IL101014A

IL101014A - 4-pyrimidinone derivatives their preparation and pharmaceutical compositions containing them

Info

Publication number: IL101014A
Application number: IL10101492A
Authority: IL
Original assignee: Synthelabo
Priority date: 1991-02-20
Filing date: 1992-02-19
Publication date: 1996-06-18
Also published as: AU650319B2; HU9200532D0; IE920525A1; DK0500409T3; MX9200690A; ZA921203B; ES2086090T3; PL293531A1; JPH04346980A; DE69209113T2; KR920016434A; IL101014A0; NZ241659A; FR2672892A1; ATE135695T1; RU2073675C1; HU211886A9; DE69209113D1; FI920720A7; PL168617B1

Abstract

1. Compounds, existing in three tautomeric forms, corresponding to the general formulae (I), (I') and (I'') <IMAGE> in which R1 = linear or branched (C1-7)alkyl, linear or branched (C3-9)alkenyl, cyclo(C3-7)alkyl(C1-6)alkyl, R2 = H, linear or branched (C1-7)alkyl, cyclo(C3-7)alkyl(C1-3)alkyl, aryl(C1-3)alkyl optionally substituted in the ring, aryloxy(C1-3)alkyl optionally substituted in the ring, arylthio(C1-3)alkyl optionally substituted in the ring, arylsulphonyl(C1-3)alkyl optionally substituted in the ring, heteroaryl(C1-3)alkyl optionally substituted in the ring, R3 = CO2H 1H-tetrazol-5-yl, NHCOR11, NHSO2R11, CONHSO2R11, CONHOR12, where R11 = CH3, CF3 or optionally substituted phenyl, R12 = H, CH3 or optionally substituted phenyl, as well as their pharmaceutically acceptable organic or inorganic salts. Therapeutic application.t [EP0500409A1]

Description

101014/2 lniN 0> >D0n Π1ΠΡΊ >-|>ΪΟΓΙ1 IDJDD , ) 11 > 1 >Q > ~1 > 3-4 ¾ ΠΠ^ΙΠ 4-PYRIMIDINONE DERIVATIVES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM SYNTHELABO S.A.

C: 14103 1-1062 The present invention relates to novel substituted 4-pyrimidinone compounds, derivatives thereof, their preparation and their application in therapy.

The compounds of the invention have the formula (I) wherein R 1 represents either a straight or branched (C-,_7)alkyl group or a straight or branched (C3_9 )alkenyl group or a cyclo(C3_7 )alkyl (C, _g )alkyl group, 101014/1 la R2 represents either an atom of hydrogen, or a straight or branched y)alkyl group, or a ^)alkyl group optionally substituted on the ring, or a phenoxy(C-^.g ) alkyl group optionally substituted on the ring, or a group optionally substituted on the ring, or a heteroarylfC^.^alkyl group optionally substituted on the ring, where heteroaryl is thienyl, pyridinyl or thiazolyl, and R^ is a CO2H or lH-tetrazol-5-yl group.

The invention further includes the organic or inorganic pharmaceutically acceptable salts of the compounds of formula (I) .

NOTICE .UNDER THE REGISTRAR'S CIRCULAR NO. 23 (P) OF APRIL 5, 1 2 Since the invention is defined in the appended claims, it will be apparent that the passages of the present specification which fall outside the scope of the claims do not relate directly to the invention.

European patent application EP 04073^2 describes pyrimidine compounds of the following formula wherein R^ could be a biphenyl-4-ylmethyl group substituted by a -C00H or a lH-tetrazolyl group and Z could be an oxygen atom, which are useful as angiotensin II antagonists.

The preferred compounds of the invention are compounds having the formula (I) wherein R-^ represents a straight or branched (C-^_y)alkyl group, R2 represents either a straight or branched (C^_y)alkyl group, or a cyclotC-^.yJalkyliC-j^^alkyl group, or an aryl(C, _3)alkyl group optionally substituted on the ring, or a heteroaryl (Cn _ 3 ) alkyl group optionally substituted on the ring, R3 is a C02H or a lH-tetrazol-5-yl group.

Among them, the preferred compounds having the formula (I) are those wherein, represents a straight propyl, butyl or pentyl group, R2 represents an arylmethyl, arylethyl, or a heteroarylethyl group, optionally substituted on the ring, R3 is a C02H or a 1H-tetrazol-5-yl group.

The most preferred compounds are the compounds having the formula (I) wherein, R-, represents a straight butyl group, R2 represents a benzyl or phenethyl or pyridylethyl or thienylethyl or thiazolylethyl group, optionally substituted on the ring, R3 is a C02H or a 1 H-tetrazol-5-yl group.

