AU657478B2 - New benzimidazole derivatives, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them - Google Patents

Abstract

The invention relates to the products: <IMAGE> in which: R represents an alkyl or alkenyl, either R1B, R2B, R3B and R5B represent hydrogen, or one of R2B and R5B represents hydrogen or -CH2-O-R10, R10 represents hydrogen, alkyl or alkenyl or <IMAGE> and one of R1B and R3B represents halogen and the other -OR6, -CO2R7 or -R11, in which: R6 and R7 represent hydrogen, alkyl or alkenyl, R11 is: a) optionally substituted alkyl, b) alkenyl, c) acyl or formyl, d): <IMAGE> or one of R1B, R2B, R3B and R5B represents hydrogen and the others are -CH2-O-R10, -OR6, -CO2R7, -R11 or <IMAGE>, R4B represents carboxyl, free, esterified or salified, or tetrazolyl, or -(CH2)m-SO2-X-R12, m representing 0 to 4 and either (-X-R12) represents NH2 or X represents a bond or -NH-, -NH-CO-NH- or -NH-CO- and R12 represents alkyl, alkenyl or aryl, products (IB) being in all the possible isomeric forms, as well as the salts, to a process for their preparation and to their use as medicaments.

Description

AUSTRALIA

Form PATENTS ACT 1952 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: A6h 478 Complete Specification Lodged: S. .Accepted: Lapsed: Published: oo..

Priority:

S.

S0 Related Art: so TO BE COMPLETED BY APPLICANT Name of Applicant ROUSSEL-UCLAF s 0 00 too. *e 0 Address of Applicant 35 Boulevard des Invalides, 75007, Paris, France Actual Inventors: Address for Service: Michel FORTIN, Daniel FRECHET, Gilles HAMON, Simone JOUQUEY and Jean-Paul VEVERT CALLINAN LAWRIE, Patent Trade Mark Attorney, 278 High Street, Kew, Victoria 3101, Australia.

Complete Specification for the invention entitled: "NEW BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM" The following statement is a full description of this invention, including the best method of performing it known to me:- 1A New benzimidazole derivatives, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them.

The present invention relates to new benzimidazole derivatives, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them.

A sibject of the present invention is the products of formula 4 e 0 0*0 0 :o o 0e o S* o 00 *00 .0 **0 20/914GV78246.SPE1 N

R

5

A

NR

R4A in which: R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, RIA, R2A, R 3 A and R5A are such that: either RIA, R2, R3A and RSA are identical and represent a hydrogen atom, or R 2 A and RSA are such that one represents a hydrogen atom or a -CH 2

-O-R

0 radical, in which R1 represents a hydrogen atom or or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, and the other represents a hydrogen atom, and RA and R 3 A are such that one represents a hydrogen atom and the other is chosen from the radicals -OR 6

-CO

2 R, and -R1, in which radicals: R and Ry, identical or different, represent a hydrogen atc' or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms,

R,

1 is chosen from the group formed by: a) alkyl radicals having at most 4 carbon atoms,optionally substituted by one or more radicals chosen from: halogen atoms, the optionally acylated hydroxyl radical, linear or branched alkyloxy or alkenyloxy radicals having 35 at most 5 carbon atoms, the free, esterified or salified carboxy radical, the radical: Ra

-N

in which R a and Rb, identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having 1 to 4 carbon atoms optionally substituted by a halogen atom or a hydroxy radical, b) linear or branched alkenyl radicals having 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the inrmyl radical, RA represents a free, esterified or salified carboxy radical, a cyano radical, or a tetrazolyl radical, optionally salified, except the compounds in which R represents a radical alkyl, RA R 2 A and 5A represent hydrogen and R 3

A

represents hydrogen or (CH 2 )n-COD in which n represents 0 or 1 and D represents hydrogen, hydroxyl, amino, alkylamino, dialkylamino, halogen and alcoxy, the said products of formula (IA) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral or organic acids and mineral or organic bases of the said products of formula (IA).

Thus a subject of the present invention is the products of formulae as defined above and corresponding to the 25 formula R, 4 4* 4 *4* 4 4 4*4 P 7 I

I

O- I in which: R R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, 35 R 1

R

2

R

3 and R 5 are such that: either R 1

R

2

R

3 and Rs are identical and represent a hydrogen atom, or R 2 and R 5 are such that one represents a hydrogen atom or a -CH2-O-R, radical and the other represents a hydrogen atom, 4 and R, and R 3 are such that: one represents a hydrogen atom and the other is chosen from the radicals -OR 6 -C0 2 R. and -CH 2 which radicals R10, R 6

R

7 and R 8 identical or different, represent a hydrogen 0@

B

0 0 *00 0 0000 0000 *0*0 0* 0c 0 U 0~ 0000

U

000 0' 1~ 1~ L atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms,

R

4 represents a free, esterified or salified carboxy radical, the said products of formula being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral or organic acids and mineral or organic bases of the said products of formula In the products of formulae (E3, (IA) and and in what follows: the term linear or branched alkyl radical preferably designates methyl, ethyl, propyl or isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals but can also represent a pentyl radical and in particular tert-pentyl, the term linear or branched alkenyl radical preferably S 15 designates a vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, or 2-butenyl radical but can also represent a l-pentenyl, 2pentenyl or also 3-pentenyl radical, the term halogen atom preferably designates the bromine S" atom, but can also represent a fluorine, chlorine or iodine atom, the alkyloxy and alkenyloxy radicals that can be repre- S sented by O-R 10 and -0-R 6 are formed for example with the 4 alkyl and alkenyl radicals as defined above, for alkyloxy radicals there can be mentioned preferably 25 methoxy or ethoxy radicals, but also propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy or also pentoxy radicals, for alkenyloxy radicals there can be mentioned preferably vinyloxy or propenyloxy radicals, for esterified carboxy radicals, there can be mentioned preferably a (lower alkyloxy or alkenyloxy carbonyl) group such as methoxycarbonyl or ethoxycarbonyl, but also propoxycarbonyl, butoxycarbonyl, butenyloxycarbonyl, tertbutoxycarbonyl, or also pentoxycarbonyl radicals, the term acyl radical preferably designates a radical having at most 7 carbon atoms such as the formyl, acetyl, propionyl, butyryl or benzoyl radical, but can also represent a valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl radical, the term acyloxy radical preferably designates the groups containing one of the acyl radicals as defined above and linked to an oxygen atom, such as for example acetoxy or benzoyloxy, the term aryl radical designates monocyclic radicals or radicals constituted by condensed rings, carbocyclic or heterocyclic, it being understood that the heterocyclic radicals can contain one or more heteroatoms chosen from oxygen, nitrogen or sulphur atoms and that when these heterocyclic radicals contain more than one heteroatom, the heteroatoms of these heterocyclic radicals can be identical or different.

The term monocyclic radical preferably designates radicals which contain 5 or 6 links, «as carbocyclic monocyclic radicals, there can be mentioned the 15 phenyl radical; among the heterocyclic monocyclic radicals, there can be Smentioned, for example, the following radicals: thienyl, a ua 'r furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, 2-D pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl such as delta 2-pyrrolinyl, imidazolinyl such as delta 2-imidazolinyl, pyrazolinyl such as delta 3pyrazolinyl, as well as the isomers of position of the heteroatom or heteroatoms that these radicals can contain such as, for example, isothiazolyl or isoxazolyl radicals.

The term radical constituted by condensed rings preferably designates radicals which contain 8 to 14 links: among the radicals constituted by carbocyclic condensed rings there can be mentioned, for example, the naphthyl and Ie*• phenanthryl radicals, among the radicals constituted by heterocyclic condensed rings there can be mentioned, for example, benzothienyl, naphtho- [2,3-b]-thienyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3Hindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, the naphthyridinyl, imidazopyridyl, quinoxa-linyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl,

I.

d -9 phenoxazinyl, indolinyl, isoindolinyl or also condensed polycyclic systems constituted by heterocyclic monocyclics as defined above, such as for example furo-[2,3-b]-pyrrole or thieno-[2,3-b]-furane.

As examples of such an aryl radical, there can be mentioned the following radicals: phenyl, naphthyl, thienyl such as thien-2-yl and thien-3-yl, furyl such as fur-2-yl, pyridyl such as pyrid-3-yl, pyrimidyl, pyrrolyl, thiazolyl, isothiazolyl, diazolyl, triazolyl, tetrazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, 3- or 4-isoxazolyl; condensed heterocyclic groups containing at least one heteroatom chosen from sulphur, ;:itrogen and oxygen, for i example benzothienyl such as benzothien-3-yl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, 15 indolyl or purinyl.

a a: Such aryl radicals can be optionally substituted such as for example the N-substituted pyrrolyl radical, for example N- S* a methylpyrrolyl, the substituted 3- or 4-isoxazolyl radical, for example, 3-aryl-5-methylisoxazol-4-yl, the aryl group being, for example, a phenyl or halophenyl group; the groups Ra R S-N and N a d Rb Rd S which represent an amino radical optionally substituted by one or two identical or different radicals, designate for example monoalkyl and dialkylamino radicals in which the alkyl radicals can take the meanings indicated above, such as for example, methyl, ethyl, isopropyl, butyl, isobutyl, these radicals being optionally substituted, such as for example in hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl or also ethoxyethyl, trifluoromethyl, pentafluoromethyl; the amino radical can also be substituted by one or two alkenyl radicals as defined above and such as for example vinyl, allyl, 1-propenyl and 1-butenyl radicals; among the substituents of these amino radicals, there can also be mentioned aryl and aralkyl radicals such as, for example, i the following radicals: phenyl, benzyl, phenethyl, naphthyl, indolyl, indolinyl, thienyl, furyl, pyrrolyl, pyridyl, pyrrolidinyl, piperidino, morpholino, piperazinyl, these radicals being able to be substituted by one or more radicals as defined above, such as for example in methyl-piperazinyl, fluoromethylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl.

the -(CH 2 )m-SO 2

-X-R

12 radical can represent for example the radicals in which (CH 2 )m represents the alkylene values of the alkyl radicals indicated above such as, for example, methylene, ethylene, n-propylene, isopropylene, isobutylene or tert-butylene and R.2 can represent an alkyl radical chosen from the values defined above, or an aryl radical also chosen from the values indicated above for this radical, such as for example phenyl, biphenyl, naphthyl, tetrazolyl; the alkyl radical that can be represented by the R12 radical can be optionally substituted by an aryl radical chosen from the values defined above in order to form an aralkyl radical.

These alkyl, aryl and aralkyl radicals can themselves be 20 substituted as is indicated above for these radicals.

There can be mentioned, for example and in a nonexhaustive manner, the following radicals: -SO 2

-NH

2 -SO2-NH-

CH

3 -SO2-NH-CF 3 -SO2-NH-C 6

H

5 -S0 2

-NH-CH

2

-C

6

H

5 s The radical R preferably represents a propyl, 1-propenyl, 25 butyl or 1-butenyl radical but can also represent an isopropyl, sec-butyl, tert-butyl and 2-butenyl radical.

o The addition salts with mineral or organic acids and mineral or organic bases of the products of formulae (IA) and can be, for example, the salts formed with the 30 following acids: hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic such as for example methanesulphonic, ethanesulphonic, propanesulphonic, alkyldisulphonic such as for example methanedisulphonic, 1,2ethanedisulphonic, arylmonosulphonic such as benzenesulphonic and aryldisulphonic.

The salts formed with hydrochloric acid are notably -9preferred.

The carboxy radical or radicals of the products of formula can be salified by mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammoniumn or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,Ndimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, Nmethylglucamine.

to.

0:0.09 0 6 20/9/94GV79246.SP,9 Among the products in which RA, represents an alkyloxy radical, there can be mentioned for example the products in which

R

2 A, R 3 A and RSA represent a hydrogen atom.

In the preferred products indicated above the alkyl and alkyloxy radicals contain 1 to 5 carbon atoms and preferably represent respectively: for the alkyl radicals, ethyl and methyl radicals, and for the alkyloxy radicals, methoxy and ethoxy radicals.

