FR2761071A1 - DERIVATIVES OF QUINOLEIN-2 (1H) -ONE AND DIHYDROQUINOLEIN-2 (1H) - ONE, THEIR PREPARATION AND THEIR APPLICATION IN THERAPEUTICS - Google Patents

Abstract

The invention concerns compounds of formula (I) in which <o>---</o> represents a single or double bond; G represents (G) in position 3 or 4; m = 2 to 4; Z represents a nitrogen atom or a -CH- group; R1 and R2 each represent independently of each other, a hydrogen or halogen atom, an amino, hydroxy, nitro, cyano, (C1-C6) alkyl, (C1-C6) alkoxy, trifluoromethyl, trifluoromethoxy, -COOH, -COOR4, -CONH2, -CONHR4, -CONR4R5, -SR4, -SO2R4, -NHCOR4, -NHSO2R4, -N(R4)2 group; R3 represents a hydrogen atom, a (C1-C4) alkyl, -(CH2)pOH, -(CH2)pNH2, -(CH2)nCOOH, -(CH2)nCOOR4, -(CH2)nCN, -(CH2)n-tetrazolyl, -(CH2)nCONH2, -(CH2)nCONHOH, -(CH2)pSH, (CH2)nSO3H, -(CH2)nSO2NH2, -(CH2)nSO2NHR4, -(CH2)nSO2NR4R5, -(CH2)nCONHR4, -(CH2)nCONR4R5, -(CH2)pNHSO2R4, -(CH2)pNHCOR4, -(CH2)pOCOR4 group; R4 and R5 are each a (C1-C4) alkyl group; n = 1 to 4; p = 2 to 4; and A represents a benzo group optionally substituted or not. The invention is applicable in therapeutics.

Description

The present invention relates to derivatives of quinolin-2 (1H) -one and

of dihydroquinolin-2 (1H) -one, their

preparation and their application in therapy.

The compounds of the invention correspond to the formula (I) N Ri (CH) -N z "'

1 0 1

N) -Z (0

R2 R3 in which - = - represents either a single bond or a double bond, m is equal to 2, 3 or 4, the group N

(CH2) N Z

X-

being in position 3 or 4 of quinolin-2 (1H) -one or dihydroquinolin-2 (1H) -one,

Z represents either a nitrogen atom or a -CH- group

R1 and R2 each independently represent either a hydrogen atom, or a halogen atom, or an amino group, or a hydroxy group, or a nitro group, or a cyano group, or a (Cl-C6) alkyl group, either a (C1-C6) alkoxy group, or a trifluoromethyl group, or a trifluoromethoxy group, or a -COOH group, or a -COOR4 group, or a -CONH2 group, or a - group CONHR4, either a -CONR4R5 group, or a -SR4 group, or a -SO2R4 group, or a -NHCOR4 group, or a -NHSO2R4 group, or a - N (R4) 2 group o R4 and R5 are each a ( Cl-C4) alkyl, R3 represents either a hydrogen atom, or a (C1-C4) alkyl group, or a - (CH2) pOH group, or a - (CH2) pNH2 group, or a - (CH2) group nCOOH, either a - (CH2) nCOOR4 group, or a - (CH2) nCN group, or a - (CH2) ntetrazol-5-yl group, or a - (CH2) nCONH2 group, or a (CH2) nCONHOH group, either a - (CH2) pSH group, or a - (CH2) nSO3H group, or a - (CH2) nSO2NH2 group, either a group - (CH2) nSO2NHR4, or a group (CH2) nSO2NR4Rs, or a group - (CH2) nCONHR4, or a group (CH2) nCONR4R5, or a group - (CH2) pNHSO2R4, or a group (CH2) pNHCOR4 , or a group - (CH2) pOCOR4 o R4 and R5 are each a (C1-C4) alkyl group, n is equal to 1, 2, 3 or 4 and p is equal to 2, 3 or 4 and A represents either a optionally substituted phenyl, or a substituted or unsubstituted heterocycle having 5 or 6 atoms among which one, two or three are heteroatoms chosen from nitrogen, oxygen and sulfur atoms, the other 15 atoms being carbon atoms, the said heterocycle not being a thienyl group and being able, for example, to be chosen from furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl groups and their positioning isomers , as well as their addition salts with acids or bases

pharmaceutically acceptable.

Certain compounds of formula (I) may exist as racemates, pure enantiomers or as a mixture

enantiomers which also form part of the invention.

According to the invention, the compounds of formula (I) comprising a quinolin-2 (1H) -one substituted in position 4 can be

synthesized according to scheme 1.

4- (acetyloxy) -2H, 3H-pyran-2,6-dione is reacted with a compound of formula (II) (in which R1 and R2 are as defined above and R3 is a hydrogen atom or a (Cl-C4) alkyl group) at room temperature in a polar solvent such as acetic acid. After drying, the compound of formula (III) thus obtained is cyclized in the presence of an inorganic or organic acid, preferably anhydrous, such as concentrated sulfuric acid, polyphosphoric acid, Scheme 1 o

R1H O0CH R HOOC>

R3 * 3

(II) (III)

C COOH R0C COOR6

R Ri

N N0 C

(IV (V

N 'H 0 0 / N O

R2 R2

R3 R3

(IV) (yII) R10

COOH COOR6

Ri1R

N N

HNZ $ / A A NN

(IV) (V)

OH / 1-Y

R (H (CH2) M

R2 R3

AR 3

(VI) (VII)

R HNz N

(VIII)

(Ib) R 3 # H or trifluoromethanesulfonic acid at a temperature between 10 and 150 C and a 2-oxo-1,2-dihydroquinoline-4-acetic acid, substituted or not, of formula (IV) is obtained which it is esterified with an alcohol of formula R6OH (o R6 is a (C1C4) alkyl group), by any esterification method, preferably by the action of thionyl chloride. Then the ester of formula (V) thus obtained is reduced with a hydride in an aprotic solvent such as, for example, lithium aluminum hydride in dioxane or sodium borohydride in excess in tetrahydrofuran at reflux. , or lithium borohydride in tetrahydrofuran at room temperature to obtain an alcohol of formula (VI) (in which m is equal to 2); the compounds of formula (VI), in which m is equal to 3 or 4, are obtained from those where m is equal to 2 by

approval techniques known to those skilled in the art.

Then the compounds of formula (VI) (in which m is equal to 2, 3 or 4) are activated into compounds of formula (VII) (in which Y represents a leaving group such as a chlorine or bromine atom) by example by reaction with chloride

of thionyl in refluxing chloroform or dibromotri-

phenylphosphorane at room temperature in dichloro-

methane or in compounds of formula (VII) (in which Y represents a leaving group such as the 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. Finally, the compounds of formula (VII) are reacted with a compound of formula (VIII) (in which A is as defined above) with or without 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 is obtained

(Ia) or (Ib).

In a variant according to the invention, to prepare a compound of formula (Ib) (in which R3 is different from a hydrogen atom), it is possible to carry out the alkylation of the corresponding compound of formula (Ia) (in which R3 represents a hydrogen atom) using an electrophilic agent of the R3Br or R3I type, such as for example tert-butyl bromoacetate, bromomethanesulfonamide, N-methylbromomethanesulfonamide, bromoacetamide, N-methylbromoacetamide, N, N- dimethylbromoacetamide or 2bromoethyl acetate in the presence of a base such as sodium or potassium hydride, in a solvent

aprotic such as tetrahydrofuran or dimethylforma-

mid, in the presence or absence of a transfer catalyst

phase, such as tetrabutylammonium bromide.

If it is desired to prepare the compounds of formula (Ib) in which R3 represents a group - (CH2) nCOOH, a deesterification of the corresponding compounds of formula (Ib) is carried out.

in which R3 represents a group - (CH2) nCOOR4.

If it is desired to prepare the compounds of formula (Ib) in which R3 represents a group - (CH2) pOH, a deacetylation of the corresponding compounds of formula (Ib) is carried out.

in which R3 represents a group - (CH2) pOCOR4.

To obtain a compound of formula (I) in which R1 and / or R2 represent a cyano group, -CONH2, -COOH, -COOR4, -SR4 or -S02R4 o R4 is a (C1-C4) alkyl group, the cyclization of compound of formula (III) in quinolinone of formula (IV) being disadvantaged, the synthesis of the compounds of formulas (V) and (VI) corresponding is rather carried out according to the

diagrams 2 and 3.

According to scheme 2, a compound of formula (Va) corresponding to a compound of formula (V) (in which R1 represents an iodine atom, R2 and R6 are as defined above and R3 is an atom of iodine) is reacted. hydrogen or a (C1-C4) alkyl group) with a cyanide salt in the presence of a copper salt in a polar solvent such as dimethylformamide

or N-methylpyrrolidone, or with trimethyl cyanide

silyl in the presence of a palladium catalyst, preferably

rence of tetrakis (triphenylphosphine) palladium [0] in triethylamine at reflux to obtain a compound of formula (Vb) which can either be converted into a compound of formula (VId) then into a compound of formula (VIe) (in which R7 is a hydrogen atom or a (C1-C4) alkyl group), or Scheme 2

NC OH ROO00C OH

O R2

R3 R3

(VId) (VIe)

COOR6 COOR- COOR6

I NC H2NOC

-

I CCOOR2

R2 R-2 0R

R Pl R3 (Va) (Vb) (Vc)

converting into a carboxamide derivative of formula (Vc) by conventional methods known to those skilled in the art.

According to scheme 3, a compound of formula (VIa) corresponding to a compound of formula (VI) (in which R125 represents an iodine atom, R2 is as defined above and R3 is a hydrogen atom or a group

(C1-C4) alkyl) with a thiolate such as sodium thiomethoxide in the presence of tetrakis (triphenylphosphine) palla-

dium [0] in an alcohol, such as ethanol, propanol or n-butanol to prepare a compound of formula (VIb) (wherein R4 is a (C1-C4) alkyl group) which may be

converting by oxidation into a compound of formula (VIc).