The compounds of choice are those having the formula (I) wherein, R1 represents a straight butyl group, R2 represents a phenylmethyl group, a 4-carboxyphenylmethyl group, a phenylethyl group, a 4-methoxyphenylethyl group, a 4-fluorophenylethyl group, a 3, 4, 5-trimethoxyphenylethyl group, a 3-fluoro-4-methoxyphenylethyl group, a 3-pyridinylethyl group, a 4-pyridinylethyl group, a 5- ( 4-methylthiazol)-yl-ethyl group or a 3-thienylethyl group, R3 is a C02H or a 1 H-tetrazol-5-yl group.

The compounds of formula (I) can be expressed as tautomeric forms (I) (Γ) (I") which are part of the invention.

The compounds of the invention may be present either in a free form or in the form of organic or inorganic pharmaceutically acceptable salts .

The following scheme provides the preparation of the compounds of the invention: 101014/2 In a first step, a β-ketoester of the general formula (II), in which R, is as defined above and R4 represents a methyl or ethyl group, is condensed with a derivative of the general formula (III), wherein L represents a leaving group such as chloro, bromo, iodo, p-toluenesulfonyloxy or methanesulfonyloxy and R5 represents either a carboxylic group C02R6, wherein R6 is a methyl, ethyl, 1 , 1 -dimethylethyl or benzyl group, either a nitro group, either a 1 //-tetrazol-5-yl group protected, for example, by a triphenylmethyl substituent or 1 , 1 -dimethylethyl substituent, to yield β-ketoester s derivatives of the' general formula (IV), in which applications (253310, 291969, 323841, 400835, 400974, 401030). The reaction is carried out in a solvent such as methanol, ethanol, 1 , 1 -dimethylethanol or dimeth lformamide at a temperature between - 20°C and - 80 °C, in the presence of a base such as sodium hydride, or sodium methylate or potassium 1 , 1 -dimethylethylate and optionally in the presence of a catalyst such as lithium, magnesium or zinc bromide or iodide .

In a second step, a β-ketoester of the general formula (IV) is condensed with an amidine of the general formula (V) to give a pyrimidinone of the general formula (VI), wherein R1 , ¾ and R5 are as defined above. The reaction is carried out by heating, between 40°C and 120°C, a mixture of the two compounds, optionally in a solvent such as methanol, ethanol, butanol or toluene, and optionally in the presence of a base such as sodium methylate, potassium carbonate, sodium acetate, pyridine, triethylamine or 4-dimethylaminopyridine .

In a third step, the deprotection and/or the transformation of the group R5 into the group R3 is performed, depending on the nature of the group: • when R5 is a carboxylic ester, the compounds of general formula (VI) are converted, by an acidic or a basic hydrolysis, to the compounds of general formula (I) wherein Rn and R2 are as defined above and R3 is a C02H group; the C02H group can further be transformed, under classical conditions, by activation by means of various reagents and then by reaction with amines or sulfonamides, to obtain compounds of general formula (I) wherein R3 is a C0NHS02R-| ^ or CONHOR-, 2 group and R-, , R2, R-, -, , R-, 2 are as defined above, •when R5 is a triphenylmethyl-1 //-tetrazol-5-yl or a 1 , 1 -dimethylethyl-1 H-tetrazol-5-yl group, it is deprotected in an acidic medium, under classical conditions, to yield compounds of general formula (I) wherein R3 is the 1 H-tetrazol-5-yl group and and R2 are as defined above, •when R5 is a nitro group, it is transformed into an amino group by reduction, to yield the compounds of general formula (VI) which are converted, by acylation or sulfonylation under 6 classical conditions, to compounds of general formula (I) wherein R3 is a NHCOR 1 1 or a NHS02R11 group and R, , R2 and R1 1 are as defined above.

The following examples illustrate the preparation of the compounds of general formula (I).

The analyses confirm their structure.

Example 1 4 ' - [ ( 6-butyl-2-ethyl-4-oxo-1 , 4-dihydro-pyrimidin-5-yl )methyl ] [ 1 , 1 ' -biphenyl ] -2-carboxylic acid . 1 .1. methyl ' - [ ( 2-methoxycarbonyl ) -3-oxoheptyl ] [ 1 , 1 ' -biphenyl ] -2-carboxylate .

