FR2693196A1 - Derivatives of benzopyranone or benzothiopyranone, process for their preparation and pharmaceutical composition containing them - Google Patents

Abstract

Compounds of general formula (I), wherein X is an oxygen or sulphur atom, one of R1, R2, R3, R4, R5 and R6 is a group of formula (a), and R7 is an optionally substituted phenyl group or a group of formula (b).

Description

 The subject of the invention is new (thio) pyranic compounds having a pharmacological activity, especially as PAF-acetone antagonists.

A number of antagonistic compounds of
PAF-acether having a piperazinyl group are described, in particular in the following documents: EP284 359, EP-318,235, EP-368,670, DE-3,933,881, DE3,933,882, EP-279,681, EP-350,145 and EP. -395,446.

dans laquelle A1 est une liaison simple, un groupe carbonyle ou alkylène inférieur, la chaîne alkylène pouvant être interrompue par un groupe carbonyle et R1 est un hétérocycle éventuellement substitué par un groupe alkyle inférieur.In particular, EP-350 145 discloses substituted PAF-acetone-substituted piperazines, the general formula of which is:

wherein A1 is a single bond, a carbonyl or lower alkylene group, the alkylene chain being interrupted by a carbonyl group and R1 is a heterocycle optionally substituted by a lower alkyl group.

dans laquelle
X représente un atome d'oxygène ou de soufre, Rl, R2, R3, R4, R5 et R6 représentent un atome d'hydrogène, un groupe alkyle en Cl-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en C1-C7, alkoxy en C1-C7 ou acyloxy en C1-C7, ou un groupe de formule

dans laquelle
Z représente un atome d'oxygène ou de soufre, m et p sont des nombres de 0 à 4, n représente 0 ou 1, à la condition que la somme m + n + p représente un nombre inférieur à 6, q représente 0 ou 1,
R7 représente un groupe phényle non substitué ou substitué par 1 à 5 groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en C1-C7, alkoxy en C1-C7 ou acyloxy en C1-C7, ou un groupe de formule

dans laquelle les lignes en pointillés représentent une liaison éventuelle,
R8, Rg, R10, R1l, R12 et R13, identiques ou différents, représentent un atome d'hydrogène, d'halogène, un groupe alkyle en C1-C7, alkoxy en C1-C7, phényle ou pyridyle,
R14 représente un atome d'hydrogène, un groupe alkyle en
C1-C7, acyle en C1-C7 ou tertiobutoxycarbonyle, ou
R13 et R14 pris ensemble représentent un groupe =CH2-CH2=CH-, sous réserve qu'un et un seul des groupes R1 à R6 représente le groupe

New compounds having a pyranic or thiopyranic group have been discovered which exhibit potent PAFacetin antagonist activity.
The subject of the invention is compounds of general formula I

in which
X represents an oxygen or sulfur atom, R1, R2, R3, R4, R5 and R6 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group; or an optionally aromatic heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by one or more identical or different groups chosen from halogen, hydroxy and cyano. , nitro, amino, (di) (C 1 -C 7) alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 1 -C 7 acyloxy, or a group of formula

in which
Z represents an oxygen or sulfur atom, m and p are numbers from 0 to 4, n represents 0 or 1, with the proviso that the sum m + n + p represents a number less than 6, q represents 0 or 1
R7 represents a phenyl group which is unsubstituted or substituted with 1 to 5 identical or different groups chosen from halogen, hydroxy, cyano, nitro, amino, (di) (C1-C7) alkylamino, acetamido, phenyl, trifluoromethyl, C1-alkyl; -C7, C1-C7 alkoxy or C1-C7 acyloxy, or a group of formula

in which the dashed lines represent a possible bond,
R8, R8, R10, R11, R12 and R13, which may be identical or different, represent a hydrogen, halogen, a C1-C7 alkyl, a C1-C7 alkoxy, phenyl or pyridyl group,
R14 represents a hydrogen atom, an alkyl group
C1-C7, C1-C7 acyl or tertiobutoxycarbonyl, or
R13 and R14 together represent a group = CH2-CH2 = CH-, with the proviso that one and only one of R1 to R6 represents the group

Z, m, n, p, q and R7 being as defined above, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.

dans laquelle R1, R3, R4, R5 et R6 représentent un atome d'hydrogène, un groupe alkyle en C1-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en C1-C7, alkoxy en
C1-C7 ou acyloxy en C1-C7,
X, Z, m, n, p, q et R7 étant tels que définis précédemment.A first group of preferred compounds of formula I consists of the compounds of general formula II below

in which R1, R3, R4, R5 and R6 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms of which 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C1-C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, alkoxy
C1-C7 or C1-C7 acyloxy,
X, Z, m, n, p, q and R7 being as defined above.

dans laquelle
R1, R2, R3, R4 et R5 représentent un atome d'hydrogène, un groupe alkyle en C1-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogène, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en C1-C7, alkoxy en C1-C7 ou acyloxy en Choc7,
X, Z, m, n, p, q et R7 étant tels que définis précédemment.A second group of preferred compounds of general formula I consists of the compounds of general formula III below

in which
R1, R2, R3, R4 and R5 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms of which 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C1- C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or Choc7 acyloxy,
X, Z, m, n, p, q and R7 being as defined above.

Advantageously, one of the groups R1 and
R2 is selected from hydrogen, phenyl unsubstituted or substituted with one to five substituents, including one to three substituents, the same or different, selected from halogen, methyl and methoxy; and a thienyl or furanyl group, the other being a hydrogen atom or the group

Z, m, n, p, q and R7 being as defined above.

The groups R3, R4, R5 and R6 are preferably chosen from a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group and the group

Z, m, n, p, q and R7 being as defined above.

advantageously,
m represents 2 or 3,
n represents 0,
p represents 0,
q represents I, and
Z represents an oxygen atom.

dans lesquels R8 représente le groupe pyridyle, R1o et R1l représentent un atome d'hydrogène ou un groupe alkyle en
C1-C4, R14 représente un atome d'hydrogène, un groupe alkyle en C1-C4, acyle en C1-C6 ou alkoxycarbonyle en C1 C6. Among the preferred R7 groups, mention may be made of 3,4,5-trimethoxyphenyl group, or a group chosen from the following groups

in which R 8 represents the pyridyl group, R 10 and R 11 represent a hydrogen atom or an alkyl group
C1-C4, R14 represents a hydrogen atom, a C1-C4 alkyl group, a C1-C6 acyl group or a C1-C6 alkoxycarbonyl group.

et

Advantageously, R7 is chosen from groups f

and

R8, R1o R1l and R14 being as defined above.

dans laquelle
X représente un atome d'oxygène ou de soufre,
R1 représente un atome d'hydrogène, un groupe alkyle en
C1-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (enC1- C7) amino, acétamido, phényle, trifluorométhyle, alkyle en C1-C7, alkoxy en C1-C7 ou acyloxy en C1-C7,
R3 représente un atome d'hydrogène ou d'halogène, un groupe alkyle en C1-C7, ou un groupe alkoxy en C1-C7,
Z représente un atome d'oxygène ou de soufre, m représente 2 ou 3, et
R7 représente un groupe phényle non substitué ou substitué par 1 à 5 groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en C1-C7, alkoxy en C1-C7 ou acyloxy en C1-C7, ou un groupe de formule

dans laquelle les lignes en pointillés représentent une liaison éventuelle,
R8, Rg, R10, R1l, R12 et R13, identiques ou différents, représentent un atome d'hydrogène, d'halogène, un groupe alkyle en C1-C7, alkoxy en C1-C7, phényle ou pyridyle,
R14 représente un atome d'hydrogène, un groupe alkyle en C1-C7, acyle en C1-C7 ou tertiobutoxycarbonyle, ou
R13 et R14 pris ensemble représentent un groupe =CH2-CH2=CH-, ainsi que leurs sels correspondants obtenus par addition d'un acide minéral ou organique pharmaceutiquement acceptables.A subgroup of preferred compounds of general formula II is represented by the compounds of general formula IV:

in which
X represents an oxygen or sulfur atom,
R1 represents a hydrogen atom, an alkyl group
C1-C7, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) (C 1 -C 7) alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 1 -C 7 acyloxy,
R3 represents a hydrogen or halogen atom, a C1-C7 alkyl group, or a C1-C7 alkoxy group,
Z represents an oxygen or sulfur atom, m represents 2 or 3, and
R7 represents a phenyl group which is unsubstituted or substituted with 1 to 5 identical or different groups chosen from halogen, hydroxy, cyano, nitro, amino, (di) (C1-C7) alkylamino, acetamido, phenyl, trifluoromethyl, C1-alkyl; -C7, C1-C7 alkoxy or C1-C7 acyloxy, or a group of formula

in which the dashed lines represent a possible bond,
R8, R8, R10, R11, R12 and R13, which may be identical or different, represent a hydrogen, halogen, a C1-C7 alkyl, a C1-C7 alkoxy, phenyl or pyridyl group,
R14 represents a hydrogen atom, a C1-C7 alkyl group, a C1-C7 acyl or a tertiobutoxycarbonyl group, or
R13 and R14 together represent a group = CH2-CH2 = CH-, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.

dans laquelle
X représente un atome d'oxygène ou de soufre,
R1 représente un atome d'hydrogène, un groupe alkyle en C1-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1
C7) amino, acétamido, phényle, trifluorométhyle, aîkyle en C1-C7, alkoxy en C1-C7 ou acyloxy en C1-C7,
Z représente un atome d'oxygène ou de soufre, m représente 2 ou 3, et
R7 représente un groupe phényle non substitué ou substitué par 1 à 5 groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C) amino, acétamido, phényle, trifluorométhyle, alkyle en C1-C7, alkoxy en C1-C7 ou acyloxy en C1-C7, ou un groupe de formule

dans laquelle les lignes en pointillés représentent une liaison éventuelle,
R8, Rg, R1or R1l, R12 et R13, identiques ou différents, représentent un atome d'hydrogène d'halogène, un groupe alkyle en C1-C7, alkoxy en C1-C7, phényle ou pyridyle,
R14 représente un atome d'hydrogène, un groupe alkyle en
C1-C7, acyle en C1-C7 ou tertiobutoxycarbonyle, ou
R13 et R14 pris ensemble représentent un groupe =CH2-CH2=CH-, ainsi que leurs sels correspondants obtenus par addition d'un acide minéral ou organique pharmaceutiquement acceptables.A subgroup of preferred compounds of the general formula III is represented by the compounds of the general formula V

in which
X represents an oxygen or sulfur atom,
R1 represents a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups chosen from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C1);
C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or C1-C7 acyloxy,
Z represents an oxygen or sulfur atom, m represents 2 or 3, and
R 7 represents a phenyl group which is unsubstituted or substituted with 1 to 5 identical or different groups chosen from halogen, hydroxy, cyano, nitro, amino, (di) (C 1 -C) alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 4 alkyl; -C7, C1-C7 alkoxy or C1-C7 acyloxy, or a group of formula

in which the dashed lines represent a possible bond,
R8, Rg, R1or R11, R12 and R13, which may be identical or different, represent a hydrogen atom of halogen, a C1-C7 alkyl group, a C1-C7 alkoxy group, a phenyl group or a pyridyl group;
R14 represents a hydrogen atom, an alkyl group
C1-C7, C1-C7 acyl or tertiobutoxycarbonyl, or
R13 and R14 together represent a group = CH2-CH2 = CH-, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.