Diagram 3 H

3 5 IROH / ^ OH R402S OH

R2 R2 R2

R3 R 3 R 3

(VIa) (VIb) (VIc) To obtain the compounds of formula (I) in which R1 and / or R2 represent a nitro, amino, -NHCOR4, -NHSO2R4 or -N (R4) 2 group, R4 being a group ( C1- C4) alkyl, the synthesis of the corresponding compounds of formula (VII) is carried out according to scheme 4. Scheme 4 x H (CH2) m R402SHN (CH2) m

N 0 R N 0

R2 2

R3 R3

(VIIa) V / (VIIe)

/ X / X

x.X Ix (CH 2) m 02N (CH2) H N (CH2) m (R4) 2N

H2 N O

R N 0 R2 N 0 R2 N 0

RR2 I

2 'J2 IK

R3 R3R3

R3 (VIIb) (VIIc) (VIIf) x R40CHN (CH 2) m

R2 0

R3 (VIId) The nitration of a compound of formula (VIIa) corresponding to a compound of formula (VII) (in which R1 is a hydrogen atom, X is a halogen atom and R3 is a hydrogen atom) is carried out. or a (Cl-C4) alkyl group) to obtain a compound of formula (VIIb) which is converted into a compound of formula (VIIc) by reduction with hydrogen, which compound is converted either into a compound of formula ( VIId) by reaction with a carboxylic acid chloride of formula R4COCl, either in a compound of formula (VIIe) by reaction with a sulfonic acid chloride of formula R4SO2Cl, or in a compound of formula (VIIf) by N-dialkylation reaction . Then these compounds are reacted with a compound of formula (VIII)

according to diagram 1.

In order to prepare the compounds of formula (I) in which R1 and / or R2 represent a hydroxy group, it is possible to carry out dealkylation of the corresponding alkoxylated compound of formula (I) (in which R1 and / or R2 represent an alkoxyl group) in standard conditions known to those skilled in the art, such as for example an acid treatment

48% hydrobromic in water.

According to the invention, the compounds of formula (I) comprising a 3,4dihydroquinolin-2 (1H) -one substituted in position 3

can be synthesized according to scheme 5.

An ortho-nitro-benzaldehyde of formula (IX) (in which R1 and R2 are as defined above) is reacted with α- [ybutyrolactonylidene] triphenylphosphorane under reflux of an aprotic solvent such as tetrahydrofuran or toluene and obtains a compound of formula (X) which is converted into dihydroquinolinone of formula (XI) (in

which m is equal to 2), by a reduction reaction

cyclization, either under hydrogen in an acetic acid / tetrahydrofuran mixture in the presence of palladium, or under hydrogen in tetrahydrofuran in the presence of platinum and anhydrous ortho-phosphoric acid when R1 or R2 represents a halogen atom, or without additional hydrogen , in the presence of zinc and concentrated hydrochloric acid in N-methyl pyrrolidone, when R1 or R2 represents a group -OSO2CF3. Then, if it is desired to obtain a compound of formula (Ic) (in which R3 represents a hydrogen atom and m is equal to 2), the alcohol of formula (XI) obtained above is oxidized to aldehyde of formula

(XII), preferably with 1,1,1-triacetoxy-l, l-dihydro-l, 2-

Diagram 5

O O

R1 (CHS) 3P R1 0

CHO

NO NO2

R2 N 2 R2 N2

(IX) (X)

R1 R1

XX (CH2 mp (CH2 "PH

R2 H R2

H H

(XIII) (XI)

R1 R1

(CH2 mOH, (CHI2) CNlCH

N O R2 0

R2 H

R3 H

(I) (XIV) (XII)

(AT)

(VIII)

R1

3 0 (CH2) 'Y

Ri N

R 2 0 (VIII) C 2m.- \ -

3 N

R2 I

3

(XV c) (IC), R3 = H and m = 2 (Id), R3 = H and m # 2 (Ie), R3 # H and m = 2 (If), R3 # H and m # 2 benzodioxol- 3 (1H) -one (Dess-Martin reagent) in dichloromethane or by the tetrapropylammonium perruthenate / N-methyl morpholine N-oxide system, in the presence of 4 A molecular sieve, also in dichloromethane and the compound thus obtained is condensed. with a compound of formula (VIII), by a reductive amination reaction in

presence of titanium tetraisopropoxide and cyanoboro-

sodium hydride in ethanol.

To prepare the compounds of formula (Id) (in which R3 represents a hydrogen atom and m is equal to 3 or 4), the compound of formula (XI) or the corresponding compound of formula (XII) is carried out ( in which m is equal to 2), an approval of one or two methylenic units according to methods known to those skilled in the art then one continues

according to diagram 5.

When it is desired to prepare a compound of formula (Ie) o R3 is different from a hydrogen atom, then the alcohol of formula (XI) (in which m is equal to 2) is converted into a compound of formula ( XIII) (in which P represents a protective group such as for example a trialkylsilyl group), by reaction with a compound such as for example tert-butyldimethylsilyl chloride, then the compound (XIII) thus obtained is reacted with an electrophilic agent of R3Br or R3I type (in which R3 is as defined above) in the presence of a base such as sodium hydride, at a temperature between room temperature and the reflux of tetrahydrofuran. After deprotection, for example by means of tetrabutylammonium fluoride in tetrahydrofuran, an alcohol of formula (XIV) (in which m is equal to 2) is obtained which is converted into a derivative of formula (XV) (in which Y represents a group leaving for example a chlorine or bromine atom and m is equal to 2), for example by reaction with thionyl chloride in chloroform or dibromotriphenylphosphorane in dichloromethane or in compounds of formula (XV) (in which Y represents a leaving group such as the methanesulfonyloxy, trifluoromethanesulfonyloxy or paratoluenesulfonyloxy groups), 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 compound of formula (XV) is condensed with a compound of formula (VIII) in pure phase or in a solvent such as acetonitrile or dimethylformamide, at a temperature between 20 and C, in the presence of a base such than sodium bicarbonate. If one wants to prepare a compound of formula (If) (in which m is equal to 3 or 4), one carries out on the compound of formula (XI) or on the corresponding compound of formula (XIV) (in which m is equal to 2) approval of one or two methylenic units according to methods known to man

of the trade then we continue according to diagram 5.

It is also possible to obtain the compounds of formulas (Ie) and (If) (in which R3 is different from a hydrogen atom) respectively from the corresponding compounds of formulas (Ic) and (Id) (in which R3 represents a hydrogen atom), by alkylation with an electrophilic agent by means of a base such as sodium hydride or potassium hydroxide in a solvent such as tetrahydrofuran, in the presence or absence of a catalyst of

phase transfer such as tetrabutylammonium bromide.

The starting compounds are commercially available or described in the literature or can be prepared according to methods which are described therein or which are known from

the person skilled in the art.

Thus 4- (acetyloxy) -2H, 3H-pyrane-2,6-dione is prepared at

from 3-oxo-glutaric acid according to E.G. FRANDSEN and N. JACOBSEN, J. Chem. Soc. Perkin I, pp 933-6 (1978). The cyclization process is adapted from those described in the European patent applications EP0364327 and EP0577325.

The introduction of a nitrile on the compounds of formula (V) is carried out according to the methodology described by N. CHANTANI and

T. HANAFUSA, J. Org. Chem. 51, pp 4714-4716 (1986).

The aromatic nucleophilic substitution of iodinated aryls, by

thiolates is based on the method of T. MIGITAL et al.

Bull. Chem. Soc. Japan, 53, pp 1385 (1980).

5-Methoxy-2-nitrobenzaldehyde is prepared from -hydroxy-2nitrobenzaldehyde according to Galun et al. J. Het. Chem. 16, p 221 (1979). Α [γ-butyrolactonylidene] triphenylphosphorane is prepared according to H. Zimmer et al. J. Het. Chem. 2, p 95 (1965) and

Helv. Chim. Acta 46, p 1580 (1963), from a-bromobu-

tyrolactone. The method of synthesis of the compounds of formula (V) by a reduction-cyclization reaction is described in T. Jean and

coll., J. Med. Chem., 16, p 663 (1973).

The methods of hydrogenation in the presence of a halogen or of a triflate are published in German patent DE3006748 and in T. Rossi et al., J. Am. Chem. Soc., 115, p 5843

(1993), respectively.

The method of oxidation of alcohols by the Dess-Martin reagent is described in D. Dess and J. Martin J. Org. Chem. 48, p 4155 (1983) and R. Ireland and L. Liu, J. Org.

Chem. 58, p 2899 (1993).

The method of oxidation of alcohols by tetrapropylammonium perruthenate / N-methyl morpholine N-oxide is adapted from that described by W. Griffith et al. J. C. S. Chem. Comm., P 1625

(1987).

The method of bromination of silylated alcohols and ethers by dibromotriphenylphosphorane is inspired by those of J. Aizpurua J. Org. Chem., 51, p 4941 (1986) and by J. Sandri

et al. Synth. Common. 22, p 2945 (1992).

4-piperazin-1-ylfuro [3,2, c] pyridine was prepared at

from 3-furanacrylic acid and 1-methyl-4-

piperazin-1-ylpyrrolo [3,2, c] pyridine from N-methyl-

pyrrole-2-carboxaldehyde according to known methods such as for example that described by J.S. New et al., J. Med. Chem.,

32, pp 1147-1156 (1989) and by F. Eloy et al. J. Het.

Chem., 8, p 57 (1971).

7-methoxyisoquinolin-1 (2H) one is prepared according to the method described by J.F. Ajao, J. Het. Chem., 22, p 329-331,

(1985).

The examples which follow illustrate the invention. The micro

analyzes and 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. 25) 7-Fluoro-2-oxo-4- [2- [4- (1 (H) pyrrolo [3,2-c] hydrochloride

pyridin-4-yl) piperazin-1-yl] ethyl] -l, 2-dihydroquinoline-1-

acetamide (2: 1)

1.1. 4- (2-chloroethyl) -7-fluoro-2-oxo-1,2-dihydroquinoline-

1-acetamide

1.1.1. 3- (acetyloxy) -5 - [(3-fluorophenyl) amino] -5- acid

oxopent-2-enoïque In a 1 liter flask, 20 g (180 mmol) of 3-fluorobenzeneamine are dissolved in 85 ml of acetic acid, the solution is stirred at room temperature and 36 g (212 mmol) of 4 (acetyloxy) -2H, 3H-pyrane-2,6-dione. After 3 hours of stirring at room temperature, the reaction medium is poured into 1.5 liters of ice-cold water and the mixture is stirred for 15 minutes. The product is recovered in the form

of a white solid which is wrung out and rinsed successively

ment with water and ether and dried under vacuum.

37.38 g of product are obtained.

