AU651740B2 - Quinoline derivatives, process for their preparation, and their therapeutic applications - Google Patents

Abstract

Compounds corresponding to the formula (I) <IMAGE> in which, R1 represents either a 1H-tetrazol-5-yl group or a CO2H group, R2 represents either a (C1-7)alkyl group or a (C2-6)alkenyl group, R3 and R4 represent, each independently of the other, either a hydrogen atom, or a halogen atom, or a cyano group, or a (C1-7)alkyl group, or a (C3-7)cycloalkyl(C1-4)alkyl group, or an aryl group, or an aryl(C1-4)alkyl group, or an aryl(C2-4)alkenyl group, or a group -(CH2)mCOR5 in which m = 0 to 4 and R5 represents a hydrogen atom, an OH group, a (C1-6)alkoxy group or a group NR7R8, R7 and R8 representing, each independently of the other, a hydrogen atom or a (C1-4)alkyl group, or R3 and R4 represents, each independently of the other, a group -(CH2)n-R6 in which n = 1 to 4 and R6 represents an OH group, a (C1-6)alkoxy group, a (C1-4)alkoxy(C1-4)alkoxy group or a (C3-7)cycloalkyl(C1-4)alkoxy group, and their pharmaceutically acceptable organic or inorganic salts. Application in therapeutics.

Description

o~ 6 51 740

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Synthelabo ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

INVENTION TITLE:

B

C~r Quinoline derivatives, process for their preparation, applications and their therapeutic 1 r iro rr o~ra a r a u 1 Iic I 1I rl

I

r 1 11 r The following statement is a full description of this invention, including the best method of performing it known to me/us:i. la- The present invention relates to quinoline derivatives, their preparation and their therapeutic applications.

The compounds of the invention are of the general formula (I) o* .15 a t 9I ou a 0 O 2 0 S u in which RI represents either a 1H-tetrazol-5-yl group, or a CO 2 H group,

R

2 represents either a (Cl 7 )alkyl group or a (C 26 )alkenyl group, R3 and R 4 represent, independently of each other, either a hydrogen atom or a halogen atom or a cyano group or a (C.7)alkyl group or a (C 3 7 )cycloalkyl(Cl.

4 )alkyl group or an aryl group or an aryl(C,.

4 )alkyl group or an aryl(C 26 )alkenyl group or a (CH 2 )m-COR 5 group in which m 0 to 4 and R, represents a hydrogen atom, an OH group, a (C 1 6 )alkoxy group or an NRy 7 R group, R 7 and R 8 representing, independently of each other, a hydrogen atom or a 4 )alkyl group or a (CH 2 )n-R 6 group in which n 1 to 4 and R 6 represents an OH group, a 6 )alkoxy group, a 4 )alkoxy(C,.

4 )alkoxy group or a

(C

3 7 )cycloalkyl(C 1 4 )alkoxy group.

The preferred compounds of the invention are those for which R i represents either a 1H-tetrazol-5-yl group or a 2

CO

2 H group,

R

2 represents a (C 1 7 )alkyl group,

R

3 represents either a halogen atom or a (C 1 .7)alkyl group or an aryl(C.

4 )alkyl group,

R

4 represents either a (CH 2

),-COR

5 group in which m 0 to 4 and PR represents a hydrogen atom, an OH group, a (C 1 6 )alkoxy group or an NR, 7 R group, R 7 and R representing, independently of each other, a hydrogen atom or a

(C

1 4 )alkyl group, or a (CH 2

-R

6 group in which n 1 to 4 and R 6 represents an OH group or a (C,.)alkoxy group.

Finally, the preferred compounds are those for which R

I

represents a 1H-tetrazol-5-yl group,

R

2 represents a butyl group,

R

3 represents either a chlorine atom or an ethyl group or a phenethyl group,

R

4 represents a CH 2 OH, CHO, CO 2 H, CO2CH 3 C0 2

C

2

H

5 or CH 2

OCH

3 group.

The compounds of the invention may be in free form or S' in the form of pharmaceutically acceptable organic or inorganic salts.

The compounds of the invention for which R, represents a 1H-tetrazol-5-yl group may be prepared according to the scheme in Appendix I.

S* In a first stage, 4-methylbenzenamine(para-toluidine) is reacted at the reflux temperature with a benzaldehyde of formula in which X represents a bromine or iodine atom, in the presence of a catalyst such as 4-methylbenzenesulphonic acid (para-toluenesulphonic acid or PTSA), in solution in benzene. After cooling, propiolic acid is added and the mixture I 3 is heated at the reflux temperature in order to obtain a compound of formula (III).

In a second stage, a mixture of the compound (III) and of copper(I) cyanide in a solvent such as pyridine is heated in order to obtain 2-(6-methylquinolin-2-yl)benzonitrile

(IV).

In a third stage, 2-(6-methylquinolin-2-yl)benzonitrile is reacted with an organometallic azide such as trimethyltin azide or a metallic azide such as sodium azide in order to obtain a compound over which a stream of gaseous hydrochloric acid is passed in order to obtain 6-methyl- 2-[2-(lH-tetrazol-5-yl)phenyl]quinoline The first reaction is carried out in a solvent such as xylene at the reflux temperature; the second reaction is carried out in a solvent such as toluene/tetrahydrofuran mixture at room temperature.

In a fourth stage, the tetrazole group of 6-methyl- 2-[2-(lH-tetrazol-5-yl)phenyl]quinoline is protected with a protecting group of formula CR 1 3

R

4

R

15 in which R 1 3

R

1 4 and Rs each represent independently of each other a (C1.

