CA2232007A1 - 1-acyl-3-phenyl-3-(3-piperidinopropyl)piperidine derivatives as human nk3 receptor selective antagonists - Google Patents

1-acyl-3-phenyl-3-(3-piperidinopropyl)piperidine derivatives as human nk3 receptor selective antagonists Download PDF

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CA2232007A1
CA2232007A1 CA002232007A CA2232007A CA2232007A1 CA 2232007 A1 CA2232007 A1 CA 2232007A1 CA 002232007 A CA002232007 A CA 002232007A CA 2232007 A CA2232007 A CA 2232007A CA 2232007 A1 CA2232007 A1 CA 2232007A1
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hydrogen
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Daniel Bichon
Xavier Emonds-Alt
Patrick Gueule
Vincenzo Proietto
Didier Van Broeck
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Sanofi Aventis France
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    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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Abstract

Compounds of formula (I), a method for obtaining them and pharmaceutical compositions containing them are described. The compounds are useful as human NK3 receptor antagonists.

Description

Novel human NK3 receptor-selecffve antagonist compounds, method for obtaining them and pharmaceutical compositions containing them The present invention relates to novel selective human NK3 receptor antagonist compounds for the preparation of drugs useful in the treatment of 5 psychiatric diseases, diseases of psychosomatic origin, hypertension and, in general, any central or peripheral pathological condition in which neurokinin B and the NK3 receptor are involved in the interneuronal regulatory processes, to a method of obtaining said compounds and to the pharmaceutical compositions in which they are present as the active principle.
Diseases of psychosomatic origin are understood as meaning diseases which originate in the central nervous system (CNS) and have pathological consequences on the peripheral nervous system.
In recent years, numerous research studies have been carried out on tachykinins and their receptors. Tachykinins are distributed throughout both thecentral nervous system and the pelipheral nervous system. The tachykinin receptors have been recognized and are classified into three types: NK" NK2, NK3.
Substance P (SP) is the endogenous ligand of the NKI receptors, neurokinin A
(NKA) that of the NK2 receptors and neurokinin B (NKB) that of the NK3 receptors.
The NK~, NK2 and NK3 receptors have been identified in different species.
Thus the NK3 receptors have been identified in the guinea-pig, the rat and the monkey (Br. J. Pharmacol., 1990, 22, 767 - 773); Neurochem. Int., 1991, ~, 149 -165); they have also been identified in man (FEBS Letters, 1992, 299 (1), 90 - 95).
A review by C.A. Maggi et al. Iooks at the tachykinin receptors and their antagonists and gives an account of the pharmacological studies and the applications in human therapeutics (J. Autonomic Pharrnacol., 1993, ~, 23 - 93). The following non-peptide compounds may be mentioned among the specific NKI receptor antagonists: CP-96345 (J. Med. Chem., 1992, 35, 2591 -2600), RP-68651 (Proc. Natl. Acad. Sci. USA, 1991, 88, 10208 - 10212) and SR 140333 (Curr. J. Pharmacol., 1993, 250~ 403 - 413).
In the case of the NK2 receptor, the non-peptide selective antagonist SR 48968 has been described in detail ~Life Sci., 1992, ~Q PLIOI - PL106).
As far as the human NK3 receptor is concerned, the non-peptide selective antagonist (+)-N-[ I -[3-[1 -benzoyl-3-(3,4-dichlorophenyl)piperid-3-yl]propyl]-4-phenylpiperid-4-yl]-N-methylacetamide hydrochloride, or SR 142801, has been described (EP-A-0 673 928; Peptides and their antagonists in tissue injury, Montreal, Canada, 1994, July 31 - August 3. (~n~ n J. Physiol. Pharmacol., ~ 2 1994, 72 (suppl. 2), 25, Abst. m. o. 9.; Life Sci., 1994, 56 (1), 27 - 32; British Pharmacol. Society, Canterbury, 1995, April 6 - 8; Eur. J. Pharmacol., 1995, 278(1),17-25; 1st Eur. Congress Pharmacol., Milan, 1995, June 16 - 19).
Patent applications EP 474 561 and EP 512 901 describe neurokinin 5 antagonists, more particularly NKI or NK2 receptor antagonists. Pharmacological studies of peptide and non-peptide NKI and NK2 receptor antagonists have shown that their affinities for these receptors, and their pharmacological activities, are very dependent on the species; this is very probably the result of small differences in the amino acid sequences, inducing very slight structural variations in thesereceptors ~om one species to another (J. Autonomic Pharmacol., 1993, ~, 23 -93). Some experimental data, confirmed by pharmacological characterization of the compounds forming the subject of the present invention, seem to indicate that a comparable situation exists for the NK3 receptor. In particular, the human NK3 receptor differs from the NK3 receptor of the rat.
Non-peptide compounds have now been found which have a very strong affinity for the human NK3 receptor and a high specificity for said receptor. These compounds can be used for the preparation of drugs useful in the treatment of psychiatric diseases, diseases of psychosomatic origin and any central or peripheral diseases in which neurokinin B and the NK3 receptor are involved in the interneuronal regulatory processes.
Very strong affinity for the human NK3 receptor is understood as me~ning an affinity characterized by an inhibition constant Ki which is generally less than 5. 10-9 M.
In ligand binding studies, the inhibition constant Ki is defined by the Cheng-Prusoff relationship (in Receptor Binding in Drug Research, eds. R.A.
O'BRIEN. Marcel Dekker, New York, 1986):

Ki=
I+[L]
Kd [L]: concentration of the ligand, Kd: dissociation constant of the ligand, IC50: concentration which inhibits ligand binding by 50%.
High specificity for the human NK3 receptor is understood as meaning that the inhibition constant (Ki) for the human NK3 receptor is generally at least 100 times lower than the inhibition constant (Ki) for the NK2 receptor or the inhibition constant for the NKI receptor of different species.

~ 3 Thus, according to one of its aspects, the present invention relates to eompounds of the formula l I R2 B-(CH2)3-C-CH2-N-T-A-Z (I) in which:
- Rl is hydrogen;
5 - R2 is the methyl group;
- or Rl and R2 together form a group -(CH2)3- or -~CH2)4-;
- Arl is a phenyl whieh is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (Cl-C4)aLkoxy, a (C~-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being 10 identieal or different; a thienyl whieh is unsubstituted or substituted by a halogen atom; a benzothienyl which is unsubstituted or substituted by a halogen atom; a naphthyl which is unsubstituted or substituted by a halogen atom; an indolyl whieh is unsubstituted or N-substituted by a (C ,-C4)alkyl or a benzyl; an imidazolyl which is unsubstituted or substituted by a halogen atom; a pyridyl 15 which is unsubstituted or substituted by a halogen atom; or a biphenyl;
- T is a group -CH2-; a group -CO-; a group -COO-; or a group -CONR3- in which R3 is a hydrogen or a (Cl-C4)aLkyl;
- A is a direct bond; a group -(CH2)t-, in which t is one, two or three; or a vinylene group;
20 - or -T-A- is the group -SO2-;
- Z is an optionally substituted, mono-, di- or tri-cyclic aromatic or heteroaromatic group; and - Bis:
- i - either a group B~ of the formula J~ N-25 in which J~ is:
- i~ either a group Ar2- (CH2)X-C
X
in which:
- x is zero or one;

~ 4 - Ar2 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl, a (Cl-C4)alkyl, a (Cl-C4)aLkoxy and a methylenedioxy, said substituents being identical or different; a pyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is S unsubstituted or substituted by a (Cl-C4)alkyl; and - Xl is a group selected from:
(1) hydrogen;
(2) (Cl-C7)alkyl;
(3) formyl;
10 (4) (Cl-C7)alkylcarbonyl;
(S) -(CH2)m~0R4;
(6) ~(CH2)m-ocoRs;
(7) -(CH2)m-0CONH-(C I -C7)alkyl;
(8) -O-CH2CH2-OR6;
(9)~(CH2)n~SR2;
( 10) -CH2-S(O)j-(C l-C7)alkyl;
( 1 1 ) -NR8Rg;
(12) -(CH2)p-NRIoRl l;
(13) -NRI2CORl3;
20 (14)-NRI4COCORls;
(15) -(CH2)p-NRI4C(=WI)Rl6;
(16) ~(CH2)m~NRI4COORl7;
(l7) ~(CH2)m~NRl4s02Rl8;
( 18) ~(CH2)m-NRI4C(=Wl)NRl9R2o;
25 ( l 9) ~(CH2)n~COOR2l;
(20) ~(cH2)n-c(=wl)NRl9R2o;
(21 ) -co-NR22-NR23R24;
(22) -CN;
~N
R2 /~S~R R

~0 (24) N ~

~ S

or Xl forms a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring;
in which groups:
- m is zero, one or t~,vo;
5 - n is zero or one;
- p is one or two;
- j is one or two;
- Wl is an oxygen atom or a sulfur atom;
- R4 is a hydrogen or a (C~-C7)alkyl;
10 - Rs is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
- R6 is a hydrogen; a (Cl-C7)alkyl; a formyl; or a (Cl-C7)alkylcarbonyl;
- R7 is a hydrogen or a (Cl-C7)alkyl;
- R8 and Rg are each independently a hydrogen or a (Cl-C7)alkyl; R9 can also be a 15 (C3 C7)cycloalkylmethyl, a benzyl or a phenyl;
- or R8 and R9, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thio-molpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
20 - Rlo and Rll are each independently a hydrogen or a (Cl-C7)alkyl; Rll can also be a (C3-C7)cycloalkylmethyl or a benzyl;
- Rl2 is a hydrogen or a (Cl-C7)alkyl;
- Rl3 is a hydrogen; a (C~-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl;
25 a thienyl; a pyrrolyl; or an imidazolyl;
- or Rl2 and Rl3 together are a group -(CH2)U-, in which u is three or four;
- Rl4 is a hydrogen or a (Cl-C7)alkyl;
- Rl5 is a (Cl-C4)alkoxy;
- Rl6 is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or 30 substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl;
a thienyl; a pyrrolyl; or an imidazolyl;
- Rl7 is a (Cl-C7)alkyl or a phenyl;
- Rl8 is a (Cl C7)alkyl; an amino which is free or substituted by one or two (Cl-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or poly-35 substituted by a substituent selected from a halogen atom, a (C~-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C I -C7)alkoxy, a carboxyl, a (C I -~ 6 C7)alkoxycarbonyl, a (Cl-C7)aLkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (Cl-C7)alkyls, said substituents being identical or different;
- Rlg and R20 are each independently a hydrogen or a (Cl-C7)alkyl; R20 can also be S a (C3-C7)cycloaL~cyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C~-C4)aLIcoxy; a benzyl; a phenyl; or a (Cl-C7)aL'cyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a (C~-C3)alkoxycarbonyl or a carbamoyl which is unsub-stituted or substituted by one or two (Cl-C7)alkyls;
- or Rlg and R20, together with the nitrogen atom to which they are bonded, form a 10 heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
- R21 is a hydrogen or a (Cl-C7)alkyl;
- R22 is a hydrogen or a (Cl-C7)alkyl;
- R23 and R24 are each independently a hydrogen or a (Cl-C7)alkyl;
- R2s is a hydrogen or a (Cl-C7)aLkyl; and - R26 and R27 are each independently a hydrogen or a (Cl-C7)alkyl; R27 can also be a formyl or a (Cl-C7)alkylcarbonyl;
- i2 - or a group Ar2--CH=C~
20 in which Ar2 is as defined above;
- i 3 - or a group Ar2--C-CH-in which Ar2 is as defined above;
-i4- or a group Ar2--ICH-CH-OH
in which Ar2 is as defined above;
I

-i5- or a group Ar2 ICl -CH-N-O-(CH2)r-in which:
- Ar2 is as defined above;
- Aml is an amino group substituted by two (Cl-C4)alkyls; and - r is two or three;

~ 7 - i6 - or a group Ar2-w2- ICH--in which:
- Ar2 is as defined above;
- W2 is an oxygen atom; a sulfur atom; a sulfinyl; a sulfonyl; or a group -NLI-;S - Ll is a hydrogen; a (Cl-C4)alkyl; a (Cl-C4)alkylcarbonyl; or a group -(CH2)v-Am2;
- v is one, two or three; and - Am2 is an amino group which is unsubstituted or monosubstituted or disubstituted by a (Cl-C4)alkyl; Am2 can also be a pyrrolidino, piperidino or 10 morpholino group;
- ii - or a group B2 of the formula -in which J2 is:
- ii I - either a group Ar2-N

- ii2 - or a group Ar2-CH2-N

-ii3- or a group Ar2- ICl-N/
/
-ii4- or a group Ar2-CI H-N
OH
-ii5- or a group Ar2-C-N
N-O-(CH2)r-Aml in which:
20 - Ar2 is as defined above;
- r is two or three; and - Am~ is as defined above;
- iii - or a group B3 of the formula -25 in which J3 is:

~ 8 113~8 - a group :R29-C-N-CH-in which:
- W3 iS an oxygen atom; a sulfur atom; or a group NR30, in which R30 is a hydrogen or a (Cl-C3)alkyl;
- R2g is a hydrogen; a (C~-C6)alkyl; a (C3-C6)alkenyl in which one vinylic carbon atom is not bonded to the nitrogen atom; a 2-hydroxyethyl; a (C3-C7)cycloalkyl; a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a trifluoromethyl, a (Cl-C4)alkyl, a (Cl-C4)aL~oxy, a nitro, an amino and a hydroxyl, said substituents being identical or different; or a 6-membered heteroaryl cont~ining one or two nitrogen atoms as heteroatoms, said heteroaryl being unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a trifluoromethyl, a (Cl-C4)alkyl, a (Cl-C4)alkoxy, a nitro, an amino and a hydroxyl, said substituents being identical or different;
15 - R29 is a hydrogen; a (Cl-C6)alkyl which is unsubstituted or substituted by a hydroxyl and/or by one, two or three fluorine atoms; a (C3-C6)cycloalkyl; a (Cl-Cs)alkoxy (only when W3is an oxygen atom); a (C3-C6)cycloalkoxy (only when W3 iS an oxygen atom); or a group -NR3lR32 containing from zero to seven carbon atoms, R2g being other than an unsubstituted (C I -C4)alkyl when simultaneously W3is an oxygen and R28 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl, a (Cl-C4)alkyl and a (Cl-C4)alkoxy, said substituents being identical or different; a pyridyl; or a pyrimidyl;
- or R28 and R29 together form a divalent hydrocarbon group L2, in which the l-position is bonded to the carbon atom carrying the substituent W3, the divalent hydrocarbon group L2 being selected from a trimethylene, a cis-propenylene, a tetramethylene, a cis-butenylene, a cis,cis-butadienylene, a pentamethylene and a cis-pentenylene, said divalent hydrocarbon group L2 being unsubstituted or substituted by one or two methyls; and 30 - R3l and R32 are each independently a hydrogen, a (Cl-C5)alkyl or a (C3-C6)cycloalkyl; or R31 and R32, together with the nitrogen atom to which they arebonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;

~ 9 - iv - or a group B4 of the formula W4~ N-in which:
- W4 is a (C,-C8)alkyl or a (C3-C8)cycloalkyl, said alkyl and cycloalkyl groups 5 being unsubstituted or substituted by one or more substituents selected from ahalogen atom; a (C3-C6)cycloaLkyl; a cyano; a nitro; a hydroxyl; à (Cl-C4)alkoxy;
a formyloxy; a (C,-C4)alkylcarbonyloxy; an arylcarbonyl; a heteroarylcarbonyl;
an oxo; an imino which is unsubstituted or substituted on the nitrogen atom by a(Cl-C6)alkyl, a (C3-C6)cycloalkyl, a formyl, a (Cl-C4)alkylcarbonyl or an 10 arylcarbonyl; a hydroxyimino which is unsubstituted or substituted on the oxygen atom by a (C~-C4)alkyl or a phenyl; a group -NR33R34 cont~ining from zero to seven carbon atoms; a group -NR3sR36; a group -C(=NR37)NR3gR3g, in which the group -NR38R39 contains from zero to seven carbon atoms; and a group -CON(OR40)R4l, said substituents being identical or dirrelelll, - R33 and R34 are each independently a hydrogen, a (C,-Cs)alkyl or a (C3-C6)cycloalkyl; or R33 and R34, together with the nitrogen atom to which they arebonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
- R3s is a hydrogen or a (Cl-C4)alkyl;
- R36 is a formyl; a (Cl-C4)alkylcarbonyl; an arylcarbonyl; a heteroarylcarbonyl; or a group -C(=Ws)NR38R39, in which the group -NR38R39 contains from zero to seven carbon atoms;
- Ws is an oxygen atom; a sulfur atom; a group NR37; or a group CHR42;
- R37 is a hydrogen or a (Cl-C4)alkyl; or R37 and R39 together form an ethylene group or a trimethylene group;
- R38 and R39 are each independently a hydrogen, a (Cl-Cs)alkyl or a (C3-C6)cycloalkyl; or R38 and R39, together with the nitrogen atom to which they arebonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl; or R38 is a hydrogen or a (C~-C4)alkyl and R3g and R37 together form an ethylene group or a trimethylene group;
- R40 and R41 are each independently a (Cl-C3)alkyl;
- R42 is a cyano; a nitro; or a group SO2R43;

:

~ 10 - R43 is a (Cl-C4)alkyl or a phenyl;
and when W4 is a cyclic group or when a substituent of W4 is a cyclic group or contains a cyclic group, said cyclic groups can also be substituted on a carbon atom by one or more (Cl-C3)alkyls; and when a substituent of W4 contains an aryl group 5 or a heteroaryl group, said aryl or heteroaryl groups can also be monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C~-C4)alkyl, a (Cl-C4)alkoxy, a cyano, a trifluoromethyl and a nitro, said . substituents being identical or different;
- v - or a group Bs of the formula W?~ ~N-in which:
- W6 and W7 are each a hydrogen; or W6 is a hydrogen and W7is a hydroxyl;
- W8 is an aryl or a heteroaryl which are unsubstituted or substituted by an aryl, an arylcarbonyl, a heteroaryl or a heteroarylcarbonyl; said aryl or heteroaryl groups can also be monosubstituted or polysubstituted on the aromatic or heteroaromaticmoiety and on a carbon atom by a substituent selected from a halogen atom; a cyano; a trifluoromethyl; a nitro; a hydroxyl; a (Cl-Cs)alkoxy; a formyloxy; a (Cl-C4)alkylcarbonyloxy; a group -NR33R34 cont~ining from zero to seven carbon atoms; a group -NR3sR36; a group -C(=NR37)NR38R39, in which the group -NR38R39 contains from zero to seven carbon atoms; a group -COOR44; a group -CONR4sR46, in which the group NR4sR46 contains from zero to seven carbon atoms; a mercapto; a group -S(O)sR47; a (Cl-Cs)alkyl; a formyl; and a (Cl-C4)alkylcarbonyl, said substituents being identical or different; when W6 and W7are each a hydrogen, W8 is other than a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl and a (Cl-C4)alkoxy, said substituents being identical or different; a pyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C,-C4)alkyl;
- or W7 iS a.hydrogen and W6 and W8, together with a diradical W9 and the piperidine carbon atom to which they are bonded, form a spiro ring in which W8 is a phenyl substituted in the ortho position by a diradical W9, which is itselfjoined to W6, said phenyl being unsubstituted or substituted by a substituent selected from a halogen atom, a (Cl-C3)alkyl, a (Cl-C3)alkoxy, a hydroxyl, a (Cl-~ 11 C3)alkylthio, a (Cl-C3)alkylsulfinyl and a (Cl-C3)alkylsulfonyl; the diradical Wg is a methylene, a carbonyl or a sulfonyl; and W6 is an oxygen atom or a group -NR48-, in whieh R48 is a hydrogen or a (Cl-C3)alkyl;
- R33, R34, R3s, R36, R37, R38 and R39 a}e as defined above for the group B4;
S - R44 is a hydrogen; a (Cl-C5)alkyl; an aryl; a heteroaryl; an arylmethyl; or a heteroarylmethyl;
- R45 and R46 are each independently a hydrogen, a (Cl-Cs)alkyl or a (C3-C6)cycloalkyl; or R4s and R46, together with the nitrogen atom to whieh they arebonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, 10 thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
- s is zero, one or two;
- R47 is a (Cl-C6)alkyl; a (C3-C6)cycloalkyl; an aryl; or a heteroaryl;
and when Wg or a substituent of W8 contains a cyclic group, said cyclic group ean 15 also be substituted by one or more methyls; and when a heteroaryl group forming part of W8 or of a substituent of W8 contains a nitrogen atom as the heteroatom,said nitrogen atom can also be substituted by a (Cl-Cs)alkyl; and when W8 or a substituent of W8 eontains a (Cl-Cs)alkyl, (Cl-Cs)alkoxy, formyl or (Cl-C4)-alkylcarbonyl group, said (Cl-Cs)alkyl, (Cl-Cs)alkoxy, formyl or (Cl-C4)alkyl-20 carbonyl groups can also be substituted by a hydroxyl, a (Cl-C3)alkoxy or one or more halogen atoms, with the proviso that a carbon atom bonded to a nitrogen atom or to an oxygen atom is not substituted by a hydroxyl or an alkoxy group, and with the proviso that a earbon atom in the a-position of a (Cl-C4)alkylcarbonyl group is not substituted by a chlorine, bromine or iodine atom;
25 - vi - or a group B6 of the formula ~J
in which J4 is:
10\ ~
- vil - either a group C
W /
in which:
30 - W10 is a phenyl which is unsubstituted or monosubstituted to trisubstituted by a substituent seleeted from a halogen atom, a (Cl-C6)alkoxy, a (Cl-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a benzyl which is unsubstituted or monosubstituted to trisubstituted by a substituent selected from a halogen atom, a (C~-C6)alkoxy, a (Cl-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a naphthyl which is unsubstituted or monosubstituted to trisubstituted by a substituent selected from a halogen atom, a S (C~-C6)alkoxy, a (Cl-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a pyridyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected from a halogen atom, a (Cl-C6)alkyl and a (C ~ -C6)alkoxy, said substituents being identical or different; a thienyl; a pyrimidyl; or an imidazolyl; and 10 - Wl, is a group -CONHR49;
- R49 is a group CH3-CHOH-CH-COO-(CI-C6)alkyl;
a group (cl-c6)alkyl-oco-cH2-cH2-cH-coo-(cl-c6)alkyl;
a group -cH2cH2N(cH3)2;
R50\ o - vi2 - or a group: N--C
N~C\

Rsl R50 o -Vi3- ora group: ~ C~
O'~ N
[~

R
/o - vi4 - or a group: N C
N

15 in which:

~ 13 - R50 is a hydrogen, a (Cl-C6)alkyl or a benzyl; and - Rsl is from one to three substituents selected from a hydrogen, a halogen atom, a trifluoromethyl, a (Cl-C6)alkyl and a (Cl-C6)alkoxy, said substituents being identical or different;
5 - vii - or a group B7 of the formula Wl3 W,~(C~HN)f ~W~W16 (CH2)g in which:
- f and g are each independently zero, one, two, three, four or five, with the proviso that f + g is equal to one, two, three, four or five;
10 - Wl2 is a direct bond; a (Cl-C3)alkylene which is unsubstituted or substituted by an oxo, a group ORs2, a halogen, a trifluoromethyl or a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, a cyano, a halogen and a trifluoromethyl; a group -S(O)k-; a group (C,-C3)alkylene-S(O)k-; a group -S(O)k-(CI-C2)alkylene; a group -S(O)k-NH-; a group -S(O)j-NR52-; a group -S(O);-NRs2-(CI-C2)aLkylene; a group -CONR52-; a group -CONRs2-(C~-C2)alkylene; a group -COO-; or a group -COO-(CI-C2)alkylene;
- Wl3 is a group -NRs3-; an oxygen atom; a sulfur atom; a sulfinyl; or a sulfonyl, with the proviso that when Wl2 is a direct bond and when W14 iS a (Cl-20 C3)alkylene, Wl3 is a group -NR53-;
- W14is a direct bond; a (Cl-C3)aL~cylene which is unsubstituted or substituted by an oxo, a group ORs2, a halogen, a trifluoromethyl or a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a group ORs2, a halogen and a trifluoromethyl; a group -S(O)k-; a group (Cl-25 C3)alkylene-S(O)k-; a group -S(O)k-(CI-C2)alkylene; a group -NHS(O)j-; a group -NH-(CI-C2)alkylene-S(O)j-; a group -S(O)jNRs2-; a group -S(O)j-NRs2-(CI-C2)alkylene; a group -NHCO-(C I -C2)alkylene; a group -NRs2-CO-; a group -NR52-(C,-C2)alkylene-CO-; a group -OCO-; or a group (C,-C2)alkylene-OCO-;
- Wl5-Wl6 together form two adjacent atoms of a cyclic radical of the formula W--W
/
said cyclic radical being a phenyl, a naphthyl or a heteroaryl group selected from ~ 14 a benzimidazolyl, a benzofuranyl, a benzoxazolyl, a furanyl, an imidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, an oxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, a pyrimidyl, a pyrrolyl, a quinolyl, a tetrazolyl, a thi~Ai~7:olyl, a thiazolyl, a thienyl and a triazolyl, and said phenyl, naphthyl or 5 heteroaryl cyclic radical being unsubstituted or mono-, di- or tri-substituted by ~ Rs4;
- k is zero, one or two;
- j is one or two;
- Rs2 is a hydrogen; a (Cl-C6)alkyl which is unsubstituted or monosubstituted or10 disubstituted by a substituent selected independently from a hydroxyl, an oxo, a cyano, a halogen atom, a trifluoromethyl and a phenyl which is itself unsubstituted or substituted by a hydroxyl, a (Cl-C3)aLkyl, a cyano, a halogen, a trifluoromethyl or a (Cl-C4)alkoxy; a phenyl, a pyridyl or a thiophene, said phenyl, pyridyl or thiophene being unsubstituted or mono-, di- or tri-substituted 15 by a substituent selected independently from a hydroxyl, a (Cl-C4)aLkyl, a cyano, a halogen atom and a trifluoromethyl; or a (C,-C3)alkoxy;
- Rs3 is a hydrogen; a (Cl-C8)alkyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a group -ORs2, an oxo, a group -NHCORs2, a group -NRssRs6~ a cyano, a halogen atom, a trifluoromethyl and a 20 phenyl which is itself unsubstituted or substituted by a hydroxyl, a cyano, ahalogen atom or a trifluoromethyl; a group -S(O)Rs7; a group -CO2Rs7; a group -SO2Rs7; a group -CORs7; or a group -CONRs6Rs7;
- Rs4 is a hydrogen; a (Cl-C6)alkyl which is unsubstituted or monosubstituted ordisubstituted by a hydrogen or a hydroxyl; an oxo; a group -ORs2; a halogen 25 atom; a trifluoromethyl; a nitro; a cyano; a group -NRssRs6; a group -NRsscoRs6; a group -NRssco2Rs6; a group -NHS(O)jRs2; a group -NR ssS(O)jRs6; a group -CONRssRs6; a group -CORs2; a group -CO2Rs2; a group -S(O)jRs2; or a heteroaryl group, said heteroaryl being selected from a benzimidazolyl, a benzofuranyl, a benzoxazolyl, a furanyl, an imidazolyl, an 30 indolyl, an isoxazolyl, an isothiazolyl, an oxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, a pyrimidinyl, a pyrrolyl, a quinolyl, a tetrazolyl, a thi~ 701yl, a thiazolyl, a thienyl and a triazolyl, and said heteroaryl being unsubstituted or monosubstituted or disubstituted by Rss;
- Rss is Rs2;
35 - Rs6 is Rs2;
- or Rss and Rs6, together with the atoms to which they are bonded, form a five-, six- or seven-membered, saturated monocyclic heterocycle cont~ining one or two heteroatoms, said heteroatoms being selected independently from a nitrogen atom, an oxygen atom and a sulfur atom, said heterocycle being unsubstituted or monosubstituted or disubstituted by a substituent selected from a hydroxyl, an 5 oxo, a cyano, a halogen atom and a trifluoromethyl;
- Rs7 is a (Cl-C6)aL~yl which is unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, an oxo, a cyano, a group -ORs2, a group -NRssR56, a group -NRssCORs6, a halogen atom, a trifluoromethyl and a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, an oxo, a cyano, a group -NHR5z, a group -NR55R56, a group -NRssCORs6, a halogen atom, a trifluoromethyl and a (Cl-C3)aL~yl;
- R58 is a hydrogen; a (C~-C6)alkyl which is unsubstituted or monosubstituted or disubstituted by a hydrogen or a hydroxyl; an oxo; a group -OR52; a trifluoromethyl; a nitro; a cyano; a group -NRs5R56; a group -NRssCORs6; a group -NR55CO2R56; a group -NHS(O)jR52; a group -NR55S(O)jR56; a group -CONR55R56; a group -COR52; a group -CO2R52; a group -S(O)jR52; or a phenyl, and the group B7 being other than the group Bs when W7 is a hydrogen and W6 and W8, together with a diradical Wg and the piperidine carbon atom to which they are bonded, form a spiro ring;
- viii - or a group Bg of the formula Wl I~N~N--Wlg W20 in which:
- W17is a direct bond; a double bond; or a divalent hydrocarbon radical;
- Wlg is a radical which is joined to the carbon atom of the heterocycle either by a single bond when Wl7 is a double bond, or by a double bond in the other cases;
- Wlg is an unsubstituted or optionally substituted heteroatom;
- W20 is a hydrocarbon radical of which the l-position is joined to Wl9; and - the meanings of Wl7, Wl8, Wl9 and W20 are selected from:
(a) Wl7 is a direct bond; Wlg is an oxo or thioxo group; Wl9 is an oxy or thio group or a group NR59; and W20 is a hydrocarbon radical L3; or (b) Wl7 is a direct bond; Wlg is a group NR60; W~g is a group NR6l; and W20 is a hydrocarbon radical L3; or (c) Wl7 is a double bond; W18 is a group OR61, SR6l or NR62R63; Wlg is a nitrogen atom; and W20 is a hydrocarbon radical L3; or (d) Wl7 is a methylene which is unsubstituted or substituted by one or two methyl groups; Wlg is an oxo or thioxo group or a group NR64; Wlg is an oxy, thio, sulfinyl or sulfonyl group or a group NR6~; and W20 is a hydrocarbon radical L4; or (e) Wl7 is a direct bond; Wl8 is an oxo or thioxo group or a group NR64;
S Wlg is a nitrogen atom; and W20 is a hydrocarbon radical Ls; or (f) Wl7 is a methine group which is unsubstituted or substituted by one or two methyl groups; Wlg is an oxo or thioxo group or a group NR64; Wlg is a nitrogen atom; and W20 is a hydrocarbon radical L6; and (g) Wl7 is a cis-vinylene group which is unsubstituted or substituted by one 10 or two methyl groups; Wlg is an oxo or thioxo group or a group NR64; Wlg is a nitrogen atom; and W20 is a hydrocarbon radical L7;
- Rsg is a hydrogen; a (Cl-C3)aLkyl; a group -CH2COOR65; or a group -CH2CONR66R67;
- R60 is a hydrogen; a (Cl-C3)aLkyl; a cyano; a nitro; or a (Cl-C3)alkylsulfonyl1 5 group;
- R6l is a hydrogen or a (Cl-C3)alkyl;
- R62 and R63 are each independently a hydrogen or a (Cl-C3)alkyl;
- or R62 and R63, together with the nitrogen atom to which they are bonded, form a heterocycle selected ~om pyrrolidine, piperidine, morpholine, thiomorpholine (or20 its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
- R64 is a hydrogen or a (Cl-C3)alkyl;
- R6s is a hydrogen or a (Cl-C3)alkyl;
- R66 and R67 are each independently a hydrogen; a (Cl-C3)aLkyl; a phenyl; or a 25 benzyl;
- L3 is an ethylene, a cis-vinylene, a trimethylene or a tetramethylene, said hydro-carbon radical L3 being unsubstituted or substituted by one or two methyl groups;
- L4 is an ethylene or a trimethylene, said hydrocarbon radical L4 being unsub-stituted or substituted by one or two methyl groups;
30 - Ls is a prop-2-en-1-yliden-3-yl which is unsubstituted or substituted by one or two methyl groups;
- L6 is a cis-vinylene which is unsubstituted or substituted by one or two methyl groups; and - L7 is a methine which is unsubstituted or substituted by a (C,-C3)alkyl;
35 - ix - or a group Bg of the formula CA 02232007 l998-03-l2 ~ 17 ~ Js N-in which Js is:
- a group /w22 W2l N--C
Il X2 5 in which:
- X2 is a (C~-C6)aLkyl; a group -CH2-OR6g; a group -CH2-SR6g; a group -CH2-S(O)R69; a group -CH2-SO2R69; a group -COOR68; a group -C(=W24)NR70R7l; a group -C(R6g)(OR72)(OR73); a group -CH2NR6gC(=W24)R74;
a group -CH2-NR6gCOOR74; or a group -CH2NR68C(=W24)NR70R7l;
10 - W2l is a direct bond and W22 is a hydrocarbon radical of which the l-position is joined to W21, the hydrocarbon radical W22 being selected from a trimethylene, atetramethylene, a cis-l-butenylene and a cis,cis-butadienylene;
- or W2l is a group NR7s and W22 is a hydrocarbon radical selected from an ethylene, a trimethylene and a cis-vinylene;
15 - or W2l is a nitrogen atom and W22 is a cis,cis-prop-2-en-1-yliden-3-yl radical of which the 1-position is joined to W2~;
- W23 is an oxygen atom or a sulfur atom;
- W24 is an oxygen atom or a sulfur atom;
- R68 is a hydrogen or a (Cl-C6)alkyl;
20 - R6g is a (Cl-C6)alkyl;
- R70 and R71 are each independently a hydrogen; a (Cl-C6)alkyl which is unsubstituted or substituted by a hydroxyl or a (C,-C3)alkoxy; an c~-HO-(CI-C6)alkyl; an c~-(C I -C3)alkoxy-(C I -C6)alkyl; an c3-phenyl-(C I -C6)alkyl; an ~)-R76OOC-(C~-C6)alkyl; or an ~-R77R7gNCO-(CI-C6)alkyl;
25 - or R70 and R7l, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a methyl group or an ethyl group;
- R72 and R73 are each independently a (Cl-C3)alkyl;
30 - or R72 and R73 together forrn a divalent hydrocarbon radical selected from an ethylene and a trimethylene;