Yield = 74% Melting point = 133-134 C

1.1.2. 5 (7) -fluoro-2-oxo-1,2-dihydroquinoline-4- acid

acetic In a 250 ml round-bottomed flask containing 115 ml of concentrated sulfuric acid, 37 g are introduced in small quantities

(131 mmol) 3- (acetyloxy) -5 - [(3-fluorophenyl) amino] - acid

-oxopent-2-enoique and the mixture is heated for minutes at 45 ° C. then for 2 hours at 100 ° C. After cooling, the reaction medium is poured into 1 liter

of ice water and stirred for 15 minutes. The solid obtained is filtered off, washed with water and dried for 48 hours over phosphorus pentoxide at 50 ° C. under vacuum. 24.36 g of a mixture of 82% of 7-fluoro-2- acid are obtained.

oxo-1,2-dihydroquinoline-4-acetic and 18% of 5-fluoro-2-oxol, 2-dihydroquinoline-4-acetic acid which is used as is in the following step.

Yield = 84% Melting point = 250 C (melting with decomposition) 1.1.3 Methyl 7-fluoro-2-oxo-1,2-dihydroquinoline-4-acetate 24.81 g ( 122 mmol) of 5 (7) -fluoro-2oxo-1,2-dihydroquinoline-4-acetic acid and ml of methanol. The suspension thus obtained is cooled in an ice bath, placed under stirring and 24.5 ml (336 mmol) of thionyl chloride are added dropwise over 20 minutes. The reaction medium is left under stirring overnight at room temperature and then for 3 hours at 50 ° C. Evaporated in vacuo, the residue is taken up in 250 ml of dichloromethane, 110 ml of an ice-cold aqueous solution of hydrogen carbonate are added. 3% sodium and the mixture is allowed to stir. The organic phase is recovered, washed with water and dried over sodium sulfate.

sodium and concentrate. 27 g of a mixture of esters are obtained.

The isomers are separated by triturating the residue successively in 500, 400 and then 300 ml of absolute ethanol under reflux. After the last trituration, a white solid is obtained which is filtered off, rinsed with ethanol and dried under vacuum.

17.54 g of the 7-fluoro isomer are obtained.

Yield = 66% Melting point = 257-258 C 1.1.4 7-fluoro-4- (2hydroxyethyl) quinolin-2 (1H) -one In a 500 ml flask, with magnetic stirring, the mixture is

introduced 10.49 g (44.64 mmoles) of 7-fluoro-2-oxo-l, 2-

Methyl dihydroquinoline-4-acetate, 300 ml of anhydrous tetrahydrofuran then 6.75 g (178 mmoles) of 98% powdered sodium borohydride. The mixture is brought to reflux temperature and heated for 24 hours at this temperature. The reaction medium is cooled in an ice bath, 15 ml of methanol and then 5 g (132 mmol) of 98% powdered sodium borohydride are added dropwise. The mixture is again heated at reflux temperature for 24 hours. The reaction medium is evaporated off, the residue is taken up in a dichloromethane: acid mixture.

1N aqueous hydrochloric acid (1: 1) and the precipitate is collected.

It is filtered off, washed with dichloromethane and triturated in ether. Finally, it is filtered off and dried under vacuum.

6.85 g of product are obtained.

Yield = 74% Melting point = 224 C 1.1.5. 4- (2-chloroethyl) -7fluoroquinolin-2 (1H) -one Into a 250 ml flask, 160 ml of chloroform, 3 drops of dimethylformamide, 2 drops of pyridine, 4.3 g (20.77 mmoles) of 7-fluoro-4- (2-hydroxyethyl) quinolin-2 (1H) -one then 7 ml of thionyl chloride and the mixture is heated at reflux temperature for 4 hours. The reaction medium is left to cool to 5-10 C and poured into 150 ml of a saturated aqueous solution of sodium hydrogencarbonate previously cooled to -10 C. The mixture is stirred for 10-15 minutes then the precipitate is filtered off. , washed with water and dried in vacuo. The organic phase is filtered, dried over sodium sulfate and concentrated. The solids thus obtained are collected. 4.78 g of product are obtained. Quantitative yield Melting point = 185-186 C

1.1.6. 4- (2-chloroethyl) -7-fluoro-2-oxo-1,2-dihydroquinole-

ine-1-acetamide

A 1.0 g (4.44 mmol) of 4- (2-chloroethyl) -7-fluoroquinolin-

2 (1H) -one suspended in 20 ml of tetrahydrofuran cooled to 0 C, 0.39 g (7.1 mmol) of freshly ground potassium hydroxide, 0.43 g (1.33 mmol) of bromide are added of tetrabutylammonium then drop by drop a solution of 0.9 g (6.66 mmol) of 2-bromoacetamide in 13 ml of tetrahydrofuran. The mixture is stirred for 1 hour at 0 C and then overnight at room temperature. The reaction medium is concentrated to dryness and the residue is taken up in ml of dichloromethane. The insoluble matter is filtered off, the filtrate is washed with water, dried over sodium sulphate, filtered and evaporated. The residue is purified by chromatography on

silica gel column eluting with a dichloro-gradient

methane: methanol containing traces of ammonia (98: 2,

: 5 then 90:10).

1 g of product is obtained in the form of an off-white solid.

Yield = 83% Melting point = 200 C 1.2. 4-piperazin-1-yl-1Hpyrrolo [3,2-c] pyridine

1.2.1. 1 - [(3,4-dimethoxyphenyl) methyl] -1H-pyrrole-2-

carboxaldehyde To a suspension cooled to 0 C of 4 g (94.6 mmol) of 60% sodium hydride in 30 ml of anhydrous dimethylformamide, under nitrogen, a solution of 3 g (31.5 mmol) is added dropwise. ) of 1H-pyrrole-2-carboxaldehyde in ml of dimethylformamide then the mixture is stirred at 0 C for 30 minutes. Then 11.7 g (63 mmol) of 4- (chloromethyl) -1, 2-dimethoxybenzene are added dropwise and the mixture is stirred for 3 hours at room temperature. The reaction medium is hydrolyzed with 30 ml of water and then extracted with ether. The organic phase is collected, washed with 3 volumes of water, dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on a silica gel column, eluting with an n-heptane: ethyl acetate (8: 2, 7: 3 gradient).

then 6: 4).

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

Efficiency = 90%

1.2.2. 3- [1 - [(3,4-dimethoxyphenyl) methyl] -1H-pyrrole-2-

ethyl prop-2-enoate A 1.4 g (34 mmol) of 60% sodium hydride washed beforehand with diisopropyl ether and suspended in 25 ml of anhydrous tetrahydrofuran is added dropwise to at room temperature, 6 ml (30 mmol) of triethyl phosphonoacetate in 20 ml of tetrahydrofuran. The mixture is left under stirring at this temperature for 20 minutes and then a solution of 7 g is added dropwise.

(28.57 mmol) of 1 - [(3,4-dimethoxyphenyl) methyl] -1H-pyrrole-

2-carboxaldehyde in 60 ml of anhydrous tetrahydrofuran. The reaction medium is heated at 55 ° C. for 3 hours and then cooled to 5 ° C. It is hydrolyzed with 60 ml of water and extracted with ether. The organic phase is recovered, it is

dried over magnesium sulfate, filtered and evaporated.

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

Quantitative yield

1.2.3. 3- [1 - [(3,4-dimethoxyphenyl) methyl] -1H-pyrrol- acid

2-yl] prop-2-enoique A mixture of 16 g is heated for 8 hours at 60 C.

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

ethyl pyrrole-2-prop-2-enoate and 10 g (0.25 mol) of sodium hydroxide in 50 ml of dioxane and 25 ml of water.

The reaction medium is concentrated to 2/3, cooled in an ice bath and acidified to pH 2 with an aqueous solution of 6N hydrochloric acid. The precipitate is filtered off, rinsed successively with water and with ether and we dry it

under vacuum.

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

1.2.4. 1 - [(3,4-dimethoxyphenyl) methyl] -1,5-dihydro-4H-

pyrrolo [3,2-c] pyridin-4-one A a mixture of 13 g (45.3 mmol) of 3- [1 - [(3,4-

dimethoxyphenyl) methyl] -1H-pyrrol-2-yl] prop-2-enoic and 7.5 ml (54.3 mmol) of triethylamine in 60 ml of dioxane, under a nitrogen atmosphere and at 5 C, is added drip

in 10 minutes 10.7 ml (49.8 mmol) of diphenylphosphoryl-

azide and then the mixture was stirred for 2.5 hours at room temperature. The reaction medium is diluted with a volume of a saturated aqueous solution of sodium chloride and then extracted with ether. The organic phase is recovered, dried over magnesium sulfate, filtered and evaporated. The residue is taken up in 30 ml of dichloromethane and this 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 then heated to 210 ° C. for 15 minutes then the temperature of the reaction medium is allowed to return to room temperature. The gum obtained is triturated in 300 ml of n-pentane and it is purified by chromatography on a silica gel column, eluting with dichloromethane and then with a dichloromethane: methanol mixture.

(98: 2).

* 10.4 g of product are obtained in the form of an amorphous yellow solid. Yield = 85% Melting point = 120 C 1.2.5 4-chloro-l - [(3,4dimethoxyphenyl) methyl] -lH-pyrrolo [3,2-c] pyridine Heated at reflux temperature for 2 hours a mixture of 6.5 g (24 mmol) of 1 - [(3,4-dimethoxyphenyl) methyl] -l, 5-dihydro-4H-pyrrolo [3,2c] pyridin-4-one and of 32 ml (0, 36 mole) of phosphoryl chloride. The reaction medium is evaporated to dryness, the residue is taken up in 200 ml of dichloromethane and 50 ml of water are added. The aqueous phase is neutralized to pH 7 with a saturated aqueous solution of sodium bicarbonate and the organic phase is recovered. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate,

filter and evaporate.

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

Yield = 55% 1.2.6. 1 - [(3,4-dimethoxyphenyl) methyl] -4- [4 (phenylmethyl) piperazin-1-yl] -lH-pyrrolo [3,2-c] pyridine Heated at 130 C in an autoclave for 60 hours a

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 concentrated to dryness and the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol mixture (98: 2 then: 5). 3.8 g of product are obtained in the form of a dark beige oil. Yield = 68% 1.2.7. 4- [4 (phenylmethyl) piperazin-1-yl] -lH-pyrrolo [3,2-c] pyridine To 450 ml of liquid ammonia cooled to -70 C is added in small portions 4.0 g (178 mmol ) of sodium then after dissolution, a solution of blue color to

which is added 3.8 g (8.87 mmol) of 1 - [(3,4-dimethoxy-

phenyl) methyl] -4- [4- (phenylmethyl) piperazin-1-yl] -1H-pyrrolo [3,2c] pyridine dissolved in 35 ml of anhydrous tetrahydrofuran. The mixture is left for 30 minutes at this temperature and ammonium chloride is added until the reaction medium is discolored. Evaporated for one hour and the residue is taken up in 300 ml of ethyl acetate, washed with water, the organic phase is recovered, dried over sodium sulfate, filtered and evaporated to dryness. The residue thus obtained is purified by chromatography on a silica gel column, eluting with a mixture.

dichloromethane: methanol (95: 5 then 90:10).

