative represented by the general formula (II):

wherein:
is a double bond, or a single bond R1 is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, or allyl; R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; R4 is hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms; A is alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C.ident.C-; and R5 is an organic group having any one of the following fundamental structures:

wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylendioxy; R6 is alkyl having 1 to 5 carbon atoms, or allyl; X- denotes an anion to form a pharmacologically acceptable salt; and the general formula (II) comprises (+), (-), and (~) isomers.

11. The antipruritic according to claim 10, wherein the morphinan quaternary ammonium salt derivative is represented by the general formula (II), wherein R1 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl, benzyl, or phenetyl; R2 and R3 are hydrogen, hydroxy, acetoxy, or methoxy independently; R4 is hydrogen, or a straight or branched alkyl having 1 to 5 carbon atoms; A is -CH=CH- or -C.ident.C-: and R6 is methyl.

12. The antipruritic according to claim 11, wherein the morphinan quaternary ammonium salt derivative is represented by the general formula (II), wherein R4 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

13. The antipruritic according to claim 11, wherein the morphinan quaternary ammonium salt derivative is represented by the general formula (II), wherein R5 is an organic group having any one of the following fundamental structures:

wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

14. The antipruritic according to claim 13, wherien the morphinan quaternary ammonium salt derivative is represented by the general formula (II), wherein R4 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

15. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) a morphinan-N-oxide derivative represented by the general formula (III):

or its pharmacologically acceptable acid addition salt, wherein:
is a double bond, or a single bond;
R1 is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms; alkenyl having 4 to 7 carbon atoms, or allyl;
R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having l to 5 carbon atoms or alkyl having 1 to 5 carbon atoms;
R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms;
R4 is hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms;
A is alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C.ident.C-; and R5 is an organic group having any one of the following fundamental structures:

wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy; and the general formula (III) comprises (+), (-), and (~) isomers.

16. The antipruritic according to claim 15, wherein the morphinan-N-oxide derivative is represented by the general formula (III), wherein R1 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl, benzyl, or phenetyl; R2 and R3 are hydrogen, hydroxy, acetoxy, or methoxy independently; R4 is hydrogen or a straight or branched alkyl having 1 to 5 carbon atoms and A is -CH=CH- or -C.ident.C-.

17. The antipruritic according to claim 16, wherein the morphinan-N-oxide derivative is represented by the general formula (III), wherein R4 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

18. The antipruritic according to claim 16, wherein the morphinan-N-oxide derivative is represented by the general formula (III), wherein R5 is an organic group having any one of the following fundamental structures:

wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

19. The antipruritic according to claim 18, wherein the morphinan-N-oxide derivative is represented by the general formula (III), wherein R4 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

20. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) a compound represented by the general formula (VI):

or its pharmacologically acceptable acid addition salt, wherein:
X and Y are independently hydrogen or chlorine;
Z is CH2, O, or S; and the general formula (V) comprises (+), (-), and (~) isomers.

21. An antipruritic that is a medicinal preparation comprising:

(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) a compound represented by the general formula (VII):

or its pharmacologically acceptable acid addition salt, wherein:
X and Y are independently hydrogen or chlorine;
and the general formula (VII) comprises (+), (-), and (~) isomers.

22. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) 17-cyclopropylmethyl-3,14.beta.-dihydroxy-4,5.alpha.-epoxy-17-methyl-6.beta.- (N-methyl-trans-3-(3-furyl)acrylamido)morphinanium idodide.

23. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) l7-cyclopropylmethyl-3,14.beta.-dihydroxy-4,5.alpha.-epoxy-17-methyl-6.beta.-(N-methyl-3-methoxycinnamamido)morphinanium iodide.

24. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan-N-oxide.

25. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-(N-methyl-3-methoxycinnamamido)morphinan-N-oxide.

26. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-[N-methyl-3-(4-trifluoromethylphenyl)propyolamido]morphinan-N-oxide.

27, An antipruritic that is a medicinal preparation comprising:

(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) 17-cyclopropylmethyl-4,5.alpha.-epoxy-3,14.beta.-dihydroxy-6.beta.-[N-methyl-3-(3-methylphenyl)propyolamido]morphinan-N-oxide.

28. An antipruritic that is a medicinal preparation comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) (-)-17-(cyclopropylmethyl)-3,14.beta.-dihydroxy-4,5.alpha.-epoxy-6.beta.-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride.

29. The antipruritic according to any one of claims 1 to 28, which is for treating a complication of dermatosis or visceral disease.

30. A morphinan quaternary ammonium salt derivative represented by the general formula (II):

wherein:
is a double bond, or a single bond;
R1 is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, -114a-cycloalkenylalkyl having 5 to 7 atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms or allyl;
R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, or alkyl having 1 to 5 carbon atoms; R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms,,or alkoxy having 1 to 5 carbon atoms; R4 is hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms; A is alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C=C-;
and R5 is an organic group having any one of the following fundamental structures:
wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy; R6 is alkyl having 1 to 5 carbon atoms, or allyl; X- denotes an anion to form a pharmacologically acceptable salt; and the general formula (II) comprises (+), (-), and (~) isomers.