To a stirred solution of 16 g of methyl 3-oxo-heptanoate in 145 ml of methanol chilled in an ice bath, a solution of 5.57 g of sodium methylate (prepared from 2.36 g of sodium in 60 ml of methan l, is added. The mixture is stirred at room temperature for 1 hour and then chilled on an ice bath. A solution of 40.12 g of methyl ' - (bromomethyl ) [ 1 , 1 ' -biphenyl ] -2-carboxylate in 60 ml of methanol is added dropwise. .·· The mixture is stirred at room temperature for 24 hours. It is concentrated at reduced pressure. The residue is taken up in dichloromethane, washed with an aqueous 1 N solution of hydrochloric acid and then with water. It is dried on sodium sulfate and evaporated in vacuo to obtain 42.4 g of the product, used as such in the following step. 1 .2. methyl 4 ' - [ ( 6-butyl-2-ethyl-4-oxo- 1 , 4-dihydro-pyrimidin-5-yl)methyl] [1 , 1 * -biphenyl ] -2-carboxylate .

A mixture of 0.48 g of propanimidamide and 2.5 g of the foregoing compound is heated in an argon atmosphere, at 90°C, for 7 hours. The compound is purified by chromatography on silica gel column, eluting with a mixture of dichloromethane and methanol to give 1.1 g of the product in the form of syrup, directly used in the following' step . 101014/2 7 1.3. 4 ' - [ ( 6-butyl-2-eth l-4-oxo-1 , 4-dihydro-pyrimidin-5-yl ) methyl ] [ 1 , 1 ' -biphenyl ] -2-carboxylic .

A solution of 1.1 g of the foregoing compound and 1.4 g of sodium hydroxide is refluxed for 2 hours in a mixture of 30 ml methanol and 3 ml of water. It is concentrated at reduced pressure. The aqueous phase is washed with ether, filtered and acidified with an aqueous 3 N solution of hydrochloric acid. The precipitate is filtered and racrystaiiized in methanol to obtain 0.55 g of the compound in the form of a white powder.

Melting point = 207°C Example 2 ' - [ ( 6-butyl-2-phenylmethyl-4-oxo-1 , 4-dihydro-pyrimidin-5-yl ) methyl ][ 1 , 1 ' -biphenyl ] -2-carboxylic acid.

Following example 1, a mixture of 0.56 g of benzene-ethanimideamide and 1.7 g of methyl 41 -[( 2-methoxycarbonyl ) -3-oxoheptyl ][ 1 , 1 ' -biphenyl ] -2-carboxylate is heated at 95°C, under an atmosphere of argon, for 4 hours. The product is purified by chromatography on alumina, by eluting with a mixture of dichloromethane and methanol, to obtain 1.0 g of the product. This product is redissolved in a mixture of 30 ml of methanol and 3 ml of water in the presence of 1.0 g of sodium hydroxide. It is refluxed for 3 hours and concentrated under reduced pressure. The residue is taken up in water. The aqueous phase is washed with ether, filtered and acidified with an aqueous 3 N solution of hydrochloric acid. The precipitate is filtered and recristallized in methanol to obtain 0.60 g of the compound in the form of a white powder.

Melting point = 219°C Example 3 4 * - [ [ 6-butyl-2- ( 2-phenylethyl ) -4-oxo-1 , 4-dihydro-pyrimidin-5-yl Jmethyl ] [ 1 , 1 ' -biphenyle ] -2-carboxyli acid . 8 oxoheptyl ] [ 1 , 1 ' -biphenyl ] -2-carboxylate is heated at 95°C, for 6 hours. The product is purified by chromatography on silica gel column, by eluting with a mixture of dichloromethane and methanol, to obtain 1.0 g of the product in the form of a syrup. This product is redissolved in a mixture of 30 ml of methanol and 3 ml of water in the presence of 1.1 g of sodium hydroxide. It is refluxed for 3 hours and concentrated under reduced pressure. The residue is taken up in water. The aqueous phase is washed with ether, filtered and acidified with an aqueous 3 N solution of hydrochloric acid. The precipitate is filtered and recrysta llized in methanol to obtain 0.60 g of the compound in the form of a white powder.

Melting point = 194°C Example 4 6-butyl-2-(2-phenylethyl)-5-[ [ 2 ' - ( 1 tf-tetrazol-5-yl ) [1 , 1 '-biphenyl ] -4-yl ] methyl ] -pyrimidin-4 ( 1 H) -one . 4.1. methyl 3-oxo-2- [ [ 2 ' - ( 1 -triphenylmethyl-1 H- tetrazol-5-yl ) t 1 , 1 ' -biphenyl ] -4-yl ] methyl ]heptanoate .