1.4 g of product are obtained in the form of a thick beige oil. Yield = 56% 1.2.8. 4-piperazin-1-yl-1H-pyrrolo [3,2-c] pyridine The hydrogen 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 20% palladium hydroxide. The reaction medium is cooled to room temperature and filtered through Celite. The filtrate is concentrated to dryness and 15 ml of ethyl acetate are added to the residue. After

trituration is filtered off and dried under vacuum.

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

Yield = 83% Melting point = 145 C 1.3. 7-Fluoro2-oxo-4- [2- [4- (1H-pyrrolo hydrochloride

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

dihydroquinoline-1-acetamide (2: 1)

Has a mixture of 0.1 g (0.5 mmol) of 4-piperazin-1-yl-1H-

pyrrolo [3,2-c] pyridine, 0.06 g (0.72 mmol) of sodium bicarbonate and 0.05 g of potassium iodide dissolved in ml of acetonitrile and 2 ml of dimethylformamide, are added

0.3 g (1.08 mmol) of 4- (2-chloroethyl) -7-fluoro-2-oxo-1,2-

dihydroquinoline-1-acetamide. The mixture is heated for 48 hours at 70 ° C. and evaporated to dryness. The residue is triturated in 65 ml of dichloromethane and filtered off. The solid thus obtained is taken up in 300 ml of an ethyl acetate: methanol (95: 5) mixture and washed with a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on a silica gel column, eluting with a dichloromethane: methanol (95: 5) mixture.

containing traces of ammonia.

0.2 g of product is obtained in the form of a base.

0.2 g of base is taken up in 7 ml of methanol and 0.52 ml of a 2N hydrochloric ether solution is added. An off-white solid is obtained which is filtered off and rinsed with water.

ether and dried in vacuo at 40 C.

165 mg of hydrochloride is obtained in the form of a solid.

White.

Yield = 64% Melting point = 240 C Example 2 (compound n 3)

3- [2- (4-furo [3,2-c] pyridin-4-ylpiperazin-1- hydrochloride

yl) ethyl -6-methoxy-1 -methyl - 3,4-dihydroquinolin-2 (1H) -one (2: 1)

2.1. 3- (2-chloroethyl) -6-methoxy-1-methyl-3,4-dihydroqui-

nolin-2 (1H) -one

2.1.1. 3 - [(5-methoxy-2-nitrophenyl) methylene] dihydrofuran-

2 (3H) -one To 5.0 g (27 mmoles) of 5-methoxy-2-nitrobenzaldehyde in ml of toluene, 8.3 g (24 mmoles) of c- [ybutyrolactonylidene] triphenylphosphorane are added. The reaction mixture is refluxed for 6 hours and allowed to cool overnight. We wring out the precipitate

formed and dried in vacuo.

4.0 g of the expected product are obtained.

Yield = 62% Melting point = 98 C

2.1.2. 3- (2-hydroxyethyl) -6-methoxy-3,4-dihydroquinoline-

2 (1H) -one A mixture of 5 g (20 mmol) of 3 - [(5methoxy-2-nitrophenyl) methylene] dihydrofuran is subjected to 40 psi (0.3 MPa) at room temperature for 9 hours for 9 hours. -2 (3H) -one and 0.7 g of 5% palladium on charcoal in 100 ml of tetrahydrofuran and 0.60 ml of acetic acid. The catalyst is filtered off and the filtrate evaporated. We take the residue

in a minimum of dichloromethane o the product crystallizes.

3.4 g of the expected product are obtained.

Yield = 77% Melting point = 90 C

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

6-methoxy-3,4-dihydroquinolin-2 (1H) -one

A 2.4 g (10.84 mmol) of 3- (2-hydroxyethyl) -6-methoxy-3,4-

dihydroquinolin-2 (1H) -one and 1.36 g (20 mmol) of imidazole in 20 ml of dimethylformamide at room temperature, one

add 4.0 g (26.5 mmol) of tert-butyldimethyl chloride

silylated and the solution stirred at this temperature for 3 hours. The solvent is then evaporated off in vacuo and the residue is taken up in 300 ml of ether. This solution is washed twice with water and the organic phase is dried over

magnesium sulfate and then concentrated.

3.5 g of product are obtained in the form of a colorless oil. Quantitative yield

2.1.4. 3- (2-hydroxyethyl) -6-methoxy-1-methyl-3,4-dihydro-

quinolin-2 (1H) -one A 3.6 g (11.23 mmol) of 3- [2 - [[(1,1-dimethylethyl)

dimethylsilyl] oxy] ethyl] -6-methoxy-3,4-dihydroquinoline-

2 (1H) -one in 100 ml of tetrahydrofuran, 0.6 g (15 mmol) of sodium hydride at% is added at room temperature. The mixture is left in contact for 60 minutes, then 1.6 ml (25.6 mmol) of methyl iodide are added and the mixture is stirred for hours at room temperature. We evaporate to dryness, we

the residue is taken up in 100 ml of water and extracted with ether.

Then the organic phase is dried over magnesium sulfate and concentrated. The residue is taken up in 80 ml of tetrahydrofuran and 10 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran is added and the mixture is then stirred at room temperature for 2 hours. It is evaporated to dryness and the residue is taken up in 300 ml of ether. This solution is washed several times with water, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica gel column, eluting with a mixture.

dichloromethane: methanol (98: 2).

1.5 g of product are obtained in the form of an oil Yield = 57%

2.1.5. 3- (2-chloroethyl) -6-methoxy-1-methyl-3,4-dihydroqui-

nolin-2 (1H) -one

A 1.5 g (6.37 mmol) of 3- (2-hydroxyethyl) -6-methoxy-1-

methyl-3,4-dihydroquinolin-2 (1H) -one dissolved in 30 ml of chloroform at room temperature, 0.7 ml (9, 6 mmol) of thionyl chloride is added dropwise. After the addition, the solution is brought to reflux temperature for 1 hour, allowed to cool to room temperature and the mixture is allowed to stir for a period of time.

night at this temperature. The solvents are evaporated off and the expected product is obtained quantitatively in the form of an oil which is used as it is in the following step 5.

2.2. 3- [2- (4-furo [3,2-c] pyridin-4-yl hydrochloride

piperazin-1-yl) ethyl] -6-methoxy-1-methyl-3,4-

dihydroquinolin-2 (1H) -one (2: 1)

A mixture of 1 g (3.9 mmol) of 3- (2-chloroethyl) -6-methoxy-1- is heated at reflux temperature for 7 hours.

methyl-3,4-dihydroquinolin-2 (1H) -one, 0.8 g (3.9 mmol) of 4piperazin-1-ylfuro [3,2-c] pyridine and 0.65 g (7.8 mmoles) of sodium bicarbonate in 20 ml of acetonitrile. The reaction medium is filtered and the filtrate is evaporated. The residue is purified by chromatography on a silica gel column, eluting with a methanol: dichloromethane mixture (4:96) containing traces of ammonia. 1 g of base is obtained in the form of a white solid. The hydrochloride is prepared in a mixture of 3N hydrochloric ether and methanol. 0.87 g of hydrochloride is obtained. Yield = 45% Melting point = 229-231 C Example 3 (Compound # 26) 7-Fluoro-4- [2- [4- (1-methylpyrrolo [3,2-c] pyridin-4-yl hydrochloride ) piperazin-1-yl] ethyl] quinolin-2 (1H) -one (2: 1) A mixture of 0.3 g (1.39 mmol) of 1-methyl-4-piperazin- is heated to 60 ° C. 1-ylpyrrolo [3.2, c] pyridine, 0.47 g (2.08 mmol) of 4- (2-chloroethyl) -7-fluoroquinolin-2 (1H) - one and 0.117 g (1.39 mmol) ) sodium bicarbonate in

10 ml of dimethylformamide. After 72 hours, 0.25 g (1.10 mmoles) of 4- (2-chloroethyl) -7-fluoro- are added again.

quinolin-2 (1H) -one, the reaction medium is continued to be heated with stirring for 24 hours and then evaporated to dryness. The residue is taken up in 250 ml of dichloromethane, the solution is washed with water and the solvent is evaporated off. The organic phase is recovered, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting with an ethyl acetate: methanol mixture (97: 3 then 94: 6).

containing traces of ammonia.

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

Melting point = 261 C This solid is taken up in 10 ml of methanol and 0.55 ml of 2N hydrochloric ether is added.

ether and dried in vacuo at 40 ° C.

0.18 g of hydrochloride is obtained in the form of a solid.

egg shell.

Yield = 28% Melting point = 213 C (melting with decomposition) Example 4 (compound n 30)

7-Fluoro-4- [2- (4-thiazolo [4,5-c] pyridin-4- hydrochloride

ylpiperazin-1-yl) ethyl] -quinolin-2 (1H) -one (2: 1) 4.1. 4-piperazin-lylthiazolo [4,5-c] pyridine 4.1.1. 4-Chloro-3-nitropyridine A mixture of 20.48 g (0.146 mol) of 5nitropyridin-4 (3H) -one and 70 ml of phosphoryl chloride is heated at 85 ° C. for 2 hours then the reaction medium is evaporated off at dry. 200 g of crushed ice are added, the pH is adjusted to 7 with a concentrated aqueous ammonia solution and 200 ml of water are added. The mixture is extracted 3 times with 300 ml of dichloromethane, the organic phases are combined,

dried over sodium sulfate, filtered and concentrated.

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

Yield = 99% 4.1.2. 3-aminopyridine-4-thiol

Has a solution of 14.3 g (90.22 mmol) of 4-chloro-3-

nitropyridine in 160 ml of methanol with stirring at room temperature, a solution of 11 g (196 mmol) of potassium hydroxide in 65 ml of methanol previously saturated with gaseous hydrogen sulphide is added. The mixture is brought to reflux temperature for 5 minutes and then evaporated to dryness. The residue is triturated in ether and filtered off. 25.5 g of potassium salt are obtained in the form of an orange solid. A solution of 70 g (310 mmol) of tin chloride dihydrate in 125 ml of a concentrated hydrochloric acid solution is heated to 70 ° C. then 12.78 g (45.1 mmol) of the salt are added in small portions. of potassium previously obtained in suspension in 50 ml of a concentrated solution of hydrochloric acid. The mixture is heated for 3 hours at reflux temperature, the reaction medium is cooled to 5 ° C. and the pH is adjusted to 6-7 with a concentrated sodium hydroxide solution. We wring out the salts

and extracted with 3 times 250 ml of boiling absolute ethanol.