A quite particular subject of the invention is the products of formula as defined above, in which R represents a butyl radical and RI,, R 2 A, R 3 A and RsA represent a hydrogen atom, the said products of formula (IA) being in all the possible racemic, enantiomeric and diastereoismeric isomer forms, as well as the addition salts with mineral or organic acids and mineral or organic bases of the said products of formula A more particular subject of the invention is the products of formula as defined above, in which R represents a butyl radical, RA, R 2 A and R 5 A represent

*S

0 f S ft I ft ftf ftOft ft t o ftftft f ftf •t f f ft •t f ftf 2U0/94GV78246.SP-E10 a hydrogen atom, and R 3 A is chosen from the radicals -OR 6 -C0 1

R

7 and in which radicals: R. and identical or different, represent a hydrogen atom or a linear or branched alky! or alkenyl radical containing at Dote o* p as most 5 carbon atoms.

R

11 is chosen from the group formed by: a) alkyl radicals having at most 4 carbon atoms, optionally substituted by one or more radicals chosen from: halogen atoms, the optionally acylated hydroxy radical, linear or branched alkyloxy or alkenyloxy radicals having at most 5 carbon atoms, free, esterified or salified carboxy radicals, the radical:

-N

Rb in which R, and Rb, identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having 1 to 4 carbon atoms, optionally substituted by a halogen atom or a hydroxy 0:44 radical, b) linear or branched alkenyl radicals having 2 to 5 carbon atoms, *9 9 20 c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, R 4 A having the meaning indicated above, the said products of formula (IA) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral or organic acids and mineral 25 or organic bases of the said products of formula (IA).

Notably a subject of the invention is the products of formula (IA) as defined above, in which R represents a butyl radical and RIA, R2 and R 5 A represent a hydrogen atom, and R 3 represents hydrogen; a carboxy radical free or esterified by an alkyl radical containing at most 4 carbon atoms; a formyl radical; an alkyl or alkenyl radical containing at most 4 carbon atoms; the alkyl radical being optionally substituted by one or more radicals chosen from halogen atoms, hydroxy or acyloxy radicals, amino radicals optionally substituted by one or two alkyl radicals containing at most 4 carbon atoms; the said products of formula (IA) being in a±l the possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with the mineral or organic acids 13 and mineral or organic bases of the said products of formula Among the products which are a subject of the invention, there can be mentioned quite particularly: methyl 4 (2-butyl-lH-benzimidazol-1-yl)--methyl3-biphenyl-2carboxylate and its salts, [(2-butyl-1H-benzimidazol-1-y -methyl] -biphenyl-2-carboxylic acid and its salts, 2-butyl-1- '-carboxy-biphenyl-4-yl) -methyl] -1H-benzimi-dazole- 7-carboxylic acid and its salts, [2-butyl-7- (2-hydroxy ethyl) -l1-benzimidazol-1-yl]-me'-hyl] biphenyl-2-carboxylic acid and its salts, [(2-butyl-7-formyl-1H-benzimidazol-1-yl) -methyl] -biphenyl-2carboxylic acid and its salts, is 2-butyl-1-[ [2'-(lH-tetrazol-5-yl)-(1,1'-biphenyl)-4-yl]-methyl]lH-benzimidazole-7-carboxylic acid and its salts.

20,9/94GV78246.Srfl43 Also a subject of the invention is a preparation process for products of formula (I) R1B R5

B

R

2 B (IB)

/CH

2

R

3

B

R

B

4B in which: R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, RI, R 2 B, R3B and R 5 are such that: either R1, R2B, R 38 and R 5 are identical and represent a hydrogen atom, or R 2 g and R 5 B are such that one represents a hydrogen atom and the other represents a hydrogen atom or a -CH 2 -O-Rl radical, in which R10 represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, or one of R 2 and Re 5 represent the radical

R

c 0** S 0. R d Sin which R c and Rd, identical or different, represents the values defined hereafter for Ra and Rb and RI, and R3B are such that one represents a hydrogen atom and the other is chosen from the radicals -OR 6 -C0 2

R

7 and in which radicals: S. R 6 and Ry, identical or different, represent a hydrogen atom Se or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, 35 RI is chosen from the group formed by: a) alkyl radicals having at most 4 carbon atoms, optionally substituted by one or more radicals chosen from: halogen atoms, S the optionally acylated hydroxyl radical, linear or branchedalkyloxy or alkenyloxy radicalshaving at most 5 carbon atoms, aryl radicals optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro, amino radicals, alkoxy radicals containing at most 4 carbon atoms, phenyl, benzyl radicals, free, salified or esterified carboxy radicals and tetrazolyl radicals, the free, esterified or salified carboxy radical, the radical: Ra

N

^Rb in which Ra and Rb, identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having 1 to 4 carbon atoms and aryl radicals, all these radicals being optionally substituted by one or more radicals chosen from halogen atoms, or the hydroxyl, trifluoromethyl, cyano, nitro or amino radical, alkoxy radicals containing at most 4 carbon atoms, phenyl or benzyl radicals, free, salified or esterified carboxy radicals and tetrazolyl radicals, b) linear or branched alkenyl radicals having 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl S 25 radical, d) the radical: 0* 8

*-N

Rb in which Ra and Rb have the meaning indicated above, or one at most of RR, R 2 B, R 3 B and Rs, represents a hydrogen atom, and the others are chosen from the radicals -CH 2 -O-Ri 0

-OR

6

-CO

2

R

7 and the radical 35 R

-N

S.Rd T in which R 6

R

7 R1, R1, Rc and Rd have the values indicated above, f- T 1

R

4 B represents a free, esterified or salified carboxy radical, or a tetrazolyl radical, or a -(CH 2 )m-SO 2

-X-R

2 radical in which m represents an integer from 0 to 4 and either (X-R 2 represents NH 2 or X represents a single bond, or the radicals -NH-CO- NH- or -NH-CO- and R 12 represents an alkyl, alkenyl or aryl radical, these radicals being optionally substituted, the said products of formula being in all the possible racemic, enantiomeric or diastereoisomericisomer forms, as well as the addition salts with mineral or organic acids and mineral or organic bases of the said products of formula characterized in that: either a product of formula

RIB'

NRB'

R I (IVB) HN

R

2

B

R

3

B'

in which R has the meaning indicated above and RiB, R 21 R3B, and RSB, have the meanings indicated above for R 1 B, R 2 B, R3B and RS respectively in which the optional reactive functions are 25 if desired protected by protective groups, is reacted with a 44to compound of formula Hal 30

(VB)

4 4* 4* 4 4 ./7 in which Hal represents a halogen atom and R 4 B, has the meaning indicated above for R 4 B in which the optional reactive functions are, if desired, protected by protective groups, in order to obtain a product of formula (IXB):

(IXB)

S

*OS.

S

*5 5 95 *r

S

S.

in which R, RIB,, R 2

R

3 R5B and R 4 B, have the meanings indicated above, 20 or a) a compound of formula

(VIB):

R

1

B'

(VIB)

55 S *.fO

R

3

B'

in which RlBI, R 2

R

3 B and R5B, have the previous meanings, is reacted with the compound of formula (II): R-C-Rg(II) 0 in which R 9 represents a hydroxy or alkyloxy radical or a halogen atom and R has the meaning indicated above, in order to obtain the product of formula (XB): 0 02 NR 5

B

C1 1

(XB)

R NH R 2

B'

RB'

in which R, RiB,, R 2

R

3 B' and R5B, have the previous meanings, b) a compound of formula (VIB,):

RB'

RsB

(VIB,)

1 5

HN

15

H

2 N R 2

B'

R

3

B'

S. in which RIB,, R 2 BB R 3 B' and RSB, have the previous meanings, is reacted with the compound of formula (II) as defined above in order to obtain the product of formula

RB'

the compound of formula a defined above, I

IXI(X

RB R B e

R-

30 in which RiB, R 2B', R 3 R5B, and R have the meanings indicated previously, which is subjected to a nitration reaction in order to obtain the compound of formula (Xg) as defined above, which product of formula (XB) is reacted with the compound of formula (VB) as defined above, in order to obtain a product of formula

(XIB):

I 0^

R.B'

(XIB)

in which R, R R 2

R

3 B, R5B, and R 4 B' have the previous meanings, which is subjected to a selective reduction reaction of the nitro function, in order to obtain the product of 15 formula

(XIIB):

d aa *i a wag.

a e g a a a- .a i lb

S

*0

S.

o *9s

(XIIB)

R B'

I

*f 30 in which R, RiB,, R2B,, R 3

R

5 B, and R 4 B, have the previous Smeanings, which is subjected to a cyclization reaction in order to obtain the products of formula (IXB) as defined above, or the compound of formula (VIg) is reacted with the compound of formula (VB) as defined above, in order to obtain a product of formula

(VIIB):

.2A RN 1 HN R 2

B'

I

H R B' (VIIB)

N)

R

4

B'

in which RIB,, R 2 B R 3 R5B' and R 4 B, have the meanings indicated above, which is subjected to a selective reduction reaction of the nitro radical in order to obtain a product of i formula (VIIIB): HN R RB'

I

BCH 2 R B (VIIIB) R4

B

494" in which R1BIB R2B,, R3B R5B and R4B, have the meanings indicated above, which is reacted with the product of formula S 30 (III): R-C-R (III) in which X represents an oxygen atom or an NH radical, Rg and R have the meaning indicated above, in order to obtain after cyclisation a product of formula (IXB) as defined above, which product of formula (IXg), if desired and if necessary, is subjected to one or more of the following reactions, in any order: frl* an elimination reaction of the optional protector groups, a salification reaction by a mineral or organic acid or base in order to obtain the corresponding salt, an esterification or salification reaction of the acid function, an acid or alkaline hydrolysis reaction of the ester function into an acid function, a conversion reaction of an alkyloxy radical into a hydroxy radical, a conversion reaction of a haloalkyl radical into an alkylene radical, a substitution reaction of a halogen atom by an amino radical, a substitution reaction of a hydroxy radical by a halogen atom, a reduction reaction of an esterified carboxy radical into a hydroxyalkyl radical, B an oxidation reaction of a hydroxyalkyl radical into an esterifid carboxy radical, 00 20 an oxidationreaction of a hydroxymethyl radical into aformyl radical, a resolution reaction of the racemic forms into resolved products, a conversion reaction of a free, salified or esterified carboxy function, into a tetrazolyl radical, the said products of formula (Ig) thus obtained being in all so the possible racemic, enantiomeric and diastereoisomeric isomer forms.

In the preferred conditions for implementing the 30 invention, the ave process is carried out in the following manner: The reaction of the compound of formula (VB) in which the halogen atom preferably represents a bromine atom on the anion of the imidazole of formula (IVB) prepared for example by the action of an alkaline agent such as sodium or potassium hydride or also of a sodium or potassium alcoholate such as for example sodium methylate, can be carried out, for example, in an organic solvent such as dimethylformamide or -I AL, 1 i 1tetrahydrofuran.

The addition reaction of the compounds of formula (II) on the free amine function of the compounds of formula (VIB) or (VIB,) in order to obtain the products of formula (XB) or respectively can be carried out by simple heating to a temperature of about 120 0 C to 170 0 C: a compound of formula (II) can be for example valeric acid, used in this case preferably in excess relative to the compound of formula (VIB) or

(VIB,).

The nitration reaction of the products of formula (XB,) in order to give the products of formula (XB) can be carried out for example in the presence of nitric acid in a solvent such as for example acetic anhydride and acetic acid at a temperature of between 0 and 10 0 The addition reaction of the compounds of formula (VB) on the amide function of the compounds of formula (XB) in order to obtain the products of formula (XIB) can be carried out at ambient temperature or by heating to a temperature of between 20°C and 150 0 C, preferably in the presence of an alkaline S 20 agent such as for example triethylamine, soda, sodium methylate or ethylate or also sodium hydride in a solvent such as for example tetrahydrofuran or dimethyl-formamide.

The reduction of the nitro radical of the products of Sformula (XIB) into an amino radical in order to obtain the 25 products of formula (XIIB) can be carried out according to the usual methods known to a man skilled in the art, notably by catalytic hydrogenation in the presence of palladium hydroxide in a solvent such as for example ethanol or by zinc in a solvent such as for example acetic acid in the presence of sodium acetate or also by sodium borohydride.

The cyclization reaction of the products of formula (XIIB) in order to obtain the products of formula (IXB) can be carried out by simple heating or in the presence of a catalyst such as for example thionyl chloride, phosphorous pentachloride or also phosphoric anhydride in a solvent such as for example tetrahydrofuran or dimethylformamide.