To a solution of 0.97 g of potassium 1 , 1 -dimethylethylate in 15 ml of dimethylformamide, chilled on an ice bath, under an atmosphere of argon, a solution of 1.3 g of methyl 3-oxo-heptanoate in 13 ml of dimethylformamide is added, followed by 1.67 g of lithium bromide and a solution of 5 g of 5-[4'-(bromomethyl) [1,1 ' -biphenyl ] -2-yl ] -1 -triphenylmethyl-1 H-tetrazole in 25 ml of dimethylformamide. The reaction mixture is stirred for 5 hours at room temperature and then diluted with 300 ml of ether. The mixture is washed twice with 100 ml of water and then with 100 ml of a saturated aqueous solution of ammonium chloride. It is dried on magnesium sulfate and evaporated in vacuo to obtain 4.6 g of the product in the form of a yellow oil used as such in the following step. 4.2. 6-butyl-2- ( 2-phenylethyl ) -5- [ [ 2 ' - ( 1 -triphenylmethyl-1 H-tetrazol-5-yl ) [1,1 ' -biphenyl ] -4-yl ] methyl ] -pyrimidin-4 ( 1 H) - 101014/2 9 foregoing compound is heated, under an atmosphere of argon, at 90°C, for 2 hours. The residue is taken up in 120 ml of dichloromethane and the mixture is washed twice with 50 ml of an aqueous 1 M solution of potassium carbonate and then with 50 ml of an aqueous 0.1 N solution of hydrochloric acid. It is dried on magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 0.85 g of the compound in the form of a whitish foam. 4.3. 6-butyl-2- ( 2-phenylethyl ) -5- [ [ 2 ' - ( 1 H-tetrazol-5-yl ) [ 1 , 11 -biphenyl ] -4-yl ] methyl ] -pyrimidin- ( 1 H) -one . 0.6 g of the foregoing compound is dissolved in a mixture of 5 ml of methanol and 3 ml of diethylether . 2.7 ml of a 1.57 M solution of hydrochlori acid in diethylether are added. The mixture is left at r oo*t\ temperature for 2 hours and then evaporated. The residue is taken up in 70 ml of an aqueous solution of sodium hydroxide. It is washed three times with 30 ml of ether and acidified with hydrochloric acid. The precipitate is filtered and recrystallized in methanol to obtain 0.22 g of the compound in the form of a white powder. Melting point = 226-228°C Example 5 4 ' - [ ( 2 , 6-dibutyl-4-oxo-1 , 4-dihydro-pyrimidin-5-yl)methyl] [1,1' -biphenyle ] -2-carboxylic acid.

Following example 1, a mixture of 1.1 g of pentanimidamide and 2.5 g of methyl 4 ' - [ ( 2-methoxycarbonyl ) -3-oxoheptyl ] -[ 1 , 11 -biphenyl ] -2-carboxylate is heated at 90°C, under an atmosphere of argon, for 10 hours. The product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 1.2 g of product. 1 g of the foregoing product is dissolved in a mixture of 30 ml of methanol and 1 ml of water in the presence of 1.2 g of sodium hydroxide. The mixture is refluxed for 4 hours and concentrated under reduced pressure. The residue is taken up I010 J42 10 acid. The precipitate is filtered and recrystall ized in methanol to obtain 0.45 g of the compound in the form of a white powder.

Melting point = 119°C Example 6 4 ' - [ [ 6-butyl-2- (3,3' -dimethyl ) butyl- -oxo-1 , 4-dihydro-pyrimidin-5-yl Imethyl ] [ 1 , 1 ' - biphenyl ] -2-carboxylic acid.

Following example 1, a mixture of 1.3 g of 4 , -dimethyl-pentanimidamide and 2 g of methyl 41 - [ ( 2-methoxycarbonyl ) -3-oxoheptyl ] [ 1 , 1 ' -biphenyl ] -2-carboxylate is heated at 100°C, under an atmosphere of argon, for 8 hours. The product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 1.48 g of the product.

The foregoing product is dissolved in a mixture of 60 ml of methanol and 6 ml of water in the presence of 1.67 g of sodium hydroxide. The mixture is refluxed for 6 hours and concentrated under reduced pressure. The residue is taken up in 25 ml of water. The aqueous phase is washed with 25 ml_of ether, filtered and acidified with an aqueous 2 N solution of hydrochloric acid. The precipitate is filtered, rinsed with water and recrystallized in methanol to obtain 0.6 g of the compound in the form c n white powder.

Melting point = 222°C Example 7 4 ' -t [6-butyl-2-[2-( thiophen-3-yl) ethyl ]-4-oxo-1 , 4-dihydro-pyrimidin-5-yl Jmethyl ][ 1 , 11 -biphenyl ] -2-carboxylic acid.

Following example 1, a mixture of 1.2 g of 3-thiophenpro-panimidamide and 2.2 g of methyl 4 '-[( 2-methoxycarbonyl ) -3-oxoheptyl ][ 1 , 11 -biphenyl ] -2-carboxylate is heated at 110°C, under an atmosphere of argon, for 3.5 hours. The product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 101014/2 11 methanol and 2 ml of an aqueous 10 N solution of sodium hydroxide. The mixture is refluxed for 3 hours and concentrated under reduced pressure. The residue is taken up in 120 ml of water. The aqueous phase is washed with 3 x 40 ml of ether, filtered and acidified with an aqueous 6 N solution of hydrochloric acid. The precipitate is filtered, rinsed with water and recrystallizea in methanol to obtain 0.41 g of the compound.