Among the preferred compounds, there may be mentioned 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 [(4-oxo-2-phenyl-4H-1) benzopyran-3-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid, hydrate;
4 (4R) - [[4- [3- (4-Oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] -1-piperazinyl] carbonyl] -2- (3-pyridinyl) acid Thiazolidinecarboxylic acid, 1,1-dimethyl ester;
4 (4R) - [[4- [3- (4-Oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] -1-piperazinyl] carbonyl] -2- (3-pyridinyl) acid Thiazolidinecarboxylic acid, 1,1-dimethyl ester, dioxalate; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[2- (4-chlorophenyl) -4-oxo-4H-1-benzopyran-3-yl) oxy] propylpiperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[2- (4-chlorophenyl) -4-oxo-4H-1-benzopyran-3-yl) oxy] propyl] piperazine. salt with 1.5 equivalents of oxalic acid, hydrate, 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[2- (4-chlorophenyl) -4) oxo-4H-1-benzopyran-3-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[2- (4-methoxyphenyl) -4-oxo-4H-1-benzopyran-3-yl) oxy] propylpiperazine, salt with 1.5 equivalents of oxalic acid; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[2- (4-chlorophenyl) -4-oxo-4H-1-benzopyran-3-yl) oxy] propylpiperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[2- (4-chlorophenyl) -4-oxo-4H-1-benzopyran-3-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid; 1 - [[2- (3-pyridinyl) -5,5-dimethyl-4 (4S) -thiazolidinylacarbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3) yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -5,5-dimethyl-4 (4S) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran) 3-yl) oxy] propyl] piperazine, dioxalate, hydrate; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine, trihydrochloride, trihydrate; 1 - [[2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine, oxalate ; 1 - [[2- (3-pyridinyl) -5,5-dimethyl-4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3 -yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -5,5-dimethyl-4 (4R) -thiazolidinyl] carbamyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran) 3-yl) oxy] propyl] piperazine, dioxalate, hydrate; 1 - [[2- (3-pyridinyl) -4 (R, S) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4 (R, S) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid, dihydrate; 4- (3,4,5-trimethoxybenzoyl) -1- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine; 4- (3,4,5-trimethoxybenzoyl) -1- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine, oxalate; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2- (3,4,5-trimethoxyphenyl) -4H-1-benzopyran) 3 yl) oxylpropylpiprazine; 1- [2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2- (3,4,5-trimethoxyphenyl) -4H-1-benzopyran) 3 yl) oxy] propyl] piperazine, dioxalate, trihydrate; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-1-benzopyran-3-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-4H-1-benzopyran-3-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid, hydrate; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-4H-1-benzopyran-3-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-4H-1-benzopyran-3-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid, dihydrate; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2- (2-thienyl) -4H-1-benzopyran-3-yl] oxy] propylpiperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2- (2-thienyl) -4H-1-benzopyran-3-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-7-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-7-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid, hydrate; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [2 [(4-oxo-2-phenyl-4H-1-benzopyran-7-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [2 [(4-oxo-2-phenyl-4H-1-benzopyran-7-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid;
4 (4R) - [[4- [3 - [[2- (4-methylphenyl) -4-oxo-4H-1-benzopyran-7-yl) oxy] propyl] piperazinyl] carbonyl] -2- (3) pyridinyl) -3-thiazolidinecarboxylic-1,1-dimethylethyl ester;
4 (4R) - [[4- [3 - [[2- (4-methylphenyl) -4-oxo-4H-1-benzo-pyran-7-yl) oxy] propyl] piperazinyl] carbonyl] -2- ( 3-pyridinyl) -3-thiazolidinecarboxylic-1,1-dimethylethyl ester, salt with 1.5 equivalents of oxalic acid; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(2- (4-methylphenyl) -4-oxo-4H-1-benzopyran-7-yl) oxy] propylpiperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(2- (4-methylphenyl) -4-oxo-4H-1-benzopyran-7-yl) oxy] propyl] piperazine, oxalate, hydrate; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-8-yl) oxy] propyl] piperazine; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-8-yl) oxy] propyl] piperazine, salt with 1.5 equivalents of oxalic acid; 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3- [4-oxo-3-phenyl-4H-1-benzopyran-2-yl) thio] propyl] piperazine ; and 1- [2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3- [4-oxo-3-phenyl-4H-1-benzopyran-2-yl) thio] propyl] piperazine; salt with 1.5 equivalents of oxalic acid, hemihydrate.

 By "C1-C6 alkyl group" is meant straight-chain or branched-chain groups, especially methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl and heptyl groups.

 By "C1-C7 alkoxy group" is meant straight or branched chain groups, especially methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy and heptyloxy groups.

 The term "C 1 -C 7 acyl group" means straight or branched chain alkyl groups bonded to a carbonyl function, in particular the acetyl and propionyl groups.

 The term "C 1 -C 7 acyloxy group" means straight or branched chain alkyl groups bonded to a carbonyloxy function, in particular the acetoxy and propionyloxy groups.

The term "halogen" refers to fluorine, chlorine, bromine or iodine atoms,
The term "heterocycle" denotes a ring with an aromatic or non-aromatic character comprising from 3 to 10 heteroatoms of the same nature or different chosen from oxygen, sulfur and nitrogen atoms, in particular the furyl, tetrahydrofuranyl, thienyl and imidazolyl groups, pyridyl, quinolinyl, tetrazolyl, thiazolyl, pyridazinyl and pyrimidinyl.

 The physiologically acceptable salts are those formed with the compounds of formula I to V with, in particular, oxalic, fumaric, maleic, citric, methanesulphonic, hydrochloric, hydrobromic and lactic acids.

dans laquelle X est tel que défini ci-dessus et R'1, R' 2'
R'3, RT4, R'5 et R'6 représentent un atome d'hydrogène, un groupe alkyle en Q-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en Q-C7, alkoxy en C1-C7 ou acyloxy en C1-C7, l'un parmi R'1, R'2, R' 3, Rt4, R' et R' 6 représentant un groupe de formule

z, m, n et p étant tels que définis ci-dessus, pour obtenir un composé de formule générale I que lTon convertit si on le souhaite en un sel correspondant par addition d'un acide minéral ou organique pharmaceutiquement acceptable.The compounds of the invention may be prepared by a process which comprises reacting a compound of general formula VI
Wherein R7 is as defined above and X1 represents a leaving group, especially a group selected from halogen, azido, cyano, (C1-C7) alkylsulfonyloxy, (C5-C9) arylsulfonyloxy, alkyl (C1-C7) aryl (C5-C9) sulfonyloxy and, -CO R15, R15 being selected from a halogen atom, a hydroxy group, a C1-C8 alkoxy group, an amino group, a group (di ) C 1 -C 7 alkylamino and OCOR 7 group, R 7 being as defined above with a compound of the general formula VII

wherein X is as defined above and R'1, R '2'
R'3, RT4, R'5 and R'6 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having 3 to 10 atoms including 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups selected from halogeno, hydroxy, cyano, nitro, amino, (di) alkyl (C 1 -C 7) amino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 1 -C 7 acyloxy, one of R'1, R'2, R '3, Rt4, R 'and R' 6 representing a group of formula

z, m, n and p being as defined above, to obtain a compound of general formula I which is converted if desired to a corresponding salt by addition of a pharmaceutically acceptable inorganic or organic acid.

 The compounds of general formula VI are commercially available compounds or can be prepared by those skilled in the art using known methods.

 As the compounds of formula VI, acid halides, such as acid chlorides, bromides and iodides, azidic derivatives, symmetrical acid anhydrides, esters or sulphonate derivatives, especially tosylates, are particularly preferred. and mesylates.

 When the compound of formula VI is used in the form of carboxylic acid (X1 = COOH), it is advantageous to carry out the reaction in the presence of a condensing agent, such as dicyclohexylcarbodiimide or 1,1 '-carbonyl-diimidazole.

 The reaction conditions depend on the nature of the compounds of formula VI and VII, in particular the reactivity of the compound of formula VI.

The reaction is generally carried out in an inert organic solvent, for example, pyridine, tetrahydrofuran, dioxane, diethyl ether,
N, N-dimethylformamide, benzene, toluene, xylene, dichloromethane, chloroform and acetonitrile.

 It may be advantageous to add to the reaction medium a base, for example an organic base, such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, or a mineral base such as potassium carbonate or carbonate. sodium, sodium hydrogen carbonate, sodium hydroxide or potassium hydroxide.

 The temperature may vary depending on the nature of the compound of the general formula VI. It is advantageously between zero degrees Celsius and the reflux temperature of the solvent.

 The compounds of general formula VI and VII are involved in the reaction in equimolar amounts or with an excess of one with respect to the other.

dans laquelle X est tel que défini précédemment, et R"1,
R"2, R"3, RIT4, R"5 et R"6 représentent un atome d'hydrogène, un groupe alkyle en Q-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en Q-C7, alkoxy en C1-C7 ou acyloxy en C1-C7, l'un parmi R"1, R"2, R"3, R"4, R"6 représentant un groupe de formule

dans laquelle
Z, m, n et p sont tels que définis précédemment, et X2 représente un groupe choisi parmi les groupes halogène, alkyl (en C1-C7) sulfonyloxy, aryl (en C5-Cg) sulfonyloxy, et alkyl (en C1-C7) aryl (en C5-C9) sulfonyloxy, avec un composé de formule générale IX

dans laquelle R20 représente un atome d'hydrogène, ou un groupe protecteur de la fonction amine, pour obtenir un composé de formule générale X

dans laquelle X est tel que défini précédemment et R"'1,
R"'2, R"'3 , R'N4, RII5 et R"'6 représentent un atome d'hydrogène, un groupe alkyle en Q-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en Q-C7, alkoxy en C1-C7 ou acyloxy en Q-C7, l'un parmi les groupes RIII, R'n2, R"'3, R",4, Rl"5 et R"'6 représentant le groupe de formule

dans laquelle m, n, p et R20 sont tels que définis cidessus, que l'on déprotège éventuellement pour obtenir un composé de formule générale VII.The compounds of general formula VII can be prepared by a process comprising reacting a compound of general formula VIII

wherein X is as defined above, and R "1,
R "2, R" 3, RIT4, R "5 and R" 6 represent a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl or benzyl group, or a heterocycle optionally aromatic compound having 3 to 10 atoms, including 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) C 1 -C 7 alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 1 -C 7 acyloxy, one of R "1, R" 2, R " 3, R "4, R" 6 representing a group of formula

in which
Z, m, n and p are as defined above, and X2 represents a group chosen from halogen, (C1-C7) alkylsulphonyloxy, (C5-Cg) arylsulphonyloxy, and (C1-C7) alkyl groups. C 5 -C 9 arylsulfonyloxy, with a compound of the general formula IX

wherein R20 represents a hydrogen atom, or a group protecting the amine function, to obtain a compound of general formula X

wherein X is as previously defined and R "'1,
R "'2, R"' 3, R'N4, RII5 and R "'6 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms, of which 1 to 4 heteroatoms chosen from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by one or more identical or different groups chosen from halogeno, hydroxy, cyano, nitro; amino, (di) C 1 -C 7 alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 1 -C 7 acyloxy, one of RIII, R'n 2 , R "'3, R", 4, R1 "5 and R"' 6 representing the group of formula

in which m, n, p and R 20 are as defined above, which is optionally deprotected to obtain a compound of general formula VII.