~ 18 - R74 is a hydrogen or a (Cl-C6)alkyl;
- R75 is a hydrogen or a (Cl-C6)aLkyl;
- R76 is a hydrogen or a (Cl-C3)alkyl; and - R77 and R7g are each independently a hydrogen or a (Cl-C3)alkyl;
5 - x - or a group Blo of the formula / \
/
in which J6 is:
- a group W25-C /
X
in which:
10 - Xl is as defined above for the group Bl, Xl being other than hydrogen when W2s is a (Cl-C7)alkyl or a (C3-C7)cycloalkyl;
- W2s is a (C,-C7)alkyl or a (C3-C7)cycloalkyl; W25 can also be a group -NR7gRgowhen Xl is a hydrogen, a cyano, a carboxyl, a (Cl-C7)alkoxycarbonyl or a group -CONRIgR20; and 15 - R7g and Rgo are each independently a (Cl-C7)aLkyl;
- or R7g and Rgo, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine and perhydroazepine, with the proviso that:
20 1/ when simultaneously:
- R2 is a methyl group or Rl and R2 together form a group -(CH2)3-;
- Arl is a 3,4-dichlorophenyl;
- T is a group -CH2-; a group -CO-; a group -COO-; or a group -CONR3;
- A is a direct bond; a group -(CH2)t- in which t is one, two or three; or a vinylene 25 group;
- or -T-A- is the group -SO2-; and - Z is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a (Cl-C4)alkyl, a (Cl-C4)alkoxy or a nitro, B is a group Bl of the formula Jl N-in which Jl is a group ~ 19 Ar2-(CH2)x~

in which:
- xiszero;
- Ar2 is a pyrid-2-yl or a phenyl which is unsubstituted or substituted by a halogen, 5 a methyl or a (Cl-C4)alkoxy; and - Xl is other than a group selected from:
formyl;
(C I -C6)alkylcarbonyl;
-(CH2)m-OR4 in which m is zero or one and R4 is a hydrogen or a (Cl-C7)alkyl;
10 -(CH2)m-OCORs in which m is zero or one and Rs is a hydrogen or a (Cl-C6)alkyl;
-(CH2)m-OCONH(CI-C7)alkyl in which m is one;
-NR8R9 in which R8 and Rg are each independently a hydrogen or a (Cl-C7)alkyl;
Rg can also be a (C3-C7)cycloalkylmethyl, a benzyl or a phenyl; or Rg and Rg, 15 together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine andperhydroazepine;
-(CH2)p-NRIoRll in which p is one and Rlo and Rll are each independently a hydrogen or a (C~-C7)alkyl; Rll can also be a (C3-C7)cycloalkylmethyl or a 20 benzyl;
-NR~2COR~3 in which Rl2 is a hydrogen or a (Cl-C4)alkyl and Rl3 is a hydrogen, a (Cl-C7)alkyl, a phenyl, a benzyl, a pyridyl or a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; or Rl2 and Rl3 together are a group -(CH2)U- in which u is three or four;
25 -(CH2)p-NRI4C(=Wl)RI6 in which p is one, Wl is an oxygen atom, Rl4 is a hydrogen or a (Cl-C4)alkyl and Rl6 is a hydrogen, a (Cl-C7)alkyl, a phenyl, a benzyl, a pyridyl or a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls;
-(CH2)m-NRI4COORl7 in which m is zero or one, Rl4 is a hydrogen or a (Cl-30 C4)alkyl and Rl7 is a (Cl-C7)alkyl or a phenyl;
~(CH2)m-NRI4SO2Rl8 in which m is zero or one, Rl4 is a hydrogen or a (Cl-C4)alkyl and Rl8 is a (Cl-C7)alkyl, an amino which is free or substituted by oneor two (Cl-C7)alkyls, or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (Cl-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C I -C7)alkoxy, a carboxyl, a (C I -C7)alkoxycarbonyl, a (Cl-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (Cl-C7)alkyls, said substituents being identical or different;
-(CH2)m-NR14C(=WI)NRl9R20 in which m is zero or one, W~ is an oxygen atom, Rl4 is a hydrogen or a (Cl-C4)aLkyl and R~g and R20 are each independently a hydrogen or a (Cl-C7)alkyl; R20 can also be a (C3-C7)cycloaL~yl, a (C3-C7)cycloalkylmethyl, a hydroxyl, a (Cl-C4)alkoxy, a benzyl or a phenyl; or Rl9 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine;
-(CH2)n-COOR2l in which n is zero and R21 is a (Cl-C7)aL~yl;
-(CH2)n-C(=WI)NRlgR20 in which n is zero, W~ is an oxygen atom and R~g and R20 are as defined above; and -CN;
or Xl does not form a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring;
or Ar2 and Xl, together with the carbon atom to which they are bonded, are otherthan a group of the formula ~ ~
2/when Rl is hydrogen, R2 is the methyl group, Arl is the 3,4-dichlorophenyl group and T-A-Z is the thenoyl group, B is the group Bl in which J~ is the group Ar2-(CH2)x~ IC\

in which x is one, Ar2 is the phenyl group and X~ is other than hydrogen;
25 3/when Rl is hydrogen, R2 is the methyl group, Arl is the 3,4-dichlorophenyl group and T-A-Z is the 2,4-dichlorobenzoyl group, B is the group Bl in which J~ is the group Ar2-(CH2)x~l \

in which x is one, Ar2 is the phenyl group and X~ is other than hydrogen; or ~ 21 4/ when Rl and R2 together form a group -(CH2)3-, Arl is the 3,4-dichlorophenyl group and T-A-Z is the 2-(3-methoxyphenyl)acetyl group, B is the group Bl in which Jl is the group Ar2-(CH2)x~
Xl in which x is one, Ar2 is phenyl and Xl is other than hydrogen;
and their salts, where apl)lopl;ate, with mineral or organic acids.
The compounds of formula (I) according to the invention include the optically pure isomers as well as the racemates.
It is possible to form salts of the compounds of formula (r). These salts include those with mineral or organic acids which permit a suitable separation or cryst~lli7~tion of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic or camphosulfonic acid, as well as those with mineral or organic acids which form pharmaceutically acceptable saltssuch as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen-phosphate, methanesulfonate, methylsulfate, maleate, fumarate, naphthalene-2-sulfonate, glycolate, gluconate, citrate, isethionate, benzenesulfonate and para-toluenesulfonate.
More particularly, the radical Z can be a phenyl group, which can be unsubstituted or may contain one or more substituents.
When Z is a phenyl group, it can be monosubstituted or disubstituted, especially in the 2,4-position but also, for example, in the 2,3-, 4,5-, 3,4- or 3,5-position; it can also be trisubstituted, especially in the 2,4,6-position but also, for example, in the 2,3,4-, 2,3,5-, 2,4,5- or 3,4,5-position, tetrasubstituted, for example in the 2,3,4,5-position, or pentasubstituted.
The radical Z can also be a bicyclic aromatic group such as 1- or 2-naphthyl or 1-, 2-, 3-, 4-, 5-, 6- or 7-indenyl, in which one or more bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, oxo, alkylcarbonylamino, alkoxycarbonyl, thioalkyl, halogen, alkoxy and trifluoromethyl groups, in which the alkyls are Cl-C4.
The radical Z can also be a group Z- selected from pyridyl, thi~ zolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, ~ 22 thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrirnidinyl, pyridazinyl, indolizinyl, phth~l~7inyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl and chromanyl, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally 5 to contain one or more substituents such as alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl and thioalkyl groups, in which the aLkyl and alkoxy groups are Cl-C4.
In the present description the alkyl or alkoxy groups are linear or branched;
halogen atom is understood as meaning a chlorine, bromine, fluorine or iodine 10 atom.
In the present description, when B is a group B4 or Bs, aryl is understood as meaning a phenyl radical or a Cg-CIo ortho-fused bicyclic carbocyclic radical inwhich at least one of the rings is aromatic; heteroaryl is understood as meaningeither a five- or six-membered monocyclic aromatic heterocycle Cont~inin~ from 15 one to four heteroatoms, said heteroatoms being selected from an oxygen atom, a sulfur atom and a nitrogen atom, and said heterocycle being bonded by a carbon atom of the ring, or an eight- to ten-membered ortho-fused bicyclic aromatic heterocycle cont~inin~ from one to four heteroatoms as defined above.
In the substituents of the group Z = phenyl, (Cl-CIO)alkyl is understood as meaning for example a methyl, an ethyl, an n-propyl, an isopropyl, an n-butyl, an isobutyl, a sec-butyl, a tert-butyl, a pentyl or n-pentyl, a hexyl or n-hexyl, a heptyl or n-heptyl, an octyl or n-octyl, a nonyl or n-nonyl or a decyl or n-decyl; (C3-Cg)-cycloalkyl optionally substituted by a methyl is understood as meaning for example a cyclopropyl, a cyclobutyl, a cyclopentyl, a 1-, 2- or 3-methylcyclopentyl, a 25 cyclohexyl, a 1-, 2-, 3- or 4-methylcyclohexyl, a cycloheptyl or a cyclooctyl; (Cl-CIO)alkoxy is understood as mt-~ning for example a methoxy, an ethoxy, an n-propoxy, an isopropoxy, an n-butoxy, an isobutoxy, a sec-butoxy, a tert-butoxy, a pentoxy, a hexyloxy, a heptyloxy, an octyloxy, a nonyloxy or a decyloxy; (C3-C8)cycloalkoxy optionally substituted by a methyl is understood as meaning for 30 example a cyclopropoxy, a cyclobutoxy, a cyclopentoxy, a 1-, 2- or 3-methylcyclo-pentoxy, a cyclohexyloxy, a 1-, 2-, 3- or 4-methylcyclohexyloxy, a cycloheptyloxy or a cyclooctyloxy; (C I -C I o)alkylthio is understood as meaning for example amethylthio, an ethylthio, an n-propylthio, an isopropylthio, an n-butylthio, an isobutylthio, a sec-butylthio, a tert-butylthio, a pentylthio, a hexylthio, a heptylthio, 35 an octylthio, a nonylthio or a decylthio; (Cl-C6)alkylcarbonyloxy is understood as meaning for example an acetoxy, a propionyloxy, a butyryloxy, a valeryloxy, a caproyloxy or a heptanoyloxy; (C,-C6)aL~ylcarbonylamino is understood as meaning for example an acetylamino, a propionylamino, a butyrylamino, an isobutyrylamino, a valerylamino, a caproylamino or an heptanoylamino; (Cl-C4)alkoxycarbonyl is understood as me~ning for example a methoxycarbonyl, an 5 ethoxycarbonyl, an n-propoxycarbonyl, an isopropoxycarbonyl, an n-butoxycarbonyl, an isobutoxycarbonyl, a sec-butoxycarbonyl or a tert-butoxycarbonyl; and (C3-C7)cycloaL~oxycarbonyl is understood as meaning for example a cyclopropoxycarbonyl, a cyclobutoxycarbonyl, a cyclopentoxycarbonyl, a cyclohexyloxycarbonyl or a cycloheptyloxycarbonyl.
The invention relates particularly to compounds of formula (I) in which:
- Z is Z- as defined above;
- R~ and R2 together form a group -(CH2)3-;
- Arl is a 3,4-dichlorophenyl;
- T is a group -CO-;
15 - A is a direct bond; and - B is as defined for a compound of formula (I), and their salts, where applo~.liate, with mineral or organic acids.
Among these compounds, those of the formula ,CH2, 2 (I ) ~Cl Cl in which:
- Z- is as defined above; and - B- is a group of the formula J- N-25 in which J- is:
- i- - either a group of the structure :

~ 24 W-Rl9 ~ C~
N--C
R2/ ll o O
in which:
- W- is a phenyl or a benzyl and Rlg and R20 are as defined for a compound of forrnula (I);
5 - or W- is a group -NR~7gRgo in which R7g and R80 are as defined for (I) and Rlg and R20 are each hydrogen;
- i-- - or a group of the structure R--N C~
<~
in which:
10 - R is hydrogen, a methyl group, an acetyl group, a methoxycarbonyl group, a dimethylaminocarbonyl group or a methanesulfonyl group, and their salts, especially pharmaceutically acceptable salts, are advantageous. Among these compounds, those of the formula ,CH2, l H2 ICH2 B ~(CH2)3~l--CH ~N-CO (I.. ) ~Cl Cl in which:
- B- is as defined for a compound of formula (I-); and - Z-- is a pyridyl, for example a 4-pyridyl, a 2-thienyl, a 3-thienyl, a 2-furyl or a 3-furyl, 20 and their salts, especially pharmaceutically acceptable salts, are particularly advantageous.
Among these compounds, those of the formula ~ 25 G~-(CH2)~ C N-CO Z-- (I--a) in which:
- Z'- is as defined for a compound of formula (I'-), and their salts, especially pharmaceutically acceptable salts, are of very greatS interest.
Advantageously the radical Z is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen atom, more particularly a chlorine, fluorine or iodine atom, a trifluoromethyl, a (Cl-C4)alkyl, a hydroxyl or a (Cl-C4)alkoxy; a naphthyl which is unsubstituted or monosubstituted or 10 polysubstituted by a halogen, a trifluoromethyl, a (Cl-C4)alkyl, a hydroxyl or a (C~-C4)alkoxy; a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imi(l~7:olyl.
The invention relates particularly to compounds of formula (I) in which:
- Z is Z' and is:
15 . a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl;
a nitro; an amino which is unsubstituted or monosubstituted or disubstituted by a (C~-C4)alkyl; a benzylamino; a carboxyl; a (Cl-C10)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (Cl-20 C10)alkoxy; a (C3-C8)cycloalkoxy which is unsubstituted or monosubstituted orpolysubstituted by a methyl; a mercapto; a (Cl-C~0)alkylthio; a formyloxy; a (Cl-C6)alkylcarbonyloxy; a formylamino; a (Cl-C6)alkylcarbonylamino; a benzoyl-amino; a (Cl-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (Cl-C4)alkyl; a 25 ureido which is unsubstiblted or monosubstituted or disubstituted in the 3-position by a (Cl-C4)alkyl or a (C3-C7)cycloalkyl; and a (pyrrolidin-1-yl)-carbonylamino, said substituents being identical or different;
. a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (Cl-C4)alkyl, a hydroxyl or a (Cl-C4)alkoxy; or 30 . a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imidazolyl, and their salts with mineral or organic acids.
The substituent Arl is preferably a phenyl group which is advantageously substituted by two chlorine atoms, more particularly in the 3- and 4-positions.
According to the present invention, the preferred compounds are those in which simultaneously:
- zisZ';
- Arl is a 3,4-dichlorophenyl;
- Rl and R2 together form a group -(CH2)3 or -(CH2)4-; and - B, T and A are as defined for a compound of formula (I), 10 and their salts, especially pharmaceutically acceptable salts.
When B is a group B3, W3 is advantageously an oxygen or sulfur atom, R2g is hydrogen, a (Cl-C6)alkyl, a (C3-C7)cycloalkyl, preferably cyclohexyl, or a (C3-C4)aLk-2-en-l-yl, preferably allyl, and R29 is hydrogen, a (Cl-C6)alkyl, a trifluoro-methyl or a (Cl-C4)aL~cylamino, preferably methylamino, or, only when R2g is other 15 than hydrogen, R29 is a di(CI-C5)aL~ylamino, preferably dimethylamino, or R28 and R2g together are a 1,3-propylene, 1,4-butylene or cis,cis-1,4-butadienylene group.
Consequently the compounds of formula (I) in which B is B3 and W3, R2g and R2g are as just defined, and their salts, especially pharm~celltically acceptable salts, are advantageous products.
The compounds of this subclass of forrnula (I) in which simultaneously:
- B is a group B3 in which:
. either W3 is oxygen, R29 is a (Cl-C4)alkyl or a trifluoromethyl and R28 is a (Cl-- C6)alkyl, especially an ethyl;
. or W3 is oxygen, R28 is an allyl or a cyclohexyl and R29 is a methyl;
. or W3is oxygen, R28 is an ethyl and R29 is a methylamino or a dimethylamino;
. or W3is oxygen and R28 and R29 together form a 1 ,3-propylene, 1 ,4-butylene or cis,cis-1,4-butadienyl group;
. or W3is sulfur and R28 and R29 together form a 1,4-butylene group;
- Rl and R2 together form a group -(CH2)3- or -(CH2)4-;
30 - Arl is a 3,4-dichlorophenyl;
Z = Z'; and - T and A are as defined above for a compound of formula (I), and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
When B is a group B4, W4 iS advantageously a (C~-C8)alkyl group substituted by a hydroxyl, oxo, hydroxyimino, (Cl-C4)alkoxyimino, (Cl-~ 27 C4)aLkanoyloxy, (Cl-C4)alkanoylamino or (Cl-C4)alkoxy group or at the same time by an oxo group and a hydroxyl or (Cl-C4)alkoxy group or a group -NR33R34.
Consequently the compounds of formula (I) in which B is a group B4 and W4 is an alkyl group substituted by a hydroxyl, oxo, hydroxyimino, (Cl-C4)alkoxyimino, (C~-C4)alkanoyloxy, (Cl-C4)alkanoylamino or (Cl-C4)alkoxy group or at the same time by an oxo group and a hydroxyl or (Cl-C4)alkoxy group or a group -NR33R34, and their salts, especially pharmaceutically acceptable salts, are advantageous products.
The compounds of this subclass of formula (I) in which ~imlllt~neously:
- B is B4 in which: W4 iS l-hydroxypropyl, l-hydroxyethyl, l-hydroxybutyl, 2-hydroxybut-2-yl, 4-hydroxyhept-4-yl, 2-hydroxyethyl, 1-hydroxyiminopropyl (syn or anti), l-methoxyiminopropyl (syn or anti), 2-acetoxyethyl, 2-acetamidoethyl, carboxyl, ethoxycarbonyl or pyrrolidin-1-ylcarbonyl;
- Rl and R2 together form a group -(CH2)3- or -(CH2)4-;
- Arl is a 3,4-dichlorophenyl;
- Z = Z'; and - T and A are as defined above for a compound of formula (I), and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
When B is a group Bs, W6 is advantageously a hydrogen, W7is a hydroxyl and Wg is a phenyl which is unsubstituted or substituted by a methoxy, a hydroxyl, a methylthio or a methylsulfinyl; or W6 and W7 are hydrogen and Wg is a pyridyl,pyrimidyl or thienyl group substituted by a halogen, especially chlorine or fluorine, or by one of the following groups: cyano, trifluoromethyl, hydroxyl, (Cl-Cs)alkoxy, especially methoxy or ethoxy, formyloxy, (C I -C4)alkylcarbonyloxy, especially acetoxy, amino, methylamino, dimethylamino, acetamido, imidazolin-2-yl, carboxyl, methoxycarbonyl, benzyloxycarbonyl, ethoxycarbonyl, carbamoyl, N,N-dimethylcarbamoyl, pyrrolidinocarbonyl, N-methylcarbamoyl, methylthio, methylsulfinyl, methylsulfonyl, (C I -C4)alkyl, especially methyl, ethyl, propyl, butyl, isopropyl, 2-methylpropyl or tert-butyl, formyl or (Cl-C4)alkylcarbonyl, especially acetyl or propionyl; an indenyl, naphthyl, furyl, pyrrolyl, 1,3 ,4-oxadiazol-2-yl or benz[d]isoxazol-3-yl group which is unsubstituted or substituted by one of the substituents mentioned above for the pyridyl, pyrimidyl or thienylgroups; an imidazol-2-yl substituted by one of the substituents mentioned above for the pyridyl, pyrimidyl or thienyl groups, except for a (Cl-C4)alkyl; or a phenylgroup substituted by one of the substituents mentioned above for the pyridyl, pyrimidyl or thienyl groups, except for halogens and hydroxyl, trifluoromethyl, (Cl-C4)alkyl and (Cl-C4)aL~coxy groups; or W7 iS hydrogen and W6 and W8, together with a diradical Wg and the piperidine carbon atom to which they are bonded, form a spiro ring in which W8 is a phenyl substituted in the ortho position by the diradical Wg, which is itselfjoined to W6, said phenyl being unsubstituted or substit-uted by a methoxy, a hydroxyl, a methylthio or a methylsulfinyl; the diradical Wg is a methylene or a carbonyl; and W6 is an oxy group. Consequently the compounds of ffirmula (I) in which B is B5 and W6, W7 and Wg are as just def1ned, and their salts, especially pharmaceutically acceptable salts, are 10 advantageous products.
The compounds of this subclass of formula (I) in which simultaneously:
- B is a group B5 in which: W7is a hydroxyl, W6 is a hydrogen and W8 is a phenyl;
or W6 and W7 are hydrogen and W8 is selected from the following groups:
S-methyl- 1,3 ,4-oxadiazol-2-yl, 4-ethoxycarbonylimidazol-2-yl, 2-fluoropyrid-3-yl, 2-methylthiophenyl, 4-methylthiophenyl, 2-methylsulfinylphenyl, 4-methylsulfinylphenyl and 4-(N-methylcarbamoyl)phenyl; or W7 iS hydrogen and W6 and W8, together with the piperidine to which they are bonded, form a spiro[isobenzofuran- 1 (3H),4'-piperid]- 1 '-yl group or a 3-oxospiro[isobenzofuran-1 (3h7),4'-piperid]- 1 '-yl group;
20 - R~ and R2 together form a group -(CH2)3- or -(CH2)4-;
- Arl is a 3,4-dichlorophenyl;
- Z = Z'; and - T and A are as defined above for a compound of formula (I), and their salts, especially pharmaceutically acceptable salts, are particularly 25 preferred.
Another group of preferred compounds of the invention consists of the compounds of formula (I) in which Rl, R2, Arl, T, A and Z are as defined above for (I) and B is the group B6.
The particularly ~lef~.led compounds of formula (I) are those in which 30 simultaneously:
- B is a group B6;
- Rl and R2 together form a group -(CH2)3- or -(CH2)4-;
- Arl is a 3,4-dichlorophenyl;
- Z = Z'; and 35 - T and A are as defined above for a compound of formula (I), and their salts, especially pharmaceutically acceptable salts.

When B is a group B7, f is advantageously one and g is two, or f is one and g is one and Wl2, Wl3, W,4, Wls and W,6, together with the carbon atom to which they are bonded, form one of the structures 1 to 201 described below, optionallysubstituted by a halogen, a (C~-C7)alkyl or a (C~-C7)alkoxy:

N C ~ CH3 o ~ ~ o ~ ,~

O ~ ~ ~ CUl \N ~ C/ ~ ' /
CH3 1~l CIH3 CIH3 CH3 N C ~ ~ \ ~ ~ , CH3 CH3 ~ CH3 CH3~ ~~ ,~

~~ ~N' , ~ \ O ~ C N-S

CIH3"o fH3 fH3 HN -S
N-S / N ~ / o~ N ~ / o ~ C
~,C~ O=S~ "S~

CA 02232007 l998-03-l2 _ 30 o H / O ~ 'S C~

o" ~ N HN ~ ~ O~S~ ~ /

H ~ ~ ¢ ~ ~ O ~ N ~ C/ N C~

N ~ ~ N ~ / N

N~/
.

ICH3 ICH3 CH3 ICH3 o O~ N~ / ,S C O"S'N'C / ~N
~\ 0'~\ ~\ ~\
N ~ y N ~ y N~ ~ / N ~ /

ICH3 C~H3 1~l o ICH3,o ICH3 N ~ / N-S' ~ N -S ~ N
O~C~ ~C~ ~C~ O=S C~
N ~ ~ = N ~ ~ N~

,5 C~ N S' o ~ C NO\ ~47//

NS\ ~ / ~~NS~ H ~ C, O~ ,CH3 H ~ CH3 OCH3 "S~ ~ / N C N C N C

N C, CH3~ ,S~ / CH3' ~3~C/

CA 02232007 l998-03-l2 ~ 32 C~ ~ ~ N'C / o~S,N~C ~ o~ ,N~ , CH3~ ~ ~ CH3~ N -S~ \N-S
~C~ O~C~ ~C/ ~C~

CH3 o N ~ / HN -S / o HN
o=s~c\ O~s~\ o~C\ o~

~"~ 0~"~

HN C ~ ,CH3 O='~N ~ C / \ ~N/

~ 33 \~N/ \~/ CH3~ ,1 CH3 CH3~ N/ ~ / "S C

ICH3 ICH3 O ICH3CH3 O, o S c / ~ ~ ~ ~ N--S ' ICH3~/~ ICH3 CH3 \\,O
N -S ~ N ~ ~ o N ~ ~ HN -S' \ ~N O=S~ ~N~\ o',S\ ~Nr\ ~ N

o HN ~ O C ~ S C ~ 'S C , CA 02232007 l998-03-l2 ~ 34 ~S C / H ~ C ~ ,5~ ~ O

N ~ CH3 C~H,~ ~ N/

CH3~ ~ CH3~ 'C / ~'Y ~'~' CH3 ICH3 CH3~N ~ O CH3~N ~
',S C ~ ~ - ~ N ~ N

3 \ ~ r O~5 ~ C /

~ 35 12 1~3 ~-'S ~ C ~ ~S C HN C ~ ~''S'CH3 S ~S

O ~ N ~ C / ~ ~ '~ / ~ ~ '' '' , ~ S

CH3~N I ~ CH3~N,S~C / CH3~ ,5~ ~ ,N~

O~ N~ ~ O~S,N~C ~ O~S,N~C ~ CH3~N ~ C /
)=( \ ~" )=( \ ~ \ )=~ \
~S ~,,S ~S ~S

CH ~ C ~ N

~S;~C~ O ~ ~ o =~

S ~ C , ~S C ~ ~S C ~ HN C

148 149 lS0 151 O ,C ~ o ,~ O ~ N ~ C / OCI

Cl~3'N ~'C / ~ CH3~ ~ ~ ~ CH3~

~C ~ \~C-- , S C-- S C--C 3 ~ CH3~ ~~

~ 37 ,N~\ ~ ~5 C , O ~

0~ S~C~ ~~Sy\ o~S~C\

HN C~ ~ ,CH3 o ~ ~ /

OCH3 N C~ ~ CH3 CH3~ 3~ / N ~ N~/

_ CH3 ~ , CH3~ ~~ CH3~ CH3~ ~" "~
N -S ~ N ~ ~ o ,N ~ ~ HN -S, ~C~ O=S C~ "S~C~ O~C~

N ~/ N // N ~/ N~

',s C\ ~ C S C N

~s~c~ CIH3 O ~ \ /N--CH3 \< ~/ \N~C/
N ~ \

Consequently the compounds of formula (I) in which B is B7 and g, f, Wl2, Wl3, Wl4, Wls and Wl6 are as just defined, and their salts, especially pharm~celltically acceptable salts, are advantageous products.
S The compounds of this subclass of formula (I) in which simultaneously:
- B is a group B7 selected from:
a) a 1 -methanesulfonylspiro(indoline-3,4'-piperid- 1 '-yl) b) a 1 -benzyloxycarbonylspiro(indoline-3 ,4'-piperid- 1 '-yl) c) a spiro(indoline-3,4'-piperid-1'-yl) d) a 1 -acetylspiro(indoline-3 ,4'-piperid- 1 '-yl) e) a 1 -propionylspiro(indoline-3,4'-piperid- 1 '-yl) ~ 39 f) a 1 -formylspiro(indoline-3 ,4'-piperid- 1 '-yl) g) a I -tert-butylcarbonylspiro(indoline-3 ,4'-piperid- 1 '-yl) h~ a 1 -methylaminocarbonylspiro(indoline-3 ,4'-piperid- 1 '-yl) i) a 1 -ethoxycarbonylspiro(indoline-3,4'-piperid- 1 '-yl) j) a 1-ethanesulfonylspiro(indoline-3,4'-piperid-1'-yl) k) a l-isoplol)anesulfonylspiro(indoline-3,4'-piperid-1'-yl) 1) a 1 '-methyl- 1 -methanesulfonylspiro(indoline-3 ,4'-piperidinio- 1 ') iodidern) a 1 -(2-aminoacetyl)spiro(indoline-3 ,4'-piperid- 1 '-yl) n) a 1 -methylspiro(indol-2-one-3 ,4'-piperid- 1 '-yl) o) a 2-methylspiro(isoindol-1-one-3,4'-piperid-1'-yl) p) a spiro(2-oxotetrahydroquinoline-4-4'-piperid-1'-yl) q) a 1 -methylspiro(2-oxotetrahydroquinoline-4,4'-piperid- 1 '-yl) r) a spiro(2,3-dihydrobenzothiophene-3,4'-piperid-1'-yl) s) a 5-fluorospiro(2,3-dihydrobenzofuran-3,4'-piperid- 1 '-yl) t) a spiro(2,3-dihydrobenzofuran-3,4'-piperid-1'-yl) u) a spiro(2,3 -dihydrobenzothiophene-3 ,4'-piperid- 1 '-yl) I -oxide v) a spiro(2,3 -dihydrobenzothiophene-3,4'-piperid- 1 '-yl) 1,1 -dioxide w) a 5-fluoro- 1 -methanesulfonylspiro(indoline-3 ,4'-piperid- 1 '-yl) x) a 1 -methanesulfonyl-5-methoxyspiro(indoline-3,4'-piperid- 1 '-yl) y) a 1 -methanesulfonyl-5-methylspiro(indoline-3 ,4'-piperid- 1 '-yl) z) a 5-chloro-1-meth~n,osnlfonylspiro(indoline-3,4'-piperid-1'-yl) aa) a 7-fluoro-1-meth~ntosnlfonylspiro(indoline-3,4'-piperid-1'-yl) ab) a 1 -acetyl-5 -fluorospiro(indoline-3 ,4'-piperid- 1 '-yl) ac) a 1 -acetyl-5-chlorospiro(indoline-3 ,4'-piperid- 1 '-yl) ad) a 1-acetyl-5-methylspiro(indoline-3,4'-piperid-1'-yl) ae) a 1 -acetyl-6-fluorospiro(indoline-3,4'-piperid- 1 '-yl) af) a 1 -acetyl-4-fluorospiro(indoline-3 ,4'-piperid- 1 '-yl) ag) a 1 -(N,N-dimethylcarbamoyl)spiro(indoline-3 ,4'-piperid- 1 '-yl);
- Rl and R2 together forrn a group -(CH2)3- or -(CH2)4-;
- Arl is a 3,4-dichlorophenyl;
- Z = Z'; and - T and A are as defined above for (I), and their salts, especially phartn~ceutically acceptable salts, are particularly ~cr~llcd.
When B is a group B8, W17iS advantageously a direct bond or a methylene group, preferably a direct bond, Wl8 is an oxo, thioxo, imino, methylimino or ~ 40 ethylimino group, preferably an oxo or thioxo group, Wl9 is an oxy or thio group or a group NH, preferably an oxy group or a group NH, and W20 is an ethylene, cis-vinylene or trimethylene group. Consequently the compounds of formula (I) in which B is B8 and W17, W18, W19 and W~o are as just defined, and their salts, S especially ph~ ceutically acceptable salts, are advantageous products.
The compounds of this subclass of formula (I) in which simultaneously:
- B is a group B8 in which: Wl7 is a direct bond, W~8 is an oxo or thioxo group,Wl9 is an oxy group or a group NH and W20 is an ethylene or trimethylene group;
- Rl and R2 together form a group -(CH2)3- or -(CH2)4-;
- Arl is a 3,4-dichlorophenyl;
- Z = Z'; and - T and A are as defined above for (I), and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
Another group of preferred compounds of the invention consists of the compounds of formula (I) in which R~, R2, Ar" T, A and Z are as defined above for (I) and B is the group B9.
The particularly pler~lled compounds of formula (I) are those in which simultaneously:
- B is a group Bg in which: X2 is a group -COOR68 or a group -C(=W24)NR70R7l and W2l, W22 and W23, together with the nitrogen atom, form a 2-oxopiperidino group or a 2-oxoperhydropyrimidin-1-yl group;
- R~ and R2 together form a group -(CH2)3- or -(CH2)4-;
- Arl is a 3,4-dichlorophenyl;
- Z = Z'; and - T and A are as defined above for (I), and their salts, especially pharmaceutically acceptable salts.
Another group of preferred compounds of the invention consists of the compounds of formula (I) in which Rl, R2, Arl, T, A and Z are as defined above for (I) and B is the group Blo.
The particularly preferred compounds of formula (I) are those in which simultaneously:
- B is a group Blo;
- Rl and R2 together forrn a group -(CH2)3- or -(CH2)4-;
- Arl is a 3,4-dichlorophenyl;
- Z = Z'; and ~ 4 - T and A are as defined above for (I), and their salts, especially pharmaceutically acceptable salts.
The more particularly pler~ d compounds of formula (I) are those in which ~imlllt~neously:
5 - B is a group Blo in which J6 is a group W2s Cl \ .
X
in which:
- W25 is a piperid-l-yl and Xl is a hydrogen, or W2s is an azetidin-1-yl, a pyrrolidin-1-yl, a pirerid-1-yl, a morpholin-4-yl, a thiomorpholin-4-yl or a 10 perhydroazepin-1-yl and X~ is a carbamoyl;
- Rl and R2 together form a group -(CH2)3-;
- Arl is a 3,4-dichlorophenyl;
z = Z';
- T is a group -CO-; and 15 - A is a direct bond, and their salts, especially pharmaceutically acceptable salts.
Another group of preferred compounds of the invention are those of the formula ,CH2, ICH2 ICH2 (Ia) Ba-(CH2)3-CI \CH /N-CO
Ar' 20 in which:
- Ar' I is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (Cl-C4)aLkoxy, a (Cl-C4)-aL~yl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different;
25 - A' is a direct bond or a group -CH2-;
- Z' is as defined above; and - Ba is a group Bla of the formula A