Melting point = 184-185°C Example 8 41 - I [ 6-butyl-2- ( phenylsulfonyl )methyl-4-oxo-1 , -dihydro-pyrimidin-5-yl ]methyl ] [1,1 ' -biphenyl ] -2-carboxylic acid.

Following example 1, a mixture of 2.6 g of 2-phenylsulfonyl-ethanimidamide and 2 g of methyl 41 - [ ( 2-methoxycarbonyl ) -3-oxoheptyl ][ 1 , 11 -biphenyl ] -2-carboxylate is heated at 80°C, under an atmosphere of argon, for 6 hours. The product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain . 0.5 g of the product.

The foregoing product is dissolved in a mixture of 15 ml of methanol and 1.5 ml of water containing 0.5 g of sodium hydroxide. The mixture is refluxed for 3.5 hours and concentrated under reduced pressure. The residue is taken up in 150 ml of water. The aqueous phase is washed with 3 x 80 ml of ether, filtered and acidified with an aqueous 3 N solution of hydrochloric acid. The precipitate is filtered, rinsed with water and recrystal'lized in ethanol to obtain 0.19 g of the compound.

Melting point = 210-212°C Example 9 41 - [ [ 6-butyl-2- ( 2-chlorophenoxy )methyl-4-oxo-1 , 4-dihydro-pyrimidin-5-yl]methyl] [ 1 , 1 ' - biphenyi ] -2-carboxylic acid.

Following example 1, a mixture of 1.2 g of 2- ( 2-chloro 101014/2 12 at 80°C, under an atmosphere of argon, for 4 hours . 0.5 g of 2- ( 2-chlorophenoxy )ethanimidamide are added twice at 1 hour and 2.5 hours after the beginning of the reaction. The product is purified by chromatography' on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 0.8 g of the product.

The foregoing product is dissolved in a mixture of 20 ml of methanol and 2 ml of water containing 0.8 g of sodium hydroxide. The mixture is refluxed for 4.5 hours and concentrated under reduced pressure. The residue is taken up in 150 ml of water. The aqueous phase is washed with 3 x 80 ml of ether, filtered and acidified with an aqueous 3 N solution of hydrochloric acid. The precipitate is filtered, rinsed with water and recrystallized in ethanol to obtain 0.29 g of the compound.

Melting point = 159-164°C Example 10 4 ' - [ [ 6-butyl-2- [ 2- ( 4-carboxyphenyl ) ethyl ] -4-oxo-1 , -dihydro-pyrimidin-5-yl ]methyl ] [ 1 , 11 -biphenyle ] -2-carboxylic acid.

Following example 1, a mixture of 1.4 g of 4-methoxycarbonyl-benzenepropanimidamide and 2 g of methyl 4 ' - [ ( 2-methoxy-carbonyl ) -3-oxoheptyl ] [ 1 , 1 ' -biphenyl ] -2-carboxylate is heated at 90°C, under an atmosphere of argon, for 3 hours. The product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 1.3 g of the product. 1.1 g of the foregoing product are dissolved in a mixture of 25 ml of methanol and 2 ml of an aqueous 10 N solution of sodium hydroxide. The mixture is refluxed for 3 hours and concentrated under reduced pressure. The residue is taken up in water. The aqueous phase is washed with ether and with ethylacetate . It is acidified with an aqueous solution of hydrochloric acid. The oil is extracted with dichloromethane and the extracts are concentrated. The residue is recrystallized in methanol containing a few drops of 101014/2 13 Example 11 6-butyl-2- [ 2- ( 3 , 4-methylenedioxyphenyl ) ethyl ] - 5- [ [ 2 ' - ( 1 //-tetrazol-5-yl) [1,1' -biphenyl ] -4-yl Jmethyl ] -pyrimidin-4 ( 1 H) -one .

Following example 4.2, a mixture of 1,4 g of 3 , 4-methylene-dioxybenzenepropanimidamide and 2.6 g of methyl 3-oxo-2- [ [ 21 -( 1 -triphenylmethyl-1/f-tetrazol-5-yl) [1,1' -biphenyl ] -4-yl Imethyl Jheptanoate in 3 ml of toluene is refluxed for 4 hours. It is evaporated under vacuum and the product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 1 g of the product.