The extracts are combined, filtered and concentrated.

4.53 g of product are obtained in the form of a beige solid.

Yield = 77% Melting point = 175-177 OC 4.1.3. thiazolo [4,5c] pyridine 3.20 g (25.4 mmol) of 3-aminopyridine-4-thiol dissolved in 100 ml of triethylformate containing 4 drops of a concentrated sulfuric acid solution. The reaction medium is allowed to cool to room temperature and the insoluble material is filtered off. The filtrate is evaporated and the residue is purified by chromatography on a column of silica gel, eluting

with ethyl acetate containing traces of ammonia.

1.77 g of product are obtained in the form of a pink solid.

blade. Yield = 51% Melting point = 111 C 4.1.4. thiazolo [4,5c] pyridine 5-oxide To a solution of 2.60 g (19.12 mmol) of thiazolo [4,5-c] pyridine in 280 ml of chloroform is added 4.5 g (21.03 mmol ) 3-chloroperbenzoic acid and the mixture is brought to reflux temperature for 2 hours. The reaction medium is evaporated and the residue is triturated twice with 150 ml of ether. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane: methanol (9: 1) mixture containing traces of ammonia. 2.8 g of product are obtained as a pale yellow solid. Yield = 96% Melting point = 168-170 C 4.1.5. 4- chlorothiazolo [4,5-c] pyridine A mixture of 2.80 g (18.42 mmol) of thiazolo [4,5-c] pyridine 5-oxide and 40 ml of chloride is heated to reflux temperature. of phosphoryl for 1.5 hours then the reaction medium is evaporated to dryness. The residue is taken up in 300 ml of chloroform and the solution is washed with 200 ml of a concentrated aqueous solution of sodium bicarbonate. The organic phase is recovered, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on a silica gel column, eluting with an n-heptane: ethyl acetate (6: 4) mixture containing traces.

ammonia.

2.04 g of product are obtained in the form of a pale yellow solid. Yield = 65% Melting point = 191-192 C 4.1.6. 4-piperazin-lylthiazolo [4,5-c] pyridine A mixture of 1 g (5.87 mmol) of 4-chlorothiazolo [4,5-c] pyridine and 3 is heated in an autoclave at 120 ° C. for 72 hours. , 54 g (41.1 mmol) of piperazine in 30 ml of absolute ethanol. The reaction medium is evaporated to dryness and the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol mixture.

(90:10 then 85:15) containing traces of ammonia.

0.86 g of product is obtained in the form of a brown oil.

Yield = 67% 4.2. 7-Fluoro-4- [2- (4-thiazolo [4,5-c] pyridin-4-ylpiperazin-1-yl) ethyl] -quinolin-2 (1H) -one (2: 1) hydrochloride at 57 C for 48 hours a mixture of 0.76 g (3.45 mmol) of 4piperazin-1-ylthiazolo [4,5-c] pyridine,

1.46 g (6.56 mmol) of 4- (2-chloroethyl) -7-fluoro-1-

methylquinolin-2 (1H) -one, 0.49 g (5.83 mmol) of sodium bicarbonate and 0.1 g of potassium iodide in ml of acetonitrile and 3 ml of dimethylformamide. The temperature of the reaction medium is allowed to return to room temperature and the mixture is diluted with 400 ml of ether. The solid is filtered off and taken up in 200 ml of chloroform. Washed with a concentrated aqueous solution of sodium bicarbonate then with water. The organic phase is recovered, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on a silica gel column, eluting first with an ethyl acetate: methanol (95: 5) mixture then with a dichloromethane: methanol (95: 5) mixture.

then 90:10) containing traces of ammonia.

0.67 g of base is obtained in the form of a pale yellow solid.

Yield = 48% Melting point = 261-262 C The hydrochloride is prepared in 2N hydrochloric ether

according to the method described in example 3.2.

Melting point = 254-255 C Example 5 (compound 34) 7fluoro-N-methyl-2-oxo-4- [2- (4-thiazolo hydrochloride)

[4,5-c] pyridin-4-ylpiperazin-1-yl) ethyl] -l, 2-dihydroquinolinei-

ne-l-acetamide (2: 1)

5.1. 7-Fluoro-2-oxo-4- [2- (4-

thiazolo [4,5-c] pyridin-4-ylpiperazin-1-yl) ethyl] -1,2-

dihydroquinoline-1-acetic (2: 1) 4.1 ml of a 0.5 M solution of tert-butyl bromoacetate in tetrahydrofuran are added dropwise to a mixture of 0.66 g (1, 63 mmol) of 7-fluoro-4- [2 (4-thiazolo [4,5-c] pyridin-4-ylpiperazin-1-yl) ethyl] quinolin-2 (1H) -one, 0.119 g (2.11 mmoles) of fresh potassium hydroxide

ground and 0.105 g (0.325 mmol) of tetrabutylammo- bromide

nium in 25 ml of tetrahydrofuran at 0-5 ° C. After minutes at 0-5 ° C., the temperature is allowed to return to room temperature and stirring is continued for 15 hours. The solvent is evaporated off in vacuo and the residue is taken up in ml of dichloromethane, washed with water, the organic phase is dried over sodium sulfate and concentrated. The crude product is purified by chromatography on silica gel, eluting with a methanol / dichloromethane mixture (5:95).

containing traces of ammonia and 0.81 g of N-

tert-Butyl acetate as a thick colorless oil.

Yield = 96% To 0.8 g (1.54 mmol) of this oil, 50 ml of a 3N solution of hydrochloric acid in ethyl acetate are added and the mixture is stirred at room temperature for 20 hours. It is evaporated to dryness, the white solid obtained is triturated with ether and it is

vacuum dries.

0.661 g of hydrochloride is obtained which is used as it is

in the next step.

Efficiency = 80%

5.2. 7-Fluoro-N-methyl-2-oxo-4- [2- (4-

thiazolo [4,5-c] lpyridin-4-ylpiperazin-1-yl) ethyl] -1,2-

dihydroquinoline-1-acetamide (2: 1)

A 0.325 g (0.6 mmol) of 7-fluoro-2- acid hydrochloride

oxo-4- [2- (4-thiazolo [4,5-c] pyridin-4-ylpiperazin-1-yl) ethyl] -1,2dihydroquinoline-1-acetic in 22 ml of dichloromethane, added 0.3 ml of triethylamine and 0.275 g

(0.72 mmol) O- (1H-benzotriazol-1- hexafluorophosphate)

yl) - N, N, N ', N'-tetramethyluronium and the mixture is stirred for 30 minutes at room temperature. Then gaseous methylamine is bubbled through the mixture for one hour and then stirring is continued for 2 hours at this temperature. The reaction medium is then diluted in 400 ml of chloroform and then washed successively with a saturated aqueous solution of ammonium chloride, a 3% aqueous solution of sodium bicarbonate and then a saturated aqueous solution of sodium chloride. The organic phase is recovered, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane: methanol mixture (97: 3, 95: 5 then 93: 7) containing traces of ammonia. 5 0.21 g of base is obtained in the form of an amorphous solid of

off-white color.

Yield = 72% The base is taken up in 10 ml of methanol and 0.54 ml of 2N hydrochloric ether is added. The solid is filtered off, rinsed with ether and dried under vacuum at 40 ° C. obtains 0.23 g of hydrochloride in the form of a white solid. Melting point = 181 C (melting with decomposition) Example 6 (compound no 16) 7-fluoro-4- [2- [4- (7-methoxyisoquinolin-1-yl) piperazin-lyl] ethyl] quinolin-2 hydrochloride (1H) -one (2: 1) 6.1. 7-methoxy-1-piperazin-lylisoquinoline 6.1.1. 1-Chloro-7-methoxyisoquinoline 38 g (0.217 mol) of 7methoxyisoquinolin-1 (2H) -one in 20 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 adding solid sodium bicarbonate. The mixture is extracted with dichloromethane and the organic phase is recovered. It is dried over sodium sulfate, filtered and concentrated. The residue is taken up in a mixture of 500 ml of ether and 100 ml of n-pentane in the presence of

activated charcoal. It is filtered and the filtrate is evaporated.

34 g of product are obtained.

Yield = 81% Melting point = 74-75 C

6.1.2. 4- (7-methoxyisoquinolin-1-yl) piperazin-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, are added dropwise. 3 ml (43.25 mmol) of a solution of 2.5 M n-butyllithium in hexane. The mixture is left under stirring for 15 minutes at this temperature and then 4 g (20.67 mmol) of 1-chloro-7methoxyisoquinoline dissolved in 75 ml of tetrahydrofuran are added dropwise. Stirring is continued for 0.5 hour then the reaction medium is hydrolyzed by adding 400 ml of an ice-cold aqueous solution saturated with ammonium chloride. Extracted with ether, the organic phase is recovered, washed with water, dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on a silica gel column, eluting with an ethyl acetate: n-heptane mixture.

(1: 3 then 2: 3).

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

broken.

Yield = 87% Melting point = 136-138 C 6.1.3. 7-methoxy-lpiperazin-1l-ylisoquinoline Stirred for 16 hours at room temperature a

6.1 g (17.78 mmol) suspension of 4- (7-methoxyisoqui-

1,1-dimethylethyl nolin-1-yl) piperazin-1-carboxylate in 50 ml of ethyl acetate and 75 ml of 3 N hydrochloric ethyl acetate. The white solid obtained is filtered off, rinsed with water. ethyl acetate then with ether and dried under vacuum at C. 5.56 g of hydrochloride are obtained in the form of a

pale yellow solid.

Melting point = 211-213 C

The solid is dissolved in 70 ml of water, the pH is adjusted to 10-

11 with sodium hydrogencarbonate solution and

extracted with chloroform.

