FR2761073A1 - Pyrazino indolone derivatives - Google Patents

Abstract

Pyrazino1,2-a indol-1-one derivatives of formula (I), their salts with acids and bases, and their hetero atom position isomers, are claimed, where R1, R2 = H, halogen, amino,1-4C alkylamino, OH, NO2, CN, 1-6C alkyl or alkoxy, CF3, CF3O, -COOH, -COOR4, -CONH2, -CONHR4, -CONR4R5, -SR4, -SO2R4, -NHCOR4, -NHSO2R4, or -N(R4)2; R4, R5 = 1-4C alkyl; R3 = H, 1-6C alkyl, -(CH2)p-OH, -(CH2)pNH2, -(CH2)n COOH, -(CH2)nCOOR4, -(CH2)nCN, -(CH2)n tetrazol-5-yl, -(CH2)nCONH2, -(CH2)nCONHOH, -(CH2)pSH, -(CH2)nSO3H, -(CH2)nSO2NH2, -(CH2)nSO2NHR4, -(CH2)nSO2NR4R5, -(CH2)nCONHR4, or -(CH2)pOCOR4; n = 1, 2, 3 or 4; p = 2, 3 or 4; Q = either 2 H atoms, or =O; Z = N or -CH-; A = phenyl, optionally substituted, or an optionally substituted 5- or 6-membered heterocycle having 1-3 hetero atoms (O, N, S) this heterocycle may be, for example furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.

Description

The subject of the present invention is pyrazino [1,2-a] indole derivatives.

l-one, their preparation and their

therapeutic application.

  The compounds of the invention have the formula (I) NI

N 9 (I)

NOT

  Wherein R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, an amino group or a (C 1 -C 4) amino group; ) alkyl, either a hydroxy group, a nitro group, a cyano group, a (C1-C6) alkyl group, a (C1-C6) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, or a -COOH group, -COOR4 group, -CONH2 group, -CONHR4 group, -CONR4R5 group, -SR4 group, -SO2R4 group, -NHCOR4 group, or - NHSO2R4, that is a group - N (R4) 2, where R4 and R5 are each a (C1-C4) alkyl group, R3 represents either a hydrogen atom, a (C1-C6) alkyl group or a - ( CH2) pOH, either a - (CH2) pNH2 group, a - (CH2) nCOOH group, a (CH2) nCOOR4 group, a - (CH2) nCN group, or a (CH2) n -tetrazol-5 group or a group - (CH2) nCONH2, a (CH2) nCONHOH group or a group e - (CH2) pSH, either a - (CH2) nSO3H group, a - (CH2) nSO2NH2 group, a - (CH2) nSO2NHR4 group, a (CH2) nSO2NR4R5 group or a - (CH2) nCONHR4 group either a (CH2) nCONR4R5 group, a - (CH2) pNHSO2R4 group, a (CH2) pNHCOR4 group, or a - (CH2) pOCOR4 group where R4 and R5 are each a (C1-C4) alkyl, n is equal to 1, 2, 3 or 4 and p is 2, 3 or 4, Q is either two hydrogen atoms or one oxygen atom, Z is either a nitrogen atom or a -CH group -, A represents either an optionally substituted phenyl group or a substituted or unsubstituted heterocycle having 5 or 6 atoms, of which one, two or three are heteroatoms chosen from nitrogen, oxygen and sulfur atoms, the other atoms being carbon atoms, said heterocycle being for example selected from furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thienyl, thiadiazolyl, pyridine yl, pyrimidinyl, pyrazinyl, pyridazinyl and their positional isomers of heteroatoms, as well as their addition salts to acids or bases

pharmaceutically acceptable.

  According to the invention, to prepare the compounds of formula (Ia) which correspond to the compounds of formula (I) in which R1 and R2 represent either a hydrogen atom, or a halogen atom, a hydroxy group, or a (C1-C6) alkyl group, either a (C1C6) alkoxy group, a trifluoromethyl group or a trifluoromethoxy group, a -SR4 group or a -SO2R4 group, R3 is different from a hydrogen atom, Q represents two hydrogen atoms and A and Z are as previously defined, then one can

use diagram 1.

  A compound of formula (II) (in which R 1 and R 2 are as defined above) is reacted with ethanedioyl dichloride at room temperature in an aprotic solvent such as ether to prepare an intermediate compound which is taken up by an alcohol comprising from 1 to 4 carbon atoms and a compound of formula (III) is obtained which is treated with a hydride in a solvent Scheme R 1 O

-I ----

N NN

R R R2

2H H H

(II) (III) (IV)

OP OP

Ri Ri

-X) - NN OCH2CH3

R2 \ R \ 3

H 2 H

(V) (VI)

OP OP Ri

R2 NOCH2CH3 R2 2 3

R2 NCN 3NH2

(VII (VIII)

OP

0L

R1 -R O

I N 2N-R

R NNH R

(Ix) (X) OH

R

R N -H

(XIII)

Figure 1 (continued)

(XIII) (X)

v y Y, oA

R1 CHO R1

o

N -R3

R2R

(XIV) (XI

HN Z (XII) NI

N / A

c z

3 0 NR1

  / RiN-R 2 / (Ia), R 3 # H (Ib), R 3 = aprotic H, for example lithium hydride and

  of aluminum in tetrahydrofuran at room temperature. A compound of formula (IV) is thus obtained, the alcohol function of which is protected by a protective group P, for example by treatment with (1,1-dimethyl) chloride.

  ethyl) dimethylsilyl in the presence of a weak base such as imidazole and a compound of formula (V) is obtained which is subjected to lithiation directed by successive treatments

  with a strong base like for example n-butyllithium at -

  70 C in an aprotic solvent such as tetrahydrofuran, with gaseous carbon dioxide and finally with a strong base such as tert-butyllithium at -70 C in an aprotic solvent such as tetrahydrofuran to prepare a dianion which is treated with a carbonyl electrophilic agent such as ethyl chloroformate to obtain a compound of formula (VI). The compound of formula (VI) thus obtained is then treated with a base in an aprotic polar solvent, for example sodium hydride in dimethylformamide at room temperature and then with chloroacetonitrile to obtain a compound of formula (VII) which is reduces the nitrile function by conventional techniques known to those skilled in the art, for example by Raney nickel, diborane or hydrogen in the presence of palladium or platinum, and a compound of formula (VIII) is obtained which is cyclized by heating in the presence of a base in a polar solvent such as for example sodium ethoxide in ethanol to obtain a compound of formula (IX). Then, if it is desired to obtain a compound in which R 3 is different from a hydrogen atom, the compound of formula (IX) is reacted with an electrophilic agent, for example by the action of sodium hydride in tetrahydrofuran at 0.degree. -5 C then action of methyl iodide or 2-bromoethyl acetate or by alkylation under phase transfer conditions catalyzed by a transfer agent such as tetrabutylammonium in the presence of an inorganic base such as hydroxide of potassium in an aprotic solvent such as tetrahydrofuran with an electrophile such as 2-bromoacetamide and there is obtained a compound of formula (X) in which R 3 is as defined above which is converted into a compound of formula (XI) in which Y represents a leaving group such as a chlorine or bromine atom, for example by treatment with thionyl chloride in chloroform at the reflux temperature or by dibromotriphenylphosphorane in the dic hloromethane or chloroform at ambient temperature or in a compound of formula (XI) in which Y represents a leaving group such as

  methanesulfonyloxy, trifluoromethanesulphonyl

  nyloxy or para-toluenesulfonyloxy, for example by reaction with a sulfonic anhydride or a sulfonic acid chloride in the presence of a base such as pyridine or triethylamine. Finally, the compounds of formula (XI) are reacted with a compound of formula (XII) (wherein A is as defined above) with or without an aprotic or protic solvent, in the presence of an inorganic base between 20 C and 150 OC. preferably in acetonitrile or dimethylformamide in contact with sodium bicarbonate

  and a compound of formula (Ia) is obtained.

  If it is desired to prepare compounds of formula (Ib) which correspond to the compounds of formula (I) in which R1 and R2 represent either a hydrogen atom, a halogen atom, a hydroxy group or a group (C1 -C6) alkyl, either a (C1-C6) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -SR4 group or a -SO2R4 group, R3 is a hydrogen atom, Q represents two atoms of hydrogen and A and Z are as defined above, then the compound of formula (IX) is deprotected according to standard techniques known to those skilled in the art to obtain a compound of formula (XIII) which is converted into a compound of formula (XIV) for example by treatment with pyridinium dichromate in dichloromethane buffered with sodium acetate in the presence of a drying agent such as molecular sieve 4A and then the compound of formula (XIV) thus obtained is condensed with a compound of formula (XII) with a reducing ammination action in the presence, for example, of titanium tetraisopropoxide and sodium cyanoborohydride

in methanol or ethanol.

  When it is desired to prepare compounds of formula (Ic) which correspond to compounds of formula (I) in which R1 and / or R2 represent either an amino group, a (C1-C4) alkyl group or a group nitro, a cyano group, a -COOH group, a -COOR4 group, a -CONH2 group, a -CONHR4 group, a -CONR4R5 group, an -NHCOR4 group, or a -NHSO2R4 group, or a group -N (R4) 2 o R4 and R5 are each a (C1-C4) alkyl group, R3 is different from a hydrogen atom, Q represents two hydrogen atoms and A and Z are such that

  previously defined it is possible to use diagram 2.

  Ortho iodization of the amine function of a

  compound of formula (XV) in which R1 and / or R2 represent

  either a nitro group or a cyano group, for example with iodine monochloride in an aprotic solvent such as acetonitrile at room temperature and a compound of formula (XVI) is obtained which is converted into a compound of formula (XVII) by a palladium salt catalyzed coupling / heterocyclization reaction, for example by

  1- (trimethylsilyl) -4 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -

  1-butyne in the presence of palladium (II) acetate, lithium chloride and 60-80 C potassium acetate in a polar aprotic solvent such as dimethylformamide. Subsequently, the compound (XVII) thus obtained is treated in an acidic medium, for example with 48% hydrofluoric acid, and a compound of formula (IV) is obtained in which R 1 and / or R 2 represent either a nitro group or a group cyano, a compound whose alcohol function is protected by a protective group P, for example by treatment with (1,1-dimethylethyl) dimethylsilyl chloride in the presence of a weak base such as imidazole in a solvent such as dichloromethane and a compound of formula (V) is obtained which is converted into a compound of formula (XVIII) for example by the action of bis (1,1-dimethylethyl) dicarbonate, [2 - [(1,1-dimethylethoxy) carbonylimino] -2 phenylacetonitrile, (1,1-dimethylethoxy) carbonyl azide, but

  preferably by treatment with (1,1-dimethylethyl) -2,4,5-

  trichlorophenylcarbonate in an aprotic solvent such as Scheme 2

C (CH3)

3 3 OH 3J

R1 R1 R3 R

_NH2 -. H - S-i - --_

R2 NH, R2 NH2 R2 \ R2 \

H H

(XV) (XVI) (XVII) (IV)

(XV) (IV)

OP OP

Ri Ri

R2 R2 C (CH3) 3

H

(V) (XVIII)

OP OP / Ri 0F o

N OCH 2CM3

R2 \

2N OCHCH2CH3 H

(XIX) C (CH 3) 3 (VIO

(XIX) (VI)

OP

R1 R1

OP RlNON-H

R2 OCH2CH3

Br

(XX) (IX)

Figure 2 (continued) OP

R

R1 (x)

R: 2-R3

(X) Y R1 oN-R3

R2 -

(XI) qw (XII)

N- \ I D

z N "Ri

R2 \ - N-R3

R2 IC)

  ('c) tetrahydrofuran after treatment with sodium hydride, and then the compound (XVIII) thus obtained is treated with an organolithium such as lithium diisopropylamide,

  (1,1-dimethylethyl) lithium or 2,2,6,6-tetramethyl lithium

  thylpiperidine in the presence or absence of N, N, N ', N'-tetramethylethylenediamine at low temperature in an aprotic solvent such as tetrahydrofuran or ether, to prepare an intermediate compound which is acylated with an electrophilic agent such as, for example, ethyl chloroformate and a compound of formula (XIX) is obtained which is reacted

  with a nucleophilic agent such as 2- (methyl)

  amino) ethanol at reflux temperature in ethanol to obtain a compound of formula (VI) wherein R1 and / or R2

  represent either a nitro group or a cyano group.