2 )alkyl group or an aryl group; in this stage, the compound is reacted with a protecting agent such as for example trityl chloride, at room temperature in a solvent such as dichloromethane in the presence of a base such as N-methylmorpholine or triethylamine and a compound of formula (VI) is obtained in which R 1 3

R

14 and

R

15 are as previously defined. The protection of the tetrazole group preferably occurs in position 2.

In a fifth stage, the methyl group in position 6 of the quinoline of formula (VI) is functionalised by introducing therein a departing group. If the departing group is a bromo 4 radical, then a compound of formula (VI) is reacted with N-bromosuccinimide in order to obtain a compound of formula (VII) in which CR 13

R,

4

R

15 is as previously defined; the reaction is carried out at the reflux temperature in a solvent such as carbon tetrachloride in the presence of an initiator such as benzoyl peroxide or a,a' or azobisisobutyronitrile.

In a sixth stage, a compound of formula (VII) is reacted with an imidazole of formula (VIII) in which Rg, R 3 and

R

4 are as previously defined, in order to give a derivative of formula The reaction is carried out in a solvent such as dimethylformamide at a temperature of 0°C to 50°C in the presence of a base such as potassium carbonate.

In a seventh stage, deprotection of the tetrazolyl group is carried out in order to obtain a compound of formula (I a).

The compounds of the invention for which R

I

represents a CO 2 H group may be prepared according to the scheme in Appendix II.

In a first stage, 4-methylbenzenamine (para- I 20 toluidine) is reacted at the reflux temperature with a benzaldehyde of formula (II) in which X represents a bromine or an iodine atom in the presence of a catalyst such as i 4-methylbenzenesulphonic acid (para-toluenesulphonic acid or PTSA) in solution in benzene. After cooling, propiolic acid is added and the mixture is heated at the reflux temperature in order to obtain the compound of formula (III).

In a second stage, a mixture of the compound (III) and copper(I) cyanide in a solvent such as pyridine is heated in order to obtain 2-(6-methylquinolin-2-yl)-benzonitrile I- 5 In a thizd stage, 2-(6-methylquinolin-2-yl)benzonitrile is reacted with an alcohol R-OH where R is a branched or unbranched (C 1 4 )alkyl radical, 4n the presence of an acid, for example sulphuric acid, in order to obtain a quinoline of formula in which R is as previously defined.

In a fourth stage, the methyl group in position 6 of the quinoline is functionalised by introducing therein a departing group. If the departing group is a bromo radical, then the quinoline of formula is reacted with N-bromosuccinimide in order to obtain the quinoline of formula (VII') in which R is as previously defined; the reaction is carried out in a solvent such as carbon tetrachloride in the presence of an initiator such as benzoyl peroxidc or a,a'-azobisisobutyronitrile at the reflux temperature.

In a fifth stage, the quinoline of formula (VII') is reacted with an imidazole of formula (VIII), in which R 2

R

3 and R4 are as previously defined, in order to give a derivative of formula The reaction is carried out in dimethylformamide at a temperature of 0°C to 50 0 C in the presence of a base such as potassium hydroxide or potassium carbonate.

In a sixth stage, the ester functional group of the quinoline of formula is hydrolysed in order to obtain a compound of formula (I b).

The intermediate compounds are novel and are part of the invention. They are of the formula (X) 6

(X)

in which W represents either a methyl group or a -CH 2

R

1 1 group in which

R

11 represents a chlorine atom, a bromine atom or a departing group OR 1

R

12 being a group such as a tosyl group or a mesyl group, Z represents either a halogen atom or a cyano group or a group or a 1H-tetrazol-5-yl group protected by a protecting group of formula CR 1 3 Rl 4

R,

1

R

1

R

14 and R 1 representing independently of each other a (Ci.

2 )alkyl group or an aryl group, or a COOR group, R being a branched or unbranched (C.

4 )alkyl group.

The starting compounds are commercially available or S are described in the literature or can be prepared using S methods which are described therein or which are known to a person skilled in the art.

20 The following examples illustrate the invention.

Microanalyses and IR and NMR spectra confirm the structure of the compounds obtained.

Example 1 2-butyl-4-chloro-l-[[2-[2-( hydrochloride.

1.1 2-(2-bromophenyl)-6-methylquinoline g (270 mmol) of 2-bromobenzaldehyde are heated to 7 the reflux temperature, in a round-bottomed flask fitted with a Dean-Stark, with 29.5 g (276 mmol) of para-toluidine and 0.5 g of para-toluenesulphonic acid in solution in one liter of benzene. When the removal of water has been completed (about ml), 8.3 ml (135 mmol) of propiolic acid are added to the reaction medium previously cooled to around 50°C. A substantial release of CO 2 is observed and the mixture is refluxed for 3 hours. The reaction is monitored by thin-layer chromatography in a dichloromethane and hexane mixture (70/30). Under our experimental conditions, it was necessary to add a 20 excess of propiolic acid followed by refluxing for 1 hour in order to bring the reaction to completion. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica column, eluting with a dichloromethane and hexane mixture (70/30).

22 g of the expected derivative are recovered in the S form of a crystallised compound.

wt. 22 g m.p. 92°C Yield 27 S 1 H NMR (200 MHz, CDC1 3 6 2.55 3H), 7.25-7.70 7H), 20 8.02-8.15 2H).