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

Yield = 99% Melting point = 86-87 C

6.2. 7-Fluoro-4- [2- [4- (7-methoxyisoquino- hydrochloride

lein-1-yl) piperazin-1-yllethyl] quinolin-2 (1H) -one (2: 1) A mixture of 0.5 g (2.04 mmol) of 7-methoxy is heated at 55 C for 96 hours -lpiperazin-l-ylisoquinoline,

0.92 g (4.13 mmol) of 4- (2-chloroethyl) -7-fluoroquinolin-

2 (1H) -one, 0.34 g (4.08 mmol) of sodium bicarbonate and 0.1 g of potassium iodide in 20 ml of an acetonitrile: dimethylformamide (8: 1) mixture. The temperature of the reaction medium is allowed to return to room temperature and the mixture is diluted with 50 ml of ether. The precipitate is filtered off and taken up in 150 ml of chloroform. Washed with a saturated aqueous solution of sodium bicarbonate then with water. We recover the organic phase, we

dried over sodium sulfate, filtered and evaporated.

The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane: methanol mixture.

(98: 2, 95: 5 then 90:10) containing traces of ammonia.

0.454 g of base is obtained in the form of a white solid.

Yield = 52% Melting point = 257-258 C The hydrochloride is prepared in 2N hydrochloric ether

according to the method described in example 3.2.

Melting point = 227 C (melting with decomposition) Example 7 (compound n 11)

7-Fluoro-4- [2- [4- (7-hydroxyisoquinolin-1- hydrochloride

yl) piperazin-1-yllethyl] quinolin-2 (1H) -one (2: 1) Heated at reflux temperature for 10 hours

0.25 g (0.58 mmol) of 7-fluoro-4- [2- [4- (7-methoxyisoquino-

lein-1-yl) piperazin-1-yl] ethyl] quinolin-2 (1H) -one in 20 ml of a 48% aqueous solution of hydrobromic acid. The reaction medium is cooled to 5 ° C., the precipitate obtained is filtered off, rinsed with water and dried under vacuum.

at 40 C.

0.33 g of hydrobromide (2: 1) is obtained which is taken up in

ml of absolute ethanol saturated with gaseous hydrochloric acid.

The resulting suspension is stirred for 6 hours at 30 ° C. and cooled to room temperature. The precipitate is recovered, filtered off, rinsed with ethanol and

dries it under vacuum at 40 C.

0.27 g of hydrochloride is obtained.

Yield = 98% Melting point = 225-227 C Example 8 (compound na 44) 7-fluoro-4- [2- (4- [1,2,5] thiadiazolo [3,4-c] pyridin-4- ylpiperazin-lyl) ethyl] quinolin-2 (1H) -one 8.1. 4-piperazin-1-yl- [1,2,5] thiadiazolo [3, 4-c] lpyridine 8.1.1. 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 to 80 ° C. of 229.5 g (1.02 mol) of tin chloride dihydrate in 375 ml of concentrated hydrochloric acid. The mixture is then heated at 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 mixture of benzene: chlo-

roform (1: 1). At the same time, the filtrate is extracted with 3 times 400 ml of ethyl acetate. The organic phases are combined, dried over sodium sulfate and

concentrated.

11.58 g of product are obtained in the form of a solid of

peach colored.

Yield = 60% Melting point = 162 C 8.1.2. 4-chloro- [1,2,5] thiadiazolo [3,4-c] pyridine A 0.2 g (1.4 mmol) of 2-chloro-3,4diaminopyridine suspended in a mixture of 0.56 ml ( 6.94 mmol) of pyridine and 6 ml of dichloromethane at room temperature, 0.20 ml (2.8 mmol) of thionyl chloride are added dropwise and the mixture is left with stirring for one hour. 0.1 ml (1.4 mmol) of thionyl chloride is then added and stirring is continued for 2 hours. The reaction medium is evaporated to dryness, the residue is taken up

the residue with 6 ml of water and extracted with dichlorome-

thane.

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

Yield = 84% Melting point = 115-117 C 8.1.3. 4- (piperazin-lyl) - [1,2,5] thiadiazolo [3,4-c] pyridine Heated at reflux temperature for 2 hours a

mixture of 0.18 g (1.05 mmol) of 4-chloro- [1,2,5] thia-

diazolo [3,4-c] pyridine and 0.46 g (5.34 mmol) of piperazine in 6 ml of isoamyl alcohol. The reaction medium is evaporated off, the residue is taken up in 75 ml of

dichloromethane and this solution is washed with 10 ml of water.

The organic phase is recovered, dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane: methanol (9: 1) mixture containing traces of ammonia. 0.17 g of product is obtained in the form of a yellow solid.

blade.

Efficiency = 72%

8.2. 7-fluoro-4- [2- (4- [1,2,5] thiadiazolo [3,4-c] pyridin-4-

ylpiperazin-1-yl) ethyl] quinolin-2 (1H) -one A mixture of 0.245 g is heated at 50 C for 48 hours

(1.09 mmol) of 4- (2-chloroethyl) -7-fluoroquinoline-2 (1H) -

one, 0.16 g (0.723 mmol) of 4- (piperazin-1-yl) -1, 2.5-

thiadiazolo [3,4-c] pyridine, 0.122 g (1.45 mmol) of sodium bicarbonate and 0.04 g of potassium iodide in 8 ml of an acetonitrile: dimethylformamide (3: 1) mixture. We

again add 0.326 g (1.45 mmol) of 4- (2-chloroethyl) -

7-fluoroquinoline-2 (1H) -one and 0.121 g (1.44 mmol) of potassium bicarbonate and heating continued for 72 hours. Evaporated to dryness, the residue is taken up in 5 ml of water and the precipitate is filtered off. It is rinsed with ether and dried in vacuo. The residue is purified by chromatography on a column of silica gel, eluting first with

ethyl acetate then with a dichloromethane mixture: m-

thanol (9: 1) containing traces of ammonia.

0.2 g of base is obtained in the form of a yellow solid.

Yield = 67% Melting point = 200-202 C Example 9 (compound 45) 7-fluoro-2-oxo-4- [2- (4- [1,2,5] -thiadiazolo hydrochloride

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

ne-1-acetamide (2: 1) To a suspension cooled to 0 C of 0.12 g (0.292 mmol) of 7-fluoro-4- [2- [4- (1,2,5-thiadiazolo [3, 4-c] pyridin-4-yl) piperazin-1-yl] ethyl] quinolin-2 (1H) -one, 0.068 g (1.21 mmol) of freshly ground potassium hydroxide, 0.037 g (0.115 mmol) of tetrabutylammonium bromide in 10 ml of tetrahydrofuran, 2.6 ml of a solution of 1.5 M 2-bromoacetamide in tetrahydrofuran are added dropwise. The mixture is stirred for 48 hours at room temperature. The reaction medium is concentrated to dryness, the residue is taken up in 100 ml of dichloromethane and this solution is washed with water. The organic phase is recovered, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on a gel column of

silica eluting first with a mixture of ethyl acetate: m-

thanol (9: 1) containing traces of ammonia and then with a dichloromethane: methanol (9: 1) mixture containing traces of ammonia.

0.07 g of product is obtained in the form of a solid.

Yield = 52% The hydrochloride is prepared in 2N hydrochloric ether

according to the method described in example 3.2.

Melting point = 194-196 C Example 10 (Compound No.50) 7-fluoro-4- [2- (4-pyrido [3,4-b] pyrazin-5-yl piperazin-1yl) ethyl] quinolin- hydrochloride 2 (1H) -one (2: 1) 10.1. 5-piperazin-1-ylpyrido [3,4-b] pyrazine 10.1.1. 5-chloro-pyrido [3,4-b] pyrazine A mixture of 2 g (13.93 mmol) of 2-chloro-3,4-diaminopyridine and 11.2 ml ( 97.5 mmol) of a 40% aqueous solution of glyoxal with 65 ml of propan-2-ol. The temperature of the reaction medium is allowed to return to ambient temperature, 600 ml of water are added and the mixture is extracted 3 times with ether. The organic phases are combined, dried over sulphate of

magnesium, filtered and concentrated.

2.17 g of product are obtained in the form of a yellow solid.

Yield = 94% Melting point = 139 C 10.1.2. 5-piperazin-lylpyrido [3,4-b] pyrazine A mixture of 2.13 g (12.86 mmol) of 5-chloro-pyrido [3,4-b] pyrazine and 7 is heated for 15 hours at 75 ° C. , 75 g

(89.97 mmol) of piperazine in 40 ml of isoamyl alcohol.

The reaction medium is cooled to 5 ° C. and filtered. 20 ml of water are added to the filtrate and it is extracted twice with ml of dichloromethane. The organic phases are collected, dried over sodium sulfate, filtered and concentrated. Filtered on silica, eluting successively with dichloromethane containing traces of ammonia, a dichloromethane: methanol (9: 1) mixture containing traces of ammonia then a dichloromethane: methanol (8.5: 1) mixture containing traces of 'ammonia. We triturate the product

obtained in ether and dried in vacuo.

2.31 g of product are obtained in the form of a yellow solid.

Yield = 84% Melting point = 194 C 10.2. 7fluoro-4- [2- (4-pyrido [3,4-b] pyrazin-5-ylpiperazin-1-yl) ethyl] quinolin2 (1H) -one hydrochloride (2: 1) Heated to 55 C for 52 hours a mixture of 0.3 g (1.4 mmol) of 5-piperazin-1-ylpyrido [3,4-b] pyrazine, 0.5 g

(2.23 mmol) of 4- (2-chloroethyl) -7-fluoroquinoline-2 (1H) -

one and 0.2 g (2.38 mmol) of sodium bicarbonate in ml of a mixture of acetonitrile: dimethylformamide (4: 1). The acetonitrile is evaporated off and 20 ml of water are added. The solid is filtered off with suction, rinsed with ether, taken up in 12 ml of a dichloromethane: methanol (7: 3) mixture and filtered. The filtrate is concentrated and the residue is purified by chromatography on a silica gel column, eluting successively with an ethyl acetate: methanol (95: 5) mixture containing traces of ammonia and then with an ethyl acetate: methanol mixture. (9: 1) containing traces of ammonia.

0.18 g of base is obtained in the form of a pale yellow solid.

Yield = 32% The base is taken up in 5 ml of methanol and 0.37 ml of 3N hydrochloric ethyl acetate. The precipitate is filtered off and filtered.

rinsed with ether and dried in vacuo at 40 C.

0.16 g of hydrochloride is obtained.

