FR2711992A1 - New heterocyclic derivatives, process of preparation and pharmaceutical composition containing them - Google Patents

Abstract

The subject of the invention is compounds of general formula I: in which: X represents an oxygen or sulphur atom or a &rdurule& N-R group, one among R1, R2, R3, R4, R5 and R6 represents the group of formula in which: Z represents an oxygen or sulphur atom, A represents a linear or branched C1-C7 alkylene group and R7 is a nitrogenous heterocyclic group containing from 5 to 10 ring members and optionally comprising another heteroatom chosen from O, S and N-R10. These compounds have a PAF-acether antagonist activity.

Description

The subject of the invention is novel heterocyclic compounds having a

pharmacological activity,

  especially as PAF-acetone antagonists.

  A number of PAF-acetyl antagonist compounds having a piperazinyl group are

  described, in particular in the following documents:

  284,359, EP-318,235, EP-368,670, DE-3,933,881, DE-

  3,933,882, EP-279,681, EP-350,145 and EP-395,446.

  EP-284,359 discloses piperazines and

  1.4-disubstituted homopiperazine antagonists of PAF-

  which have a corresponding general structure

having the formula: O '(CH2) n

R-XN N-X-R

  wherein: R is an optionally substituted phenyl group, R1 is a fused polycyclic group, X is CH2, CO, or CS, and

n represents 2 or 3.

  EP-318 235 discloses 1,4-piperazines

  disubstituted PAF-acetone antagonists which have a general structure of the formula: embedded image Wo / 1, R3

  \ R

N N-X

  Wherein A is an optionally substituted phenyl group or

  an optionally substituted heterocycle.

  R1, R2, R3 may be independently of one another a lower alkyl group, and

X is CH2, CO, or CS.

  EP-368 670 discloses piperazine trisubsti-

  antagonists of PAF-acether which have a general structure of formula:

R - 0 - R 2

  in which: A is an optionally substituted phenyl group, or a polycyclic group, optionally heterocyclic, R1, R2 and R3 are alkyl, R6 is H, (halo) alkyl, alkenyl, R6 is H, (halo) alkyl, alkenyl , X is CH2, CO, CS, Z is a bond, O, S, SO, SO2, C, CO2, and n represents a number of 0

to 2.

  DE-3,933,882 discloses trisub-

  antagonists of PAF-acether which have a general structure of formula:

H3C-0 0-CH3

C30 0CH3

N N

H3C

0

H3C-0 - O

H3C in which:

  R is an alkyl, cycloalkyl or phenyl group,

substituted or phenylalkyl.

  DE-3 933 881 discloses trisub-

  antagonists of PAF-acether which have a general structure of formula:

H3C-O 0 -CH3

CH

  In which: RX is an alkoxy, cycloalkoxy or substituted phenyl group,

phenylalkyl or amino.

  EP-350 145 discloses substituted PAF-acetyl antagonist piperazines having the following general formula:

0

N N-AI-RI

  St N'H A1 being a single bond, a carbonyl or lower alkylene group, the alkylene chain being interrupted by a carbonyl group and R 1 being a heterocycle optionally substituted by a lower alkyl group. EP-279 681 discloses, in particular, PAF-substituted substituted piperazines which have a general structure of formula: ## STR2 ## wherein R 7 is a group comprising a group

  monocyclic or polycyclic aromatic aryl or polycyclic aryl

  non-aromatic condensed clique, in particular phenyl

naphthyl.

  EP-395 446 discloses substituted PAF-acetyl antagonist piperazines which have a general structure of the formula:

H3C-O O-CH3

R3 / O

N N

  Wherein R 2 is especially hydrogen, halogen, lower alkyl or lower alkoxy. New compounds possessing a pyranic or thiopyranic group have now been discovered

  which exhibit potent PAF-antagonist activity

  acether. The subject of the invention is compounds of general formula I:

R3 R2

R4 I

R5 X

  R6 wherein X represents an oxygen or sulfur atom, or a

  in which R represents a hydrogen atom

  or a C1-C7 alkyl group, one of R1, R2, R3, R4, R6 and R6 represents the group of the formula

-Z-A-N-C0-R7

  in which: Z represents an oxygen or sulfur atom, A represents a linear or branched C1-C7 alkylene group, and R.sub.5 is a nitrogenous heterocyclic group containing 5 to 7 members and optionally comprising another heteroatom selected from O , S and N-R 10, wherein R 10 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 acyl, C 6 -C 10 aryl or tert-butoxycarbonyl, R 4 being optionally substituted on carbon by 1 to 8 identical or different substituents chosen

  halogen, C1-C7 alkyl, C1-C6 alkoxy,

  C ", trifluoromethyl, nitro, cyano, phenyl, benzyl, pyridyl, piperidino and piperazino,

  R1 and R2, when they are not as defined above

  above, independently of one another represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a C6-C1 aryl group, a C1-C4 alk (C1-C4) aryl group, C6-C1 or a heterocycle having 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1 to 5 substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, C1-alkyl -C7, alkoxy

  C1-C7, C1-C7 acyl, acetylamino, amino, alkyl (C1-

  C7) amino and dialkyl (C1-C7) amino, R3, R4, R5 and R6, when not as defined above, represent independently of each other a hydrogen atom, d halogen, hydroxy, nitro, cyano, trifluoromethyl, C0-C7 alkyl, C1-C7 alkoxy, C1-C7 acyl, amino, C1-C7 alkylamino, C1-C7 dialkyl amino , acetylamino, C 6 -C 10 aryl, C 1 -C 4 alk (C 1 -C 4) aryl or a heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and their pharmaceutically acceptable salts

acceptable.

  A first group of compounds of general formula I is represented by the compounds of general formula II: R3

R R

Z-A-N N-CO-R7 II

  R6 wherein: X, A, Z, R1, R3, R4, R5, R6 and R7 are as defined above. A second group of compounds of general formula I is represented by the compounds of general formula III R

R3 R2

/ \ 4 È, Ri

R7-CO-N N-A-Z

0 III

  R5 wherein: X, A, Z, R1, R2, R3, R4, R5, and R7 are as previously defined, the group:

-Z-N-N-CO-R7

  being attached in position 5, 6, 7 or 8 of the heterocycle.

  R7 preferably represents a group of formula: R11 lR <tER11 Z

R N

  Wherein: z1 represents a sulfur, oxygen atom, a -CH =, CH2, CH2-CH2 or -CH = CH- group, a -N = or N-R1o group, Ri0 being as defined at claim 1, R1l represents a hydrogen atom or a C1-C12 alkyl group, R12, R13, R14 and R1s independently of one another represent a hydrogen atom, halogen, an alkyl group; in C1-C7, a nitrogen heterocycle having from 5 to 6

  optionally substituted by a halogen atom

  ne, nitro, cyano, trifluoromethyl, C 1 -C 7 alkyl or C 1 -C 7 alkoxy, or

  Ri0 and Rs, when taken together, may form

  a group = CH -CH = CH-, as well as their salts

pharmaceutically acceptable.

  R 7 is in particular chosen from the following groups: ## STR2 ##

R1 KN4 11 1 2 3

1 10 30

  Z1, R0, Rn, R12 and R13 are as defined above.

  Preferably, Z1 represents a sulfur atom or the group -CH = CH-, and R12 or R13 represent the pyridyl group. Among the preferred R7 groups, mention may be made of pyridyl, pyrrolo [1,2-c] thiazolyl, thiazolidinyl, furyl, tetrahydrofuryl, thienyl, imidazolyl, pyridazinyl and pyrimidinyl groups, optionally

  substituted by one or more, in particular from 1 to

  selected from C 1 -C 7 alkyl, C 1 -C 7 alkoxy, trifluoromethyl, nitro, cyano, phenyl, benzyl,

  pyridyl, piperidino or piperazino.

  Particularly preferred groups R 7 are thiazolidinyl, pyridyl, thiazolyl and pyrrolo [1,2-c] thiazolyl groups optionally substituted with one or more, preferably 1 to 5, substituents as defined above, chosen in particular from an atom

  of halogen and C4-C7 alkyl.