31. A morphinan quaternary ammonium salt derivative according to claim 30, wherein R1 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl, benzyl, or phenetyl; R2 and R3 are hydrogen, hydroxy, acetoxy, or methoxy independently; R4 is hydrogen, or a straight or branched alkyl having 1 to 5 carbon atoms; A is -CH=CH- or -C=C-; and R6 is methyl.

32. A morphinan quaternary ammonium salt derivative according to claim 31, wherein R4 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

33. A morphinan quaternary ammonium salt derivative according to claim 31 represented by the general formula (II), wherein R5 is an organic group having any one of the following fundamental structures:
wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

34. A morphinan quaternary ammonium salt derivative according to claim 33 represented by the general formula (II), wherein R4 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

35. A morphinan-N-oxide derivative or its pharmacologically acceptable salt with an added acid represented by the general formula (III):
wherein is a double bond or a single bond; R1 is alkyl having 1 to 5 carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, or allyl; R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, or alkyl having 1 to 5 carbon atoms; R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; R4 is hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms; A is alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C=C-;
and R5 is an organic group having any one of the following fundamental structures:
wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy; and the general formula (III) comprises (+), (-), and (~) isomers.

36. A morphinan-N-oxide derivative or its pharmacologically acceptable salt with an added acid according to claim 35, wherein R1 is methyl, ethyl, propyl, butyl, isobutyl, cyclopropylmethyl, allyl, benzyl, or phenetyl; R2 and R3 are hydrogen, hydroxy, acetoxy, or methoxy independently; R4 is hydrogen, or a straight or branched alkyl having 1 to 5 carbon atoms; and A is -CH=CH- or -C=C-.

37. A morphinan-N-oxide derivative or its pharmacologically acceptable salt with an added acid according to claim 36, wherein R4 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

38. A morphinan-N-oxide derivative or its pharmacologically acceptable salt with an added acid according to claim 36 represented by the general formula (III), wherein R5 is an organic group having one of the following fundamental structures:
wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

39. A morphinan-N-oxide derivative or its pharmacologically acceptable salt with an added acid according to claim 38 represented by the general formula (III) , wherein R4 is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

40. A drug comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) the morphinan quaternary ammonium salt derivative as defined in any one of claims 30 to 34.

41. A drug comprising:
(i) a pharmacologically acceptable carrier, vehicle or excipient, and (ii) the morphinan-N-oxide derivative or salt as defined in any one of claims 35 to 39.

42. A method for producing a compound represented by the general formula (II) characterized in that a tertiary amine represented by the general formula (VIII) is quaternized with an alkylating agent:

wherein in the above general formulas (VIII) and (II), is a double bond, or a single bond; R1 is alkyl having 1 to carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, or allyl; R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms or alkyl having 1 to 5 carbon atoms; R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; R4 is hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms; A is alkylene having 1 to 6 carbon atoms, -CH=CH-, or -C=C-; and R5 is an organic group having any one of the following fundamental structures:
wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

43. A method according to claim 42, wherein the alkylating agent is alkyl iodide having 1 to 5 carbon atoms, alkyl bromide having 1 to 5 carbon atoms, alkyl chloride having 1 to 5 carbon atoms, alkyl methanesulfonate having 1 to 5 carbon atoms, dialkyl sulfate having 1 to 5 carbon atoms, allyl iodide, allyl bromide, or allyl chloride.

44. A method for producing a compound represented by the general formula (III) characterized in that a tertiary amine represented by the general formula (IX) is oxidized with an oxidizing reagent:

wherein in the above general formulas (IX) and (III), is a double bond, or a single bond; R1 is alkyl having 1 to carbon atoms, cycloalkylalkyl having 4 to 7 carbon atoms, cycloalkenylalkyl having 5 to 7 carbon atoms, aralkyl having 7 to 13 carbon atoms, alkenyl having 4 to 7 carbon atoms, or allyl; R2 is hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms or alkyl having 1 to 5 carbon atoms R3 is hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbon atoms, or alkoxy having 1 to 5 carbon atoms; R4 is hydrogen, a straight or branched alkyl having 1 to 5 carbon atoms, or aryl having 6 to 12 carbon atoms) A is alkylene having 1 to 6 carbon atoms, -CH=CH-,or -C.ident.C-; and R5 is an organic group having any one of the following fundamental structures:
wherein the organic group may have at least one substituent selected from the group consisting of alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, alkanoyloxy having 1 to 5 carbon atoms, hydroxy, fluorine, chlorine, bromine, iodine, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy, and methylenedioxy.

45. A method according to claim 44, wherein the oxidizing reagent is a peroxide selected from the group consisting of organic carboxylic acids, hydrogen peroxide, tertiary butyl hydroperoxide, cumene hydroperoxide, and ozone.

46. The drug according to claim 40 or 41, which is for treating pruritus.