The addition reaction of the compounds of formula (VB) on the free amine function of the compounds of formula (VIB) in f order to obtain the products of formula (VIIB) can be carried out in the same conditions as those described above for the addition of the compounds of formula (VB) on the products of formula (IVg).

The reduction of the nitro radical of the products of formula (VIIB) into an amino radical in order to obtain the products of formula (VIIIB) can be carried out according to the usual methods known to a man skilled in the art, notably in the same conditions as those described above for the reduction of the nitro radical of the products of formula

(XIB).

The addition reaction of the compounds of formula (III) on the free amine radical of the products of formula (VIIIB) followed by the cyclization of the products thus obtained can be carried out according to various reaction conditions known to a man skilled in the art, preferably in an organic solvent 1*6' such as for example tetrahydrofuran or dimethylformamide at a S: temperature of between 20 0 C and 200°C.

SThe compound of formula (III) can be, for example, when X S 20 represents NH, ethyl pentanimidoate and when X represents 0, for example, valeric acid.

According to the values of RB,, R 2

R

3 B, and R 5 the products of formula (IXB) constitute or do not constitute the products of formula (Ig).

The various reactive functions that can be carried by some of the compounds defined above can, if necessary, be protected: they may be, for example, free hydroxy or carboxy radicals which can be protected by the easily-eliminated appropriate protective groups.

30 The following non-exhaustive list of examples of *6 protection of reactive functions can be mentioned: the hydroxy radicals can be protected for example by trimethylsilyl, methoxymethyl or tetrahydropyranyl radicals, the carboxy groups can be protected for example in the form of esters formed with easily cleavable esters such as benzyl or tert-butyl esters or esters known in the chemistry of the peptides.

The elimination of these protective groups can be carried i. \9 4 out in the usual conditions known to a man skilled in the art, notably by acid hydrolysis carried out with an acid such as hydrochloric, benzenesulphonic, paratoluenesulphonic, formic or trifluoroacetic acid.

A list of different protective groups which can be used will be found for example in the Patent BF 2,499,995.

The products described above can, if desired, be subjected to salification reactions by a mineral or organic acid carried out according to the usual methods known to a man skilled in the art.

The optional conversions of ester functions into an acid function of the products described above can be, if desired, carried out in the usual conditions known to a man skilled in the art, notably by acid hydrolysis with sulphuric or hydrochloric acid, or also by alkaline hydrolysis for example with soda or potash in an alcohol medium such as, for example, in methanol.

I° The optional alkyloxy functions such as notably methoxy of the products described above can be, if desired, converted into an alcohol function in the usual conditions known to a .man skilled in the art, for example by boron tribromide in a solvent such as for example methylene chloride, by pyridine hydrobromide or hydrochloride or also by hydrobromic or hydrochloric acid in water or acetic acid under reflux.

i 25 The optional conversion of a haloalkyl radical into an alkylene radical of the products described above can be, if desired, carried out in the usual conditions known to a man skilled in the art, notably by saponification and dehalogenation for example in the presence of aqueous soda in an alcohol such as for example methanol.

The optional substitution reaction of a halogen atom by an amino radical of the products described above can be, if desired, carried out in the usual conditions known to a man skilled in the art, notably by treatment of the halogen compound with an amine derivative such as for example dimethylamine at ambient temperature in a solvent such as an alcohol such as for example ethanol or methanol.

The substitution reaction of a hydroxy radical by a *l a '3 halogen atom can be carried out in the usual conditions known to a man skilled in the art such as notably by chlorination with thionyl chloride.

The chlorinated derivative can be in its turn optionally substituted by an amine derivative such as for example dimethylamine.

The reduction reaction of an esterified carboxy radical into a hydroxyalkyl radical can be carried out in the usual conditions known to a man skilled in the art, such as notably by the action of lithium-aluminium hydride, diisobutylaluminium hydride or also other reducing agents known to a man skilled in the art.

The oxidation reaction of a hydroxyalkyl radical into an esterified carboxy radi:al can be carried out in the usual conditions known to a man skilled in the art, such as notably by an oxidizing mixture such as BOWERS reagent, followed by an esterification, for example with diazomethane.

The oxidation reaction of the hydroxymethyl radical into a formyl radical can be carried out in the usual conditions 20 known to a man skilled in the art, such as notably by the action of activated manganese dioxide in methylene chloride.

The optional optically active forms of the products of formula (IB) can be prepared by resolution of the racemics according to the usual methods known to a man skilled in the 25 art. The salts formed with optically active bases can for example be used.

The compounds of formula (IB) as defined above as well as their addition salts with acids have use'fl pharmaco-logical properties.

The products are endowed with antagonistic properties for the angiotensin II receptor and are thus notably inhibitors of the effects of angiotensin II, in particular of the vasoconstricting effect and also of the trophic effect at the level of the myocytes.

These properties justify their use in therapeutics and a subject of the invention is also, as medicaments, the products as defined by formula (IB) above, the said products of formula 47) (IB) being in all the possible racemic or optically active 1 V isomer forms, as well as the addition salts with pharmaceutically acceptable mineral or organic acids and mineral or organic bases of the said products of formula (IB).

A subject of the invention is in particular, as medicaments, the products of formula (IB) as defined above in which R represents a butyl or 1-butenyl radical and R1B represents a hydrogen atom, and quite particularly the products of formula (Ig) as defined above in which R represents a butyl radical and RIB, R2B and Rgg are identical and each represents a hydrogen atom and R 3 B represents a hydrogen atom, a carboxy radical free or esterified by an alkyl radical containing at most 4 carbon atoms; a formyl radical; an alkyl or alkenyl radical containing at most 4 carbon atoms; an alkyl radical substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, acyloxy radicals, amino radicals optionally substituted by one or two alkyl radicals containing at most 4 carbon atoms and free, S. salified or esterified carboxy radicals, R 4 B represents a e* free, salified or esterified carboxy radical, an optionally 20 salified cyano or tetrazolyl radical, as well as the addition salts with pharmaceutically acceptable mineral or organic acids and mineral or organic bases of the said products of formula

(IB).

A more particular subject of the invention is, as 25 medicaments, the following products of formula (IB): Methyl 4'-[(2-butyl-lH-benzimidazol-1-yl)-methyl]-biphenyl-2carboxylate, *g.e 4'-[(2-butyl-lH-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylic acid, 2-butyl-l-[[2'-carboxy biphenyl-4-yl]-methyl]-iH-benzimidazole-7-carboxylic acid, 4'-[[2-butyl-7-(2-hydroxy ethyl)-1H-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylic acid, 4'-[(2-butyl-7-formyl-1H-benzimidazol-l-yl)-methyl]-biphenyl- 2-carboxylic acid, 2-butyl-1-[[2'-(lH-tetrazol-5-yl)-(1,1'-biphenyl)-4-yl]methyl ]-H-benzimidazole-7-carboxylic acid, as well as their addition salts with pharmaceutically 1 a7 acceptable mineral or organic acids and mineral or organic bases. he medicaments which are a subject of the invention can be used in the treatment of arterial hypertension, cardiac insufficiencies, renal insufficiencies and in the prevention of post-angioplastic recurrences of stenosis.

They can also be used in the treatment of some gastrointestinal and gynaecological disorders and in particular for their relaxing effect at the level of the uterus.

The invention extends to pharmaceutical compositions containing as active ingredient at least one of the medicaments as defined above.

These pharmaceutical compositions can be administered by buccal or rectal route, by parenteral route or by local route as a topical application on the skin and mucous membranes.

These compositions can be solid or liquid and can be presented in all the pharmaceutical forms currently used in human medicine such as, for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable A e o* preparations, ointments, creams, gels and aerosol 20 preparations; they are prepared according to the usual methods. The active ingredient can be incorporated with the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, 0 4 paraffin derivatives, glycols, various wetting, dispersing or emulsifying agent, and preservatives.

SThe usual dosage, variable according to the product used, the patient treated and the affection in question, can be, for example, 1 to 100 mg per day for an adult, by oral route.

The starting compounds of formulae (III), (IVB), (VIg) and (VIB,) are commercially available or can be prepared according to the usual methods known to a man skilled in the art.

The preparation of some of the compounds of formula (IVg) is described in: J. Amer. Chem. Soc. (1937) i9, 178.

The other products of formula (IVB) can be prepared by the action of a compound of formula (III) as defined abovs if with a product of formula (XIII): R 1BI

H

2 N 5B'

R

3

BI

(XIII)

in which R 1 R R 38 and Rg,, have the meaning indicated above.

The operating conditions are the same as those indicated above for the action of the products of formula (III) on the products of formula (VIII.).

Some of the compounds of formula (XIII) are commercially available, such as for example methyl 3,4-diaminobenzoate, marketed for example by LANCASTER.

An example of the preparation of these compounds of formula (XIII) is given in: Journal of the Chemical Society, Chemical Communications, (1957) 2197-2201.

Among the compounds of formulae (II) and (III) there are found for example ethyl pentanimidoate which can be prepared, for example, by the action of gaseous hydrochloric acid in ethanol on valeronitrile, marketed, for example, -y LONZA.

An example of the preparation of these compounds of formula (III) is given in J. Amer. Chem. Soc. (1942), 64, 1827.

S. S *5

S

I

-S 5 A preparation process for the products of formula as defined above can consist of subjecting methyl iodo-benzoate I! marketed for example by JANSSEN, to the action of S: iodotoluene, marketed for example by FLUKA, the reaction is carried out for example in the presence of powdered copper at a temperature of 100 0 C to 300 0 C, iin order to obtain a product of formula S s 31 H3o the esterified carboxy radical of which can, if desired, be liberated from the alkyl radical by standard methods known to a man skilled in the art or as indicated abov-., for example acid or alkaline hydrolysis, which can be subjected to a bromination reaction on the methyl radical by standard methods known to a man skilled in the art, for example by the action of N-bromosuccinimide in carbon tetrachloride.

The preparation of some of the compounds of formula (V) or or also some of the conversions of the R4B radical of the products of formula (IX can be found, for example, in 20 the Patent US 4,880,804 or EP 0,253,310.

th* The compound of formula (VIg) can be for example orthonitroaniline, in the form of the product marketed for example by UCB.

The products of formula (VI can also be prepared, for S 25 example, by the process described in: .o V Canadian journal of chemistry, (1977), 55 pp 1653-1657.

S, The products of formula (VI which are aniline

B

.derivatives are commercially available such as for example 2,4-dimethoxy aniline from ALDRICH or can be prepared as well as is indicated for example in the following references: BEILSTEIN volume XII, 3rd supplement p. 1662 BEILSTEIN volume XIII, 3rd supplement p. 2128.

Finally a subject of the present invention is, as new industrial products and notably as intermediate products necessary for the preparation of products of formula (IB), the compounds of formulae (IVB), (rTIB), (VIIIB), (XB) and In addition to the products des.ribed in the examples which illustrate the invention without however limiting it, the following products constitute products which can be obtained within the scope of the present invention: these products of formula (I)are such that R represents a butyl radical, R 4 A represents a carboxy radical and RIA, R 2 A, R 3

A

and RSA have the meanings indicated in the table below: 0* .500.

00 0.

so I I 3,

S

4 51 so .4one

HT

H

H

H

CH

2 0H

CH

2 0H

CH

2 0H CH 2 0H CH 2

OH

CH 2 0H

CH

2 0H

CH

2 0H

CH

2 0H 0CH 3

OCH

3 0CH 3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3

OCH

3 Cl Cl Cl Cl Cl Cl

C)-

Cl Cl

OH

COOMe

CH

3

OH

COOMe

COOH

CH 3 CH 2

OH

CH

2 Cl CH 2 -C 2

-OH

CH 2 -CH 2 -Cl

OH

COOMe

COOH

CH3 CH 2 COi CH 2 -CH 2

-OH

CH 2 -CH 2 -Cl.

OH

COOMe

COOH

CH 3 Cl CH 2

OH

CH 2

C

CH 2 -CH 2 -O11 CH1 2 -CH 2

-CJ

I I I I RIB R2B R 5B R3B

A

a*go 0 0.o 0@ I R 1 IB RI Rb- R I OHi I H H IOHI OH I H I H COOMe I I OH H I H ICF! 3 I OH I H I H Ici I OH I H I H ICH 2 0HI I OH I H I H ICH 2 C1 OH I H I H I CH 2 -CH 2 -OH I I OH I H I H I CH 2

-CH

2 -C1I The following examples illustrate the invention without however limiting it.