  The compound of formula (VI) thus obtained is then reacted with 1,2-dibromoethane under phase transfer conditions in the presence of an aqueous solution of 25% sodium hydroxide and a phase transfer catalyst such as tetrabutylammonium bromide at room temperature to prepare the compound of formula (XX) which is cyclized in a sealed tube in the presence of ammonia and ethanol at a temperature between 80 and 130 ° C. and a compound of formula ( IX) in which R1 and / or R2

  represent either a nitro group or a cyano group.

  Then, if it is desired to obtain a compound in which R 3 is different from a hydrogen atom, then the compound of formula (IX) is reacted with a base and an electrophilic agent, for example by the action of sodium hydride in the tetrahydrofuran at 0-5 ° C., then methyl iodide or 2-bromoethyl acetate, or by alkylation under transfer-catalyzed phase transfer conditions such as tetrabutylammonium in the presence of an inorganic base such as potassium hydroxide in an aprotic solvent such as tetrahydrofuran with an electrophile such as 2-bromoacetamide and there is obtained a compound of formula (X) in which R 3 is as defined above which is converted into a compound of formula (XI) wherein Y represents a leaving group such as a chlorine or bromine atom, for example by treatment with thionyl chloride in chloroform at reflux temperature or by dibromotriphenylphosphorane in dichloromethane or chloroform at ambient temperature or in a compound of formula (XI) in which Y represents a leaving group such as methanesulfonyloxy, trifluoromethanesulfonyloxy or para-toluenesulfonyloxy groups, for example by reaction with a sulphonic anhydride or a dichloromethane sulfonic acid in the presence of a base such as pyridine or triethylamine. Finally the compounds of formula (XI) are reacted with a compound of formula (XII) (wherein A is as defined above) with or without an aprotic or protic solvent, in the presence of an inorganic base between 20 ° C. and 150 ° C. preferably in acetonitrile or dimethylformamide in contact with sodium bicarbonate and there is obtained a compound of formula (Ic) in which R 1 and / or R 2 represent either a nitro group or a cyano group. The compounds of formula (Ic) in which R1 and / or R2 are either an amino group, a (C1-C4) alkyl amino group, a -COOH group, a -COOR4 group or a -CONH2 group are prepared. , a -CONHR4 group, a -CONR4R5 group, an -NHCOR4 group, a -NHSO2R4 group or a -N (R4) 2 group; R4 and R5 are each a (C1-C4) alkyl group, from the corresponding compounds of formula (Ic) in which R1 and / or R2 represent either a nitro group or a cyano group by means of

  classics known to those skilled in the art.

  If it is desired to prepare compounds of formula (Ic), in which R 1 and / or R 2 represent either an amino group, a (C 1 -C 4) alkyl group or a nitro group, a cyano group or a -COOH group either a -COOR4 group, -CONH2 group, -CONHR4 group, -CONR4R5 group, -NHCOR4 group, -NHSO2R4 group, or -N (R4) 2 o R4 and R5 group. are each a (C 1 -C 4) alkyl group, R 3 is a hydrogen atom, Q represents two hydrogen atoms and A and Z are as previously defined, then the compound of formula (IX) is deprotected according to known conventional techniques of the skilled person and continues according to the various stages described

  previously for compounds of formula (Ib).

  If it is desired to prepare the compounds of formula (Id) and (Ie) in which Q represents an oxygen atom and R1, R2, R3, A and Z are as defined on pages 1 and 2, then the

diagram 3.

  A compound of formula (VI) in which R1, R2 and P are as defined above is reacted with a compound of formula ClCH2CO2R in which R represents a (C2-C6) alkyl group in the presence of a strong base such that sodium hydride in an aprotic solvent such as dimethylformamide and there is obtained a compound of formula (XXI) which is converted into a compound of formula (XXII) in which Y represents a leaving group such as a chlorine or bromine atom, for example by treatment with thionyl chloride in chloroform at reflux temperature or by dibromotriphenylphosphorane in dichloromethane or chloroform at room temperature or in a compound of formula (XXII) in which Y represents a leaving group such as groups methanesulfonyloxy, trifluoromethanesulfonyloxy or para-toluenesulfonyloxy, for example by reaction with a sulfonic anhydride or a sulfonic acid chloride in the presence of a base such as pyridine or triethylamine. The compounds of formula (XXII) are then reacted with a compound of formula (XII) (wherein A is as defined above) with or without an aprotic or protic solvent, in the presence of an inorganic base between 20 ° C. and 150 ° C. preferably in acetonitrile or dimethylformamide in contact with sodium bicarbonate and a compound of formula (XXIII) is obtained. Finally, if it is desired to prepare a compound of formula (Id) in which R 3 is different from a hydrogen atom, then the compound of formula (XXIII) is reacted with a compound of formula R 3 NH 2 and then the compound (XXIV) and the obtained under standard conditions known to those skilled in the art, for example at the reflux temperature in chlorobenzene. If one wants to prepare a compound of Diagram 3 OP OP

N O> CH2CH3

NOCH2CH3 R22

R2 CHC3 O

HO GOLD

) - (VI) (XXI)

  N R1.o A z (X XI) __. R YR2U Ri OR 1 S OROi

(XXII) R2 N OCH2CH3

N \ X OR

  z (XXIII) N 1 (XXIVI) / Ni) OH 2 H N-R 3

R, I

2 H O (! R3

H

N '-I AD

(XXIV)

z N R1 3 l0

N N-R3

  (Id), R3 # H (Ie), R3 = H formula (Ie) wherein R3 represents a hydrogen atom, then the compound of formula (XXIII) is directly cyclized under standard conditions known to those skilled in the art , for example in the presence of ammonia at a temperature between 20 and 150 C. The starting compounds are commercially available or described in the literature or may be prepared according to methods described therein or which are known from

the skilled person.

  Thus the compounds of formula (III) are prepared according to the method described by L. Humber, J. Med. Chem. 12, pp. 391-395

(1976).

  The lithiation method of the compounds of formula (V) is that described by A. Katritzky et al., Tetrahedron Lett., 26, pp. 5935-5938 (1985) and J. Bergman et al., J. Org.

Chem., 57, pp. 2495-2497 (1992).

  The synthesis of a lactam from a compound of formula (VIII) is inspired by the method described by S. Inaba et al., Chem. Pharm. Bull., 20, No. 8, pp. 1628-1636 (1972) and those described in US Patents 4022778, and

  German DE 1906254, DE 2005845 and DE 2017857.

  The coupling / heterocyclization method is described by T. Sakamoto et al., Heterocycles, 24, No. 1, pp. 31-32 (1986), R. Larock et al., J. Amer. Chem. Soc., 113, pp. 6689-6690 (1991), T. Jeschke et al., Tetrahedron Lett., 34, No. 40, pp. 6471-6474, (1993), Chen et al., Tetrahedron Lett., 38, 38, pp. 6981-6984 (1994) and in the US patent

5382592.

  The ortho-lithiation method used for the compounds of formula (XIX) is that described by A. Lévy et al., J. Org.

Chem., 46, pp. 157-164 (1981).

  The cyclization process of the compounds of formula (XX) is

  that described in European Patent No. EP 572863.

  4-Piperazin-1-ylthieno [3,2-c] pyridine is synthesized according to J. S. New et al., J. Med. Chem., 32, No. 6, pp.

1147-1156 (1989).

  1- (Trimethylsilyl) -4 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -1-butyne is prepared according to the method described in US Pat.

US Patent 5382592.

  7-Methoxyisoquinolin-1 (2H) -one is prepared according to the method described by J.F. Ajao et al., J.Het. Chem., 22,

pp. 329-331 (1985).

  The following examples illustrate the invention. The micro-

  analyzes and the IR, NMR and mass spectra confirm the

structure of the compounds obtained.

  The numbers of the compounds exemplified refer to those of the table, given below which illustrates the chemical structures and the physical properties of some compounds.

according to the invention.

  The ratio (x: y) corresponds to the ratio (acid: base).

  Example 1 (Compound No. 6) 8-Fluoro-2-methyl-10- [2- (4-yleno [3,2-c] pyridin-4-ylpiperazin-1-yl) ethyl] -3,4-dihydropyrazino hydrochloride [ 1, 2-a] indol-1 (2H) -one (2: 1)

  1.1. 10- (2-chloroethyl) -8-fluoro-2-methyl-3,4-dihydropyra-

  zino [1,2-a] indol-1 (2H) -one 1.1.1. 5-Fluoro-α-oxo-1H-indole-3-ethyl acetate To a solution cooled to 0 ° C. under a nitrogen atmosphere of 0 g (74 mmol) of 5-fluoro-1H-indole in 100 ml. ml of ether

  a solution of 15.2 ml (170 mmol) is added dropwise.

  the) of ethanedioyl dichloride in 50 ml of ether, the mixture is stirred at room temperature for 2 hours, the reaction medium is evaporated to dryness and taken up in 150 ml of absolute ethanol. This solution is stirred at ambient temperature for one hour and then concentrated to dryness. The residue is triturated in ether, the pink solid is filtered off.

  thus obtained and dried under vacuum.

16.7 g of product are obtained.

  Yield = 96% Melting point = 234 C 1.1.2. 5-fluoro-lH-indole-3éthanol

  To a solution of 7.0 g (29.79 mmol) of 5-fluoro-α-oxo-1H-

  indole-3-ethyl acetate in 50 ml of anhydrous tetrahydrofuran at room temperature, 210 ml (210 mmol) of a 1 M lithium aluminum hydride solution in tetrahydrofuran are then added dropwise and the mixture is then stirred for 20 hours at this temperature. The reaction medium is then cooled to 0 ° C. and slowly acidified to pH 3-4 with an aqueous solution of 0.5 N hydrochloric acid. The mixture is extracted with ethyl acetate and the phase is dried.

  organic over sodium sulfate, filtered and concentrated.

  The residue is purified by chromatoflash on silica, eluting with

  with a mixture of n-heptane: ethyl acetate (1: 1 and then 2: 3).

  4.6 g of product is obtained in the form of a yellow oil

clear.

Yield = 85%

  1.1.3. 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -5-

fluoro-lH-indole

  To a solution of 4.5 g (25.13 mmol) of 5-fluoro-1H-indole-

  3-ethanol and 1.80 g (27.6 mmol) of imidazole in 75 ml of dichloromethane with stirring at room temperature,

  4.16 g (27.6 mmol) of (1,1-dimethyl)

  ethyl) dimethylsilyl and stirred at this temperature for 48 hours. The reaction medium is diluted in 250 ml of dichloromethane, washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by filtration on silica in

  eluting first with n-heptane and then with a mixture n

  heptane: ethyl acetate (95: 5 then 90:10) containing

traces of ammonia.

  7.2 g of product are obtained in the form of a beige oil.

Yield = 98%

  1.1.4. 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxyléthyl] -5-

  Ethyl fluoro-1H-indole-2-carboxylate To a solution cooled to -70 ° C. of 6.0 g (20.47 mmol) of

  3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxyléthyl] -5-fluoro-

  1H-indole in 50 ml of anhydrous tetrahydrofuran, under a nitrogen atmosphere, 14 ml (22.4 mmol) of a solution of 1.6 M n-butyllithium in hexane are added. The mixture is allowed to stir for 0.5 hours at -70 ° C., carbon dioxide is bubbled into the solution for 0.5 hours and then the mixture is allowed to stand at this temperature for 0.5 hours. The reaction mixture is evaporated to dryness at

  0 C and the residue is taken up in 50 ml of tetrahydrofuran.

  This solution is cooled to -70 ° C. under nitrogen and then 13.2 ml (22.44 mmol) of a 1.7M solution of tert-butyllithium in pentane are added dropwise. The bright yellow solution thus obtained is stirred at -70 ° C. for 1 hour and then 2.2 ml (23 mmol) of ethyl chloroformate are added rapidly in one go. This solution is stirred at -70 ° C. for 1 hour, the temperature of the reaction medium is allowed to rise to -30 ° C., it is hydrolysed at -60 ° C. by the addition of ml of a saturated aqueous ammonium chloride solution and the residue is extracted. mix several times with ether. The organic phases are washed with water and then with a saturated aqueous solution of sodium chloride. It is then dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromotoflash on silica eluting with n-heptane then

  with n-heptane: ethyl acetate (95: 5).