  When they do not represent the group:

-Z-N-N-CO-R7

  as defined above, Ri and R2 represent

  preferably a hydrogen atom, a C 1 -C 6 alkyl group or

  C7, phenyl or benzyl, and R3, R4, R5 and R6 are preferably hydrogen or halogen. Among the preferred compounds, there may be mentioned the following:

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-

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

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-

  [3 - [(4-methyl-2-oxo-2H-1-benzopyran-7-yl) oxy] propyl] PIPE

razine;

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-

  [3 - [(2-oxo-2H-1-benzopyran-3-yl) oxy] propyl] piperazine;

  1 - [[(2R, 4R) -3-acetyl-2- (3-pyridinyl) -4-thiazolidine

  nyl] carbonyl] -4- [3 - [(6-chloro-2-oxo-2H-1-benzopyran-4-

yl) oxy] propyl] piperazine;

  1 - [[(4S) -5,5-dimethyl-2- (3-pyridinyl) -4-thiazolidine

  nyl] carbonyl] -4- [3 - [(4-methyl-2-oxo-2H-1-benzopyran-7-

yl) oxy] propyl] piperazine;

  1 - [(3-pyridinyl) carbonyl] -4- [3 - [(4-methyl-2-oxo-2H-1)

  benzopyran-7-yl) oxy] propyl] piperazine;

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl-4-

  [3 - [(2-oxo-2H-l-benzothiopyran-4-yl) oxy] propyl] PIPE

razine;

  1 - [[(2R, 4R) -3-acetyl-2- (3-pyridinyl) -4-thiazolidine

  nyl] carbonyl] -4- [3 - [(2-oxo-2H-l-benzothiopyran-4-yl) oxy] propyl] piperazine;

  (4R) -4 - [[4- [3 - [(2-oxo-2H-1-benzothiopyran-4-yl) oxy] -

  propyl] -1-piperazinyl] carbonyl] -2- (3-pyridinyl) -3

  1,1-dimethylethyl thiazolidinecarboxylate;

  1 - [[3- (3-pyridinyl) -1H, 3H-pyrrolo [1,2-c] thiazol-7-

  yl] carbonyl] -4- [3 - [(2-oxo-2H-l-benzothiopyran-4-yl) oxy] -

propyl] piperazine;

  1 - [[(4R) -5,5-dimethyl-2- (3-pyridinyl) -4-thiazolidine

  nyl] carbonyl] -4- [3 - [(4-methyl-2-oxo-2H-l-benzopyran-7-

yl) oxy] propyl] piperazine;

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-

  [3- [3-benzyl-2-oxo-2H-l-benzopyran-4-yl) oxy] propyl] PIPE

razine;

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-

  [3 - [(2-oxo-3-phenyl-2H-1-benzopyran-4-yl) oxy] propyl] PIPE

razine;

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-

  [3 - [(6-chloro-2-oxo-2H-1-benzopyran-4-yl) oxy] propyl] PIPE

razine;

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-

  [3 - [(2-oxo-4-phenyl-2H-l-benzopyran-7-yl) oxy] propyl] PIPE

razine;

  1 [[2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3-

  [(2-oxo-2H-l-benzothiopyran-4-yl) oxy] propyl] piperazine;

  1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -

  4- [3 - [(1-methyl-2-oxo-1,2-dihydro-4-quinolinyl) oxy] pro-

  pyl] piperazine, and their pharmaceutically acceptable salts.

  ble. "C 1 -C 7 alkyl group" means straight or branched chain groups, especially methyl, ethyl, propyl, isopropyl or butyl groups,

  tert-butyl, isobutyl, pentyl, hexyl and heptyl.

  "C 1 -C 7 alkoxy group" means straight or branched chain groups, especially methoxy, ethoxy, propoxy, butoxy, pentoxy,

hexyloxy and heptyloxy.

  "Cl-C7 acyl group" means straight or branched chain alkyl groups bonded to a carbonyl function, especially acetyl groups and

propionyl.

  By "C 1 -C 7 acyloxy group" is meant straight or branched chain alkyl groups bonded to a carbonyloxy function, especially acetoxy and propionyloxy groups. The term "halogen" denotes fluorine, chlorine, bromine or iodine atoms. The term "heterocycle" refers to a saturated or unsaturated ring with aromatic or non aromatic character, comprising from 3 to 10 atoms, including 1 to 4 heteroatoms of the same nature or different selected from oxygen, sulfur and nitrogen atoms, in particular the groups

previously mentioned for R7.

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

and lactic.

  The compounds of the invention may be prepared by a process which comprises reacting a compound of general formula IV:

R3 R2

  R 'R6 in which: X represents an oxygen or sulfur atom, or a

  N-R group, in which R represents a hydrogen atom

  gene or a C1-C8 alkyl group, one of R'1, R '2, R' 3, R'4, R '5 and R'6 represents the group of formula:

-Z-A-N N-H

  in which: Z represents an oxygen or sulfur atom, and A represents a linear or branched C1-C7 alkylene group,

  R'1 and R'2, when they are not as defined above

  above, independently of one another represent a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, a C1-C4 alk (C1-C4) aryl group, C6-C10 or a heterocycle having 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1 to 5 substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, C1-alkyl -C7, alkoxy

  C1-C7, C1-C7 acyl, acetylamino, amino, C1-C7 alkyl

  C7) amino and dialkyl (C1-C7) amino, and R '3, R' 4, R 'and R' 6, when not as defined above, represent independently of each other a hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, C1-C7 alkyl, C1-C7 alkoxy, C1-C7 acyl, amino, C1-C7 alkyl group;

  amino, dialkyl (C 1 -C 7) amino, acetylamino, C 6 aryl

  C10, C1-C4 alk (C1-C4) aryl or a heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, with a compound of formula V: V R7-X1 in which R7 is a nitrogen-containing heterocyclic group having from 5 to 7 members and optionally comprising another heteroatom selected from O, S and N-R10, R10 being a hydrogen atom, a C1-C7 alkyl group, a C1-C acyl group; , C 6 -C 10 aryl or tert-butoxycarbonyl group, R 7 being optionally substituted on the carbon atoms by 1 to 8 identical or different substituents chosen

  from a halogeno group, C1-C7 alkyl, C1-C6 alkoxy

  C7, trifluoromethyl, nitro, cyano, phenyl, benzyl, pyridyl, piperidino and piperazino, and X1 represents a leaving group selected from halogen,

  azido, cyano, (C 1 -C 7) alkylsulphonyloxy, aryl (C 5)

  Cg) sulfonyloxy, C 1 -C 7 alkyl) C 5 -C 9 arylsulfonyl-

  loxy, and COR15, R15 being selected from a halogen atom,

  ne, hydroxy, C1-C8 alkoxy, amino, C1-C7 alkylamino, dialkyl (C1-C7) amino, and OCO-R7, R7? being as defined above, to obtain a compound of general formula I which is optionally converted to a corresponding salt by addition of a mineral acid or

  organic pharmaceutically acceptable.

  As the compounds of formula V, 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 V 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 IV and V, in particular the reactivity of the compound of formula V. 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 hydrogencarbonate, hydroxide

sodium or potassium.

  The temperature may vary depending on the nature of the compound of general formula V. It is advantageously between zero degrees Celcius and the

reflux temperature of the solvent.

  The compounds of general formula IV and V are involved in the reaction in equimolar amounts or

  with an excess of one compared to the other.

  The compounds of the general formula IV can be prepared by a process comprising reacting a compound of the general formula VI:

VI

  Wherein X is as defined for the compounds of formula I, one of R "1, R" 2 R "3, R" 4, R "5 and R 6 represents a group:

-Z-A-X2

  wherein Z and A are as defined for compounds of formula I, and X2 represents a leaving group, and the others from R "1, R" 2, R "3, R" 4, R "s and R" 6 represent respectively a group R1, R2, R3, R4, R5 and R6 as defined for the compounds of formula I, with a compound of general formula VII:

H-N N-R16 VII

  wherein R16 represents a hydrogen atom or a group protecting the amine function, to obtain a compound of general formula VIII:

X

  Wherein: X is as defined above, one of R "1, R" '2, Rt3, R "' 4, R" '5 and R "6 represents the group:

-Z-A-N N-R16

  Z, A and R16 being as defined above, the others

  from R'1 ", R" '2, R "' 3, R'4, R" '5 and R' "6 respectively representing

  R 1, R "2, R" 3, R "4, R" 5 and R "6 as defined above, and where appropriate deprotecting the amine function of the compound of formula VIII to obtain a compound of

  formula IV as defined above.

  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 whose phenyl group is substituted or unsubstituted,

  ethoxy, methoxy, tert-butoxycarbonyl or trimethylsilyl

  the. 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

  at 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, for example, it will be advantageous to use from 3 to 6 moles of the compound of formula VII for one mole of compound of

formula VI.

  The method of deprotection of the compound of general formula VIII depends on the protecting group used and is among those known to those skilled in the art. She

  is advantageously carried out in acidic medium.

  The compounds of general formula VI can be prepared by reaction of a compound of general formula IX:

R IV R "4

3 '2 R

R " '

  Wherein: X is as defined above and one of R1IV, R2IV, R3IV, R4IV, R5IV and R6IV represents a group ZH, Z being as defined above, the others from R1IV, R2IV, R3IV, R4IV, Rs5IV and R6IV respectively representing the groups R1, R2, R3, R4, R5 and R6 as defined above with a compound of general formula X:

X2-A-X3 X

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

of monosubstitution.

  X3 may especially be a halogen atom, such as chlorine, bromine or iodine, or a sulphonyloxy group,

  for example p-toluenesulfonyloxy or methylsulphonyloxy.

  The reaction conditions vary depending on the nature of the compounds of formula IX and X and

from that of X2 and X3.

  They are easily determined by those skilled in the art so as to obtain the monoreaction 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

formulas I and IV.

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

  than 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 IX and of formula VII are compounds that are commercially available or that may be

  be prepared by techniques known in the literature.

ture.