JI~N--~ 42 in which JlaiS a group Ar2a-(CH2)~-CI \
Xla in which:
- xiszero;
- Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by 5 a substituent selected from a halogen atom, a hydroxyl, a (Cl-C4)alkoxy, a (Cl-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and - Xla is a group selected from:
. hydrogen;
10 . (C,-C7)alkyl;
. -(CH2)m-OR4 in which m is two and R4is a hydrogen or a (Cl-C7)alkyl;
. -(CH2)m-OCORs in which:
m is two and R5 is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl; or m is zero or one and R5 is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
. -(CH2)m-OCONH(CI-C7)alkyl in which m is zero or two;
. -O-CH2-CH~-OR6 in which R6 is a hydrogen; a (C~-C7)alkyl; a formyl; or a (Cl-C7)alkylcarbonyl;
20 . -(CH2)n-SR7 in which n is zero or one and R7is a hydrogen or a (Cl-C7)alkyl;
. -CH2-S(O)j-(CI-C7)alkyl in which j is one or two;
. -NR8R9 in which R8 and R9, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
25 . -(CH2)p-NRIoRll in which p is two and Rlo and Rll are each independently a hydrogen or a (Cl-C7)alkyl; Rll can also be a (C3-C7)cycloalkylmethyl or a benzyl;
. -NRI2CORl3 in which Rl2 is a hydrogen or a (Cl-C7)alkyl and Rl3 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
30 . -NR,4COCORI5 in which Rl4 is a hydrogen or a (Cl-C7)alkyl and Rls is a (Cl-C4)alkoxy;
. -(CH2)p-NRI4C(=Wl)RI6 in which p is two, Wl is an oxygen atom or a sulfur atom, R,4is a hydrogen or a (C,-C7)alkyl and Rl6 is a hydrogen; a (Cl-C7)alkyl;
a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more ~ 43 methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; and p is one, Wl is a sulfur atom and Rl4 and Rl6 are as just defined, or Wl is an oxygen atom, Rl4 is as just defined and Rl6 is a vinyl, a fi~yl, a thienyl, a pyrrolyl or an imitl~z~lyl;
. -(CH2)m-NRI4COORl7 in which m is two, Rl4 is a hydrogen or a (C~-C~)alkyl and Rl7 is a (Cl-C7)alkyl or a phenyl;
. ~(CH2)m-NRI4SO2Rlg in which m is two, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl8 is a (Cl-C7)alkyl; an amino which is free or substituted by one or two (Cl-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or poly-substituted by a substituent selected from a halogen atom, a (Cl-C7)alkyl, a trifluoromethyl, a hydroxyl, a (Cl-C7)alkoxy, a carboxyl, a (Cl-C7)alkyl-carbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (Cl-C7)alkyls, said substituents being identical or dirr~
. -(CH2)m-NRI4C(=Wl)NRl9R20 in which m is two, Wl is an oxygen atom or a sulfur atom, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rlg and R20 are each independently a hydrogen or a (Cl-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C I -C4)alkoxy; a benzyl; a phenyl; or a (Cl-C7)alkyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a (C I -C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (Cl-C7)alkyls; or Rlg and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl; and m is zero or one, Wl is a sulfur atom and Rl4,Rlg and R20 are as just defined, or Wl is an oxygen atom, Rl4 and Rlg are each independently a hydrogen or a (C I -C7)alkyl and R20 is a (C I -C7)alkyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a (Cl-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (Cl-C7)alkyls; or Rlg and R20, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
. -(CH2)n-COOR2l in which n is one and R2l is a hydrogen or a (Cl-C7)alkyl; and n is zero and R2l is a hydrogen;
. -(CH2)n-C(=WI)NRlgR20 in which n is one, Wl is an oxygen atom or a sulfur atom and Rlg and R20 are each independently a hydrogen or a (Cl-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (Cl-~ 44 C4)aLkoxy; a benzyl; a phenyl; or a (Cl-C7)alkyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a (Cl-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (Cl-C7)alkyls; or Rlg and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)aLkyl; and n is zero, Wl is a sulfur atom and Rlg and R20 are as just defined, or Wl is an oxygen atom, Rlg is a hydrogen or a (Cl-C7)aL~yl and R20 is a (Cl-C7)aL~yl substituted by a hydroxyl, a ~CI-C3)alkoxy, a phenyl, a carboxyl, a (Cl-C3)aLkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (Cl-C7)alkyls; or Rlg and R20, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (Cl-C4)aL'cyl;
. -CO-NR22NR23R24 in which R22 is a hydrogen or a (Cl-C7)alkyl and R23 and R24 are each independently a hydrogen or a (Cl-C7)alkyl;
~ ~N
R2 ~ S NR26R27 in which R2s is a hydrogen or a (C l -C7)alkyl and R26 and R27 are each independently a hydrogen or a (Cl-C7)alkyl; R27 can also be a formyl or a (Cl-C7)alkylcarbonyl; and ~0 N~N'~NH ' and their salts, especially pharmaceutically acceptable salts.
Among these compounds, those of the forrnula CH2, CH2 ~ (I~a) ~/'CI
Cl in which:
- B'a is a group B'la of the formula J'l,~N--in which J'la is a group Ar2a-(CH2)x-CI \
X la in which:
- xiszero;
- Ar2a is as defined for a compound of formula (Ia); and - X'la is a group selected from:
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (Cl-C7)alkyl; a formyl; or a (C~-C7)alkylcarbonyl;
. -NRI2CORl3 in which Rl2 is a hydrogen or a (Cl-C7)alkyl and Rl3 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
. -NRI4COCORls in which Rl4 is a hydrogen or a (Cl-C7)alkyl and Rls is a (Cl-C4)alkoxy;
. -(CH2)p-NRI4C(=Wl)Rl6 in which p is one, Wl is an oxygen atom, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl6 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
. -(CH2)m-NRI4C(=Wl)NRlgR20 in which m is zero, Wl is an oxygen atom, Rl4 is a hydrogen or a (Cl-C7)alkyl, Rlg is a hydrogen or a (Cl-C7)alkyl and R20 is a (Cl-C7)alkyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a(Cl-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (Cl-C7)alkyls;
. -CO-NR22-NR23R24 in which R22 is a hydrogen or a (C~-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C~-C7)alkyl;
~ ~N

in which R2s is a hydrogen or a (C I -C7)alkyl and R26 and R27 are each independently a hydrogen or a (Cl-C7)alkyl; R27 can also be a formyl or a (Cl-C7)aLkylcarbonyl; and ~ ~0' N 'N'~NH
and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
Among these compounds, those of the formula ~ , CH2 ~ CH (I~a) X" ~
Cl Cl S in which:
- X"la is a group selected from:
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (Cl-C7)alkyl; a formyl; or a (C~-C7)aL'cylcarbonyl, preferably a hydrogen or an acetyl;
. -NRI2CORl3 in which Rl2 is a hydrogen or a (C~-C7)alkyl, preferably a hydrogen, and Rl3 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl, preferably a furyl or a thienyl;
. -NRI4COCORl5 in which Rl4 is a hydrogen or a (Cl-C7)alkyl, preferably a hydrogen, and Rls is a (Cl-C4)alkoxy, preferably an ethoxy; and ~ ~N

in which R2s is a hydrogen or a (Cl-C7)alkyl, preferably a hydrogen, and R26 and R27 are each independently a hydrogen or a (Cl-C7)alkyl; R27 can also be a formyl or a (Cl-C7)alkylcarbonyl; R26 and R27 are preferably a hydrogen; and ~ ~0 N 'N'~NH ' and their salts, especially pharmaceutically acceptable salts, are more particularly 20 plc;f~l-ed.
Another group of preferred compounds of the invention are those of the formula ~CH2, H2 ICH2 (Ib) b 2 3 1 --CH2 /
Ar'l in which:
- Ar' I is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (Cl-C4)alkoxy, a (Cl-C4)-alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or S different;
- A' is a direct bond or a group -CH2-;
- Z' is as defined above; and - Bb is a group Blb of the formula A

J,~N--10 in which Jlb is a group Ar2a-(CH2)x~cl \
X,b in which:
- x is one;
- Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by 15 a substituent selected from a halogen atom, a hydroxyl, a (C,-C4)alkoxy, a (Cl-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and - Xlb is a group selected from:
. hydrogen;
20 . (C1-C7)alkyl;
. formyl;
. (Cl-C7)alkylcarbonyl;
~(CH2)m-oR4;
. -(CH2)m-0COR5;
25 . -(CH2)m-OCONH-(C I -C7)alkyl;
. -O-CH2CH2 -OR6;
~ ~(CH2)n~SR7;
. -CH2-S(O)j-(C I -C7)alkyl;
. -NR8Rg;

-(cH2)p-NR I oRI l;
. -NR12CORl3;
. -NR14COCORlS;
~ -(CH2)p-NR14C(=Wl)R16;

~ 48 . -(CH2)m-NRl4cOoRl7;
~-(CH2)m-NRl4sO2Rl8;
. -(CH2)m-NR14C(=Wl)NRl9R20;
. -(cH2)n-cooR2 1;
5 .-(CH2)n-C(=W~ gR20;
. -CO-NR22-NR23R24;
. -CN;
~N
R25 S ~'TR26R27 ~0 N' ~H;
N
10 . or Xlb forms a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring, in which groups:
- m is zero, one or two;
- n is zero or one;
15 - p is one or two;
- j is one or two;
- W~ is an oxygen atom or a sulfur atom;
- R4 is a hydrogen or a (Cl-C7)alkyl;
- R5 is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloaLkyl which is unsubstituted or 20 substituted by one or more methyls; a phenyl; or a pyridyl;
- R6 is a hydrogen; a (Cl-C7)alkyl; a formyl; or a (C~-C7)aL~ylcarbonyl;
- R7 is a hydrogen or a (Cl-C7)alkyl;
- R8 and Rg are each independently a hydrogen or a (Cl-C7)alkyl; R9 can also be a (C3-C7)cycloalkylmethyl, a benzyl or a phenyl;
25 - or R8 and Rg, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, perhydroazepine and piperazine which is unsubstituted or substituted i~i the 4-position by a (Cl-C4)alkyl;
- Rlo and Rll are each independently a hydrogen or a (Cl-C7)alkyl; Rl~ can also be 30 a (C3-C7)cycloalkylmethyl or a benzyl;
- Rl2 is a hydrogen or a (Cl-C7)alkyl;

~ 49 - R~3 is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloaLkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl;
a thienyl; a pyrrolyl; or an imidazolyl;
- or Rl2 and R~3 together are a group -(CH2)U- in which u is three or four;
5 - Rl4 is a hydrogen or a (Cl-C7)alkyl;
- Rls is a (Cl-C4)alkoxy;
- Rl6 is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl;
a thienyl; a pyrrolyl; or an imidazolyl;
10 - Rl7 is a (Cl-C7)alkyl or a phenyl;
- Rlg is a (Cl-C7)alkyl; an amino which is free or substituted by one or two (Cl-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or poly-substituted by a substituent selected from a halogen atom, a (Cl-C7)alkyl, a tri-fluoromethyl, a hydroxyl, a (Cl-C7)alkoxy, a carboxyl, a (Cl-C7)alkoxycarbonyl, 15 a (C ~-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (Cl-C7)alkyls, said substituents being identical or different;
- R~g and R20 are each independently a hydrogen or a (C~-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (Cl-C4)alkoxy; a 20 benzyl; a phenyl; or a (C~-C7)alkyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a (C,-C3)alkoxycarbonyl or a carbamoyl which is unsub-stituted or substituted by one or two (Cl-C7)alkyls;
- or Rlg and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thio-25 morpholine, perhydroazepine and piperazine which is unsubstituted orsubstituted in the 4-position by a (C,-C4)alkyl;
- R2, is a hydrogen or a (Cl-C7)alkyl;
- R22 is a hydrogen or a (Cl-C7)alkyl;
- R23 and R24 are each independently a hydrogen or a (C~-C7)alkyl;
30 - R2s is a hydrogen or a (C~-C7)alkyl; and - R26 and R27 are each independently a hydrogen or a (Cl-C7)alkyl; R27 can also be a formyl or a (C~-C7)alkylcarbonyl, with the proviso that:
- when Ar'l is the 3,4-dichlorophenyl group and -A'-Z' is the 3-methoxybenzyl 35 group, Bb is the group B Ib of the formula ~ 50 Jl~ N--in which Jlbis the group Ar2a-(CH2)x~cl \
Xlb in which x is one, Ar2a is a phenyl group and Xlb is other than hydrogen, 5 and their salts, especially pharmaceutically acceptable salts.
Among these compounds, those of the formula , CH2, B'b-(CH2)3-C /N-CO~ (I~) Cl Cl in which:
10 - B'b is a group B'lb ofthe formula A

J'~ N--in which J'lbis a group Ar2a-(CH2)x~cl \
X'lb in which:
- x is one;
- Ar2a is as defined for a compound of formula (Ib); and - X'lb is as group selected from:
(C I -C7)alkyl;
. -(CH2)m-OR4 in which m is one or two and R4 is a hydrogen or a (Cl-C7)alkyl;
-(cH2)m-OcORs in which:
m is zero and R5 is a (C3-C7)cycloalkyl which is unsubstituted or substituted byone or more methyls; a phenyl; or a pyridyl; or m is one or two and Rs is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
. -(CH2)m-OCONH-(CI-C7)aLkyl in which m is zero, one or two;
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (Cl-C7)alkyl; a formyl; or a (Cl-C7)alkylcarbonyl;
5 . -(CH2)n-SR7 in which n is zero or one and R7 is a hydrogen or a (Cl-C7)alkyl;
. -CH2-S(O)j-(CI-C7)alkyl in which j is one or two;
. -NR8Rg in which R8 is a hydrogen or a (Cl-C7)alkyl and Rg is a (C3-C7)cyclo-alkylmethyl or a benzyl; or R8 and Rg, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
. -(CH2)p-NRIoRll in which p is one or two and Rlo and Rll are each independently a hydrogen or a (Cl-C7)alkyl; Rll can also be a (C3-C7)cyclo-alkylmethyl or a benzyl;
. -NRI2CORl3 in which Rl2 is a hydrogen or a (Cl-C7)alkyl and Rl3 is a (C3-C7)-cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; or Rl2 and Rl3 together are a group -(CH2)u- in which u is three or four;
20 . -NRI4COCORls in which Rl4 is a hydrogen or a (C~-C7)alkyl and Rls is a (Cl-C4)alkoxy;
. -(CH2)p-NRI4C(=Wl)Rl6 in which p is one or two, Wl is an oxygen atom or a - sulfur atom, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl6 is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
. -(CH2)m-NRI4COORl7 in which m is zero, one or two, R~4 is a hydrogen or a (C~-C7)alkyl and R~7 is a (Cl-C7)alkyl or a phenyl;
. -(~CH2)m-NRI4SO2Rl8 in which m is zero, one or two, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl8 is a (Cl-C7)alkyl; an amino which is free or substituted byone or two (Cl-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C,-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C,-C7)alkoxy, a carboxyl, a (Cl-C7)alkoxycarbonyl, a (Cl-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (Cl-C7)alkyls, said substituents being identical or different;

~ 52 . -(CH2)m-NRI4C(=Wl)NRlgR20 in which m is zero, one or two, Wl is an oxygen atom or a sulfur atom, R~4 is a hydrogen or a (C~-C7)alkyl and R~9 and R20 are each independently a hydrogen or a (Cl-C7)alkyl; R20 can also be a (C3-C7)-cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (Cl-C4)alkoxy; a benzyl; a S phenyl; or a (Cl-C7)alkyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a (Cl-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (Cl-C7)aLkyls; or Rl9 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
. -(CH2)n-COOR2~ in which n is one and R2l is a hydrogen or a (C~-C7)alkyl;
. -(CH2)n-C(=WI)NRl9R20 in which n is zero or one, Wl is an oxygen atom or a sulfur atom and Rl9 and R20 are each independently a hydrogen or a (Cl-C7)-alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C,-C4)alkoxy; a benzyl; a phenyl; or a (C,-C7)alkyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a (Cl-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C~-C7)alkyls; or Rl9 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, perhydroazepine and piperazine which is unsubstituted or sub-stituted in the 4-position by a (C,-C4)alkyl;
. -CO-NR22-NR23R24 in which R22 is a hydrogen or a (C~-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C~-C7)alkyl;
~N

R /~ S ~R26R27 in which R2s is a hydrogen or a (C I -C7)alkyl and R26 and R27 are each independently a hydrogen or a (C,-C7)alkyl; R27 can also be a formyl or a (Cl-C7)alkylcarbonyl; and ~0 N~ ~iNH ' and their salts, especially pharmaceutically acceptable salts, are particularly preferred.

~ 53 Among these compounds, those of the formula ~CH2, ~H2>~ ICH2 ICH2 ~ (I~b) X lb --'Cl Cl in which:
5 - Xl'lb is a group selected from:
-(CH2)p-NRloRI I in which p is one and Rlo and Rl I are each a hydrogen;
. -(CH2)p-NRI4C(=Wl)Rl6 in which p is one, Wl is an oxygen atom, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl6 is a (Cl-C7)alkyl, preferably an ethyl;
. ~(CH2)m-NRI4COoRl7 in which rn is zero, Rl4 is a hydrogen and Rl7 is a (Cl-C7)aL~yl, preferably an ethyl; and . -(CH2)n-C(=Wl)NRI9R20 in which n is zero, Wl is an oxygen atom and Rlg and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl, preferably pyrrolidine, and their salts, especially pharmaceutically acceptable salts, are more particularly preferred.
Another group of preferred compounds of the invention are those of the formula CH--CH
c\H2 /CH2 (Ic) BC-(CH2)3- IC--CH ,N-CO-A'-Z' Ar' in which:
- Ar' I is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (Cl-C4)alkoxy, a (Cl-C4)-aL~yl, a trifluoromethyl and a methylenedioxy, said substituents being identical or 25 different;
- A' is a direct bond or a group -CH2-;
- Z' is as defined above; and - Bc is a group Blc of the formula J~ N--in which Jlc is a group Ar2a-(CH2)x~cl \

S in which:
- x is zero or one;
- Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (Cl-C4)alkoxy, a (Cl-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being 10 identical or different; and - Xlb is as defined above for a compound of formula (Ib), and their salts, especially pharmaceutically acceptable salts.
Among these compounds, those of the formula CH--CH
C\H2 /CH2 (I'c) f CH2 ~

~-Cl Cl in which:
- B'c is a group B'lC ofthe forrnula A

J'I~N--in which J'lc is a group Ar2a-(CH2)x~cl \
. X'lb in which:
- x is zero or one;
- Ar2a is as defined for a compound of formula (Ic); and - X'lb is a group selected from:

~ 55 . (Cl-C7)aLkyl;
. -(CH2)m-OR4 in which m is one or two and R4 is a hydrogen or a (Cl-C7)alkyl;
. -(CH2)m-OCOR5 in which m is zero and Rs is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl; andm is one or two and Rs is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
. -(CH2)m-OCONH-(GI-C7)alkyl in which m is zero, one or two;
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (C~-C7)alkyl; a formyl; or a (C~-1 0 C7)aL'cylcarbonyl;
. -(CH2)n-SR7 in which n is zero or one and R7 is a hydrogen or a (Cl-C7)alkyl;
. -CH2-S(O)j-(CI-C7)alkyl in which j is one or two;
. -NRgRg in which R8 is a hydrogen or a (Cl-C7)alkyl and Rg is a (C3-C7)cyclo-alkylmethyl or a benzyl; or Rg and Rg, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
. -(CH2)p-NRIoRll in which p is one or two, Rlo is a hydrogen or a (Cl-C7)alkyl and Rl I is a hydrogen, a (Cl -C7)alkyl, a (C3-C7)cycloalkylmethyl or a benzyl;
. -NRI2COR~3 in which Rl2 is a hydrogen or a (Cl-C7)alkyl and Rl3 is a (C3-C7)-cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; or Rl2 and Rl3 together form a group -(CH2)U in which u is three or four;
25 . -NRI4COcORls in which Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl5 is a (Cl-C4)alkoxy;
. -(CH2)p-NRI4C(=Wl)Rl6 in which p is one or two, Wl is an oxygen atom or a sulfur atom, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl6 is a hydrogen; a (Cl-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
. -(CH2)m-NRI4COORl7 in which m is zero, one or two, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl7 is a (Cl-C7)alkyl or a phenyl;
. -(CH2)m-NRI4SO2Rlg in which m is zero, one or two, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rl8 is a (Cl-C7)alkyl; an amino which is free or substituted byone or two (Cl-C7)alkyls; or a phenyl which is unsubstituted or ~ 56 monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C I -C7)alkyl, a trifluoromethyl, a hydroxyl, a (C I -C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (Cl-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (Cl-C7)alkyls, said S substituents being identical or dirrel ellt, . -(CH2)m-NRI4C(=Wl)NRlgR20 in which m is zero, one or two, Wl is an oxygen atom or a sulfur atom, Rl4 is a hydrogen or a (Cl-C7)alkyl and Rlg and R20 are each independently a hydrogen or a (Cl-C7)alkyl; R20 can also be a (C3-C7)-cycloaLkyl; a (C3-C7)cycloaLkylmethyl; a hydroxyl; a (Cl-C4)alkoxy; a benzyl; a phenyl; or a (Cl-C7)alkyl substituted by a hydroxyl, a (Cl-C3)alkoxy, a phenyl, a carboxyl, a (Cl-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (Cl-C7)alkyls; or Rl9 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (Cl-C4)alkyl;
. -(CH2)n-COOR2l in which n is one and R2l is a hydrogen or a (Cl-C7)alkyl;
. -(CH2)n-C(=WI)NRlgR20 in which n is zero or one, Wl is an oxygen atom or a sulfur atom and Rl9 and R20 are each independently a hydrogen or a (Cl-C7)-alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (Cl-C4)alkoxy; a benzyl; a phenyl; or a (Cl-C7)alkyl substituted by a hydroxyl, a (Cl-C3)aL~coxy, a phenyl, a carboxyl, a (Cl-C3)aL~coxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (Cl-C7)alkyls; or Rlg and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thio-morpholine, perhydroazepine and piperazine which is unsubstituted or sub-stituted in the 4-position by a (Cl-C4)alkyl;
. -CO-NR22-NR23R24 in which R22 is a hydrogen or a (Cl-C7)alkyl and R23 and R24 are each independently a hydrogen or a (Cl-C7)alkyl;
\~N

R25/~ S ~R26R27 in which R2s is a hydrogen or a (C I -C7)alkyl and R26 and R27 are each independently a hydrogen or a (Cl-C7)alkyl; R27 can also be a formyl or a (Cl-C7)alkylcarbonyl; and ~ 57 . ~0 N~

and their salts, especially pharmaceutically acceptable salts, are particularly preferred.
The following compounds:
S1 -benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin- 1 -ylcarbonyl)-piperid-1 -yl]propyl]piperidine;
1 -benzoyl-3-(3,4-dichlorophenyl)-3-[3 -(4-piperidinopiperid- 1 -yl)-propyl]piperidine;
1 -benzoyl-3 -(3 ,4-dichlorophenyl)-3 -[3 -(4-carbamoyl-4-piperidinopiperid- 1-10yl)propyl]piperidine;
3-[3-[4-(acryloyl-N-methylamino)-4-phenylpiperid- 1 -yl]propyl- 1 -benzoyl-3-(3,4-dichlorophenyl)piperidine;
3-[3-[4-(2-aminothiazol-4-yl)-4-phenylpiperid- 1 -yl]propyl]- 1 -benzoyl-3-(3,4-dichlorophenyl)piperidine;
153 -[3 -(4-acetyl-4-benzylpiperid- 1 -yl)propyl]- 1 -benzoyl-3 -(3 ,4-dichloro- phenyl)piperidine;
3-[3-[4-(acetylamino)-4-benzylpiperid-1 -yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
1 -benzoyl-3-[3-~4-benzyl-4-(propionylaminomethyl)piperid- 1 -yl]propyl]-3-20(3 ,4-dichlorophenyl)piperidine;
l -benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid- 1 -yl]propyl]-3-(3 ,4-dichlorophenyl)piperidine;
1 -benzoyl-3-[3-[4-benzyl-4-(pyrrolidin- 1 -ylcarbonyl)piperid- 1 -yl]propyl]-3 -(3 ,4-dichlorophenyl)piperidine;
251-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(dimethylaminocarbonyl)-4-phenylpiperid- I -yl]propyl]perhydroazepine;
1 -benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)-4-phenyl-piperid- I -yl]propyl]piperidine;
3 -[3 -[4-(2-acetoxyethoxy)-4-phenylpiperid- 1 -yl]propyl] -1 -benzoyl-3 -(3 ,4-30dichlorophenyl)piperidine;
1 -benzoyl-3 -(3 ,4-dichlorophenyl)-3 -[3 -[4-(2-furoylamino)-4-phenylpiperid-1 -yl]propyl]piperidine;
1 -benzoyl-3-(3 ,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenyl-piperid- 1 -yl]propyl]piperidine;

~ 58 3-(3,4-dichlorophenyl)- 1 -isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin- 1-ylcarbonyl)piperid- 1 -yl]propyl]piperidine;
1 -benzoyl-3-(3,4-dichlorophenyl)-3-[3-spiro(indoline-3,4'-piperid- 1'-yl)propyl]piperidine;
S 1 -benzoyl-3 -(3 ,4-dichlorophenyl)-3 -[3 -[1 -acetylspiro(indoline-3 ,4'-piperid-1 '-yl)]propyl]piperidine;
3-(3 ,4-dichlorophenyl)-3 -[3 -[4-phenyl-4-(pyrrolidin- 1 -ylcarbonyl)piperid-1 -yl]propyl]- 1 -(2-thenoyl)piperidine;
3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin- 1 -ylcarbonyl)piperid-10 1 -yl]propyl]- 1 -(3-thenoyl)piperidine;
3 -(3 ,4-dichlorophenyl)- 1 -(2-furoyl)-3 -[3 -[4-phenyl-4-(pyrrolidin- 1-ylcarbonyl)piperid- 1 -yl]propyl]piperidine;
3-(3,4-dichlorophenyl)- 1 -(3-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin- 1-ylcarbonyl)piperid- 1 -yl]propyl]piperidine;
l S 3-[3-[4-(2-amino- 1,3 ,4-oxadiazol-5-yl)-4-phenylpiperid- 1 -yl]propyl]- 1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
I -benzoyl-3 -(3 ,4-dichlorophenyl)-3 -[3 -[4-(ethoxalylamino)-4-phenyl-piperid- 1 -yl]propyl]piperidine;
1 -benzoyl-3 -(3 ,4-dichlorophenyl)-3 -[3-(4-carbamoyl-4-morpholinopiperid-l-yl)propyl]piperidine;
1 -benzoyl-3-(3,4-dichlorophenyl)-3-[3-[ 1 -(methoxycarbonyl)spiro-(indoline-3 ,4'-piperid- 1 '-yl)]propyl]piperidine;
l-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1 -(N,N-dimethylcarbamoyl)spiro-(indoline-3 ,4'-piperid- 1 '-yl)]propyl]piperidine; and 1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methanesulfonyl)spiro(indoline-3,4'-piperid- 1 '-yl)]propyl]piperidine, in the form of racemates or one of their (+) or (-) enantiomers, and their salts, especially pharmaceutically acceptable salts, are very particularly preferred according to the present invention.
The invention further relates, where they exist, to the solvates of the compounds of the invention and their salts, namely the compounds of formulae (I), (I'), (I--), (I''a), (Ia), (I'a), (I"a), (Ib), (I'b), (I"b), (Ic) and (I'c) and their salts.
The compounds according to the invention are obtained by known methods, particularly those described in patent applications EP-A-474 561 and EP-A-512 901.

~ 59 One of the methods suitable for obtaining the compounds of forrnula (I) and their salts is described below.
According to this method:
1) a compound of the formula s IRl R2 E-O-(CH2)3- IC-CH2-NH (II) Arl in which Ar~, Rl and R2 are as defined for a compound of formula (I) and E is hydrogen or an O-protecting group, is treated:
- either with a halogenated derivative of the formula Hal-CH2-A-Z aII) in which Hal is a halogen atom, preferably bromine, and A and Z are as defined for a compound of formula (I), when it is desired to prepare a compound of formula (I) in which T is a group -CH2-;
- or with a functional derivative of an acid of the formula HO-CO-A-Z . (IIIa) in which A and Z are as defined above, when it is desired to prepare a compound of formula (I) in which T is a group -CO-;
- or with a chloroformate of the formula Cl-COO-A-Z (IIIb) 20 in which A and Z are as defined above, when it is desired to prepare a compound of formula (I) in which T is group -COO-;
- or with an isocyanate of the formula O=C=N-A-Z (IIIc) in which A and Z are as defined above, when it is desired to prepare a compound of 25 formula (I) in which T is a group -CO-NR3- in which R3 is hydrogen;
- or with a carbamoyl chloride of the formula Cl-CO-N-A-Z (IIId) in which A and Z are as defined above and R'3 is a (C~-C4)alkyl, when it is desired to prepare a compound of formula (I) in which T is -CONR3- in which R3 is a (Cl-30 C4)alkyl;
- or with a sulfonyl chloride of the formula Cl-SO2-Z (IIIe) .

in which Z is as defined above, when it is desired to prepare a compound of formula (I) in which -T-A- is a group -SO2-, to give a compound of the formula IR' R2 E-O-(CH2)3-C-CH2-N-T-A-Z (IV) Ar, 2) the O-protecting group, if present, is removed from the compound of formula (IV), by reaction with an acid or a base, to give the alcohol of the formula HO-(CH2)3-CI-CH2-N-T-A-Z (V) Arl o 3) the alcohol (V) is treated with a compound of the formula G-SO2-CI (VI) in which G is a methyl, phcnyl, tolyl or trifluoromethyl group, to give a compound of the formula IR' R2 G-SO2-O-(CH2)3-f-CH2-N-T-A-Z (VII) Ar, 1S4) the compound (VII) is reacted:
- either with a cyclic secondary amine of the formula J~NH (VlIla) in which J', i3:
X', *either a group Ar2-(CH2),~-C, 20 in which Ar2 and x are as defined for (I) and X'l is either Xl as defined for (I), or a precursor of Xl, it being understood that when X'~ contains a hydroxyl group or an amino group, these groups c~n be protected;
* or a group Ar2-CH=C
in which Ar is as defined for (I);

.

* or a group Ar2- ICl-CH-in which Ar2 is as defined for (I);
* or a group Ar2-(~- I H-OH
in which Ar2 is as defined for (I);

* or a group Ar2- ICl -CH-N-O-(CH2)r-Aml in which Ar2, Am~ and r are as defined for (I);
* or a group Ar2-W2-CI H-in which Ar2 and W2 are as defined for (I);
- or with a cyclic secondary amine of the formula J2 NH (VIIIb) in which J2 is as defined above for (I);
- or with a cyclic secondary amine of the formula J3 NH (VIIIc) \
in which J3 is as defined above for (I);
1S- or with a cyclic secondar,v amine of the formula W4~NH (VIIId) in which W4is as defined above for (I);
- or with a cyclic secondary amine of the formula >~\NH (VIIIe) W8 ~--in which W6, W7 and W8 are as defined above for (I);
- or with a cyclic secondary amine of the formula (vIIIf) in which J4 is as defined above for (I);
- or with a compound of the formula Wl3 wl~(c\HN2)f (VIIIg) ~W~Wl6 (CH2)g 5 in which f, g, Wl2, Wl3, Wl4, Wl5 and Wl6 are as defined above for (I);
- or with a cyclic secondary amine of the formula ,N~NH (VIIIh) Wl9 W20 in which Wl7, Wl8, Wlg and W20 are as defined above for (I);
- or with a cyclic secondary amine of the formula Js ~H (VIIIi) in which J5 is as defined above for (I);
- or a cyclic secondary amine of the formula J 6 NH (VIIIj) in which J'6 is a group W2s-C

s X'~
in which W2s is as defined above for (I) and X'l is Xl as defined for (I), or a precursor of Xl, it being understood that when X'l contains a hydroxyl group or an amino group, these groups can be protected; and S) after deprotection of the hydroxyl groups or amino groups, if applopliate, 20 or conversion of X'l to Xl, if applo~liate, the resulting product is optionally converted to one of its salts with a mineral or organic acid.
In one variant of the method:

.

1') the nitrogen atom of the compound of formula (II) is protected to give a compound of the formula Rl 1 2 E-O-(CH2)3- 1 -CH2-N-Pr (XVII) . Arl .
in which Ar~, Rl and R2 are as defined for a compound of formula (I), E is s hydrogen or an O-protecting group and Pr is an N-protecting group such as the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group;
2') the O-protecting group is eventually removed from the compound of formula (XVII), by reaction with an acid or a base, to give the alcohol of the formula Rl R2 HO-(CH2)3-CI-CH2-N-Pr (XVIII) Arl 3') the alcohol (XVm) is treated with a compound of formula (VI) as defined above to give a compound of the formula Rl R2 G-SO2-O-(CH2)3-CI-CH2-N-Pr (XIX) Ar~
4') the compound (XIX) is reacted with a compound of formula (Vma), (Vmb), (Vmc), (Vmd), (Vme), (VIIIf), (Vmg), (Vmh), (Vmi) or (VIIIj) as defined above to give a compound of the formula R~ R2 B-(CH2)3- IC-CH2-N-Pr (XX) Arl in which B is as defined for a compound of formula (I), it being understood thatwhen B contains a hydroxide group or an amino group, these groups can be protected;
S') the protecting group Pr is selectively removed from the compound of formula (XX) to give the compound of the formula .

I ~ ~
B-(CH2)3-C-CH2-NH (XXI) Arl 6') the compound of formula (XXI) is treated with a compound of forrnula (III), (IIIa), (IIIb), (IIIc), (IIId) or (IIIe) as defined above; and 7') after deprotection of the hydroxyl groups or amino groups, if s appropriate, the resulting product is optionally converted to one of its salts with a mineral or organic acid.
More particularly, the compounds of formula (r) and their salts, especially pharmaceutically acceptable salts, are prepared by the variant of the general method described above in which:
1 o 1-) a compound of the formula , CH2, (XlX- ) ~ 1 in which G is a methyl, phenyl, tolyl or trifluoromethyl group and Pr is an N-protecting group such as the trityl, tert-butoxycarbonyl or benzyloxycarbonyl 15 group, is reacted with a compound of the formula J- NH (VIII-) in which J- is as defined for a compound of formula (I-), to give a compound of the forrnula , CH2, (XX- ) B -(CH2)3-l ~ CH /N~Pr [~Cl Cl .

2-) the protecting group Pr is selectively removed from the compound of formula (XX-) to give the compound of the formula , CH2, (XXI-) 3-) the compound of formula (XXr) is treated with a functional derivative 5 of an acid of the formula HO-CO-Z (III ) in which Z- is as defined for a compound of formula (I-); and 4-) after deprotection, if applopliate, the resulting product (r) is optionally converted to one of its salts with a mineral or organic acid.
During any one of the steps for the preparation of the compounds of formula (I) or (r), and more particularly when using compounds of formula (vma), (Vmb), (vmc), (vme), (Vmf), (vmg), (Vmh), (vmi), (vmj) or (VIIr) or intermediates of formula (II), (rV), (XX), (XXI), (XX-) or (XXr), it may be necessary and/or desirable to protect the reactive or sensitive functional groups, 5 such as the amine, hydroxyl or carboxyl groups, present on any one of the molecules in question. This protection can be effected using the conventional protecting groups such as those described in Protective Groups in Organic Chemistry, J.F.W. McOmie, published by Plenum Press, 1973, and in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wutts, published by John 20 Wiley & Sons, 1991. The protecting groups can be removed in an a~lopliate subsequent step by using the methods known to those skilled in the art which do not affect the rest of the molecule in question.
Thus, when E is an O-protecting group, it is selected from the conventional O-protecting groups known to those skilled in the art, for example tetrahydropyran-25 2-yl, benzoyl and a (Cl-C4)alkylcarbonyl.
The O protecting groups which may be used to obtain a compound of formula (I) in which X~ contains a hydroxyl are the conventional O-protecting groups known to those skilled in the art, as defined above for E.