 Piperazines of the general formula IX are commercially available compounds or can be prepared in a simple manner by those skilled in the art.

 Protecting groups of the amine function are well known to those skilled in the art and there may be mentioned by way of illustration benzyloxycarbonyl groups in which the phenyl group is substituted or unsubstituted, ethoxy, methoxy, tertiobutoxycarbonyl or trimethylsilyl.

 The reaction is preferably carried out in an inert organic solvent, such as those described above for the preparation of the compound of general formula I, at temperatures ranging from room temperature to the reflux temperature of the solvent.

 The products of general formula VIII and IX are engaged in the reaction in equimolar quantities or with an excess of one with respect to the other, for example advantageously 3- to 6 moles of piperazine of formula IX will be used for one mole of compound of formula VIII.

 The method of deprotection of the compound of general formula X depends on the protecting group used and is among those known to those skilled in the art. It is advantageously carried out in an acid medium.

dans laquelle X est tel que défini précédemment et RIVl,
RIV2, RIV3, RIV4, RIV5 et RIV6 représentent un atome d'hydrogène, un groupe alkyle en Q-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en Q-C7, alkoxy en C1-C7 ou acyloxy en C1-C7, un des groupes RIV1, RIV2, RIV3, RIV4, RIV5, et RIV6 représentant un groupe ZH, Z étant tel que défini précédemment avec un composé de formule générale XII

dans laquelle X2 est un groupe partant tel que défini précédemment et X3 est un groupe partant choisi parmi les groupes X2, mais différent de X2, de sorte que X3 soit un meilleur groupe partant que X2 de manière à favoriser la produit de monosubstitution.The compounds of general formula VIII can be obtained by reacting a compound of general formula XI

wherein X is as previously defined and RIV1,
RIV2, RIV3, RIV4, RIV5 and RIV6 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms of which 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C1- C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or C1-C7 acyloxy, one of RIV1, RIV2, RIV3, RIV4, RIV5, and RIV6 being ZH, Z being as defined above with a compound of general formula XII

wherein X2 is a leaving group as defined above and X3 is a leaving group selected from X2 groups, but different from X2, so that X3 is a better leaving group than X2 so as to favor the monosubstitution product.

 The reaction conditions vary depending on the nature of the compounds of formula XI and that of X2 and X3.

 They are easily determined by those skilled in the art so as to obtain the mono-reactive product with X3.

 The reaction is advantageously carried out in an inert organic solvent, such as the solvents mentioned above for the preparation of the compounds of formulas I and VII.

 It is furthermore advantageous to add to the reaction medium an organic or inorganic base such as those mentioned above.

 The reaction temperature varies between room temperature and the reflux temperature of the solvent. It is chosen in such a way as to favor monosubstitution.

 The compounds of formula XI are prepared by techniques known in the literature, in particular according to the Algar-Flynn-Oyamada method (J. Algar and J.P.

Flynn, Proc. Roy. Irish Acad. 1.42 B (1934); T.

Oyamada, J. Chem. Japan 55, 1256 (1934), or according to the techniques described by G. P. Ellis: chromenes, chromanones and chromones, John Willey and Sons (1977).

dans laquelle X est tel que défini précédemment et RVl, RU2, RU3, RU4, RV5 et RV6 représentent un atome d'hydrogène, un groupe alkyle en Q-C7, un groupe cycloalkyle en C3-C6, un groupe phényle ou benzyle, ou un hétérocycle éventuellement aromatique ayant de 3 à 10 atomes dont 1 à 4 hétéroatomes choisis parmi 0, S et N, les groupes phényle, benzyle et hétérocyclique étant éventuellement substitués par un ou plusieurs groupes identiques ou différents choisis parmi halogèno, hydroxy, cyano, nitro, amino, (di)alkyl (en C1-C7) amino, acétamido, phényle, trifluorométhyle, alkyle en C1-C7) alkoxy en C1-C7 ou acyloxy en C1-C7, l'un parmi RV1, RV2, RV3, RV4, RV5 et RV6 étant un groupe ZH, Z étant tel que défini précédemment avec un composé de formule XIV

The compounds of general formula VIII can also be obtained by reacting a compound of general formula XIII

wherein X is as defined above and RV1, R2, RU3, RU4, RV5 and RV6 are hydrogen, C1-C7alkyl, C3-C6cycloalkyl, phenyl or benzyl, or an optionally aromatic heterocycle having from 3 to 10 atoms, of which 1 to 4 heteroatoms chosen from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by one or more identical or different groups chosen from halogeno, hydroxy, cyano, nitro; amino, (di) C 1 -C 7 alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl) C 1 -C 7 alkoxy or C 1 -C 7 acyloxy, one of RV1, RV2, RV3, RV4 Wherein RV5 and RV6 are ZH, Z being as previously defined with a compound of formula XIV

X3, m, n and p being as defined above and G being a conventional protecting group of the alcohol function, selected from groups well known to those skilled in the art, including tetrahydropyranyl and acetyl groups, to obtain a compound of general formula XIII in which one of RV1, RV2, RV3, RV4, RV5 and RV6 represents the group

le composé ainsi obtenu étant mis à réagir avec un composé de formule X2-Y, Y étant un groupe partant tel que ceux définis précédemment pour obtenir le composé de formule générale VIII.Z, m, n, p and G being as defined above, the compound thus obtained being deprotected by a method known to those skilled in the art to obtain a compound of general formula XIII in which RV1, RV2, RV3, RV4, RV5 and RV6 represent the group

the compound thus obtained being reacted with a compound of formula X2-Y, Y being a leaving group such as those defined above to obtain the compound of general formula VIII.

 The subject of the invention is also the new intermediate compounds of formulas VII and VIII as defined above.

 The compounds of the invention are active in pharmacology as antagonists of PAF acether.

PAF acether (Platelet Activating Factor,
PAF, PAF acether, AGEPC, acetylglycerylether phosphorylcholine) is a phospholipid produced or activated by different types of cells in animals and humans, such as for example and not exclusively macrophages, monocytes, platelets, mast cells and neutrophils.

 Its structure was determined as 1-hexadecyl / octadecyl-2-O-acetyl-sn-glyceryl-3-phosphoryl-choline.

 PAF is involved in multiple biological activities and thus appears as an important mediator in various physiological processes including for example and without limitation anaphylaxis, thrombosis, shock, eye diseases, kidney diseases, gastric ulcers, rejection of transplants, asthma.

 PAF plays a major role in inflammatory phenomena. It is one of the most powerful agents described increasing capillary permeability.

 PAF causes aggregation and degranulation of platelets and neutrophils in animals and humans.

 The action of PAF is via specific receptors.

 The PAF antagonist activity of the compounds of the invention is demonstrated by the platelet aggregation test and by the inhibitory effect of bronchospasm.

 The results are reported below.

 Inhibition of platelet aggregation induced by PAF acether.

 The PAF acether antagonist activity is demonstrated in the platelet aggregation inhibition test according to a method inspired by that used by LEVY (Febs Letters, 1983, 154 (2), 262-263) on guinea pig platelets. .

 The tests determine a concentration of compound that inhibits at 50 * (IC 50) a PAF-induced liminary aggregation. When the product is given orally, an ED50 is defined analogously.

 Inhibition of bronchospasm induced by PAF acether.

 Intravenous injection of PAF causes bronchoconstriction and hypotension in the anesthetized guinea pig.

The effective dose (ED 50) is the dose of product that inhibits this effect by 50%.

 The assay is performed according to a method described by Desquand S. (European Journal of Pharmacology 127, 1986, 83-95).

 Representative activities of the compounds of the present invention are given in the table below.

Table: PAF antagonist activity results acether compounds of the invention

<tb> COMPOUND <SEP> Salt <SEP> Inhibition <SEP> Inhibition
<tb> EXAMPLE <SEP> P <SEP><SEP> aggregation <SEP> bronchospasm
<tb><SEP> platelet <SEP> in <SEP> IV <SEP> guinea pig
<tb><SEP> vitro guinea-pig <SEP> DEY <SEP> mg / kg <SEP>
<tb><SEP> IC <SEP> 50 <SEP> nM
<tb><SEP> 1 <SEP> 3HCl, <SEP> 3H20 <SEP> 3.8 <SEP> 0.003
<tb><SEP> 5 <SEP> 1.5 <SEP> C2H204 <SEP> 10 <SEP> 0.004
<tb><SEP> 11 <SEP> C2H2O4, <SEP> H2O <SEP> 3.8 <SEP> 0.10
<Tb>
The compounds of the invention are characterized by an absence of toxicity in animals.

 The invention also relates to a pharmaceutical composition containing as active ingredient a compound according to the invention as defined above and a pharmacologically acceptable vehicle.

 These pharmaceutical compositions that can be administered in mammals are used in oral, intravenous, intraarterial, cutaneous, intestinal or aerosol administration. These new products have a long duration of action.

 Daily dosages may vary from 0.1 mg to 100 mg of active ingredient depending on the age of the patient and the severity of the condition being treated.

 The products of the general formula 1 are combined in the pharmaceutical form with excipients, flavorings and dyes suitable for forming tablets, for example. They can also be in liposomal form, microcapsules or nanocapsules, film-coated tablets, capsules, solutions, injectable solutions, suppositories, aerosols or creams. The excipients used may be for example microcrystalline cellulose, lactose, polyvidone, sodium starch glycolate, talc, magnesium stearate. The excipients for the liposomal forms, the microcapsules and nanocapsules may be polyalkylcyanoacrylates, or phospholipids.

 The coating of the tablets may be carried out with additives such as hydroxypropyl methylcellulose, various acrylic polymers, propylene glycol and titanium dioxide.

 Oral preparations may contain artificial flavors and sweeteners such as sucrose or aspartame.

 Injectable solution preparations are made with water which contains stabilizing, solubilizing agents such as sodium chloride, mannitol and sorbitol and / or buffers suitable for injectable solutions.

 Suppository preparations may contain excipients such as semisynthetic glycerides.

 The cream preparations are made inter alia by the addition of nonionic surfactants.

 The preparations for administration by aerosol can be made from the micronized active ingredient, combined with a surfactant such as sorbitan trioleate, in a carrier gas such as CFC 11 and 12.

 The compounds of the invention strongly inhibit the biological activities of the PAF acether by antagonizing the PAF acether receptors. They can be used for the treatment or prophylaxis of diseases characterized by an excess of PAF acether, such as, for example: prevention of platelet aggregation, hypotension, cardiovascular diseases (thrombosis, cardiac ischaemia). and cerebral, intravascular alterations, heart rhythm disorders), lung diseases (bronchial asthma, acute and chronic bronchitis, anaphylactic states, pulmonary edema, respiratory distress syndrome), inflammatory diseases, immunological disorders, dermatological disorders (allergies, urticaria, psoriasis), shock (anaphylactic, septic, endotoxic), ulcers (gastric, duodenum), rejections of organ transplantation, burns, kidney diseases (nephritis, glomerulonephritis) , liver diseases, pain, fever.

 The compounds of this invention may also be used in combination with any other therapeutically useful substance, for example, thrombolytics, phosphodiesterase inhibitors, stable analogues of prostacyclin, cyclooxygenase inhibitors, thromboxane synthetase inhibitors, tromboxane A 2 antagonists, anticoagulants (K antagonists, heparins, low molecular weight heparins), peripheral and central vasodilators, serotonin S 2 receptor antagonists, antihistamines, potassium channel activators, and s mimetics.