  2.41 g of product are obtained in the form of a white solid.

  Yield = 32% Melting point = 112 ° C

  1.1.5. 1-cyanomethyl-3- [2 - [[(1,1-dimethylethyl) dimethyl

  ethyl silyl] oxy] ethyl] -5-fluoro-1H-indole-2-carboxylate To a suspension of 1.0 g (25.0 mmol)% sodium hydride in 15 ml of dimethylformamide at room temperature a solution of 7.40 g (20.27 mmol) of 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -5-fluoro-1H-indole-2-carboxylate is added dropwise. of ethyl in ml of dimethylformamide. It is stirred for 0.75 hours at room temperature and 1.90 ml (30 mmol) of 2-chloroacetonitrile are added dropwise. The mixture is stirred for 16 hours at this temperature and then poured into ml of a mixture of water and crushed ice. Extracted several times with ether and the organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica eluting with n-heptane: ethyl acetate (98: 2, 95: 5, then 90:10) containing

traces of ammonia.

  4.11 g of product is obtained in the form of a pale beige solid. Yield = 60% Melting point = 108 ° C

  1.1.6. 10- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -

  8-fluoro-3,4-dihydropyrazino [1,2-a] indol-1 (2H) -one

  To 2.20 g (5.45 mmol) of 1-cyanomethyl-3- [2 - [[(1,1-dimethyl)

  ethyl) dimethylsilyl] oxy] ethyl] -5-fluoro-1H-indole-2

  ethyl carboxylate dissolved in 25 ml of tetrahydrofuran

  3.0 g of activated 50 A Raney nickel, previously washed with ethanol and then with tetrahydrofuran, are added at room temperature. The mixture is stirred for 16 hours under a pressure of 0.1 MPa (1 atm) of hydrogen at room temperature. The reaction mixture is then filtered through celite, rinsed several times with ethanol and concentrated

the filtrate to dry.

  We obtain a solid. Melting point = 100-105 ° C. The solid is taken up in 100 ml of absolute ethanol, 0.10 g (1.47 mmol) of sodium ethoxide are added and the solution is heated at 60 ° C. for 1.25 hours. . The reaction medium is evaporated to dryness and then taken up in 200 ml of ethyl acetate. This solution is washed with water and the phase is dried

  organic over sodium sulfate, filtered and concentrated.

  The residue is purified by chromatoflash on silica eluting with a n-heptane: ethyl acetate (1: 1) mixture containing

traces of ammonia.

  1.0 g of product is obtained in the form of a white solid. Yield = 66% Melting point = 132 ° C

  1.1.7. 10- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -

  8-fluoro-2-methyl-3,4-dihydropyrazino [1,2-a] indol-1-

(2H) one

  To a solution of 1.0 g (2.76 mmol) of 10- [2 - [[(1,1-

  dimethylethyl) dimethylsilyl] oxy] ethyl] -8-fluoro-3,4-

  dihydropyrazino [1,2-a] indol-1 (2H) -one in 20 ml of anhydrous tetrahydrofuran at room temperature is added

  in portions 0.12 g (3.03 mmol) of 60% sodium hydride.

  After stirring for 0.5 hour at ambient temperature, 0.4 ml (6.40 mmol) of methyl iodide are added dropwise and

  stirring is continued at this temperature for 2 hours.

  Then 0.5 ml of methanol and then 50 ml of a saturated aqueous solution of ammonium chloride are added and the mixture is extracted with ether. The organic phases are washed with a saturated aqueous solution of sodium chloride and then dried

  on magnesium sulfate, filter and concentrate.

1.02 g of product is obtained.

  Yield = 99% 1.1.8. 10- (2-chloroethyl) -8-fluoro-2-methyl-3,4-dihydropyrazino [1,2-a] indol-1 (2H) -one A 1.80 g (4.78 mmol) 2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -8-fluoro-2-methyl-3,4-dihydropyramino [1,2-a] indol-1- (2H) one in 30 ml of chloroform at room temperature, 1.13 ml (14.36 mmol) of thionyl chloride are added and the solution is heated at 55 ° C. for 2 hours. The reaction mixture is evaporated to dryness. The residue is taken up in 200 ml of dichloromethane and washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated. 1.33 g of product under

form of an off-white solid.

  Yield = 100% Melting point = 164 C 1.2. 8-fluoro2-methyl-10- [2- (4-thieno) hydrochloride

  [3,2-c] pyridin-4-ylpiperazin-1-yl) ethyl] -3,4-

  dihydropyrazino [1,2-a] indol-1 (2H) -one (2: 1) A mixture of 0.80 g (0.80 mmol) of 4-piperazin-lylthieno [3] was heated at 60 ° C. for 72 hours. , 2-c] pyridine,

  0.20 g (0.88 mmol) of 10- (2-chloroethyl) -8-fluoro-2-methyl-

  3,4-dihydropyrazino [1,2-a] indol-1 (2H) -one, 0.07 g (0.83 mmol) of sodium bicarbonate and 0.06 g (catalytic amount) of potassium iodide in 12 ml of acetonitrile: dimethylformamide (5: 1). The reaction mixture is evaporated to dryness and the residue is taken up in 150 ml of chloroform. The solution is washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica eluting with a mixture of ethyl acetate: methanol (95: 5

  then 95:10) containing traces of ammonia.

  0.17 g of product is obtained in base form.

  Yield = 52% The hydrochloride salt is prepared in a methanol: 2N hydrochloric ether mixture. Melting point = 186 ° C. Example 2 (compound No. 8)

* 7-fluoro-2-methyl-10- [2- [4- (7-methoxyisopropyl) hydrochloride

  quinolin-1-yl) piperazin-1-yl] ethyl] -3,4-dihydropyrazino [1,2-a] indol (2H) -one (2: 1)

  2.1. 10- (2-chloroethyl) -7-fluoro-2-methyl-3,4-dihydro-

  pyrazino [1,2-a] indole-1 (2H) -one 2.1.1. 6-fluoro-α-oxo-1H-indole-3-ethyl acetate To a solution cooled to 0 ° C. under a nitrogen atmosphere of 7 g (51.81 mmol) of 6-fluoro-1H-indole in 75 ml of ether,

  a solution of 10.6 ml (119 mmol) is added dropwise.

  ethanedioyl dichloride in 25 ml of ether. The mixture is stirred at ambient temperature for 2 hours and the reaction medium is then evaporated to dryness and taken up in ml of absolute ethanol. This solution is stirred at ambient temperature for one hour and then concentrated to dryness. The residue is triturated in ether and the residue is filtered off.

pink solid and dried under vacuum.

11.5 g of product are obtained.

  Yield = 95% Melting point = 226 C 2.1.2. 6-fluoro-lH-indole-3éthanol

  To a solution of 8.5 g (36.17 mmol) of 6-fluoro-α-oxo-1H-

  indole-3-ethyl acetate in 50 ml of anhydrous tetrahydrofuran at room temperature, 217 ml (217 mmol) of a 1 M lithium aluminum hydride solution in tetrahydrofuran are then added dropwise and the mixture is then stirred for 4 hours at this temperature. The reaction medium is then cooled to 0 ° C. and slowly acidified to pH 3-4 with an aqueous solution of 0.5 N hydrochloric acid. The mixture is extracted with ethyl acetate and the phase is dried.

  organic over sodium sulfate, filtered and concentrated.

  3.9 g of product are obtained in the form of a beige oil

blade.

Yield = 60%

  2.1.3. 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -6-

fluoro-lH-indole

  To a stirred solution of 12.0 g (67 mmol) of 6-fluoro-1H-

  indole-3-ethanol and 4.76 g (70 mmol) of imidazole in ml of dichloromethane at room temperature are added

  11.11 g (73 mmol) of (1,1-dimethylethyl)

  thylsilyl and stirred at this temperature overnight. The reaction medium is diluted in 200 ml of dichloromethane, washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by filtration on silica in

eluent with n-heptane.

  17.0 g of product are obtained in the form of a colorless oil.

Yield = 86%

  2.1.4. 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxyléthyl] -6-

  Ethyl fluoro-1H-indole-2-carboxylate To a solution cooled to -70 ° C. of 8.0 g (27.3 mmol) of

  3- [2- [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -6-fluoro

  1H-indole in 50 ml of anhydrous tetrahydrofuran, under an argon atmosphere, 12.0 ml (30 mmol) of a 2.5 M solution of n-butyllithium in hexane are added. The mixture is left stirring for 0.5 hours at -70 ° C., carbon dioxide is bubbled into the solution for 0.5 hours and then the mixture is allowed to stand at this temperature for 0.5 hours. The reaction mixture is evaporated to dryness at 0 ° C. and the residue is taken up in 50 ml of tetrahydrofuran, the solution is cooled to -70 ° C. under nitrogen and then 17.6 ml (30 mmol) of a solution of 1.7 M tert-butyllithium in pentane. The orange solution thus obtained is stirred at -70 ° C. for 1 hour and then 3.0 ml (31 mmol) of ethyl chloroformate is rapidly added all at once. This solution is stirred at -70 ° C. for 1 hour, the temperature is allowed to rise to -30 ° C., the reaction medium is hydrolysed at -60 ° C. by the addition of 100 ml of a saturated aqueous ammonium chloride solution and the mixture is extracted. mix several times with ether. The organic phases are washed with water and then with a saturated aqueous solution of sodium chloride. It is then dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica eluting with n-heptane and

  with a mixture of n-heptane / ethyl acetate (85:15).

  6.51 g of product is obtained in the form of a white solid.

  Yield = 65% Melting point = 130 ° C

  2.1.5. 1-cyanomethyl-3- [2 - [[(1,1-dimethylethyl) dimethyl

  ethyl silyl] oxylethyl] -6-fluoro-1H-indole-2-carboxylate To a suspension of 0.47 g (19.5 mmol) of 60% sodium hydride in 10 ml of dimethylformamide at room temperature, a solution of 6.50 g (17.8 mmol) of 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -6-fluoro-1H-indole-2-carboxylate is added dropwise. ethyl in 20 ml of dimethylformamide. After stirring for 45 minutes at room temperature, 1.7 ml (26.7 mmol) of 2-chloroacetonitrile are added dropwise. The mixture is stirred for 4 hours at this temperature and then the mixture is poured into ml of a mixture of water and crushed ice. Extracted several times with ether and the organic phases are dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica eluting with n-heptane: ethyl acetate (95: 5, 90:10 then 85:15). We

  4.0 g of product is obtained in the form of a pale yellow oil.

Yield = 56%

  2.1.6. 10- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxyléthyll-

  7-fluoro-3,4-dihydropyrazino [1,2-a] indol-1 (2H) -one

  To 3.60 g (8.91 mmol) of 1-cyanomethyl-3- [2 - [[(1,1-

  dimethylethyl) dimethylsilyl] oxy] ethyl] -6-fluoro-1H-indole-2-

  ethyl carboxylate dissolved in 30 ml of tetrahydrofuran

  At room temperature, 2.70 g of activated Raney nickel 50 g, previously washed with ethanol and then with tetrahydrofuran, are added. The mixture is stirred for 16 hours under a pressure of 0.1 MPa (1 atm) of hydrogen at room temperature. The reaction mixture is then filtered through Celite and rinsed several times with ethanol. The filtrate is concentrated to dryness and then the residue is taken up in 100 ml of absolute ethanol. 0.10 g (1.47 mmol) of sodium ethoxide are added and the solution is heated at 60 ° C. for 1.5 hours. The reaction medium is evaporated to dryness and then taken up in 200 ml of ethyl acetate. This solution is washed with water and the organic phase is dried over sodium sulphate, filtered and filtered.

we concentrate.

  The residue is purified by chromatoflash on silica eluting with a n-heptane: ethyl acetate (1: 1) mixture containing

traces of ammonia.

  2.5 g of product are obtained in the form of a white solid.

  Yield = 78% Melting point = 128 ° C

  2.2.7. 10- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -

  7-fluoro-2-methyl-3,4-dihydropyrazino [1,2-a] indol-1-

  (2H) to a solution of 2.40 g (6.62 mmol) of 10- [2 - [[(1,1-

  dimethylethyl) dimethylsilyl] oxyléthyl] -7-fluoro-3,4-

  dihydropyrazino [1,2-a] indol-1 (2H) -one in 50 ml of anhydrous tetrahydrofuran at room temperature is added

  in portions 0.30 g (7.29 mmol) of 60% sodium hydride.