EXAMP~a 1: Mothyl -((2-butyl-iH-benzimidazol-1-yl)-methyl)biphenyl-2-carboxylate hydrochloride A solution of 2 g of 2-butyl-lH-benzimidazole (prepared according to W.O. Pool, HJ HARWOOD and AW RALSTON J. Amer.

Chem. Soc., (1937) 59, 178) in 3 cm 3 of dimethylformamide is added to a suspension of 650 mg of sodium methylate in 5 cm 3 of dimethylformamide cooled down to o0C. The mixture is agitated for 15 minutes while being allowed to return to ambient temperature. A solution of 3.6 g of methyl 4'- (bromomethyl)-biphenyl-2-carboxylate (obtained according to EP 0,253,310) in 5 cm 3 of dimethylformamide is added over minutes.

15 Agitation is carried out for 4 hours at 400C, the dimethylformamide is evaporated off and 50 cm 3 of an aqueous solution of sodium bicarbonate is added. After extraction three times with 100 cm 3 of ethyl acetate, the extracts are washed with water, dried, filtered and evaporated to dryness.

The residue (4.6 g) is chromatographed on silica (eluant: ethyl acetate cyclohexane 1.8 g of desired product is obtained in the form of a base.

Salification: A solution of hydrochloric ethyl acetate is added to a solution of 500 mg of the base obtained above in isopropanol until an acid pH is obtained. The ethyl acetate is evaporated off, the product is crystallized from isopropanol, separated, washed with isopropanol, and dried under reduced pressure at 100°C. 350 mg of hydrochloride is obtained, M.p. 1550C, which is recrystallized twice from isopropanol. In this way 230 mg of the desired product is obtained in the form of the hydrochloride, M.p. 155-160°C.

Analysis for C 26

H

27

N

2 0 2 1C 435.01 C H Cl N calculated 71.79 6.25 8.15 6.44 found 72.00 6.2 8.3 6.3 IR Spectrum (CHC1 3 Absorption complex 2800 2000 cm-1 (of the type: N Q -H) W j f

II

-1 0 1723 cm II-1

-C-OCH

3 1438 cm C=C 1620 cm 1 C=N 1599 cm 1 Aromatic 1558 cm-1 1510 cm-1 -1 1488 cm 1 EXAMPLE 2: 4'-[(2-butyl-lH-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid 0.8 cm 3 of 2N soda is added to a solution of 500 mg of the ester obtained in Example 1 in the form of a base in 8 cm 3 of methanol. Agitation is carried out for 4 hours under reflux. The methanol is evaporated off, the resultant mixture is cooled down to +10 0 C and acidified to a pH of 5-6 with 2N hydrochloric acid, then agitated for 30 minutes at +10 0

C,

separated, washed with water, dried at 80 0 C under reduced pressure. 400 mg of product is obtained, M.p. 190 0 C, which is recrystallized twice from isopropanol in order to obtain 125 mg of the desired product. M.p. 234 0

C.

Analysis for C 25

H

24

N

2 0 2 384.48 C H N calculated 78.10 6.29 7.28 found 78.00 6.3 7.2

U

Oe

U~

*9 U9

U.

.9

U

009S

I.

9U.

IR Spectrum (Nujol) 25 C=O 1682 cm-1 Aromatic 1615 cm 1 heteroaromatic 1597 cm 1 -1 1518 cm PREPARATION 1: Methyl 4'-[N-[2-(methoxycarbonyl)-6-nitrophenyl] -N-(pentanoyl)-aminomethyl]-biphenyl-2-carboxylate STAGE A: 2-amino-3-nitro benzoic acid a) acetylation: 0.65 cm 3 of concentrated sulphuric acid is added to a suspension cooled down to +10°C of 12 g of 2-amino-3-nitro toluene and 14.4 cm 3 of acetic anhydride and the mixture is agitated for one hour at ambient temperature. 50 cm 3 of water is added, followed by agitation for 15 minutes, separating, washing with water then with ether, and drying at 100 C under I 4 I reduced pressure. 13.6 g of desired product is obtained.

M.p. 156 0

C.

b) oxidation: 13.4 g of the compound obtained above is added to a suspension of 29.48 g of potassium permanganate and 21.44 g of magnesium sulphate in 1470 cm 3 of water. The mixture is agitated for 3 hours at 100 0 C, allowed to return to ambient temperature, then cooled down to 0 C The insoluble part is filtered off, 10 cm 3 of concentrated hydrochloric acid (pH 2-3) is added to the filtrate which has been cooled down to 0°C Extraction is carried out 4 times with 500 cm 3 of ethyl acetate, the extracts are washed with water, dried, Sfiltered and evaporated under reduced pressure. 16.1 g of product is obtained which is crystallized from ethyl ether in 15 order to collect 12.1 g of the desired product. M.p. 192 0

C.

.e c) hydrolysis: 12 g of the previously obtained product is agitated for 4 hours at 1200C with 75 cm 3 of water with 5% concentrated S hydrochloric acid, the mixture is allowed to return to ambient temperature, cooled down to 0°C +5 0 C, agitated for one hour at this temperature, separated, washed with water then with ether, and dried at 100°C under reduced pressure. 8.8 g of Ithe desired product is obtained. M.p. 210 0

C.

a STAGE B: Methyl 2-amino-3-nitro benzoate 25 A suspension of 1 g of the acid obtained in Stage A, cm of methanol and 1.4 cm 3 of 95-97% sulphuric acid is agitated under reflux for 48 hours. The methanol is evaporated off, 100 cm 3 of water is added, alkalization is W carried out by adding sodium bicarbonate, followed by extracting 3 times with 200 cm 3 of methylene chloride. The extracts are washed with water, dried, filtered and evaporated under reduced pressure. 1 g of expected product is obtained.

M.p. 96 0

C.

STAGE C: Methyl 3-nitro-2-pentanamido benzoate 850 mg of product obtained in Stage B above and 5 cm 3 of valeryl chloride are agitated under reflux for one hour.

After evaporation to dryness the residue is taken up in 80 cm 3 of ethyl ether, treated with activated charcoal, filtered and 4

A

v' f .314.

yt, evaporated under reduced pressure. 1.3 g of product is obtained which is crystallized from a mixture of isopropyl ether and pentane, and 1 g of desired product is collected.

M.p. 58 0

C.

An analytical sample was prepared by dissolution in cm 3 of isopropyl ether under reflux, filtration and concentration to 5 cm 3 The medium is left at rest for 18 hours at ambient temperature, separated, and washed with isopropyl ether. 710 mg is obtained. M.p. This 710 mg is dissolved in 25 cm 3 of hot isopropyl ether, treated with activated charcoal, filtered, and concentrated to 10 cm 3 This medium is left at rest at ambient temperature for one hour, separated, and washed with isopropyl ether. 380 mg of the desired product is obtained.

15 M.p. 60 0

C.

Analysis for C 13

H

16

N

2 0 5 280.27 C H N calculated 55.71 5.75 10.00 found 55.8 5.38 9.9 *6 i a. S a.

a,

S

*e IR Spectrum (CHC1 3 NH complex C=O complex -1 3400 cm (ep) 3330 cm 1 (max) 1730 cm 1 (ep) 1708 cm 1 (max) 1608 1588 1499 cm-1 1608 1588 1499 cm 25 Aromatic (I Amide II

NO

2 1540 1360 cm STAGE D: Methyl 4'-[N-[2-(methoxycarbonyl)-6-nitro phenyl]-N- (pentanoyl)-aminomethyl]-biphenyl-2-carboxylate 170 mg of sodium hydride at 50% in oil is added to a solution of 1 g of the product obtained in Stage B above in cm 3 of dimethylformamide. Agitation is carried out for minutes after the release of hydrogen has finished then 1.09 g of methyl 4'-(bromomethyl)-biphenyl-2-carboxylate (preparation EP 0,253,310) is added and agitation is carried out for one hour at ambient temperature. The solvent is evaporated off and the residue is taken up 3 times in 250 cm 3 of ethyl A l a 'I It "I acetate then washed 3 times with 50 cm 3 of water, dried, filtered and evaporated under reduced pressure. 2 g of product is obtained which is chromatographed on silica (eluant: methylene chloride methanol 99-1). 1.6 g of the desired product is collected.

IR Spectrum (CHC1 3 C=O complex 1726 and 1670 cm 1

NO

2 1538 and 1352 cm 1 Aromatics 1600 and 1576 cm-

I

EXAMPLE 3: Methyl 2-butyl-l-[2'-(methoxycarbonyl)-biphenyl-4yl]-methyl] -IH-benzimidazole-7-calboxylate hydrochloride a) hydrogenation: 365 mg of palladium at 18% on activated charcoal is added to a solution of 730 mg of the compound obtained in Stage D of 15 preparation 1 in 15 cm of tetrahydrofuran. Agitation is carried out for one hour 30 minutes under a hydrogen atmosphere (109 cm of hydrogen is absorbed), the catalyst is *6 filtered off, the residue is rinsed with methylene chloride and evaporated to dryness under reduced pressure, and 730 mg of product is obtained.

b) cyclization: 730 mg of the above product is dissolved in 5 cm 3 of ethyl acetate and 5 cm of isopropanol and a large excess of a solution of hydrochloric acid in ethyl acetate is added. The 25 mixture is heated to 50°C for 5 minutes and left for i minutes at ambient temperature, the solvents are evaporated off and the residue is taken up 3 times in 3 cm 3 of ethyl acetate. After separating and washing with ether, 640 mg of 040 the desired product is obtained. M.p. 160°C.

190 mg of the above product is recrystallized from isopropanol, and 163 mg of the expected product is obtained.

M.p. 160°C.

Analysis for C 28

H

28

N

2 0 4 HCl 492.99 C H Cl N calculated 68.21 5.93 7.19 5.68 found 67.8 5.8 7.3 IR Spectrum Absocption complex type .N a-H 2380 cm 1 .P 9 I 1 I lb 0 lb0 0000 0004 0oi ''lb.

00 U .t lb 04 lb .4 0S 0 lb C=O 1727 and 1721 cm 1 EXAMPLE 4: 2-butyl-l-[(2'-carboxy biphenyl-4-yl)-methyl]-iHbenzimadasole-7-carboxylic acid A solution of 440 mg of the product obtained in Example 3 with 10 cm 3 of ethanol, 1 cm 3 of water and 1 cm 3 of caustic soda lye is agitated for one hour under reflux. The athanol is evaporated off, the residue is dissolved in water (10 cm 3 and the solution is acidified to pH 3-4 with acetic acid.

After separating, 360 mg of product is obtained, M.p. 160 0

C,

then at 250 0 C, 450 mg of product obtained as above is recrystallized from 15 cm 3 of methanol, 5 drops of acetic acid and 5 cm 3 of water. 370 mg of product is obtained, M.p. 255 0 C, which is dissolved in 20 cm 3 of methanol and 10 cm 3 of methylene chloride under reflux. The solution is filtered, 15 the methylene chloride is evaporated off and one drop of acetic acid and 5 cm 3 of water are added. After one night at ambient temperature, separation is carried out and 330 mg of product is obtained. M.p. 255°C.

Analysis for C 2 6H 24

N

2 0 4 428.47 C H N calculated 72.88 5.65 6.54 found 73.0 5.6 IR Spectrum (nujol) General absorption OH/NH region C=0 1704 cm-1 NMR Spectrum (DMSO)

CH

3 0.88 (t)

CH

2 1.39 (m)

CH

2 1.76 (m) CH2-C= 2.87 (m)

N-CH

2 5.90 (s) C6h 4 6.88 7.23 (d,l) 7 other H aromatics 7.20 to 7.90 (m) mobile H's approx. 12.95 (m) PREPARATION 2: Methyl 4'-[N-[[2-nitro-6-[(pentanoyloxy)methyl]-phenyl]-N-pentanoyl]-aminomethyl]-biphenyl-2carboxylate STAGE A: 2-amino-3-nitrobenzyl alcohol 0 0 0 0*

I,

9 9 &age 990 *a .9 .9 9* 9 S*0 t e 4 9 9 *9 0 aJ cm 3 of diisobutylaluminium hydride (in a 1.0 M solution in hexane) is added over one hour 30 minutes and at a temperature of between +7 and to a solution of 3.54 g of the product obtained in Stage B of Preparation 1 in 90 cm 3 of tetrahydrofuran. The resultant mixture is agitated for minutes then, 40 cm 3 of tetrahydrofuran with 10% water is added over 15 minutes, with further agitation, then 10 cm 3 of water is added and agitation is continued for 30 minutes at ambient temperature, 350 cm 3 of methylene chloride with methanol is added, agitation is carried out for 15 minutes, followed by filtering and evaporating to dryness under reduced pressure. The residue obtained, 3.3 g, is crystal-lized from cm 3 of isopropyl ether. 2.22 g of the desired product is obtained. M.p. 110°C.