Similarly, 2-(2-iodophenyl)-6-metiylquinoline is prepared from 2-iodobenzaldehyde.

m.p. 77-77.5°C 1.2 2-(6-methylquinolin-2-yl)benzonitrile A mixture containing 15 g (50 mmol) of the compound previously obtained in 1.1 and 5 g (56 mmol) of copper(I)cyanide in 60 ml of pyridine is heated at 160 0 for 12 hours under argon. The reaction is monitored by thin-layer 8 -I 8 chromatography (TLC) in dichloromethane. The pyridine is evaporated under reduced pressure and the residue is taken up in dichloromethane. The organic pnase is washed several times with an aqueous solution of ammonium hydroxide until the aqueous phase is colorless. After a last wash with water, the organic phase is dried over magnesium sulphate and the solvent is evaporated. The residue is taken up in petroleum ether.

wt. 9.6 g m.p. 157 C Yield 78 1.3 6-methyl-2-[2-(1H-tetrazol-5-yl)phenyl]quinoline hydrochloride 9.6 g (39.29 mmol) of the nitrile previously obtained in 1.2 and 14.96 g (72.7 mmol) of trimethyltin azide are introduced into 110 ml of xylene. This mixture is refluxed for 15 hours. After cooling, the solid is filtered and suspended in 115 ml of toluene and 7 ml of tetrahydrofuran. The mixture, 0 which is cooled using an ice bath, is subjected to bubbling of hydrochloric gas for 2 hours. The insoluble fraction is recovered by filtration, then washed with toluene and with water.

wt. 13 g i' 1.4 6-methyl-2-[2-[2-(trip' ylmethyl) -H-tetrazol- 80.5 g (0.219 mol) of the compound previously obtained in 1.3, 60 ml (0.547 mol) of N-methylmorpholine and 73.1 g (0.262 mol) of trityl chloric" are added to one litre of dichloromethane at room temperature. The solution is stirred overnight, taken up in water, and the organic phae is washed i 9 twice with water and then dried. The solvent is evaporated and the residue is crystallised from a minimum amount of ether.

wt. 119 g m.p. 176-177'C Yield 87 1.5 6-bromomethyl-2-[2-[2-(triphenylmethyl)-lH-tetrazolg (0.189 mol) of the compound previously obtained in 1.4 is added to 300 ml of carbon tetrachloride and the mixture is heated to around 60°C until complete dissolution has taken place. 3.7 g (0.208 mol) of N-bromosuccinimide and 60 mg (0.0037 mol) of a,a'-azobisisobutyronitrile are added all at once at this temperature. The mixture is refluxed for 2 to 3 hours until the N-bromosuccinimide disappears. 100 ml of water and 300 ml of dichloromethane are added to the cooled mixture.

The organic phase is washed several times with water and then dried. The solvent is evaporated and the residue is triturated in diisopropyl ether. A 90 pure product is obtained which will be used as it is.

wt. 10.3 g 0 S'20 1.6 2-butyl-4-chloro-l-[[2-[2-[2-(triphenylmethyl)- 1H-tetrazol-5-yl]phenyl]quinolin-6-yl]methyl]-1H-imidazole- S" a) 2-butyl-5-chloroimidazole-4-methanol 9.52 g (0.071 mol) of N-chlorosuccinimide are introduced, at a temperature of between 0 and 5°C, into 10 g (0.065 mol) of 2-butylimidazole-4-methanol in suspension in 200 ml of ethyl acetate. The mixture is stirred overnight while maintaining this temperature. The solution is 10 filtered and the solid is washed with 20 ml of ice-cold ethyl acetate, drained and washed with water in order to remove traces of succinimide and starting product, and then dried.

wt. 7.3 g m.p. 143*C Yield 73 b) 2-butyl-4-chloroimidazole-5-carboxaldehyde A solution containing 17.3 g (0.092 mol) of the compound previously obtained, dissolved in 52 ml of acetic acid, is added dropwise, so that the temperature of the medium is kept between 22 and 28*C, to 133 g (0.243 mol) of ammonium cerium nitrate solubilised in 200 ml of water. The reaction medium is allowed to stand for 3 to 5 hours until the solution becomes colourless. The medium is cooled and the pH is adjusted to 5-6 by adding 10 N sodium hydroxide. The product formed is extracted using 3 portions of ether and the organic phase is washed with sodium bicarbonate, dried and the solvent is evaporated. 16.4 g of compound are obtained which are recrystallised from cyclohexane.

wt. 13.9 g m.p. 92-93*C Yield 81 c) 2-butyl-4-chloro-l-[[2-[2-[2-(triphenylmethyl)-lH-tetrazol- 20 5-yl]phenyl]quinolin-6-yl]methyl]-lH-imidazole-5-carboxaldehyde 5.11 g (0.037 mol) of potassium carbonate and 19.1 g (0.028 mol), in portions, of the compound previously obtained in 1.5 are added, while cooling on an ice bath, to 5.07 g (0.027 mol) of 2-butyl-4-chloroimidazole-5-carboxaldehyde in solution in 40 ml of dimethylformamide. The mixture is stirred under argon overnight, allowing the temperature to return to room temperature. The reaction medium is poured into water, and the solid formed is recovered and dried. The compound obtained is purified by passing through a silica column, eluting with a 11 toluene/ethyl acetate mixture (90/10).

wt. 11.9 g m.p. 165'C Yield 57 1.7 2-butyl-4-chloro-l-[[2-[2-(1H-tetrazol- 5-yl)phenyl]quinolin-6-yl]methyl]-1H-imidazole-5-carboxaldehyde ml (0.040 mol) of 4 N hydrochloric acid are added to 11 g (0.015 mol) of the compound previously obtained in 1.6, in solution in 130 ml of tetrahydrofuran. The mixture is stirred under an argon atmosphere overnight at room temperature.