.

The N-protecting groups which may be used to obtain a compound of formula (I) in which Xl contains an amino group are the conventional N-protecting groups known to those skilled in the art, for example the trityl, methoxytrityl, tert-butoxycarbonyl or benzyloxycarbonyl group.
s In step 1) of the method or in step 6') of the variant, when using a halogenated derivative of formula (III), the reaction is carried out in an inertsolvent such as tetrahydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, inthe presence of a base such as potassium tert-butylate, sodium hydride or lithium diisopropylamide, at a temperature between 0~C and 80~C.
In step 1), in step 6') or in step 3-), the functional derivative of the acid (ma) or (m ) used is the acid itself or one of the functional derivatives which react with amines, for example an anhydride, a mixed anhydride, the acid chloride or an activated ester such as the paranitrophenyl ester.
When using the acid of formula (ma) or (m-) itself, the reaction is carried out in the presence of a coupling agent used in peptide chemistry, such as 1,3-dicyclohexylcarbodiimide or benzotriazol- 1 -yloxytris(dimethylamino) phospho-nium hexafluorophosphate, in the presence of a base such as triethylamine or N,N-diisopropylethylamine, in an inert solvent such as dichloromethane or N,N-dimethylformamide, at a temperature between 0~C and room temperature.
When using an acid chloride, the reaction is carried out in an inert solvent such as dichloromethane or benzene, in the presence of a base such as triethylamine or N-methylmorpholine, at a temperature between -60~C and room temperature.
When using a chloroformate of formula (mb), the reaction is carried out in 2s an inert solvent such as dichloromethane, at a temperature between 0~C and room temperature, in the presence of a base such as triethylamine.
When using an isocyanate of formula (mc), the reaction is carried out in an inert solvent such as dichloromethane or benzene, at room temperature.
When using a carbamoyl chloride of formula (md), the reaction is carried out in a solvent such as toluene or 1,2-dichloroethane, at a temperature between0~C and 11 0~C, in the presence of a base such as triethylamine.
When using a sulfonyl chloride of formula (me), the reaction is carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine, at a temperature between -20~C and room temperature.

In step 2) of the method or in step 2') of the variant, the compound of formula (IV) or the compound of formula (XVII) thus obtained is deprotected, if app~ .iate~ by the methods known to those skilled in the art. For example, when E is a tetrahydropyran-2-yl group, the deprotection is effected by acid hydrolysis 5 using hydrochloric acid in a solvent such as ether, methanol or a mixture of these solvents, or using pyridinium p-toluenesulfonate in a solvent such as methanol, or else using an Amberlyst'l9 resin in a solvent such as methanol. The reaction is carried out at a temperature between room temperature and the reflux temperatureof the solvent. When E is a benzoyl group or a (Cl-C4)alkylcarbonyl group, the 0 deprotection is effected by hydrolysis in an ~lk~line medium using, for example, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in an inert solvent such as water, methanol, ethanol, dioxane or a mixt~re of these solvents, at a temperature between 0~C and the reflux temperature of the solvent.
In step 3) of the method or in step 3') of the variant, the reaction of the alcohol of formula (V) or the alcohol of formula (XVm) with a sulfonyl chloride of formula (VI) is carried out in the presence of a base such as triethylamine, pyridine, N,N-diisopropylethylamine or N-methylmorpholine, in an inert solvent such as dichloromethane, benzene or toluene, at a temperature between -20~C and the 20 reflux temperature of the solvent.
In step 4) or in step 4'), the compound (VII) or the compound (XIX) thus obtained is reacted with a compound of formula (Vma), (Vmb), (VIIIc), (Vme), (Vmf), (Vmg), (Vmh), (Vmi) or (Vmj); in step 1-), the compound (XIX-) is reacted with a compound of formula (Vm-). The reaction is carried out in an inert 2s solvent such as N,N-dimethylformamide, acetonitrile, methylene chloride, toluene, isopropanol or a mixture of these solvents, in the presence or absence of a base.
When using a base, it is selected from organic bases such as triethylamine, N,N-diisopropylethylamine and N-methylmorpholine, or from alkali metal carbonates and bicarbonates such as potassium carbonate, sodium carbonate and sodium 30 bicarbonate. In the absence of a base, the reaction is carried out using an excess of the compound of formula (Vma), (Vmb), (Vmc), (Vme), (Vmf), (Vmg), (VIIIh), (Vmi), (Vmjj or (Vm-) and optionally in the presence of an alkali metal iodide such as potassium iodide or sodium iodide. The reaction is carried out at a temperature between room temperature and 1 00~C.

.

In step 5') of the variant or in step 2-), the compound of formula (XX) obtained or the compound of formula (XX-) obtained is deprotected by the methods known to those skilled in the art.
The compounds of formula (I) according to the invention are finally s obtained after deprotection of the hydroxyl groups or amino groups, if appropl iate, or conversion of X' I to Xl, if ~plupliate.
The compounds of formula (I) or (r) are isolated in the form of the free base or a salt by the conventional techniques.
Thus, when the compound of formula (I) or (I-) is obtained in the form of the free base, salification is effected by treatment with the chosen acid in an organic solvent. Treatment of the free base, dissolved for example in an ether such as diethyl ether, in an alcohol such as propan-2-ol, in acetone, in dichloromethane or in ethyl acetate, with a solution of the chosen acid in the same solvent gives the corresponding salt, which is isolated by the conventional techniques.
The hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen-phosphate, methanesulfonate, oxalate, maleate, fumarate, naphthalene-2-sulfonateand benzenesulfonate, for example, are prepared in this way.
When the reaction has ended, the compounds of formula (I) or (I-) can be isolated in the form of one of their salts, for example the hydrochloride; in this case, if necessary, the free base can be prepared by neutralization of said salt with a mineral or organic base such as sodium hydroxide or triethylamine, or with an alkali metal carbonate or bicarbonate such as sodium or potassium carbonate or bicarbonate.
The compounds of formula (~) are obtained by known methods, particularly those described in patent applications EP-A-0 428 434, EP-A-0 474 561 and EP-A-0 512 901.
In particular, a compound of formula (II) in which Rl and R2 together form a group -(CH2)3- and E is a hydrogen can be prepared according to SCHEME 1 below:

.

CH2-CN + 2 CH2=CH-COOCH3 (lX) CN
CH300C-(CH2)2- 1 -(CH2)2-COOCH3 (X) Ar, .

CH2 ~ ,~ o 1 2 1 ( CH3OOC-(cH2)2-cl --CH ' C ~CH2\C~O
1 2 1 (XII) Hooc-(cH2)2-cl --CH ,NH

, CH2, Cl H2 CH2 (II): R, + R2 = -(CH2)3-Ho-(cH2)3-cl --CH ~NH E = H
Arl In step ~, the reaction of a compound of formula (IX) with methyl acrylate, in the presence of a base such as Tritona~' B or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), gives the compound of formula (X). The reaction is carried out in an inert solvent such as 1,4-dioxane or tetrahydrofuran, at a temperature between 60~C and s the reflux temperature of the solvent.
In step ~, the compound of formula (X) is hydrogenated in the presence of a catalyst such as Raney~9 nickel to give the compound of formula (XI). The reaction is carried out in an inert solvent such as an alkanol, preferably ethanol or 2-methoxyethanol, at a temperature bet~,veen room temperature and 60~C and at a I o pressure between atmospheric pressure and 20 bar.
In step 3, the compound of formula (XI) is hydrolyzed in an alkaline medium using, for example, an alkali metal hydroxide such as sodium hydroxide orpotassium hydroxide, in a solvent such as water, methanol or a mixture of these solvents, at a temperature between room temperature and the reflux temperature of 15 the solvent.
The resulting compound of formula (XII) is reduced in step 4 to give the expected compound of formula (II). The reduction is effected by means of a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride or borane in THF, in an inert solvent such as tetrahydrofuran, 1,2-dimethoxyethane or 20 toluene, at a temperature between room temperature and the reflux temperature of the solvent.
In particular, a compound of formula (II) in which Rl and R2 together form a group -(CH2)4- and E is the O-protecting group tetrahydropyran-2-yl (THP) can be prepared according to SCHEME 2 below:

.

Arl-CH2-CN + Br-(CH2)3-COOcH2cH3 base O
CH3CH20C-(CH2)3-CH-CN (XIII) Ar 2' [~
O O-(CH2)3-Br (Cl H2)3-COOCH2CH3 ~ ~-(CH2)3- IC-CN (XIV) Ar 3' (CH2)3-coocH2cH3 O-(cH2)3-c-cH2-NH2 (XV) Ar 4' CH--CH
CH2 C~ (XVI) /~ O-(CH2)3- lC--CH ,NH
Ar' 5' ,CH2--CH2~
CH2 CH2 (II): Rl + R2 = -(CH2)4-~O~(CH2)3~l --CH ,NH E=THP
Arl .

In step 1' of SCHEME 2, a compound of formula (~) is treated with a strong base, such as sodium hydride, lithium diisopropylamide or potassium tert-butylate, to give a carbanion, which is reacted with ethyl 4-bromobutanoate to give the compound of formula (XIII).
s The reaction is carried out in an inert solvent such as an ether (for example tetrahydrofuran or 1,2-dimethoxyethane), an amide (for example N,N-dimethyl-formamide) or an aromatic hydrocarbon (for example toluene or xylene), at a temperature between -70~C and +60~C.
In step ~, the reaction of the compound of formula (Xm) with 2-(3-bromo-lo propoxy)tetrahydropyran, in the presence of a strong base such as sodium hydride, lithium diisopropylamide or potassium tert-butylate, under the operating conditions described in step I ' above, gives the compound of formula (XIV).
The nitrile derivative of formula (XIV) is reduced in step 3' to give the primary amine of formula (XV). The reduction is effected by means of hydrogen, in the presence of a catalyst such as Raney~ nickel, in an inert solvent such as an alkanol, for example methanol, by itself or mixed with a saturated solution of ammonia in the same solvent, at a temperature between room temperature and SO~C.
In step 4', the cyclized compound of formula (XVI) is obtained by renu~ulg a solution of the compound of formula (XV) in an aromatic solvent such as toluene or xylene.
In step 5', the compound of formula (XVI) is reduced to give the expected compound of formula (II). The reduction is effected by means of a reducing agentsuch as lithium aluminum hydride, diisobutylalllminum hydride, sodium borohydride or borane in THF, in an inert solvent such as tetrahydrofuran, diethyl ether, I ,2-dimethoxyethane or toluene, at a temperature between room temperature and the reflux temperature of the solvent.
The compounds of formula (m~, (ma), (mb), (mc), (md), (me) or (m-) are known or are prepared by known methods.
The piperidines of formula (Vma) are known or are prepared by known methods such as those described in EP-A-0 428 434, EP-A-0 474 561, EP-A-0 512 901 and EP-A-0 515 240.
The piperidines of formula (VIIIa) can also be prepared by methods well known to those skilled in the art, such as those described in the following publications:

J. Heterocyclic Chem., 1986, ~, 73 - 75;
J. Chem. Soc., 1950, 1469;
J. Chem. Soc., 1945, 917;
J. Pharm. Sci., 1972, ~, 1316 - 1317;
s J. Org. Chem., 1957, 22, 1484 - 1489;
Chem. Ber., 1975, 108, 3475 - 3482.
The compounds of formula (Vma) are generally prepared in a form protected on the piperidine nitrogen; the compounds of forrnula (Vma) themselvesare obtained after a deprotection step.
Different methods of obtaining the compounds of formula (Vma), in which the different substituents are as defined for formula (I), unless stipulated otherwise, will be indicated below as examples.
For example, when Ar2 is a pyrid-2-yl group, X'~ is hydroxyl and x is zero in a piperidine of formula (Vma), 2-bromopyridine is reacted with N-15 benzylpiperid-4-one in a solvent, in the presence of butyllithium, in order to prepare N-benzyl-4-hydroxy-4-(pyrid-2-yl)piperidine; 4-hydroxy-4-(pyrid-2-yl)piperidine is then obtained by deprotection in a basic medium.
Furthermore, a compound of formula (Vma) in which X'l is a group -(CH2)m-0R4 in which R4 is hydrogen and m is one or two is prepared by reducing 20 a compound of formula (VIIIa) in which X'l is a methoxycarbonyl or, respectively, a methoxycarbonylmethyl by the method described in Chem. Ber., 1975, 108, 3475 -3482.
A compound of formula (Vma) in which X I is a group -(CH2)m-OR4 in which R4 is a (C~-C7)alkyl can also be prepared by alkylating a compound of 2s formula (Vma) in which X'~ is a group -(CH2)m-OH by the methods known to those skilled in the art.
A compound of formula (Vma) in which X', is a group -O-CH2-CH2-OR6 in which R6 is hydrogen can also be prepared by reacting a compound of formula (Vma) in which X'l is a benzoyloxy- with ethylene glycol in the presence of an 30 acid such as sulfuric acid.
The compounds of formula (Vma) in which X'~ is a group -O-CH2CH2-OR6 in which R6 is a (Cl-C7)alkyl are prepared by an identical reaction using a 2-(C, -C7)alkoxyethanol.
The compounds of formula (Vma) in which X'l is a group -O-CH2CH2-35 OR6 in which R6 is a formyl are prepared by reacting formic acid with a compound .

of formula (Vma) in which X'l is a group -O-CH2CH2-OH. The compounds of formula (Vma) in which X'l is a group -O-CH2CH2-OR6 in which R6 is a (Cl-C7)-alkylcarbonyl are prepared by reaction with a C2-C8 acid chloride in the presence of a base such as triethylamine.
s The compounds of formula (Vma) in which X'l is a group -(CH2)n-SR7 or a group -CH2-S(O)j-(CI-C7)alkyl are known or are prepared by known methods such as those described in WO 95/12577.
The compounds of formula (Vma) in which X'l is a group -(CH2)m-OCOR5 (Rs other than hydrogen) are prepared by reacting an acid chloride RsCOCl (Rs lo other than hydrogen) with a compound of formula (Vma) in which X'l is a group-(CH2)m-OH, in the presence of a base such as triethylamine.
The compounds of formula (Vma) in which X'l is a group -(CH2)m-OCORs in which Rs is hydrogen are prepared by reacting formic acid with a compound of formula (VIIIa) in which X'l is a group -(CH2)m-OH.
The compounds of formula (Vma) in which X'l is a group (Cl-C7)alkyl-NHCOO-(CH2)m- are obtained by reacting a carbamoyl chloride, (Cl-C7)alkyl-NHCOCl~ with the compounds of formula (Vma) in which X'l is a group -(CH2)m-OH. The same compounds are prepared by reacting an isocyanate, (Cl-C7)aLkyl-N=C=O, with the compounds of formula (VIIIa) in which X'~ is a group 20 ~(CH2)m~0H.
The compounds of formula (Vma) in which X'l is a hydroxyl and which carry a protecting group on the piperidine nitrogen can undergo a Ritter reaction with acetonitrile in order to prepare the compounds of formula (Vma) in which X'l is an ~cet~mido. The compounds of formula (Vma) in which X', is a group 25 -NRgRg in which R8 and Rg are each hydrogen are then prepared by hydrolysis in an acid medium.
A compound of forrnula (Vma) in which X'~ is a group -NR8Rg in which R8 and Rg are each hydrogen can also be prepared by hydrolyzing in a strong acid medium, for example hydrochloric acid, a compound of formula (Vma) in which 30 X~l is an isocyanato group.
A compound of formula (Vma) in which X'l is a group -NR8R9 in which R8 is hydrogen and Rg is a (Cl-C7)alkyl, or a (C3-C7)cycloalkylmethyl or a benzyl, can be prepared by reducing a compound of formula (Vma) in which X'l is a group -NRI2CORl3 in which Rl2 is hydrogen and R~3 is a hydrogen or a (C~-C6)alkyl or, 35 respectively, a (C3-C7)cycloalkyl or a phenyl. The reaction is carried out by means .

of a reducing agent such as lithium ~ mimlm hydride, in a solvent such as tetra-hydrofuran, at the reflux temperature of the solvent.
The compounds of formula (Vma) in which X' I is a group -NR8R9 in which Rg is a (Cl-C7)alkyl can be prepared by an identical reaction from the compoundss of formula (Vma) in which X'l is a group -NRI2CORl3 in which Rl2 is a (Cl-C7)alkyl.
A compound of formula (Vma) in which X' I is a group -NRgRg in which Rg and Rg, together with the nitrogen atom to which they are bonded, form a hetero-cycle is prepared by applying or adapting Bruylants' reaction (Bull. Soc. Chim.
0 Belges, 1924, ~, 467, and Tetrahedron Letters, 1988, 29 (52), 6827 - 6830).
A compound of formula (Vma) in which X'l is a group -CH2-NRloRIl in which Rlo and Rll are each hydrogen is prepared by reducing a compound of formula (Vma) in which X'l is a cyano. This reduction is effected by the methodswell known to those skilled in the art.
1S A compound of formula (Vma) in which X'l is a group -CH2-CH2-NRIoRll in which Rlo and Rl l are each a hydrogen is prepared from a compound of formula(Vma) in which X'l is a group -CH2-CH2-OH by applying or adapting the method described in J. Med. Chem., 1989, ;~, 391 - 396.
The compounds of formula (Vma) in which X'l is a group -(CH2)p-NRIoRll in which Rlo is a hydrogen or a (Cl-C7)alkyl and Rl~ is a (Cl-C7)alkyl, a (C3-C7)-cycloalkylmethyl or a benzyl can be prepared by reducing a compound of formula (Vma) in which X'l is a group -(CH2)p-NRI4C(=Wl)Rl6 in which Rl4 is a hydrogen or a (Cl-C7)alkyl, Rl6 is a hydrogen, a (Cl-C6)alkyl, a (C3-C7)cycloalkyl or a phenyl and Wl is an oxygen atom.
2s The compounds of formula (Vma) in which X'l is a group -NRI2CORl3 in which Rl2 is a hydrogen or a (Cl-C7)alkyl and Rl3 is hydrogen or respectively a (Cl-C7)alkyl, an optionally substituted (C3-C7)cycloalkyl, a phenyl, a benzyl, avinyl, a pyridyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl are obtained by reacting formic acid in acetic anhydride or, respectively, an ~plopliate acid chloride Rl3COCl, in the presence of a base such as triethylamine, with a compound of formula (VIIIa) in which X'l is a group -NHRI2. In particular, a compound of formula (Vma) in which X'l is a group -NRI2CORl3 in which Rl3 is an ethyl radical can be prepared by hydrogenating, in the presence of a catalystsuch as palladium on charcoal, a compound of formula (Vma) in which X'l is an 3s acryloylamino or acryloyl-N-(CI-C7)alkylamino group.

A compound of formula (Vma) in which X'l is a group -NRI2CORI3 in which Rl2 and Rl3 together are a group -(CH2)3- or -(CH2)4- is prepared by applying or adapting the method described in J. Med. Chem., 1985, ~, 46 - 50.
A compound of formula (Vma) in which X'~ is a group -NRI4COCORls in s which Rls is a (C~-C4)aLIcoxy is prepared by reacting a compound of the formula Cl-COCORls with a compound of formula (VIIIa) in which X'l is a group -NHRI4.
The compounds of formula (Vma) in which X'l is a group -(CH2)p-NRI4c(=wl)Rl6 in which Wl is an oxygen atom, p is 1 or 2, Rl4 is a hydrogen or a(C~-C7)alkyl and Rl6 is a hydrogen or respectively a (Cl-C7)aL~cyl, a phenyl, a 0 benzyl, a pyridyl, an optionally substituted (C3-C7)cycloalkyl, a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl are obtained by reacting formic acid in acetic anhydride or, respectively, an apl~lol)l;ate acid chloride Rl6COCl, in the presence of a base such as triethylamine, with a compound of formula (Vma) in which X'l is a group -CH2-NHRI4 or -CH2-CH2-NHRI4.
s A compound of formula (Vma) in which X' ~ is a group -(cH2)p-NRI4C(=Wl)Rl6 in which Wl is a sulfur atom is obtained from a corresponding compound of formula (Vma) which is protected on the piperidine nitrogen and in which Wl is an oxygen atom by reaction with phosphorus pentasulfide or with Lawesson's reagent, 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-disphosphetane-2,4-20 disulf1de, followed by deprotection of the piperidine nitrogen.
A compound of formula (Vma) in which X' I is a group -(CH2)m~
NRI4COORl7 is prepared by reacting a chloroforrnate of the formula ClCOORI7 with a compound of formula (Vma) in which X'l is a group ~(CH2)m~NHRI4~ in the presence of a base such as triethylamine.
It is also possible to prepare a compound of forrnula (Vma) in which X'l is a group -(CH2)m-NRI4COORl7 in which m = 0 and Rl4 is hydrogen by reacting a compound Rl70H with a compound of formula (VIIIa) in which X'~ is an isocyanato group (-N=C=O).
A compound of formula (Vma) in which X', is an isocyanato group is 30 prepared from a compound of formula (Vma) in which X'l is a carboxyl group by the method described in Organic Synthesis, 51, 48 - 52.
A compound of formula (Vma) in which X', is a group ~(CH2)m~
NR~4SO2RI8 is prepared by reacting a sulfonyl chloride ClSO2RI8 with a compound of formula (Vma) in which X'l is a group -(CH2)m-NHRI4, in the 3s presence of a base such as triethylamine.

Likewise, the compounds of formula (Vma) in which X' I is a group ~(CH2)m-NR~4CONRlgR20 in which Rlg is a hydrogen and R20 is a (C~-C7)alkyl are prepared by reaction with an isocyanate of the formula R20N=C=O in which R20 is a (Cl-C7)aL~yl.
The compounds of formula (Vma) in which X'l is a group ~(CH2)m~
NRI4CONRlgR20 in which Rlg is a (Cl-C7)alkyl are prepared by reaction with a carbamoyl chloride of the formula ClCONRIgR20.
A compound of formula (VIIIa) in which X'l is a group ~(CH2)m~
NRI4CONRl9R20 can also be obtained by reacting a compound HNRIgR20 with a lo compound of formula (Vma) in which X'l is a group ~(CH2)m-NRI4COoRl7 in which Rl7 is a phenyl.
A compound of formula (Vma) in which X' I is a group -(CH2)m-NRI4CONRl9R20 in which m = 0 and Rl4 is hydrogen can also be prepared by reacting a compound NHRIgR20 with a compound of formula (Vma) in which X' 1S is an isocyanato group.
A compound of formula (Vma) in which X' I is a group ~(CH2)m~
NRl4C(=WI)NRlgR20 in which Wl is a sulfur atom is prepared by reacting a compound of formula (Vma), protected on the piperidine nitrogen, in which X'l isa group ~(CH2)m-NRI4CONRl9R2o with phosphorus pentasulfide or with 20 Lawesson's reagent.
A compound of formula (Vma) in which X'l is a group -CONRIgR20 is prepared by reacting a compound of formula (Vma) in which X'l is a carboxyl with a compound of formula HNRI9R20 by the methods well known to those skilled in the art.
Likewise, the compounds of formula (Vma) in which X'l is a group -CH2-CONRI9R20 are prepared by reacting a compound of formula (Vma) in which X' is a group -CH2-COOR2l in which R2l is hydrogen with a compound HNRIsR20.
A compound of formula (Vma) in which X' I is a group (CH2)n~
C(=WI)NRlgR20 in which Wl is a sulfur atom is prepared, by the above-mentioned 30 methods, from a compound of corresponding formula (Vma) in which Wl is an oxygen atom.
A compound of formula (Vma) in which X'l is a carboxyl can be prepared by hydrolyzing a compound of formula (Vma) in which X'l is a cyano by the methods known to those skilled in the art.

.

A compound of formula (Vma) in which X'l is a carboxymethyl can be prepared by the method described in Chem. Ber., 1975, ~, 3475 - 3482.
A compound of formula (Vma) in which X'l is a (Cl-C7)alkoxycarbonyl or a (Cl-C7)aL~oxycarbonylmethyl can be prepared from a compound of formula 5 (Vma) in which X'l is a carboxyl or, respectively, a carboxymethyl by means of an esteri~lcation reaction by the methods well known to those skilled in the art.
In particular, a compound of formula ~Vma) in which Ar2 is an optionally substituted phenyl radical, x is one and X'l is a (C~-C7)alkoxycarbonyl is prepared by reacting a protected 4-(C I -C7)alkoxycarbonylpiperidine with an optionally 10 substituted benzyl halide in the presence of a base such as sodium hydride, potassium tert-butylate or sodium diisopropylamide, in a solvent such as tetra-hydrofuran, N,N-dimethylformamide or dimethyl sulfoxide, at a temperature between -78~C and room temperature. The expected compound of formula (VIIIa) is obtained after a deprotection step.
15 A compound of formula (Vma) in which X'l is a group -CO-NR22-NR23R24 is prepared by reacting a hydrazine HNR22-NR23R24 with a compound of formula (VIIIa) in which X'l is a chloroformyl.
A compound of formula (VIIIa) in which X'l is a group ~N

R25 S ~\NR26R27 in which R26 and R27 are each independently a hydrogen or a (Cl-C7)alkyl is prepared by reacting a compound of formula (VIIIa) in which X'l is a group -CO-fH-R25 Hal in which Hal is a halogen atom, preferably bromine, with a thiourea in which one25 of the amino groups is free or substituted by one or two (Cl-C7)alkyls.
A compound of formula (VIIIa) in which X'l is a group ~N

in which R27 is a formyl or respectively a (Cl-C7)alkylcarbonyl is prepared by reacting formic acid in acetic anhydride or, respectively, an acid chloride (Cl-.

C7)allcyl-COCI, in the presence of a base such as triethylamine, with the above compound of formula (Vma), protected on the piperidine nitrogen, in which R27 ishydrogen. The expected compound is obtained after a deprotection step.
The compound of formula (VIIIa) in which X'l is a group -CO-fH-R2s Hal in which Hal is a bromine atom is obtained by the bromination, by the conventional methods, of a compound of formula (VIIIa) in which X'~ is a group -CO-CH2-R2s.
A compound of formula (VIIIa) in which X'l is a group N~ ~H
N
0 can be prepared by reacting a protected compound of formula (Vma) in which X'l is a carbazoyl group (-CONH-NH2) with cyanogen bromide by the method described in J. Org. Chem., 1961, 26, 88 - 95. The compound of formula (Vma) in which X'l is a carbazoyl group is obtained by reacting hydrazine with a compoundof formula (Vma) in which X'l is a chloroformyl, which is itself obtained by reacting thionyl chloride with a compound of formula (Vma) in which X'l is a carboxyl.
The piperazines of formula (Vmb) are known or are prepared by known methods such as those described in EP-A-0 428 434.
The piperidines of formula (Vmc) are known or are prepared by known 20 methods such as those described in WO 94/10146.
The piperidines of formula (Vmd) are known or are prepared by known methods such as those described in EP-A-0 625 509.
The piperidines of formula (VIl[e) are known or are prepared by known methods such as those described in EP-A-0 630 887.
The piperidines of formula (Vmf) are known or are prepared by known methods such as those described in WO 94/26735.
The compounds of formula (VIIIg) are known or are prepared by known methods such as those described in WO 94/29309.
The piperidines of formula (Vmh) are known or are prepared by known 30 methods such as those described in WO 95/05377.

.

The piperidines of formula (Vmi) are known or are prepared by known methods such as those described in WO 95/12577.
The piperidines of formula (Vmj) are known or are prepared by known methods.
In particular, the piperidines of formula (VIIIj) in which J'6 is a group W2s-C /
X', in which X'l is other than hydrogen and W2s is a (Cl-C7)alkyl or a (C3-C7)cycloalkyl are prepared by the procedures described above for the plepal~lion of the piperidines of formula (VIIIa).
A piperidine of formula (VIIIj) in which J'6 is a group X'l in which W2s is a group -NR79R80 and X'l is a cyano is prepared by means of a Strecker reaction between a l-benzylpiperid-4-one and a compound of the formula NHR7gRgo in the presence of sodium cyanide. The compound of expected formula 5 (Vmj) is obtained after a deprotection step. Hydrolysis of the cyano group in a strong medium by the methods known to those skilled in the art gives the corresponding piperidines of formula (Vmj) in which X'l is a carboxyl. The latter compounds can be used to obtain the corresponding piperidines of formula (Vmj) in which X'l is a (C~-C7)alkoxycarbonyl or a group -CONRl9R20 by the methods 20 known to those skilled in the art, for example by means of esterification or, respectively, by the methods of peptide coupling.
The piperidines of formula (Vm ) are also known or can be prepared by known methods. In particular, when J- is a group of the structure W

the piperidine of formula (Vm-) is prepared by one of the methods described above for the compounds of formula (Vma) in which X'l is a group -CONRIgR20, especially by reacting a carboxylic acid of the formula .

~CNH (VIIIa-) HOOC
with an amine of the formula NHR~9R20.
When J- is a group of the structure R ~ ~ ~

s the piperidine of formula (Vm ) is prepared by methods described in WO 94/29309.
The enantiomers of the compounds according to the invention, of the formula IRl Rl 2 B-(CH2)3-C*-CH2-N-T-A-Z (I*) Ar~
0 in which:
- "*" denotes that the carbon atom carrying this label has the determined (+) or (-) absolute configuration; and - R~, R2, Arl, T, A, Z and B are as defined for the compounds of formula (I), and their salts with mineral or organic acids, are novel compounds which form part S ofthe invention.
The enantiomers of formula (I*) can be isolated by resolution of the racemic mixtures of the compounds of formula (I). It is preferable, however, to resolve the racemic mixtures at the stage of an intermediate which can be used to prepare a compound of formula (I), as described in patent applications EP-A-0 474 561, EP-A-0 512 901, EP-A-0 591 040 and EP-A-0 612 716.
The compounds of formula (I) above also include those in which one or more hydrogen, carbon or iodine atoms have been replaced by their radioactive isotope, for example tritium, carbon 14 or iodine 125. Such labeled compounds are useful in research, metabolic or pharmacokinetic studies and in biochemical assays 2s as receptor ligands.

.

The affinity of the compounds of formula (I) for the tachykinin receptors was evaluated in vitro by means of several biochemical assays using radioligands:
1-) The binding of [l2sI]BH-SP (substance P labeled with iodine 125 using Bolton-Hunter's reagent) to the NKI receptors of rat cortex, guinea-pig ileum and 5 human Iymphoblastic cells.
2-) The binding [l75IlHis-NKA to the NK2 receptors of rat bladder or the binding [12sI]NPy to the NK2 receptors of guinea-pig ileum.
3-) The binding [~Z5I]His[MePhe7]NKg to the NK3 receptors of rat cerebral cortex, guinea-pig cerebral cortex and gerbil cerebral cortex and to the human NK3 o cloned receptors expressed by CHO cells (Buell et al., FEBS Letters, 1992, 299, 90 - 95)-The assays were performed according to X. Emonds-Alt et al. (Eur. J.
Pharmacol., 1993, 250, 403 - 413).
The compounds according to the invention strongly inhibit the binding of 15 [l2sI]His[MePHe7]NKB to the NK3 receptors of guinea-pig and gerbil cerebral cortex and to the human NK3 cloned receptors: the inhibition constant Ki is generally less than 5.10-9 M. For the same compounds, it was found that the inhibition constant (Ki) for the NK3 receptors of rat cerebral cortex is generally greater than 1 o-8 M and that the inhibition constant (Ki) for the NK2 receptor of rat 20 duodenum and the NKI receptors of rat cortex is generally greater than or equal to The compounds according to the present invention were also evaluated in vivo on two animal models.
In the gerbil, a rotational behavior is induced by the intrastriatal 25 ~(1ministration of the specific NK3 receptor agonist senktide; it was found that a unilateral ~tlmini~tration of senktide to gerbil striatum leads to strong contralateral rotations which are inhibited by the compounds according to the invention, lmini~tered either intraperitoneally or orally.
This result shows that the compounds according to the invention pass 30 through the blood-brain barrier and that they are capable of blocking the characteristic action of the NK3 receptors in the central nervous system. They may thus be used for the treatment of any NKB-dependent pathological condition of the central nervous system, such as psychiatric diseases, or any pathological condition mediated by the NK3 receptor in the central nervous system, such as psychosomatic 35 diseases.

.

In the guinea-pig, an intravenous or intracerebroventricular injection of senktide induces hypertension which is suppressed by the oral or intravenous al1ministration of the compounds according to the invention.
This result shows that the compounds according to the invention act on the s cardiovascular system and that they are capable of blocking the characteristic action of the NK3 receptors in said system, especially hypertension (Nakayama etal., Brain Res., 1992, ~2~, 339 - 342; Takano and Kamiya, Asia Pacific J.
Pharmacol., 1991, ~, 341 - 346; Saigo et al., Neuroscience Letters, 1993, 159, 187 -190).
o In the guinea-pig, the inhalation of substance P, for example, induces bronchial hyperreactivity to acetylcholine and hypersensitivity to histamine, for example in the plasmic extravasation. An NK3 antagonist blocks these two characteristic processes of respiratory pathological conditions like asthma.
In these tests, the compounds according to the invention are active at doses varying from 0.1 mg to 30 mg per kg, a-1mini~tered orally, intravenously or intra-peritoneally.
The compounds of the present invention are generally a-1mini~tered in dosage units. Said dosage units are preferably form~ tecl into pharmaceutical compositions in which the active principle is mixed with a ph~rm~ceutical excipient.
According to another of its aspects, the present invention relates to ph~ ceutical compositions cont~ining, as the active principle, a compound of formula (I) or one of its pharmaceutically acceptable salts which has a very high affinity for the human NK3 receptor, said affinity being characterized by an 2s inhibition constant Ki generally of less than 5.10-9 M in ligand binding studies.
The compounds of formula (I) and their ph~rm~ceutically acceptable salts can be used in daily doses of 0.01 to 100 mg per kilogram of body weight of the m~mm~l to be treated, preferably in daily doses of 0.1 to 50 mg/kg. In hllm~n~ the dose can preferably vary from 0.5 to 4000 mg per day, more particularly from 2.5to 1000 mg, depending on the age of the subject to be treated or the type of treatment: prophylactic or curative.
Examples of diseases which can be treated using the compounds and their pharmaceutically acceptable salts are diseases associated with a dysfunction of the dopaminergic systems, such as schizophrenia and Parkinson's disease, diseases associated with a dysfunction of the noradrenergic and serotoninergic systems, .

such as anxiety, vigilance disorders and humor disorders, all forms of epilepticdisease, particularly grand mal, dementia, neurodegenerative diseases, peripheral diseases in which the central nervous system and/or the peripheral nervous system participate via neurokinin B acting as a neurotransmitter or neuromodulator, such 5 as pain, migraine and acute or chronic inflamm~tion, cardiovascular disorders,particularly hypertension, cardiac insufficiency and rhythm disorders, respiratory disorders (asthma, rhiniti~, cough, bronchitis, allergy, hypersensitivity), disorders of the gastrointestinal system, such as esophageal ulcer, colitis, stress-related disorders, irritable bowel syndrome (IE~S) and acidic secretion, emesis/nausea o (following chemotherapy, postoperative, due to travel sickness or due to vestibular disorders), disorders of the urinary system (incontinence, nervous bladder), diseases of the immune system (rheumatoid arthritis) and, more generally, any neurokinin B-dependent pathological condition.
In the pharmaceutical compositions of the present invention for oral, 15 sublingual, inhalational, subcutaneous, intramuscular, intravenous, transdermal, local or rectal ar1mini~tration, the active principles can be a-lmini~tered to ~nim~ls and humans in unit forms of ~-1mini.ctration, mixed with conventional pharma-ceutical carriers. The applopliate unit forms of a~lmini~tration include forms for oral a~1mini~tration, such as tablets, gelatin capsules, powders, granules and 20 solutions or suspensions to be taken orally, forms for sublingual and buccal a~lmini~tration, forms for subcutaneous, intraml-~c~ r~ intravenous, intranasal or intraocular aflmini.ctration and forms for rectal a~lministration.
When a solid composition in the form of tablets is prepared, the main active principle is mixed with a pharmaceutical vehicle such as silica, gelatin, starch, 2s lactose, magnesium stearate, talcum, gum arabic or the like. The tablets can be coated with sucrose various polymers or other applvpliate substances or else they can be treated so as to have a sustained or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the 30 active principle with a diluent, such as a glycol or a glycerol ester, and introducing the mixture obtained into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir can contain the active principle together with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, a flavoring and an appl~,pliate color.