  Thus, when the compound of formula IX is a benzopyran, it can be prepared by a method described in the following references: Shah V.R. et al., J. Org. Chem. 1960, 25, 677; Dallacker, F. et al., Annalen der Chemie, 1961, 643, 97; Eistert B. et al., Ber., 1963, 96, 1234; Pechmann et al., Ber., 1883, 16, 2119; Russel et al., Org. Syn., 1941, 21, 23;

  Woods et al., J. Org. Chem., 1962, 27, 3703.

  When the compound of formula IX is a benzothiopyran, it can be prepared as described by

  Jamkhandi P.S. et al., Monatsh., 1963, 94 (6), 1271.

  When the compound of formula IX is a quinolone, it may be prepared as described in any of the following references: Buckle et al., J. Med. Chem., 1975, 18, 7, 726; Ziegler et al., Monat. Chemie, 1965, 96, 418;

  Schopf et al., Ber. Deutsch. Chem. Ges., 1956, 89, 2877.

  The compounds of formula V are commercially available or can be readily prepared by those skilled in the art following the method described by Passarotti C. et al., Acta Toxicol. Thér., 1988,

  9 (3), 297, or in DE-2 221 647, or EP-0 115 979.

  The subject of the invention is also the intermediate compounds of general formula IV:

R3 R

2 IV

* R / R1

R4

RI X /

  RI in which: X represents an oxygen or sulfur atom, or

  XN-R group, in which R represents a hydrogen atom

  gene or a C1-C7 alkyl group, one of R'1, R'2, R'3, R'4, R'5 and R'6 represents the group of formula:

-Z-A-N N-H

  in which: Z represents an oxygen or sulfur atom, and A represents a linear or branched C1-C7 alkylene group,

  R'1 and R'2, when they are not as defined above

  above, represent independently of each other a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, a C1-C4 alk (C1-C4) aryl group, C6-C10 or a heterocycle having 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1 to 5 substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, C1-alkyl groups; -C7, alkoxy

  C1-C7, C1-C7 acyl, acetylamino, amino, C1-C7 alkyl

  C7) amino and dialkyl (C1-C7) amino, and R '3, R'4, R'5 and R'6, when not as defined above, independently represent one of the other a hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 acyl, amino, C 1 -C 7 alkyl group;

  amino, dialkyl (C 1 -C 7) amino, acetylamino, C 6 aryl

  C10, C1-C4 alk (C6-C10) aryl or a heterocycle having 3 to 10 atoms, of which 1 to 4 heteroatoms selected from

oxygen, sulfur and nitrogen.

  The compounds of the invention are active in

  pharmacology as antagonists of PAF-acether.

  PAF-acether (Platelet Activating Factor, PAF, PAF-Acetyl, AGEPC, acetylglyceryl ether phosphoryl choline) is a phospholipid produced or activated by various cell types in animals and humans, such as, for example, and non-exclusively macrophages, monocytes, platelets,

mast cells and neutrophils.

  Its structure was determined as 1-0-

  hexadecyl / octadecyl-2-0-acetyl-sn-glyceryl-3-phosphoryl

  choline. PAF is involved in multiple

  biological activities and thus appears as a media

  important in various physiological processes including for example and without limitation anaphylaxis, thrombosis, shock, ocular diseases, kidney diseases, gastric ulcers,

rejection of transplants, asthma.

  PAF plays a major role in the phenomena

  inflammatory diseases. I1 is one of the most

  powerful described increasing capillary permeability.

  PAF causes aggregation and degranulation

  platelets and neutrophils in animals and

in humans.

  PAF has shown a particular activity in the field of osteoporosis. This is reflected in osteoclasts (Wood D.A., Hapak L.K., Sims S.M., Dixon S. J., J. Biol Chem 1991, 266, 15369-15376).

  and osteoblasts (Tatakis D.N., Dziak R., J. Dent.

  Res. 1991, 70: 496) by an increase in the concentration

  intracellular calcium The action of the PAF on

  osteoclasts causes stimulation of the resorp-

  In vitro bone formation (Zheng, Z.G., Wood D.A., Sims S.M.,

  Dixon S.J., Am. J. Physiol. 1993, 264-E74-E81).

  The action of the PAF is done through

specific receptors.

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

bronchopasme.

  The results are reported below.

  Inhibition of platelet aggregation

induced by PAF-acether.

  The PAF-acetone 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 50% (IC 50) a limited aggregation

  induced by PAF-acether. 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 test is carried out 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.

  below. Table: Results of the PAF-acetone antagonist activity of the compounds of the invention: COMPOUND Salt Inhibition Inhibition EXAMPLE platelet bronchospasm aggregation I.V. guinea pig in vitro-guinea pig DE5mg / kg IC 50 nM

1 1.5 C2H204, 12.004

H20

7 1.5 C2H204, 0.9 0.008

___ 0.5 H2O

11 1.5 C2H204 3.2 0.012

  The compounds of the invention are characterized

  by an absence of toxicity in the animal. The invention also relates to a pharmaceutical composition

containing as an ingredient

  active a compound according to the invention as defined above

  above and a pharmacologically acceptable vehicle.

  These pharmaceutical compositions

  mammals are used in administration

  oral, intravenous, intraarterial, cutaneous, intestinal

  nal or aerosol. These new products have a

long duration of action.

  Daily dosages may vary from 0.1 mg to 500 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 I are associated in the pharmaceutical form with excipients, flavors 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. Excipients for liposomal forms, microcapsules and nanocapsules may be

  polyalkylcyanoacrylates, or phospholipids.

  The coating of the tablets can be achieved

  with additives such as hydroxypropylmethylcellulose

  se, different 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 containing stabilizers, solubilizers, such as sodium chloride, mannitol and sorbitol and / or buffers

  suitable for injectable solutions.

  Suppository preparations can

  contain excipients such as semi-glycerides

  synthetic. 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 inhibit strong

  the biological activities of the PAF-acether, by antagonizing the PAF-acether receptors. They

  can be used for treatment or prophylaxis

  laxity of diseases characterized by an excess of PAF-

  such as: prevention of aggregation

  platelet function, hypotension, cardiovascular disease (thrombosis, cardiac and cerebral ischemia, intravascular alterations, cardiac arrhythmias), pulmonary diseases (bronchial asthma, acute and chronic bronchitis, anaphylactic conditions, pulmonary edema, respiratory distress syndrome), inflammatory diseases, immunological disorders, dermatological disorders

  (allergies, urticaria, psoriasis), shock (anaphylactic

  that, septic, endotoxic), ulcers (gastric, duodenum), organ transplant rejections, burns, kidney diseases (nephritis, glomerulone

  phritis), liver diseases, pain, fever.

  The action of PAF on bone resorption (osteoclasts) and on bone formation (osteoblasts) gives these compounds a therapeutic interest in the treatment and prevention of rheumatoid arthritis,

periodontitis and osteoporosis.

  The compounds of this invention can also be used in combination with any other substance

  therapeutic use, for example thrombolytic

  phosphodiesterase inhibitors, analogs

  Prostacyline stable drugs, cyclooxygenase inhibitors, thromboxane synthetase inhibitors, thromboxane A2 antagonists, anticoagulants (anti-K antagonists, heparins, heparins

  low molecular weight), peripheral vasodilators

  serotonin S2 receptor antagonists, antihistamines, activators of

  potassium channels, and the pimetics.

  The following examples illustrate the invention without limitation. In nuclear magnetic resonance (NMR) data, the chemical shifts 6 are expressed in p.p.m relative to the T.M.S. The melting points are taken on Kofler bench (PFk) or apparatus of

Gallenkamp (PFg).

Example 1

  Preparation of 1 [[(4R) -2- (3-pyridinyl) -4-

  thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-2H-1-benzopyran-4-

  yl) oxy] propyl] piperazine, of formula: embedded image

  ml of xylene 15.2 g (0.063 mol) of 4 - [(3-chloropropyl) -

  oxy] -2-oxo-2H-1-benzopyran and 21.9 g (0.0254 moles) of anhydrous piperazine. After cooling, it is taken up in water. The aqueous phase is extracted with methylene chloride. The organic solvents are evaporated after drying over sodium sulfate. The residual oil is chromatographed on silica. 6.5 g of compound are thus obtained. I.R .: 2950, 2825, 1720, 1620, 930, 750 cm -1. RMNSH (CDCl3): 1.6-3.5 (13H, massive) -4.2 (2H, triplet)

  J = 6 Hz) -5.65 (1H, singlet) -7.0-7.9 (4H, massive).

  2) Preparation of 1 [[(4R) -2- (3-pyridinyl)]

  4-thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-2H-1-benzopyran-4-

  yl) oxy] propyl] piperazine (title compound): 6.5 g (0.0225 mole) of the compound are reacted with

  obtained in 1) with 4.7 g (0.0225 mol) of acid (4R) 2- (3-

  pyridinyl) -4-thiazolidinecarboxylic acid in 100 ml of dimethylformamide at 0 ° C. in the presence of 3 g (0.0225 mol) of hydrated hydroxybenzotriazole and 4.6 g (0.0225 mol) of dicyclohexylcarbodiimide. The mixture is kept at 0 ° C. for one hour and then allowed to come to room temperature overnight. It is diluted with 100 ml of ethyl acetate and the solid which forms is filtered off. The filtrate is washed with sodium bicarbonate solution and the solid formed is removed by filtration. The organic phase is washed with water and then with a sodium chloride solution. The organic phase is concentrated under reduced pressure after having been dried over sodium sulphate. The residual oil is chromatographed on

  silica column (eluent system: CHCl 3, 30 / MeOH 40).