The hydrochloride salt of the expected product crystallises from the reaction medium. It is recovered by filtration and washed with 10 ml of ice- cold tetrahydrofuran.

wt. 7.4 g m.p. 185°C (dec) Yield 94 'H NMR (200 MHz, DMSO): 6 0.8 3H), 1.2-1.4 2H), 1.5-1.65 2H), 5.8 2H), 7.6-8.0 8H), 8.6 1H), 9.7 1H) Example 2 2-butyl-4-chloro-l-[[2-[2-(lH-tetrazol- 5-yl)phenyl]quinolin-6-yl]methyl]-IH-imidazole-5-carboxylic acid ml of methanol, 241 mg (3.7 amil) of potassium cyanide, 64 Al of acetic acid and 1.5 g of manganese dioxide are added to 344 mg (0.73 mmol) of the aldehyde derivative previously obtained in 1.6. The mixture is stirred for 48 hours at room temperature. The methyl ester formed is recovered after filtration and evaporation. 2.55 ml (2.55 mmol) of lN sodium -12 hydroxide are immediately added and the solution is left for 3 hours at room temperature. The pH of the solution is adjusted to 3.5 and the insolubles are filtered, washed and dried.

wt. 230 mg m.p.=170*C (dec) Yield 70 'H NMR (200 MHz, DMSO): 6 0.8 3H), 1.2-1.4 2H), 1.5-1.65 2H), 2.65 2H), 5.8 2H), 7.45-8 8H), 8.6 1H) Example 3 2-butyl-4-chloro-l-[[2-[2-(H-tetrazol- 5-yl)phenyl]quinolin-6-yl]methyl]-1H-imidazole-5-methanol 3.1 2-butyl-4-chloro-1-[[2-[2-[2-(triphenylmethyl)- 1H-tetrazol-5-yl]phenyl]quinolin-6-ylJmethyl]-lH-imidazole- 330 mg (6.9 mmol) of sodium borohydride are added in small portions to 1.65 g (2.3 mmol) of the compound obtained in 1.6, in solution in 150 ml of methanol. After reacting for S minutes, the mixture is concentrated and poured in a 2N 20 solution of sodium hydroxide. The compound obtained is extracted with dichloromethane. The crude product thus obtained is purified by chromatography on a silica column with a chloroform/ethyl acetate (80/20) mixture.

wt. 1.12 g m.p. 1750C Yield 68 3.2 2-butyl-4-chloro-1-ll2-12-(1H-tetrazol- 5-yl)phenylJquinolin-6-yl]methyl]-H-imidazole-5-methanol 1.1 g of the compound obtained previously in 3.1 is -13 dissolved in a mixture containing 31 ml of tetrahydrofuran, 31 ml of methanol and 5 ml of acetic acid. The solution is refluxed for 24 hours. The solvents are evaporated, the residue is triturated in ether and the insolubles are recovered by filtration. The product is recrystallised in 2-butanone.

wt. 450 mg m.p. 150-1520C Yield 62% IH NMR (400MHz, DMSO): 6 0.75 3H), 1.25 (mn, 2H), (mn, 2H), 2.53 (mn, 2H), 4.36 2H), 5.2 1H), 5.46 2H), 7.53, (mn, 3H), 7.7-7.79 (mn, 4H), 7.93 lH), 8.3 1H).

Example 4 2-butyl-4-phenethyl-l-[ [2-[2-(lH-tetrazol- 5-yl)phenyl]quinolin-6-yljmethyl]-lH-imidazole-5-carboxaldehyde 4.1 2-buatyl-4-phenylethenylimidazole-5-carboxaldehyde 10.2 g of (E)-P-tri-n-butylstannylstyrene and 1 g of tetrakis(triphenylphosphine)palladium(0) are added to 6 g of 2-n-butyl-4-iodoimidazole-5-carboxaldehyde under an argon atmosphere in 80 ml of dry toluene. The mixture is refluxed for 6 hours. The solution is clarified by filtration after adding animal charcoal and the solvent is evaporated. The residue is taker, dp in hexane in order to remove the tin derivatives. The compound obtained is purified in hydrochloride or oxalate form.

hydrochloride in.p. 225*C (dqcomposition) oxalate in.p. 2170C wt. g Yield 99 4.2. 2-butyl-4-phenethylimidazole-5-carboxaldehyde 14 A solution of 2.5 g of the compound obtained previously in 4.1 and dissolved in 50 ml of ethanol is subjected to catalytic hydrogenation at room temperature and at atmospheric pressure in the presence of palladium on carbon as S 5 catalyst, After 30 minutes, the catalyst is removed by filtration and the solvent is evaporated. 2.5 g of the expected compound are obtained in the form of a gum. The compound obtained is purified in hydrochloride form.

Hydrochloride m.p. 179.5C 4.3 2-butyl-4-phenethyl- 1-[[2-[2-[2-(triphenylmethyl)-1H-tetrazol-5-yl]phenyl]quinolin- 6-yl]methyl]-1H-imidazole-5-carboxaldehyde This compound is obtained by reaction between 2-butyl-4-phenethylimidazole-5-carboxaldehyde and the bromine-containing derivative described in Example according to the process described in Example 1.6.

S m.p. 142.5°C 4.4 2-butyl-4-phenethyl-l-[[2-[2-(lH-tetrazol- 5-yl)phenyl]quinolin-6-yl]methyl]lH-imidazole-5-carboxaldehyde This compound is obtained by detritylation of the compound obtained previously in 4.3 by heating for 24 hours in Smethanol at the reflux temperature.