The following examples illustrate the invention without limitation. In the nuclear magnetic resonance (NMR) data, the chemical shifts 6 are expressed in ppm relative to the TMS. The melting points are taken on a Kofler bench (PFk) or apparatus of
Gallenkamp (PFg).

1) Préparation du 3-[(3-chloropropyl)oxy]-4-oxo-2-phényl- 4H-l-benzopyrane de formule

Example 1
Preparation of 1-CC2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3-E (4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine of formula

1) Preparation of 3 - [(3-chloropropyl) oxy] -4-oxo-2-phenyl-4H-1-benzopyran of Formula

59.6 g (0.25 moles) of 3-hydroxy-4-oxo-2-phenyl-4H-1-benzopyran are reacted with 41.1 g of
K2CO3 in 600 ml of dimethylformamide at 60 ° C. for one hour. 78.9 g of 1-bromo-3-chloropropane are added rapidly. It is stirred for 5 hours at 50 ° C. It is concentrated under reduced pressure. It is taken up in water and extracted with methylene chloride. It is dried over sodium sulphate and concentrated under reduced pressure. 26.7 g of an orange oil are thus obtained, which crystallizes in diisopropyl ether to give the above compound.

PFk = 50 C
IR: 1645, 1615, 1470, 1400, 1200.

 R.M.N.H1 (CDCl3): 2.1 (2H, quintuplet) -3.6 (2H, triplet) 4.1 (2H, triplet) -7.85 (9H, bulk).

2) Preparation of 1- [3- [z ((4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine of formula

Refluxed for 4 hours in 500 ml of xylene 17 g (0.054 mol) of the compound obtained in 1) and 18.6 g (0.216 mol) anhydrous piperazine. Cool and add 300 ml of water. The xylene is decanted and the aqueous phase is extracted with methylene chloride. The solvents are evaporated after drying over sodium sulfate. 4 g of a pure yellow oil are obtained in the TLC system (CHCl380 / MeOH20)
IR: 695, 760, 850, 1145, 1200, 1640, 1715.

3) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolyl dinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) ) oxy] propyl] piperazine (title compound)
4 g of the compound obtained in 2) are reacted with 2.3 g (0.011 mol) of 2- (3-pyridinyl) -4 (4R) thiazolidinecarboxylic acid in 60 ml of dimethylformamide at 0 ° C. in the presence of 1.5 g. (0.011 mol) of hydrated hydroxybenzotriazole and 2.3 g (0.011 mol) of dicyclohexycarbodiimide. Allowed to warm to room temperature overnight. The dicyclohexylurea formed is filtered.

The medium is concentrated under reduced pressure, taken up in 100 ml of ethyl acetate, washed with water, filtered and dried over sodium sulfate. The residue is chromatographed on a silica column using CHCl 3 60 / MeOH 40 as eluent. 5.5 g of the title compound is thus obtained in the form of a thick oil.

I.R .: 1680, 1650, 1480, 1430, 910.

5.5 g (0.011 mol) of the title compound are dissolved in 100 ml of acetone. 1.35 g (0.015 mol) of oxalic acid in solution in a sufficient quantity of acetone are added. A solid is formed. One hour is left stirring. It is filtered off, rinsed with acetone and dried under vacuum at room temperature. 2.2 g of crystals are obtained at room temperature.

4 g of oxalate crystals of PFk = 110 ° C. are obtained.

IR = 3500, 2600, 1720, 1620, 1640, 1475, 1410, 1210.

Elemental analysis (Q1H32N404S, 1, 5C2H204, H2O)
CHNSO
Calculated 57.53 5.25 7.89 4.51 23.13
Found 57.58 5.16 7.77 4.92
9 g of the title compound in base form are dissolved in 150 ml of acetone and 50 ml of ethanol are added. 5 ml of concentrated HCl are added dropwise. A pasty precipitate forms. It is further diluted with 100 ml of acetone. The solid formed is decanted and stirred with 250 ml of acetone. Stirred for one hour, drained and dried under vacuum at room temperature.

8.4 g of this solid are recrystallized from 150 ml of acetone and 120 ml of ethanol. It is allowed to stand overnight, cooled with ice, and ether is added until cloudiness appears. A solid is formed, drained, washed with ether, dried. 6 g of white crystals are thus obtained, corresponding to the trihydrochloride trihydrate of the title product.
PFk = 1700C
IR: 1660, 1635, 1610, 1550, 1470.

 NMRH1 (CDCl3): 1.9 (2H, multiplet) -2.3 3.5 (12H, solid) -3.65 (1H, triplet) -4.11 (2H, triplet) -7.28, 7 (13H, massive).

Elemental analysis (C31H32N4O4S, 3HCl, 3H2O)
CH C1 NOS
Calculated 51.70 5.74 14.77 7.78 15.55 4.45
Found 51.82 5.87 14.67 7.52 15.25 4.19
2 g of the title compound are dissolved in 60 ml of chloroform. 1.1 g (0.0114 mol) of methanesulfonic acid are added dropwise while cooling in an ice bath. The solid formed is filtered off, rinsed with ethyl ether and recrystallized from 100 ml of ethanol. 1.6 g of a crystalline product are thus obtained.

PFg: 175 - 1800C.

IR: 1660, 1635, 1615, 1560, 1470, 1200 cm -1.

1) Préparation du 2- ( 4-chlorophényl ) -4-oxo-4H-1-benzopy- rane, de formule

Elemental analysis (C31H32 N4O4S, 3CH3SO3H, 2H2O)
CHNOS
Calculated 46.34 5.49 6.36 27.24 14.55
Found 46.18 5.41 6.54 26.94 14.25
Example 2
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2- (4-chlorophenyl) -4H-1-benzopyran) 3-yl] oxy] propyl] piperazine, of formula:

1) Preparation of 2- (4-chlorophenyl) -4-oxo-4H-1-benzopyran of Formula

To a mixture of 110 g (0.78 mole) of p-chlorobenzaldehyde and 106.2 g (0.78 mole) of o-hydroxyacetophenone in 1.5 l of ethanol is added 225 ml of 30% sodium hydroxide. 45 minutes. Stir at room temperature for one day. 8 liters of ethanol and 200 ml of 30% NaOH are added.

It is heated to 50 OC. The mixture is cooled to 15 ° C. and 1 liter of 15% H 2 O 2 is rapidly added, stirred until a precipitate appears, and allowed to stand overnight.

It is filtered off, suspended in 5 l of water. Acidified with 500 ml of 9N H 2 SO 4. We wring and rinse with water. It is dried and recrystallized in 2.5 l of acetone. 26.3 g of product are obtained.

PFk = 2060C.

I.R .: 3280, 1680, 1300, 895.

2) Preparation of 2- (8-chlorophenyl) -3- (3-chloropropyl) oxy] -4-oxo-4H-1-benzopyran

26.3 g (0.0965 mol) of product obtained in 1) and 13.3 g of K 2 CO 3 in 430 ml of dimethylformamide are placed in a reactor. The mixture is heated for 30 minutes at 40 ° C. and 16.8 g (0.106 mol) of 1-bromo-3-chloropropane are added over 20 minutes.

It is heated for 5 hours at 40 ° C. and stirred overnight at room temperature. The medium is concentrated under reduced pressure and taken up in methylene chloride.

 After washing with water, it is evaporated again under reduced pressure after drying over sodium sulphate. An oil is obtained which crystallizes. After recrystallization from 600 ml of hexane, 24.5 g of product are obtained.

PFk = 80C.

I.R .: 1635, 1615, 1470, 1195.

NMR H1 (CDCl3): 2.25 (2H, quintuplet) -3.7 (2H, triplet) -4.2 (2H, triplet) -7.2-8.5 (8H, bulk).

3) Preparation of 1- [3-EE2- (4-chlorophenyl) -4-oxo-4H-1-benzopyran-3-yl] oxy] propyl] piperazine

24 g (0.0687 mol) of the product obtained in 2) and 23.7 g (0.27 mol) of anhydrous piperazine are refluxed for 4 hours in 285 ml of xylene. A semicrystalline mass is formed in the medium. After decantation, this mass is taken up in 600 ml of N HCl. Wash with ether. The aqueous phase is then basified with 10% NaOH. The oily precipitate formed is extracted with CHCl3.

After drying over sodium sulfate and concentrating in vacuo, 14.4 g of a thick oil is obtained which is the product of formula above.

IR: 3220, 1640, 1475, 1410, 1200.

NMR H1 (CDCl3): 1.8 (2H, quintuplet) -2.2 2.6 (4H, solid) -2.7 3.1 (4H, solid) -4.1 (2H triplet) -7.2 8 , 4 (8H, massive).

4) Preparation of 1-E [2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2- (4-chlorophenyl) -4H- 1 benzopyran-3-yl] oxy] propyl] piperazine, (composed of title)
A reactor containing 14.4 g (0.0361 mol) of product obtained in 3) is cooled to 0 ° C., 7.6 g (0.0361 mol) of 2- (3-pyridinyl) -4 (4R) acid are obtained. thiazolidinecarboxylic acid, 4.9 g of hydrated hydroxybenzotriazole and 150 ml of dimethylformamide.

7.5 g (0.0361 moles) of dicyclohexylcarbodiimide are then added. It is maintained for 1 hour at 0 ° C. and stirred overnight at room temperature and concentrated under vacuum.

The residual oil is taken up in CHCl2. It is washed with saturated NaHCO 3 solution and then with saturated NaCl solution, dried over sulfate and concentrated in vacuo.

The residue is taken up in acetone and an insoluble material is removed. 21 g of a thick orange oil are thus obtained.

Elution on a silica column with AcOEt 60 - CHC1330 - MeOH 10 system.

19.5 g of a yellow oil of the title product are thus obtained.

IR: 3300, 1620, 1470, 1240, 760.

19.5 g (0.033 mole) of the title compound are dissolved in 300 ml of acetone and a solution of 4.5 g (0.0495 mole) of oxalic acid in a sufficient amount of acetone is added. . Stirred for 30 minutes and filtered, rinsed with acetone and then with ether.

17 g of white crystals of oxalate are obtained.

PFk = 140 C.

I.R .: 1720, 1640, 1470, 1200.

1 H NMR (deuterated DMSO): 2.1 (2H, quintuplet) -2.8 4.6 (15H, solid) -5.55 and 5.65 (1H, 2 singlet) -7.0 9.0 (12H) , massive) -10,0 (exchangeable solid).

Elemental analysis (C31H31ClN4O4S, 1.5 C3H2O4, H2O).

1) Préparation du 2-(4-méthoxyphényl)-4-oxo-4H-1-benzopy- rane

CH Cl NOS
Calculated 54.87 4.87 4.76 7.52 23.68 4.30
Found 54.38 4.74 7.14 4.32
In the same manner as in Example 2, the following compounds were obtained:
Example 3
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2- (4-methoxyphenyl) -4H-1-benzopyran-3- yl] oxy] propyl] piperazine of formula:

1) Preparation of 2- (4-methoxyphenyl) -4-oxo-4H-1-benzopyran

PFK = 233C.

I.R .: 1700, 1610, 1570, 1260, 1020.

2) Preparation of 3-C (3-chloropropyl) oxy-2- (4-methoxyphenyl) -4-oxo-4H-1-benzopyran

PFk = 66 C. (hexane)
IR: 1635, 1605, 1555, 1505, 1270.

NMR H1 (CDCl3): 2.2 (2H, quintuplet) -3.7 (2H, triplet) 3.95 (3H, singlet) -4.2 (2H, triplet) -6.8 8.4 (8H, massive ).