Melting point = 198-200 C Example 11 (compound 6) 7fluoro-4- [2- [4- (6-fluoroisoquinolin-1-yl) piperazin-lyl] ethyl] quinolin-2 (1H) -one hydrochloride (2: 1) 11.1. 6-fluoro-1-piperazin-lylisoquinoline 11.1.1. 6-fluoro-3,4-dihydroisoquinolin-1 (2H) -one To a solution cooled to 5 C of 5 g (33.3 mmoles) of -fluoroindan-1-one in 20 ml of chloroform, with vigorous stirring, it is adds 40 ml of concentrated sulfuric acid then 2.7 g (41.6 mmol) of sodium azide in small fractions over 90 minutes. The temperature of the reaction medium is allowed to return slowly to room temperature and then the mixture is stirred overnight at this temperature. The reaction medium is poured onto 150 g of crushed ice and the pH is adjusted to 7-8 with potassium carbonate. It is extracted with dichloromethane and the organic phase is dried over sodium sulfate, filtered and concentrated. The residue is purified by chromatography on a silica gel column, eluting progressively with an n-heptane: ethyl acetate mixture.

(3: 7, 2: 8 then 1: 9).

2.5 g of product are obtained.

Yield = 45% Melting point = 112 C 11.1.2. 6-fluoroisoquinolin-1 (2H) -one

A 3 g (18.16 mmol) of 6-fluoro-3,4-dihydroisoquinolin-

1 (2H) -one in 130 ml of dioxane, 10.72 g (47.22 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone are added and the mixture is heated to temperature reflux for hours. The reaction medium is evaporated to dryness and the residue is taken up in 300 ml of chloroform. This solution is washed twice with a saturated aqueous solution of sodium bicarbonate and then with water. We dry the phase

organic over sodium sulfate, filtered and concentrated.

The residue is purified by chromatography on a silica gel column, eluting with a dichloromethane: methanol mixture.

(95: 5).

1.49 g of product are obtained.

Yield = 50% Melting point = 222 C 11.1.3. 1-Chloro-6fluoroisoquinoline A mixture of 0.37 g (2.27 mmol) of 6-fluoroisoquinolin-1- (2H) -one and 6 ml of oxyphosphoryl chloride is heated at 90 ° C. for 1.5 hours. The reaction medium is evaporated to dryness and the residue is taken up in 100 ml of chloroform. This solution is washed with a saturated aqueous sodium bicarbonate solution and the organic phase is recovered. We

dried over sodium sulfate, filtered and concentrated.

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

Quantitative yield.

Melting point = 93 C 11.1.4. 6-fluoro-1l-piperazin-1l- ylisoquinoline

To a solution of 1.05 g (5.67 mmol) of 4- (1,1-dimethyl-

ethyl) piperazine-carboxylate in 30 ml of anhydrous tetrahydrofuran at C, under nitrogen, 2.27 ml (5.67 mmol) of a solution of 2.5 M n-butyllithium in hexane are added dropwise. The mixture is left under stirring for 15 minutes at this temperature and then 0.41 g (2.26 mmol) of 1-chloro-6-fluoroisoquinoline dissolved in 15 ml of tetrahydrofuran is added dropwise. Stirring is continued for 15 minutes at -70 ° C. then the reaction medium is hydrolyzed by adding 20 ml of a saturated aqueous solution of ammonium chloride. Extracted with ethyl acetate, the organic phase is recovered, dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on a column of silica gel in

eluting with a mixture of ethyl acetate: n-heptane (3: 7).

0.35 g of product is obtained in the form of an amorphous white solid. Yield = 75% The product obtained is taken up in 6 ml of a 4N hydrochloric dioxane solution and the mixture is stirred at room temperature for 7 hours. 100 ml of chloroform are added and washed with saturated aqueous sodium bicarbonate solution. The organic phase is recovered, dried over magnesium sulfate, filtered and evaporated to dryness.

0.24 g of product is obtained in the form of a beige oil.

Efficiency = 98%

11.2. 7-fluoro-4- [2- [4- (6-fluoroisoqui- hydrochloride

nolin-1-yl) piperazin-1-yl] ethyl] quinolin-2 (1H) -one (2: 1) A mixture of 0.245 g (1.06 mmol) of 1 is heated at 55-60 C for 72 hours. (piperazin-1-yl) -6-fluoroisoquinoline,

* 0.574 g (2.54 mmol) of 4- (2-chloroethyl) -7-fluoroquino-

leine-2 (1H) -one and 0.267 g (3.18 mmol) of sodium bicarbonate in 12 ml of an acetonitrile: dimethylformamide (2: 1) mixture then the temperature of the reaction medium is allowed to return to room temperature. 100 ml of chloroform are added, the solution is washed with water and the organic phase is recovered. It is dried over sodium sulfate, filtered and evaporated to dryness. The residue is purified by chromatography on a silica gel column, eluting successively with ethyl acetate then with a dichloromethane: methanol (95: 5 then 90:10) mixture containing

traces of ammonia.

0.10 g of base is obtained.

Yield = 23% Melting point = 190-195 C (melting with decomposition) The hydrochloride is prepared in a mixture of methanol: hydrochloric ether. Melting point = 240-243 C Legend of the table

- in the column ---

represents a double laison; represents a

single bond.

- in the "pos" column: the number corresponds to the position of the chain on quinoline or on dihydroquinoline. - in the “Salt” column: HCl represents a hydrochloride and (x: y) the ratio (acid: base); the absence of any mention

means that the compound is in the form of the base.

- in the "Melting point" column: (d) corresponds to a melting with decomposition

Board

Ri (CH2) mN z I 2) m / _ (I)

R2 N

R3 N N '') 'NO point R1 R2 R3 pos m Z Melting salt (O

A (C)

NOT

"" 'HC1

1 | 6-CH3-H -H 3 2 -N- 180

(2: 1) O "0

NOT -

HC1

2 6 -OCH3-H -H 3 2 -N- - 246 O

(2: 1) -4

N0.0I N _ _ Point of N R1 R2 R3 - - -pos m Z Melting salt (C) N HCl

3 6-OCH3 -H -CH3 3 2 -N-: 1) 229-23

(2: 1)

N __ _ NHCl

4 7-F -H -H 4 2 -N- - 182- 184

(2: 1) N HC1

7-F -H -H 4 2 -N- 260-264

F (2: 1)

N 6 7-F -H -H 4 2 -N- 240- 243 b

(2: 1) -4

F O

-J HO

8I, -90 H- -N- R- H- 6 8

HDI N at

(T: 7)

Sú? -0LZ -N- tgà-

-N- ___ IDH- H- J-L. AT

IDH N N (Do) uoI sn; IaS Z m sod ___% {% {T {oN ap u! Od \ I N N) '> Point of NO Ri R2 R3 pos m Z Melting salt (Oc) N HC1

7-F -H -H 4 2 -N- 244-246

(2: 1) OH N HCl il 7-F -H -H 4 2 -N- 225-227 (2: 1) OH N HC1

12 7-F -H -CH3 4 2 -N- 212-214

\ / (2: 1) I%

OH -4 N A / "'n Point of N R1 R2 R3 pos m Z Fusion salt

AC (C)

N HCl

13 7-F -H -H 4 2 -N- 218-220

(2: 1) OCH3 N HC1

14 7-F -H -CH2CONH2 4 2 -N- (2: 1) 208-210

/ - F-H -4 (2: 1)

OCH3 N HC1

7-F -H -CH2CONH2 4 2 -N- 226-228

OCH3 (2: 1)

k __OCH3

(P) 9LI -N- ||| H- H- H- 61

HDI N HDzOS NH

| ZE- | _ | <| -N- | __ H- H- | -.L 81

N N O 9g \ - -N- tH H - H- L Li N úHDO (P) L7 -N- t H- H - - L 91 IDH N (DO) | UoESfnj 1 | tS sod - _ | {- oN ap DUTOd N N "" 'Point of N R1 R2 R3 pos m Z Melting salt

A (C)

N HCl 6-Cl -H -CH3 4 2 -N-- 290 (d) (2: 1) No

___ HC1

21 7-F -H -CH2CONH2 4 2 -N- 262

NNO (2: 1>) o

22 6-CH3 -H -H 4 2 -N- - - 220

No 23 6-CH3 -H -H 4 2 -N- 219 (d) o HD- N

| HDI | S | - - | SL | 9

r- (I: lP) CIg-- | P __ H- H- | -L 9 IDH N [HD-. N (P) 0 - N- g _HO HH-.qL 9z IDH N HNI 0LI t, 7-N- 17 _ HNOD "HD- H- - LE IDH N HNM (Do) uo! Sn; las w usod E - - oN ap JUTOd / N r-4 $ / N

(P) 861I1 -N- E - HNOD'HD-H-to -ú Iú

HDI \ N

r- -

SP) -861 -N- H - H- H E- Loc IDH N HD ../ SN

9S -N- 17S 17 __H- H- toI-L6E

TDH N HN / N SS -ESE -N- z 9 H- I-L IDH N uo! sn4IqS Z ,, - sod N-- - [oN ap JuIod \ N- /

) '| (P) 581 -N- | | (úHD) NOD HD- H | - L S

r- IDH N s N

(P) 181 -N- _ úHD (H) NODZHD- H- -L toú

HDI N o '/ S N 8 | t (1:) | SN * | 00-S61 | - N- | HOz (_ D) - H- - L ú E iDH N S / N

E81 -8LI -N- | EHDODO (HD) - H- to-L | E

IDH N (DO) uo! snl TlS Z w sod - oN ep JU! Od N \ _--) r-I.I

HN N

961-X61 -N- i HNOD HD- H- to- tl 6E IDH N

FHN N

A1E-0 + E -N- E = _ H- H- 4- 8 [

IDH N Ln \ O OSI 1 -N- z t __ HNOD7HD- H- q- L IDH N

961-0S61 -N- FI 1 H- H- to -L 9

HDI uoTsn; las z w sod - 'z1 oN Gp qUTOd \ / N due N XI1 7HN | ODD- <aH = | - H | d- E -4 DN N. SN (P) (1: EN- Za _ NOHD-H- à-LLt IDH N NN goúlz-eú -N- t - HH -.- L TIDH N -4 IDH \ / N HN NN -Nt gH- H- Ot '0

0OT -9LT TDH

\ N uo! sn; las z w sod oN ap 3u! od

NOT\_ _ _ _

9SE-SSE -NE 9 zHNODZHD- H-.4 - L9t N 99E, - -N- E t9 H - H - à.4- 997 -4 r- o N 'N 961-9S6I -N- - 9 tHNODZHD- H- to -L 9 NN 'N NN \ I /

9OE-OO6T -N- - HNO - H -.- L 9

(Do) TD uoT n Z msd-O- -N__ H- H- T H p4uTod \ /

\ _ - - _ _ _

N "No point R R2 R3 - - -pos m Z Melting salt (C) N _N 0HCl

48 7-F -H -CH3 4 2 -N- _ N268

(<2: 1)

NOT

4 9 7-F -H -H - 4 2 -N- -224

Ul N w HCl

7-F -H -H 4 2 -N- 198-200

(2: 1)

N N

NOT

51 7-F -H -H 4 2 -N- - 266

N C o% o -4 Sú?: -, ú9 N 'N HD - H - a-L 71S

-4E-> EZ: IDH

o; o | uoTsn; | IlSa Z (od -) o- - N ap UTOd \ N The compounds of the invention have been the subject of pharmacological studies which have demonstrated their serotonin antagonist properties and their interest as

substances with therapeutic activity.