1 H NMR (200MHz, CDC1 3 [sic] 0.8 3H), 1.25 2H), 1.6 2H), 2.5 2H), 3.1 4H), 5.75 2H), 7-7.5 (m, 11H), 7.6 1H), 7.75 1H), 7.9 1H), 9.55 1H).

Example 2-butyl-4-phenethyl-1-[ [2-[2-(1H-tetrazolphenyl quinolin-6-yl]methyl] -1H- imidaz ole-5 -methanol.

5.1 2-butyl-4-phenethyl-l-[[2-[2-[i-(triphenylmethyl)- 1H-tetrazol-5-yljphenyljquinolin-6-yljmethyl]-1H-imidazole- This compound is obtained from the compound obtained previously in 4.3, according to the process described in Example 3.1.

M.P. 150 0

C

5.2 2-butyl-4-phenethyl-1-[[2-[2-(lH-tetrazolphenyl) quinolin-6-ylJ methyl] This compound is obtained by detritylation of the compound obtained previously in 5.1 by heating for 24 hours in methanol at the ref lux temperature.

IH NMR (200MHz, CDCl 3 -DMSO) a 0. 8 3H) 1. 3 (in, 2H) 1. 6 h (in, 2H), 2.65 2H), 2.9 (in, 4H), 4.15 2H), 5.4 211), 7.15-7.9 (mn, 13H), 8.1 1H).

;s Example-6 [2-butyl-4-chloro-5-(methoxymethyl) -li-imidazol- 1-yljmethyl]-2-[2-(1H-tetrazol-5-yl)phenyl]quinoline 1.5 g of the compound described in Example 3 are introduced into 36 ml of methanol and 0.18 ml of concentrated sulphuric acid are added. The mixture is refluxed for 15 hours, the methanol is evaporated and the residue is taken up in a 16 mixture of 1 N sodium hydroxide and toluene. The aqueous phase is recovered and acidified to pH 3 with hydrochloric acid. The precipitate formed is filtered and it is purified by chromatography on a silica gel column, eluting with a dichloromethane/methanol/acetic acid mixture (95/5/0.1).

wt. 0.4 g m.p. 102*C (dec) Yield 40 The following table illustrates the structures and the physical properties of some compounds according to the invention.

00i II i t t t*' 3 I -4,9

A,

4 4 4 4 0 4 44 *4 Table No R, R 2 RR4Sel F 1 -CN 4 H (CH 2 3

CH

3 -C1 -CHO HCI 185 (d&c) 2 -CN 4 H (CH 2 3

CH

3 -C1 -CH 2 0H -150-152* 3 -C-1 4 H (CH 2 3

CH

3 -C1 -COOH 170 (ddc) 4 -CN 4 H (CH 2 3

CH

3 phdndthyle -CHO

-CN

4 H (CH 2 3

CH

3 phdndthyle -CH 2 OH 184 (d4§c) 6 -CN 4 H (CH 2 3

CH

3 -cl -CN 138 (dd&) 7 -CN 4 H (CH 2 3

CH

3 -C1 -CH 2

OCH

3 -98 (dec) 8 -CN 4 H (CH 2 3

CH

3 -C1 -COOCH 3 -181-184 9 -CN 4 H (CH 2 3

CH

3 -CI -CH 2

OC

2 Hs 170-172,5

-CN

4 H (CH 2 3

CH

3 -C1 -CHO 186 (d6c) 11 CN 4 H (CH 2 3

CH

3 -Cl -CH 2 O (CHA) 2 157,5-160 4 a a a a a a a a a a S- aa aaaa, I 0O No RR 2

R

3 R4Sel F (OC) 12 -CN 4 H (CH 2 3

CH

3 -Cl -CH 2 O (CH 2 3

CH

3 -91 (dec) 13 -CN 4 H (CH 2 3

CH

3 -Cl -CH 2

OCH

2 CH (CH 3 2 9 0 (ddc) 14 -CN 4 H (CH 2 3

CH

3 -Cl -CH 2 OCH (CH 3

CH

2

CH

3 98 (dec)

-CN

4 H (CH 2 3

CH

3 -Cl -C11 2 0 (CH 2 2 0CH 3 119,5-122,5 16 -CN 4 H (CH 2 3

CH

3 -Cl -CH 2 O (CH 2 2

CH

3 139-140 17 -CN 4 H (CH 2 3

CH

3 -Cl -CH 2 OCH~cC 3

H

7 83 (dec) 18 -CN 4 H (CH 2 4

CH

3 -Cl- CHO HCi 188 (d&c) 19 -CN 4 H (CH 2 4

CH

3 -Cl -CH 2 OH 160-163

-CN

4 H -CH 2

CH

3 -Cl -CHO 197-199 21 -CN 4 H (CH 2 4

CH

3 -Cl -COOCH 2

CH

3 142-144 22 -CN 4 H (CH 2 2

CH

3

-C

2

H

5

-COOCH

2

CH

3 196 (dec) 23 -CN 4 H (CH 2 3

CH

3 -Cl -COOCH 2

CH

3 151-152 24 -CN 4 H -CH 2

CH

3 -Cl -COOCH 2

CH

3 188-189

-CN

4 H (CH 2 4

CH

3 -Cl -CH 2

OCH

3 106-108 26 -CN 4 H -CH 2

CH

3 -Cl -COOH -250 27 -CNH -(CH 2 2

CH

3

-C

2 4 5 -COOH H 2 0 177

A

No R, R 2 R3R 4 Sel F 28 -CJ 4 H (CH 2 2

CH

3 -Cl -CHO 180,5 29 -CNgH (12) 213 -Cl -CH 2 OH 166 (dec)