.

8s The water-dispersible granules or powders can contain the active principle mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal ~lmini~tration is effected using suppositories, which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.
Palt;llt~l~l, intranasal or intraocular ~lministration is effected using aqueoussuspensions, isotonic saline solutions or injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
Administration by inhalation is effected using an aerosol which also contains, for example, sorbitan trioleate or oleic acid, as well as trichlorofluoro-methane, dichlorofluoromethane, dichlorotetrafluoroethane or any other biologically compatible propellant gas; it is also possible to use a system cont~ining the active principle, by itself or in association with an excipient, in powder form.
The active principle can also be presented in the form of a complex with a cyclodextrin, for example a-, ~- or y-cyclodextrin, 2-hydroxypropyl-,~-cyclodextrin or methyl-,13-cyclodextrin.
The active principle can also be form~ te~l as microcapsules, with one or more carriers or additives if ~plup~iate.
In each dosage unit, the active principle of formula (I) is present in the amounts commensurate with the daily doses envisaged. In general, each dosage unit is apl)lul!liately adjusted according to the dosage and the intended type of ~lmini~tration~ for example tablets, gelatin capsules and the like, sachets, ampoules, syrups and the like, or drops, so that said dosage unit contains from 0.5 to 1000 mg of active principle, preferably from 2.5 to 250 mg, for ~-lmini~tration one to four times a day.
The above-mentioned compositions can also contain other active products which are useful for the desired therapeutics, such as, for example, bronchodilators, antitussives or ~ntihi~t~mines.
By virtue of their very high affinity for the human NK3 receptor and their high selectivity, the compounds according to the invention may be used in radio-labeled form as laboratory reagents.

.

For example, they make it possible to characterize, identify and locate the human NK3 receptor in tissue sections or the NK3 receptor in the whole animal byautoradiography .
The compounds according to the invention also make it possible to sort or screen molecules as a function of their affinity for the human NK3 receptor. This is carried out by means of a reaction in which the radiolabeled ligand forming the subject of the present invention is displaced from its human NK3 receptor.
The following abbreviations are used in the Preparations and in the Examples:
Me, OMe: methyl, methoxy Et, OEt: ethyl, ethoxy ~tOH: ethanol MeOH: methanol Ether: diethyl ether Iso ether: diisopropyl ether DMF: dimethylforrnamide DMSO: dimethyl sulfoxide DCM: dichloromethane THF: tetrahydrofuran AcOEt: ethyl acetate KzCO3: potassium carbonate Na2CO3: sodium carbonate KHCO3: potassium hydrogencarbonate NaHCO3: sodium hydrogencarbonate 2s NaCl: sodium chloride Na2SO4: sodium sulfate MgSO4: magnesium sulfate NaOH: sodium hydroxide AcOH: acetic acid H2SO4: sulfuric acid HCI: hydrochloric acid Ethereal hydrogen chloride: sa~urated solution of hydrochloric acid in ether .

BOP: benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate KCN: potassium cyanide DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene s NH4Cl: ammonium chloride M.p.: melting point B.p.: boiling point RT: room temperature Silica H: silica gel 60H marketed by Merck (DARMSTADT) NMR: nuclear magnetic resonance o: chemical shift s: singlet bs: broad singlet rs: resolved singlet d: doublet t: triplet qd: quadruplet sept: septuplet mt: multiplet us: unresolved signals PREPARATION 1. 1 4-(Pyrrolidin-l-ylcarbonyl)pipe1idine hydrochloride A) l-tert-Butoxycarbonyl-4-carboxypiperidine 8.6 g of triethylamine and 20 ml of water are added to a solution of 10 g of isonipecotic acid in 100 ml of dioxane and the mixture is heated to 60~C. 20.25 g of di-tert-butyl carbonate are then added dropwise and the mixture is stirred for 1 hour at 60~C and refluxed for 30 minutes. It is concentrated under vacuum, the residue is taken up with water and acidified to pH 3 by the addition of 2 N HCl solution and the precipitate formed is filtered off to give 17 g of the expectedproduct.
B) 1-tert-Butoxycarbonyl-4-(pyrrolidin-1-ylcarbonyl)piperidine 1.32 g of triethylamine, 2.5 g of the compound obtained in the previous step and then 5.31 g of BOP are added to a solution of 0.77 g of pyrrolidine in 20 ml of DCM and the mixture is stirred for l hour at RT. It is concentrated under vacuum, 3s the residue is taken up with water and extracted with ether, the organic phase is .

washed with water, with 10% NaOH solution, with water, with a buffer solution ofpH 2, with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 2.25 g of the expected product.
C) 4-(Pyrrolidin-l-ylcarbonyl)piperidine hydrochloride 20 ml of 6 N HCl solution are added to a solution of 2.25 g of the compound obtained in the previous step in 40 ml of MeOH and the mixture is stirred for 1 hour at RT. The solvent is concentrated under vacuum, the residue is taken up with acetone and the solvent is evaporated off under vacuum to give 1.75 g of the expected product after cryst~ 7~tion from AcOEt.
PREPARATION 1.2 4-Carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride A) 1- E3enzyl-4-cyano-4-(piperid- 1 -yl)piperidine A solution of 5.3 g of sodium cyanide in 20 ml of water is added dropwise at RT to a solution of 18.9 g of 1-benzylpiperid-4-one and 12.16 g of piperidinehydrochloride in 25 ml of MeOH and 25 ml of water and the mixture is stirred for48 hours at RT. The precipitate formed is filtered off, washed with water and dried under vacuum to give 27 g of the expected product.
B) l-Benzyl-4-carbamoyl-4-(piperid-1-yl)piperidine 10 g of the compound obtained in the previous step are added to 50 ml of 95% sulfuric acid and the mixture is heated at 100~C for 45 min~ltes After cooling to RT, the reaction mixture is poured onto 100 g of ice, 250 ml of DCM are added, with cooling, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum. The solid product obtained is recrystallized from 300 ml of anacetonitrile/toluene mixture (65/35; v/v) to give 9.7 g of the expected product,2s m.p.= 150-160~C.
C) 4-Carbamoyl-4-(piperid- l-yl)piperidine dihydrochloride 10 g of ammonium formate and 2.5 g of 5% palladium on charcoal are added to a solution of 9.7 g of the compound obtained in the previous step in 200 ml of MeOH and the mixture is stirred for 2 hours at RT. It is filtered on Célite~9 and the filtrate is evaporated under vacuum. The residue is dissolved in 2 N HClsolution, rendered alkaline to pH 13 by the addition of 40% NaOH solution and extracted with chloroform, the organic phase is dried over MgSO4 and the solventis evaporated off under vacuum. The product obtained is dissolved in an MeOH/
DC~ mixture, acidified to pH 1 by the addition of ethereal hydrogen chloride andevaporated under vacuum to give 5 g of the expected product, m.p. = 1 85~C.

.

PREPARATION 1.3 4-(Acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride A) 1-Benzyl-4-hydroxy-4-phenylpiperidine This compound is prepared by reacting phenyllithium with 1-benzylpiperid-s 4-one by the method described in EP-A-474 561.
B) 4-Acetamido-1-benzyl-4-phenylpiperidine This compound is prepared by reacting acetonitrile with the compound obtained in the previous step by the method described in EP-A-474 561.
C) 4-Amino-1-benzyl-4-phenylpiperidine dihydrochloride A mixture of 50 g of the compound obtained in the previous step, 90 ml of concentrated HCI solution and 210 ml of water is refluxed for 48 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with an EtOH/toluene mixture and the solvents are evaporated off under vacuum. The residue is dissolved in 100 ml of hot MeOH, 500 ml of acetone are added and the mixture is stirred, with cooling in an ice bath. The crystals formed are filtered off, washed with acetone and then with ether and dried to give 48.9 g of the expectedproduct.
D) 1-Benzyl-4-(formylamino)-4-phenylpiperidine 110 ml of acetic anhydride are added dropwise to a solution of 48.9 g of the compound obtained in the previous step and 25 g of sodium formate in 340 ml of formic acid and the reaction mixture is then left to stand overnight at RT, withstirring. It is concentrated under vacuum, the residue is taken up with water, rendered alkaline by the addition of concentrated NaOH solution and extracted with DCM, the organic phase is dried over MgSO4 and the solvent is evaporated 2s off under vacuum to give 38.8 g of the expected product after crystallization from an iso ether/pentane mixture, m.p. = 140~C.
E) 1-Benzyl-4-(methylamino)-4-phenylpiperidine A solution of 38.8 g of the compound obtained in the previous step in 400 ml of THF is added slowly to a suspension of 12.5 g of lithium alllminllm hydride in 100 ml of T~F and the reaction mixture is refluxed for 3 hours. After cooling, a solution of 5 ml of concentrated NaOH in 45 ml of water is added, the inorganic salts are filtered off and the filtrate is concentrated under vacuum to give 38 g of the expected product.

3s .

F) 4-(Acryloyl-N-methylamino)-1-benzyl-4-phenylpiperidine A solution of 1.5 g of the compound obtained in the previous step and 1.5 ml of triethylamine in 40 ml of DCM is cooled to 0 - 5~C, 0.5 ml of acryloyl chloride is added dropwise and the reaction mixture is stirred, the temperature 5 being allowed to rise to RT. It is poured into water, the resulting mixture isdecanted, the organic phase is washed with water and with 2 N NaOH solution and dried over MgSO~ and the solvent is evaporated off under vacuum to give 1.3 g ofthe expected product after cryst~ tion from an ether/pentane mixture.
G) 4-(Acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride A solution of 1.3 g of the compound obtained in the previous step in 30 ml of 1,2-dichloroethane is cooled to 0~C, 0.5 ml of 1-chloroethyl chloroformate isadded dropwise and the reaction mixture is then refluxed for 2 hours. It is concentrated under vacuum and the residue is taken up with 15 ml of MeOH, refluxed for 30 minutes and concentrated under vacuum to give 0.65 g of the expected product after cryst~lli7~tion from AcOEt.
PREPARATION 1.4 4-(2-Aminothiazol-4-yl)-4-phenylpiperidine p-toluenesulfonate monohydrate A) 4-(2-Bromoacetyl)-4-phenylpiperidine hydrobromide 8 g of bromine are added rapidly at RT to a suspension of 11.98 g of 4-acetyl-4-phenylpiperidine hydrochloride in 200 ml of DCM and the reaction mixture is left to stand overnight at RT, with stirring. It is diluted by the addition of 200 ml of ether and the precipitate formed is filtered off and washed with ether to give 17.88 g of the expected product after drying under vacuum.
2s B) 4-(2-Aminothiazol-4-yl)-4-phenylpiperidine p-toluenesulfonate monohydrateA mixture of 7.26 g of the compound obtained in the previous step, 1.52 g of thiourea and 150 ml of EtOII is refluxed for 3 hours. The reaction mixture isconcentrated under vacuum, the residue is taken up with water and rendered aLIcaline to pH 13 by the addition of 10% NaOH solution and the precipitate formed is filtered off and washed with water and then with ether to give 4.46 g of the expected product in the form of the free base after recrystallization from EtOH. l g of the base is dissolved in acetone and 0.73 g of p-toluenesulfonic acid mono-hydrate is added to give 1.5 g of the expected product in the form of crystals, m.p. = 220 - 222~C.
3s .

PREPARATION 1.5 4-Acetyl-4-benzylpiperidine hydrochloride A) 4-Cyanopiperidine 25 g of isonipecotamide (or piperidine-4-carboxamide) are added in small portions to 70 ml of POC13 and the reaction mixture is refluxed for 4 hours. It is concentrated under vacuum, the residue is taken up with ice, rendered alkaline to pH 13 by the addition of concentrated NaOH solution and extracted with DCM and then 4 times with ether, the combined organic phases are dried over MgSO4 and the solvents are evaporated off under vacuum. The oil obtained is distilled unde}
o reduced pressure to give 6.4 g of the expected product, b.p. = 108 - 1 1 0~C under 18 mm of mercury.
B) 4-Cyano-1,4-dibenzylpiperidine A solution of 15 g of the compound obtained in the previous step in 250 ml of THF is cooled to -50~C, 190 ml of a 1.5 M solution of lithium diisopropylamide in cyclohexane are added dropwise and the mixture is stirred for 30 minlltes at -50~C. 34 ml of benzyl bromide are then added and the reaction mixture is stirred, the temperature being allowed to rise to RT. After 3 hours at RT, it is poured into a mixture of ice and concentrated HCl, ether is added and the precipitate formed is filtered off and washed with water. The precipitate is taken up with water, rendered alkaline to pH 13 by the addition of concentrated NaOH solution and extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 31.7 g of the expected product after cryst~lli7~tion from pentane, m.p. = 92~C.
C) 4-Acetyl- 1 ,4-dibenzylpiperidine hydrochloride 2s 55 ml of a 1.6 M solution of methyllithium in ether are added to a solution of 20 g of the compound obtained in the previous step in 400 ml of ether and thereaction mixture is stirred for 3 hours at RT. It is poured into iced water, theresulting mixture is dec~nte~l, the organic phase is dried over MgS04 and the solvent is evaporated off under vacuum. The residue is taken up with 400 ml of water, 40 ml of concentrated HCl are added and the mixture is refluxed for 2 hours.
After one night at RT, the crystalline product formed is filtered off and washedwith a small amount of acetone and then with ether to give 17.6 g of the expected product after drying, m.p. = 246~C.

D) 4-Acetyl-4-benzylpiperidine hydrochloride A mixture of 3 g of the compound obtained in the previous step, 0.3 g of 10% palladium on charcoal, 50 ml of EtOH and 10 ml of water is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate iss evaporated under vacuum to give 1.8 g of the expected product after crystallization from acetone, m.p. = 195~C.
PREPARATION 1.6 4-(Acetylamino)-4-benzylpiperidine p-toluenesulfonate A) 1,4-Dibenzy1-4-carboxypiperidine 0 6 g of the compound obtained in step B of PREPARATION 1.5 are added to a solution of 25 ml of water, 25 ml of concentrated H2SO4 and 25 ml of AcOH
and the reaction mixture is heated at 140~C for 5 hours. After cooling, it is poured onto ice, the pH is brought to 6.5 by the addition of concentrated NaOH solutionand the mixture is stirred until cryst~ tion takes place. The crystalline product 15 is filtered offand washed with water. The product is taken up with MeOH, filtered off and washed with ether to give 3 g of the expected product, m.p. = 262~C.
B) 1,4-Dibenzyl-4-isocyanatopiperidine A mixture of 2 g of the compound obtained in the previous step and 1.6 g of phosphorus pentachloride in 40 ml of chloroform is heated at 60~C for 1 hour.20 The reaction mixture is concentrated under vacuum, the residue is taken up with 40 ml of acetone, a solution of 2 g of sodium azide in 5 ml of water is added and the mixture is stirred for 30 minlltcs at RT. It is concentrated under vacuum at RT, the residue is taken up with ether, the organic phase is washed with saturated Na2CO3 solution and with water and dried over MgSO4 and the solvent is evaporated off 25 under vacuum. The residue is taken up with 40 ml of toluene and refluxed for 1 hour. It is concentrated under vacuum to give 2 g of the expected product in theform of an oil.
C) 4-Amino-1,4-dibenzylpiperidine dihydrochloride A mixture of 1 g of the compound obtained in the previous step and 20 ml 30 of 8 N HCl is refluxed for 45 minutes. It is concentrated under vacuum and the residue is dissolved in the minimum amount of EtOH and poured into ether. The precipitate formed is filtered off, washed with ether and dried to give 1 g of the expected product, m.p. = 199~C (dec.).

.

D) 4-Acetylamino-1,4-dibenzylpiperidine 0.23 ml of acetyl chloride is added to a solution of 1 g of the compound obtained in the previous step and 1.4 ml of triethylamine in 20 ml of DCM and the reaction mixture is stirred for 15 minutes at RT. It is washed with water and with saturated Na2SO4 solution and dried over MgSO4 and the solvent is evaporated offunder vacuum to give 0.75 g of the expected product after cryst~lli7~tion from iso ether, m.p. = 134~C.
E) 4-(Acetylamino)-4-benzylpiperidinep-toluenesulfonate A mixture of 0.746 g of the compound obtained in the previous step, 0.44 g 0 of p-toluenesulfonic acid monohydrate, 0.2 g of 10% palladium on charcoal and 30 ml of EtOH is stirred for 48 hours under a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated under vacuum to give 0.88 g of theexpected product in the form of a foam.
PREPARATION 1.7 s 4-Benzyl-4-cyanopiperidine A) 4-Cyano-1-tritylpiperidine A solution of 6.4 g of the compound obtained in step A of PREPARATION
1.5 in 60 ml of DCM is cooled to 5~C, 10.8 ml of triethylamine are added, 18 g of trityl chloride are then added slowly and the reaction mixture is stirred, the temperature being allowed to rise to RT. It is washed with water and with a buffer solution of pH 2, the organic phase is dried over MgS04 and the solvent is evaporated off under vacuum to give 19 g of the expected product after crystallization from iso ether, m.p. = 206~C.
B) 4-Benzyl-4-cyano- 1-tritylpiperidine A solution of 5 g of the compound obtained in the previous step in 50 ml of THF is cooled to -50~C, 9.5 ml of a 1.5 M solution of lithium diisopropylamide in cyclohexane are added dropwise and the mixture is stirred for 30 minutes at -50~C.
1.7 ml of benzyl bromide are then added and the reaction mixture is stirred for 30 minutes. It is poured into a mixture of ice and a buffer solution of pH 2 and extracted with ether, the extract is washed with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 5.69 g of the expected product after cryst~ ion from iso ether.
C) 4-Benzyl-4-cyanopiperidine A mixture of 5.7 g of the compound obtained in the previous step, 25 ml of 3s formic acid and 25 ml of water is heated at 60~C for 1 hour. After cooling to RT, .

the insoluble material is filtered off and washed with water and the filtrate isevaporated under vacuum. The residue is taken up with water, rendered alk~line to pH 13 by the addition of concentrated NaOH solution and extracted with ether, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuums to give 2.5 g of the expected product.
PREPARATION 1.8 4-Benzyl-4-(ethoxycarbonylamino)piperidine p-toluenesulfonate A) 1 ,4-Dibenzyl-4-(ethoxycarbonylamino)piperidine p-toluenesulfonate A mixture of 1 g of the compound obtained in step B of PREPARATION
0 1.6 and 20 ml of EtOH is refluxed for 24 hours. It is concentrated under vacuum, the oil obtained is dissolved in 5 ml of acetone, 0.55 g of para-toluenesulfonic acid monohydrate is added and ether is then added until cryst~lli7~tion takes place. The crystals formed are filtered off, washed with ether and dried to give 1.38 g of the expected product, m.p. = 154~C.
B) 4-Benzyl-4-(ethoxycarbonylamino)piperidinep-toluenesulfonate A mixture of 1.3 g of the compound obtained in the previous step, 0.15 g of 10% palladium on charcoal and 20 ml of EtOH is stirred for 24 hours under a hydrogen atmosphere. The catalyst is filtered off and the filtrate is concentrated under vacuum to give I g of the expected product in the form of a foam.
PREPARATION 1.9 4-Benzyl-4-(pyrrolidin- 1 -ylcarbonyl)piperidine p-toluenesulfonate A) 1,4-Dibenzyl-4-(pyrrolidin-1-ylcarbonyl)piperidine 0.5 g of pyrrolidine and then 3.8 g of BOP are added to a solution of 2.2 g of the compound obtained in step A of PREPARATION 1.6 and 2.5 ml of triethyl-amine in 50 ml of DCM and the reaction mixture is stirred for 1 hour at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, with 1 N NaOH solution, with water and with saturated NaClsolution and dried over MgSO4 and the solvent is evaporated off under vacuum.
The residue is chromatographed on silica using DCM and then a DCM/MeOH
mixture (90/10; v/v) as the eluent. The product obtained is taken up with an ether/
1 N EICI mixture, the resulting mixture is decanted, the aqueous phase is rendered alkaline to pH 13 by the addition of I N NaOH and extracted with DCM, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuumto give 0.64 g of the expected product after cryst~lli7~tion from iso ether, m.p. =
3s 129~C.

.

B) 4-Benzyl-4-(pyrrolidin- 1 -ylcarbonyl)piperidine p-toluenesulfonate A mixture of 0.64 g of the compound obtained in the previous step, 0.33 g ofp-toluenesulfonic acid monohydrate, 0.1 g of 10% palladium on charcoal and 10 ml of EtOH is hydrogenated at RT and at atmospheric pressure. The catalyst is s filtered off and the filtrate is evaporated under vacuum to give 0.75 g of the expected product in the form of a foam.
PREPARATION 1.10 4-(Acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate A) 4-(Acetyl-N-methylamino)- l-benzyl-4-phenylpiperidine A solution of 30 g of the compound obtained in step E of PREPARATION
1.3 and 16.5 ml of triethylamine in 300 ml of DCM is cooled to 0 - 5~C, 8 ml of acetyl chloride are added dropwise and the reaction mixture is stirred for 30 minutes at RT. It is washed twice with water and with 2 N NaOH solution, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum15 to give 31.6 g of the expected product after cryst~lli7~tion from an iso ether/pentane mixture, m.p. = 104~C.
B) 4-(Acetyl-N-methylamino)-4-phenylpiperidinep-toluenesulfonate A mixture of 5 g of the compound obtained in the previous step, 2.9 g of p-toluenesulfonic acid monohydrate, 0.5 g of 10% palladium on charcoal and 80 ml 20 of EtOH is hydrogenated for 3 hours at 25~C and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum to give 5.7 g of the expected product after cryst~lli7~tion from acetone, m.p. = 165~C.
PREPARATION 1.11 4-Phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine hemihydrate 25 A) l-tert-Butoxycarbonyl-4-carboxy-4-phenylpiperidine 30 ml of water and 32.9 g of K2CO3 are added to a mixture of 30 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate and 300 ml of dioxane, the resulting mixture is then heated to 60~C and 18.2 g of di-tert-butyl dicarbonate are added dropwise. The reaction mixture is subsequently heated for 2 hours at 60~C
30 and then for 30 minutes under reflux. After cooling to RT, it is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with a buffer solutiori of pH 2, acidified to pH 4 by the addition of 2 N HCI, washed with a buffer solution of pH 2, with water and with saturated NaCI solution and driedover MgSO4 and the solvent is evaporated off under vacuum to give 23.7 g of the 3s expected product.

.

B) l-tert-Butoxycarbonyl-4-(pyrrolidin-1-ylcarbonyl)-4-phenylpiperidine 9.29 g of triethylamine and then 3.27 g of pyrrolidine are added to a solution of 14 g of the compound obtained in the previous step in 200 ml of DCM.The mixture is cooled in an ice bath, 22.4 g of BOP are added and the reaction s mixture is stirred, the temperature being allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, three times with 10% NaOH solution, with water, three times with a buffer solution of pH 2, with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 16.4 g of the 0 expected product.
C) 4-Phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine hemihydrate Concentrated HCl solution is added to a solution of 16.4 g of the compound obtained in the previous step in 200 ml of MeOH until the pH is 1, and the reaction mixture is stirred for 5 hours at RT. It is concentrated under vacuum, the residue is 15 taken up with acetone and the solvent is evaporated off under vacuum to give a white solid, which is recrystallized from propan-2-ol. The product obtained is taken up with 10% NaOH solution and extracted with DCM, the organic phase is washed with 10% NaOH solution and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 7 g of the expected20 product after crystallization from ether, m.p. = 1 26~C.
PREPARATION 1.12 4-(N,N-Dimethylaminocarbonyl)-4-phenylpiperidine A) I-tert-Butoxycarbonyl-4-(N,N-dimethylaminocarbonyl)-4-phenylpiperidine 8.1 g of triethylamine and then 4.9 g of dimethylamine hydrochloride are 2s added to a solution of 6.1 I g of the compound obtained in step A of PREPARATION 1.11 in 20 ml of DCM and 20 ml of DMF. The mixture is cooled in an ice bath, 9.73 g of BOP are added and the resulting mixture is stirred for 3 hours, the temperature being allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with 30 water, with a buffer solution of pH 2, with 10% NaOH solution, with water andwith saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 6.45 g of the expected product.
B) 4-(N,N-Dimethylaminocarbonyl)-4-phenylpiperidine Concentrated HCl solution is added to a solution of 6.4 g of the compound 35 obtained in the previous step in 80 ml of MeOH until the pH is 1, and the mixture is stirred for 4 hours at RT. It is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed three times with 10% NaOH
solution and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 3.2 g of the expected product after 5 cryst~lli7 1tion from ether, m.p. = 95~C.
PREPARATION 1.13 4-(2-Hydroxyethoxy)-4-phenylpiperidine hydrochloride A) l-Benzyl-4-hydroxy-4-phenylpiperidine This compound is prepared by reacting phenyllithium with l-benzylpiperid-4-one by the method described in EP-A-474 561.
B) 4-(Benzoyloxy)-l-benzyl-4-phenylpiperidine A solution of 2.67 g of the compound prepared in the previous step and 2.5 ml of triethylamine in 30 ml of DCM is cooled to O - 5~C, 1.22 ml of benzoyl chloride are added and the reaction mixture is stirred for 1 hour, the temperature being allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and with 1 N NaOH
solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 2.4 g of the expected product after cryst~ tion from pentane.
C) l-Benzyl-4-(2-hydroxyethoxy)-4-phenylpiperidine hydrochloride A mixture of 2.3 g of the compound obtained in the previous step, 7 ml of H2SO4 and 60 ml of ethylene glycol is heated at 60~C for S hours. The reaction mixture is poured onto ice, rendered alkaline by the addition of concentrated NH40H solution and extracted with DCM, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DCM and then a DCM/MeOH mixture (96/4, v/v) as the eluent. The product obtained is dissolved in DCM and acidified to pH I by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 1 g of the expected product.
D) 4-(2-Hydroxyethoxy)-4-phenylpiperidine hydrochloride A mixture of 3.3 g of the compound obtained in the previous step, 0.4 g of 10% palladium on charcoal and 100 ml of EtOH is hydrogenated at RT and at atmospheric pressure. The catalyst is filtered off on Célite~ and the filtrate is concentrated under vacuum to give 2.2 g of the expected product, m.p. = 168 -1 72~C.

.

PREPARATION 1.14 4-Amino-4-phenylpiperidine dibenzenesulfonate 26.95 g of the compound obtained in step C of PREPARATION 1.3 are dissolved in 50 ml of water, rendered ~Ik~line to pH 12 by the addition of s concentrated NaOH solution and extracted with DCM, the organic phase is washed with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporatedoff under vacuum. The oil obtained is taken up with 300 ml of EtOH, 25 g of benzenesulfonic acid and 2.2 g of 5% palladium on cha}coal are added and the mixture is then hydrogenated at 40~C and at atmospheric pressure. The catalyst is filtered off on Célite and washed with MeOH and the filtrate is concentrated under vacuum. The residue is taken up with acetone and the precipitate formed is filtered off to give 29.7 g of the expected product, m.p. = 276 - 278~C.
PREPARATION 1.15 4-(2-Amino- 1,3 ,4-oxadiazol-5 -yl)-4-phenylpiperidine p-toluenesulfonate A) l-(Benzyloxycarbonyl)-4-carboxy-4-phenylpiperidine A mixture of 37.7 g of 4-carboxy-4-phenylpiperidine p-toluenesulfonate, 53.3 g of 30% aqueous NaOH solution and 250 ml of water is cooled to 5~C. A
solution of 18 g of benzyl chloroformate in 60 ml of acetone is added rapidly at5~C and the reaction mixture is stirred overnight, the temperature being allowed to rise to RT. It is washed twice with ether and, after decantation, the aqueous phase is acidified to pH 1 by the addition of concentrated HCl and then 2 N HCl. The precipitate formed is filtered off, dried, taken up with ether and filtered off again to give 30.6 g of the expected product, m.p. = 142 - 144~C.
B) l-(Benzyloxycarbonyl)-4-(chloroformyl)-4-phenylpiperidine A mixture of 17.1 g of the compound obtained in the previous step, 24 g of thionyl chloride and 150 ml of 1,2-dichloroethane is refluxed for 1 hour. It is concentrated under vacuum, the residue is taken up with chloroform and the solvent is evaporated off under vacuum. The residue is taken up with an ether/pentane mixture and the solvents are evaporated off again under vacuum to give 20 g of the expected product in the form of a gum, which is used as such.
C) l-(Benzyloxycarbonyl)-4-carbazoyl-4-phenylpiperidine A solution of 16 g of hydrazine monohydrate in 40 ml of EtOH is cooled to -50~C, a solution of 11.44 g of the compound obtained in the previous step in 20ml of 1 ,2-dimethoxyethane is added dropwise and the mixture is stirred, the temperature being allowed to rise to RT. It is concentrated under vacuum, the .

residue is taken up with water and extracted with DCM, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is taken up with an EtOH/
benzene mixture and the solvents are evaporated off under vacuum to give 11.2 g of the expected product in the form of a gum, which is used as such.
D) 4-(2-Amino- 1,3,4-oxadiazol-5-yl)- 1 -(benzyloxycarbonyl)-4-phenylpiperidine A solution of 3.39 g of cyanogen bromide in 10 ml of EtOH is added at RT
to a solution of 11.2 g of the compound obtained in the previous step in 60 ml of EtOH and the reaction mixture is refluxed for 1 hour. It is concentrated to 50 ml of o EtOH and water is then added dropwise until the volume of the reaction mixture is 400 n11. The crystalline product formed is filtered off, washed with water, thenwith DCM, with AcOEt and with ether to give 8 g of the expected product.
E) 4-(2-Amino- 1,3,4-oxadiazol-5-yl)-4-phenylpiperidine p-toluenesulfonate A mixture of 7.85 g of the compound obtained in the previous step, 3.95 g of p-toluenesulfonic acid monohydrate, 0.8 g of 10% palladium on charcoal, 350 ml of 95~ EtOH and 10 ml of water is hydrogenated at 50~C and at atmospheric pressure. After 3 hours, the catalyst is filtered off on CéliteE9 and the filtrate is concentrated under vacuum. The residue is taken up with acetone and the crystalline product formed is filtered off and washed with acetone and then withether to give 7.65 g of the expected product, m.p. = 183 - 185~C.
PREPARATION 1.16 4-Carbamoyl-4-(morpholin-4-yl)piperidine A) l-Benzyl-4-cyano-4-(morpholin-4-yl)piperidine 2.5 ml of morpholine and then 5. I g of Na2S20s are added to a mixture of 5 g of 1-benzylpiperid-4-one and 1.9 g of potassium cyanide in 50 ml of an EtOH/water mixture (50/50; v/v) and the resulting mixture is heated at 60~C for 2 hours. A further 2.5 ml of morpholine are added and the reaction mixture is stirred overnight at RT. Water is added and the crystalline product formed is filtered off to give 5.5 g of the expected product.
B) l-Benzyl-4-carbamoyl-4-(morpholin-4-yl)piperidine A mixture of 14 g of the compound obtained in the previous step and 50 ml of 95% sulfuric acid is heated at 100~C for 2 hours. After cooling to RT, the reaction mixture is poured onto 100 g of ice, the pH is brought to 7 by the addition of concentrated NH40H solution, the mixture is extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated .

off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (100/5; v/v to 100/10; v/v) as the eluent to give 3.4 g of the expected product after cryst~ tion from iso ether.
C) 4-Carbamoyl-4-(morpholin-4-yl)piperidine 3.1 g of ammonium formate and 0.8 g of 5% palladium on charcoal are added to a solution of 3.4 g of the compound obtained in the previous step in 50 ml of MeOH and the mixture is stirred for 2 hours at RT. The catalyst is filtered off on Célite~9 and the filtrate is evaporated under vacuum to give 2.2 g of the expected product after cry~t~lli7~tion from propan-2-ol.
PREPARATIONS 1.17 to 1.21 The following are obtained by carrying out the procedure described in PREPARATION 1.16 and replacing the morpholine in step A with thiomorpholine, azetidine, pyrrolidine, perhydroazepine, di-n-heptylamine and di-n-butylamine:
- 4-carbamoyl-4-(thiomorpholin-4-yl)piperidine (1.17);
- 4-carbamoyl-4-(azetidin-1-yl)piperidine (1.18);
- 4-carbamoyl-4-(perhydroazepin-1-yl)piperidine (1.19);
- 4-carbamoyl-4-(di-n-heptylamino)piperidine (1.20);
- 4-carbamoyl-4-(di-n-butylamino)piperidine (1.21).
PREPARATIONS 1.22 to 1.26 The following are obtained by carrying out the procedure described in PREPARATION 1.9, starting from the 1,4-dibenzyl-4-carboxypiperidine obtained in step A of PREPARATION 1.6 and replacing the pyrrolidine with azetidine, piperidine, morpholine, perhydroazepine and 1-methylpiperazine:
- 4-benzyl-4-(azetidin-1-ylcarbonyl)piperidine p-toluenesulfonate (1.22);
- 4-benzyl-4-(piperidin-1-ylcarbonyl)piperidine p-toluenesulfonate (1.23);
- 4-benzyl-4-(morpholin-4-ylcarbonyl)piperidine p-toluenesulfonate (1.24);
- 4-benzyl-4-(perhydroazepin- 1 -ylcarbonyl)piperidine p-toluenesulfonate (1.25);
- 4-benzyl-4-(4-methylpiperazin-1-ylcarbonyl)piperidine p-toluenesulfonate (1-26)-PREPARATIONS 1.27 to 1.31 The following are obtained by carrying out the procedure described in PREPARATION 1.11, steps B and C, and replacing the pyrrolidine in step B with azetidine, piperidine, morpholine, perhydroazepine and 1-methylpiperazine:
3s - 4-(azetidin-1-ylcarbonyl)-4-phenylpiperidine (1.27);

.