The foregoing product is dissolved in a mixture of 15 ml of methanol and 5 ml of tetrahydrofuran containing 1 ml of acetic acid. The solution is refluxed for 5 hours and evaporated under vacuum. The residue is triturated with ether. The precipitate is filtered and rinsed with 3 x 30 ml of ether to obtain 0.45 g of the compound.

Melting point = 230-232°C Example 12 6-butyl-2-[2-(napht-2-yl)ethyl]-5-[[2'-(1tf-tetrazol-5-yl ) [ 1 , 1 ' -biphenyl ] -4-yl ] methyl ] -pyrimidin-4 ( 1 H) -one .

Following example 4.2, a mixture of 1.75 g of 3-(napht-2-yl )propanimidamide and 3.3 g of methyl 3-oxo-2- [ [ 2 ' - ( 1 - [ 1 , 1 -dimethylethyl ] -1 H- te razol-5-yl ) [ 1 , 1 ' -biphenyl ] -4-yl ]methyl ] -heptanoate is heated at 100°C, for 3.50 hours. The product is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 2.9 g of the product in the form of a pale yellow paste. 1.5 g of the foregoing product are dissolved in a 30 % solution of hydrobromic acid in acetic acid. It is heated at 90°C, for 5 hours and evaporated under vacuum. The residue is taken up with dichloromethane. The organic phase is washed with water and dried on sodium sulfate. The solvent is on silica gel column by eluting with a mixture of dichloro-methane and methanol, to obtain 0.63 g of the product in the form of a white powder.

Melting point = 163-166°C The following table illustrates the structures and physical properties of some compounds according to the invention. 15 Table Compound R2 1 C4H9 CH3- 2 C4Hg C2H5- 3 C4Hg C6H5- 4 C4H9 C6H5~CH2~ 5 C4H9 C6H5~ ( CH2)2- 6 C4H9 1 /-tet 7 C4H9 6H5~CH2~ 1 //-tet 16 Compound R! R2 8 C4Hg 4-Cl-C6H4-CH2- 9 C4H9 3-CH30-C6H4-CH2- 10 C4H9 C6H5~ ^ ^H2 ) 3~ 11 C4H9 C4Hg- 12 C4H9 ( CH3) 2~ ( CH2) 2~ 13 C4H9 (CH3)3-C-(CH2)2- 14 C4H9 c-C5H9-(CH2)2- 15 C4H9 c-CgH-|i- ( CH2) ~ 16 C4H9 3-Cl-C6H4-CH2- 17 C4H9 naphtyl-1 -CH2- 18 CH3 C6H5(CH2)2- 19 C2H5 C6H5(CH2)2- 20 C3H7 C'6H5(CH2)2- 21 C-C5H9-(CH2)2 C6H5(CH2)2- 22 C5Hn C6H5(CH2)2- 23 C4H9 thienyl-2- (CH2)2- 17 Compound R2 24 C4H9 thienyl-3- (CH2)2- 25 C4H9 C6H5-OCH2- 26 C4Hg C6H5~SCH2~ 27 C4Hg CgHg—S02CH2_ 28 C4Hg 4-Cl-C6H4-OCH2- 29 C4H9 3-Cl-C6H4-OCH2- 30 C4Hg 2-Cl-C6H4-OCH2- 31 C4Hg 4-CH3O-C6H4-OCH2- 32 C4H9 3-CH30-C6H4-OCH2- 33 C4Hg 4-H02C-C6H4-OCH2- 34 C4Hg 3-H02C-C6H4-OCH2- 35 C4Hg 4-CH3-C6H4-(CH2)2- 36 C4Hg 4-CH30-C6H4- (CH2)2- 37 C4Hg 3, 4-OCH20-C6H4-(CH2)2- 38 C4Hg 4-H02C-C6H4- (CH2)2- 39 C4Hg 4-CH30-C6H4-(CH2)2- 1 /-tet 18 Compound R2 40 C4Hg 3, 4-OCH20-C6H4-(CH2)2- 1 /i-tet 41 C4Hg 4-F-C6H4-(CH2)2- 1 ]7-tet 42 C4H9 3-F-C6H4-(CH2)2- 1 //-tet 43 C4Hg 3,4-F2-C6H3-(CH2)2- 1 iY-tet 44 C4Hg 4-CH3S-C6H4-(CH2)2- 1 /f-tet 45 C4Hg naphtyl-2- (CH2)2- 46 C4Hg naphtyl-1-(CH2)2- 47 C4Hg 3 , 4- ( CH30 ) 2-C6H3- ( CH2) 2- 1 J/-tet 48 C4Hg 3-CH30-C6H4-(CH2)2- 1 ii-tet 49 C4Hg 3 , 4 , 5- ( CH30 ) 3-C6H2- ( CH2) 2- 1 /f-tet 50 C4Hg 3—CF3-C8H4- ( CH2) 2~ 1 f-tet 51 C4Hg 4-Cl-C6H4-(CH2)2- 1 //-tet 52 C4Hg 4-CF3-C6H4-(CH2)2- 1 tf-tet 53 C4Hg 2 , 4- (CH30 ) 2-C6H3- (CH2) 2- 1 /i-tet 54 C4Hg 3-Cl-C6H4-(CH2)2- 1 //-tet 55 C4Hg pyridin l-3- (CH2)2- 1H-tet 19 Compound R2 56 C4H9 pyridinyl-4- (CH2)2- I.V-tet 57 C4H9 3-F, 4-CH30-C6H3-(CH2)2- 1 J/-tet 58 C4H9 4-H02C-C6H4-CH2- 1 i¥-tet 59 C4H9 3-H02C-C6H4-CH2- 1 iV-tet 60 C4H9 4-CH3SO-C6H4- ( CH2) 2- 1 H-tetr 61 C4H9 4-CH3S02-C6H4- ( CH2) 2- 1 H-tet 62 C4H9 3 , 5- ( CH30 ) 2-C6H3- (CH2) 2- 1//-tet 63 C4H9 ( 4-methylthiazol) -5-yl- (CH2)2- 1 tf-tet 64 C4H9 1 H-tet 65 C4H9 CH3- 1 H-tet 66 C4H9 napthyl-2- ( CH2) 2- 1 tf-tet I 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 Γ ¾ 1 -angiotensin II to rabbit adrenal corte .