-CN

4 H (CH 2 20113 -Cl -COOCH 2

CH

3 176* 31 -CN 4 H (CH 2 4

CH

3 -cl -COOH 185" 32 -CN 4 H (CH 2 3

CH

3

-CH

2

CH

3

-COOCH

2

CH

3 182* 33 -CN 4 H (12) 313 -Cl -coo (CH 2 2

CH

3 193* 34 -CN 4 H (CH 2 3 C1 3

(CH

2 2

CH

3 -00011 184*

-CN

4 H -(C1 2 3

CH

3

(CH

2 3

CH

3 -COOH 1810 36 -CN 4 H -(CH 2 2

CH

3

(CH

2 2

CH

3 -00011 187* 37 -CN 4 H -(C1 2 2

CH

3

(CH

2 3 0H 3 -COOH 180* 38 -CN 4 H -(CH 2 3

CH

3 -0112013 -COOH 180* 39 -CN 4 H (12) 213 (12) 213 -COOCH 2

CH

3 110*

-CN

4 H (CH 2 2

CH

3 (C1 2 3

CH

3

-COOCH

2 CH, 96,5* 41 -CN 4 H (CH, 2 3011 (C' 2 2013__ -COOCHICH 3 -206*

-CN

4 H (C11 2 3 CH, (012) 3 C11 3

-COOCH

2

CH

3 112* 1 4 0 i Legend for the table HC1 denotes hydrochloride dec denotes decomposition

CN

4 H denotes the lH-tetrazol-5-yl group cC 3

H

7 denotes the cyclopropyl group *a product characterised by NMR spectrum (see corresponding example)

MO

0) mh 20 The compounds of the invention have been the subject of pharmacological studies which have demonstrated their antagonistic properties to angiotensin II.

Test of binding of r 3 H1-angiotensin II to rabbit adrenal cortex 2 to 3-kg Fauves de Bourgogne male rabbits are used.

After sacrificing them by cervical dislocation, the adrenal glands are excised and the cortex is dissected on a culture plate cooled using ice. It is placed in 10 ml of an ice-cold buffer solution at 10 mM of tris(hydroxymethyl)aminomethane containing 0.33 M sucrose and 1 mM ethylenediaminetetraacetic acid where the pH had been adjusted to 7.4 with hydrochloric acid. The tissue is homogenised by means of an electric Potter apparatus using 13 to and fro movements of the piston at a speed of 1200 revolutions per minute. The volume of the preparation is adjusted to 25 ml with tris-sucrose buffer before centrifuging for 15 min at 1075 x g. The supernatant is kept. The pellet is again homogenised after re-suspending in ml of tris-sucrose buffer by passing through an electric Potter and then centrifuged under the conditions previously described.

The supernatant obtained is added to the first supernatant and they are centrifuged for 30 min at 47 800 x g. The pellets are finally taken up in 150 volumes (that is to say 100 mg of tissue in 15 ml of buffer) in a 50 mM solution of tris-HCl buffer containing 150 mM of NaCl, 5 mM of ethylenediaminetetraacetic acid, 1.25 Ag/ml of bacitracin, 100 PM of phenylmethylsulphonyl fluoride and 0.2 of bovine serum albumin (pH 7.4 at 21 This suspension contains the adrenal cortex microsomes and will be used as it is in the studies described below.

Aliquot fractions of 100 Al of suspension are incubated in the presence of 3 Hj-angiutensin II (New England Nuclear, with a specific activity of 61 Ci/mmol) in a final volume of 1 ml of tris-HCl buffer the composition of which has previously been described. After incubating for 30 minutes at the microsomes are recovered by filtration on 0.45 Am Millipore HAWPTM cellulose nitrate filters previously conditioned by soaking in a 1 solution of bovine serum albumin. The filters are washed three times with 5 ,Li of icecold tris-HCl buffer. The amount of radioactivity bound to the tissue and retained on the filters is measured by scintillation spectrometry.

The non-specific binding of 3 H]-angiotensin II is measured by incubation in the presence of 1 AM of non- *q.o radioactive angiotensin II. This non-specific binding o represents 5 to 10 of the total amount of radioactivity bound on the filter. The specific binding is the difference between the total radioactivity recovered on the filter and the nonspecific radioactivity. The bindi'ng of [AH]-angiotensin is o. measured in the presence of various concentrations of the test compounds and the TC 50 the concentration of the test compound which inhibits 50 of the specific binding of 3 H]-angiotensin II, is graphically determined.

The IC 50 values of the compounds of the invention are between 5 nM and 10 AM.

I 22 Inhibition of the response to angiotensin II on rat blood pressure Male rats (Sprague-Dawley, Charles River France) weighing 250 to 280 g are used, they are anaesthetized with sodium pentobarbital (55 mg/kg and are maintained under artificial respiration (HarvardTM respirator; frequency of respiration of 70 ml per minute, volume of air 1 ml per 100 g of body weight). The animals are "spinalised" by means of a metal rod introduced through the orbit of the right eye and taken down along the length of the vertebral column. The right and left vagus nerves are sectioned (bivagotomy); the right carotid artery is ligatured, the left carotid artery being catheterised in order to measure the blood pressure using a pressure cell (Statham TM ?23Db type). A femoral vein is c-atheterised for the purpose of administering various compounds.

The mean blood pressure variations induced by angiotensin administered intravenously at the dose of 0.5 .g/kg before administering the compounds of the invention and those induced by angiotensin administered under the same conditions minutes after intravenous administration of the compounds of the invention or 30 minutes after their oral administration are measured. The compounds of the invention are administered at 4 do;es ranging from 0.0 to 100 mg/kg.