Thus, the compounds of the invention were subjected to a test for inhibiting the vasopressor effect of serotonin. Male rats (Sprague-Dawley, Charles River France) weighing 250-300 g are used, which are anesthetized with pentobarbital

sodium (60 mg / kg / i.p.) and kept under breathing

artificial tion (Harvard Respirator TM -breathing frequency of 70 ml per minute, volume of air 1 ml per 100 g of body weight). The animals are amyelated with the help of a metal rod, introduced through the orbit of the right eye down the length of the spine. The right and left vagus nerves are cut (bivagotomy), the right carotid artery is ligated, the left carotid artery being catheterized in order to measure the arterial pressure using a pressure cell (StathamTM P23Db type). A femoral vein is catheterized for the administration of various compounds. The increases in mean arterial pressure induced by serotonin administered intravenously at a dose of 30 gg / kg are measured. The compounds of the invention or the vehicle are administered 5 minutes (for IV studies) or 75 minutes (for oral studies) before administration of serotonin. The compounds of the invention are administered at doses ranging from 0.001 to mg / kg. The percentage inhibition of the control response to serotonin is used to assess the potential

serotonin antagonist of the compounds of the invention.

The compounds of the invention were also the subject of an assay for inhibiting the binding of [3H] spiroperidol to

rat cerebral cortex serotonin 5-HT2 receptors.

For this test, rat brains 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 at pH = 7.4, 120 mmol of NaCl and 5 mmol of KCl.

The homogeneous mixture is centrifuged at 40,000 x g for minutes then, twice, the pellet is collected, washed by suspending it in the same buffer mixture, homogenized again and centrifuged. Finally, the final pellet is diluted in the same buffer 5 mixture at a rate of 500 mg of wet tissue per 10 ml of buffer. The tissue is then subjected to a prior incubation of 10 minutes at 37 C in the presence of 10 gm / l of pargyline, then to an incubation of 20 minutes at 37 C in the presence of 3H-spiroperidol (specific activity: 19 Ci per mmol) at the concentration of 0.3 nM and of the compound to be studied at

concentrations ranging from 0.0001 to 100 MM.

Aliquots of 1 ml are taken and filtered under vacuum, the filters are washed twice with 5 ml of cold buffer, they are then washed.

dries and the radioactivity is measured.

To evaluate the activity of the compounds, the curve of the percentage inhibition of the specific binding of 3H-spiroperidol is plotted as a function of the concentration of displacer drug. The IC50, concentration

which inhibits 50% of specific binding.

Specific binding is defined as binding

displaced by 100 iM of 5-HT.

The IC50s of the compounds of the invention are less than 1 #M.

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

1988, 94, 1123).

Saphenous veins from Beagles or Anglopoitevin dogs are taken under pentobarbital anesthesia administered by intravenous injection. The vessel is cut into a 0.4 cm wide helix and then divided into 0.5 cm long segments. Each fragment, mounted between two greenhousefins, is placed in a tank for isolated organs containing 20 ml of a physiological Krebs solution of the following composition (mM): NaCl 118; KCl 4.7; MgCl2 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% 02-5% CO2) at pH 7.4 is connected to a Hugo Sachs type 351 isometric sensor under a basal tension of 2 g and connected to a Gould polygraph 2400S allowing the recording of blood pressure variations. Data acquisition is automated by a microcomputer system. After a 90-minute rest interspersed with 5 frequent rinses during which the basal pressure is readjusted, the organ is stimulated with 3 µM of norepinephrine in order to check its viability. A contractile concentration-response curve to sumatriptan 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 rinsed abundantly, 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 is constructed.

The contraction responses obtained in the presence of the compound are expressed as a percentage of the maximum contraction observed during the first curve with Sumatriptan. The curves are analyzed by non-linear regression in order to determine the Emax (maximum response) and the EC50 (concentration producing 50% of the maximum response). The antagonist potential of the compounds is estimated by calculating the dissociation constant KB according to the equation KB = [concentration of the compound in M] / (CR - 1) o CR represents the ratio of the EC50 of Sumatriptan in the presence and in the 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 serotonin antagonist properties. 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, thrombosis (alone or as an adjunct to

thrombolysis), arteritis, intermittent claudication, restenosis after angioplasty and various disease states associated with atherosclerosis, microcirculation disorders or pulmonary dysfunctions.

They can also be used, alone or in combination with other substances in vascular transplant procedures. The compounds of the invention can be used in combination with other substances with cardiovascular or cardiopulmonary activity, such as antithrombotics, thrombolytics, 3-blockers, calcium channel blockers, thromboxane antagonists,

thromboxane synthetase inhibitors.

To this end, these compounds can be presented in all forms suitable for oral or parenteral administration, such as tablets, dragees, gelatin capsules, capsules, topical ocular formulations in association 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 (7)

Claims 1. Compounds of formula (I) R1 N (CH2) m-N Z R N 0 R2 R3 in which = --- represents either a single bond or a double bond, m is equal to 2, 3 or 4, the group N (CH2-N / Z X being in position 3 or 4 of quinolin-2 (1H) -one or dihydroquinolin-2 (1H) -one, Z represents either a nitrogen atom or a -CH- group R1 and R2 each independently represent either a hydrogen atom, or a halogen atom, or an amino group, or a hydroxy group, or a nitro group, or a cyano group, or a (C1-C6) alkyl group, either a (C1-C6) alkoxy group, or a trifluoromethyl group, or a trifluoromethoxy group, or a -COOH group, or a -COOR4 group, or a -CONH2 group, or a - group CONHR4, either a -CONR4R5 group or a -SR4 group, or a -SO2R4 group, or a -NHCOR4 group, or a -NHSO2R4 group, or a -N (R4) 2 group o R4 and R5 are each a (C1 -C4) alkyl, R3 represents either a hydrogen atom, or a (C1-C4) alkyl group, or a - (CH2) pOH group, or a - (CH2) pNH2 group, or a - (CH2) nCOOH group , either a - (CH2) nCOOR4 group, or a - (CH2) nCN group, or a - (CH2) ntetrazol-5-yl group, or a - (CH2) nCONH2 group, or a (CH2) nCONHOH group, or a group - (CH2) pSH, either a group - (CH2) nSO3H, or a group - (CH2) nSO2NH2, so it a group - (CH2) nSO2NHR4, or a group (CH2) nSO2NR4R5, or a group - (CH2) nCONHR4, or a group - (CH2) nCONR4R5, or a group - (CH2) pNHSO2R4, or a group - (CH2 ) pNHCOR4 or a group - (CH2) pOCOR4 o R4 and R5 are each a (C1C4) alkyl group, n is equal to 1, 2, 3 or 4 and p is equal to 2, 3 or 4 and A represents either a optionally substituted phenyl, or a substituted or unsubstituted heterocycle having 5 or 6 atoms among which one, two or three are heteroatoms chosen from nitrogen, oxygen and sulfur atoms, the other 15 atoms being carbon atoms, the said heterocycle not being a thienyl group and being able, for example, to be chosen from furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl groups and their positioning isomers , in the form of racemates, pure enantiomers or a mixture of enantiomers, as well than their addition salts with acids or bases pharmaceutically acceptable. 2. Process for preparing the compounds of formula (Ia) N (CH) N z Ri AH <(Ia) R) N O R2 H in which R1, R2, m, Z and A are as defined in claim 1 and compounds of formula (Ib) N "" '(lb) (CH2) - N Z (Ib) Ri R 0 O R2 R3 in which R1, R2, R3, m, Z and A are as defined in claim 1, a process characterized in that a compound of formula (VII) is reacted Y R1 (CH2) m -g (VII) R N 0 R2 1 R3 wherein R1, R2, R3 and m are as defined in claim 1 and Y represents a leaving group with a compound of formula (VIII) N HN Z HNZ (VIII) in which Z and A are as defined in claim 1. 3. Process for preparing the compounds of formula (Ic) H35, R N N A (Ic) R2 I H in which R1, R2, Z and A are as defined in claim 1 and compounds of formula (Id) R. (CH2> -N "N N (Id) N RD, 2 1 H in which R1, R2, Z and A are as defined in claim 1 and m is equal to 3 or 4, a process characterized in that a compound of formula (XII) R1 (CH2) mOH ( XII) R2 N O 21I H wherein R1, R2 and m are as defined in claim 1 with a compound of formula (VIII) N HN Z A H2 Z \ (VIII) A, wherein Z and A are as defined in claim 1.30 4. Process for preparing the compounds of formula (Ie) Ri N (CH2) 2- NZ \ Z CH352A (Ie) R2 N R3 in which R1, R2, R3 (other than a hydrogen atom), Z and A are as defined in claim 1 and compounds of formula (If) Ri N / X (CH2) m- NZ (If ) NA (If) R2 N R3 in which R1, R2, R3 (other than a hydrogen atom), Z and A are as defined in claim 1 and m is equal to 3 or 4, a process characterized in that a compound of formula (XV) R1 15. (CH2) Y (Xv) R2 N O R3 in which R1, R2, R3 (other than a hydrogen atom), and m are as defined in claim 1 and Y represents a leaving group with a compound of formula (VIII) NOT HN Z / HZ (VIII) wherein Z and A are as defined in claim 1. 5. Process for the preparation of compounds of formula (Ib) N (CH) m-N z / Ri m A <(lb) N O R2 R3 in which R1, R2, R3, m, Z and A are as defined in claim 1 and R3 is different from a hydrogen atom, a process characterized in that a compound of formula ( Ia) N (CH2) mN z / (Ia) N 0 R2 N O H in which R1, R2, m, Z and A are as defined in the claim 1 with an electrophilic agent. 6. Medicinal product characterized in that it contains a compound according to claim 1. 7. Pharmaceutical composition characterized in that it contains a compound according to claim 1 in combination with any pharmaceutically acceptable excipient.