3) Preparation of 1- [3 - [[2- (4-methoxyphenyl) -4-oxo-4H] -benzopyran-3-yl] oxy] propyl] piperazine

Yellow oil.

I.R .: 1730, 1635, 1605, 1505, 1460, 1250, 1025.

4) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2- (4-methoxyphenyl) -4H-1-benzopyran) 3-yl] oxy] propyl] piperazine (title compound)
Yellow oil.

IR: 3300, 1735, 1640, 1605, 1470, 1260, 1030, 750.

oxalate
PFK: 130 - 40 C (acetone + ethanol)
IR: 1720, 1640, 1605, 1260.

1) Préparation du 2-(4-méthoxyphényl)-4-oxo-4H-1-benzopy- rane

Example 4
Preparation of 1-CC2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2- (4-methoxyphenyl) -4H-1-benzopyran-3- yl] oxy] propyl] piperazine

1) Preparation of 2- (4-methoxyphenyl) -4-oxo-4H-1-benzopyran

PF = 195 C.

IR: 3295, 1610, 1560, 760.

2) Preparation of 3 - [(3-chloropropyl) oxy] -2- (4-methylphenyl) -4-oxo-4H-1-benzopyran

PFk = 70 C (hexane)
IR: 1630, 1465, 1390.

3) Preparation of 1- [3 - [[2- (4-methoxyphenyl) -4-oxo-4H-1-benzopyran-3-yl] oxy] propyl] piperazine

Yellow crystallizing oil.

IR: 1640, 1615, 1560, 1465, 1400, 1200.

NMR H1 (CDCl3): 1.5 3.0 (15H, bulk) -3.4 (1H, singlet exchangeable with D2O) -4.05 (2H, triplet) -7.0 8.4 (8H, bulk) .

4) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2- (4-methoxyphenyl) -4H- 1-Benzopyran-3-yl] oxy] propyl] piperazine (title compound)
Yellow oil.

I.R .: 2920-2950, 1630, 1465, 1410, 1300, 1200.

oxalate
PFK = 125-30 C (acetone + ethanol).

I.R .: 1720, 1640, 1615, 1470, 1410.

1) Préparation du 4-oxo-2- ( 2-thiényl ) -4H-1-benzopyrane

Elemental analysis (C32H34N + OsS, 1.5 C2H204)
CHNOS
Calculated 59.56 5.28 7.94 22.67 4.54
Found 59.95 5.36 7.87 4.76
Example 5
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2-thienyl-4H-1-benzopyran-3-yl]) oxy] propyl] piperazine

1) Preparation of 4-oxo-2- (2-thienyl) -4H-1-benzopyran

PFk = 208 C
IR: 1605, 1560, 1480, 1430, 1120.

2) Preparation of 3 - [(3-chloropropyl) oxy] -4-oxo-2- (2-thienyl) -4H-1-benzopyran

PFk = 72 C
IR: 1640, 1620, 1610, 1575, 1470.

3) Preparation of 1- [3 - [[4-oxo-2- (2-thienyl) -4H-1-benzopyran-3-yl] oxy] propyl] piperazine
Yellow oil.

IR: 1640, 1610, 1570, 1470, 1430.

4) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2-thienyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine
Amorphous solid.

IR: 1640, 1610, 1565, 1465, 1425, 1240, 1205.

oxalate
PFK = 135-140 ° C (acetone / ethanol: 3/1, V / V)
IR: 1720, 1640, 1610, 1565, 1425.

1) Préparation du 3-C(3-chloropropyl) oxyl -4-oxo-4H-1- benzothiopyrane

Elemental analysis (C29H30N4O4S2, 1.5 C2H204)
CHNOS
Calculated 55.08 4.77 8.03 22.93 9.19
Found 54.94 4.96 8.12 9.09
Example 6
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-4H-1-benzothiopyran-3-yl] oxy] propyl ] piperazine of formula

1) Preparation of 3-C (3-chloropropyl) oxyl-4-oxo-4H-1-benzothiopyran

PFk = 850C
IR: 1620, 1595, 1200, 745.

2) Preparation of 1- [3 - [[4-oxo-4H-1-benzothiopyran-3-yl] oxy] propyl] piperazine

Oil.

IR: 1620, 1595, 1570, 1550, 1465, 1445.

NMR H1 (CDCl3): 1.6 3.6 (12H, massive) -4.0 (2H, triplet) -6.95 (1H, singlet) 7.2 7.7 (3H, massive) -8.2 8.7 (1H, massive).

3) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-4H-1-benzothiopyran-3-yl] oxy] ] propyl] piperazine (title compound)
Yellow oil.

IR: 1630, 1595, 1575, 1200, 800.

oxalate
PFg = 92-960C (isopropanol)
IR: 1720, 1620-1660, 1190.

1) Préparation du 7-[3-chloropropyl)oxy]-4-oxo-2-phényl- 4H-l-benzopyrane

Elemental analysis (C25H28N4O3S2, 1.5 C2H2O4, H2O)
CHNOS
Calculated 51.75 5.11 8.62 24.62 9.86
Found 51.42 5.02 8.41 9.72
Example 7
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl) carbonyl] -4- [3 - [[4-oxo-2-phenyl-4H-1-benzothiopyran-7-yl] oxy ] propyl] piperazine of formula

1) Preparation of 7- [3-chloropropyl) oxy] -4-oxo-2-phenyl-4H-1-benzopyran

PFk = 114 ° C
IR: 1630, 1610, 1580, 1365, 1380.

NMRH1 (CDCl3): 2.3 (2H, quintuplet) -3.8 (2H, triplet) -4.2 (2H, triplet) -6.7 (1H, singlet) -6.8 7.1 (2H, massive) -7.2 8.2 (6H, massive).

2) Preparation of 1- [3 - [[4-oxo-2-phenyl-4H-1-benzopyran-7-yl] oxy] propyl] piperazine

Yellow oil
IR: 1630, 1605, 1445, 1380, 1360.

3) Preparation of E [2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2-phenyl-4H-1-benzopyran-7-yl) oxy] propyl ] piperazine (composed of the title)
Orange oil.

IR: 1630, 1610, 1450, 1035.

oxalate
PFk = 160 C
IR: 1635, 1450, 110, 1185.

1) Préparation du 7-[(2-chloroéthyl)oxy]-4-oxo-2-phényl- 4H-l-benzopyrane

Elemental analysis (C31H32N4O4S, 1.5 C2H2O4, H2O)
CHN
Calculated 53.53 5.25 7.89
Found 57.49 4.99 7.43
Example 8
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [2 [(4-oxo-2-phenyl-4H-1-benzopyran-7-yl) oxy] ethyl] piperazine

1) Preparation of 7 - [(2-chloroethyl) oxy] -4-oxo-2-phenyl-4H-1-benzopyran

PFK = 1300C (isopropanol)
IR: 1625, 1595, 1260, 1175.

2) Preparation of 1- [2 - [[4-oxo-2-phenyl-4H-1-benzopyran-7-yl] oxy] ethyl] piperazine

Mp = 138 C 3) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [2 - [(4-oxo-2-phenyl-4H-1-benzopyran) 7-yl) oxy] ethyl] piperazine (title compound)
Oil.

IR: 1630, 1605, 1445, 1375, 1030.

oxalate
PFk = 1200C
IR: 1730, 1640, 1455, 1390, 1255.

1) Préparation du 3-[(3-chloropropyl)oxy]-4-oxo-4H-1- benzopyrane

Example 9
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-4H-1-benzopyran-3-yl] oxy] pro pyl] piperazine of formula

1) Preparation of 3 - [(3-chloropropyl) oxy] -4-oxo-4H-1-benzopyran

PFk = 95 C
IR: 1650, 1610, 1460, 1265, 1200
1 H NMR (CDCl 3): 2.3 (2H, multiplet) -3.8 (2H, triplet) 4.2 (2H, triplet) -7.2 8.4 (5H, bulk).

2) Preparation of 1-E3 [[4-oxo-4H-1-benzopyran-3-yl] oxy] propyl] piperazine

Oil.

IR: 1690, 1610, 1460, 1320 3) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-4H] 1-Benzopyran-3-yl) oxy] propyl] piperazine (title compound)
Oil.

1 H NMR (CDCl 3): 2.05 (2H, multiplet) 2.2 3.9 (15H, bulk) -4.05 (2H, triplet) -5.6 (multiplet) -5.9 (singlet) 7, 1 9.0 (9H, massive).

oxalate
PFg = 85-90C
IR: 1640, 1205.

1) Préparation du 8-[(3-chloropropyl)oxy]-4-oxo-2-phényl- 4H-lbenzopyrane

Elemental analysis (C25H28N4O4S, 1.5 QH2O4, 2H2O)
CHNOS
Calculated 51.60 5.41 8.60 29.46 4.92
Found 51.37 5.10 8.41 4.81
Example 10
Example of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2-phenyl-4H-1-benzopyran-8-yl] oxy ] propyl] piperazine

1) Preparation of 8 - [(3-chloropropyl) oxy] -4-oxo-2-phenyl-4H-benzopyran

PFk = 1280C
IR: 1640, 1580, 1570, 1380, 1285 2) Preparation of 1- [3 - [[4-oxo-2-phenyl-4H-1-benzopyran-8-yl] oxy] propyl] piperazine

PFk = 130 C
IR: 1645, 1590, 1580, 1380.

3) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran) 8yl) oxy] propyl] piperazine (title compound)
Yellow oil.

1) Préparation du 7-[(3-chloropropyl)oxy]-2-(4-méthylphé- nyl ) -4-oxo-4H-1-benzopyrane

oxalate
PFk = 1900C
IR: 1720, 1640, 1580, 1280
Example 11
Preparation of 1 [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[2- (4-methylphenyl) -4-oxo-4H-1-benzopyran] -7 -yl] oxy] propyl] piperazine

1) Preparation of 7 - [(3-chloropropyl) oxy] -2- (4-methylphenyl) -4-oxo-4H-1-benzopyran

PFk = 1300C
IR: 1630, 1600, 1440, 1375, 1360, 1175.

2) Preparation of 1- [3 - [[2- (4-methylphenyl) -4-oxo-4H-1-benzopyran-7-yl] oxy] propyl] piperazine

PFk = 110 C
IR: 1640, 1635, 1445, 1175.

3) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[2- (4-methylphenyl) -4-oxo-4H-1-benzopyran] 7-yl] oxy] propyl] piperazine (title compound)
Oil.

I.R .: 1630, 1440, 1370, 1170, 760.

oxalate
PFk = 145 C
IR: 1630, 1445, 1375.

Elemental analysis (C32H34N4O4S, QH2O4, H2O)
CHNOS
Calculated 60.16 5.64 8.26 22.67 4.72
Found 60.38 5.71 8.22 4.57
Example 12
Preparation of 4 (4R) - [[4- [3- (4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] 1,1-dimethylethyl ester 1-piperazinyl] carbonyl] -2- (3-pyridinyl) -3-thiazolidinecarboxylic acid, of formula

Prepared from 3- (N-tert-butyloxycarbonyl) -2- (3-pyridinyl) -4-thiazolidinecarboxylic acid and from the compound obtained in Step 2) of Example 1.

Yellow oil.

I.R .: 1700, 1660, 1640, 1370, 760.

oxalate
PFk = 125C.

PFg = 110-115 ° C.