The percentage inhibition of the control response to angiotensin II is used to evaluate the antagonistic potential of the compounds of the invention to angiotensin II.

The compounds of the invention or their suitable salts may be used as active therapeutic substances, 23 particularly for the treatment of various forms of hypertensive pathologies and of cardiac, renal or pulmonary insufficiencies as well as for the treatment of glaucoma.

The invention further provides a pharmaceutical composition which comprises a compound of the invention and a pharmaceutically acceptable carrier or diluent. The compounds of the invention or their suitable salts may also be used in combination with other substances possessing cardiovascular activity such as diuretics, a-blockers, P-blockers, calcium antagonists or angiotensin I uonverting enzyme inhibitors.

The compounds of the invention or their suitable salts may be provided in any pharmaceutical forms suitable for treatment by means of oral, parenteral, intramuscular or rectal administration tablets, capsules, hard gelatin capsules, sterile solutions or suspensions, suppositories and the like.

For the treatment of glaucoma, the compounds of the invention, may be provided in the form of tablets, hard gelatin S capsules, injectable solutions or topical eye formulations.

«The compositions of the invention may be administered t^ patients in an amount which may range from 1 to 1000 mg per day and per patient, in one or more doses.

i -24- APPENDIX I H c H3-

(IV)

13141 H4 3

C

N- (IV (Vi) NI 4 *R3 4 0N) (Ia) At 25 APPENDIX II H 3cNH H x

I

0 4 4t44 .414.* 4 0 *4 *404 o 40 44 H 3 c Bc

R

(Vi) (mI) 44 (Ib)

WF~

I

"-1

I'

25a Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

ar ar a oo a oa a oror a a~nn oa a* ca r a a.

I

c r r rr 1 a :rr Ir 1 r~ r~ a a r+*r rr rr a 94O526,p:%operda27348-92.14425

Claims (1)