Male Fauves de Bourgogne rabbits (2-3 kg body weight) are used. Rabbits are sacrificed by cervical dislocation, the adrenal gland excised and the cortex rapidly dissected at 4°C. Tissues are homogenized in 10 ml of ice-cold 10 mM tris (hydroxymethyl ) aminomethane buffer solution, containing 0.33 M sucrose and 1 mM ethylenediaminetetraacetic acid, adjusted to pH 7.4 with hydrochloric acid, in an electrical Potter apparatus 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 g. The supernatant is kept, the pellet is rehomogenized in 10 ml of tris-sucrose buffer and centrifuged as described above. Both supernatants are pooled and centrifuged for 30 min at 47 800 g. The resulting pellet is resuspended in 150 volumes (i.e. 100 mg of tissue in 15 ml of buffer) of an incubation buffer containing 50 mM tris-HCl, 150 mM NaCl, 5 mM ethylenediaminetetraacetic acid, 1.25 p.g/ml bacitracin, 100 μΜ phenylmethylsulfonylfluoride and 0.2 % bovine serum albumin (pH = 7.4 at 25°C) .

Corticoadrenal microsomes (100 μΐ of suspension) are incubated in the presence of 2 nH [ H] -angiotensin II (New England Nuclear, specific activity 61 Ci/mmol) in a final volume of 0.5 ml of incubation buffer for 30 min at 25°C. Following incubation, the microsomes are harvested by filtration on 0.45 urn Millipore HAWP™ cellulose nitrate filters, pretreated with bovine serum albumin, and washed using three 5 ml aliquots of ice-cold tris-HCl buffer.

Membrane bound radioactivity retained by the filters is quantified using liquid scintillation spectrometry.

Specific [3H] -angiotensin II binding is defined as the amount of filter-retained radioactivity that could be inhibited by incubation in the presence of 1 μΜ of unlabelled angiotensin 21 •II. It represents 90 to 95 % of the total amount of filter-retained radioactivity. 3 Specific [ H] -angiotensin II binding is measured in the presence of various concentrations of the test compounds and the Ί.0Χ, the concentration of the test compound which inhibits 50 % of specific [¾] -angiotensin II binding, is graphically determined.

The ICJO values of the compounds of the invention are between 5 nM and 10 μΜ .

Inhibition of pressor response to angiotensin II in rat.

Male Sprague-Dawley rats (250-280 g body weight; Charles River France) are anesthetized with sodium pentobarbital (55 mg/kg i.p.) and maintained under artificial respiration T M (Harvard respirator; rate 70 ml per minute, volume of air 1 mi per 100 g body weight). The animals are pithed through the orbit of the right eye with a metal rod. The right and left vagus nerves are sectionned (bivagotomy ) ; the right carotid artery is ligatured, the left carotid artery being catheterized in order to measure the blood pressure using a T H pressure cell (Statham P23Db type). A femoral vein is catheterized for i.v. administration of drug.

Blood pressure is measured after i.v. administration of 0.5 μg/kg angiotensin II. Compounds of the invention or saline vehicle are administered 5 min (for i.v. studies) or 60 min (for p.o. studies) before injection of angiotensin II.