15 An analytical sample was obtained by recrystallizing 170 mg of the above product, hot and cold, from isopropyl ether.

80 mg of pure product is collected. M.p. 112 0

C-

Analysis for C 7

H

8

N

2 0 3 168.15 C H N calculated 50.00 4.80 16.66 found 49.8 4.8 16.5 IR Spectrum (CHC1 3 OH 3604 cm 1

=C-NH

2 3498 3390 cm 1 NH2 def 1624 cm" 1

(F)

NO

2 1520-1345 cm 1 complex Aromatic 1580 cm 1 STAGE B: 3-nitro-2-pentanamido benzyl pentancate 1.5 g of the product obtained in Stage A and 15 cm 3 of valeroyl chloride are agitated for 6 hours 'Lt ambient temperature. 80 cm 3 of essence G (B.p.40-7 0 is added, separation is carried out and 2.55 g of the desired product is obtained, M.p. 82°C. After recrystallization of 118 mg of the above product from isopropyl ether, 72 mg of product is collected, M.p. 84°C.

Analysis for C 17

H

24

N

2 0 5 336.38 C H N calculated 60.70 7.19 8.33 .9 $9.

found IR Spectrum

=C-NH

C=0 60.7 7.3 (CHC1 3 3426 cm- 1 1734 and 8.4 1702 cm- 1 Aromatics

NO

2 1610 1588 1538 1480 cm- 1 Amide II STAGE C: Methyl [2-nitro-6-[ (pentanoyloxy)-methyl]phenyl] -N-pentanoyl ]-aminomethyl]-biphenyl-2-carboxylate 240 mg of sodium hydride at 50% in oil is added to a solution of 1.35 g of the product obtained in Stage B above in 13.5 cm 3 of dimethylformamide. The mixture is agitated for 15 minutes then 1.35 g of methyl 4'-(bromomethyl)-biphenyl-2-carboxylate (preparation according to EP 0,253,310); agitation is carried out for 30 minutes at ambient temperature, followed by extraction 3 times with 50 cm 3 of methylene chloride, and the extracts are washed with water, dried, filtered and evaporated to dryness under reduced pressure. The residue (2.7 g) is chromatographed on silica, (eluant: cyclohexane ethyl acetate 2.05 g of the desired product is obtained, Ubad as it is (Rf 0.20 (cyclohexane ethyl acetate

B

o 4 t *o• ICC 7;C_ w~a.

i tr.

ic~ 20/9/94GV78246.SPE,40 41- EXAMPLE5:4'-[[2-butyl-7-(hydroxymethyl)-1H-benzimidazol-1-yl]methyl]-biphenyl-2-carboxylic acid The operation is carried out as in Example 4, starting with 400 mg of Methyl A'-[[2-butyl-7-[(pentanoyloxy)-methyl]-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate hydrochloride. 290 mg of desired product is obtained 250 0 C) which is recrystallized from aqueous ethanol in a slightly acetic medium, then from ethanol on its own, in order to collect 207 mg of the expected product, M.p. 250 0

C.

Analysis for C 26

H

26

N

2 0 3 414.51 C H N calculated 75.34 6.32 6.76 found 75.2 6.3 6.8 IR Spectrum (CHC1 3 Absorptions OH/NH approx.

C=0 1688 cm 1 Aromatic 3480 cm- 1 *o *5

S

S~

*5 a 225 Heterocycle NMR Spectrum (DMSO) 300 MHz

CH

3 0.87 ppm (t)

CH

2 1.36 ppm (m)

CH

2 1.73 ppm (m) CH, 1.81 ppm (m)

C

6

H

4 -CH1-O- 4.52 (s)

C

6

H

4 6.91 (d) 7.28 (d) the other aromatics approx. 7.08 2H 7.32 1H approx. 7.54 2H 7.70 1H 5.50 EXAMPLE6:Methyl4 [2-butyl -7-(hydroxymethyl) -H-benzimidazol- 1-yl]-methyl]-biphenyl-2-carboxylate A solution of 823 mg Methyl 4'-[[2-butyl-7-[(pentanoyloxy)methyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate hydrochloride in 8.2 cm 3 of ethanol and 1.6 cm 3 of 2N soda is agitated for 30 minutes. Then 10 cm 3 of water is added, followed by separating and drying, and 600 mg of the expected product is 1598 1518 cm- 1 5* S S

'S

S3 S S

S

S

S. S S. Sr 3 21/9/9478246.SPE,41 -42obtained 138 C) which is recrystallized from ethyl acetate then isopropanol, M.p. 140 0

C.

Analysis for C 2 7

H

28

N

2 0 3 428.51 C H N calculated 75.67 6.59 6.54 found 75.8 6.5 IR Spectrum (CHC1 3 OH 3600 cm- C=0 1722 cm EXAMPLE 7: Methyl 4'-r [2-butyl-7-(chloromethyl)-IH-benzimidazol- 1-yl]-methyl]-biphenyl-2-carboxylate hydro-chloride A solution of 1 cm 3 of thionyl chloride in 5 cm 3 of methylene chloride is added to a solution of 250 mg of the product obtained in Example 6 in 25 cm 3 of methylene chloride, and agitation is carried out for 15 minutes. After evaporation to dryness, the residue is crystallized from a mixture of ethyl acetate and ether. 250 mg of desired product is obtained. M.p. 150°C.

Analysis for C 27

H

8 Cl2N202 483.43 C H Cl N calculated 67.08 5.84 14.66 5.80 found 67.0 5.9 14.4 5.9 IR Spectrum (CHC1 3 C=0 1724 cm" i 4 0: EXAMPLE 8: [2-butyl-7-(chloromethyl)-1H-benzimidrzol-l-yl]- 25 methyl]-biphenyl-2-carboxylic acid 350 mg of the product obtained in Example 5 in 5 cm 3 of thionyl chloride is agitated for 2 hours at ambient temperature.

After evaporation, about 5 g of ice then 20 cm 3 of water are added and agitation is carried out overnight at ambient temperature. The water is decanted, the residue is taken up in 30 cm 3 of methylene chloride, dried, filtered and evaporated to dryness under reduced pressure.

360 mg of the expected product is obtained in the form of an oil. CCM Rf 0.40 (methylene chloride methanol *35 PREPARATION 3: Methyl 4'-[N-[2-nitro-6-[ (2-pentanoyloxy)-ethyl]phenyl]-. -pentanoyl]-aminomethyl]-biphenyl-2-

AI)

219/94GV78246.SP 42 4 1 1 1 carboxylate STAGE.A: 2-(2-pentanamido phenyl)-ethyl pentanoate The operation is carried out as in Stage B of Preparation 2 starting with 5 cm 3 of 2-amino phenethyl alcohol. 10.06 g of expected product is obtained, M.p. 59C. An analytical sample was prepared by 2 successive recrystallizations from essence G on 1.1 g of product, and 610 mg of purified product is obtained.

M.p. 62 0

C.

Analysis for C 18

H

27 3 NO 305.42 C H N calculated 70.79 8.91 4.59 found 70.9 9.2 4.6 o IR Spectrum (CHC1 3 15 3360 cm 1 -C-NH 13430 cm- C=0 1684 cm- Amide II 1530 cm -1 1720 cm 0 STAGE B: 2-(3-nitro-2-pentanamido phenyl)-ethyl pentanoate 7.1 cm 3 of acetic acid is added at a temperature of between 0° and +10 0 C to a solution of 9.1 g of the product obtained in Stage A above in 50 cm 3 of acetic anhydride.

Agitation is carried out for 2 hours between 00 and 100°, 150 cm 3 of water is added, followed by separating and washing with water. 9.90 g of product is obtained which is chromatographed on silica (eluant: ethyl acetate cyclohexane 30-70); and 5.89 g of desired product is obtained, M.p. 117°C.

859 mg of the above product is recrystallized from isopropyl ether then from ether, and 494 mg of the expected product is collected. M.p. 120°C.

Analysis for C 18 i 26

N

2 0 5 350.42 C H N calculated 61.7 7.48 7.99 found 61.5 7.5 ;.9 IR Spectrum 330 cm 1 -C-NH 13420 cm 1 C=O 1725 cm-1 11700 cnf1 Aromatics 1605 cW- 1 Amide 1I 1583 cm-' 1st NO 2 band 1535 cm-' 1478 cm7I (complex) 2nd NO 2 band 1348 cmf 1 STAGE C: Methyl 4'-tN-[[2-nitro-6-[(2-pentanoyloxy)-ethyl]phenyl -N-pentanoyl3-aminomethyl]-biphenyl-2-carboxylate The operation is carried out as in Stage C of Preparation 2 starting with 3.5 g of the product obtained in Stage B above, using 480 xg of sodium hydride at 50% in oil and 3.05 g of methyl 4'-(bromomethyl)-biphenyl-2-carboxylate (preparation EP 0,253,310). After chromatography on silica (eluant: ethyl acetate cyclohexane 5.19 g of the desired product is obtained.

IR Spectrum (CHCl 3 (PE 580) C=O 1728 crrf 1666 cnf 1

CH

3 of 1438 cm- 1

OCH

3 N 1534 cmf 1 EXAMPLE 9: Methyl 4'-j[2-butyl-7-(2-hydroxy ethyl)--, benzimidazol-1-yl3-methyl]-biphenyl-2-carboxylate 2.42 g of methyl 4'-[[2-butyl-7-2-(pentanoyloxy)ethyl] -1H-benzimidazol-1-yl3-methyl]-biphenyl-2-carboxylate with 20 cm 3 0* 0* 9c

I'

of methanol and 5.5 cm 3 of IN soda is agitated for 30 minutes at ambient temperature. The methanol is evaporated off, followed by extraction with methylene chloride, the extracts are washed with water and evaporated to dryness under reduced pressure. The residue is crystallized Zrom ethyl acetate, and 1.59 g of desired product is obtained. M.p. 139 0 C. An analytical sample was prepared by recrystallizatixon of 110 mg of the above product from ethyl acetate and 79 mg of product is collected. M.p. 139°C.

Analysis for C 23

H

30

N

2 0 3 442.56 C H N e 44 e.g.

4.CO 4 4. 4 44 4.

*5 4* 4 4 CS *5

S

S..

4 4 CC S 4 S 4 4404 0.

a. 05 0@ 4 .4.5 calculated 75.99 6.83 6.33 found 75.8 6.8 6.2 IR Spectrum (CHC1 3 15 OH 3615 cm Associated 13550 cm-1 1720 cm 1 io EXAMPLE 4'-[[2-butyl-7-(2-hydroxy ethyl)-IH-benzimidazol- 1-yl]-methyl]-biphenyl-2-carboxylic acid The operation is carried out as in Example 4 starting with 400 mg of the product obtained in Example 4 3. 371 mg of expected product is obtained, M.p. 174°C. The product is recrystallized twice from ethanol, and 96 mg of desired product is collected. M.p. 175°C.

25 Analysis for C 27

H

28

N

2 0 3 1/2 C 2

H

5 0H 451.574 C H N calculated 74.48 6.92 6.20 found 74.15 7.0 6.2 IR Spectrum Absorption OH/NH region ,C=O 1680 cm 1 Conjugated system 1592 cm-1 Aromatic 1512 cm" 1 NMR Spectrum (DMSO) 250 MHz Presence of about 0.4 mol of ethanol

CH

3 0.87 (t)

CH

2 1.37 (m)

CH

2 1.73 (m) 'I V If

CH

2 C6lls i 2

C

2 2. 80 (t) 2.88 3.62 9 9.

easa

S

9909 a. 9 a.

*0 0* S 9 a a.

4.

a.