- 4-(piperidin-1-ylcarbonyl)-4-phenylpiperidine (1.28);
- 4-(morpholin-4-ylcarbonyl)-4-phenylpiperidine (1.29);
- 4-(perhydroazepin-1-ylcarbonyl)-4-phenylpiperidine (1.30);
- 4-(4-methylpiperazin-1-ylcarbonyl)-4-phenylpiperidine (1.31).
s PREPARATION 1.32 4-(N-Methylcarbamoyl)-4-phenylpiperidine A) l-tert-Butoxycarbonyl-4-(N-methylcarbamoyl)-4-phenylpiperidine 1.98 g of triethylamine and then 0.49 g of methylamine hydrochloride are added to a solution of 1.5 g of the compound obtained in step A of PREPARATION 1.1 1 in 5 ml of DCM and S ml of DMF. The mixture is cooled in an ice bath, 2.39 g of BOP are added and the reaction mixture is stirred for 24 hours, the temperature being allowed to rise to RT. It is concentrated under vacuum and the residue is extracted with ether, washed with water and with saturated NaCl solution, dried over MgSO4 and evaporated under vacuum to give ls 1.4 g of the expected product.
B) 4-(N-Methylcarbamoyl)-4-phenylpiperidine 4 ml of concentrated HCl are added to a solution of 1.4 g of the compound obtained in the previous step in 30 ml of MeOH and the mixture is stirred for 1 hour at RT. It is concentrated under vacuum, the residue is extracted with DCM, washed with water and twice with 10% NaOH solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 0.6 g of the expected product.
-PREPARATION 1.33 4-(N-n-Butylcarbamoyl)-4-phenylpiperidine A) I-tert-Butoxycarbonyl-4-(N-n-butylcarbamoyl)-4-phenylpiperidine 2s This compound is prepared by the procedure described in step A of PREPARATION 1.32, starting from 1.0 g of the compound obtained in step A of PREPARATION 1.1 1 and 0.24 g of n-butylamine. This gives 1.3 g of the expected product, which is used as such in the next step.
B) 4-(N-n-Butylcarbamoyl)-4-phenylpiperidine This compound is prepared by the procedure described in step B of PREPARATION 1.32. This gives 0.4 g of the expected product.
PREPARATION 1.34 4-(N,N-Diethylcarbamoyl)-4-phenylpiperidine trifluoroacetate A) I-tert-Butoxycarbonyl-4-(N,N-diethylcarbamoyl)-4-phenylpiperidine This compound is prepared by the procedure described in step A of PREPARATION 1.32, starting from 1.5 g of the compound obtained in step A of PREPARATION 1.1 1 and 0.8 g of diethylamine hydrochloride. This gives 1.7 g of the expected product.
s B) 4-(N,N-Diethylcarbamoyl)-4-phenylpiperidine trifluoroacetate 1.7 g of the compound obtained in the previous step are dissolved in 20 ml of trifluoroacetic acid and the solution is stirred at RT for 30 minutes. It is concentrated under vacuum, the residue is taken up with ether and the mixture isevaporated under vacuum to give 2.8 g of the expected product in the form of an 0 oil.
PREPARATION 1.35 4-Carbamoyl-4-phenylpiperidine A) l-tert-Butoxycarbonyl-4-carbamoyl-4-phenylpiperidine A solution of 1.5 g of the compound obtained in step A of PREPARATION
1.11, 0.99 g of triethylamine and 2.39 g of BOP in 10 ml of DCM is cooled to -20~C and ammonia gas is then bubbled into the solution. The temperature is allowed to rise to RT and the reaction mixture is stirred for 2 hours. It is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed with water, with a buffer solution of pH 2, with water, with 10% NaOH
20 solution, with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 1.32 g of the expected product.
B) 4-Carbamoyl-4-phenylpiperidine This compound is prepared by the procedure described in step B of PREPARATION 1.32, starting from 1.32 g of the compound obtained in the 2s previous step. This gives 0.41 g of the expected product.
PREPARATION 1.36 4-(N-Isopropylcarbamoyl)-4-phenylpiperidine A) l-tert-Butoxycarbonyl-4-(N-isopropylcarbamoyl)-4-phenylpiperidine This compound is prepared by the procedure described in step A of 30 PREPARATION 1.32, starting from 1.5 g of the compound obtained in step A of PREPARATION 1.11 and 0.29 g of isopropylamine. This gives 1.61 g of the expected product.
B) 4-(N-Isopropylcarbamoyl)-4-phenylpiperidine .

This compound is prepared by the procedure described in step B of PREPARATION 1.32, starting from 1.61 g of the compound obtained in the previous step. This gives 1.1 g of the expected product.
PREPARATION 2.1 s 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidine hydrochloride A) M ethyl 4-cyano-4-(3,4-dichlorophenyl)heptanedioate In a three-necked flask, 37.2 g of 3,4-dichlorophenylacetonitrile and 34.43 g of methyl acrylate are dissolved in 20 ml of dioxane; 1 ml of DBU is added and the mixture is heated for 2 hours at 60~C, evaporated, diluted with 400 ml of ethyl acetate, then washed with dilute HCl and NaCI solution, dried over MgSO4 and evaporated. The expected product is cryst~lli7e~1 from 100 ml of ethyl acetate and 100 ml of ether with 100 ml of heptane to give 47 g of product.
B) Methyl 3-[5-(3,4-dichlorophenyl)-2-oxopiperid-5-yl]propionate 40 g of the compound prepared in step A are dissolved in 500 ml of 2-lS methoxyethanol, 2 g of Raney nickel are added and the mixture is hydrogenated at 40~C under atmospheric pressure for 3 days. It is filtered and evaporated to give the expected product in the form of an oil (39 g).
C) 3-[5-(3,4-Dichlorophenyl)-2-oxopiperid-5-yl]propanoic acid 17 g of the compound prepared in the previous step are dissolved in 250 ml of methanol, 2.8 g of potassium hydroxide and 10 ml of water are added and the mixture is then refluxed for 2 hours. It is evaporated to dryness and the oil obtained is taken up with 200 ml of water and washed with 100 ml of ethyl acetate.
The aqueous phase is acidified with 30% HCI solution and the precipitate formed is then filtered off and dried. It is recrystallized from hot methanol to give 18.3 g 2s of the expected compound.
D) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidine hydrochloride 5 g of the compound obtained in the previous step are dissolved in 20 ml of THF, 75 ml of borane (concentration: I M in THF) are added and the mixture is refluxed for 24 hours under nitrogen. 25 ml of methanol and 50 ml of 4 N HCl areadded, the mixture is stirred for 30 minutes and 40% sodium hydroxide is then added until the pH exceeds 10. The mixture is extracted 3 times with 150 ml of DCM and the organic phase is dried over MgSO4 and evaporated. The residue is dissolved in DCM with a 4 N solution of HCI in ether. After evaporation, a foam is obtained and the expected product (4.5 g) crystallizes from an AcOEt/ether mixture.

.

PREPARATION 2.2 3 -(3 ,4-Dichlorophenyl)-3-[3-tetrahydropyran-2-yloxy)propyl]perhydro-azepine A) Ethyl 5-cyano-5-(3,4-dichlorophenyl)pentanoate s 11.8 g of a 55% dispersion of sodium hydride in oil are suspended in 100ml of THF and cooled in an ice bath, a solution of 50 g of 3,4-dichlorophenylaceto-nitrile in 50 ml of THF is added dropwise and the reaction mixture is stirred for 3 hours at RT. It is cooled again in an ice bath, a solution of 52.4 g of ethyl 4-bromobutanoate in 50 ml of THF is added dropwise and the ~ sLul~ iS stirred 0 overnight at RT. It is concenkated under vacuum, the residue is taken up withwater and extracted with ether, the organic phase is washed with water, with a buffer solution of pH 2, with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture (100/5;1S v/v) as the eluent to give 36.9 g of the expected product.
B) Ethyl 5-cyano-5-(3,4-dichlorophenyl)-8-(tetrahydropyran-2-yloxy)octanoate 5 g of a 55% dispersion of sodium hydride in oil are suspended in 100 ml of DMF and cooled to -20~C, a solution of 25.4 g of 2-(3-bromopropoxy)tetrahydro-pyran and 34.2 g of the compound obtained in the previous step in 100 ml of DMF
is added dropwise and the reaction mixture is stirred overnight at RT. It is concentrated under vacuum, the residue is taken up with a mixture of water and abuffer solution of pH 4 and extracted with AcOEt, the organic phase is washed with a buffer solution of pH 4, with water and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using toluene and then a toluene/AcOEt mixture ( 100/10; v/v) as the eluent to give 36 g of the expected product.
C) Ethyl S-(aminomethyl)-5-(3,4-dichlorophenyl)-8-(tetrahydropyran-2-yloxy)-octanoate 30 ml of a saturated solution of ammonia in MeOH and 2 g of Raney~' nickel are added to a solution of 16.7 g of the compound obtained in the previous step in 200 ml of MeOH and the mixture is then hydrogenated at 40~C and at atmospheric pressure. The catalyst is filtered off on CéliteE9 and the filtrate is concentrated under vacuum. The residue is extracted with ether, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and 3s the solvent is evaporated offunder vacuum to give 15.1 g of the expected product.

.

D) 6-(3,4-Dichlorophenyl)-6-[3-(tetrahydropyran-2-yloxy)propyl]perhydroazepin-2-one A solution of 15.1 g of the compound obtained in the previous step in 150 ml of xylene is refluxed for 48 hours. After cooling to RT, the reaction mixture is s concentrated under vacuum to give 13.5 g ofthe expected product.
E) 3-(3,4-Dichlorophenyl)-3-[3-tetrahydropyran-2-yloxy)propyl]perhydroazepine A solution of 14 g of the compound obtained in the previous step in 200 ml of THF is added dropwise to a suspension of 4 g of lithium alllminl-m hydride in100 ml of THF and the mixture is then refluxed for 2 hours. After cooling to RT,4 ml of water, 12 ml of 10% NaOH solution and 4 ml of water are added in succession. The inorganic salts are filtered off on Célite~9 and the filtrate isconcentrated under vacuum. The residue is extracted with DCM, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 13 g of the expected product.

1 -Benzoyl-3-(3 ,4-dichlorophenyl)-3-[3 -[4-(pyrrolidin- 1 -ylcarbonyl)piperid-l-yl]propyl]piperidine hydrochloride 1.5 hydrate A) l-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine A solution of 16.22 g of the compound obtained in PREPARATION 2.1 and 18.2 g of triethylamine in 250 ml of DCM is cooled in an ice bath and a solution of 14.06 g of benzoyl chloride in 10 ml of DCM is added dropwise. The mixture is stirred for 1 hour, the temperature being allowed to rise to RT. The excess benzoyl chloride is removed by the addition of MeOH and the reaction mixture is then concentrated under vacuum. The residue is taken up with MeOH
and the solvent is evaporated off under vacuum. The residue is extracted with ether, washed with water, with 2 N HCl solution, with 5% NaHCO3 solution and with saturated NaCl solution, dried over MgSO4 and evaporated under vacuum.
The l-benzoyl-3-(3,4-dichlorophenyl)-3-(3-benzoyloxypropyl)piperidine thus obtained as an intermediate is dissolved in 150 ml of MeOH, 10% NaOH solution is added and the mixture is heated for 1 hour at 50 - 60~C and concentrated under vacuum. The residue is extracted with ether, washed with water, with 2 N HCl solution, with 5% NaHCO3 solution and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 18 g of the expected product in the form of an oil.

.

B) 1 Benzoyl-3-(3,4-dichlorophenyl)-3-[3-methanesulfonyloxy)propyl]piperidine A solution of 16.8 g of the compound obtained in the previous step and 5.18 g of triethylamine in 100 ml of DCM is cooled in an ice bath, a solution of5.40 g of methanesulfonyl chloride in 10 ml of DCM is added dropwise and the 5 mixture is then stirred for 30 minutes, the temperature being allowed to rise to RT.
It is concentrated under vacuum, the residue is extracted with AcOEt, washed with water, with 2 N HCl solution and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 19.6 g of the expected product in the form of an oil.
Proton NMR spectrum at 200 MHz in DMSO-d6 1 to 2.35 ppm: us: 8H
3.15 ppm: s: 3H
3.2 to 4.6 ppm: us: 6H
6.8to7.8ppm:us: 8H
C) l-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine hydrochloride 1.5 hydrate 0.56 g of 4-(pyrrolidin-1-ylcarbonyl)piperidine hydrochloride is dissolved in water, the solution is rendered alkaline by the addition of 10% NaOH solutionand extracted with DCM, the organic phase is washed with saturated NaCl solution20 and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is taken up with 5 ml of DMF and 5 ml of acetonitrile, 1 g of the compound obtained in the previous step and then 0.88 g of K2CO3 are added and the reaction mixture is heated at 100~C for 4 hours. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is 2s washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silicaH using DCM and then a DCM/MeOH mixture (95/5; v/v) as the eluent. The product obtained is taken up with AcOEt and acidified by the addition of ethereal hydrogen chloride and the precipitate forrned is filtered off to give 0.8 g of the 30 expected product, m.p. = 146~C.

1 -Benzoyl-3 -(3 ,4-dichlorophenyl)-3-[3-(4-piperidinopiperid- 1 -yl)propyl]-piperidine dihydrochloride hemihydrate A mixture of 0.55 g of 4-piperidinopiperidine, 1.3 g of the compound obtained in step B of EXAMPLE 1 and 1.14 g of K2CO3 in 10 ml of a DMF/

.

acetonitrile mixture (50/50; v/v) is heated at 100~C for 3 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washcd twice with water and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed s on silica H using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent.
The product obtained is dissolved in AcOEt, a stream of HCl gas is bubbled into the solution until the pH is 1, and ether is added until precipitation occurs. This gives 0.53 g of the expected product after filtration and drying, m.p. = 265~C
(dec.).

1 -Benzoyl-3 -(3 ,4-dichlorophenyl)-[3 -[4-carbamoyl-4-(piperid- 1 -yl)piperid-l-yl]propyl]piperidine dihydrochloride 1.5 hydrate 2.6 g of 4-carbamoyl-4-(piperid-1-yl)piperidine dihydrochloride are dis-solved in water, the solution is rendered alkaline by the addition of concentrated NaOH solution and extracted with DCM, the extract is dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is taken up with 10 ml of acetonitrile, 1.55 g of the compound obtained in step B of EXAMPLE l are added and the reaction mixture is refluxed for 2 hours. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, with 1 N NaOH solution and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a gradient of a DCM/MeOH mixture (99/l; v/v to 93/7; vlv) as the eluent. The product obtained is taken up with DCM and acidif1ed by the addition of ethereal hydrogen chloride and the mixture is evaporated under vacuum to give2 g of the expected product, m.p. = 210~C.

3-[3 -[4-(Acryloyl-N-methylamino)-4-phenylpiperid- 1 -yl]propyl]- 1 -benzoyl-3-(3,4-dichlorophenyl)piperidine hydrochloride A mixture of 0.27 g of 4-(acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride, 0.45 g of the compound obtained in step B of EXAMPLE 1 and 0.3 g of K2CO3 in 3 ml of DMF is heated at 80~C for 2 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica3s using a gradient of a DCM/MeOH mixture (99/1; v/v to 95/5; v/v) as the eluent.

The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.2 g of the expected product, m.p. = 128~C.

3-[3-[4-(2-Aminothiazol-4-yl)-4-phenylpiperid- 1 -yl]propyl]- 1 -benzoyl-3-(3,4-dichlorophenyl)piperidine dihydrochloride monohydrate A mixture of 1.04 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4 in the form of the free base), 1.88 g of the compound obtained in step B of EXAMPLE 1 and 1.1 g of K2CO3 in 20 ml of a 10 DMF/acetonitrile mixture (50/50; v/v) is refluxed for 2 hours. The reaction mixture is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a gradient of a DCM/MeOH mixture (98/2; v/v to 95/5; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product after crystallization from AcOEt, m.p. = 162 - 164~C.

3-[3-(4-Acetyl-4-benzylpiperid- 1 -yl)propyl]- l-benzoyl-3-(3,4-dichloro-20 phenyl)piperidine hydrochloride hemihydrate 1.2 g of 4-acetyl-4-benzylpiperidine hydrochloride are dissolved in the minimum amount of water, the solution is rendered alkaline to pH 13 by the addition of concentrated NaOH solution and extracted with ether and the organic phase is dried over MgSO4 and filtered. 1 g of the compound obtained in step B of 25 EXAMPLE 1 is added to the filtrate and the mixture is concentrated under vacuum.
The residue is taken up with 5 ml of DMF and heated at 70~C for 3 hours. The reaction mixture is poured into iced water and extracted with ether, the organicphase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is 30 chromatographed on silica H using DCM and then a DCM/MeOH mixture (95/5;
v/v) as the eluent. The product obtained is taken up with DCM and acidified to pH
1 by the addition of ethereal hydrogen chloride and the mixture is evaporated under vacuum to give 0.84 g of the expected product after crystallization from iso ether.
Proton NMR spectrum at 200 MHz in DMSO-d6 .

0.9to2.4ppm:us: 15H
2.5 to 4.6 ppm: us: 12H
6.8to7.9ppm:us: 13H
9.9to 10.6ppm:2bs: lH
s EXAMPLE 7 3-[3-[4-(Acetylamino)-4-benzylpiperid- 1 -yl]propyl]- 1 -benzoyl-3-(3 ,4-dichlorophenyl)piperidine hydrochloride dihydrate A mixture of 0.44 g of 4-(acetylamino)-4-benzylpiperidine p-toluene-sulfonate, 0.50 g of the compound obtained in step B of EXAMPLE 1 and 0.53 g lo of K2CO3 in 5 ml of DMF is heated at 90~C for 2 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with 2 NNaOH and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a gradient of a DCM/MeOH mixture (99/1; v/v to 93/7; v/v) as the eluent. The 15 product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.38 g of the expected product, m.p. = 158~C (dec.).

1 -Benzoyl-3-[3 -(4-benzyl-4-cyanopiperid- 1 -yl)propyl]-3-(3 ,4-dichloro-20 phenyl)piperidine hydrochloride monohydrate This compound is prepared by the procedure described in EXAMPLE 4,starting from 2.5 g of 4-benzyl-4-cyanopiperidine, 5 g of the compound obtained in step B of EXAMPLE 1, 3.7 g of K2CO3 and 50 ml of DMF. The product obtained is chromatographed on silica H using DCM and then a DCM/MeOH mixture (97/3;
25 v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the solvent is evaporated off under vacuum to give 2.8 g of the expected product after cryst~lli7~ion from iso ether.

3-[3-[4-(Aminomethyl)-4-benzylpiperid-l-yl]propyl]-l-benzoyl-3-(3,4-30 dichlorophenyl)piperidine dihydrochloride hemihydrate A mixture of2.3 g of the compound obtained in EXAMPLE 8 and 0.3 g ofRaney~ nickei in 100 ml of EtOH is hydrogenated for 72 hours at RT and at atmospheric pressure. The catalyst is filtered off and the filtrate is concentrated under vacuum. The residue is chromatographed on silica H using DCM and then a 3s DCM/MeOH mixture (85/lS; v/v) as the eluent. The product obtained is taken up .

with ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.08 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 0.8to2.3ppm:us: 12H
s 2.6 to 4.5 ppm: us: 14H
6.9to8.0ppm:us: 13H
8.4 ppm: bs: 3H

1 -Benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid- 1 -yl]propyl]-3-0 (3,4-dichlorophenyl)piperidine hydrochloride A solution of 0.6 g of the compound obtained in EXAMPLE 9 and 0.18 ml of triethylamine in 10 ml of DCM is cooled to 0~C, 0.1 ml of propionyl chloride is added dropwise and the mixture is stirred for 5 minutes. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed twice with water and dried over MgSO4 and the solvent is evaporated off under vacuum.
The residue is chromatographed on silica H using DCM and then a DCM/MeOH
mixture (95/5; v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.37 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 0.7to2.3ppm:us: 17H
2.55to4.5ppm:us: 14H
6.8to8.0ppm:us: 14H
9.0 to 10 ppm: 2 bs: lH
2s EXAMPLE 11 1 -Benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid- 1 -yl]propyl]-3-(3,4-dichlorophenyl)piperidine hydrochloride hemihydrate This compound is prepared by the procedure described in EXAMPLE 7, starting from 0.5 g of 4-benzyl-4-(ethoxycarbonylamino)piperidine p-toluene-sulfonate, 0.5 g of the compound obtained in step B of EXAMPLE 1 and 0.52 g of K2CO3 in 5 ml of DMF. This gives 0.32 g of the expected product, m.p. = 142~C
(dec.).

.

~XAMPLE 12 1 -Benzoyl-3-[3-[4-benzyl-4-(pyrrolidin- 1 -ylcarbonyl)piperid- 1 -yl]propyl]-3-(3,4-dichlorophenyl)piperidine hydrochloride hemihydrate A mixture of 4-benzyl-4-(pyrrolidin- 1 -ylcarbonyl)piperidine p-toluene-S sulfonate, 0.65 g of the compound obtained in step B of EXAMPLE 1 and 0.7 g of K2CO3 in 6 ml of DMF is heated at 80~C for 3 hours. The reaction mixture is poured into iced water and the precipitate formed is filtered off and washed with water. The precipitate is dissolved in AcOEt, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (95/5;
v/v) as the eluent. The product obtained is taken up with ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.56 g of the expected product.
Proton NMR spectrum at 200 MHz in DMSO-d6 0.9to2.45ppm:us: 16H
2.5 to 4.6 ppm: us: 16H
6.8to7.8ppm:us: 13H
9.9tolO.6ppm:rs: lH

3-[3-[4-(Acetyl-N-methylamino)-4-phenylpiperid- 1 -yl]propyl]- 1 -benzoyl-3-(3,4-dichlorophenyl)perhydroazepine hydrochloride 0.3 hydrate A) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-(tetrahydropyran-2-yloxy)propyl]-perhydroazepine A solution of 13 g of the compound obtained in PREPARATION 2.2 and 2s 6.8 g of triethylamine in 200 ml of DCM is cooled in an ice bath, a solution of 4.96 g of benzoyl chloride in 30 ml of DCM is added dropwise and the reaction mixture is stirred for 5 minutes. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water, with 5% NaHCO3 solution, with water and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 16.5 g of the expected product.
B) 1-Benzoyl-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)perhydroazepine A stream of HCl gas is bubbled into a solution of 16.5 g of the compound obtained in the previous step in 200 ml of MeOH until the pH is <1, and the 3s reaction mixture is stirred for 10 minutes. It is concentrated under vacuum, the .

residue is taken up with a saturated solution of HCl gas in MeOH and the solvent is evaporated off under vacuum. The residue is exkacted with DCM, the organic phase is washed with 5% NaHCO3 solution and with saturated NaCI solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 13.7 g of s the expected product.
C) l-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-meth~neslllfonyloxy)propyl]-perhydroazepine A solution of 5 g of the compound obtained in the previous step and 1.5 g of triethylamine in 100 ml of DCM is cooled in an ice bath, a solution of 1.55 g of 0 methanesulfonyl chloride in 20 ml of DCM is added dropwise and the mixture isstirred for 5 minlltes It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water, with 5%
NaHCO3 solution, with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum to give 5.7 g of the expected product.
D) 3-[3 -[4-(Acetyl-N-methylamino)-4-phenylpiperid- 1 -yl]propyl]- 1 -benzoyl-3-(3,4-dichlorophenyl)perhydroazepine hydrochloride 0.3 hydrate A mixture of 1.2 g of 4-(acetyl-N-methylamino)-4-phenylpiperidine p-toluenesulfonate, 1.2 g of the compound obtained in the previous step and 1.2 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50/50; v/v) is refluxed for 3 hours.
After cooling to RT, the reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed three times with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using DMC and then a 2s DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken upwith ethereal hydrogen chloride and the solvent is evaporated off under vacuum to give 0.63 g of the expected product after solidification in ether, m.p. = 125~C.EXAMPLE 14 1 -Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(N,N-dimethylaminocarbonyl)-4-phenylpiperid-l-yl]propyl]perhydroazepine hydrochloride hemihydrate This compound is prepared by the procedure described in step D of EXAMPLE 13, starting from 0.69 g of 4-(N,N-dimethylaminocarbonyl)-4-phenyl-piperidine, 1.2 g of the compound obtained in step C of EXAMPLE 13 and 1.2 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50/50; v/v). This gives 0.65 g of 3s the expected product, m.p. = 150~C.

.

1 -Benzoyl-3-(3 ,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin- 1 -yl-carbonyl)piperid- 1 -yl]propyl]perhydroazepine hydrochloride hemihydrate This compound is prepared by the procedure described in step D of s EXAMPLE 13, starting from 0.96 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonyl)-piperidine, 1.5 g of the compound obtained in step C of EXAMPLE 13 and 1.5 g of K2CO3 in 10 ml of a DMF/acetonitrile mixture (50/50; v/v). This gives 0.34 g of the expected product, m.p. = 135~C.

3-[3-[4-(2-Aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)perhydroazepine dihydrochloride 1.5 hydrate This compound is prepared by the procedure described in step D of EXAMPLE 13, starting from 0.77 g of 4-(2-aminothiazol-4-yl)-4-phenylpiperidine (compound of PREPARATION 1.4 in the form of the free base), 1.2 g of the compound obtained in step C of EXAMPLE 13 and 1.2 g of K2CO3 in 20 ml of a DMF/acetonitrile mixture (50/50; v/v). This gives 0.8 g of the expected product after crystallization from AcOEt, m.p. = 1 78~C.

1 -Benzoyl-3 -(3 ,4-dichlorophenyl)-3 -[3 -[4-(2-hydroxyethoxy)-4-phenyl-piperid-l-yl]propyl]piperidine hydrochloride monohydrate A mixture of 1 g of 4-(2-hydroxyethoxy)-4-phenylpiperidine hydrochloride, 1.7 g of the compound obtained in step B of EXAMPLE 1 and 0.65 g of K2CO3 in 15 ml of DMF is heated at 60~C for 2 hours and the reaction mixture is then stirred overnight at RT. It is poured into water and extracted with DCM, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; vlv) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride andthe precipitate formed is filtered off to give 1.2 g of the expected product, m.p. =
120- 123~C.

3-[3-[4-(2-Acetoxyethoxy)-4-phenylpiperid-1 -yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine hydrochloride 1.5 hydrate A solution of 0.6 g of the compound obtained in EXAMPLE 17 and 0.5 ml of triethylamine in 25 ml of DCM is cooled to 0 - 5~C, 0.085 ml of acetyl chloride .

is added and the mixture is stirred for 3 hours, the temperature being allowed to rise to RT. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is s chromatographed on silica using DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 1.2 g of the expected product, m.p. = 105 - 107~C.

1-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-l-yl]propyl]piperidine hydrochloride hemihydrate A) 3 - [3 -(4-Amino-4-phenylpiperid- 1 -yl)propyl]- 1 -benzoyl-3 -(3 ,4-dichlorophenyl)-piperidine A mixture of 6.81 g of 4-amino-4-phenylpiperidine dibenzenesulfonate, 5.2 g of the compound obtained in step B of EXAMPLE 1 and 6.1 g of K2C03 in 30 ml of a DMF/acetonitrile mixture (50/50; v/v) is heated at 1 00~C for 5 hours. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum.
The residue is chromatographed on silica H using a DCM/MeOH mixture (from 99/1; v/v to 85/15; v/v) as the eluent to give 3.6 g ofthe expected product.
B) l-Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenylpiperid-1-yl]propyl]piperidine hydrochloride hemihydrate A solution of 1.5 g of the compound obtained in the previous step and 2s 0.54 g of triethylamine in 10 ml of DCM is cooled to O - 5~C, 0.35 g of 2-furoyl chloride is added and the mixture is stirred for 2 hours 30 minlltes7 the temperature being allowed to rise to RT. It is concentrated under vacuum, the residue is extracted with DCM, the organic phase is washed with water, with 5% NaHCO3 solution, with water and with saturated NaCl solution and dried over MgS04 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (97/3; v/v) as the eluent. The product obtained is dissolved in AcOEt, a stream of HCl gas is bubbled into the solution until the pH is 1, and ether is added until precipitation occurs. This gives 1.27 g of the expected product after filtration and drying, m.p. = 180 - 1 82~C.

.

1 -Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenyl-piperid-1-yl]propyl]piperidine hydrochloride monohydrate This compound is prepared hy the procedure described in step B of s EXAMPLE 19, starting from 1.5 g of the compound obtained in step A of EXAMPLE 19, 0.55 g of triethylamine and 0.4 g of 2-thenoyl chloride in 10 ml of DCM[. The residue is chromatographed on silica H using DCM and then a DCM[/MeOH mixture (95/5; v/v) as the eluent. The product obtained is taken up with DCM and acidified to pH 1 by the addition of ethereal hydrogen chloride and0 the precipitate obtained is filtered off to give 0.99 g of the expected product, m.p. =
198 - 200~C.

3 -(3,4-Dichlorophenyl)- 1 -isonicotinoyl-3 -[3 -[4-phenyl-4-(pyrrolidin- 1 -ylcarbonyl)piperid- 1 -yl]propyl]piperidine dihydrochloride trihydrate, (+) isomer (compound of formula I--a, Z-- = 4-pyridyl) A) 3-(3,4-Dichlorophenyl)-3-(3-hydroxypropyl)piperidine hydrochloride, (+) isomer 5 ml of 40% NaOH solution are added to a solution of 10 g of the compound obtained in PREPARATION 2.1 in 20 ml of water, the mixture is extracted with DCM, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 9 g of an oil. 2.7 g of the oil obtained aredissolved in 50 ml of propan-2-ol, 2.36 g of 10-camphosulfonic acid, (+) isomer,are added and the mixture is heated to the reflux temperature. After cooling, cryst~lli7~tion and filtration of the crystals formed (3.86 g), the latter are dissolved 2s in 10% NaOH solution and extracted with chloroform, the organic phase is dried over MgSO4 and the solvent is evaporated off under vacuum to give 2.3 g of product in the form of an oil, from which the hydrochloride is prepared. The optical rotation of the hydrochloride is measured.
[o~]D25= +5.5~ (c = 0.1; MeOH) A second crystallization is carried out using 2.12 g of the oil obtained and 1.84 g of 10-camphosulfonic acid, (+) isomer, in 40 ml of propan-2-ol. After ~lk~1i7~tion with NaOH, extraction with chloroform, drying over MgSO4 and evaporation, 2.1 g of the expected product are obtained in the form of an oil, from which the hydrochloride is prepared.
[a]D25= +6.5~ (c = 0.1; MeOH) .

B) l-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidine, (+) isomer 0.61 g of di-tert-butyl dicarbonate is added to a solution of 0.9 g of the compound obtained in the previous step and 0.6 g of triethylamine in 100 ml of 5 DCM and the mixture is stirred for 30 minutes at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with a buffer solution of pH 2, with 1 N NaOH solution and with saturated NaCI solutionand dried over MgSO4 and the solvent is evaporated off under vacuum to give 1.1 g of the expected product in the form of an oil.
10 C) l-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-[3-(methanesulfonyloxy)-propyl]piperidine, (+) isomer A solution of 22 g of the compound obtained in the previous step and 6.86 g of triethylamine in 150 ml of DCM is cooled to 0 - 5~C, 7.13 g of methanesulfonyl chloride are added and the mixture is stirred for 1 hour at 0 - 5~C and then for 2 15 hours at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The product obtained is taken up with ether and the mixture is then evaporated under vacuum to give 26.4 g of the expected product in the form of an oil.
20 D) l-(tert-Butoxycarbonyl)-3-(3,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-l-yl]propyl]piperidine, (+) isomer A mixture of 17 g of 4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperidine, 25.5 g of the compound obtained in the previous step and 22.7 g of K2CO3 in 100 ml of aDMF/acetonitrile mixture (50/50; v/v) is heated at 100~C for 3 hours 30 minutes.2s It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is taken up with pentane and the precipitate formed is filtered off to give 33 g of the expected product, m.p. = 133 - 137~C.
30 [a]D20 = +33.2~ (c = 0.5, MeOH) E) 3 -(3,4-Dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin- 1 -ylcarbonyl)piperid- 1 -yl]propyl]piperidine dihydrochloride, (+) isomer Concentrated HCI solution is added to a solution of 25.8 g of the compound obtained in the previous step in 200 ml of MeOH until the pH is 1, and the mixture 35 is heated at 40~C for 3 hours. It is concentrated under vacuum and the product .

obtained is crystallized from an AcOEt/ether mixture to give 17 g of the expected product, m.p. = 170~C.
[a]D20 = +13~ (c = 0.5; MeOH) F) 3 -(3,4-Dichlorophenyl)- 1 -isonicotinoyl-3 -[3 -[4-phenyl-4-(pyrrolidin- 1 -yl-s carbonyl)piperid-l-yl]propyl]piperidine dihydrochloride trihydrate, (+) isomer A solution of 1.7 g of the compound obtained in the previous step and 0.9 g of triethylamine in 10 ml of DCM is cooled to 0 - 5~C, 0.6 g of isonicotinoyl chloride hydrochloride is added and the mixture is stirred for 1 hour at RT. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (93/7; v/v) as the eluent. The product obtained is dissolved in AcOEt, a stream of HCl gas is bubbled into the solution until the pH is 1, and ether is added until precipitation occurs. This gives 0.27 g of the expected product after filtration and drying, m.p. = 140 - 142~C.
[a]D20 = +11.6~ (c = 0.5; MeOH) 1 -Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[spiro(indoline-3,4'-piperid- 1 '-yl)-propyl]piperidine dihydrochloride 1.5 hydrate A mixture of 1 g of the compound obtained in step B of EXAMPLE 1, 0.7 g of spiro(indoline-3,4'-piperidine) dihydrochloride and 0.8 g of K2CO3 in 10 ml of DMF is heated at 70 - 80~C for 3 hours. The reaction mixture is poured into water and the precipitate formed is filtered off and dried. The precipitate is chromato-graphed on silica using DCM and then a DCM/MeOH mixture (94/6; v/v) as the 2s eluent. The product obtained is dissolved in DCM and acidified to pH I by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.5 g of the expected product, m.p. = 192 - 195~C.