I.R .: 1700, 1640, 1610, 1470, 1200.

Preparé à partir d'acide 3-(N-tertiobutyloxycarbonyl)-2- (3-pyridinyl)-4-thiazolidine-carboxylique et à partir du composé préparé à l'étape 2) de l'exemple 11.Elemental analysis (C36H40N4O6S, 2C2H2O4)
CHNOS
Calculated 57.41 5.30 6.70 26.77 3.83
Found 57.71 5.60 6.90 3.77
Example 13
Preparation of 4 (4R) - [[4- [3- (4-oxo-2- (methylphenyl) -4H-1-benzopyran-7-yl] oxy] propyl] 1,1-dimethylethyl ester 1-Piperazinyl] carbonyl-2- (3-pyridinyl) -3-thiazolidinecarboxylic of formula

Prepared from 3- (N-tert-butyloxycarbonyl) -2- (3-pyridinyl) -4-thiazolidinecarboxylic acid and from the compound prepared in step 2) of Example 11.

Oil.

I.R .: 1700, 1660, 1640, 1445, 1170.

oxalate
PFk = 1500C
IR: 1700, 1630, 1445, 1375.

Elemental analysis
CHNOS
Calculated 59.61 5.62 6.95 26.33 3.97
Found 59.82 5.52 7.19 3.83
Example 14
Preparation of 1 - [[2- (3-pyridinyl) -5,5-dimethyl-4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl) -4H-1-benzopyran) 3-yl) oxy] propyl] piperazine, of formula:

Prepared from 5,5-dimethyl-2- (3-pyridinyl) 4 (4R) -thiazolidinecarboxylic acid and the compound of Step 2) of Example 1.

Oil.

IR: 1645, 1620, 1565, 1470, 1420
oxalate
PFk = 120 - 125 C
PFg = 118-120C
IR: 1730, 1640, 1615, 1470
Elemental analysis (C33H36N4O4S, 2C2H2O4, H2O)
CHNOS
Calculated 56.76 5.40 i, 15 26.57 4.09
Found 56.81 5.50 7.15 3.66
Example 15
Preparation of 1 - [[2- (3-pyridinyl) -5,5-dimethyl-4 (4S) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran) 3-yl) oxy] propyl] piperazine, of formula:

Prepared from 5,5-dimethyl-2- (3-pyridinyl) -4 (4S) -thiazolidinecarboxylic acid and the compound of Step 2) of Example 1.

Oil.

oxalate
PFg = 110-112 ° C
IR: 1735, 1640, 1615, 1470, 1205
Elemental analysis (C33H36N4O4S, 2C2H2O4mH2O)
CHNOS
Calculated 56.76 5.40 7.15 26.57 4.09
Found 56.85 5.49 6.93 3.90
Example 16
Preparation of 1 - [[3- (3-pyridinyl) -1H, 3H-pyrrolo [1,2c] thiazol-7-yl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H) -1benzopyran-3-yl) oxy] propyl] piperazine, of formula

Prepared from 3- (3-pyridinyl) -1H, 3H-pyrrolo [1,2-c] thiazolecarboxylic acid and the compound obtained in step 2) of Example 1.

Amorphous solid.

IR: 1640, 1610, 1565, 1470, 1435, 1250
oxalate
PFk = 178 C
IR: 1720, 1640, 1615, 1250, 1200.

NMR (Deuterated DMSO): 1.5 4.5 (16H, massive) -6.3 6.8 (3H, massive) -7.2 8.8 (11H, massive) -10.2 (2H exchangeable, massive) .

1) Préparation du 4-oxo-3-phényl-2-thiol-4H-1-benzopyrane

Elemental analysis (C34H32N4O4S, C2H2O4)
CHNOS
Calculated 63.33 5.02 8.21 18.75 4.70
Found 63.34 4.82 8.24 4.78
Example 17
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3-E (4-oxo-3-phenyl-4H-1-benzopyran-2-yl) thio] propyl] piperazine, of formula

1) Preparation of 4-oxo-3-phenyl-2-thiol-4H-1-benzopyran

In a reactor containing 31.8 g (0.15 mole) of (2hydroxy) phenylbenzylketone, 34.2 g (0.45 mole) of carbon disulfide and 140 ml of dimethylsulfoxide are added dropwise in 1 hour. a solution of 17.5 g (0.267 mol) of potassium hydroxide in 25 ml of water.

It is stirred for 4 hours at ambient temperature and the reaction medium is poured into a mixture of 11 ml of ice water and 300 ml of concentrated HCl. Let stand overnight and squeeze. After recrystallization from 1.5 l of ethanol, 28.5 g of the above product are obtained.

PFk = 196-8C.

2) Preparation of 1-C3CC4-oxo-3-phenyl-4H-1-benzopyran-2-yl] thio] propyl] piperazine.

5 g (0.019 mol) of compound of step 1) and 3.3 g (0.0589 mol) of potassium hydroxide in 250 ml of ethanol are heated at 40 ° C. for 15 minutes. 5.2 g (0.0215 moles) of 1- (3-chloropropyl) piperazine dihydrochloride are then added in the form of hemihydrate by spatula tips in 2 hours. Refluxed for 6 hours.

An insoluble material is filtered off and taken up in water. It is taken up in methyl chloride, washed with normal sodium hydroxide solution, dried over sodium sulfate and the solvents are evaporated off under reduced pressure. 2.9 g of compound of the above formula are thus obtained in the form of an amorphous mass.

I.R .: 2950, 2820, 1635, 1620, 1540, 1470, 1370.

3) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-3-phenyl-4H-1-benzopyran)] 2yl) thio] propyl] piperazine (title compound)
Oil.

IR: 1635, 1465, 1365, 950.

oxalate
PFg = 122 - 4 C
IR: 1720, 1620, 1465, 1370, 1285, 1220.

1) Préparation de l'acide 2-(3-pyridinyl)-4(R,S)-thiazo- lidinecarboxylique

Elemental analysis (C31H32N4O3S2, 1.5 QH2O4, 0.5H2O)
CHNOS
Calculated 56.96 5.06 7.81 20.35 8.94
Found 57.25 5.44 7.65 8.82
Example 18
Preparation of 1 - [[2- (3-pyridinyl) -4 (R, S) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl) -1H-1-benzopyran -3 yl) oxypropyl] piperazine, of formula

1) Preparation of 2- (3-pyridinyl) -4 (R, S) -thiazolidinecarboxylic acid

In a reactor containing 12.1 g (0.1 mol) of D, L cysteine and 150 ml of water, 10.7 g (0.01 mol) of solubilized 3-pyridinecarboxaldehyde in 100 ml of ethanol are added. After one night, an insoluble material is filtered off and concentrated under reduced pressure. The residue is washed with diisopropyl ether and then recrystallized from 300 ml of ethanol. 15 g of product of the above formula are obtained.

PFk = 165 - 1700C
IR: 2200-2700, 1720, 1320.

2) Preparation of 1 - [[2- (3-pyridinyl) -4 (R, S) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl) -1H-1-benzopyran) -3 yl) oxy] propyl] piperazine, (title compound).

Prepared from the compound of step 1) above and the compound of step 2) of example 1.

Thick oil.

oxalate
PFk = 70-75C
IR: 3450, 1720, 1640, 1610, 1470, 1200.

Elemental analysis (C31H32N4O4S, 1.5 QH2O4, 2H2O)
CHNOS
Calculated 56.41 4.98 7.42 26.29 4.41
Found 56.11 5.40 7.70 26.39 4.41
Example 19
Preparation of 4- (3,4,5-trimethoxybenzoyl) -1- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine

5 g (0.015 mol) of 3 - [(3-chloropropyl) oxy] -4-oxo-2-phenyl-4H-1-benzopyran and 4.5 g (0.01588 mol) of 3.4 are reacted, 5-trimethoxybenzoyl piperazine in 75 ml of dimethylformamide in the presence of 2.6 g of potassium carbonate and 0.5 g of potassium iodide for 5 hours at 70 ° C. is evaporated under reduced pressure, the residue is taken up in methylene and washed with water. The mixture is evaporated and the residue is chromatographed on a silica column in the system (AcOEt 60, CHCl330, MeOH 10) to give 4.5 g of the compound of formula above in the form of an oil.

NMR H1 (CDCl3): 1.1 3.7 (12H, solid), 3.8 (9H, singlet) -4.05 (2H, triplet) -6.55 (2H, singlet) -7.2 7.7 (5H, massive) -7.7 8.4 (4H, massive).

oxalate
PFk = 173-75C
IR: 1720, 1635, 1590, 1470, 1435, 1130.

Elemental analysis (C32H34N20v, QH2O4)
CHNO
Calculated 62.95 5.59 4.32 27.13
Found 62.92 5.69 4.31
Example 20
Preparation of 1 - [[2- (3-pyridinyl) -4-thiazolyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl) -1H-1-benzopyran-3-yl) oxy] propyl] piperazine, of formula

The compound is obtained from 2- (3-pyridinyl) -4-thiazolecarboxylic acid and from the compound of step 2) of Example 1.

Thick oil.

I.R .: 1680, 1640, 1470, 1405, 1205.

NMRH1 (CDCl3): 1.9 (2H, multiplet) -2.2 2.8 (6H, bulk) -3.6 4.3 (6H, bulk) -7.1 8.4 (12H, bulk) -8.6 8.7 (1H, solid) -9.0 9.1 (1H, solid).

Oxalate (C31H28N4O4S, QH2O4)
Mp = 184 ° C (EtOH)
IR: 1635, 1605, 1465, 1400.

NMR (Deuterated DMSO): 1.8 2.2 (2H, solid) -2.8 3.2 (6H, bulk) -3.8 4.2 (6H, bulk) -7.3 8.5 (12H, massive) -8.7 8.8 (1H, massive) -9.1 9.15 (1H, massive).

1) Préparation du 2-(3,4,5-triméthoxyphényl)-4-oxo-4H-l benzopyrane

Elemental analysis:
CHNOS
Calculated 61.67 4.71 8.72 19.92 4.99
Found 61.81 4.82 8.78 4.99
Example 21
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[4-oxo-2- (3,4,5-trimethoxyphenyl)] - 4H-1-benzopyran-3-yl] oxy] propyl] piperazine, of formula

1) Preparation of 2- (3,4,5-trimethoxyphenyl) -4-oxo-4H-1 benzopyran

PFk = 186 C
IR: 3280, 1620, 1405, 1130.

2) Preparation of 3 - [(3-chloropropyl) oxy] -2- (3,4,5-trimethoxyphenyl) -4-oxo-4H-1 benzopyran

PFk = 114-6 ° C (isopropyl ether / ethanol, 200/30, V / V)
IR: 1630, 1505, 1130.

NMR H1 (CDCl3): 2.2 (2H, quintuplet) -3.6 (2H, triplet) -3.95 (9H, singlet) -4.1 (2H, triplet) -7.2 7.7 (5H, massive) -8.05 8.25 (1H, massive).

3) Preparation of 1- [3- [[2- (3,4,5-trimethoxyphenyl) -4-oxo-4H-1-benzopyran-3-yl] oxy] propyl] piperazine.

Thick oil.

1 H NMR (CDCl 3): 1.5 3.3 (13H, bulk) -3.9 (9H, singlet) -4.05 (2H, triplet) -7.1 7.8 (5H, bulk) -8, 05 8.3 (1H, massive).

4) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] -4- [3 - [[4-oxo-2- (3,4,5-trimethoxyphenyl) 4H-1) benzpyran-3-yl] oxy] propyl] piperazine (title compound)
Oil.

NMRH1 (CDCl3): 2.6 3.8 (14H, solid) -3.9 (9H, singlet) -4.1 (2H, triplet) -5.5 and 5.9 (1H, 2 singlet) - 7.2 9 (10H, massive).

oxalate
PFg = 108 - 112 C
IR: 1720, 1640, 1610, 1465, 1130.

elemental analysis (C34H38N4O7S2C2H2O4, 3H2O)
CHNOS
Calculated 51.81 5.49 6.36 32.69 3.64
Found 51.56 5.27 6.02 3.61
Example 22
Preparation of 1- [2- (3-pyridinyl-4 (4R) -thiazolidinyl) carbonyl] -4- [3 - [(7-methoxy-4-oxo-2-phenyl) -1H-benzopyran-3-yl) oxy ] propyl] piperazine.

1) Preparation of 3-E (3-chloropropyl) oxy] -7-methoxy-4-oxo-2-phenyl-4H-1-benzopyran.

 The compound is prepared according to the procedure described in Example 1.

PFK-88-90C.

IR = 1630, 1605, 1445, 1255, 1205 coma.

2) Preparation of 1- [3-E (7-methoxy-4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propylapiperazine.

 The compound is prepared according to the procedure described in Example 1. The product is in the form of an amorphous solid.

IR = 1645, 1630, 1450, 1260, 1215 cm -1
3) Preparation of 1-EE2- (3-pyridinyl- (4r) -thiazolidinyl] carbonyl] 4- [3 - [(7-methoxy-4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine (title compound).

 This compound is prepared according to the procedure described for Example 1. The product is in the form of an amorphous solid.

IR = 1645, 1625, 1445, 1260, 1210 cm -1.

oxalate
PFx = 115-120C.

IR = 1720-1740, 1660-1610, 1450 coma.

Example 23
Preparation of IE [2- (3-pyridinyl) -4,5-dihidro-4 (4R) -Triawolyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl) H-1-benzopyran-3- yl) oxy] propyl] piperazine

This product is prepared from 1- [3-
C (4-Oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine and 2- (3-pyridinyl) -4,5-dihydro-4 (4R) thiazolecarboxylic acid according to the procedure described for Example 1. The product is purified on a silica column using the AcOEt 60 eluent system.
CHCl 3 - MeOH 10, then the system CHCl 3 60 - Me OH 40.

The product is obtained in the form of a thick oil.

oxalate
PFG = 186-1880C
IR = 1640, 1615, 1470, 1195 cm -1.

Elemental analysis (C31H30N4O4S, C2H2O4, H2O)
CHNOS calculated 59.80 5.17 8.45 21.73 4.85 found 60.07 4.94 8.48 21.71 5.25
Example 24
Preparation of 1-E [2- (4-pyridinyl-4 (4R) -thiazolidinyl] carbonyl] -4- [3- [4-oxo-2-phenyl-4H-1-benzopyran-3-yl] oxy] propyl] piperazine.

This product is prepared from 1- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine and 2- (4-pyridinyl) - 4 (4R) -thiazolidinecarboxylic acid, according to the procedure described for example 1. The product is purified on a silica column using the eluent system AcOEt 60 - CHCl3 30 - MeOH 10, then the system CHC13 60 - MeOH 40 The product obtained is in the form of a thick oil.

IR = 1645, 1470, 1200, 1150, 1110.

oxalate
PFg = 128 ° C
IR = 1720, 1640, 1610, 1470, 1200 c, -1.

Elemental analysis: (C 31 H 23 N 4 O 4 S, 1, C 2 H 2 O 4, H 2 O)
CHNOS calculated 57.53 5.25 7.89 24.79 4.51 found 57.39 4.82 7.52 24.99 4.83
Example 25
Preparation of 1-E [2- (2-pyridinyl-4 (4R) -thiazolidinyl] carbonyl] -4- [3- [4-oxo-2-phenyl-4H-1-benzopyran-3-yl] oxy] propyl] piperazine.

This product is prepared from 1- [3 - [(4-oxo-2-phenyl-4-1-benzopyran-3-yl) oxy] propyl] piperazine and 2- (2-pyridinyl) -4-acid. (4R) -thiazolinecarboxylique.

according to the procedure described for example 1. The product is purified on a silica column using the eluent system AcOEt 60 - CHCl 3 - MeOH 10. The product is in the form of a thick oil.

oxalate
PFa = 110-115 ° C
IR = 1645, 1610, 1470, 1200 cm -1.

Elemental analysis: (C31H32N4O4S, 1.5 C2H204)
CHNOS calculated 59.03 5.10 8.10 23.13 4.69 found 58.57 5.32 7.91 4.56
Example 26
Preparation of 1- [2- (3-pyridinyl-4 (4R) thiazolidinyl) carbonyl] -4- [3 - [[2- (4-fluorophenyl) -4-oxo4H-1-benzopyran-3-yl] oxy ] propyl] piperazine.

1) Preparation of 3 - [(3-chloropropyl (oxy) -2- [4-fluorophenyl] -4-oxo-4H-1-benzipropyran.

This product is prepared according to the procedure described in Example 1.

PFk = 94-96 C
IR = 1645, 1620, 1505, 1470, 1200, 1165 cm -1.

préparée selon le mode opératoire décrit dans l'exemple 1. Le produit se présente sous forme d'une huile épaisse.2) Preparation of 1- [3 - [(2- (4-fluorophenyl) -4-oxo-4H-1-benzopyran-3-yl) oxy] propyl] piperazine

prepared according to the procedure described in Example 1. The product is in the form of a thick oil.

IR = 1650, 1605, 1515, 1475, 1245, 1205 c, -1.

 3) Preparation of 1 - [[- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [[- 2- (4-fluorophenyl) -4-oxo-4H-1-benzopyran] -3- yl] oxy] propyl] piperazine (title compound).

 The product is prepared according to the procedure described in Example 1. The product is in the form of an amorphous solid.

oxalate
PFk = 130-135 ° C
IR = 1720, 1630, 1610, 1465, 1410 cm -1.

Elemental analysis: (C 31 H 31 F N 4 O 4 S, 2 C 2 H 2 O 4)
CHFNOS calculated 55.70 4.67 2.52 7.42 25.44 4.25 found 55.88 5.00 2.68 7.61
Example 27
Preparation of 1 - [[2- (3-pyridinyl) -4 (R) -thiazolidinyl] carbonyl] -4- [3- [4-oxo-2-phenyl-4H-1-benzopyran-5-yl] oxy] propyl ] piperazine.

préparé selon le mode opératoire décrit dans l'exemple 1.l) Preparation of 5 - [(3-chloropropyl) oxy] -4-oxo-2-phenyl-4H-1-benzopyran

prepared according to the procedure described in Example 1.

PFK = 120-122 ° C (diisopropyl ether)
IR: 1650, 1605, 1480, 1450, 1375, 1100 cm -1.

préparée selon le mode opératoire décrit dans l'exemple 1. Le produit se présente sous la forme d'une huile épaisse.2) Preparation of 1- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran-5-yl) oxy] propyl] piperazine

prepared according to the procedure described in Example 1. The product is in the form of a thick oil.

IR: 1650, 1605, 1480, 1460, 1380, 1270, 1095 cm -1.

 3) Preparation of 1 - [[2- (3-pyridyl) -4- (4R) -thiazolidinyl] carbonyl] -4- [3 - [(4-oxo-2-phenyl-4H-1-benzopyran) -5- yl) oxy] propyl] piperazine (title compound) prepared according to the procedure described in Example 1. The product is in the form of an amorphous solid.

IR: 1645, 1605, 1460, 1380, 1270, 1095 cm -1.

Oxalate.

PFK = 85-90C
IR: 1740-1720, 1635, 1490, 1470, 1095 cm -1.

Example 28
Preparation of 1- [2- [3- (3-pyridinyl-4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(6-chloro-4-oxo-2-phenyl-4H-1-benzopropyran) -3- yl) oxy] piperazine.

1) Preparation of 6-chloro-3 - [(3-chloropropyl) oxy] -4-oxo-2-phenyl-4H-1-benzopyran.

 The compound is prepared according to the procedure described in Example 1.

PFK = 70-72 ° C (diisopropyl ether).

IR: 1640, 1610, 1365, 1195 cm -1.

2) Preparation of 1- [3 - [(6-chloro-4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine.

 The compound is prepared according to the procedure described in Example 1.

PFx = 90-94C.

IR: 1640, 1605, 1560, 1470, 1445, 1195 cm -1.

 3) Preparation of 1 - [[2- (3-pyridinyl 4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(6-chloro-4-oxo-2-phenyl-4H-1-benzopyran) 3-yl) oxy] propylpiperazine (title compound).

 The product is in the form of an amorphous solid.

IR: 1645, 1605, 1470, 1435, 1195 cm -1.

oxalate
PFK = 125-1300C
IR: 1720, 1640, 1610, 1470, 1440, 1190 cm -1.

Example 29
Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) thiazolidinyl] carbonyl] -4- [3 - [(6-methoxy-4-oxo-2-phenyl) -1H-benzopyran-3-yl ) oxy] propyl] piperazine.

1) Preparation of 3 - [(3-chloropropyl) oxy] -6-methoxy-4-oxo-2-phenyl-4H-1-benzopyran.

 The compound is prepared according to the procedure described in Example 1.

PFK = 84-86 C (diisopropyl ether)
IR: 1635, 1615, 1490, 1170 cm -1.

H1 NMR (CDCl3) 2.2 (2H, quintuplet) -3.65 (2H, triplet)
3.90 (3H, singlet) - 4.1 (2H, triplet) - 7.05 7.7 (6H, bulk) - 7.80 8.20 (2H, bulk).

2) Preparation of 1-3 - [(6-methoxy-4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl] piperazine.

 The compound is prepared according to the procedure described in Example 1 by reaction of the above compound with piperazine.

PFx = 105-110 ° C (diisopropyl ether)
IR: 1630, 1490, 1215 cm -1.

 3) Preparation of 1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4- [3 - [(6-methoxy-4-oxo-2-phenyl-4H) -1- benzopyran-3-yl) oxy] propyl] piperazine (title compound).

 The compound is prepared according to the procedure described in Example 1. The compound obtained is in the form of an amorphous oil.

IR: 1640, 1610, 1485, 1440, 1215, 1030 cm-1.

Oxalate.

KPK = 108-112 ° C
IR: 1720, 1620-1660, 1490 cm -1.