The compounds of the invention are administered at doses ranging from 0.01 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 for the treatment of various forms of hypertensive pathologies and of coronary, cardiac, renal or pulmonary insufficiencies as well as for the treatment of glaucoma.

The compounds of the invention or their suitable salts may 22 also be used in combination with other substances possesxng cardiovascular activity such as diuretics, a-blockers, β-blockers, calcium antagonists or angiotensine I converting enzyme inhibitors .

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

For the treatment of glaucoma, the compounds of the invention or their suitable salts may be provided in the form of tablets, hard gelatin capsules, injectable solutions or topical ocular formulations.

The compositions of the invention may be administered to patients in an amount which may range from 1 to 1000 mg per day and per patient, in one or more doses. 23

Claims

1. Compounds, in three tautomeric forms, having the general formulas (I), (ΐ') and (I"), (0 (Γ) (Γ) wherein represents either a straight or branched (C-,_7)alkyl group or a straight or branched ( C3 _ 9 ) alkenyl group or a cyclo (C3 _ 7 ) alkyl (C η _g ) alkyl group, 101014/1 23a R2 represents either an atom of hydrogen, or a straight or branched group, or a phenyl (C-^^alkyl group optionally substituted on the ring, or a phenoxyCC^.^alkyl group optionally substituted on the ring, or a group optionally substituted on the ring, or a heteroaryl (C-^_^) alkyl group optionally substituted on the ring, where heteroaryl is thienyl, pyridinyl or thiazolyl, and is a CO2H or lH-tetrazol-5-yl group, and their organic or inorganic pharmaceutically acceptable salts.

2. Compounds as defined in claim 1, characterized in that represents a straight or branched (C^_y)alkyl group, and R2 represents either a straight or branched (C-^y ) alkyl group, or a group optionally substituted on the ring, or a heteroaryl (C-^.-^alkyl group optionally substituted on the ring, where heteroaryl is thienyl, pyridinyl or thiazolyl.

3. · Compounds as defined in claim 2, characterized in that R-L represents a straight propyl, butyl or pentyl group, and R2 represents a benzyl or phenethyl or a heteroarylethyl group, optionally substituted on the ring, where heteroaryl is thienyl, pyridinyl or thiazolyl. 101014/2 24

4. Compounds as defined in claim 3. characterized in that represents a straight butyl group, and R2 represents a benzyl or phenethyl or pyridinylethyl or thienylethyl or thiazolylethyl group, optionally substituted on the ring.

5. Compounds as defined in claim 4, characterized in that R2 represents a benzyl group, a 4-carboxybenzyl group, a phenethyl group, a 4-methoxyphenethyl group, a 4-fluorophenethyl group, a 3.^ ,5~trimethoxyphenethyl group, a 3"fluoro-4-methoxyphenethyl group a 3~pyridinylethyl group, a 4-pyridinylethyl group, a 5~ (4-methylthiazol) -ylethylgroup or a 3~ thienylethyl group.

6. A method for preparing compounds as defined in claim 1, characterized in that a β-ketoester of the formula (II), in which R-^ is as defined in claim 1 and Rjj represents a methyl or an ethyl group, is reacted with a derivative of the 25 formula (III) wherein L represents a leaving group and R5 represents either a carboxylic group C02R6, wherein R6 is a methyl, ethyl, 1 , 1 -dimethylethyl or benzyl group, either a nitro group either a protected lH-tetrazol-5-yl group, to yield a compound of formula (IV), wherein R.,, R4 and R5 are as defined in claim 1 and above, which compound is reacted with an amidine of formula (V) wherein R2 is as defined in claim 1 , to obtain a compound of formula (VI) 101014/2 26 wherein R^ , R2 and R^ are as defined in claim 1 and above, then the R^ group is transformed and/or deprotected, in accordance with the nature of this group, to obtain, after transformation, a compound of formula (I) .

7. The method as defined in claim 6, characterized in that the compounds of formula (VI) wherein R^ is a triphenylmethyl-lH-tetrazol-5-yl or a 1 , l-dimethylethyl-lH-tetrazol-5-yl group, are subjected to deprotection in an acidic medium, to yield compounds of general formula (I) wherein R^ is the lH-tetrazol-5~yl group and R^ and R2 are as defined above.

8. The method as defined in claim 6, characterized in that the compounds of formula (VI) wherein ^ is a carboxylic ester and R-j^ and 2 are as defined in claim 1 are converted, by an acidic or basic hydrolysis, to the compounds of general formula (I) wherein R-^ and R2 are as defined above and R^ is a CO2H group. 9· A pharmaceutical composition, characterized in that it contains a compound defined by any of claims 1 to 5. in association with any appropriate excipient. For the Applicants, Sanford T. Colb & Co. C: 14103 I-IO62.