1. 26- THE CLAI.MS DEFINING THE I14VENTION ARE AS FOLLOWS: 1. A compound which is a quinoline derivative of the formula (I) NN in which Ri represents either 1Li-tetrazol-5-yl, or CO 2 H, R 2 represents either 7 )alkyl or 2 6 aknl R 3 and R~ represent, independently of each other, hydrogen, halogen, cyano group, (Cl. 7 )alkyl, 7 )cycloalkyl(Cj,)alkyl, aryl, aryl(Cl,.)alkyl, aryl C.)alkenyl, -(CH 2 ),-COI in which m 0 to 4 and R, represents hydrogen, -OH, (C1. 6 )alkoxy, or- NR 7 R, R 7 and P. representing, independently of each other, hydrogen or 4 .)alkyl group, or a -(CH 2 )n-R 6 group in which n 1. to 4 and R 6 represents -OH, 6 )alkoxy, -(Cl,,)alkoxy- (C,.,,)alkoxy, or (C, 3 7 )cycloalky1(C,.,.)alkoxy group, or a pharmaceutically acceptable salt thereof. .1 A compound according to Claim 1 wherein R, represents (C1. 7 )alkyl, R, represents either halogen or alkyl or aryl alkyl, and R. represents either -(CH 2 ),-COR 1 in which m and N 1 are as defined in claim 1, or -(CH 2 6 in which n =1 to 4 and R 6 represents -OH or -(C 1 6 )alkoxy. 3. A compound according to claim 2 which is 4- yl Imethyl)I- 1H- imidazole- 5-ethylcarboxyl ate or a salt thereof. a* 0 00 00*0 0 9, 7 O 9 It 6 L---r -27- 4. A compound according to claim 2 which is 4- ethyl-2-propyl-l-[[2-[2-(lH-tetrazol-5-yl)phenyl]quinolif- 6 acid or a salt thereof. A compound according to claim 2 wherein R 1 represents R 2 represents butyl, R 3 represents either chlorine, or ethyl or phenethyl, and R 4 represents CH 2 0H, CHO, CO 2 H, CO 2 CH 3 C0 2 C 2 H. or CH 2 OCH 3 6. A compound according to claim 5 which is 2-butyl-4-chloro-l-f f2-f2-(1H-tetrazol-5-yl)phenyl quinolin- 6-yi]methyl]-l1-imidazole-5-carboxaldehyde or salt thereof. 7. A compound according to claim 5 which is 2-butyl-4-chloro-l-( (2-(2-(lH-tetrazol-5lpelquni- 6-yl]methyl]-li-imidazole-5-carboxylic acid or salt thereof. 8. A compound according to claim 5 which is 2-butyl-4-chlor-l-( lE-tetraZOl-5-ylhenyl )cuinolin- 6-yl]methylI- 1H-imidazole-5-methanol or salt thereof. 9. A compound according to claim 5 which is [2-butyl-4-chloro-5- (methoxymethyl) -lH-imidazol- 1-ylmethyl-2-(2- l'-tetrazol-5-yl) phenyl]quinoline or salt thereof. A process for preparing a compound as claimed in any one of the preceding claims, which process comprises reacting 4-methylbenzenamine with a benzaldehyde of formula (II) H x N)'f in which X represents a bromine or iodine atom, in the presence ,f propiolic acid, reacting the resulting compound (III) 28 (III) with copper(I) cyanide, and then either reacting the resulting 2-(6-methylquinolin- 2-yl)benzonitrile (IV) (IV) 0 4 00 with an organometallic or metallic azide, passing a stream of gaseous hydrochloric acid over the compound obtained, and then protecting the tetrazole group of the resulting 6-methyl- 2-[2-(lH-tetrazol-5-yl)phenyl]quinoline (V) 0 0* o a sr 0 00 04 00 0 a 0 81 o004 4 0 with a protecting group of formula CR 1 3 R 1 4 Ris in which R 1 3 R 1 4 and R 15 each represent independently of each other a (C 1 .)alkyl group or an aryl group, and functionalising the methyl group of the resulting compound of formula (VI) -29- CR 3 R IRIs N- H H 3 C N N(VI) by introducing therein a leaving group L wherein L is chlorine, bromine or OR 12 where R 12 is tosyl or mesyl, and then reacting the resulting compound (VII) CR13RI4R5 N N N (VII) t with an imidazole of formula (VIII) R N-- 2 NH 4 (VIII) 0 44 in which R 2 R 3 and R 4 are as defined in Claim 1, and deprotecting the tetrazolyl group of the resulting derivative of formula (IX) 44 cR 13 R 4 R 1 N-N R \N (IX) to obtain a compound of formula (Ia) and optionally converting -V 30 the compound of formula (Ia) into pharmaceutically acceptable salt thereof, N=N R/ 4 R 4 N"N NH R, /"N N J\N (Ia) ,or reacting the 2-(6-methylquinolin-2-yl)benzonitrile (IV) 4* 4 4,4. 44 4*44 (IV) in acidic medium with an alcohol of formula (VI) R-OH 4444 @4 1 II 4 *4 in which R is a branched or unbranched (C 14 )alkyl radical, functionalising the methyl group in position 6 of the resulting quinoline of formula (VII) (VI') by introducing therein a leaving group L wherein L is chlorine, 4-. 31 bromine or OR 12 where R 12 is tosyl or mesyl, and reacting the resulting quinoline of formula (VII') 0% R (VI I,. 4 4 *1 H 44 4 4 44 4 4 4 44 4444 4444 44 44 4 4 44 44 4 44 with an imidazole of formula (VIII) R 3 N-i 2 NH 4 (VI: in which R 3 and R 4 are as def ined in Claim 1, and then hydrolysing the ester functional group of the resulting quinoline of formula (IX') R 3 N R~ R 2 (1~ in order to obtain a compound of formula (Ib) and optionally II) 32 converting the compou.nd of formula (ib) into a phamaceutically i i acceptable salt thereof. (Ib) so 0 01d IO 4 11144 4 0 4 11. A process for producing a compound represented by formula substantially as described in any one of examples 1 to 6. 12. A com. as claimed in any one of claims 1 to 9 whenever prepares a process as claimed in claim 10 or 11. 13. A pharmaceutical composition which contains a compound as claimed in any one of claims 1 to 9 or 12 and a pharmaceutically acceptable carrier or diluent. 14. A composition according to claim 13 which further comprises a diuretic, an a-blocker, a p-blocker, a calcium antagonist or an angiotensin I converting enzyme inhibitor. A compound of the formula (X) N which -i -I -33- in which W represents either a methyl group or a -CH 2 R 1 1 group in which R 1 1 represents a chlorine atom, a bromine atom or a leaving group OR 1 2 R 1 2 being a tosyl group or a mesyl group, Z represents either a halogen atom or a cyano group or a 1H- group or a 1H-tetrazol-5-yl group protected by a protecting group of formula CR 13 R 14 RI 5 R 13 R 14 and R 1 representing independently of each other a (C 1 2 )alkyl group or an aryl group, or a COOR group, R being a branched or unbranched (C 1 5 )alkyl group. 16. A method for the treatment of hypertensive pathologies, cardiac, renal or pulmonary insufficiencies and glaucoma which comprises administering an effective amount of a. a compound as claimed in any one of claims 1 to 7 to a subject .l 15 in need thereof. S17. A compound according to claim 1 which is 4- ethyl-2-propyl-l-[[2-[2-(1H-tetrazol-5-yl)phenyl]quinolin-6- 18. A compound according to claim 1 which is 2- butyl-4-chloro-l-[ (H-tetrazol-5-yl )phenyl]quinolin-6- 19. Compounds of formula processes for their preparation, pharmaceutical compositions containing them or methods of treatment involving them, substantially as 0- 25 hereinbefore described with reference to the Examples. DATED this 30th day of May, 1994. Synthlabo By Its Patent Attorneys DAVIES COLLISON CAVE 940530,p:\oper\dab27348-92144,33 .7-P 1 Ni i A~BSTRACT OUTNOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION. AND THEIR THERAPEUTIC APPLICATIONS The present invention provides a compound which is a quinoline derivative of the formula (I) 4NIi~ I R2 in which Ri represents either lH -tetra zol -5 -yl, or CO 2 H, Rrepresents either (C.)lylo (C 2 6 alkenyl, to R 3 and R 4 represent, independently of each other, hydrogen, halogen, cyano group, (C 1 7 alkyl, (C 3 7 cyclc&l kyl (C 4 alkyl, aryl, aryl (C,.)alkyl, aryl (C 2 6 )alkenyl, -(CH 2 M-CORS in which m 0 to 4 and N 5 represents hydrogen, -OH, (C 1 6 alkoxy, or- NRR, R 7 and 8 representing, independently of each other, 47R8 7 hydrogen or -(C 1 4 alkyl group, or a (CH 2 n-R 6 group in which n 1 to 4 and R6 represents -OH, -(C 1 6 )alkoxy, -(C 1 4 )alkovro- IA (C. 4 )alkoxy, or (C 3 7 )cycltjalkyl(C 1 .4)alkoxy group, or a pharmaceutically acceptable salt thereof and their therapeutic applications.