1 -Benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1 -acetylspiro(indoline-3,4'-piperid-1 '-yl)propyl]piperidine hydrochloride monohydrate A mixture of I g of the compound obtained in step B of EXAMPLE 1, 1 g of l-acetylspiro(indoline-3,4'-piperidine) hydrochloride and 0.6 g of K2CO3 in 10 ml of DMF is heated at 70~C for 2 hours. The reaction mixture is poured into water and the precipitate formed is filtered off. The precipitate is dissolved in 3s DCM, the organic phase is dried over MgSO4 and the solvent is evaporated off .

under vacuum. The residue is chromatographed on silica using DCM and then a DCM/MeOH mixture (97/3; vlv) as the eluent. The product obtained is dissolved in DCM and acidified to pH 1 by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.7 g of the expected product, m.p. =189- 191~C.
The compounds according to the invention collated in TABLE I below are prepared by following the procedure described in step F of EXAMPLE 21, starting f~om the compound obtained in step E of EXAMPLE 21 and the a~ ,iate acid chlorides.

.

TABLE I
~ /~
~CN-(CH2)3~ N-CO- Z- ~ isomère (+) (I ~a) L~N--C\ ~
~CI

Salt, solvate;
Example Z-- m.p. ~C;
~a~ D

24 ~S~ HCI, lH2O;
\~ 134 - 136;
+31~ (c = 0.5; MeOH) S HCl, 0.5H20;
172;
+35.6~ (c = 0.5; MeOH) - 26 ~ HCl, 1.25H20;
120 - 122;
+47~ (c = 0.5; MeOH) 27 o HCI, 2H2O;
175;
+32.6~ (c = 0.5; MeOH) The compounds according to the invention collated in TABLE II below are prepared by following the procedures described in the previous EXAMPLES, starting from the compound obtained in step B of EXAMPLE 1 and the piperidines described in the PREPARATIONS.

_ CA 02232007 1998-03-12 TABLE II

B-(CH2)3 N-C~ (I) ~Cl Example B- Salt, solvate;
m.p. ~C or NMR
28 ~ 2HCI, 2.5H20;
(a) ~N- 202 - 204 H Nl~N,N
29 ~ HCI, H2O;
(b) ~N- 160- 162 EtO- ICl - I I -HN
O O
2HCI, H20;

(a) H2N C>~N- 165 o 31 Ol HCl, 1.2H20;
(c) MeO-C~N~CN- 175- 180 32 Me~ ¦¦ HCI, 0.5H20;
(c) /N-C~N~N- 155- 157 . CA 02232007 1998-03-12 .

Example B- Salt, solvate;
m.p. ~C or NMR
33 1I HCl, 1.3H20;
(c) oi/ ~N- 158-160 (a) This compound is prepared by the procedure described in EXAMPLE 2.
(b) This compound is prepared by the procedure described in step B of EXAMPLE 19, starting from the compound obtained in step A of EXAMPLE 19 and ethyloxalyl chloride.
s (c) This compound is prepared by the procedure described in EXAMPLE
23, starting from the compound obtained in step B of EXAMPLE 1 and the appropriate spiro(indoline-3,4'-piperidines).

Claims (33)

1. A compound of the formula which:
- R1 is hydrogen;
- R2 is the methyl group;
- or R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; a thienyl which is unsubstituted or substituted by a halogen atom; a benzothienyl which is unsubstituted or substituted by a halogen atom; a naphthyl which is unsubstituted or substituted by a halogen atom; an indolyl which is unsubstituted or N-substituted by a (C1-C4)alkyl or a benzyl; an imidazolyl which is unsubstituted or substituted by a halogen atom; a pyridyl which is unsubstituted or substituted by a halogen atom; or a biphenyl;
- T is a group -CH2-; a group -CO-; a group -COO-; or a group -CONR3- in which R3 is a hydrogen or a (C1-C4)alkyl;
- A is a direct bond, a group -(CH2)t-, in which t is one, two or three; or a vinylene group;
- or -T-A- is the group -SO2-;
- Z is an optionally substituted, mono-, di- or tri-cyclic aromatic or heteroaromatic group; and - B is:
- i - either a group B1 of the formula in which J1 is:
- i1 - either a group which:
- x is zero or one;
- Ar2 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl, a (C1-C4)alkyl, a (C1-C4)alkoxy and a methylenedioxy, said substituents being identical or different; a pyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C1-C4)alkyl; and - X1 is a group selected from:
(1) hydrogen;
(2) (C1-C7)alkyl;
(3) formyl;
(4) (C1-C7)alkylcarbonyl;
(5) -(CH2)m-OR4;
(6) -(CH2)m-OCOR5;
(7) -(CH2)m-OCONH-(C1-C7)alkyl;
(8) -O-CH2CH2-OR6;
(9) -(CH2)n-SR7;
(10) -CH2-S(O)j-(C1-C7)alkyl;
(11) -NR8R9;
(12) -(CH2)p-NR10R11;
(13) -NR12COR13;
(14) -NR14COCOR15;
(15) -(CH2)p-NR14C(=W1)R16;
(16) -(CH2)m-NR14COOR17;
(17) -(CH2)m-NR14SO2R18;
(18) -(CH2)m-NR14C(=W1)NR19R20;
(19) -(CH2)n-COOR21;
(20) -(CH2)n-C(=W1)NR19R20;
(21) -CO-NR22-NR23R24;
(22) -CN;

(23) ;

(24) ;

or X1 forms a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring;
in which groups:
- m is zero, one or two;
- n is zero or one;
- p is one or two;
- j is one or two;
- W1 is an oxygen atom or a sulfur atom;
- R4 is a hydrogen or a (C1-C7)alkyl;
- R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
- R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
- R7 is a hydrogen or a (C1-C7)alkyl;
- R8 and R9 are each independently a hydrogen or a (C1-C7)alkyl; R9 can also be a (C3-C7)cycloalkylmethyl, a benzyl or a phenyl;
or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
- R12 is a hydrogen or a (C1-C7)alkyl;
- R13 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
- or R12 and R13 together are a group -(CH2)u-, in which u is three or four;
- R14 is a hydrogen or a (C1-C7)alkyl;
- R15 is a (C1-C4)alkoxy;
- R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
- R17 is a (C1-C7)alkyl or a phenyl;

- R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, atrifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
- R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls;
- or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- R21 is a hydrogen or a (C1-C7)alkyl;
- R22 is a hydrogen or a (C1-C7)alkyl;
- R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl;
- R25 is a hydrogen or a (C1-C7)alkyl; and - R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl;
- i2 - or a group in which Ar2 is as defined above;
- i3- or a group in which Ar2 is as defined above;
- i4- or a group in which Ar2 is as defined above;

- i5- or a group in which:
- Ar2 is as defined above;
- Am1 is an amino group substituted by two (C1-C4)alkyls; and - r is two or three;
- i6- or a group in which:
- Ar2 is as defined above;
- W2 is an oxygen atom; a sulfur atom; a sulfinyl; a sulfonyl; or a group -NL1-;- L1 is a hydrogen; a (C1-C4)alkyl; a (C1-C4)alkylcarbonyl; or a group -(CH2)v-Am2;
- v is one, two or three; and - Am2 is an amino group which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; Am2 can also be a pyrrolidino, piperidino or morpholino group;
- ii - or a group B2 of the formula in which J2 is:
- ii1 - or a group - ii2 - or a group -ii3- or a group -ii4- or a group -ii5- or a group in which:
- Ar2 is as defined above;
- r is two or three; and - Am1 is as defined above;
- iii - or a group B3 of the formula in which J3 is:

a group:

in which:
- W3 is an oxygen atom; a sulfur atom; or a group NR30, in which R30 is a hydrogen or a (C1-C3)alkyl;
- R28 is a hydrogen; a (C1-C6)alkyl; a (C3-C6)alkenyl in which one vinylic carbon atom is not bonded to the nitrogen atom; a 2-hydroxyethyl; a (C3-C7)cycloalkyl;
a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a trifluoromethyl, a (C1-C4)alkyl, a (C1-C4)alkoxy, a nitro, an amino and a hydroxyl, said substituents being identical or different; or a 6-membered heteroaryl containing one or two nitrogen atoms as heteroatoms, said heteroaryl being unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a trifluoromethyl, a (C1-C4)alkyl, a (C1-C4)alkoxy, a nitro, an amino and a hydroxyl, said substituents being identical or different;
- R29 is a hydrogen; a (C1-C6)alkyl which is unsubstituted or substituted by a hydroxyl and/or by one, two or three fluorine atoms; a (C3-C6)cycloalkyl; a (C1-C5)alkoxy (only when W3 is an oxygen atom); a (C3-C6)cycloalkoxy (only when W3 is an oxygen atom); or a group -NR31R32 containing from zero to seven carbon atoms, R29 being other than an unsubstituted (C1-C4)alkyl when simultaneously W3 is an oxygen and R28 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl, a (C1-C4)alkyl and a (C1-C4)alkoxy, said substituents being identical or different; a pyridyl; or a pyrimidyl;
or R28 and R29 together form a divalent hydrocarbon group L2, in which the 1-position is bonded to the carbon atom carrying the substituent W3, the divalent hydrocarbon group L2 being selected from a trimethylene, a cis-propenylene, a tetramethylene, a cis-butenylene, a cis,cis-butadienylene, a pentamethylene and a cis-pentenylene, said divalent hydrocarbon group L2 being unsubstituted or substituted by one or two methyls; and R31 and R32 are each independently a hydrogen, a (C1-C5)alkyl or a (C3-C6)cycloalkyl;
or R31 and R32, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- iv - or a group B4 of the formula which:
W4 is a (C1-C8)alkyl or a (C3-C8)cycloalkyl, said alkyl and cycloalkyl groups being unsubstituted or substituted by one or more substituents selected from a halogen atom; a (C3-C6)cycloalkyl; a cyano; a nitro; a hydroxyl; a (C1-C4)alkoxy;
a formyloxy; a (C1-C4)alkylcarbonyloxy; an arylcarbonyl; a heteroarylcarbonyl; an oxo; an imino which is unsubstituted or substituted on the nitrogen atom by a (C1-C6)alkyl, a (C3-C6)cycloalkyl, a formyl, a (C1-C4)alkylcarbonyl or an arylcarbonyl; a hydroxyimino which is unsubstituted or substituted on the oxygen atom by a (C1-C4)alkyl or a phenyl; a group -NR33R34 containing from zero to seven carbon atoms; a group -NR35R36; a group -C(=NR37)NR38R39, in which the group -NR38R39 contains from zero to seven carbon atoms; and a group -CON(OR40)R41, said substituents being identical or different;
R33 and R34 are each independently a hydrogen, a (C1-C5)alkyl or a (C3-C6)cycloalkyl;
or R33 and R34, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
R35 is a hydrogen or a (C1-C4)alkyl;
R36 is a formyl; a (C1-C4)alkylcarbonyl; an arylcarbonyl; a heteroarylcarbonyl; or a group -C(=W5)NR38R39, in which the group -NR38R39 contains from zero to seven carbon atoms;
W5 is an oxygen atom; a sulfur atom; a group NR37; or a group CHR42;

- R37 is a hydrogen or a (C1-C4)alkyl; or R37 and R39 together form an ethylene group or a trimethylene group;
- R38 and R39 are each independently a hydrogen, a (C1-C5)alkyl or a (C3-C6)cycloalkyl;
or R38 and R39, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl; or R38 is a hydrogen or a (C1-C4)alkyl and R39 and R37 together form an ethylene group or a trimethylene group;
- R40 and R41 are each independently a (C1-C3)alkyl;
- R42 is a cyano; a nitro; or a group SO2R43;
- R43 is a (C1-C4)alkyl or a phenyl;
and when W4 is a cyclic group or when a substituent of W4 is a cyclic group or contains a cyclic group, said cyclic groups can also be substituted on a carbon atom by one or more (C1-C3)alkyls; and when a substituent of W4 contains an arylgroup or a heteroaryl group, said aryl or heteroaryl groups can also be monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C4)alkyl, a (C1-C4)alkoxy, a cyano, a trifluoromethyl and a nitro, said substituents being identical or different;
- v - or a group B5 of the formula in which:
- W6 and W7 are each a hydrogen; or W6 is a hydrogen and W7 is a hydroxyl;
- W8 is an aryl or a heteroaryl which are unsubstituted or substituted by an aryl, an arylcarbonyl, a heteroaryl or a heteroarylcarbonyl; said aryl or heteroaryl groups can also be monosubstituted or polysubstituted on the aromatic or heteroaromatic moiety and on a carbon atom by a substituent selected from a halogen atom; a cyano; a trifluoromethyl; a nitro; a hydroxyl; a (C1-C5)alkoxy; a formyloxy; a (C1-C4)alkylcarbonyloxy; a group -NR33R34 containing from zero to seven carbon atoms; a group -NR35R36; a group -C(=NR37)NR38R39, in which the group -NR38R39 contains from zero to seven carbon atoms; a group -COOR44; a group -CONR45R46, in which the group NR45R46 contains from zero to seven carbon atoms; a mercapto; a group -S(O)5R47; a (C1-C5)alkyl; a formyl;

and a (C1-C4)alkylcarbonyl, said substituents being identical or different; whenW6 and W7 are each a hydrogen, W8 is other than a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a nitro, a hydroxyl, a trifluoromethyl and a (C1-C4)alkoxy,said substituents being identical or different; a pyridyl; a thienyl; a pyrimidyl; or an imidazolyl which is unsubstituted or substituted by a (C1-C4)alkyl;
- or W7 is a hydrogen and W6 and W8, together with a diradical W9 and the piperidine carbon atom to which they are bonded, form a spiro ring in which W8 is a phenyl substituted in the ortho position by a diradical W9, which is itselfjoined to W6, said phenyl being unsubstituted or substituted by a substituent selected from a halogen atom, a (C1-C3)alkyl, a (C1-C3)alkoxy, a hydroxyl, a (C1-C3)alkylthio, a (C1-C3)alkylsulfinyl and a (C1-C3)alkylsulfonyl; the diradical W9 is a methylene, a carbonyl or a sulfonyl; and W6 is an oxygen atom or a group -NR48-, in which R48 is a hydrogen or a (C1-C3)alkyl;
- R33, R34, R35, R36, R37, R38 and R39 are as defined above for the group B4;
- R44 is a hydrogen; a (C1-C5)alkyl; an aryl; a heteroaryl; an arylmethyl; or a heteroarylmethyl;
- R45 and R46 are each independently a hydrogen, a (C1-C5)alkyl or a (C3-C6)cycloalkyl;
or R45 and R46, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- s is zero, one or two;
- R47 is a (C1-C6)alkyl; a (C3-C6)cycloalkyl; an aryl; or a heteroaryl;
and when W8 or a substituent of W8 contains a cyclic group, said cyclic group can also be substituted by one or more methyls; and when a heteroaryl group forming part of W8 or of a substituent of W8 contains a nitrogen atom as the heteroatom,said nitrogen atom can also be substituted by a (C1-C5)alkyl; and when W8 or a substituent of W8 contains a (C1-C5)alkyl, (C1-C5)alkoxy, formyl or (C1-C4)alkylcarbonyl group, said (C1-C5)alkyl, (C1-C5)alkoxy, formyl or (C1-C4)alkylcarbonyl groups can also be substituted by a hydroxyl, a (C1-C3)alkoxy or one or more halogen atoms, with the proviso that a carbon atom bonded to a nitrogen atom or to an oxygen atom is not substituted by a hydroxyl or an alkoxy group, and with the proviso that a carbon atom in the .alpha.-position of a (C1-C4)alkylcarbonyl group is not substituted by a chlorine, bromine or iodine atom;
- vi - or a group B6 of the formula in which J4 is:

- vi1 - either a group in which:
- W10 is a phenyl which is unsubstituted or monosubstituted to trisubstituted by a substituent selected from a halogen atom, a (C1-C6)alkoxy, a (C1-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a benzyl which is unsubstituted or monosubstituted to trisubstituted by a substituent selected from a halogen atom, a (C1-C6)alkoxy, a (C1-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a naphthyl which is unsubstituted or monosubstituted to trisubstituted by a substituent selected from a halogen atom,a (C1-C6)alkoxy, a (C1-C6)alkyl and a trifluoromethyl, said substituents being identical or different; a pyridyl which is unsubstituted or monosubstituted or disubstituted by a substituent selected from a halogen atom, a (C1-C6)alkyl and a (C1-C6)alkoxy, said substituents being identical or different; a thienyl; a pyrimidyl; or an imidazolyl; and - W11 is a group -CONHR49;
- R49 is a group CH3-CHOH-CH-COO-(C1-C6) alkyl;
a group (C1-C6)alkyl-OCO-CH2-CH2-CH-COO-(C1-C6)alkyl;
a group -CH2CH2N(CH3)2;

-vi2 -or a group: -vi3 -or a group: -vi4 -or a group: in which:
- R50 is a hydrogen, a (C1-C6)alkyl or a benzyl; and - R51 is from one to three substituents selected from a hydrogen, a halogen atom, a trifluoromethyl, a (C1-C6)alkyl and a (C1-C6)alkoxy, said substituents being identical or different;
- vii - or a group B7 of the formula in which:
- f and g are each independently zero, one, two, three, four or five, with the proviso that f + g is equal to one, two, three, four or five;
- W12 is a direct bond; a (C1-C3)alkylene which is unsubstituted or substituted by an oxo, a group OR52, a halogen, a trifluoromethyl or a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, a cyano, a halogen and a trifluoromethyl; a group -S(O)k-; a group (C1-C3)alkylene-S(O)k-; a group -S(O)k-(C1-C2)alkylene; a group -S(O)k-NH-; a group -S(O)j-NR52-; a group -S(O)j-NR52-(C1-C2)alkylene; a group -CONR52-; a group -CONR52-(C1-C2)alkylene; a group -COO-; or a group -COO-(C1-C2)alkylene;
W13 is a group -NR53-; an oxygen atom; a sulfur atom; a sulfinyl; or a sulfonyl,with the proviso that when W12 is a direct bond and when W14 is a (C1-C3)alkylene, W13 is a group -NR53-;
W14 is a direct bond; a (C1-C3)alkylene which is unsubstituted or substituted byan oxo, a group OR52, a halogen, a trifluoromethyl or a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a group OR52, a halogen and a trifluoromethyl; a group -S(O)k-; a group (C1-C3)alkylene-S(O)k-; a group -S(O)k-(C1-C2)alkylene; a group -NHS(O)j-; a group -NH-(C1-C2)alkylene-S(O)j-; a group -S(O)jNR52-; a group -S(O)j-NR52-(C1-C2)alkylene; a group -NHCO-(C1-C2)alkylene; a group -NR52-CO-; a group -NR52-(C1-C2)alkylene-CO-; a group -OCO-; or a group (C1-C2)alkylene-OCO-;
- W15-W16 together form two adjacent atoms of a cyclic radical of the formula said cyclic radical being a phenyl, a naphthyl or a heteroaryl group selected from a benzimidazolyl, a benzofuranyl, a benzoxazolyl, a furanyl, an imidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, an oxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, a pyrimidyl, a pyrrolyl, a quinolyl, a tetrazolyl, a thiadiazolyl, a thiazolyl, a thienyl and a triazolyl, and said phenyl, naphthyl or heteroaryl cyclic radical being unsubstituted or mono-, di- or tri-substituted by R54;
- k is zero, one or two;
- J is one or two;
- R52 is a hydrogen; a (C1-C6)alkyl which is unsubstituted or monosubstituted ordisubstituted by a substituent selected independently from a hydroxyl, an oxo, acyano, a halogen atom, a trifluoromethyl and a phenyl which is itself unsubstituted or substituted by a hydroxyl, a (C1-C3)alkyl, a cyano, a halogen, a trifluoromethyl or a (C1-C4)alkoxy; a phenyl, a pyridyl or a thiophene, said phenyl, pyridyl or thiophene being unsubstituted or mono-, di- or tri-substituted by a substituent selected independently from a hydroxyl, a (C1-C4)alkyl, a cyano, a halogen atom and a trifluoromethyl; or a (C1-C3)alkoxy;
- R53 is a hydrogen; a (C1-C8)alkyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a group -OR52, an oxo, a group -NHCOR52, a group -NR55R56, a cyano, a halogen atom, a trifluoromethyl and a phenyl which is itself unsubstituted or substituted by a hydroxyl, a cyano, a halogen atom or a trifluoromethyl; a group -S(O)R57; a group -CO2R57; a group -SO2R57; a group -COR57; or a group -CONR56R57;
- R54 is a hydrogen; a (C1-C6)alkyl which is unsubstituted or monosubstituted ordisubstituted by a hydrogen or a hydroxyl; an oxo; a group -OR52; a halogen atom; a trifluoromethyl; a nitro; a cyano; a group -NR55R56; a group -NR55COR56; a group -NR55CO2R56; a group -NHS(O)jR52; a group -NR55S(O)jR56; a group -CONR55R56; a group -COR52; a group -CO2R52; a group -S(O)jR52; or a heteroaryl group, said heteroaryl being selected from a benzimidazolyl, a benzofuranyl, a benzoxazolyl, a furanyl, an imidazolyl, an indolyl, an isoxazolyl, an isothiazolyl, an oxadiazolyl, an oxazolyl, a pyrazinyl, a pyrazolyl, a pyridyl, a pyrimidinyl, a pyrrolyl, a quinolyl, a tetrazolyl, a thiadiazolyl, a thiazolyl, a thienyl and a kiazolyl, and said heteroaryl being unsubstituted or monosubstituted or disubstituted by R58;
- R55 is R52;
- R56 is R52;
- or R55 and R56, together with the atoms to which they are bonded, form a five-, six- or seven-membered, saturated monocyclic heterocycle containing one or two heteroatoms, said heteroatoms being selected independently from a nitrogen atom, an oxygen atom and a sulfur atom, said heterocycle being unsubstituted or monosubstituted or disubstituted by a substituent selected from a hydroxyl, an oxo, a cyano, a halogen atom and a trifluoromethyl;
- R57 is a (C1-C6)alkyl which is unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, an oxo, a cyano, a group -OR52, a group -NR55R56, a group -NR55COR56, a halogen atom, a trifluoromethyl and a phenyl which is itself unsubstituted or mono-, di- or tri-substituted by a substituent selected from a hydroxyl, an oxo, a cyano, a group -NHR52, a group -NR55R56, a group -NR55COR56, a halogen atom, a trifluoromethyl and a (C1-C3)alkyl;
- R58 is a hydrogen; a (C1-C6)alkyl which is unsubstituted or monosubstituted ordisubstituted by a hydrogen or a hydroxyl; an oxo; a group -OR52; a trifluoromethyl; a nitro; a cyano; a group -NR55R56; a group -NR55COR56; a group -NR55CO2R56; a group -NHS(O)jR52; a group -NR55S(O)jR56; a group -CONR55R56; a group -COR52; a group -CO2R52; a group -S(O)jR52; or a phenyl, and the group B7 being other than the group B5 when W7 is a hydrogen and W6 and W8, together with a diradical W9 and the piperidine carbon atom to which they are bonded, form a spiro ring;
- viii - or a group B8 of the formula in which:
- W17 is a direct bond; a double bond; or a divalent hydrocarbon radical;
- W18 is a radical which is joined to the carbon atom of the heterocycle either by a single bond when W17 is a double bond, or by a double bond in the other cases;
- W19 is an unsubstituted or optionally substituted heteroatom;
- W20 is a hydrocarbon radical of which the 1-position is joined to W19; and - the meanings of W17, W18, W19 and W20 are selected from:
(a) W17 is a direct bond; W18 is an oxo or thioxo group; W19 is an oxy or thio group or a group NR59; and W20 is a hydrocarbon radical L3; or (b) W17 is a direct bond; W18 is a group NR60; W19 is a group NR61; and W20 is a hydrocarbon radical L3; or (c) W17 is a double bond; W18 is a group OR61, SR61 or NR62R63; W19 is a nitrogen atom; and W20 is a hydrocarbon radical L3; or (d) W17 is a methylene which is unsubstituted or substituted by one or two methyl groups; W18 is an oxo or thioxo group or a group NR64; W19 is an oxy, thio, sulfinyl or sulfonyl group or a group NR61; and W20 is a hydrocarbon radical L4; or (e) W17 is a direct bond; W18 is an oxo or thioxo group or a group NR64;
W19 is a nitrogen atom; and W20 is a hydrocarbon radical L5; or (f) W17 is a methine group which is unsubstituted or substituted by one or two methyl groups; W18 is an oxo or thioxo group or a group NR64; W19 is a nitrogen atom; and W20 is a hydrocarbon radical L6; and (g) W17 is a cis-vinylene group which is unsubstituted or substituted by one or two methyl groups; W18 is an oxo or thioxo group or a group NR64; W19 is a nitrogen atom; and W20 is a hydrocarbon radical L7;
- R59 is a hydrogen; a (C1-C3)alkyl; a group -CH2COOR65; or a group -CH2CONR66R67;

- R60 is a hydrogen; a (C1-C3)alkyl; a cyano; a nitro; or a (C1-C3)alkylsulfonylgroup;
- R61 is a hydrogen or a (C1-C3)alkyl;
- R62 and R63 are each independently a hydrogen or a (C1-C3)alkyl;
- or R62 and R63, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- R64 is a hydrogen or a (C1-C3)alkyl;
- R65 is a hydrogen or a (C1-C3)alkyl;
- R66 and R67 are each independently a hydrogen; a (C1-C3)alkyl; a phenyl; or a benzyl;
- L3 is an ethylene, a cis-vinylene, a trimethylene or a tetramethylene, said hydrocarbon radical L3 being unsubstituted or substituted by one or two methyl groups;
- L4 is an ethylene or a trimethylene, said hydrocarbon radical L4 being unsubstituted or substituted by one or two methyl groups;
- L5 is a prop-2-en-1-yliden-3-yl which is unsubstituted or substituted by one or two methyl groups;
- L6 is a cis-vinylene which is unsubstituted or substituted by one or two methyl groups; and - L7 is a methine which is unsubstituted or substituted by a (C1-C3)alkyl;
- ix - or a group B9 of the formula which J5 is:
- a group in which:
- X2 is a (C1-C6)alkyl; a group -CH2-OR68; a group -CH2-SR68; a group -CH2-S(O)R69; a group -CH2-SO2R69; a group -COOR68; a group -C(=W24)NR70R71; a group -C(R68)(OR72)(OR73); a group -CH2NR68C(=W24)R74; a group -CH2-NR68COOR74; or a group -CH2NR68C(=W24)NR70R71;
- W21 is a direct bond and W22 is a hydrocarbon radical of which the 1-position is joined to W21, the hydrocarbon radical W22 being selected from a trimethylene, atetramethylene, a cis-1-butenylene and a cis,cis-butadienylene;
- or W21 is a group NR75 and W22 is a hydrocarbon radical selected from an ethylene, a trimethylene and a cis-vinylene;
- or W21 is a nitrogen atom and W22 is a cis,cis-prop-2-en-1-yliden-3-yl radical of which the 1-position is joined to W21;
- W23 is an oxygen atom or a sulfur atom;
- W24 is an oxygen atom or a sulfur atom;
- R68 is a hydrogen or a (C1-C6)alkyl;
- R69 is a (C1-C6)alkyl;
- R70 and R71 are each independently a hydrogen; a (C1-C6)alkyl which is unsubstituted or substituted by a hydroxyl or a (C1-C3)alkoxy; an .omega.-HO-(C1-C6)alkyl;
an .omega.-(C1-C3)alkoxy-(C1-C6)alkyl; an .omega.-phenyl-(C1-C6)alkyl; an .omega.-R76OOC-(C1-C6)alkyl; or an .omega.-R77R78NCO-(C1-C6)alkyl;
- or R70 and R71, together with the nitrogen atom to which they are bonded, form a heterocycle selected from pyrrolidine, piperidine, morpholine, thiomorpholine (or its S-oxide) and piperazine which is unsubstituted or substituted in the 4-position by a methyl group or an ethyl group;
- R72 and R73 are each independently a (C1-C3)alkyl;
- or R72 and R73 together form a divalent hydrocarbon radical selected from an ethylene and a trimethylene;
- R74 is a hydrogen or a (C1-C6)alkyl;
- R75 is a hydrogen or a (C1-C6)alkyl;
- R76 is a hydrogen or a (C1-C3)alkyl; and - R77 and R78 are each independently a hydrogen or a (C1-C3)alkyl;
- x - or a group B10 of the formula in which J6 is:
a group in which:

- X1 is as defined above for the group B1, X1 being other than hydrogen when W25is a (C1-C7)alkyl or a (C3-C7)cycloalkyl;
- W25 is a (C1-C7)alkyl or a (C3-C7)cycloalkyl; W25 can also be a group -NR79R80when X1 is a hydrogen, a cyano, a carboxyl, a (C1-C7)alkoxycarbonyl or a group -CONR19R20; and - R79 and R80 are each independently a (C1-C7)alkyl;
- or R79 and R80, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine, with the proviso that:
1/ when simultaneously:
- R2 is a methyl group or R1 and R2 together form a group -(CH2)3-;
- Ar1 is a 3,4-dichlorophenyl;
- T is a group -CH2-; a group -CO-; a group -COO-; or a group -CONR3;
- A is a direct bond; a group -(CH2)t- in which t is one, two or three; or a vinylene group;
- or-T-A- is the group -SO2-; and - Z is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a (C1-C4)alkyl, a (C1-C4)alkoxy or a nitro, B is a group B1 of the formula in which J, is a group in which:
- x is zero;
- Ar2 is a pyrid-2-yl or a phenyl which is unsubstituted or substituted by a halogen, a methyl or a (C1-C4)alkoxy; and - X1 is other than a group selected from:
formyl;
(C1-C6)alkylcarbonyl;
-(CH2)m-OR4 in which m is zero or one and R4 is a hydrogen or a (C1-C7)alkyl;
-(CH2)m-OCOR5 in which m is zero or one and R5 is a hydrogen or a (C1-C6)alkyl;

-(CH2)m-OCONH(C1-C7)alkyl in which m is one;
-NR8R9 in which R8 and R9 are each independently a hydrogen or a (C1-C7)alkyl;
R9 can also be a (C3-C7)cycloalkylmethyl, a benzyl or a phenyl; or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine;
-(CH2)p-NR10R11 in which p is one and R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C1-C7)cycloalkylmethyl or a benzyl;
-NR12COR13 in which R12 is a hydrogen or a (C1-C4)alkyl and R13 is a hydrogen, a (C1-C7)alkyl, a phenyl, a benzyl, a pyridyl or a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; or R12 and R13 together area group -(CH2)u- in which u is three or four;
-(CH2)p-NR14C(=W1)R16 in which p is one, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C4)alkyl and R16 is a hydrogen, a (C1-C7)alkyl, a phenyl, a benzyl, a pyridyl or a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls;
-(CH2)m-NR14COOR17 in which m is zero or one, R14 is a hydrogen or a (C1-C4)alkyl and R17 is a (C1-C7)alkyl or a phenyl;
-(CH2)m-NR14SO2R18 in which m is zero or one, R14 is a hydrogen or a (C1-C4)alkyl and R18 is a (C1-C7)alkyl, an amino which is free or substituted by one or two (C1-C7)alkyls, or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, atrifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
-(CH2)m-NR14C(=W1)NR19R20 in which m is zero or one, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C4)alkyl and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl, a (C3-C7)cycloalkylmethyl, a hydroxyl, a (C1-C4)alkoxy, a benzyl or a phenyl; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine and perhydroazepine;
-(CH2)n-COOR21 in which n is zero and R21 is a (C1-C7)alkyl;