040 9 ~aa09a a I ~*9 a a *0 0 N-Cll 2

-C

6

H

5 5.71 (s) C 6 H 4 6.2(d) 7.9(d) the other aromatic H's) 6.96 1Hl 7.10 1H (7.34 Ill 7.40 to 7.60 3H /7.70 (dd) in mobile H 4.2 to beD.zimidazoi-1-yi]--methyl]-biphenyl-2-carboxylate h1 ro- 15 chlorideb A mixture of 714 mig of the product obtaine in Example 11 is agitated for 45 minutes at 80 0 C with 14 cm 3 of thionyl mixur istaen p tieswit 2 c 3 of ethyene chlrd and evaporated to dryness each time. Th /final dry extract is crystallized from ethyl acetate. 733/ of desired product is obtained, M.p. =151 OC. A microanaly ical sample was obtained by two successive recrystallizatio, from an ether ethyl acetate mixture The purified product is obtained.

M.p. 160 0

C.

Analysis for C 28

H

3 0 N 2 0 2 C1 2 97.47 C H N Cl calculated 67.60 .08 5.63 14.25 t- found 67.5 6.08 5.6 14.2 IR Spectrum CHC1 3 Absorption type +-H 0 1725 cm 1 -C-OCH 3 1434 cml Aromatic 1624 1600 1565 cm-1 Heteroaromatc 1512 1496 cm- 1 EXiAMPLE 14 2-butyi-7- (2-chloro-othyl) -1H-bensimidazol-1- Yl -moth -biphenyl-2-carboxylia acid o--n-Eapo4is 4cu 47 EXAMPLE 11: Methyl 2-butyl-7-formyl-1H-benzimieazol-l-yl] methyl] -biphenyl-2-carboxylate hydrochloride 600 mg of the product obtained in Example 6 is dissolved in cm 3 of methylene chloride and 1.2 g of activated manganese dioxide is added. The mixture is agitated f or 24 hours at ambient temperature, filtered and evaporated to dryness under reduced pressure, and 600 mg of the expected .0 20/9/94GV78246.SP,47 -48product is obtained in the form of a base.

Preparation of the hydrochloride 600 mg of the product obtained above is dissolved in 3 cm 3 of ethyl acetate and a mixture of ethyl acetate and hydrochloric acid is added, in excess.

Separation is carried out, followed by washing with ether and drying at 80°C under reduced pressure.

610 mg of the expected hydrochloride is obtained. M.p. 145 0

C.

IR Spectrum in CHC1 3 C=0 1723 1706 cm- 1 Aromatic 1618 1599 1563 1520 cm- 1 Heterocycles 1498 cm- 1 EXAMPLE (2-butyl-7-formyl-lH-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid 600 mg of the product obtained in Example 11 is dissolved in 6 cm' of ethanol, 0.8 cm 3 of water and 0.8 cm 3 of caustic soda lye and agitation is carried out for 2 hour 30 minutes at 50 0

C.

The mixture is cooled down, 30 cm 3 of water is added and acetic acid is added until a pH of 4-5 is obtained.

Agitation is carried out for 30 minutes at ambient temperature, followed by separating, washing with water and drying at 90 0 C under reduced pressure. 470 mg of product is obtained. M.p. 225 0

C.

The product obtained above is dissolved in 30 cm 3 of o methanol under reflux, followed by filtering, concentrating and leaving to crystallize at ambient temperature. The crystals are separated, washed with methanol and dried at 90 0 C under reduced pressure. 360 mg of the expected product is obtained. M.p. '.30 230 0

C.

Analysis for C 26

H

24

N

2 0 3 412.47 C H N calculated 75.7 5.87 6.79 found 75.5 5.8 6.7 IR Spectrum in Nujol C=O 1690 cm- 1 Aromatics 1600 1580 cm- 1 A/ Heterocycle 1516 cm- 1 20/994GV78246.SP E48 -49- NMR Spectrum (DMSO) 300 MHz CH3 0.88 (t) CH, 1.38 (m)

CH

2 1.75 (m) CH, 2.88 (m) C=0

N-CH,-C

6

H

5 6.05 (sl) C6H4 6.93 (d) 7.25 (d) 7.31 1H 7.42 2H the other aromatics 7.53 (td) 1H 7.69 1H 7.83 1H 8.0 1H mobile protons 10.08 and 12.75 EXAMPLE 13: 4'-[[2-butyl-7-[(dimethylamino)-methyl]-1Hbenzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid dihydrochloride 360 mg of the product obtained in Example 8 is dissolved in cm 3 of dimethylamine at 33% in ethanol and agitation is carried out for 19 hours at ambient temperature. The mixture is evaporated, extracted 3 times with 20 cm 3 of methylene chloride, washed twice with 15 cm 3 of salt water, dried, filtered and evaporated under reduced pressure. 300 mg of the expected product is obtained in the form of a base.

t*o: Preparation of the dihydrochloride The operation is carried out as in Example 11, by dissolving 300 mg of the product obtained above in 5 cm 3 of isopropanol in the presence of an excess of ethyl acetate and hydrochloric acid.

110 mg of the expected product is obtained.

260 0

C.

Analysis for C, 8

H

3 ,N0 2 2HC1 514.47 C H Cl N calculated 65.36 6.46 13.78 8.17 found 65.3 6.5 13.8 IR Spectrum in Nujol 35 C=0 1770 1680 cm-' Aromatics 1623 1597 cm" 1 Heterocycles 1514 1495 cm 1 K" 0 2/9/94GV78246.SPE,49 NMR Spectrum (DMSO) 300 MHz CH 0.92 ppm (t) CH 1.44 (m)

I

CH, 1.83 (m) 1

CH

2 3.24 (m)

=C-CH

2 -N 4.38 (m)

N-CH,-C

6

H

5 5.98 (sl) CA |7.20 (d) 7.34 (d) 7.56 1H 7.88 1H the other aromatics 7.75 1H 7.55 2H 7.47 1H approx. 7.37 masked 1H mobile protons 11.39 and 12.78 EXAMPLE 14: Methyl [2-butyl-l-[2'-(methoxycarbonyl)-biphenyl-4yl]-methyl]-lH-benzimidazol-7-acetate hydrochloride a) Preparation of the [2-butyl-l- 2 '-(methoxycarbonyl)-biphenyl- 4-vyl-methyll-lH-benzimidazol-7-acetic acid 1 g of the product obtained in Example 9 is introduced into cm 3 of acetone and 1.5 cm 3 of BOWERS reagent. The mixture is agitated for one hour at ambient temperature, filtered, the filtrate is rinsed with methylene chloride, evaporated and the residue is taken up in 50 cm 3 of water and 50 cm 3 of methanol, brought to pH 12 with IN soda, then acidified to pH 4-5 with acetic acid. After evaporation, extraction is carried out 3 .25 times with 100 cm 3 of methylene chloride, and the extracts are washed twice with 40 cm 3 of water, dried, filtered and evaporated S to dryness.

o-1.07 g of the expected product is obtained.

b) Preparation of methyl [2-butyl-l-r2-(methoxycarbonyl)biphenyl-4-yll-methyll-1H-benzimidazol-7-acetate The product obtained above is dissolved in 10 cm 3 of S methylene chloride, then esterified with about 10 cm 3 of S diazomethane in methylene chloride, evaporated to dryness and 968 mg of product is collected which is chromatographed on silica (eluant: ethyl acetate flugene 745 mg of the expected product is obtained in the form of the base.

c) Preparation of the hydrochloride o

I

o

I

I

I

o

I

I

~I

.;r 20/94GV78246.SPE,50 51 The operation is carried out as in Example 11, starting with 303 mg of the product obtained above in a mixture of ethyl acetate and hydrochloric acid. 280 mg of expected hydrochloride is obtained, M.p. 128°C.

IR Spectrum in chloroform Absorption type -NO-H approx. 2500 cm" 1 =0 1725 1714 cm-' C-OMe 1438 cm-W (F) 0 Aromatics 1623 1599 cm- 1 Heteroaromatics 1565 1512 1500 cm7 1 EXAMPLE 15: 2-butyl-1-[(2' -carboxy-biphenyl-4-yl)-methyl]-1Hbenzimidazol-7-acetic acid 745 mg of the product obtained in Example 14 is introduced at ambient temperature into 8 cm 3 of ethanol and 1.6 cm 3 of 32% soda and agitation is carried out for one hour under reflux of ethanol. The mixture is evaporated, the residue is taken up in cm 3 of water acidified to pH 5 with acetic acid, separated, washed with water and dried under reduced pressure at 80°C. 516 mg of expected product is obtained. M.p. 161 0

C.

Recrystallization is carried out from isopropanol then from methylethyl ketone. 184 mg of expected product is obtained.

M.p. 220 0

C.

Analysis for C, 2

H

26

N

2 0 4 442.52 45 C H N calculated 73.29 5.92 6.33 found 73.3 5.9 6.3 IR Spectrum Nujol OH/NH very associated general absorption C=0 1712 cm- 1 NMR Spectrum (DMSO) 300 MHz S" CH 3 0.88 (t)

CH

2 1.38 (m)

CH

2 1.75 (m) I I 5 CH 2 -C 2.33 (t) C,H-CH 3.62 (s) N-CH,-C6H 5 5.65 (s) 20/9/94GV78246.SPE,51 52 C6,H4 6.39 111 7.13 IH the other aromatics, 7.34 2H 7.43 (dd) 2H 57.54 (in) 2H 7.71 (dd) 1H1 mobile H 12.75 20/9/94GV7B246.SPE,52 EXAMPLE 16: Methyl 4'-[[2-butyl-7-[(2-dimethylamino)-ethyl]- 1H-benzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate 1.05 g of methyl 4'-[[2-butyl-7-(2-chloro-ethyl)-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate hydrochloride is introduced under agitation at ambient temperature into 25 cm 3 of dimethylamine at 33% in ethanol.

The mixture is maintained for 16 hours at 80 0 C, then evaporated under reduced pressure at 60 0 C, extracted 3 times with 60 cm 3 of methylene chloride, the extracts are washed 3 times with 20 cm 3 of water, dried and evaporated to dryness.

After chromatography on silica, (eluant: methanol methylene chloride 789 mg of the expected product is obtained. CCM: Rf 0.37 (eluant: methylene chloride methanol EXAMPLE 17: 4'-[[2-butyl-7-[2-(dimethylamino)-ethyl]-iHbenzimidazol-1-yl ]-methyl]-biphenyl-2-carboxylic acid dihydrochloride 789 mg of the product obtained in Example 16 is introduced at ambient temperature into 15 cm 3 of ethanol and 1.3 cm 3 of 32% soda.

The mixture is agitated for one hour at 85 0 C, evaporated, the residue is taken up in 10 cm 3 of water, acidified to pH with acetic acid, and extracted 3 times with 60 cm 3 of methylene chloride; the extracts are washed twice with 10 cm 3 25 of water, dried, filtered and evaporated to dryness.

The resultant product is dissolved in 5 cm 3 of methylethylketone, 5 cm 3 of a mixture of ethyl acetate and hydrochloric acid is added and the whole is left to crystallize at ambient temperature, then the crystals are 30 separated out, washed with methylethylketone and dried at under reduced pressure. After recrystallization from o acetonitrile, 429 mg of the expected product is obtained.

M.p. 218 0

C.

i,1 t Analysis for C 29

H

33

N

3 0 2 2H C1 C H Cl calculated 65.9 6.67 13.42 found 65.7 6.6 13.1 IR Spectrum Nujol OH/NH very associated general absorption >0 1708 cm 1 1690 cm-1 Aromatic 1625 cm-1 1598 cm" Heteroaromatic 1569 cm-1 1510 cm- NMR Spectrum (DMSO) 250 MHz

CH

3 0.91 (t)

CH

2 1.42 (m)

CH

2 1.82 (m)

CH

2

-C

2 1

N

7.95 8.2

L

a 0 6

S*

a 5 9**

C

6

H

5

-C

2

-CH

2 -N 3.09 2H and =C-CH 2

-CH

2 3.26 4H

N-CH

2

-C

6

H

5 6.04 (sl) 20 C 6

H

4 7.23 2H 7.34 2H 7.80 1H 7.74 1H the other aromatic H's 7.56 2H 7.44 2H 7.30 (masked) 1H the N-CH 3 's 2.65 (sl) mobile H's 11.38 EXAMPLE Methyl 2-butyl-l-[2 -cyano- (1,1'-biphenyl)-4-yl)methyl]-1H-benzimidazol-7-carboxylate STAGE A: Methyl 3-amino-2-pentanamido benzoate 560 mg of product obtained in Stage C of Preparation 1 is dissolved in 12 cm 3 of tetrahydrofuran, 280 mg of palladium at 18% on activated charcoal is added and the reaction medium is hydrogenated for 30 minutes (absorption 160 cm 3 of hydrogen).