  After stirring for 30 minutes at ambient temperature, 0.80 ml (13.2 mmol) of sodium iodide are added dropwise.

  methylated and stirred at this temperature for 2 hours.

  Then 0.5 ml of methanol and then 100 ml of a saturated aqueous solution of sodium chloride are added and the mixture is extracted with ether. The organic phase is washed with a saturated aqueous solution of sodium chloride and then dried over

  sodium sulfate, filtered and concentrated.

  2.48 g of product are obtained in the form of a white solid.

  Yield = 99% Melting point = 110 ° C

  2.1.8. 10- (2-chloroethyl) -7-fluoro-2-methyl-3,4-dihydro-

  pyrazino [1,2-a] indol-1 (2H) -one A 0.20 g (0.53 mmol) of 10- [2 - [[(1,1-dimethylethyl))

  dimethylsilyl] oxy] ethyl] -7-fluoro-2-methyl-3,4-dihydropyra-

  zino [1,2-a] indol-1 - (2H) one in 15 ml of chloroform at room temperature, 0.12 ml (1.59 mmol) of thionyl chloride are added and the solution is heated at 55 ° C. for 2 hours. The reaction medium is diluted in 150 ml of dichloromethane and washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. 0.14 g of product is obtained in the form of an off-white solid. Yield = 100% Melting point = 160 C 2.2. 7-methoxy-1-piperazin-1-ylisoquinoline 2.1.1. 1-chloro-7-methoxyisoquinoline 38.0 g (217 mmol) of 7-methoxyisoquinolin-1 (2H) -one in 120 ml of phosphoryl chloride are heated for 2 hours at reflux temperature. The reaction medium is evaporated, the residue is taken up in 700 g of ice water and neutralized by slowly adding solid sodium bicarbonate. It is extracted with dichloromethane and the phase is dried

  organic over sodium sulfate, filtered and concentrated.

  The residue is stirred in a mixture of 500 ml of ether and 100 ml of npentane in the presence of activated charcoal. Filter

  the insoluble material and the filtrate is evaporated.

34.0 g of product are obtained.

  Yield = 81% Melting point = 74-75 ° C

  2.2.2. 4- (7-méthoxyisoquinoléin-1-yl) piperazine-1-

  1,1-dimethylethyl carboxylate To 8.09 g (43.41 mmol) of (1,1-dimethylethyl) piperazinel-carboxylate in 175 ml of anhydrous tetrahydrofuran at -70 ° C. under nitrogen, 17 3 ml (43.25 mmol) of a 2.5 M solution of n-butyllithium in hexane. After 15 minutes at -70 ° C, add drop to

  drop 4.0 g (20.67 mmol) of 1-chloro-7-methoxyisoquinoline

  lein in solution in 75 ml of tetrahydrofuran. The reaction medium is stirred at -70 ° C. for 0.5 hour and then hydrolyzed by addition of 400 ml of a saturated aqueous solution of ammonium chloride. Extracted with ether and then the organic phase washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica eluting with a mixture

  ethyl acetate: n-heptane (1: 3 then 2: 3).

  6.2 g of product are obtained in the form of an off-white solid. Melting point = 138 C Yield = 87% 2.2.3. 7-methoxy-1-piperazinylisoquinoline A suspension of 6.1 g (17.78 mmol) of 1,1-dimethylethyl 4 (7-methoxyisoquinolin-1-yl) piperazine-1-carboxylate in 50 ml of acetate is stirred of ethyl and 75 ml of 3N hydrochloric ethyl acetate at room temperature for 16 hours. The white solid obtained is then filtered off, rinsed with ethyl acetate and then with ether and dried under

empty at 40 C.

  5.56 g of hydrochloride is obtained in the form of a solid

pale yellow.

  Yield = 99% Melting point = 211-213 ° C. 5.56 g of hydrochloride is taken up in 70 ml of water, the pH is adjusted to 10-11 with an aqueous solution of hydrogencarbonate

  of sodium and extracted with chloroform.

  4.20 g of product are obtained in the form of an amorphous solid.

  Yield = 99% Melting point = 86-87 ° C

  2.3. 7-fluoro-2-methyl-10- [2- [4- (7-methoxy) hydrochloride

  isoquinolin-l-yl) piperazin-l-ylléthyl] -3,4-dihydropyridine

  razino [1,2-a] indol-1 (2H) -one (2: 1) A mixture of 0.25 g (1.02 mmol) of 7-methoxy-1-piperazine is heated at 55 ° C. for 48 hours. -lylisoquinoléine,

  0.31 g (1.13 mmol) of 10- (2-chloroethyl) -7-fluoro-2-methyl-

  3,4-dihydropyrazino [1,2-a] indol-1 (2H) -one, 0.095 g (1.13 mmol) of potassium bicarbonate and 50 mg of iodide

  of potassium in 12 ml of acetonitrile: dimethyl-

  formamide (5: 1). The reaction mixture is concentrated to dryness and the residue is taken up in 150 ml of chloroform. The solution is washed with water and then with a saturated aqueous solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is then purified by chromatoflash on silica eluting with a mixture of ethyl acetate: methanol (95: 5 and then 90:10) containing

traces of ammonia.

  0.23 g of product is obtained in base form.

  Yield = 46% The hydrochloride is prepared in a methanol: 2N hydrochloric ether mixture. Melting point = 170-172 ° C. EXAMPLE 3 (Compound No. 10) 7-fluoro-1-oxo-10- [2- (4) hydrochloride 1H-pyrrolo [3,2-c] pyridin-4-ylpiperazin-1-yl) ethyl] -1,2,3,4-tetrahydropyrazino [1,2a] indole-2-acetamide (2: 1)

  3.1. 10- (2-chloroethyl) -7-fluoro-1-oxo-2,3,4-tetrahydropyranyl

razino [1,2-a] indole-2-acetamide

  3.1.1. 10- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl]

  7-fluoro-1-oxo-1,2,3,4-tetrahydropyrazino [1,2-

a] indole-2-acetamide

  To a mixture of 1.72 g (4.75 mmol) of 10- [2 - [[(1,1-

  dimethylethyl) dimethylsilyl] oxy] ethyl] -7-fluoro-2-methyl-3,4-

  dihydropyrazino [1,2-a] indol-1- (2H) one, 0.48 g (8.55 mmol) of potassium hydroxide powder and 0.536 g (1.66 mmol)

  of tetrabutylammonium bromide in 80 ml of tetrahydrofuran

  After stirring at 0.degree. C., 19 ml (9.50 mmol) of a 0.5M solution of 2-bromoacetamide in tetrahydrofuran are added dropwise with stirring. The mixture is stirred for 1 hour at 0 ° C. and then for 24 hours at room temperature, the reaction medium is then evaporated to dryness and the residue is taken up in 500 ml of chloroform. This solution is washed with water and the organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica eluting with a mixture of ethyl acetate: methanol (98: 2, 95: 5 then 93: 7) containing

traces of ammonia.

  1.48 g of a colorless glassy oil are obtained.

Yield = 74%

  3.1.2. 10- (2-chloroethyl) -7-fluoro-l-oxo-1,2,3,4-tetrahydro-

  pyrazino [1,2-a] indole-2-acetamide

  To a suspension of 1.48 g (3.53 mmol) of 10- [2 - [[(1,1-

  dimethylethyl) dimethylsilyl] oxy] ethyl] -7-fluoro-1-oxo

  1,2,3,4-tetrahydropyrazino [1,2-a] indole-2-acetamide in 75 ml of chloroform with stirring at ambient temperature, 1.05 ml (14.13 mmol) of thionyl chloride are added and then the mixture is heated at 55 ° C. for 2.5 hours. The reaction medium is diluted in 400 ml of chloroform. This solution is washed with a saturated aqueous solution of sodium bicarbonate and the solid is filtered at the interface of the phases. The filtrate is decanted, the organic phase is washed with water, dried over sodium sulfate, filtered and concentrated. The residue thus obtained is combined with the solid of the interface previously obtained and the whole is triturated twice with

  ether, the solid is filtered off and dried in vacuo.

  0.96 g of product is obtained in the form of an off-white solid. Yield = 84% Melting point = 235 C 3.2. 4-piperazin-l-yl-lHpyrrolo [3,2-c] pyridine

  3.2.1. 1 - [(3,4-dimethoxyphenyl) methyl] -LH-pyrrole-2-

  carboxaldehyde To a suspension cooled to 0 ° C. of 4.0 g (100 mmol) of 60% sodium hydride in 30 ml of dimethylformamide

  under a nitrogen atmosphere, a solution of 3.0 g (31.5 mmol) of 1H-pyrrole-2-carboxaldehyde is added dropwise.

  hyde in 10 ml of dimethylformamide. After stirring for 30 minutes at 0 ° C., a solution of 11.7 g (63 mmol) of 4 (chloromethyl) -1,2-dimethoxybenzene in 10 ml of dimethylformamide is added dropwise, followed by stirring at room temperature for 3 hours. hours. The reaction medium is hydrolysed

  at 0 C by addition of 100 ml of water and extracted with ether.

  The organic phases are washed with 3 volumes of water and then dried over magnesium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica eluting with a mixture of nheptane: ethyl acetate (8: 2, 7: 3

then 6: 4).

  7.0 g of product are obtained in the form of an orange oil.

Yield = 90%

  3.2.2. 3- [1 - [(3,4-dimethoxyphenyl) methyl] -LH-pyrrole-2-prop

  Ethyl 2-enoate To a suspension stirred at room temperature with 1.4 g (34 mmol) of 60% sodium hydride, previously washed with isopropyl ether, in 25 ml of anhydrous tetrahydrofuran, is added dropwise. a solution of 6 ml (30 mmol) of triethyl phosphonoacetate in 20 ml of tetrahydrofuran. After stirring for 20 minutes, a solution of 7 g (28.57 mmol) of 1 - [(3,4-dimethoxyphenyl) methyl] -1H-pyrrole-2-carboxaldehyde is added dropwise and the mixture is then heated to 55 ° C. during 3 hours. The reaction medium is cooled to 5 ° C. and then hydrolyzed with 60 ml of water and then extracted with ether. The organic phase is dried over magnesium sulphate, filtered

and concentrate.

  9.0 g of product are obtained in the form of a yellow oil.

Quantitative yield.

  3.2.3. 3- [1 - [(3,4-dimethoxyphenyl) methyl] -1H-pyrrol-2- acid

  Yl] prop-2-enoic A mixture of 16 g is heated at 60 ° C. for 8 hours.

  (50.79 mmol) 3- [1 - [(3,4-dimethoxyphenyl) methyl] -1H-

  pyrrole-2-prop-2-enoate ethyl and 10 g (250 mmol)

  of sodium hydroxide in 50 ml of dioxane and 25 ml of water.

  The reaction medium is then concentrated to two-thirds and acidified to pH 2 with an aqueous solution of 6 N hydrochloric acid on an ice bath. The beige precipitate thus obtained is then filtered off, rinsed with water and then with ether.

and dried under vacuum at 40 C.