-(CH2)n-C(=W1)NR19R20 in which n is zero, W1 is an oxygen atom and R19 and R20 are as defined above; and -CN;
or X1 does not form a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring;
or Ar2 and X1, together with the carbon atom to which they are bonded, are otherthan a group of the formula
2/ when R1 is hydrogen, R2 is the methyl group, Ar1 is the 3,4-dichlorophenyl group and T-A-Z is the thenoyl group, B is the group B1 in which J1 is the group in which x is one, Ar2 is the phenyl group and X1 is other than hydrogen;
3/when R1 is hydrogen, R2 is the methyl group, Ar1 is the 3,4-dichlorophenyl group and T-A-Z is the 2,4-dichlorobenzoyl group, B is the group B1 in which J1 is the group in which x is one, Ar2 is the phenyl group and X1 is other than hydrogen; or 4/ when R1 and R2 together form a group -(CH2)3-, Ar1 is the 3,4-dichlorophenyl group and T-A-Z is the 2-(3-methoxyphenyl)acetyl group, B is the group B1 in which J1 is the group in which x is one, Ar2 is phenyl and X1 is other than hydrogen;
and its salts, where appropriate, with mineral or organic acids.
2. A compound of formula (I) according to claim 1 in which:
- Z is Z' and is:
. a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom; a trifluoromethyl; a cyano; a hydroxyl;

a nitro; an amino which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a benzylamino; a carboxyl; a (C1-C10)alkyl; a (C3-C8)cycloalkyl which is unsubstituted or monosubstituted or polysubstituted by a methyl; a (C1-C10)alkoxy; a (C3-C8)cycloalkoxy which is unsubstituted or monosubstituted or polysubstituted by a methyl; a mercapto; a (C1-C10)alkylthio; a formyloxy; a (C1-C6)alkylcarbonyloxy; a formylamino; a (C1-C6)alkylcarbonylamino; a benzoyl-amino; a (C1-C4)alkoxycarbonyl; a (C3-C7)cycloalkoxycarbonyl; a carbamoyl which is unsubstituted or monosubstituted or disubstituted by a (C1-C4)alkyl; a ureido which is unsubstituted or monosubstituted or disubstituted in the 3-position by a (C1-C4)alkyl or a (C3-C7)cycloalkyl; and a (pyrrolidin-1-yl)-carbonylamino, said substituents being identical or different;
~ a naphthyl which is unsubstituted or monosubstituted or polysubstituted by a halogen, a trifluoromethyl, a (C1-C4)alkyl, a hydroxyl or a (C1-C4)alkoxy; or ~ a pyridyl; a thienyl; an indolyl; a quinolyl; a benzothienyl; or an imidazolyl;
~ Ar1 is a 3,4-dichlorophenyl;
~ R1 and R2 together form a group -(CH2)3- or -(CH2)4-; and ~ B, T and A are as defined for (I) in claim 1, and its salts with mineral or organic acids.
~ A compound of formula (I) according to claim 1 in which:
- Z is Z- and is a pyridyl, thiadiazolyl, indolyl, indazolyl, imidazolyl, benzimidazolyl, benzotriazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzisothiazolyl, quinolyl, isoquinolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzodioxinyl, isoxazolyl, benzopyranyl, thiazolyl, thienyl, furyl, pyranyl, chromenyl, isobenzofuranyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, phthalazinyl, quinazolinyl, acridinyl, isothiazolyl, isochromanyl or chromanyl group, in which one or more double bonds can be hydrogenated, it being possible for said groups to be unsubstituted or optionally to contain one or more substituents such as an alkyl, phenyl, cyano, hydroxyalkyl, hydroxyl, alkylcarbonylamino, alkoxycarbonyl or thioalkyl group, in which the alkyl and alkoxy groups are C1-C4;
R1 and R2 together form a group -(CH2)3-;
Ar1 is a 3,4-dichlorophenyl;
T is a group -CO-;
A is a direct bond; and B is as defined for a compound of formula (I) in claim 1, and its salts with mineral or organic acids.
4. A compound of the formula according to one of claims 1 or 3 of the formula in which:
- Z~ is as defined in claim 3; and - B~ is a group of the formula in which J~ is:
- i~ - either a group of the structure in which:
- W~ is a phenyl or a benzyl and R19 and R20 are as defined for a compound of formula (I) in claim 1;
- or W~ is a group -NR79R80 in which R79 and R80 are as defined for (I) in claim 1 and R19 and R20 are each hydrogen, -i~~ -or a group of the structure in which:
- R~ is hydrogen, a methyl group, an acetyl group, a methoxycarbonyl group, a dimethylaminocarbonyl group or a methanesulfonyl group, and its salts with mineral or organic acids.
5. A compound according to one of claims 1, 3 or 4 of the formula in which:
- B~ is as defined for a compound of formula (I~) in claim 4; and - Z~~ is a pyridyl, for example a 4-pyridyl, a 2-thienyl, a 3-thienyl, a 2-furyl or a 3-furyl, and its salts with mineral or organic acids.
6. A compound according to one of claims 1, 3, 4 or 5 of the formula in which:
- Z~~ is as defined in claim 5, and its salts with mineral and organic acids.
7. A compound according to claim 1 or claim 2 of formula (I) in which simultaneously:
- B is a group B3 in which:
~ either W3 is oxygen, R29 is a (C1-C4)alkyl or a trifluoromethyl and R28 is a (C1-C6)alkyl, especially an ethyl;
~ or W3 is oxygen, R28 is an allyl or a cyclohexyl and R29 is a methyl;
~ or W3 is oxygen, R28 is an ethyl and R29 is a methylamino or a dimethylamino;
~ or W3 is oxygen and R28 and R29 together form a 1,3-propylene, 1,4-butylene orcis,cis- 1,4-butadienyl group;
~ or W3 is sulfur and R28 and R29 together form a 1,4-butylene group;
- R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a 3,4-dichlorophenyl;

- Z = Z' as defined in claim 2, and - T and A are as defined above for a compound of formula (I) in claim 1, and its salts with mineral or organic acids.
8. A compound according to claim 1 or claim 2 of formula (I) in which simultaneously:
- B is B4 in which: W4 is 1 hydroxypropyl, 1-hydroxyethyl, l-hydroxybutyl, 2-hydroxybut-2-yl, 4-hydroxyhept-4-yl, 2-hydroxyethyl, 1-hydroxyiminopropyl (syn or anti), 1-methoxyiminopropyl (syn or anti), 2-acetoxyethyl, 2-acetamidoethyl, carboxyl, ethoxycarbonyl or pyrrolidin-1-ylcarbonyl;
- R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a 3,4-dichlorophenyl;
- Z = Z' as defined in claim 2: and - T and A are as defined above for a compound of formula (I) in claim 1, and its salts with mineral or organic acids.
9. A compound according to claim 1 or claim 2 of formula (I) in which simultaneously:
- B is a group B5 in which: W7 is a hydroxyl, W6 is a hydrogen and W8 is a phenyl; or W6 and W7 are hydrogen and W8 is selected from the following groups: 5-methyl-1,3,4-oxadiazol-2-yl, 4-ethoxycarbonylimidazol-2-yl, 2-fluoropyrid-3-yl, 2-methylthiophenyl, 4-methylthiophenyl, 2-methylsulfinylphenyl, 4-methylsulfinylphenyl and 4-(N-methylcarbamoyl)phenyl; or W7 is hydrogen and W6 and W8, together with the piperidine to which they are bonded, form a spiro[isobenzofuran-1(3H),4'-piperid] -1'-yl group or a 3-oxospiro[isobenzofuran-1(3H),4'-piperid]-1'-yl group;
- R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a 3,4-dichlorophenyl;
- Z = Z' as defined in claim 2; and - T and A are as defined above for a compound of formula (I) in claim 1, and its salts with mineral or organic acids.
10. A compound according to claim 1 or claim 2 of formula (I) in which simultaneously:
- B is a group B6 as defined in claim 1;
- R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a 3,4-dichlorophenyl;
- Z = Z' as defined in claim 2, and - T and A are as defined above for a compound of formula (I) in claim 1, and its salts with mineral or organic acids.
11. A compound according to claim 1 or claim 2 of formula (I) in which simultaneously:
- B is a group B7 selected from:
a) a 1-methanesulfonyl-spiro(indoline-3,4'-piperid-1'-yl) b) a 1-benzyloxycarbonyl-spiro(indoline-3,4'-piperid-1'-yl) c) a spiro(indoline-3,4'-piperid-1'-yl) d) a 1-acetyl-spiro(indoline-3,4'-piperid-1'-yl) e) a 1-propionyl-spiro(indoline-3,4'-piperid-1'-yl) f) a 1-formyl-spiro(indoline-3,4'-piperid-1'-yl) g) a 1-tert-butylcarbonyl-spiro(indoline-3,4'-piperid-1'-yl) h) a 1-methylaminocarbonyl-spiro(indoline-3,4'-piperid-1'-yl) i) a 1-ethoxycarbonyl-spiro(indoline-3,4'-piperid-1'-yl) j) a 1-ethanesulfonyl-spiro(indoline-3,4'-piperid-1'-yl) k) a 1-isopropanesulfonyl-spiro(indoline-3,4'-piperid-1'-yl) l) a 1'-methyl-1-methanesulfonyl-spiro(indoline-3,4'-piperidinio-1') iodide m) a 1-(2-aminoacetyl)-spiro(indoline-3,4'-piperid-1'-yl) n) a 1-methyl-spiro(indol-2-one-3,4'-piperid-1'-yl) o) a 2-methyl-spiro(isoindol-1-one-3,4'-piperid-1'-yl) p) a spiro(2-oxotetrahydroquinoline-4-4'-piperid-1'-yl) q) a 1-methyl-spiro(2-oxotetrahydroquinoline-4,4'-piperid-1'-yl) r) a spiro(2,3-dihydrobenzothiophene-3,4'-piperid-1'-yl) s) a 5-fluoro-spiro(2,3-dihydrobenzofuran-3,4'-piperid-1'-yl) t) a spiro(2,3-dihydrobenzofuran-3,4'-piperid-1'-yl) u) a spiro(2,3-dihydrobenzothiophene-3,4'-piperid-1'-yl) 1-oxide v) a spiro(2,3-dihydrobenzothiophene-3,4'-piperid-1'-yl) 1,1-dioxide w) a 5-fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperid-1'-yl) x) a 1-methanesulfonyl-5-methoxy-spiro(indoline-3,4'-piperid-1'-yl) y) a 1-methanesulfonyl-5-methyl-spiro(indoline-3,4'-piperid-1'-yl) z) a 5-chloro-1-methanesulfonyl-spiro(indoline-3,4'-piperid-1'-yl) aa) a 7-fluoro-1-methanesulfonyl-spiro(indoline-3,4'-piperid-1'-yl) ab) a 1-acetyl-5-fluoro-spiro(indoline-3,4'-piperid-1'-yl) ac) a 1-acetyl-5-chloro-spiro(indoline-3,4'-piperid-1'-yl) ad) a 1-acetyl-5-methyl-spiro(indoline-3,4'-piperid-1'-yl) ae) a 1-acetyl-6-fluoro-spiro(indoline-3,4'-piperid-1'-yl) af) a 1-acetyl-4-fluoro-spiro(indoline-3,4'-piperid-1'-yl) ag) a 1-(N,N-dimethylcarbamoyl)-spiro(indoline-3,4'-piperid-1'-yl);
- R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a 3,4-dichlorophenyl;
- Z = Z' as defined in claim 2; and - T and A are as defined above for (I) in claim 1, and its salts with mineral or organic acids.
12. A compound according to claim 1 or claim 2 of formula (I) in which simultaneously:
- B is a group B8 in which: W17 is a direct bond, W18 is an oxo or thioxo group,W19 is an oxy group or a group NH and W20 is an ethylene or trimethylene group;
- R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a 3,4-dichlorophenyl;
- Z = Z' as defined according to claim 2; and - T and A are as defined above for (I) for claim 1, and its salts with mineral or organic acids.
13. A compound according to claim 1 or claim 2 of formula (I) in which simultaneously:
- B is a group B9 in which: X2 is a group -COOR68 or a group -C(=W24)NR70R71 and W21, W22 and W23, together with the nitrogen atom, form a 2-oxopiperidino group or a 2-oxoperhydropyrimidin-1-yl group;
- R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a 3,4-dichlorophenyl;
- Z = Z' as defined in claim 2; and - T and A are as defined above for (I) in claim 1, and its salts with mineral or organic acids.
14. A compound according to claim 1 or claim 2 of formula (I) in which simultaneously:
- B is a group B10 as defined in claim 1;
- R1 and R2 together form a group -(CH2)3- or -(CH2)4-;
- Ar1 is a 3,4-dichlorophenyl;
- Z = Z' as defined in claim 2; and - T and A are as defined above for (I) in claim 1, and its salts with mineral or organic acids.
15. A compound according to claim 1, 2 or 14 of formula (I) in which simultaneously:
- B is a group B10 in which J6 is a group in which:
- W25 is a piperid-1-yl and X1 is a hydrogen, or W25 is an azetidin-1-yl, a pyrrolidin-1-yl, a piperid-1-yl, a morpholin-4-yl, a thiomorpholin-4-yl or a perhydroazepin-1-yl and X1 is a carbamoyl;
- R1 and R2 together form a group -(CH2)3-;
- Ar1 is a 3,4-dichlorophenyl;
- Z = Z' as defined in claim 2;
- T is a group -CO-; and - A is a direct bond, and its salts with mineral or organic acids.
16. A compound according to one of claims 1 or 2 of the formula in which:
- Ar'1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different;
- A' is a direct bond or a group -CH2-;
- Z' is as defined in claim 2; and - Ba is a group B1a of the formula in which J1a is a group in which:

- x is zero;
- Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and - X1a is a group selected from:
. hydrogen;
. (C1-C7)alkyl;
. -(CH2)m-OR4 in which m is two and R4 is a hydrogen or a (C1-C7)alkyl;
. -(CH2)m-OCOR5 in which:
m is two and R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl; or m is zero or one and R5 is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
. -(CH2)m-OCONH(C1-C7)alkyl in which m is zero or two;
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
. -(CH2)n-SR7 in which n is zero or one and R7 is a hydrogen or a (C1-C7)alkyl;
. -CH2-S(O)j-(C1-C7)alkyl in which j is one or two;
. -NR8R9 in which R8 and R9, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
. -(CH2)p-NR10R11 in which p is two and R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
. -NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
. -NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl and R15 is a (C1-C4)alkoxy;
. -(CH2)p-NR14C(=W1)R16 in which p is two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; and p is one, W1 is a sulfur atom and R14 and R16 are as just defined, or W1 is an oxygen atom, R14 is as just defined and R16 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;

. -(CH2)m-NR14COOR17 in which m is two, R14 is a hydrogen or a (C1-C7)alkyl and R17 is a (C1-C7)alkyl or a phenyl;
. -(CH2)m-NR14SO2R18 in which m is two, R14 is a hydrogen or a (C1-C7)alkyl and R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, atrifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
. -(CH2)m-NR14C(=W1)NR19R20 in which m is two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl; and m is zero or one, W1 is a sulfur atom and R14,R19 and R20 are as just defined, or W1 is an oxygen atom, R14 and R19 are each independently a hydrogen or a (C1-C7)alkyl and R20 is a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
. -(CH2)n-COOR2l in which n is one and R21 is a hydrogen or a (C1-C7)alkyl;
and n is zero and R21 is a hydrogen;
. -(CH2)n-C(=W1)NR19R20 in which n is one, W1 is an oxygen atom or a sulfur atom and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl; and n is zero, W1 is a sulfur atom and R19 and R20 are as just defined, or W1 is an oxygen atom, R19 is a hydrogen or a (C1-C7)alkyl and R20 is a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a piperazine heterocycle which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
-CO-NR22NR23R24 in which R22 is a hydrogen or a (C1-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl;

in which R25 is a hydrogen or a (C1-C7)alkyl and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; and ;

and its salts with mineral or organic acids.
17. A compound according to any one of claims 1, 2 or 16 of the formula in which:
- B'a is a group B'1a of the formula in which J'1a is a group in which:
- X is zero;
- Ar2a is as defined for a compound of formula (Ia) in claim 16; and - X'1a is a group selected from:
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
. -NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
. -NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl and R15 is a (C1-C4)alkoxy;
. -(CH2)p-NR14C(=W1)R16 in which p is one, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl;
. -(CH2)m-NR14C(=W1)NR19R20 in which m is zero, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C7)alkyl, R19 is a hydrogen or a (C1-C7)alkyl and R20 is a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls;
. -CO-NR22-NR23R24 in which R22 is a hydrogen or a (C1-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl;

in which R25 is a hydrogen or a (C1-C7)alkyl and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; and and its salts with mineral or organic acids.
18. A compound according to any one of claims 1, 2, 16 or 17 of the formula in which:
- X"1a is a group selected from:
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl, preferably a hydrogen or an acetyl;
. -NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl, preferably a hydrogen, and R13 is a vinyl, a furyl, a thienyl, a pyrrolyl or an imidazolyl, preferably a furyl or a thienyl;
. -NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl, preferably a hydrogen, and R15 is a (C1-C4)alkoxy, preferably an ethoxy; and in which R25 is a hydrogen or a (C1-C7)alkyl, preferably a hydrogen, and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; R26 and R27 are preferably a hydrogen; and and its salts with mineral or organic acids.
19. A compound according to claim 1 or claim 2 of the formula in which:
- Ar'1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different;
- A' is a direct bond or a group -CH2-;
- Z' is as defined in claim 2; and - Bb is a group B1b of the formula in which J1b is a group in which:
- x is one;
- Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and - X1b is a group selected from:
. hydrogen;
. (C1-C7)alkyl;
. formyl;
. (C1-C7)alkylcarbonyl;
. -(CH2)m-OR4;
. -(CH2)m-OCOR5;
. -(CH2)m-OCONH-(C1-C7)alkyl;
. -O-CH2CH2-OR6;
. -(CH2)n-SR7;
. -CH2-S(O)j-(C1-C7)alkyl;
. -NR8R9;
. -(CH2)p-NR10R11;
. -NR12COR13;
. -NR14COCOR15;
. -(CH2)p-NR14C(=W1)R16;
. -(CH2)m-NR14COOR17;
. -(CH2)m-NR14SO2R18;
. -(CH2)m-NR14C(=W1)NR19R20;

.-(CH2)n-COOR21;
.-(CH2)n-C(=W1)NR19R20;
.-CO-NR22-NR23R24;
.-CN;

;

;

. or X1b forms a double bond between the carbon atom to which it is bonded and the adjacent carbon atom of the piperidine ring, in which groups:
- m is zero, one or two;
- n is zero or one;
- p is one or two;
- j is one or two;
- W1 is an oxygen atom or a sulfur atom;
- R4 is a hydrogen or a (C1-C7)alkyl;
- R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
- R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
- R7 is a hydrogen or a (C1-C7)alkyl;
- R8 and R9 are each independently a hydrogen or a (C1-C7)alkyl; R9 can also be a (C3-C7)cycloalkylmethyl, a benzyl or a phenyl;
- or R8 and R9, together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
- R12 is a hydrogen or a (C1-C7)alkyl;
- R13 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;

- or R12 and R13 together are a group -(CH2)u- in which u is three or four;
- R14 is a hydrogen or a (C1-C7)alkyl;
- R15 is a (C1-C4)alkoxy;
- R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
- R17 is a (C1-C7)alkyl or a phenyl;
- R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, atrifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
- R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls;
- or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
- R21 is a hydrogen or a (C1-C7)alkyl;
- R22 is a hydrogen or a (C1-C7)alkyl;
- R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl;
- R25 is a hydrogen or a (C1-C7)alkyl; and - R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl, with the proviso that:
- when Ar'1 is the 3,4-dichlorophenyl group and -A'-Z' is the 3-methoxybenzyl group, Bb is the group B1b of the formula in which J1b is the group in which x is one, Ar2a is a phenyl group and X1b is other than hydrogen, and its salts with mineral or organic acids.
20. A compound according to any one of claims 1, 2 or 19 of the formula in which:
- B'b is a group B'1b of the formula in which J'1b is a group in which:
- x is one;
- Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and - X'1b is as group selected from:
. -(C1-C7)alkyl;
. -(CH2)m-OR4 in which m is one or two and R4 is a hydrogen or a (C1-C7)alkyl;
. -(CH2)m-OCOR5 in which:
m is zero and R5 is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl; or m is one or two and R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
. -(CH2)m-OCONH-(C1-C7)alkyl in which m is zero, one or two;
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a (C1-C7)alkylcarbonyl;
. -(CH2)n-SR7 in which n is zero or one and R7 is a hydrogen or a (C1-C7)alkyl;
. -CH2-S(O)j-(C1-C7)alkyl in which j is one or two;
. -NR8R9 in which R8 is a hydrogen or a (C1-C7)alkyl and R9 is a (C3-C7)cycloalkylmethyl or a benzyl; or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
. -(CH2)p-NR10R11 in which p is one or two and R10 and R11 are each independently a hydrogen or a (C1-C7)alkyl; R11 can also be a (C3-C7)cycloalkylmethyl or a benzyl;
. -NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is a (C3-C7)-cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; or R12 and R13 together are a group -(CH2)u- in which u is three or four;
. -NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl and R15 is a (C1-C4)alkoxy;
. -(CH2)p-NR14C(=W1)R16 in which p is one or two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
. -(CH2)m-NR14COOR17 in which m is zero, one or two, R14 is a hydrogen or a (C1-C7)alkyl and R17 is a (C1-C7)alkyl or a phenyl;
. -(CH2)m-NR14SO2R18 in which m is zero, one or two, R14 is a hydrogen or a (C1-C7)alkyl and R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a(C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
-(CH2)m-NR14C(=W1)NR19R20 in which m is zero, one or two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
. -(CH2)n-COOR21 in which n is one and R21 is a hydrogen or a (C1-C7)alkyl;
. -(CH2)n-C(=W1)NR19R20 in which n is zero or one, W1 is an oxygen atom or a sulfur atom and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls;
or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
. -CO-NR22-NR23R24 in which R22 is a hydrogen or a (C1-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl;

;

in which R25 is a hydrogen or a (C1-C7)alkyl and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; and ;

and its salts with mineral or organic acids.
21. A compound according to any one of claims 1, 2, 19 or 20 of the formula in which:
- X"1b is a group selected from:
. -(CH2)p-NR10R11 in which p is one and R10 and R11 are each a hydrogen;
. -(CH2)p-NR14C(=W1)R16 in which p is one, W1 is an oxygen atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a (C1-C7)alkyl, preferably an ethyl;
. -(CH2)m-NR14COOR17 in which m is zero, R14 is a hydrogen and R17 is a (C1-C7)alkyl, preferably an ethyl; and . -(CH2)n-C(=W1)NR19R20 in which n is zero, W1 is an oxygen atom and R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl, preferably pyrrolidine, and its salts with mineral or organic acids.
22. A compound according to claim 1 or claim 2 of the formula in which:
- Ar'1 is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different;
- A' is a direct bond or a group -CH2-;
- Z' is as defined above in claim 2; and - Bc is a group B1c of the formula in which J1c is a group in which:
- x is zero or one;
- Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and - X1b is as defined for a compound of formula (1b) in claim 19, and its salts with mineral or organic acids.
23. A compound according to any one of claims 1, 2 or 22 of the formula in which:
- B'c is a group B'1C of the formula in which J'1c is a group in which:
- x is zero or one;
- Ar2a is a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a hydroxyl, a (C1-C4)alkoxy, a (C1-C4)alkyl, a trifluoromethyl and a methylenedioxy, said substituents being identical or different; and - X'1b is a group selected from:
. (C1-C7)alkyl;
. -(CH2)m-OR4 in which m is one or two and R4 is a hydrogen or a (C1-C7)alkyl;
. -(CH2)m-OCOR5 in which m is zero and R5 is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
and m is one or two and R5 is a hydrogen; a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; or a pyridyl;
. -(CH2)m-OCONH-(C1-C7)alkyl in which m is zero, one or two;
. -O-CH2-CH2-OR6 in which R6 is a hydrogen; a (C1-C7)alkyl; a formyl; or a . (C1-C7)alkylcarbonyl;
. -(CH2)n-SR7 in which n is zero or one and R7 is a hydrogen or a (C1-C7)alkyl;
. -CH2-S(O)j-(C1-C7)alkyl in which j is one or two;
. -NR8R9 in which R8 is a hydrogen or a (C1-C7)alkyl and R9 is a (C3-C7)cycloalkylmethyl a benzyl; or R8 and R9, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
. -(CH2)p-NR10R11 in which p is one or two, R10 is a hydrogen or a (C1-C7)alkyl and R11 is a hydrogen, a (C1-C7)alkyl, a (C3-C7)cycloalkylmethyl or a benzyl;
. -NR12COR13 in which R12 is a hydrogen or a (C1-C7)alkyl and R13 is a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl; or R12 and R13 together form a group -(CH2)U in which u is three or four;
. -NR14COCOR15 in which R14 is a hydrogen or a (C1-C7)alkyl and R15 is a (C1-C4)alkoxy;
. -(CH2)p-NR14C(=WI)R16 in which p is one or two, WI is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R16 is a hydrogen or a (C1-C7)alkyl; a (C3-C7)cycloalkyl which is unsubstituted or substituted by one or more methyls; a phenyl; a benzyl; a vinyl; a pyridyl; a furyl; a thienyl; a pyrrolyl; or an imidazolyl;
. -(CH2)m-NR14COOR17 in which m is zero, one or two, R14 is a hydrogen or a (C1-C7)alkyl and R17 is a (C1-C7)alkyl or a phenyl;

-(CH2)m-NR14SO2R18 in which m is zero, one or two, R14 is a hydrogen or a (C1-C7)alkyl and R18 is a (C1-C7)alkyl; an amino which is free or substituted by one or two (C1-C7)alkyls; or a phenyl which is unsubstituted or monosubstituted or polysubstituted by a substituent selected from a halogen atom, a (C1-C7)alkyl, a trifluoromethyl, a hydroxyl, a (C1-C7)alkoxy, a carboxyl, a (C1-C7)alkoxycarbonyl, a (C1-C7)alkylcarbonyloxy, a cyano, a nitro and an amino which is free or substituted by one or two (C1-C7)alkyls, said substituents being identical or different;
-(CH2)m-NR14C(=W1)NR19R20 in which m is zero, one or two, W1 is an oxygen atom or a sulfur atom, R14 is a hydrogen or a (C1-C7)alkyl and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls; or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
. -(CH2)n-COOR21 in which n is one and R21 is a hydrogen or a (C1-C7)alkyl;
. -(CH2)n-C(=W1)NR19R20 in which n is zero or one, W1 is an oxygen atom or a sulfur atom and R19 and R20 are each independently a hydrogen or a (C1-C7)alkyl; R20 can also be a (C3-C7)cycloalkyl; a (C3-C7)cycloalkylmethyl; a hydroxyl; a (C1-C4)alkoxy; a benzyl; a phenyl; or a (C1-C7)alkyl substituted by a hydroxyl, a (C1-C3)alkoxy, a phenyl, a carboxyl, a (C1-C3)alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two (C1-C7)alkyls;
or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocycle selected from azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, perhydroazepine and piperazine which is unsubstituted or substituted in the 4-position by a (C1-C4)alkyl;
. -CO-NR22-NR23R24 in which R22 is a hydrogen or a (C1-C7)alkyl and R23 and R24 are each independently a hydrogen or a (C1-C7)alkyl;

in which R25 is a hydrogen or a (C1-C7)alkyl and R26 and R27 are each independently a hydrogen or a (C1-C7)alkyl; R27 can also be a formyl or a (C1-C7)alkylcarbonyl; and and its salts with mineral or organic acids.
24. A compound according to any one of claims 1,2,3,4,5,6,8,11,14,15 and 16 to 23 selected from:
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(pyrrolidin-1-ylcarbonyl)-piperid-1-yl]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-piperidinopiperid-1-yl)-propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-piperidinopiperid-1-yl)propyl]piperidine;
3-[3-[4-(acryloyl-N-methylamino)-4-phenylpiperid-1-yl]propyl-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
3-[3-[4-(2-aminothiazol-4-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
3-[3-(4-acetyl-4-benzylpiperid-l-yl)propyl]-l-benzoyl-3-(3,4-dichloro-phenyl)piperidine;
3-[3-[4-(acetylamino)-4-benzylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-[3-[4-benzyl-4-(propionylaminomethyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-[3-[4-benzyl-4-(ethoxycarbonylamino)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-[3-[4-benzyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(dimethylaminocarbonyl)-4-phenylpiperid-1-yl]propyl]perhydroazepine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-hydroxyethoxy)-4-phenyl-piperid-1-yl]propyl]piperidine;
3-[3-[4-(2-acetoxyethoxy)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;

1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-furoylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(2-thenoylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;
3-(3,4-dichlorophenyl)-1-isonicotinoyl-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-spiro(indoline-3,4'-piperid-1'-yl)propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-acetylspiro(indoline-3,4'-piperid-1'-yl)]propyl]piperidine;
3-(3,4-dichlorophenyl)-3-[3-[4-phenyl4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(2-thenoyl)piperidine;
3-(3 ,4-dichlorophenyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]-1-(3-thenoyl)piperidine;
3-(3,4-dichlorophenyl)-1-(2-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;
3-(3,4-dichlorophenyl)-1-(3-furoyl)-3-[3-[4-phenyl-4-(pyrrolidin-1-ylcarbonyl)piperid-1-yl]propyl]piperidine;
3-[3-[4-(2-amino-1,3,4-oxadiazol-5-yl)-4-phenylpiperid-1-yl]propyl]-1-benzoyl-3-(3,4-dichlorophenyl)piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[4-(ethoxalylamino)-4-phenyl-piperid-1-yl]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-(4-carbamoyl-4-morpholinopiperid-1-yl)propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methoxycarbonyl)spiro-(indoline-3,4'-piperid-1'-yl)]propyl]piperidine;
1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(N,N-dimethylcarbamoyl)spiro-(indoline-3,4'-piperid-1'-yl)]propyl]piperidine; and 1-benzoyl-3-(3,4-dichlorophenyl)-3-[3-[1-(methanesulfonyl)spiro(indoline-3,4'-piperid-1'-yl)]propyl]piperidine, in the form of racemates or one of their (+) or (-) enantiomers, and their salts with mineral or organic acids.
25. Solvates of the compounds according to any one of claims 1 to 24 and their salts.
26. Method of preparing a compound of formula (I) according to claim 1 and its salts, characterized in that:

1) a compound of the formula in which Ar1 R1 and R2 are as defined for a compound of formula (I) in claim 1 and E is hydrogen or an O-protecting group, is treated:
- either with a halogenated derivative of the formula Hal-CH2-A-Z (III) in which Hal is a halogen atom, preferably bromine, and A and Z are as defined for a compound of formula (I) in claim 1, when it is desired to prepare a compound of formula (I) in which T is a group -CH2-;
- or with a functional derivative of an acid of the formula HO-CO-A-Z (IIIa) in which A and Z are as defined above, when it is desired to prepare a compound of formula (I) in which T is a group -CO-;
- or with a chloroformate of the formula C1-COO-A-Z (IIIb) in which A and Z are as defined above, when it is desired to prepare a compound of formula (I) in which T is group -COO-;
- or with an isocyanate of the formula O=C=N-A-Z (IIIc) in which A and Z are as defined above, when it is desired to prepare a compound of formula (I) in which T is a group -CO-NR3- in which R3 is hydrogen;
- or with a carbamoyl chloride of the formula in which A and Z are as defined above and R'3 is a (C1-C4)alkyl, when it is desired to prepare a compound of formula (I) in which T is -CONR3- in which R3 is a (C1-C4)alkyl;
- or with a sulfonyl chloride of the formula C1-SO2-Z (IIIe) in which Z is as defined above, when it is desired to prepare a compound of formula (I) in which -T-A- is a group -SO2-, to give a compound of the formula 2) the O-protecting group, if present, is removed from the compound of formula (IV), by reaction with an acid or a base, to give the alcohol of the formula 3) the alcohol (V) is treated with a compound of the formula G-SO2-C1 (VI) in which G is a methyl, phenyl, tolyl or trifluoromethyl group, to give a compound of the formula 4) the compound (VII) is reacted:
- either with a cyclic secondary amine of the formula in which J'1 is:

* either a group in which Ar2 and x are as defined for (I) in claim 1 and X'1 is either X1 as defined for (I), or a precursor of X1, it being understood that when X'1 contains a hydroxyl group or an amino group, these groups can be protected;
* or a group in which Ar2 is as defined for (I) in claim 1;
* or a group in which Ar2 is as defined for (I) in claim 1;

* or a group in which Ar2 is as defined for (I) in claim 1;
* or a group in which Ar2, Am1 and r are as defined for (I) in claim 1;
* or a group Ar2-W2-CH-in which Ar2 and W2 are as defined for (I) in claim 1;
- or with a cyclic secondary amine of the formula in which J2 is as defined above for (I) in claim 1;
- or with a cyclic secondary amine of the formula in which J3 is as defined above for (I) in claim 1;
- or with a cyclic secondary amine of the formula in which W4 is as defined above for (I) in claim 1;
- or with a cyclic secondary amine of the formula in which W6, W7 and W8 are as defined above for (I) in claim 1;
- or with a cyclic secondary amine of the formula in which J4 is as defined above for (I) in claim 1;
- or with a compound of the formula in which f, g, W12, W13, W14, W15 and W16 are as defined above for (I) in claim 1;
- or with a cyclic secondary amine of the formula in which W17, W18, W19 and W20 are as defined above for (I) in claim 1, - or with a cyclic secondary amine of the formula in which J5 is as defined above for (I) in claim 1, - or a cyclic secondary amine of the formula in which J'6 is a group in which W25 is as defined above for (I) and X'1 is X1 as defined for (I) in claim 1, or a precursor of X1, it being understood that when X'1 contains a hydroxyl group or an amino group, these groups can be protected; and 5) after deprotection of the hydroxyl groups or amino groups, if appropriate, or conversion of X'1 to X1, if appropriate, the resulting product is optionally converted to one of its salts with a mineral or organic acid.
27. Method of preparing a compound of formula (I) according to claim 1 and its salts, characterized in that:
1') the nitrogen atom of the compound of formula (II) as defined in claim 25 is protected to give a compound of the formula in which Ar1, R1 and R2 are as defined for a compound of formula (I) in claim 1, E
is hydrogen or an O-protecting group and Pr is an N-protecting group such as thetrityl, tert-butoxycarbonyl or benzyloxycarbonyl group;
2') the O-protecting group, if present, is removed from the compound of formula (XVII), by reaction with an acid or a base, to give the alcohol of the formula 3') the alcohol (XVIII) is treated with a compound of formula (VI) as defined in claim 25 to give a compound of the formula 4') the compound (XIX) is reacted with a compound of formula (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIe), (VIIIf), (VIIIg), (VIIIh), (VIIIi) or (VIIIj) as defined in claim 25 to give a compound of the formula in which B is as defined for a compound of formula (I) in claim 1, it being understood that when B contains a hydroxide group or an amino group, these groups can be protected;
5') the protecting group Pr is selectively removed from the compound of formula (XX) to give the compound of the formula 6') the compound of formula (XXI) is treated with a compound of formula (III), (IIIa), (IIIb), (IIIc), (IIId) or (IIIe) as defined in claim 25; and 7') after deprotection of the hydroxyl groups or amino groups, if appropriate, the resulting product is optionally converted to one of its salts with a mineral or organic acid.
28. Method according to claim 27 for the preparation of a compound of formula (I~) according to claim 4 and its salts, characterized in that:
1~) a compound of the formula in which G is a methyl, phenyl, tolyl or trifluoromethyl group and Pr is an N-protecting group such as the trityl, tert-butoxycarbonyl or benzyloxycarbonyl group, is reacted with a compound of the formula in which J~ is as defined for a compound of formula (I~) in claim 4, to give a compound of the formula 2~) the protecting group Pr is selectively removed from the compound of formula (XX~) to give the compound of the formula 3*) the compound of formula (XXI*) is treated with a functional derivative of an acid of the formula HO-CO-Z* (III*) in which Z* is as defined for a compound of formula (I*) in claim 4; and 4*) after deprotection, if appropriate, the resulting product (I*) is optionallyconverted to one of its salts with a mineral or organic acid.
29. An enantiomer of a compound according to claim 1 of the formula in which:
- "*" denotes that the carbon atom carrying this label has the determined (+) or (-) absolute configuration; and - R1, R2, Ar1, T, A, Z and B are as defined for the compounds of formula (I) in claim 1, and its salts with mineral or organic acids, and their solvates.
30. Pharmaceutical composition comprising, as the active principle, a compound according to any one of claims 1 to 24 or 29 or one of its pharmaceutically acceptable salts and solvates.
31. Pharmaceutical composition according to claim 30 in the form of a dosage unit in which the active principle is mixed with at least one pharmaceutical excipient.
32. Pharmaceutical composition according to claim 31 containing 0.5 to 1000 mg of active principle.
33. Pharmaceutical composition according to claim 32 containing 2.5 to 250 mg of active principle.
CA002232007A 1995-09-14 1996-09-13 1-acyl-3-phenyl-3-(3-piperidinopropyl)piperidine derivatives as human nk3 receptor selective antagonists Abandoned CA2232007A1 (en)

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