  2.3 g of the title compound are obtained in the form of a thick oil.

  I.R .: 2960, 1720, 1670, 1420, 760 cm -1.

  The product is dissolved in acetone, and a solution of acetone containing 0.65 g of oxalic acid is added. A precipitate is formed which is filtered off and recrystallized from 50 ml of ethanol. We obtain 0.5

  g of the hydrated oxalate corresponding to the title product.

PFg = 105-110C.

I.R .: 1720, 1620, 1250.

  Elemental analysis (C 2 H 28 N 4 O 4 S, 1.5 C 2 H 2 O 4, H 2 O).

C H N 0 S

  Calculated 53.07 5.24 8.84 27.77 5.05 Found 53.14 5.06

Example 2

  Preparation of 1 [(4R) -2- (3-pyridinyl) -4-

  thiazolidinyl] carbonyl] -4- [3 - [(4-methyl-2-oxo-2H-1-

  benzopyran-7-yl) oxy] propyl] piperazine, of formula:

N <S H3C

HN

0 N 0

  1) Preparation of 1- [3 - [(4-methyl-2-oxo)

  2H-1-benzopyran-7-yl) oxy] propyl] piperazine:

H3C 0

  The product is obtained according to the

  described for the product obtained in step 1) from

  Example 1, starting from 3 - [(3-chloropropyl) oxy] -4-

  methyl-2-oxo-2H-1-benzopyran. The product obtained

  present as a thick oil.

I.R .: 1710, 1610, 1400, 1150 cm -1.

  1 H NMR (CDCl 3): 1.8-3.05 (16H, solid) -4.05 (2H, triplet)

  J = 6 Hz) -6.05 (1H, singlet) -6.7 6.9 (3H, solid) -7.2-

7.6 (1H, massive).

  2) Preparation of 1 [[(4R) -2- (3-pyridinyl)]

  4-thiazolidinyl] carbonyl] -4- [3 - [(4-methyl-2-oxo-2H-1-

  benzopyran-7-yl) oxy] propyl] piperazine (compound of the title): The compound is obtained starting from the compound obtained in 1) according to the procedure described for obtaining the compound of Example 1. The product of

  title is in the form of a thick oil.

  I.R .: 2870, 1720, 1640, 1610, 1150 cm -1.

  1 H NMR (CDCl 3): 1.8-3.9 (18H, bulk) -4.05 (2H, triplet J = 6Hz) -5, 55 and 5.9 (1H, 2 singlets) -6.05 (1H ,

singlet) -7.05-8.8 (7H, massive).

oxalate:

PFg: 121-124C.

  I.R .: 1700-1720, 1640-1650, 1620, 720 cm -1.

  Elemental analysis (C26H30N4O4S, 1.5 C2H204)

C H N O S

  Calculated 55.32 5.28 8.90 25.41 5.09 Found 54.94 5.37 8.58 5.00

Example 3

  Preparation of 1 [[(4R) -2- (3-pyridinyl) -4-

  thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-2H-l-benzopyran-3-

  yl) oxy] propyl] piperazine, of formula:

S 0

N HN {N

o0N

  1) Preparation of l- [3 - [(2-oxo-2H-l-)

  benzopyran-3-yl) oxy] propyl] piperazine: o

0H

HN N

  This product is obtained according to the

  described for the compound obtained in 1) in Example 1

  starting from 3 - [(3-chloropropyl) oxy] -2-oxo-2H-1-benzopy-

  Rane. The product obtained is a beige solid.

PFk = 65-70C.

  I.R .: 1730, 1715, 1620, 1450, 1305 cm -1.

  2) Preparation of 1 [[(4R) -2- (3-pyridinyl)]

  4-thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-2H-1-benzopyran-3-

  yl) oxy] propyl] piperazine (title compound): The compound is obtained starting from the compound obtained in 1) according to the procedure described for obtaining the compound of Example 1. The product of

  title is in the form of a thick yellow oil.

  I.R .: 1735, 1635, 1460, 1420, 1305, 1145.

oxalate:

PFk = 130 C.

  Elemental analysis (C 2 H 28 N 4 O 4 S, 1.5 C 2 H 2 O 4, H 2 O).

C H N O S

  Calculated 53.07 5.24 8.84 27.77 5.05 Found 52.79 5.32 8.54 4.99

Example 4

  Preparation of 1 [[(2R, 4R) -3-acetyl-2- (3-

  pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(6-chloro-2-

  oxo-2H-1-benzopyran-4-yl) oxy] propyl] piperazine, of formula: S; HOS tN 0

N N

CH30 353 Ci

  1) Preparation of 1- [3 - [(6-chloro-2-oxo)

  2H-1-benzopyran-4-yl) oxy] propyl] piperazine: o

O X O

HN N $

C1

  This product is obtained according to the

  described for the compound obtained in 1) in Example 1

  starting from 6-chloro-4 - [(3-chloropropyl) oxy] -2-oxo-2H-

  1-benzopyran. The formula product above is a

thick oil.

  I.R .: 1730, 1625, 1560, 1440, 1365 cm -1.

  1 H NMR (CDCl 3): 1.6-3.2 (13H, solid) -4.2 (2H, triplet)

  J = 6Hz) -5.65 (1H, singlet) -7.0-7.75 (3H, bulk).

  2) Preparation of l [[(2R, 4R) -3-acetyl-2-

  (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(6-chloro

  2-oxo-2H-1-benzopyran-4-yl) oxy] propyl] piperazine (compound

of the title).

  The title compound is obtained from the

  compound obtained in 1) and (2R, 4R) -3-acetyl-2- (3-

  pyridinyl) -4-thiazolidinecarboxylic according to the mode

  procedure described for obtaining the compound of the Exem-

  The product is chromatographed on a silica column (eluent CHCl 3 95 / MeOH 5) and then recrystallized two

once in acetone.

PFk = 165-170 C.

  I.R .: 3570, 1705, 1645, 1620, 1430, 940 cm -1.

  NMR (CDCl3 + DMSO): 2.0 (3H, singlet) -2.0-4.0 (14H, solid) -4.2 (2H, triplet J = 6Hz) -5.15 (1H, triplet J = 8.2 Hz) -5.7 (1H, singlet) -6.15 (1H, singlet) -7.1-7.8

(4H, massive) -8.3-8.9 (3H, massive).

  Elemental Analysis (C27H29ClN4O5S) C HCl N O S Calculated 58.21 5.25 6.37 10.06 14.36 5.76 Found 58.17 5.36 6.43 9.77 5.77 Oxalate: PFk = 130.135 C

  I.R .: 1715-1720, 1630-1660, 1620, 1560 cm -1.

  Elemental analysis (C27H29ClN4O5S, 2C2H2O4) C HCl N O S Calculated 50.51 4.51 4.81 7.60 28.22 4.35 Found 50.53 4.49 4.83 7.49 4.34

Example 5

  Preparation of 1 [[(4S) -5,5-dimethyl-2- (3-

  pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(4-methyl-2-

  oxo-2H-1-benzopyran-7-yl) oxy] propyl] piperazine, of formula:

S H3C O

HN..s "m CH3 CH3

NOT

  This product is obtained from the compound

  obtained in 1) to Example 2 and (4S) -5,5-dimethyl-

  2- (3-pyridinyl) -4-thiazolidinecarboxylic according to the mode

  procedure described for obtaining the compound of the Exem-

  1. The product is purified by chromatography on silica using first the system (AcOEt 60 / CHCl3 / MeOH 10) then the system (CHCl3 60 / MeOH 40). The

  product obtained is an amorphous solid.

  I.R .: 1710, 1630, 1610, 1410, 1380 cm -1.

Oxalate: mp 138 - 140 ° C (EtOH)

  I.R .: 1715, 1640, 1620, 1420, 1390 cm -1.

  Elemental analysis (C28H34N4O4S, 1.5 C2H2O4)

C H N O S

  Calculated 56.61 5.67 8.52 24.33 3.87 Found 56.41 5.80 8.48 4.78 Example 6

  Preparation of 1 [(3-pyridinyl) carbonyl] -4-

  [3 - [(4-methyl-2-oxo-2H-1-benzopyran-7-yl) oxy] propyl] PIPE

razine, of formula:

*NOT_

N N

  This compound is obtained starting from the compound obtained in 1) in Example 2 and nicotinic acid according to the procedure described for obtaining the compound of Example 1. The product is purified by chromatography on silica gel using the eluent system (CHCl3 / MeOH 20). The product obtained is in the form

a thick paste.

  I.R .: 1730, 1630, 1450, 1400, 1160 cm -1.