  13 g of product are obtained in the form of a light beige solid. Yield = 89% Melting point = 170 ° C

  3.2.4. 1 - [(3,4-dimethoxyphenyl) methyl] -l, 5-dihydro-4H-

  pyrrolo [3,2-c] pyridin-4-one to a cooled solution at 5 ° C. of 13.0 g (45.3 mmol)

  3- [1 - [(3,4-dimethoxyphenyl) methyl] -1H-pyrrol-2- acid

  Yl] prop-2-enoic and 7.5 ml (54.3 mmol) of triethylamine in 60 ml of dioxane under a nitrogen atmosphere, 10.7 ml (49.8 mmol) are added dropwise in 10 minutes. ) of diphenylphosphorylazide and then the mixture is stirred for 2.5 hours at room temperature. The reaction medium is then diluted with a volume of saturated aqueous sodium chloride solution and extracted with ether. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is taken up in 30 ml of dichloromethane and the solution is added dropwise to a mixture of 40 ml of diphenylmethane and 8.8 ml of tri-n-butylamine preheated to 210 ° C. The mixture is heated at this temperature for 15 minutes. minutes, then allow the temperature to return to room temperature. 300 ml of n-pentane are added, the dark gum thus obtained is triturated and then purified by chromatoflash on silica, eluting firstly with dichloromethane and then with a mixture of dichloromethane and methanol (98: 2). 10.4 g of product in the form of an amorphous yellow solid. Yield = 85% Melting point = 120 C 3.2.5. 4-chloro-1 - [(3,4-dimethoxyphenyl) methyl] -1H-pyrrolo [3,2-c] pyridine A mixture of 6.5 g (24 mmol) 1 - [(3,4-dimethoxyphenyl) methyl] -1,5-dihydro-4H-pyrrolo [3,2-c] pyridin-4-one and 32 ml (360 mmol) of phosphoryl chloride. The reaction medium is then concentrated to dryness, taken up in 200 ml of dichloromethane, 50 ml of water are added and, with stirring, the aqueous phase is neutralized to pH 7 with a saturated aqueous solution of sodium bicarbonate. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated.

  3.8 g of product are obtained in the form of a brown oil.

  Yield = 55% 3.2.6. 1 - [(3,4-dimethoxyphenyl) methyl] -4- [4 (phenylmethyl) piperazin-1-yl] -1H-pyrrolo [3,2-c] pyridine In an autoclave, the mixture is heated at 130 ° C. for 60 hours.

  mixture of 3.8 g (13.26 mmol) of 4-chloro-1 - [(3,4-

  dimethoxyphenyl) methyl] -1H-pyrrolo [3,2-c] pyridine, 4.63 ml (26.53 mmol) of 1- (phenylmethyl) piperazine and 3.7 ml

  (26.53 mmol) of triethylamine in 100 ml of absolute ethanol.

  The reaction medium is then concentrated to dryness and the residue is purified by chromatoflash on silica, eluting with

  a mixture of dichloromethane: methanol (98: 2 then 95: 5).

  3.8 g of product are obtained in the form of a dark beige oil. Yield = 68% 3.2.7. 4- [4- (4- (phenylmethyl) piperazin-1-yl] -1H-pyrrolo [3,2-c] pyridine To 450 ml of liquid ammonia cooled to -70 ° C., 4.0 g (178 mmol) are added in small portions. ) of sodium. After dissolution, the resulting blue solution is added to 3.8 g

  (8.87 mmol) of 1 - [(3,4-dimethoxyphenyl) methyl] -4- [4-

  (Phenylmethyl) piperazin-1-yl] -1H-pyrrolo [3,2-c] pyridine dissolved in 35 ml of anhydrous tetrahydrofuran. The mixture is left for 30 minutes at -70 ° C. and chloride is added.

  of solid ammonium until discoloration of the reaction medium.

  The ammonia is evaporated for 1 hour, the residue is taken up in 300 ml of ethyl acetate, washed with water, the organic phase is dried over sodium sulfate, filtered and concentrated. The residue is then purified by chromatoflash on silica eluting with a dichloromethane: methanol mixture.

(95: 5 then 90:10).

  1.4 g of product is obtained in the form of a thick beige oil. Yield = 56% 3.2.8. 4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine is hydrogenated under a pressure of 0.1 MPa (1 atm) at 60 ° C. for 2 hours, 1.4 g (4.8 mmol) of 4- [4- (phenylmethyl) piperazin-1-yl] -1H-pyrrolo [3,2c] pyridine in 50 ml of methanol in the presence of 150 mg of% palladium hydroxide. The reaction medium is cooled to ambient temperature and filtered on celite. The filtrate is concentrated

  dry and the residue is triturated in 15 ml of ethyl acetate.

  The beige solid obtained is filtered off and dried under vacuum.

0.80 g of product is obtained.

  Yield = 83% Melting point = 158 C 3.3. 7fluoro-1-oxo-10- [2- (4-1H-pyrrolo hydrochloride

  [3,2-c] pyridin-4-yl-piperazin-l-yl) ethyl] -l, 2,3,4-

  tetrahydropyrazino [1,2-a] indole-2-acetamide (2: 1) A mixture of 0.15 g (0.74 mmol) of 4-piperazin-1-ylH-pyrrolo [ 3,2-c] pyridine,

  0.26 g (0.81 mmol) of 10- (2-chloroethyl) -7-fluoro-1-oxo

  1,2,3,4-tetrahydropyrazino [1,2-a] indole-2-acetamide, 0.07 g (0.81 mmol) of sodium bicarbonate and 50 mg of iodide of

  potassium in 12 ml of acetonitrile: dimethyl-

  formamide (5: 1). The reaction medium is evaporated to dryness and the residue is purified by chromatography on silica eluting first with a mixture of ethyl acetate: methanol (98: 2, 95: 5 then 90:10) containing traces of ammonia then then with a mixture of dichloromethane: methanol (9: 1) containing

also traces of ammonia.

  0.1 g of product is obtained in base form.

  Yield = 27% The hydrochloride is prepared in a methanol: 2N hydrochloric ether mixture. Melting point = 108 ° C. Example 4 (compound 2)

  10- [2- (4-thieno [3,2-c] pyridin-4-ylpiperazin hydrochloride

  1-yl) ethyl] -3,4-dihydropyrazino [1,2-a] indol-1 (2H) -one (2: 1)

  4.1. 4-oxo-l, 2,3,4-tetrahydropyrazino [1,2-a] indole-5-

acetaldehyde

  4.1.1. 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -

  1H-indole To a stirred solution of tryptophol (15.55 g, 96.46 mmol) and imidazole (6.9 g, 101.28 mmol) in dichloromethane (250 mL) at room temperature was added 16 g (m.p. 11 mmol) of (1,1-dimethylethyl) dimethylsilyl chloride and the mixture is stirred at this temperature for 18 hours. The reaction medium is washed with 100 ml of water, the organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica eluting with a mixture of ethyl acetate / n-heptane

(15:85).

  26.51 g of product are obtained in the form of a colorless oil. Yield = 99%

  4.1.2. 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -

  ethyl 1H-indole-2-carboxylate To a cooled solution at -70 ° C. of 35.40 g (128.5 mmol)

  3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxylethyl] -1H-

  indole in 230 ml of anhydrous tetrahydrofuran, under a nitrogen atmosphere, 56.6 ml (141.5 mmol) of a 2.5 M solution of n-butyllithium in hexane are added. The mixture is left stirring for 30 minutes at -70 ° C., carbon dioxide is bubbled into the solution for 30 minutes and then the mixture is allowed to stand at this temperature for 30 minutes. The reaction mixture is evaporated to dryness at 0 ° C. and the residue is taken up in 230 ml of tetrahydrofuran. The solution was cooled to -70 ° C under nitrogen and then 83.2 ml (141.4 mmol) of a 1.7 M solution of tert-butyllithium in pentane was added dropwise. The orange solution thus obtained is stirred at -70 ° C. for 1 hour and 15 ml (154.2 mmol) of ethyl chloroformate are then added all at once. This solution is stirred at -70 ° C. for 1 hour and then the temperature is allowed to rise to -30 ° C. The reaction medium is hydrolyzed at -60 ° C. by the addition of 700 ml of a saturated aqueous ammonium chloride solution and the mixture is extracted. mix several times with ether. The organic phases are washed with water and then with a saturated aqueous solution of sodium chloride. It is dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatoflash on silica eluting with n-heptane and then with n-heptane: ethyl acetate (95: 5, 90:10 and then 15).

  40.7 g of product are obtained in the form of a white solid.

  Yield = 91% Melting point = 91-92 ° C

  4.1.3. 1-cyanomethyl-3- [2 - [[(1,1-dimethylethyl) dimethyl

  ethyl silyl] oxy] ethyl] -1H-indole-2-carboxylate To a stirred suspension at room temperature of 2.4 g (60 mmol) of 60% sodium hydride (washed with petroleum ether) in 25 ml of dimethylformamide, under nitrogen,

  18.48 g (53.26 mmol) of 3- [2 - [[(1,1-

  dimethylethyl) dimethylsilyl] oxy] ethyl] -lh-indole-2-

  ethyl carboxylate dissolved in 50 ml of dimethylformate

  mide. The mixture is allowed to stir for 45 minutes, 5.4 ml (85.22 mmol) of chloroacetonitrile are added and stirring is continued at room temperature for 16 hours. The reaction medium is poured into 500 g of crushed ice and extracted several times with ether. The organic phases are washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate,

  filter and concentrate. The residue is purified by chromatography

  flash on silica eluting with n-heptane: acetate mixture

of ethyl (95: 5, 90:10 then 85:15).

  16.23 g of product are obtained in the form of a white amorphous solid. Yield = 79% Melting point = 80 ° C

  4.1.4 10- [2- [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl]

  3,4-Dihydropyrazino [1,2-a] indol-1 (2H) -one

  To 16.23 g (42.05 mmol) of 1-cyanomethyl-3- [2 - [[(1,1-

  dimethylethyl) dimethylsilyl] oxy] ethyl] -1H-indole-2-

  ethyl carboxylate dissolved in 125 ml of tetrahydrofuran at room temperature is added 11.4 g of activated Raney nickel 50p, previously washed with ethanol and then with tetrahydrofuran. The mixture is stirred for 36 hours under a pressure of 0.1 MPa (1 atm) of hydrogen at room temperature. The reaction mixture is then filtered through Celite and rinsed several times with ethanol. The filtrate is concentrated to dryness and the residue is then taken up in 400 ml of absolute ethanol. 0.35 g (5.14 mmol) of sodium ethoxide are added and the solution is heated at reflux temperature for 1.5 hours. The reaction medium is evaporated to dryness and then taken up in 400 ml of ethyl acetate. This solution is washed with water and the organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by

  chromatoflash on silica eluting with a mixture of n

  heptane: ethyl acetate (1: 1 then 1: 3) containing traces

of triethylamine.

  8.34 g of product is obtained in the form of a broken white solid. Yield = 58%

  4.1.5. 10- (2-hydroxyethyl) -3,4-dihydropyrazino [1,2-a] indole

  1 (2H) -one To a stirred solution of 2.10 g (6.10 mmol) of

  10- [2- [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -3,4-

  dihydropyrazino [1,2-a] indol-1 (2H) -one in 70 ml of tetrahydrofuran is added 6.5 ml (6.83 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The reaction medium is stirred for 6 hours at room temperature and then evaporated to dryness. The residue is taken up in 300 ml of dichloromethane and the

  solution several times with water. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is then purified by chromatography on silica eluting with ethyl acetate: methanol (93: 7).

  1.23 g of product are obtained in the form of a white solid. Yield = 88% Melting point = 151-152 C10

  4.1.6. 1-oxo-1,2,3,4-tetrahydropyrazino [1,2-a] indole-10

  acetaldehyde To a mixture of 0.59 g (2.57 mmol) of 10- (2-hydroxyethyl) -

  3,4-dihydropyrazino [1,2-a] indol-1 (2H) -one, 0.74 g (9.02 mmol) of anhydrous sodium acetate and 7 g of 4A molecular sieve in 60 ml of dichloromethane, with stirring at room temperature, 1.68 g (5.15 mmol) of pyridinium dichromate are added in small amounts. The reaction mixture is stirred at this temperature for 16 hours, then diluted with ether (120 ml) and filtered through celite. The filtrate is evaporated to dryness and the residue is purified by chromatoflash on silica eluting with an acetate mixture.

  of ethyl: methanol (97.5: 2.5 then 90:10).

  0.27 g of product is obtained in the form of a yellow solid

blade.

  Yield = 46% 4.2. 10- [2- (4-Thieno [3,2-c] pyridin-4-yl-piperazin-1-yl) ethyl] -3,4-dihydropyrazino [1,2-a] indol-1 (2H) hydrochloride one (2: 1) to a mixture of 0.47 g (2.15 mmol) of 4-piperazin-1-yl

  thieno [3,2-c] pyridine and 0.41 g (1.80 mmol) of 1-oxo

  1,2,3,4-Tetrahydropyrazino [1,2-a] indole-10-acetaldehyde in 8 ml of dichloromethane, with stirring, 1.78 g (6.26 mmol) of titanium tetraisopropoxide are added. The reaction medium is stirred at room temperature for 6.5 hours and then 0.48 g (7.19 mmol) of sodium cyanoborohydride and then 5 ml of methanol are added. The mixture is stirred for 15 hours at room temperature and then diluted in 100 ml of dichloromethane and 100 ml of a saturated aqueous solution of ammonium chloride. Stirred for 10 minutes and then filtered on celite. The organic phase of the filtrate is washed with water, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on silica eluting first with a mixture of ethyl acetate: methanol (95: 5 then 90:10) containing traces of ammonia and then with a mixture of dichloromethane: methanol (95: 5 then 90 : 10)

containing traces of ammonia.