Agitation is carried out for a further 10 minutes, followed by filtering, the solvent is evaporated off under reduced pressure, the residue is taken up in isopropyl ether, separated and dried at 80 0 C under reduced pressure. 450 mg of crude product is recovered which is recrystallizedfrom

I

isopropyl ether. Analysis for C 13

H

18

N

2 0 3 250.29 C H calculated 62.38 7.25 found 62.4 7.4

N

11.19 11.1 IR Spectrum (CHC1 3

=C-NH

C=O

-1 ~1 3420 cm 3340 cm -1 1698 cm1 Max.

1680 cm1 Ep.

go a0 940 0. 6 o e 6 a 9 9 0 g o '0 9 9 0990 90 .9 O 9 0 Aromatic NH2 def. 1620, 1601, 1580, 1514 cm' Amide II STAGE B: Methyl [2-(methoxycar.bonyl)-6-aminophenyl]-npentanoyl)-aminomethyl-biphenyl-2-carboxylate 15 52 mg of sodium hydride at 50% in oil is added to a solution of 250 mg of product obtained in Stage A above in 2 cm 3 of dimethylformamide, and the mixture is agitated for minutes, then 300 mg of 4'-(bromomethyl)-biphenyl-2-nitrile is added and agitation is carried out for 15 minutes at ambient ,1o temperature. The solvent is evaporated off, 60 cm 3 of water is added and extraction is carried out with methylene chloride; the extracts are washed with water, dried and evaporated to dryness under reduced pressure. 600 mg of crude expected product is collected which is chromatographed on 25 silica (eluant: flugene ethyl acetate then crystallized from isopropyl ether then from ethyl ether.

125 mg of expected product is obtained. M.p; 80 0 C then 145 C.

Analysis for C 27

H

27

N

3 0 3 441.51 C H calculated 73.45 found 73.4 IR Spectrum (CHC1 3

=C-NH

2

-CEN

-C=0 Aromatics NH .def.

2~ 6.16 6.2

N

9.52 9.2 3496 cm 1 3395 cm 1 -1 222 cm 1722 1656 cm 1613 cmm 1597 cm 1 1588 cm- 1 cm 1588 cm 1815 cm i j Ls i- *92cr -56- STAGE C: Methyl 2-butyl-l-[2'-cyano-(1,1'-biphenyl)-4-yl)methyl]-1H-benzimidazol-7-carboxylate hydrochloride 730 mg of product obtained as in Stfge B is dissolved in cm 3 of a solution of hydrochloric acid in ethyl acetate and agitation is carried out for 10 minutes at 50 0 C. The solvent is evaporated off, the residue is taken up in a mixture of methylethylketone and ether, followed by separating and drying at 80C under reduced pressure. 715 mg of crude product is obtained which is recrystallized from ethyl acetate then from a mixture of methylethylketone and ether. 270 mg of expected product is collected. M.p. 140 0

C.

Analysis for C 2

,H

25

N

3 0 2 HC1 459.96 C H N Cl calculated 70.50 5.70 9.14 7.71 found 70.6 5.8 9.2 7.8 IR Spectrum (CHC1 3

-COCH

3 1723 cm' 1436 cm-' -C:N 2226 cm-n Complex absorptions max. to about 2450 cm 1 of the type nN *-H aromatics 1620 cm- 1598 cm- Heteroaromatics 1564 cm- 1 1496 cm-' EXAMPLE 19: Methyl 2-butyl-l-[2'-(lH-tetrazol-5-yl)-(1,1'- S biphenyl)-4-yl)-methyl]-1H-benzimidazol-7-carboxylate S a) 10 cm 3 of a saturated aqueous solution of sodium bicarbonate i3 added to a suspension containing 650 mg of the hydrochloride S prepared in Example 18 in 50 cm 3 of water, the mixture is S agitated for 10 minutes and extracted with methylene chloride with 2% methanol, the extracts are washed with water, dried, and the solvents are eliminated under reduced pressure. 600 mg of 30 base is collected.

S b) The 600 mg of above product is dissolved in 6 cm 3 of xylene S and 511 mg of trimethyltin azide is added. After agitation for 23 hours at 115-120 0 C, a further 205 mg of azide is added and heating is continued for 24 hours. The xylene is evaporated off, 30 cm 3 of water is added, agitation is carried out for S minutes, 10 cm 3 of methanol is added, followed by extraction with methylene chloride; the extracts are dried and evaporated to S dryness under reduced pressure.

S

9* 5c o S

S

I

L

9 p 209/94GV78246.SPE,56 -57- 1 g of crude product is obtained which is chromato-graphed on silica (eluant: methylene chloride methanol then the residue is crystcIlized from ether. 470 mg of expected product is obtained. M.p. 165°C.

EXAMPLE20:2-butyl-l-((2'-(1H-tetrazol-5-yl)-(1,1'-biphenyl)-4yl)-methyl]-lH-benzimidazol-7-carboxylic acid 470 mg of product obtained in Example 19 in solution in 12 cm 3 of ethanol is agitated for 2 hours under reflux in the presence of 3 cm 3 of N soda, the ethanol is evaporated off, 10 cm 3 of water is added, then drop by drop 0.8 cm 3 of acetic acid is added. Agitation is carried out for 2 hours at ambient temperature, followed by separating, washing with water and drying at 80°C under red ed pressure. 420 nig of crude product is collected which is uissolved in 10 cm 3 of a methanol methylethylketone mixture the solution is filtered, concentrated to 5 cm 3 one drop of acetic acid is added then 5 cm 3 of water is added, crystallization is started and left at +4 0

C

for 16 hours; the crystals are separated, washed with water and dried at 90°C under reduced pressure. After recrystallization from ethyl acetate, 310 mg of expected product is obtained. M.p.

approx. 210-220C.

Analysis for C 26

H

24

N

6 0 2 452.50 C H N S calculated 69.01 5.35 18.57 found 68.7 5.3 18.3 IR Spectrum Complex absorption OH/NH region S C=O 1700 cm- 1 Aromatic 1609 cm"' 1598 cm 7 Heteroaromatic 1515 cm 1 1488 cm' 1 S EXAMPLE 21: pharmaceutical composition Tablets were prepared corresponding to the following S formula: Product of Example 2 10 mg Excipient for a tablet completed at 100 mg (detail of the excipient: lactose, talc, starch, magnesium stearate).

EXAMPLE 22: pharmaceutical composition 20/9/94GV'78246.SPE,57 *4@ a aI aI a Tablets were prepared corresponding to the following formula: Product of Example 25 10 mg Excipient for a tablet completed at 100 mg (detail of the excipient: lactose, talc, starch, magnesium stearate).

PHARMACOLOGICAL RESULTS 1 Test on the anciotensin II receptor A fresh membrane preparation obtained from theliver of a rat is used. The tissue is ground up in a polytron in a Tris mM buffer pH 7.4, the grinding is followed by 3 centrifugations at 30,000 g for 15 minates, the deposits being taken up in between in the Tris buffer pH 7.4.

15 The last deposits are put in suspension in an incubation buffer (Tris 20 mM, NaCl 135 mM, KC1 10 mM, glucose mM, MgCl 2 10 mM phenylmethylsulphonyl fluoride 0.3 mi, bacitracin 0.1 mM, bis(trimethylsilyl) acetamide The aliquoted fractions of 2 ml are divided into 20 hemolysis tubes and 1125 angiotensin II (25,000 DPM per tube) and the product to be studied are added. (The product is first tested at 3 x 10- 5 M three times). When the tested product displaces by more than 50% the radioectivity linked specifically to the receptor, it is tested again according to *u 25 a range of 7 concentrations in order to determine the concentration which inhibits by 50% the radioactivity linked specifically to the receptor. In this way the 50% inhibiting concentration is determined.

The non-specific bond is determined by addition of a reference product, namely the product of Example 94 of the European Patent 0,253,310, at 10- 5 M (in triplicate). The medium is incubated at 25oC for 150 minutes, put in a water bath at 0 C for 5 minutes, filtered under vacuum, rinsed with Tris buffer pH 7.4 and the radioactivity is counted in the presence of scintillating Triton.

The result is expressed directly as the 50% inhibiting concentration (IC 50 that is as the concentration of studied product, expressed in nM, necessary to displace 50% of the -59- Results: t f..

ft...

S fr

I

*I

ft f ft f* ft t

**I

*ft *t.

Product of Example ICso in nanomoles 2 911 4 52 105 12 99 207 270 2 Revealing the antagonistic activity of angiotensin II on the isolated portal vein The portal vein of male Wistar rats (about 350 g) (IFFA Credo France) is removed after cervical dislocation and placed rapidly in a physiological solution (see below) at ambient temperature. A ring of about 1 mm diameter is mounted in a bath with an isolation mechanism, containing 20 ml of the following physiological solution (composition in mM: NaCl 118.3 KC1 4.7 MgS04 1.2 KH 2

PO

4 1.2 NaHCO, 25 glucose 11.1 CaCI 2 the medium is maintained at 37 0 C and oxygenated with an 02

CO

2 mixture. The initial pressure imposed is 1 g, the rings are left at rest for 60 to 90 minutes. In order to avoid spontaneous contractions, verapamil is added to the incubation i5 bath (1.10-6M).

At the end of the rest period angiotensin II (Ciba hypertensin) 3.10- 8 M is added to the incubation bath and left in contact with the preparation for 1 minute. This operation is repeated every 30 minutes, the tissue being washed 3 or 4 times :30 between two stimulations by angiotensin. The compound to be studied is introduced into the bath 15 minutes before a new S stimulation by angiotensin. From increasing concen-trations of S the molecule being applied, an ICs 5 (concentration which S produces a 50% inhibition of the response to angiotensin) can .45 be calculated, this being *l 21/994GV78246.SP,59 expressed in nanomoles.

Results:

S

*5

S

Sr

S

S

S

5

S

S

Product of Example IC 50 in nanomoles 4 12 2 1000 3 Test for antagonistic activity of angiotensin II in ademedullated rat Male Sprague-Dawley rats (250 to 350 g) are anaesthetized by an intra-peritoneal injection of sodiumpentobarbital mg/kg). The diastolic arterial pressure is recorded by means of a heparinized catheter (PE50) introduced into the left carotid of the animal, and connected to a pressure calculator (Gould, Pressure Processor) by means of a Gould pressure sensor.

A catheter is introduced into the right jugular vein of the animal in order to allow the injection of the molecules to be studied.

The animal is placed under assisted respiration. A Sbilateral section of the pneumogastric nerves is carried out.

The rat is then demedullated.

After a sufficient period of stabilization, the study of the 25 antagonism of the molecules vis- -vis angiotensin II (Hypertensin, CIBA) is approached in the following manner: 1 Three consecutive injections of angiotensin II (0.75 micrograms/kg) spaced 15 minutes apart permits a reproducible and stable pressure response to be obtained.

2 While keeping a time interval of 15 minutes for the administration of angiotensin II, the molecules (0.01 to mg/kg) are injected 5 minutes before the angiotensin II.

The pressure effects of angiotensin II in the presence of the antagonist are expressed as a percentage of the 21/94GV78246.SsE,60 '3 g t 61 pressure effects of angiotensin II administered on its own. The dose which inhibits the studied effect by 50% is thus determined

(ID

50 Each animal is considered to be its own control.

Results: Product of Example IC,, in mg/kg 4 0.3 1.77 12 1.97 SS S

S

0* 5 0 5* *5

S

S S

S

eSOS

SS

S S

S.