  RMNSH (CDCl3): 1.7-3.9 (12H, solid) -2.4 (3H, singletype)

  let) -4.05 (2H, triplet J = 6.7 Hz) -6.05 (1H, singlet) -

  6.5-7.9 (6H, massive) -8.6 (1H, multiplet).

maleate:

PFg = 149-152C.

  I.R .: 1730, 1630, 1580, 1395, 1375 cm -1.

  Elemental analysis (C23H25N304, C4H404)

C H N 0

  Calculated 61.94 5.58 8.03 24.45 Found 62.11 5.57 7.69

Example 7

  Preparation of 1 - [[(4R) -2- (3-pyridinyl) -4-

  thiazolidinyl] carbonyl] -4- [3- (2-oxo-2H-l-benzothiopyran-

  4-yl) oxy] propyl] piperazine, of formula: ## STR2 ##

  1) Preparation of 4- [(3-chloropropyl) oxy] -2-

  oxo-2H-1-benzothiopyran: A solution of 410 ml of dimethylformamide containing 13.5 g is heated at 40 ° C. for 30 minutes.

  g (0.098 moles) of K2CO3 and 15.5 g (0.098 moles) of 4-

  hydroxy-2-oxo-2H-l-benzothiopyran. We then sink

  17 g (0.108 mol) of 1-bromo-3-chloropropane.

  The mixture is kept at 40 ° C. for 7 hours.

  The minerals are filtered and concentrated under reduced pressure. The residue is taken up in water and extracted with methylene chloride. After drying and concentration under vacuum, a solid is obtained which is recrystallized from 350 ml of isopropanol. The product obtained is dissolved

  in hexane: a hot insoluble solid is removed.

  Hexane is evaporated to give 8.4 g of the product of formula above.

PFk = 110 C.

I.R .: 1615, 1545, 1370, 1230 cm -1.

  NMR'H (CDCl3): 2.4 (2H, quintuplet) -3.75 (2H, triplet J

  = 5.6 Hz) -4.25 (2H, triplet J = 6Hz) -6.05 (1H, singletreator

  let) -7.1-7.6 (3H, solid) -7.8 8.2 (1H, massive).

  2) Preparation of 1-benzyloxycarbonyl-4-

  [3- (2-oxo-2H-1-benzothiopyran-4-yl) oxy] propyl] piperazine: A solution of 50 ml of 2-butanone containing 5.0 g (0.0209) was refluxed for 6 hours.

  mole) of the product obtained in 1), 4.6 g of 1-benzyloxycar-

  piperazine bonyl and 3.2 g of K2CO3. After concentration under reduced pressure, the residue is taken up in water and extracted with ethyl acetate. After extraction with normal HCl, basification and acetate extraction

  of ethyl, 2.8 g of compound of formula

above.

PFk = 110 C

I.R .: 1695, 1645, 1240 cm -1.

  3) Preparation of 1- [3- (2-oxo-2H-1)

  benzothiopyran-4-yl) oxy] propyl] piperazine: HN OO

  This product is obtained according to the

  described for the compound obtained in 1) in Example 1,

  starting from 4 - [(3-chloropropyl) oxy] -2-oxo-2H-1-benzoate

  thiopyran. The product is obtained in the form of a solid

amorphous.

  I.R .: 2945, 2810, 1710, 1610-1640, 1545, 1225 cm -1.

  Alternative process: The formula product above can be

  also obtained in the following way: it is cooled to -

  10 C 50 ml solution of methylene chloride

  containing 2.8 g (0.00638 mol) of compound obtained in 2).

  A solution of 50 ml of methylene chloride containing 8.0 g (5 equivalents) of boron tribromide is added dropwise. Let it react for one hour

  at -10 C, then for 2 hours at room temperature.

  Pour on ice, decant the organic phase.

  The aqueous phase is filtered and then basified. After extraction with ethyl acetate, drying over sodium sulfate and concentration under vacuum, the product of formula above is isolated and purified as in the preceding process.

  4) Preparation of 1 - [[(4R) -2- (3-pyridine)

  nyl) -4-thiazolidinyl] carbonyl] -4- [3- (2-oxo-2H-l-benzo-

  thiopyran-4-yl) oxy] propyl] piperazine (title compound) This product is obtained from the compound

  obtained in 3) and (4R) -2- (3-pyridinyl) -4-thiazole

  dinecarboxylic acid according to the procedure described for obtaining the compound of Example 1. The product is purified by chromatography on silica gel using as eluent system (CHC13 80 / MeOH 20). The product is

  obtained in the form of a thick oil.

  I.R .: 1600 - 1660, 1420 - 1440, 1230 cm -1 Oxalate:

PFk = 130-140 C.

  I.R .: 1600 - 1640, 1405, 1230, 1120 cm -1.

  Elemental analysis (C2sH28N4O3S2, 1.5 C2H2O4, 0.5 H2O)

C H N O S

  Calculated 52.48 5.03 8.74 23.72 10.00 Found 52.43 5, 35 8.78 10.40

Example 8

  Preparation of 1 - [[(2R, 4R) -3-acetyl-2-

  (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-2H

  1-benzothiopyran-4-yl) oxy] propyl] piperazine:

0

N N N ôF

  N N This product is obtained from the compound

  obtained in 3) in Example 7 and (2R, 4R) -3-acetyl-

  2- (3-pyridinyl) -4-thiazolidinecarboxylic according to the mode

  procedure described for obtaining the compound of the Exem-

ple 1.

  PFk = 120-130C [α] 20D = + 92.6 (1% EtOH)

I.R .: 1650, 1610, 1250 cm -1.

  1 H NMR (CDCl 3): 1.95 (3H, singlet) -1.8 4.1 (14H, mas-

  sifs) -4,15 (2H, triplet J = 6 Hz) -5,1 (1H, triplet J =

  7.1 1 Hz) -6.05 (2H, singlet) -7.1 9.0 (8H, thick).

oxalate:

PFk = 130 - 135 ° C.

  I.R .: 1600 - 1660, 1405, 1220 - 1240 cm -1.

  Elemental analysis (C 27 H 30 N 4 O 4 S 2, 2 C 2 H 2 O 4)

C H N O S

  Calculated 51.80 4.77 7.80 26.71 8.92 Found 51.93 5, 20 7.85 8.56

Example 9

  Preparation of (4R) -4 [[[4- [3- (2-oxo-2H) -1-

  benzothiopyran-4-yl) oxy] propyl] -1-piperazinyl] carbonyl] -

  2- (3-pyridinyl) -3-thiazolidinecarboxylate 1,1-dimethyl-

ethyl: O>

N N

H 3C> O 0

H3C CH3

  This product is obtained from the compound

  obtained in 3) in Example 7 and (4R) -3- (N-tertiary acid)

  tyloxycarbonyl) -2- (3-pyridinyl) -4-thiazolidinecarboxyli-

  according to the procedure described for Example 1. The product is purified with the eluent system (CHCl 3 95 / Me

  OH 5) and is in the form of an amorphous solid.

  I.R .: 1700, 1660, 1620-1640, 1370 cm -1 Oxalate:

PFk = 138-145 C.

  I.R .: 1700, 1600 - 1650, 1370, 1230 - 1240 cm -1.

  Elemental analysis (C30H36N405S2, C2H2O4)

C H N O S

  Calculated 52.57 5.19 7.21 26.78 8.25 Found 52.39 5.14 7.20 8.15

Example 10

  Preparation of 1 - [[2- (3-pyridinyl) -4-

  thiazolyl] carbonyl] -4- [3 - [(2-oxo-2H-l-benzothiopyran-4-

yl) oxy] propyl] piperazine:

NOT; _NOT

O I

  This product is obtained from the compound

  obtained in 3) in Example 7 and 2- (3-pyridinyl) -4-

  thiazolecarboxylic acid according to the procedure described for Example 1. The product is purified by chromatography on silica gel using the system (CHCl 3 95 / MeOH 5) as eluent. The product is in form

a thick oil.

  I.R .: 1620, 1445, 1360, 800 cm -1 Oxalate:

PFk = 140-145 C.

  Elemental analysis (C25H24N4O3S2, 1.5 C2H204)

C H N O S

  Calculated 53.58 4.34 8.93 22.94 10.22 Found 53.20 4.48 8.84 10.50 Example 11:

  Preparation of 1 - [[(4R) -2- (3-pyridinyl) -4-

  thiazolidinyl] carbonyl] -4- [3 - [(1-methyl-2-oxo-1,2-

  dihydro-4-quinolinyl) oxy] propyl] piperazine:

S

IC1

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

  1-methyl-2-oxo-1,2-dihydroquinoline

C

  14 g (0.0799 mol) of

  hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline with 11.0 g (0.0799 moles) of K2CO3 in 350 ml of dimethylformamide

at 40 C for 15 minutes.

  13.9 g (0.0878 mol), 1-bromo-3-chloropropane are rapidly run in and maintained at 40 ° C. for 6 hours. Cooled, filtered and concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated in vacuo. The solid obtained is washed with diethyl ether and then recrystallized

in isopropanol (9 g obtained).

PFk = 120 C.

I.R .: 1665, 1635, 1235, 1125 cm -1.