  0.36 g of base is obtained in the form of an off-white solid.

  Yield = 46% The hydrochloride is prepared in methanol: 2N hydrochloric ether. Melting point = 199 ° C. (fusion with decomposition) Example 5 (Compound No. 4)

  10- [2- (4-thieno [3,2-c] pyridin-4-ylpiperazin hydrochloride

  1-yl) ethyl] pyrazino [1,2-a] indole-1,3- (2H, 4H) -dione (2: 1) 5.1. 3- (2bromoethyl) -2- (ethoxycarbonyl) -1H-indole-1-ethyl acetate

  5.1.1. 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -1

  Ethyl (Ethoxycarbonyl) -1H-indole-2-carboxylate To a suspension of 1.15 g (28.75 mmol) of 60% sodium hydride in 20 ml of dimethylformamide at room temperature is added dropwise. a solution of ethyl (8.06 g, 23.22 mmol) ethyl 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -1H-indole-2-carboxylate in 20 ml dimethylformamide. The mixture is left stirring for 1 hour at room temperature and 4.3 g (34.83 mmol) of ethyl chloroacetate are added dropwise. Stirring is continued for 4 hours at this temperature and then the mixture is poured into 400 g of a mixture of water and crushed ice. Extracted several times with ether and the organic phases washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by

  chromatoflash on silica eluting with a mixture of ethyl acetate: nheptane (5:95 then 10:90).

  9.45 g of product is obtained in the form of an amorphous solid.

egg shell.

  Yield = 94% Melting point = 59-60 ° C

  5.1.2. 3- (2-bromoethyl) -2- (ethoxycarbonyl) -lh-indol-1

  To a stirred suspension at room temperature of 6.60 g (15.64 mmol) of dibromotriphenylphosporane in 70 ml of dichloromethane was added 6.1 g (14.06 mmol) of

  3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxyléthyl] -1-

  Ethyl (ethoxycarbonyl) -1H-indole-2-carboxylate dissolved in 70 ml of dichloromethane. The mixture is stirred at this temperature for 2.5 hours then 50 ml of water are added and the mixture is extracted with dichloromethane. We dry the phase

  organic over sodium sulfate, filtered and concentrated.

  The residue is filtered through a silica pad eluting with ether and the residue is purified by chromatography on silica eluting with ethyl acetate: n-heptane (10:90,

: 85 then 20:80).

  3.35 g of product are obtained in the form of a pale pink solid. Yield = 58% Melting point = 100-101 ° C

  5.2. 2- (ethoxycarbonyl) -3- [2- (4-thieno [3,2-c] pyridin-4-

  Ylpiperazin-1-yl) ethyl] -1H-indole-1-ethyl acetate A mixture of 1.70 g (7.81 mmol) of 4-piperazin-1-ylthieno [3.2] is heated at 60 ° C. for 72 hours. pyridine, 2.72 g (7.1 mmol) of 3- (2-bromoethyl) -2 (ethoxycarbonyl) -1H-indole-1-ethyl acetate and 0.60 g (7.1 mmol) of sodium bicarbonate in 30 ml of acetonitrile. The reaction mixture is evaporated to dryness and the residue is taken up in 400 ml of dichloromethane and 150 ml of saturated aqueous sodium bicarbonate solution. The organic phase is washed with water, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is purified by chromatoflash on silica eluting with a dichloromethane: methanol (95: 5) containing traces

ammonia.

  3.30 g of product are obtained in the form of a pale beige syrup. Yield = 89%

  5.3. 10- [2- (4-thieno [3,2-c] pyridin-4- hydrochloride

  ylpiperazin-l-yl) ethyl] -pyrazino [1,2-a] indole-l, 3-

  (2H, 4H) -dione (2: 1) is heated at 80-85 C for 5 days in an autoclave

  1.50 g (2.88 mmol) of 2- (ethoxycarbonyl) -3- [2- (4-

  thieno [3,2-c] pyridin-4-yl-piperazin-l-yl) ethyl] -lh-indole-1-

ethyl acetate in the presence of 0.22 g of sodium cyanide in 60 ml of methanol saturated with ammonia. The reaction mixture is evaporated to dryness, the residue is triturated in ether and the solid is filtered off with suction. The residue is purified by chromatoflash on silica eluting with a dichloromethane / methanol mixture (95: 5 then 90:10) containing

traces of ammonia.

  0.80 g of base is obtained in the form of a beige solid.

  Yield = 33% The hydrochloride salt is prepared in a methanol: 2N hydrochloric ether mixture. Melting point = 202 ° C. (fusion with decomposition). EXAMPLE 6 (Compound No. 12) 2-methyl-oxo-10- [2- [2-methyl] -2-chlorohydrate 4- (lH-1,2,3-triazolo

  [4,5-c] pyridin-4-yl) piperazin-1-yl] ethyl] -l, 2,3,4-tetrahydro-

  pyrazino [1,2-a] indole-8-carbonitrile (2: 1)

  6.1. 8-cyano-10- (2-chloroethyl) -2-methyl-3,4-dihydro-

  pyrazino [1,2-a] indole-1 (2H) -one 6.1.1. 4-Amino-3-iodobenzonitrile To 50.0 g (0.42 mole) of 4-aminobenzonitrile dissolved in 350 ml of acetonitrile, 65.4 g (0.40 mole) of toluene were added dropwise at room temperature. iodine monochloride, and the mixture is stirred for 20 hours. The reaction medium is diluted with 600 ml of ethyl acetate and the solution is washed with a 20% aqueous solution of sodium thiosulfate and then with a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatoflash on silica eluting with a n-heptane mixture:

dichloromethane (3: 2).

  60.05 g of product are obtained in the form of white crystals.

  Yield = 61% Melting point = 120 ° C

  6.1.2. 3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -2-

  (trimethylsilyl) -1H-indole-5-carbonitrile A mixture of 8.10 g (33.2 mmol) of 4-amino-3-iodobenzonitrile, 17.0 g (66.4 mmol) is heated at 70 ° C. for 3 hours. ) 1- (trimethylsilyl) -4 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -1-butyne, 16.0 g (0.164 mole) potassium acetate, 1.40 g (33.2); mmol) of lithium chloride and 0.74 g (3.33 mmol) of palladium (II) acetate in 110 ml of dimethylformamide under argon. The reaction medium is then cooled to ambient temperature and then diluted in 700 ml of ether and 300 ml of a saturated aqueous sodium chloride solution. The organic phase is decanted and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and condensed. The black oil obtained is purified by chromatoflash on silica eluting first with n-heptane and then with ethyl acetate containing

traces of ammonia.

  7.80 g of product are obtained in the form of an oil.

  Yield = 60% 6.1.3. 5-cyano-1H-indole-3-ethanol A 17.19 g (46.21 mmol) of 3- [2 - [[(1,1-dimethylethyl)

  dimethylsilyl] oxyléthyl] -2- (trimethylsilyl) -lh-indole-5-

  carbonitrile in solution in 225 ml of acetonitrile at room temperature, 7.3 ml of 48% hydrofluoric acid is added and stirred for 1 hour. 6.0 ml of 48% hydrofluoric acid are added and the mixture is stirred at ambient temperature for 18 hours. The reaction mixture is cooled on ice and slowly neutralized with a saturated aqueous solution of sodium carbonate. Extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and condensed. The residue is purified by filtration on silica buffer, eluting first with ethyl acetate and then with a mixture of

dichloromethane: methanol (9: 1).

  8.00 g of product are obtained in the form of a pale beige solid. Yield = 93% Melting point = 132 C 6.1.4. 5-cyano-3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -1H-indole

  To a stirred solution of 7.95 g (42.74 mmol) of 5-cyano-1H-

  indole-3-ethanol and 3.50 g (51.29 mmol) of imidazole in 170 ml of chloroform and 10 ml of dimethylformamide at room temperature, 7.73 g (51.29 mmol) of , 1diméthyléthyl) dimethylsilyl. The mixture is stirred at room temperature for a weekend. The reaction medium is diluted with 700 ml of chloroform and the solution is washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and condensed. The residue is purified by chromatography on silica eluting with a mixture of n-heptane: ethyl acetate (90:10, 85:15 then 75:25).

  containing traces of triethylamine.

  9.10 g of product are obtained in the form of a beige syrup.

  Yield = 71% 6.1.5. 5-cyano-3- [2 - [[(1,1-dimethylethyl) dimethylsilyl]

  oxy] ethyl] -1H-indole-1-carboxylate 1,1-dimethyl-

  ethyl A 4.69 g (0.117 mol) of 60% sodium hydride in mineral oil previously washed with petroleum ether, suspended in 50 ml of anhydrous tetrahydrofuran cooled to 0-5 ° C. and under an atmosphere of nitrogen, add drop by drop

  a solution of 11.73 g (39.1 mmol) of 5-cyano-3- [2 - [[1,1-

  dimethylethyl) dimethylsilyl] oxy] ethyl] -1H-indole in 40 ml of anhydrous tetrahydrofuran. After stirring for 15 minutes at 0 ° C., a solution of 13.97 g (46.92 mmol) of 1,1-dimethylethyl carbonate and 2,4,5-trichlorophenyl in 20 ml of sodium chloride is added dropwise. tetrahydrofuran. The mixture is stirred for 16 hours at room temperature and then 100 ml of water are added dropwise and the mixture is extracted with ether. The organic phases are washed with water, dried over magnesium sulfate, filtered and condensed. The residue is purified by chromatoflash on silica eluting with a mixture of n-heptane: ethyl acetate (95: 5, 90:10 then 85:15) containing

traces of triethylamine.

  13.81 g of product are obtained in the form of a pale yellow wax. Yield = 88% 6.1.6 5-cyano-3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy]

  ethyl] -2 (1H) -indole-1,2-dicarboxylate of 1- (1,1-)

  dimethylethyl) and 2-ethyl to a solution cooled to -70 ° C. of 12, 30 g (30.75 mmol) of 5-cyano-3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl 1-Dimethylethyl-1H-indole-1-carboxylate and 6.97 ml (46.13 mmol) of N, N, N ', N'-tetramethylethylenediamine in 210 ml of anhydrous tetrahydrofuran under nitrogen were added dropwise. dropwise 30.75 ml (46.13 mmol) of a solution of 1.5 M tertbutyllithium in pentane. It is stirred for a period of minutes at this temperature and then a solution of 14.7 ml (0.154 mole) of ethyl chloroformate in 75 ml of tetrahydrofuran is added dropwise. Stirred at -70 ° C. for 1.5 hours and the temperature is allowed to rise to room temperature over 1 hour. The reaction medium is cooled to -60 ° C. and hydrolyzed by addition of 450 ml of a saturated aqueous solution of ammonium chloride. Extracted several times with ether and the organic phases are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and condensed. The residue is purified by chromatoflash on silica eluting with a mixture

  cyclohexane: ethyl acetate (95: 5 then 90:10).

  11.30 g of product are obtained in the form of an amorphous solid

pale yellow.

  Yield = 78% Melting point = 66-67 ° C 6.1.7. Ethyl 5-cyano-3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxylethyl] -1H-indole-2-carboxylate A solution of 4.54 g is refluxed for 2 hours.

  (9.62 mmol) of 5-cyano-3- [2 - [[(1,1-dimethylethyl) dimethyl)

  1- (1,1-dimethylethyl) -2-ethyl silyl] oxy] ethyl] -2 (1H) -indole-1,2-dicarboxylate and 10.84 g (0.144 mole) of 2- (methylamino) ethanol in 160 ml of absolute ethanol. The reaction medium is evaporated to dryness and the residue is taken up in 300 ml of dichloromethane. The solution is washed with a saturated aqueous solution of ammonium chloride and then with a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and condensed. The residue is purified by chromatoflash on silica eluting with a n-heptane: ethyl acetate (1: 1) mixture.

  containing traces of triethylamine.