Elemental analysis (C32H34 N405S, C2H2O4, H2O)
CHNOS calculated 55.1 5.14 7.14 28.54 4.09 found 54.78 4.94 6.85 28.60 4.28

Claims (21)

R13 and R14 together represent a group = CH2-CH2 = CH-, with the proviso that one and only one of R1 to R6 represents the group C1-C7, C1-C7 acyl or tertiobutoxycarbonyl, or R14 represents a hydrogen atom, an alkyl group R8, R8, R11, R11 and R13, which may be identical or different, represent a hydrogen, halogen, a C1-C7 alkyl, a C1-C7 alkoxy, phenyl or pyridyl atom,  in which the dashed lines represent a possible bond,

R7 represents a phenyl group which is unsubstituted or substituted with 1 to 5 identical or different groups chosen from halogen, hydroxy, cyano, nitro, amino, (di) (C1-C7) alkylamino, acetamido, phenyl, trifluoromethyl, C1-alkyl; -C7, C1-C7 alkoxy or C1-C7 acyloxy, or a group of formula Z represents an oxygen or sulfur atom, m and p are numbers from 0 to 4, n represents 0 or 1, with the proviso that the sum m + n + p represents a number less than 6, q represents 0 or 1  in which

R 1, R 2, R 3, R 4, R 5 and R 6 represent a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms of which 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C1-C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or C1-C7 acyloxy, or a group of formula X represents an oxygen or sulfur atom,  in which

 1. Compounds of general formula I Z, m, n, p, q and R7 being as defined above, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.  2. Compounds of general formula II

 in which R1, R3, R4, R5 and R6 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms of which 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C1-C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or C1-C7 acyloxy, X, Z, m, n, p, q and R7 being as defined in claim 1, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.  3. Compounds of general formula III

  in which R1, R2, R3, R4 and R5 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms of which 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C1- C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or acyloxy in QC 7, X, Z, m, n, p, q and R7 being as defined in claim 1, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.  4. Compounds of general formula I according to claim 1, characterized in that one of R1 and R2 is selected from hydrogen, phenyl unsubstituted or substituted with one to five substituents, including one to three substituents, the same or different, selected from halogen, methyl and methoxy; and a thienyl or furanyl group, the other being a hydrogen atom or the group

Z, m, n, p, q and R7 being as defined in claim 1, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.  5. Compounds of the general formula I according to claim 1, characterized in that the groups R3, R4, R5 and R6 are selected from a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group and the group

Z, m, n, p, q and R7 being as defined in claim 1, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.  6. Compounds of general formula I according to claim 1, characterized in that m represents 2 or 3.  7. Compounds of general formula I according to claim 1, characterized in that Z represents an oxygen atom.  8. Compounds of general formula I according to claim 1, characterized in that n is equal to 0.  9. Compounds of general formula I according to claim 1, characterized in that p is equal to 0.  10. Compounds of general formula I according to claim 1, characterized in that q is equal to 1.  11. Compounds of general formula I according to claim 1, characterized in that R7 represents the 3,4,5-trimethoxy phenyl group.  12. Compounds of general formula I according to claim 1, characterized in that R7 is selected from groups

 wherein R 8 is pyridyl, R 10 and R 11 are hydrogen or C 1 -C 4 alkyl, R 14 is hydrogen, C 1 -C 4 alkyl or C 1 -C 6 acyl, or alkoxycarbonyl in C1-C6  13. Compounds according to claim 12, characterized in that the group R7 is chosen from groups

R8, R10 R11 and R14 being as defined in claim 12.  14. Compounds of general formula IV

 in which X represents an oxygen or sulfur atom, R1 represents a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or C1-C7 acyloxy, R3 represents a hydrogen or halogen atom, a C1-C7 alkyl group, or a C1-C7 alkoxy group, Z represents an oxygen or sulfur atom, m represents 2 or 3, and R7 represents a phenyl group which is unsubstituted or substituted with 1 to 5 identical or different groups chosen from halogen, hydroxy, cyano, nitro, amino, (di) (C1-C7) alkylamino, acetamido, phenyl, trifluoromethyl, C1-alkyl; -C7, C1-C7 alkoxy or C1-C7 acyloxy, or a group of formula

 in which the dashed lines represent a possible bond, R8, R8, R20, R11, R12 and R13, which may be identical or different, represent a hydrogen, halogen, a C1-C7 alkyl, a C1-C7 alkoxy, phenyl or pyridyl group, R14 represents a hydrogen atom, a C1-C7 alkyl group, a C1-C7 acyl or a tertiobutoxycarbonyl group, or R13 and R14 together represent a group = CH2-CH2 = CH-, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.  15. Compounds of the general formula V

 in which X represents an oxygen or sulfur atom, R1 represents a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and hetero-cyclic groups being optionally substituted by one or more identical or different groups selected from halogeno, hydroxy, cyano, nitro, amino, (di) alkyl (in Q); C7) amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or C1-C7 acyloxy, Z represents an oxygen or sulfur atom, m represents 2 or 3, and R7 represents a phenyl group which is unsubstituted or substituted with 1 to 5 identical or different groups chosen from halogen, hydroxy, cyano, nitro, amino, (di) (C1-C7) alkylamino, acetamido, phenyl, trifluoromethyl, C1-alkyl; -C7, C1-C7 alkoxy or C1-C7 alkyloyl, or a group of formula

 in which the dashed lines represent a possible bond, R8, R9, R10, R11, R12 and R13, which may be identical or different, represent a hydrogen atom of halogen, a C1-C7 alkyl group, a C1-C7 alkoxy group, a phenyl group or a pyridyl group; R14 represents a hydrogen atom, a C1-C7 alkyl group, a C1-C7 acyl or a tertiobutoxycarbonyl group, or R13 and R14 together represent a group = CH2-CH2 = CH-, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid  16. Compounds according to claim 14 or 15, characterized in that they are chosen from  1 - {[(2- (3-pyridyl) -4 (4R) -thiazolidinyl] carbonyl} -4- {3 - [(4-oxo-2-phenyl-4H-1-benzopyran-3-yl) oxy] propyl} } piperazine,  1 - {[2- (3-pyridyl) -4 (4R) -thiazolidinyl] carbonyl} -4- {3 - [(4-oxo-2-thienyl-4H-1-benzopyran-3-yl) oxy] propyl} piperazine  1 - {[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl} -4- {3t [2- (4-methylphenyl) -4-oxo-4H-1-benzopyran-7-yloxy} ) propyl) piperazine, and  1 - [[2- (3-pyridinyl) -4 (4R) -thiazolidinyl] carbonyl] -4 [3 - [[4-oxo-2- (4-chlorophenyl) -4H-1-benzopyran-3-yl] oxy] propyl] piperazine, and their corresponding salts obtained by addition of a pharmaceutically acceptable inorganic or organic acid.  17. Process for the preparation of compounds of general formula I

 in which X represents an oxygen or sulfur atom, R1, R2, R3, R4, R5 and R6 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms of which 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) alkyl (in C1- C7) amino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 1 -C 7 acyloxy, or a group of formula

 in which Z represents an oxygen or sulfur atom, m and p are numbers from 0 to 4, n represents 0 or 1, with the proviso that the sum m + n + p represents a number less than 6, q represents 0 or 1 R7 represents a phenyl group which is unsubstituted or substituted with 1 to 5 identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) C1-C7 alkylamino, acetamido, phenyl, trifluoromethyl, C1-C4 alkyl, C7, C1-C7 alkoxy or C1-C7 acyloxy, or a group of formula:

 in which the dashed lines represent a possible bond, R5, R9, R10, R11, R12 and R13, which may be identical or different, represent a hydrogen, halogen, a C1-C7 alkyl, a C1-C7 alkoxy, phenyl or pyridyl atom, R14 represents a hydrogen atom, an alkyl group C1-C7, C1-C7 acyl or tertiobutoxycarbonyl, or R13 and R14 together represent a group = CH2-CH2 = CH-, with the proviso that one and only one of R1 to R6 represents the group

 z, m, n and p being as defined above, to obtain a compound of general formula I which is optionally converted to a corresponding salt by addition of a pharmaceutically acceptable inorganic or organic acid.

R'1.R'2, R'3, and R'5 and RT6 represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a phenyl or benzyl group, or a heterocycle optionally aromatic having 3 to 10 atoms including 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups selected from halogeno, hydroxy, cyano, nitro, amino (C1-C7) alkyl, amino, acetamido, phenyl, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy or C1-C7 acyloxy, one of R'1, R'2, R3 '3, R'4, R'5 and R16 representing a group of formula X is as defined above,  in which

 Wherein R7 is as defined above and X1 represents a group selected from halogeno, azido, cyano, (C1-C7) alkylsulphonyloxy, (C5-C9) arylsulfonyloxy, alkyl (C1-C7), C7) aryl (C5-C9) sulfonyloxy, and COR15, R15 being selected from a halogen atom, a hydroxy group, a C1-C8 alkoxy group, an amino group, a (di) alkyl group (in C7) amino and an OCO-R7 group, where R7 is as defined above, with a compound of general formula VII Z, m, n, p, q and R7 being as defined above, as well as their corresponding salts obtained by addition of a pharmaceutically acceptable mineral or organic acid, characterized in that a compound of general formula VI is reacted  18. Process for preparing a compound of general formula VII as defined in claim 17, characterized in that a compound of general formula VIII is reacted:

 in which X is as defined in claim 16, and R "1, R" 2, R "3, R" 4, R "5 and R" 6 represent a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group or benzyl, or an optionally aromatic heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more identical or different groups chosen from halogen, hydroxy, cyano, nitro, amino, (di) (C 1 -C 7) alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 1 -C 7 acyloxy, one of R "1, R "2, R" 3, R "4, R" 6 representing a group of formula

 in which Z, m, n and p are as defined in claim 16 and X2 represents a group selected from halogen, C1-C7 alkylsulfonyloxy, C5-C9 arylsulfonyloxy, and alkyl (C1-C7) groups. C7) C5-C9 aryl) sulfonyloxy, with a compound of formula IX

 wherein R20 represents a hydrogen atom or a group protecting the amine function, to obtain a compound of formula X

  in which X is as defined in claim 17, and R '' '1, $ R' '' 2, R '' '3, R' '' 4, R '' '5 and R' '' 6 represent a hydrogen atom, a C1-C7 alkyl group , a C 3 -C 6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms chosen from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by one or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) (C 1 -C 7) alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C1-C7 acyloxy, one of the groups R '' '1, R "' 2, R '' '3, R' '' 4, R "'5 and R"' 6 representing the group of formula

 wherein m, n, p, and R 20 are as defined above, which is optionally deprotected to give a compound of formula VII.  19. Compounds of general formula VII

 in which X is as defined in claim 1 and R 1, R 2, R '3, R' 4, R '5 and R' 6 represent a hydrogen atom, a C 1 -C 7 alkyl group, a group C3-C5 cycloalkyl, a phenyl or benzyl group, or an optionally aromatic heterocycle having 3 to 10 atoms of which 1 to 4 heteroatoms selected from 0, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted with one or more the same or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) (C 1 -C 7) alkylamino, acetamido, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or C 1 acyloxy; C7, one of R'1, R '2, R'3, R' 4, R'5 and R'6 representing a group of formula

 z, m, n and p being as defined in claim 1.  20. Compounds of general formula VIII

 in which X is as defined in claim 1 and R''1, R''2, R 3, R "4, R 5 and R" 6 represent a hydrogen atom, a C 1 -C 7 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl or benzyl group, or an optionally aromatic heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from O, S and N, the phenyl, benzyl and heterocyclic groups being optionally substituted by a or more identical or different groups selected from halogen, hydroxy, cyano, nitro, amino, (di) (C 1 -C 7) alkylamino, acetamide, phenyl, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy or acyloxy C1-C7, one of R "1, R" 2, R "3, R" 4, R "5 and R" 6 representing a group of formula

 in which Z, m, n tp are as defined in claim 1 and X 2 represents a group selected from halogen, alkyl (C 1 -C 7) sulfonyloxy, aryl (C 5 -C 9) sulfonyloxy, and alkyl (C 1 -C 9) C7) C5-C9 arylsulfonyloxy.  21. A pharmaceutical composition comprising as active ingredient a compound as defined in one of claims I to 15.