  NMR (CDCl3): 2.35 (2H, quintuplet) -3.65 (3H, singletr)

  let) -3.8 (2H, triplet J = 5.2 Hz) -4.2 (2H, triplet J =, 6 Hz) -5.95 (1H, singlet) -7.0-8.0 (4H , massive).

  2) Preparation of 1- [3 - [(1-methyl-2-oxo)

  1,2-dihydro-4-quinolinyl) oxy] propyl] piperazine:

HN

t CH3

  This product is obtained according to the

  described for the compound obtained in 1) to Example 1, starting from the compound obtained in step 1 above. The

  product is in the form of a yellow oil.

  I.R .: 1630-1665, 1595, 1240, 760 cm -1.

  3) Preparation of 1 - [[(4R) -2- (3-pyridine)

  nyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(1-methyl-2-oxo-2-

  dihydro-4-quinolinyl) oxy] propyl] piperazine (title compound): This product is obtained starting from the compound

  obtained in 2) above and (4R) -2- (3-pyridinyl) -4-

  thiazolidinecarboxylic according to the procedure described

  for Example 1. The product is purified by chromatography.

  on silica gel using the system (CHCl 3 60 / MeOH 40) as eluent. The product is presented under

form of a thick oil.

  I.R .: 1600-1660, 1585, 1425, 1240 cm -1 Oxalate: PF k = 110-120 C. I.R .: 1630, 1580, 1235, 1120 cm -1 Elemental analysis (C 26 H 31 N 5 O 3 S, 1.5 C 2 H 2 O 4)

C H N O S

  Calculated 55.40 5.64 11.14 22.91 5.10 Found 55.34 5.28

Example 12

  Preparation of 1 - [[(4R) -5,5-dimethyl-2- (3-

  pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(4-methyl-2-

  oxo-2H-1-benzopyran-7-yl) oxy] propyl] piperazine: 2o

N 5 S H3CN

HNJ CH3

  This product is obtained starting from the compound

  obtained in 1) in Example 2 and (4R) -5,5-dimethyl-

  2- (3-pyridinyl) -4-thiazolidinecarboxylic according to the mode

  described for obtaining the compound of the Exem-

  1. The product is purified by chromatography on silica gel using first the eluent system (AcOEt / CHCl 3 30 / MeOH 10), then (CHCl 3 60 / MeOH 40). The

  product is in the form of an oil.

  RMNSH (CDCl3): 1.1-3.9 (22H, massive) -4.05 (2H, triplet)

  J = 5.6 Hz) -5.6-5.9 (1H, solid) -6.1 (1H, singlet) -6.6-

9.0 (8H, massive).

maleate:

PFg = 90 - 95 C.

  I.R .: 1720, 1620, 865 cm-1 Elemental analysis (C28H34N4O4S, 2 C4H4O4, H2O)

C H N O S

  Calculated 55.94 5.74 4.25 26.96 4.14 Found 56.28 5.66 6.99 Example 13:

  Preparation of 1 - [[(4R) -2- (3-pyridinyl) -4-

  thiazolidinyl] carbonyl] -4- [3 - [(3-benzyl-2-oxo-2H-1-

  benzopyran-4-yl) oxy] propyl] piperazine: HN 0s

-

  1) Preparation of 3-benzyl-4 - [(3-bromopropyl)

pyl)) oxy] -2-oxo-2H-l-benzopyran:

-

  A solution of 125 ml of dimethylformamide containing 12.6 g is heated for 1 hour at 60 ° C.

  g (0.05 mole) of 3-benzyl-4-hydroxy-2-oxo-2H-1-benzopyramide

  gallon, 8.3 g of K 2 CO 3 and 0.5 g of KI.

  40.4 g of 1,3-dibromo are rapidly added.

  propane and heated for 5 hours at 70 C. The medium is then concentrated under reduced pressure, taken up in water and extracted with ethyl acetate. The product of formula above is in the form of a thick oil which

crystallizes in isopropanol.

I.R .: 1720, 1625, 1095, 750 cm -1.

  1H NMR (CDCl3): 2.3 (2H, quintuplet) -3.6 (2H, triplet J

  = 6 Hz) -3.15 (2H, singlet) -4.1 (2H, triplet J = 5.6 Hz) -

6.9-8.1 (9H, massive).

  2) Preparation of 1- [3 - [(3-benzyl-2-oxo)

  2H-l-benzopyran-4-yl) oxy] propyl] piperazine:

/

HNNJr9 -

  This product is obtained according to the

  described for the compound obtained in 1) to Example 1, starting from the compound obtained in 1) above. The product is purified by chromatography on silica gel using the eluent system (CHCl 3 90 / MeOH 10). The

  product is in the form of an oil.

  NMR (CDCl3): 1.4-2.9 (12H, solid) -3.9 (2H, singletreator);

  let) -3.95 (2H, triplet J = 6 Hz) -6.8-7.8 (9H, massive).

  3) Preparation of 1 - [[(4R) -2- (3-pyridine)

  nyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(3-benzyl-2-oxo-2H-

  1-Benzopyran-4-yl) oxy] propyl] piperazine (title compound): This product is obtained from the compound

  obtained in 2) and (4R) -2- (3-pyridinyl) -4-thiazole

  dinecarboxylic acid according to the procedure described for the compound of Example 1. The product is purified by chromatography on silica gel using the eluent system (CHCl 3 97 / MeOH 3). The product is presented under

form of an amorphous solid.

  I.R .: 1720, 1645, 1620, 1420, 1100 cm -1 Oxalate: mp = 105 - 110 C I. R .: 1710, 1650, 1620, 1100 cm-1 Elemental analysis (C32H34N4O4S, C2H2O4)

C H N O S

  Calculated 57.99 5.23 7.83 22.67 4.54 Found 57.59 5.10 7.46 4.27

Example 14

  Preparation of 1 - [[(4R) -2- (3-pyridinyl) -4-

  thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-3-phenyl-2H-1-

  benzopyran-4-yl) oxy] propyl] piperazine: HNo /

O

  1) Preparation of 4 - [(3-bromopropyl) oxy] -2-

oxo-3-phenyl-2H-1-benzopyran:

  This product is obtained according to the

  described for the compound obtained in step 1) of

Example 13.

  Kp = 85-90 ° C .: 1705, 1610, 1565, 1335, 1105, 765 cm -1. 1 H NMR (CDCl 3): 2.1 (2H, quintuplet) -3.4 (2H, triplet J = 6Hz) -3.75 (2H, triplet J = 5.6Hz) -7.0-8.0 ( 9H, massive).

  2) Preparation of 1- [3 - [(2-oxo-3-phenyl) -2H-

  1-Benzopyran-4-yl) oxy] propyl] piperazine: o

r-I -

HN N

  75 g (0.0417 mol) of piperazine, 5.8 g (0.0417 mol) of K 2 CO 3, 5.0 g are reacted overnight in a reactor containing 75 ml of acetone. (0.0139 mol) of the compound obtained in 1) and

  4.5 g (0.0139 mol) of tributylammonium bromide.

  Concentrated under reduced pressure, resumes

  with water and extracted with ethyl acetate. By concentration

  tion, an oil is obtained which is purified by chromato-

  silica gel graph using the system

  eluent (CHCl 3 95 / MeOH 5). The compound of formula

  above is in the form of a thick oil.

  I.R .: 1735, 1720, 1615, 1105, 1115, 760 cm -1.

  3) Preparation of 1 - [[(4R) -2- (3-pyridine)

  nyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-3-phenyl-2H-

  1-Benzopyran-4-yl) oxy] propyl] piperazine (title compound): This compound is synthesized from the product obtained in 2) and (4R) -2- (3-pyridinyl) -4-thiazole acid -

  dinecarboxylic acid according to the procedure described for the compound of Example 1. The product obtained is purified by chromatography on silica gel using the eluent system (CHCl 3 95 / MeOH 5). The title compound is in the form of an amorphous solid. Oxalate: mp = 115 ° C. I.R .: 1700, 1640, 1605, 1170-1200 cm -1 Elemental analysis (C31H32N4O4S, C2H2O4, H2O)

C H N O S

  Calculated 57.69 5.07 7.42 27.55 4.24 Found 55.97 4.94 7.34 3.84 Example 15:

  Preparation of 1 - [[(4R) -2- (3-pyridinyl) -4-

thiazolidinyl] carbonyl] -4- [3 - [(6-chloro-2-oxo-2H-1)

  benzopyran-4-yl) oxy] propyl] piperazine:

0

NHN {DN-- F

This

  1) Preparation of 6-chloro-4 - [(3-chloropropyl)

  pyl) oxy] -2-oxo-2H-1-benzopyran: A solution of 200 ml of dimethylformamide containing 19.7 ml is heated for one hour at 60 [deg.] C.

  g (0.1 mole) 6-chloro-4-hydroxy-2-oxo-2H-1-benzopyramide

  16.6 g of K 2 CO 3 and 0.5 g of KI. 63.2 g of 1-bromo-3-chloropropane are then rapidly added at room temperature and the mixture is then heated for 5 hours at 700 ° C. After treatment, we obtain with a yield

  quantitatively the compound of formula above.