  3.57 g of product is obtained in the form of a pale yellow solid. Yield = 99% Melting point = 164-165 ° C 6.1.8. Ethyl 1- (2-bromoethyl) -5-cyano-3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -1H-indole-2-carboxylate Stirring vigorously at room temperature for 2.5 hours a biphasic mixture of ethyl cyano-3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -1H-indole-2-carboxylate, 3.55 g (9.54 mmol), 0.45 g of tetrabutylammonium bromide, 45 ml of 1,2-dibromoethane and 30 ml of 25% aqueous sodium hydroxide solution. The reaction medium is then diluted in 300 ml of toluene and 1 ml of water. The organic phase is decanted and the aqueous phase is re-extracted with toluene. We dry the phases

  organic over sodium sulfate, filtered and condensed.

  4.40 g of product are obtained in the form of a beige wax.

  Yield = 96% 6.1.9. 8-cyano-10- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxylethyl] -3,4-dihydropyrazino [1,2-a] indole-1 (2H) -one In an autoclave, the mixture is heated to 100 C for 72 hours a

  solution of 4.69 g (9.79 mmol) of 1- (2-bromoethyl) -5-cyano-

  3- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] ethyl] -lh-indole

  Ethyl 2-carboxylate in 150 ml of absolute ethanol saturated with gaseous ammonia. The reaction medium is evaporated to dryness and the product is purified by chromatoflash on silica eluting with a dichloromethane: methanol mixture (98: 2, 95: 5 and then: 10). 1.65 g of product are obtained in the form of a pale yellow solid. Yield = 47% Melting point = 192 C 6.1.10. 8-cyano-10- [2 - [[(1,1-dimethylethyl) dimethylsilyl] oxylethyl] -2-methyl-3,4-dihydropyrazino [1,2-a] indole-1 (2H) -one to a solution stirred at room temperature with 0.70 g (1.89 mmol) of 8-cyano-10- [2 - [[(1,1-dimethylethyl)

  dimethylsilyl] oxyléthyl] -3,4-dihydropyrazino [1,2-a] indole

  1 (2H) -one in 15 ml of anhydrous tetrahydrofuran is added in a small amount 0.09 g (2.1 mmol) of% sodium hydride. After 30 minutes, 0.27 ml (4.34 mmol) of methyl iodide are added dropwise and the solution is stirred at room temperature for 2 hours. The reaction medium is hydrolysed by adding a few drops of methanol and then 20 ml of a saturated aqueous solution of ammonium chloride. Extracted with ether, then the organic phases are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and condensed. The residue is purified by chromatoflash on silica eluting with a n-heptane: ethyl acetate mixture (3: 7).

then 3: 8).

  0.60 g of product is obtained in the form of an off-white solid. Yield = 85% Melting point = 175 ° C

  6.1.11. 8-cyano-10- (2-chloroethyl) -2-methyl-3,4-dihydro-

  pyrazino [1,2-a] indol-1 (2H) -one A solution of 0.55 g is heated at 55 ° C. for 0.5 hour.

  (1.3 mmol) 8-cyano-10- [2 - [[(1,1-dimethylethyl) dimethyl)

  silyll] oxylethyl] -2-methyl-3,4-dihydropyrazino [1,2-a] indole-

  1 (2H) -one and 0.3 ml (3.9 mmol) of thionyl chloride in ml of chloroform. The reaction medium is evaporated to dryness and the residue is taken up in 100 ml of dichloromethane. The solution is washed twice with water and the phase is dried

  organic over sodium sulfate, filtered and then condensed.

  0.41 g of product is obtained in the form of a beige solid.

  Yield = 100% Melting point = 200 ° C

  6.2. 4-piperazin-l-yl-lH-1,2,3-triazolo [4,5-c] pyridine-1-

  1,1-Dimethylethyl carboxylate 6.2.1. 2-chloro-3,4-diaminopyridine 23.1 g (0.146 mol) of 4-chloro-3-nitropyridine are heated at 100 ° C. for 17 hours in 140 ml of saturated absolute ethanol.

  in gaseous ammonia. The reaction medium is evaporated to dryness.

  The solid obtained is added in small quantities to a solution preheated at 80 ° C. with 229.5 g (1.02 mol) of tin chloride dihydrate in 375 ml of concentrated hydrochloric acid. The mixture is then heated at the reflux temperature for 1.5 hours. The reaction medium is cooled to 5 ° C., the pH is adjusted to 8-9 with a concentrated aqueous solution of sodium hydroxide. The precipitate is filtered off and extracted for 24 hours in an extraction apparatus.

  solid-liquid using 700 ml of a benzene: chlorine mixture

  roform (1: 1). In parallel, the filtrate is extracted with 3 times 400 ml of ethyl acetate. The organic phases are combined, dried over sodium sulphate and concentrated. 11.58 g of product is obtained in the form of a solid of

peach colored.

  Yield = 60% Melting point = 162 C 6.2.2. 4-chloro-1H-1,2,3-triazolo [4,5-c] pyridine To a solution cooled to 0-5 ° C of 1.25 g (8, 70 mmol) of 2-chloro-3,4-diaminopyridine in 49 ml of 0.4 N aqueous hydrochloric acid are added in small quantities 0.66 g (9.57 mmol) of sodium nitrite. The mixture is stirred for 1 hour at 0 ° C. and then the solid is filtered off. It is rinsed with water then

  the ether and dried under vacuum at 40 ° C.

  1.17 g of product is obtained in the form of a white solid

broken.

  Yield = 87% Melting point = 240 OC (decomposition)

  6.2.3. 4- [4- (phenylmethyl) piperazin-l-yl] -LH-1,2,3

  triazolo [4,5-c] pyridine A solution of 0.4 g (2.59 mmol) of 4-chloro-1H-1,2,3-triazolo [4,5-c] was heated at 75 ° C. for 14 hours. ] pyridine and 0.50 ml (2.88 mmol) of 4- (phenylmethyl) piperazine in 16 ml of isoamyl alcohol. We squeeze the solid, we wash it to

  the ether and dried under vacuum at 40 ° C.

  0.605 g of product is obtained in the form of a yellow solid.

  Yield = 80% Melting point = 156-157 C 6.2.4. Methyl 4- [4 (phenylmethyl) piperazin-1-yl] -1H-1,2,3-triazolo [4,5-c] pyridine-1-carboxylate To a suspension cooled to 0 ° C. of 0.885 g (22.degree. 12 mmol) of 60% sodium hydride in 100 ml of dimethylformamide, a solution of 4.70 g is added dropwise.

  (15.97 mmol) 4- [4- (phenylmethyl) piperazin-1-yl] -1H-

  1,2,3-triazolo [4,5-c] pyridine in 150 ml of dimethylformate

  mide. The mixture is stirred at 0 ° C. for 30 minutes and then a solution of 6.18 g (20.77 mmol) of 1,1-dimethylethyl carbonate and 2,4,5-trichlorophenyl in 100 ml is added dropwise. of dimethylformamide. It is stirred for 14 hours at ambient temperature, and then the reaction medium is poured into 500 ml of saturated aqueous ammonium chloride solution. It is extracted twice with 250 ml of dichloromethane and the organic phase is dried over sodium sulfate, filtered and evaporated. The residue is purified by

  chromatoflash on silica eluting with a n

  heptane / ethyl acetate (75:25, 60:40 then 50:50).

  3.92 g of product are obtained in the form of a white solid.

  Yield = 58% Melting point = 148 ° C

  6.2.5. 4-piperazin-1-yl-lH-1,2,3-triazolo [4,5-c] pyridine-1-

  1,1-Dimethylethyl carboxylate Hydrogen is distilled under a pressure of 0.1 MPa (1 atm) at 60 ° C. for 13 hours 3.90 g (9.89 mmol) of 4- [4 (phenylmethyl)

  piperazin-1-yl] -1H-1,2,3-triazolo [4,5-c] pyridine-1-carboxylic acid

  methylate in 100 ml of methanol in the presence of 0.29 g of 20% palladium hydroxide. The reaction medium is allowed to cool to room temperature and is filtered through celite. The filtrate is evaporated and the residue is purified by filtration on silica eluting with a dichloromethane / methanol (9: 1) containing traces of ammonia.

  2.30 g of product are obtained in the form of a white solid.

  Yield = 77% Melting point = 197-198 C 6.3. 2-methyl-1-oxo-10- [2- [4- (1H-1,2,3-) hydrochloride

  triazolo [4,5-c] pyridin-4-yl) piperazin-1-yl] ethyl] -

  1,2,3,4-Tetrahydropyrazino [1,2-a] indole-8-carbonitrile (2: 1) A mixture of 30 mg is heated at 70 ° C. for 72 hours.

  (0.1 mmol) 8-cyano-1- (2-chloroethyl) -2-methyl-3,4-dimethylformamide.

  dihydropyrazino [1,2-a] indol-1 (2H) -one, 40 mg (0.12 mmol) of

  4-piperazin-l-yl-lH-1,2,3-triazolo [4,5-c] pyridine-1-

  1,1-dimethylethyl carboxylate, 15 mg (0.12 mmol) sodium bicarbonate and 5 mg potassium iodide. The reaction medium is evaporated to dryness and the residue is taken up in 100 ml of dichloromethane. The solution is washed with a saturated aqueous solution of sodium chloride and the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The residue is purified by chromatography on silica eluting with a mixture of ethyl acetate / methanol.

  (95: 5 then 90:10) containing traces of ammonia.

50 mg of base are obtained.

  Yield = 86% 50 mg of base are stirred for 1 hour at ambient temperature in 5 ml of 3N hydrochloric ethyl acetate.

  solid, rinsed with ether and dried under vacuum at 40 ° C.

  40 mg of product is obtained in the form of a white solid.

  Yield = 84% Melting point = 204 ° C

Board

Ni) z N R1

N N-R

R2 1N - 3

  Qul tn N NO point R1 R2 R3 Q Z Melting salt (O C)

H1 41

NOT

"HCl -

  1 L-H-H-CH 3 H, H -N-235 (d) I (2: 1)

NS 0

  -4 _ _ _ _ _ _ _ _ 1 _ _ _ _ _ _ _ w Cree p- o (% D r1 X-N- H'H úHD H - -L S

IDH \ I

  N S (P) Z | | 'X-N- | H- H- | IDH Ln SN

ú (1 -N- 0 HD- H- H

IDH N

(P) 661 -N-H'H H- H- H-

  IDH N (OD) UOTSn; jS lZ O [u TH oN ap IUTod N N NO point R1 R2 R3 Q Z Melting salt (OC) N

6 8-F -H -CH 3 H, H-N-186

(2: 1) N 'HCl

7 7-F -H -CH3H, H -N- -2 172

(2: 1) N HC1

8 7-F -H-CH 3 H, H -N-170-172

\ / (2: 1)

OCH3 N "HCl

9 7-F -H -CH 3 H, H -N-112 4

(2: 1) o -4

## STR1 ##

t'oz -N-H 'HúDH- N-

IDH N Ln HO-N- H'H úHD - H to-L O I

  ## STR1 ## ## STR1 ## II @ STH X l u 1 e uT (Do) uo! FsnjlaS Z 0 [% F -% {oN ap JuTod \ ,, N N NO point R1 R2 R3 Q Z Melting salt

AW <O (C)

N HCl

  13 8-OCH 3 --H - CH 3 H, H - N - (2: 1) 181-184

\ / (2: 1)

  F - in the column "Salt": Ln HCl represents a hydrochloride and (x: y) the ratio (salt: base); the absence of any mention means that the compound is in base form, - in the column "Melting point":

  (d) corresponds to a fusion with decomposition.

  The compounds of the invention have been the subject of pharmacological studies which have demonstrated their serotonin antagonistic properties and their interest as

  substances with therapeutic activity.