*9 .5

S

S. S a a.

S

21/9/94GV78246.S1'E,61

Claims (3)

1. 2-butyl-1 -l(2'-carboxy-biphenyl-4-yl)-methyl]-1 H-benzimidazole-7-carboxylicacid, 4'-[112-butyl-7-(2-hydroxy ethyl V-i H-benzimidazol- 1-yl]-methyll-biphenyl-2-carboxylic acid, 4'-[(2-butyl-7-formyl-1 H-benzimidazol-1 -yl)-methyll-biphenyl-2-carboxylic acid, 2-butyl- 1 H-tetrazol-5-yl)-(l1, 1 '-biphenyl)-4-ylI-methyll-1 H-benzimidazol-7- carbxylic cid, mthyl -butyl-1 -[2'-(methoxycarbonyl)-bipheny-4-yl-methylll1H- benzimidazol-7-carboxylate hydrochloride, 4'-[[2-butyl-7-(hydroxymethyl)-l1H-benzimidazol- 1-ylI-methyll-biphenyl-2-carboxylic acid, methyl 4'-[112-butyl-7-(hydroxymethyl)-1 H-benzimidazol-1 -yl]-methyl]-biphenyl- 2-carboxylate, methyl 4'-lil2-butyl-7-(chloromethyl)- 1 H-benzimidazol-1 -yl]- 2-1109*SS6.PE6 methyl] -biphenyl-2-carboxylate hydrochloride, biphenyl-2-carboxylic acid, methyl [2-butyl-7-(2-hydroxy ethyl)-lH-benzimidazol-l- yl 1-methyl ]-biphenyl-2-carboxylate, methyl 2-butyl-7-formyl-lIH-benzimidazol-1-yl]-methyl]- biphenyl-2-.carboxylate hydrochloride, 4'-4 [2-butyl-7-r (dimethylamino)-methyl]-lH-benzimidazol-l- yl ]-methylj-biphenyl-2-carboxylic acid dihydrochloride, methyl [[2-butyl--l-f 2'-methoxycarbonyl) -biphenyl-4-yl methyl ]-lH-benzimidazol-7-acetate hydrochloride, 2-butyl-l-[ -carboxy--biphenyl-4-yl)-methyl]-lH- benzimidazol-7-acetic acid, methyl [2-butyl-7-[ (2-d.1methylamino)-ethy.L]-lH- benzimidazol-l-yl ]-methyl]-biphenyl-2-carboxylate, [2-butyl-7-[2-(dimethylamino)--ethyl]'-lH-benzimidazol-l- yl i-methyl] -biphenyl-2-carboxylic acid dihydrochloride, methy.. 2-butyl-l-[2 '-cyano-(1, 1 -biphenyl)-4-yl)-methyl]-lH- benzimidazol-7-carboxylate, methyl 2-butyl-l-[1 -(lH-tetrazol-5-yl)-(l, l'-biphenyl)-4- yl) -methyl] -lH-benzimidazo*l-7-carboxylate, being in all the possible racemic, enantiomer.c and diastereoisomeric isomer forms, as well as the salts, so 25 addition salts with mineral or organic acids and mineral or organic bases thereof. 6 )Methyl (2-butyl-lH-benzimidazol-l-yl)-methyl]-, too biphenyl-2-carboxylate hydrochloride. 7 )Preparation process for products of formula S 1B N R 5 B 1 2 B (8 KY06 3B R 4 B 68 in which: R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R IB R 2 B, R 3 B and R 5 B are such that: either RIB, R2 R3B and R 5 B are identical and represent a hydrogen atom, or R2B and RSB are such that one represents a hydrogen atom and the other represents a hydrogen atom or a -CH 2 -O-R 0 radical, in which RIl represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, or one of R28 and Rse represent the radical Rc -N Rd in which R c and Rd, identical or different, represents the values defined hereafter for Ra and Rb and RIB and R 3 B are such that one represents a hydrogen atom and the other is chosen from the radicals -OR 6 -C0 2 R 7 and -R1, in which radicals: R 6 and R 7 identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, R1 is chosen from the group formed by: a) alkyl radicals having at most 4 carbon atoms, optionally substituted by one or more radicals chosen from: 25 halogen atoms, the optionally acylated hydroxyl radical, linear or branchedalkyloxy or alkenyloxy radicalshaving at most 5 carbon atoms, aryl radicals optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, trifluoro- methyl, cyano, nitro, amino radicals, alkoxy radicals 0* containing at most 4 carbon atoms, phenyl, benzyl radicals, free, salified or esterified carboxy radicals and tetrazolyl radicals, the free, esterified or salified carboxy radical, the radical: Ra h Rb-b 69 in which R a and Rb, identical or different, are chosen from hydrogen atoms, alkyl a2kenyl radicals having 1 to 4 carbon atoms and aryl radicals, all these radicals being optionally substituted by one or more radicals chosen from halogen atoms, or the hydroxyl, trifluoromethyl, cyano, nitro or amino radical, alkoxy radicals containing at most 4 carbon atoms, phenyl or benzyl radicals, free, salified or esterified carboxy radicals and tetrazolyl radicals, b) linear or branched alkenyl radicals having 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, d) the radical: Ra -N Rb in which R a and Rb have the meaning indicated above, or one at most of R1, R2B' R 3 and RB represents a hydrogen atom, and the others are chosen from the radicals -CH2-O-RIo -OR 6 -CO 2 R 7 -R 11 and the radical Rc S-N c R d 25 in which R 6 R 7 R 10 R1, R C and Rd have the values indicated above, R 4 represents a free, esterified or salified carboxy radical, S' or a tetrazolyl radical, or a -(CH 2 )m-SO 2 -X-R 12 radical in which m represents an integer 30 from 0 to 4 and either X-R 12 represents NH 2 or X represents a single bond, or the radicals -NH-CO- *c NH- or -NH-CO- and R 12 represents an alkyl, alkenyl or aryl radical, these radicals being optionally substituted, 35 the said products of formula being in all the possible racemic, enantiomeric or diastereoisomericisomer forms, as well as the addition salts with mineral or organic acids and mineral or organic bases of the said products of formula S S3-Product-f formula as defined in claim in -0 stbsited all th 9 Ca3 eing optionally-6sat t by one or more selected from the halogen atoms, the hydroxy radical, alkyl, alkenyl and alkoxy radical containing at most 4 carbon atoms, trifluoromethyl, cyan -free, salified or esterified carboxy or tetrazol radical, the said products of formula (Is) being ZI-'l the possible racemic, enantiomeric a lastereoisomeric isomer forms, as well as the add' 'on salts with mine al or organic acids and mineral ganic- bac of the said products- o--formula (Ig) characterized in that: either a product of formula (IV 8 RIB' HN N R2B1 (IV R3B' in which R has the meaning indicated above and R 1 R 28 R 3 1 and R, have the meanings indicated above for R1,, R2Bg R3B and R 5 respectively in which the optional reactive functions are 25 if desired protected by protective groups, is reacted with a compound of formula CHHal N. R 4 B, a S: in which Hal represents a halogen atom and R4a. has the meaning 35 indicated above for R4 in which the optional reactive functions are, if desired, protected by protective groups, in order to obtain a product of formula ./o.w3 N R B R'N R 2 B I (1XB) Lon 2 R 3 BI RO in which R, R 1 B'I R 2 B, R 3 E 6 R 5 B. and R 4 have the meanings indicated above, a) a compo'und of formula 02N R 5 131 I (V1 8 2 8 B R 2 B, in which R1, R2,, R 3 and R. have the previous meanings, is reacted with the compound of formula (II): R-C-R 9 II 25 0 which R 9 represents a hydroxy or alkyloxy radical or a *halogen atom and R has the meaning indicated above, in order *to obtain the product of formula RiB 300 :R NR 2 B, X 8 35 9 3 B, *99in which R, R 161 RB, R 3 and R 5 ha-ve the previous meanings, b) a compound of formula ft 113 R 5131 (VTB,) in which RW,, R 281 R 3 and have thel previous meanings, is reacted with the compound of formula (II) as defined above in order to obtain the product of formula R 1B; R 5 B, (XB 9 R 2 B I 3 in which R 18 r 2,1 R3B, and R have the meanings indicated previously, which is subjected to a nitration reaction in order to obtain the compound of formula as defined above, which product of formula is reacted with the compound of formula as defined above, in order to obtain a product of formula R 1B, .4 4 4 44 4 -4 44 4 .4 4 I. 4 4 a S 4* 4 444 a S4 4, S 44 4 445 4 4 44
2. 4. .44.44 4 4 4 S 4 .4 S 4 4 4.44 4 4 4 .5B I R 3 BI (XIB) R 4 B I 35 in which B 161 RB 6 R 3 R 5 and R 4 B, have the previous meanings, which is subjected to a selective reduction reaction of the nitro function, in order to obtain the product of formula (XII,): 0133 Rj3 RR in which R, RIB, R 2 1 R 38 R 5 and R 4 B, have the previous meanings, which is subjected to a cyclization reaction in order to obtain the products of formula as defined above, or the compound of formula is reacted with the compound of formula IV.) as defined above, in order to obtain a product of formula (V11 8 R 1B, 0O2N R 5 B, HN R2B c~ 3 ,(VI 18) a.R 4. B' 25 in which R 1 R 2 1 R 381 R 5 B' and RW 8 have the meanings indicated above, which is subjected to a reduction reaction 468 of the nitro' radical into an amino radical in order to obtain a product of formula (VIII,): 006H N R 5 B 4 0:0.0. 0 N R1 R 2 B' .1 Ur C 2 R 3 Bf (VI I 8 00.00 R /B in which R 1 ,r R2Bp 1 R3B' RSB, and R 4 have the meanings indicated above, which is reacted with the product of formula (III): R-C-R (III) II X in which X represents an oxygen atom or an NH radical, R 9 and R have the meaning indicated above, in order to obtain after cyclization a product of formula as defined above, which product of formula if desired and if necessary, is subjected to one or more of the following reactions, in any order: an elimination reaction of the protector groups which can be carried by the protected reactive functions, a salification reaction by a mineral or organic acid or base in order to obtain the corresponding salt, an esterification or salification reaction of the acid function, an acid or alkaline hydrolysis reaction of the ester function into an acid function, a conversion reaction of an alkyloxy radical into a hydroxy radical, a conversion reaction of a haloalkyl radical into an alkylene radical, a substitution reaction of a halogen atom by an amino 25 radical, a substitution reaction of a hydroxy radical by a halogen atom, IO a reduction reaction of an esterified carboxy radical into a hydroxyalkyl radical, an oxidation reaction of a hydroxyalkyl radical into an S: esterified carboxy radical, an oxidation reaction of a hydroxymethyl radical into o* aformyl radical, a resolution reaction of the racemic forms into resolved 35 products, a conversion reaction of a free, salified or esterified carboxy function, into a tetrazolyl radical, the said products of formula (IB) thus obtained being in all S the possible racemic, enantiomeric and diastereoisomeric 4- Jw isomer forms. DATED this 22nd day of December 1994. a *4 4 9 4 4 94 4*4 4 4 4 4
3. 44. 4 4404 4* *be*44 4 4.44 4 4 4 ROUSSEL-UCLAF By their Patent Attorneys: CALLINAN LAWRIE 2V 12/94 D K7-4 6. SPE,76 ABSTRACT A subject of the invention is the products of formula (Is): RIB RB R B 2 P R,B in which: R represents an alkyl or alkenyl radical containing 3 or 4 carbon atoms, R 1 I, R 28 R, and R 3 are such that: either Ri,, and R 5 represent a hydrogen atom, or R 2 and RB are such that one represents a hydrogen atom and the other represents a hydrogen atom or a -CH 2 -0-R, 0 radical, in *B which R, 0 represents a hydrogen atom or an alkyl or alkenyl radical containing at most 5 carbon atoms, or one of R2. and R,B represent the radical Rc -N Rd and RB and R3. are such that one represents a hydrogen atom and the other is chosen from the radicals -OR, -C0 2 R 7 and in which radicals: R, and R, represent a hydrogen atom or an alkyl or alkenyl radical containing at most 5 carbon atoms, is chosen from the group formed by: a) alkyl radicals having at most 4 carbon atoms, optionally substituted, 2 b) linear or branched alkenyl radicals having 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, d) the radical: Rb Rb or at most two of R2, R. 3 and RB represents a hydrogen atom, and the others are chosen from the radicals -CH,-O-RI,, -OR 6 -CO 2 R 7 -Ri and the radical -N 15 Rd R 4 rrepresents a free, esterified or salified carboxy radical, S**e a cyano radical or a tetrazolyl radical, or a -(CH2)m-SO2-X-R2 radical in which m represents an integer from 0 to 4 and either represents NH 2 or X represents a single bond, or the radicals -NH-CO- S NH- or -NH-CO- and R, 2 represents an alkyl, alkenyl or aryl C.a radical, the said products of formula being in all the possible 25 isomer forms, as well as the addition salts with acids and bases of the said products of formula (Ii). These products possess useful pharmacological properties which justify their use as medicaments.