PFk = 162-164C.

  2) Preparation of 1 - [[(4R) -2- (3-pyridine)

  nyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(6-chloro-2-oxo-2H-

  1-benzopyran-4-yl) oxy] propyl] piperazine (title compound): This compound is synthesized from the compound

  obtained in 1) in Example 4 and (4R) -2- (3-pyridinic acid)

  nyl) -4-thiazolidinecarboxylic acid according to the procedure described for Example 1. The product is purified by chromatography on silica gel using the eluent system (CHCl 3 95 / MeOH 5). The product of the title

  present as an amorphous solid.

  I.R .: 1725, 1640, 1625, 1430, 820 cm -1.

Oxalate: PFk = 135-140C

I.R .: 1725, 1625, 1565 cm -1.

Example 16

  Preparation of 1 - [[(4R) -2- (3-pyridinyl) -4-

  thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-4-phenyl-2H-1-

  benzopyran-7-yl) oxy] propyl] piperazine: N /

S 0-

HN L N o

  1) Preparation of 7 - [(3-chloropropyl) oxy] -2-

  oxo-4-phenyl-2H-1-benzopyran: A solution of 280 ml of dimethylformamide containing 33 g is heated for one hour at 60 [deg.] C.

  (0.1385 moles) 7-hydroxy-4-phenyl-2-oxo-2H-1-benzopyramide

  23 g of K 2 CO 3 and 0.5 g of KI. 85.5 g of 1-bromo-3chloropropane are added and the mixture is heated for 5 hours at 70 ° C. After usual treatment, 30 g of compound are isolated.

of formula above.

PFk = 80C.

I.R .: 1725, 1615, 1375, 1300 cm -1.

  2) Preparation of 1- [3 - [(2-oxo-4-phenyl)

  2H-1-benzopyran-7-yl) oxy] propyl] piperazine: This product is obtained starting from the compound obtained in 1) according to the procedure described for the compound obtained in 2) in the Example 14. The product is

  purified by silica gel chromatography using

  the eluent system (CHCl 3 80 / MeOH 20). The product

  is in the form of a thick oil.

I.R .: 1720, 1610, 1375, 1150 cm -1.

  3) Preparation of l - [[(4R) -2- (3-pyridine)

  nyl) -4-thiazolidinyl] carbonyl] -4- [3 - [(2-oxo-4-phenyl-2H-

  1-benzopyran-7-yl) oxy] propyl] piperazine (title compound): This compound is obtained from the compound

  obtained in 2) and (4R) -2- (3-pyridinyl) -4-thiazole

  dinecarboxylic acid according to the procedure described for obtaining the compound of Example 1. The product is chromatographed on silica gel first with the eluent system (AcOEt 60 / CHCl 3 30 / MeOH 10), then with the system (CHCl3 80 / MeOH 20). The product is presented under

form of a thick oil.

  IR: 1720 - 1740, 1645, 1615, 1380 cm -1 Oxalate: mp 128 - 130 ° C IR: 1700 - 1730, 1650, 1610, 1380 cm -1 Elemental analysis (C 31 H 32 N 4 O 4 S, 1.5 C 2 H 2 O 4, 0.5 H 2 O )

C H N O S

  Calculated 58.27 5.17 7.99 23.97 4.57 Found 58.27 5.15 7.87 4.80

Example 17

  Preparation of 1 - [[3- (3 (pyridinyl) -1H, 3H-

  pyrrolo [1,2-c] thiazol-7-yl] carbonyl] -4- [3- (2-oxo-2H-1-

  benzothiopyran-4-yl) oxy] propyl] piperazine: The compound is prepared from the product

  obtained in 1) in Example 11 and 3- (3-pyridinyl) -

  1H, 3H-pyrrolo [1,2-c] thiazolecarboxylic according to the mode

  procedure described for obtaining the compound of the Exem-

  The product is purified by chromatography on silica gel using the eluent system (CHCl 3 95 / MeOH). The product is in the form of a thick oil. 1 H NMR (CDCl 3): 1.8-4.0 (12H, solid) -4.2 (2H, triplet J = 6Hz) -4.4 (2H, doublet) -6.05 (1H, singlet) -6,2-6, 4

  (3H, massive) -7.1-9.0 (8H, massive).

oxalate:

PFk = 118-125C.

  I.R .: 1720, 1600 - 1640, 1540, 1220 cm -1 Elemental analysis (C28H28N4O3S2, C2H2O4, H2O)

C H N O S

  Calculated 52.59 4.63 7.66 26.24 8.77 Found 52.77 4.78 7.51

Claims (13)