  Thus, the compounds of the invention have been subjected to a test

  inhibiting the vasopressor effect of serotonin. Male rats (Sprague-Dawley, Charles River France) weighing 250 to 300 g are used, which is anesthetized with sodium pentobarbital (60 mg / kg / i.p.) and maintained under respiratory conditions.

  artificial respiration (Harvard Respirator TM-breathing rate of 70 ml per minute, air volume 1 ml per 100 g body weight). The animals are amyelated using a metal rod introduced through the orbit of the right eye descended along the spine. The right and left vagus nerves are divided (bivagotomy), the right carotid artery is ligated, and the left carotid artery is catheterized to measure the arterial pressure using a pressure cell (StathamTM P23Db type). A femoral vein is catheterized for the administration of various compounds. Intravenous serotonin-mediated increases in mean arterial blood pressure were measured at a dose of 30 g / kg. The compounds of the invention or the vehicle are administered for 5 minutes (for i.v. studies) or 75 minutes (for oral studies) prior to administration of serotonin. The compounds of the invention are administered at doses ranging from 0.001 to mg / kg. Percent inhibition of the serotonin control response is used to assess the potential

  serotonin antagonist of the compounds of the invention.

  The compounds of the invention have also been tested for inhibition of [3H] spiroperidol binding to

  Serotoninergic 5-HT2 receptors of rat cerebral cortex.

  For this test, the brains of rats are removed, the cortex is dissected and homogenized at 0 ° C. in 20 volumes of a mixture containing, per liter, 50 mmol of buffer.

  Tris / HCl pH 7.4, 120 mmol NaCl and 5 mmol KCl.

  The homogeneous mixture is centrifuged at 40000 x g for minutes and then the pellet is recovered twice, washed by suspending it in the same buffer mixture, homogenized again and centrifuged. Finally, the final pellet is diluted in the same buffer mixture at the rate of 500 mg of wet tissue per 10 ml of buffer. The tissue is then subjected to a pre-incubation of 10 minutes at 37 ° C. in the presence of 10 g / l of pargyline and then to a 20 minute incubation at 37 ° C. in the presence of 3H-spiroperidol (specific activity: 19 Ci per mmol) at the concentration of 0.3 nM and the compound to be studied at

  concentrations ranging from 0.0001 to 100 MM.

  1 ml aliquots are removed and filtered in vacuo, the filters are washed twice with 5 ml of cold buffer,

  dry and measure the radioactivity.

  In order to evaluate the activity of the compounds, the percentage inhibition curve of the specific binding of 3H-spiroperidol is established as a function of the concentration of displacing drug. The IC50 is determined graphically, concentration

  which inhibits 50% of the specific binding.

  The specific link is defined as the link

moved by 100 MM of 5-HT.

  The compounds of the invention were also tested in a model of Sumatriptan vasoconstriction of the isolated saphenous vein of dog (antagonist activity at the HTII receptor, according to HUMPHREY et al., In Br. J. Pharmacol.

1988, 94, 1123).

  Saphenous veins of Beagle or Anglopoitevins dogs are taken under pentobarbital anesthesia administered by intravenous injection. The vessel is cut into a helix 0.4 cm wide and divided into segments 0.5 cm in length. Each fragment, mounted between two clamps, is placed in an isolated organ container containing 20 ml of physiological Krebs solution of the following composition (mM): NaCl 118; KCl 4.7; MgCl 2 1.2; CaCl2 2.6; NaHCO3 25; Glucose 11.1; ascorbic acid 0.11. The organ, maintained at 37 ° C. under a current of carbogen (95% O 2 -5% CO 2) at pH 7.4, is connected to a Hugo Sachs isometric sensor type 351 at a basal tension of 2 g and connected to a Gould polygraph. 2400S

  allowing the recording of the tension variations.

  Data acquisition is automated by micro-system

  computer. After a rest period of 90 minutes interspersed with frequent rinses during which the basal tension is S readjusted, the organ is stimulated by 3 iM norepinephrine to verify its viability. A Sumatriptan contractile concentration-response curve is then constructed cumulatively between 10 nM and 10 MM. When the maximum contraction is obtained (plateau of the effect at two consecutive concentrations of Sumatriptan), the preparation is thoroughly rinsed by interposing periods of rest to allow the organ to return to the initial tension. The compound to be studied is then added to the organ bath 15 minutes before a second curve

  concentration-response to Sumatriptan be constructed.

  The contraction responses obtained in the presence of the compound are expressed as a percentage of the maximum contraction observed during the first Sumatriptan curve. The curves are analyzed by non-linear regression to determine the Emax (maximum response) and the EC50 (concentration producing 50% of the maximum response). The antagonistic potential of the compounds is estimated by calculation of the KB dissociation constant according to the equation KB = [concentration of the compound in M] / (CR - 1) where CR represents the ratio of EC50 of Sumatriptan in the presence and absence

  of the compound. The result is expressed as pA2 = - log KB.

  The results of these tests have shown that the compounds of the invention exhibit antagonistic properties of

serotonin.

  As such, they can be used in the treatment and prevention of various forms of pathologies involving serotonin, such as arterial, venous, pulmonary, portal, renal or ocular hypertension, cardiac, renal, ocular, cerebral ischemia, or lower limbs, heart failure, myocardial infarction, angina, coronary or peripheral vasospasms, thromboses (alone or in adjuvants to thrombolysis), arteritis, intermittent claudication, restenosis after angioplasty and various states associated with atherosclerosis, microcirculatory disorders or pulmonary dysfunctions. They can also be used alone or in combination with other substances in vascular graft procedures. The compounds of the invention may be used in combination with other substances with cardiovascular or cardiopulmonary activity, such as antithrombotics, thrombolytics, g-blockers, calcium antagonists, thromboxane antagonists,

  inhibitors of thromboxane synthetase.

  For this purpose, these compounds may be presented in any form suitable for oral or parenteral administration such as tablets, dragees, capsules, capsules, topical ocular formulations in combination with suitable excipients. These forms are dosed to allow administration of 0.1 mg to 1 g, one to several times a day. They can also be presented in any form

  suitable for transdermal administration.

Claims (8)

claims 1. Compounds of formula (I) N z N RR   Wherein R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, an amino group or a (C 1 -C 4) alkyl amino group, either a hydroxy group, a nitro group, a cyano group, a (C 1 -C 6) alkyl group, a (C 1 -C 6) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group or a -COOH group; either a COOR4 group, -CONH2 group, -CONHR4 group, CONR4R5 group, -SR4 group, -SO2R4 group, -NHCOR4 group, -NHSO2R4 group, or -N (R4) 2 group R4 and R5 are each a (C1-C4) alkyl group, R3 represents either a hydrogen atom, a (C1-C6) alkyl group or a - (CH2) pOH group, either a - (CH2) pNH2 group, a - (CH2) nCOOH group, a - (CH2) nCOOR4 group, a - (CH2) nCN group or a - (CH2) n -tetrazol-5-yl group either a - (CH2) nCONH2 group, or a - (CH2) nCONHOH group, or a group - (CH2) PSH, either a - (CH2) nSO3H group, a - (CH2) nSO2NH2 group, a - (CH2) nSO2NHR4 group, a - (CH2) nSO2NR4R5 group, or a - (CH2) nCONHR4 group either a - (CH2) nCONR4R5 group, a - (CH2) pNHSO2R4 group, a - (CH2) pNHCOR4 group or a - (CH2) pOCOR4 group where R4 and R5 are each a (C1-C4) alkyl group, n is 1, 2, 3 or 4 and p is 2, 3 or 4, Q represents either two hydrogen atoms or one oxygen atom, Z represents either a nitrogen atom or a group -CH-, A represents either an optionally substituted phenyl group, or a substituted or unsubstituted heterocycle having 5 or 6 atoms, of which one, two or three are heteroatoms selected from nitrogen, oxygen and sulfur, the other atoms being carbon atoms, said heterocycle being for example selected from furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thienyl, thia diazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and their positional isomers of heteroatoms, as well as their addition salts to acids or bases pharmaceutically acceptable.   2. Process for preparing the compounds of formula (Ia) N I Z NOT (Ia) 3 N-R3 R2   according to claim 1, wherein R1 and R2 represent either a hydrogen atom, a halogen atom, a hydroxy group, a (C1-C6) alkyl group, or a (C1-C6) alkoxy group, either a trifluoromethyl group, a trifluoromethoxy group, a -SR4 group or a -SO2R4 group, R3 is as defined in claim 1 and is different from a hydrogen atom and A and Z are as defined in claim 1, characterized in that compounds of formula (XI) Y are reacted R1 (XI) RN N-R3   Wherein R1 and R2 are either hydrogen, halogen, hydroxy, (C1-C6) alkyl, (C1-C6) alkoxy or trifluoromethyl; either a trifluoromethoxy group, a -SR4 group or a --SO2R4 group, R3 is as defined in claim 1 and is different from a hydrogen atom and Y represents a leaving group, with a compound of formula ( XII) NOT   HN z - (XII) in which A and Z are as defined in the claim 1.   3. Process for preparing the compounds of formula (Ib) -z N / A   Wherein R1 and R2 are either hydrogen, halogen, hydroxy or (C1-C6) alkyl, either a (C1-C6) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -SR4 group or a -SO2R4 group and A and Z are as defined in claim 1, characterized in that compounds of formula (XIV) are reacted R1 FCHO   in which R1 and R2 represent either a hydrogen atom, a halogen atom, a hydroxy group, a (C1C6) alkyl group, a (C1-C6) alkoxy group, or a group trifluoromethyl, either a trifluoromethoxy group, a -SR4 group or a SO2R4 group, R3 is as defined in claim 1 with a compound of formula (XII).   4. Process for the preparation of the compounds of formula (Ic) wherein R1 and / or R2 represent either an amino group or an amino group (C1-C4) alkyl, either a nitro group, a cyano group, a -COOH group, a -COOR4 group, a -CONH2 group, a -CONHR4 group, a -CONR4R5 group, or a -NHCOR4 group, or a group -NHSO2R4, that is a group -N (R4) 2 where R4 and R5 are each a (C1-C4) alkyl group, R3, A and Z are as defined in claim 1, characterized in that -soit reacts the compounds of formula (IX) OP R 1 R 1 (IX) R2 N N   Wherein R 1 and / or R 2 are either nitro or cyano and P is a protecting group, with a base and an electrophilic agent, and a compound of formula (X) OP R 1 is obtained 0 (X) N N-R (X)   In which R 3 is as defined in claim 1 and is different from a hydrogen atom, or the compounds of formula (IX) are deprotected and then the compounds of formula (X) or the compounds of formula ( IX) deprotected in compounds of formula (XI) Y R o IRa (XI) N N-R   in which R 1 and / or R 2 represent either a nitro group or a cyano group, R 3 is as defined in claim 1 and Y represents a leaving group and then is condensed with a compound of formula (XII) NOT HN z HN Z <(XII)   in which A and Z are as defined in claim 1 and compounds of formula (Ic) in which R1 and / or R2 represent either a nitro group or a cyano group, and then it is desired to obtain compounds of formula (Ic) wherein R1 and R2 are either an amino group, a (C1-C4) alkyl amino group, a -COOH group, a -COOR4 group, a -CONH2 group, a CONHR4 group, or a -CONR4R5 group, an -NHCOR4 group, an NHSO2R4 group or a -N (R4) 2 group where R4 and R5 are each a (C1C4) alkyl group, then the corresponding compounds of formula (Ic) are treated in   which R 1 and / or R 2 represent either a nitro group or a cyano group under standard conditions.   5. Process for the preparation of compounds of formula (Id) N I (z N (Id) o N N-R3   Wherein R 1, R 2, A and Z are as defined in claim 1 and R 3 is as defined in claim 1 and is different from a hydrogen atom characterized in that the compounds are reacted of formula (XXIII) NI cz NOT R1 (XXIII) RN OCH2CH3 R2 O   Wherein R 1, R 2, A and Z are as defined in claim 1 and R is (C 2 -C 6) alkyl with a compound of formula R 3 NH 2 and compounds of formula (XXIV) are obtained OR Nz Ni (XXIV) Ri N N-R3 R2 HI o N-R H that we cyclize.   6. Process for preparing the compounds of formula (Ie) NOT / (z Ni R1 (Ie) RN H   in which R1, R2, A and Z are as defined in claim 1 characterized in that the compound is cyclized of formula (XXIII).   7. Medicinal product characterized in that it contains a compound according to claim 1.   8. Pharmaceutical composition characterized in that it contains a compound according to claim 1 in association   with any pharmaceutically acceptable excipient.