  1. Compounds of general formula I: R3 R 2 R i R4 R) J X / 0 5   R6 wherein X represents an oxygen or sulfur atom, or a   N-R group, in which R represents a hydrogen atom   or a C1-C7 alkyl group, one of R1, R2, R3, R4, R6 and R6 represents the group of the formula -Z-N-N-CO-R7   in which: Z represents an oxygen or sulfur atom, A represents a linear or branched C1-C7 alkylene group, and R7 is a nitrogen-containing heterocyclic group comprising 5 to one ring and optionally comprising another heteroatom selected from 0, S and N-R10, Ro10 being a hydrogen atom, a C1-C7 alkyl group, a C1-C7 acyl group, a C6-C10 aryl group or the tert-butoxycarbonyl group, where R7 is optionally substituted on the carbon atoms by 1 to 8 identical or different substituents chosen   from a halogeno group, C1-C7 alkyl, C1-C6 alkoxy   C7, trifluoromethyl, nitro, cyano, phenyl, benzyl, pyridyl, piperidino and piperazino,   R1 and R2, when they are not as defined above   above, represent independently of each other a hydrogen atom, a C1-C7 alkyl group, a C3-C6 cycloalkyl group, a C6-C10 aryl group, a C1-C4 alk (C1-C4) aryl group, C6-C10 or a heterocycle having 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1 to 5 substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, C 4 alkyl -C7, alkoxy   C4-C7, C1-C7 acyl, acetylamino, amino, C1-C7alkyl   C7) amino and dialkyl (C1-C7) amino, R3, R4, R5 and R6, when not as defined above, independently of one another represent a hydrogen atom, d halogen, hydroxy, nitro, cyano, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 acyl, amino, C 1 -C 7 alkylamino, dialkyl (C 4 -C 7) amino , acetylamino, C 6 -C 10 aryl, C 1 -C 4 alk (C 1 -C 4) aryl or a heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and their pharmaceutically acceptable salts acceptable.   2. Compounds of general formula II: R3 R R1 R4 Z-A-N N-CO-R7 II R5 /   635 in which: X, A, Z, R1, R3, R4, Rs5, R6 and R7 are as defined in   claim 1 and their pharmaceutical salts- acceptable.   3. Compounds of general formula III R3 R2 R4 R1 R7-CO-NN-A-ZIII   In which: X, A, Z, R 1, R 2, R 3, R 4, R 5, and R 7 are as defined in claim 1, the group -Z-N-N-CO-R7   being attached in position 5, 6, 7 or 8 of the heterocycle.   4. Compounds of general formula I according to claim 1, characterized in that R7 represents a group of formula: ## STR2 ## in which z1 represents a sulfur, oxygen atom, a -CH =, CH2 group , CH 2 -CH 2 or -CH = CH-, a group - N = or N-R 10, R 10 being as defined in claim 1, R 11 represents a hydrogen atom or a C 1 -C 7 alkyl group, R 12, R 13 , R14 and R15 independently of one another represent a hydrogen atom, a halogen atom, a C1-C7 alkyl group or a nitrogen heterocycle having from 5 to 6   optionally substituted by a halogen atom   ne, nitro, cyano, trifluoromethyl, C 1 -C 7 alkyl or C 1 -C 7 alkoxy, or   R10 and R15, when taken together, may form   a group = CH -CH = CH-, as well as their salts pharmaceutically acceptable.   5. Compounds of general formula I according to claim 1, characterized in that R7 is chosen from the groups: lil R12 Z1Riz 11Z Rl N <'R 1 XN Rio Rio Rio R1 2, <Z \ r. 1 R1 NOT wherein:   Z1, R10, R11, R12 and R13 are as defined in claim cation 4.   6. Compounds according to claim 4, wherein Z1 is a sulfur atom or the group -CH = CH-, R1l being as defined in claim 4, and R12 or   R13 represent the pyridyl group.   Compounds according to claim 4, wherein R7 is pyridyl or pyrrolo [1,2-c] thiazole, optionally substituted with 1 to 5 substituents selected from halogen and C1-C7 alkyl group.   8. Compounds according to one of claims 1   to 3, wherein one of R1, R2, R3, R4, R6 and R6 represents the group -Z-N-N-CO-R7   A, Z and R7 being as defined in claim 1,   and R1 and R2, when not as defined above   above, represent a hydrogen atom, a C1-C7 alkyl group, a phenyl group or a benzyl group, and R3, R4, R5 and R6, when not as defined above, represent an atom hydrogen or a halogen atom.   9. Compounds according to claim 1, characterized in that the pharmaceutically acceptable salts are chosen from the salts obtained with a compound of formula I according to claim 1 and the acid oxalic acid or maleic acid.   10. Compounds according to claim 1, characterized in that they are chosen from:   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-   [3 - [(2-oxo-2H-l-benzopyran-4-yl) oxy] propyl] piperazine;   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-   [3 - [(4-methyl-2-oxo-2H-1-benzopyran-7-yl) oxy] propyl] PIPE razine;   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-   [3 - [(2-oxo-2H-l-benzopyran-3-yl) oxy] propyl] piperazine;   1 - [[(2R, 4R) -3-acetyl-2- (3-pyridinyl) -4-thiazolidine   nyl] carbonyl] -4- [3 - [(6-chloro-2-oxo-2H-l-benzopyran-4- yl) oxy] propyl] piperazine;   1 - [[(4S) -5,5-dimethyl-2- (3-pyridinyl) -4-thiazolidine   nyl] carbonyl] -4- [3 - [(4-methyl-2-oxo-2H-l-benzopyran-7- yl) oxy] propyl] piperazine;   1 - [(3-pyridinyl) carbonyl] -4- [3 - [(4-methyl-2-oxo-2H-1)   benzopyran-7-yl) oxy] propyl] piperazine;   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-   [3 - [(2-oxo-2H-1-benzothiopyran-4-yl) oxy] propyl] piperazine;   1 - [[(2R, 4R) -3-acetyl-2- (3-pyridinyl) -4-thiazolidine   nyl] carbonyl] -4- [3 - [(2-oxo-2H-l-benzothiopyran-4-yl) oxy] - propyl] piperazine;   (4R) -4 - [[4- [3 - [(2-oxo-2H-1-benzothiopyran-4-yl) oxy] -   propyl] -l-piperazinyl] carbonyl] -2- (3-pyridinyl) -3   1,1-dimethylethyl thiazolidinecarboxylate;   1 - [[3- (3-pyridinyl) -1H, 3H-pyrrolo [1,2-c] thiazol-7-   yl] carbonyl] -4- [3 - [(2-oxo-2H-l-benzothiopyran-4-yl) oxy] - propyl] piperazine;   1 - [[(4R) -5,5-dimethyl-2- (3-pyridinyl) -4-thiazolidine   nyl] carbonyl] -4- [3 - [(4-methyl-2-oxo-2H-l-benzopyran-7- yl) oxy] propyl] piperazine;   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-   [3- [3-benzyl-2-oxo-2H-l-benzopyran-4-yl) oxy] propyl] PIPE razine;   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-   [3 - [(2-oxo-3-phenyl-2H-l-benzopyran-4-yl) oxy] propyl] PIPE razine;   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-   [3 - [(6-chloro-2-oxo-2H-l-benzopyran-4-yl) oxy] propyl] PIPE razine;   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4-   [3 - [(2-oxo-4-phenyl-2H-1-benzopyran-7-yl) oxy] propyl] PIPE razine;   1 [[2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -4- [3-   [(2-oxo-2H-l-benzothiopyran-4-yl) oxy] propyl] piperazine;   1 - [[(4R) -2- (3-pyridinyl) -4-thiazolidinyl] carbonyl] -   4- [3 - [(1-methyl-2-oxo-l, 2-dihydro-4-quinolinyl) oxy] pro-   pyl] piperazine, and their pharmaceutically acceptable salts.   ble. 11. Process for preparing a compound of general formula I R 3 R2 R5 0 R X   wherein: X represents an oxygen or sulfur atom, or   group> N-R, in which R represents a hydrogen atom   gene or a C 1 -C 7 alkyl group, one of R 1, R 2, R 3, R 4, R 5 and R 6 represents the group of formula -Z-N-N-CO-R7   in which: Z represents an oxygen or sulfur atom, A represents a linear or branched C1-C7 alkylene group, and R7 is a nitrogen-containing heterocyclic group, comprises from 5 to 7 members and optionally comprising another heteroatom chosen from O, S and N-R 10, wherein R 10 is hydrogen, C 1 -C 7 alkyl, C 1 -C 7 acyl, C 6 -C 10 aryl or tert-butoxycarbonyl, R 7 being optionally substituted on the carbon atoms by 1 to 8 identical or different substituents chosen   from a halogeno group, C1-C7 alkyl, C1-C6 alkoxy   C7, trifluoromethyl, nitro, cyano, phenyl, benzyl, pyridyl, piperidino and piperazino,   R1 and R2, when they are not as defined above   above, independently of one another represent a hydrogen atom, a C 7 -C 7 alkyl group, a C 3 -C 6 cycloalkyl group, a C 6 -C 18 aryl group or a C 1 -C 4 alkoxy aryl group. C6-C10 or a heterocycle having 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1 to 5 substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, C1-alkyl -C7, alkoxy   C1-C7, C1-C7 acyl, acetylamino, amino, C1-C7 alkyl   C7) amino and dialkyl (C1-C7) amino, R3, R4, Rs and R6, when not as defined above, independently of one another represent a hydrogen atom, d halogen, hydroxy, nitro, cyano, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 acyl, amino, C 1 -C 7 alkylamino, dialkyl (C 1 -C 7) amino , acetylamino, C 6 -C 10 aryl, C 1 -C 4 alk (C 1 -C 4) aryl or a heterocycle having 3 to 8 atoms, of which 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, as well as its pharmaceutically acceptable salts characterized in that a compound of formula IV is reacted R3 R2 R '1   R6 IV in which: X represents an oxygen or sulfur atom, or   N-R group, in which R represents a hydrogen atom   gene or a C 1 -C 7 alkyl group, one of R ', R' 2, R '3, R' 4, R 'and R' 6 represents the group of formula: -Z-A-N N-H   in which: Z represents an oxygen or sulfur atom, and A represents a linear or branched C1-C alkylene group,   R'1 and R'2, when they are not as defined above   above, independently of one another represent a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a C 6 -C 10 aryl group or a C 1 -C 4 alkyl aryl group; C6-C10 or a heterocycle having 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1 to 5 substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, alkyl, CQ-C7, alkoxy   C, -C7, C 1 -C 7 acyl, acetylamino, amino, C 1 -C 6 alkyl   C7) amino and dialkyl (C1-C4) amino, and R '3, R' 4, R'I and R '6' when not as defined above, independently represent one of the other is hydrogen, halogen, hydroxy, nitro, cyano, trifluoromethyl, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 acyl, amino, C 1 -C 4 alkyl, )   amino, dialkyl (C 1 -C 7) amino, acetylamino, C 6 aryl   CI0, C1-C4 alk (C1-C4) aryl or a heterocycle having from 3 to 10 atoms, including 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, with a compound of formula V: V R7-Xi in which R. is a nitrogen-containing heterocyclic group having from 5 to 7 members and optionally comprising another heteroatom selected from O, S and N-R 10, wherein R 10 is a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 acyl group; -C7, C6-C10 aryl or tert-butoxycarbonyl group, R7 being optionally substituted on the carbon atoms by 1 to 8 identical or different substituents chosen   from a halogeno group, C1-C7 alkyl, C1-C6 alkoxy   C7, trifluoromethyl, nitro, cyano, phenyl, benzyl, pyridyl, piperidino and piperazino, and X1 represents a leaving group selected from halogen,   azido, cyano, (C 1 -C 4) alkylsulphonyloxy, aryl (in C   C9) sulfonyloxy, C1-C7 alkyl-C5-C9 aryl sulfonyl-   loxy, and COR15, R15 being selected from a halogen atom   ne, hydroxy, C1-C4 alkoxy, amino, C1-C4 alkyl, amino, C1-C7 dialkylamino, and OCO-R7, R7 being as defined above, to obtain a compound of general formula I which is optionally converted to a corresponding salt by addition of a mineral acid or   organic pharmaceutically acceptable.   12. Process for preparing a compound of   general formula IV according to claim 11, characterized rised by the following steps:   a) reaction of a compound of the general formula the VI: R3 R'2 R11 R   VI wherein: X is as defined in claim 11, one of R "", R ", R" 4, R "5 and R" 6 represents a group: -Z-A-X2   in which Z and A are as defined in the claim   11, and X2 represents a leaving group, and the others from R "1, R" 2, R "3, R" 4, R "5 and R" 6 respectively represent a group R1, R2, R3, R4, R5 and R6 as defined in claim 11, with a compound of general formula VII: H-N N-R16 VII   in which R16 represents a hydrogen atom or a group protecting the amine function, to obtain a compound of general formula VIII: RI "Ri 4 V 4 R1 VIII 5 X   wherein: X is as defined above, one of R '"2, RN3, R"' 4, R "'5 and R"' 6 represents the group: -Z-A-N N-R16   Z, A and R16 being as defined above, the others   from R 'R R' ', R'2 "' 3, R" '4, R "s' and R * 6 respectively representing   R 1, R "2 R" 3, R 4, R "5 and R" 6 as defined above, b) if appropriate, deprotection of the amine function of the compound of formula VIII as defined above. above, to obtain a compound of formula   general IV as defined in claim 11.   A pharmaceutical composition comprising as active ingredient a compound as defined in one of claims 1 to 10.