IE911950A1 - New benzimidazole derivatives, their preparation process,¹the new intermediates obtained, their use as medicaments and¹the pharmaceutical compositions containing them - Google Patents

New benzimidazole derivatives, their preparation process,¹the new intermediates obtained, their use as medicaments and¹the pharmaceutical compositions containing them

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IE911950A1
IE911950A1 IE195091A IE195091A IE911950A1 IE 911950 A1 IE911950 A1 IE 911950A1 IE 195091 A IE195091 A IE 195091A IE 195091 A IE195091 A IE 195091A IE 911950 A1 IE911950 A1 IE 911950A1
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radical
radicals
formula
products
carbon atoms
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IE195091A
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Roussel Uclaf
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Priority claimed from FR909007135A external-priority patent/FR2663028B1/en
Priority claimed from FR909015811A external-priority patent/FR2670489B1/en
Priority claimed from FR9103778A external-priority patent/FR2674523A1/en
Application filed by Roussel Uclaf filed Critical Roussel Uclaf
Publication of IE911950A1 publication Critical patent/IE911950A1/en

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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C233/00—Carboxylic acid amides
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms

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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

NEW BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR USE AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM < ΕΝ l υ KJBUC iNSHfeCTIGN UNDER . >*··. ifT 1 ΠΊΟΝ 69 AND RUtyE 11 7 ,·, MO ’ it APPLICATION ....... coPClFTCATtON Fn£Q.~ τ LL ROUSSEL-UCLAF, a French Body Corporate, of 35, Boulevard des Invalides, 75007 Paris, France - 1 6015 la 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 subject of the present invention is the products of formula (Ιβ): r n in which: R represents a linear or branched alkyl or alkenyl radical 25 containing 3 or 4 carbon atoms, R1B' R2B' R3B and R5B are suck that: either R1B, R2B' R3B and R5B are identical and represent a hydrogen atom, or R2β and R5B are such that one represents a hydrogen atom 30 and the other represents a hydrogen atom or a -CH2-O-R1Q 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 R2B and R5B represent the radical in which Rc and R^, identical or different, represents the values defined hereafter for Ra and Rb and R1B and R3B are 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: or one at most of R1B, R2B' R3B an<1 R5B rePresents a hydrogen 10 atom, and the others are chosen from the radicals -CH2-O-R1Q, -0Rg, -CO2R?, "Rjj and the radical ^Rd R4B represents a free, esterified or salified carboxy radical or a tetrazolyl radical, or a -(CH2)m-SO2-X-R12 radical in which m represents an integer from 0 to 4 and either (-X-R12) represents NH2 or X represents a single bond, or the radicals -NH-, -NH-CONH- or -NH-CO- and R12 represents an alkyl, alkenyl or aryl radical, the said products of formula (Ιβ) being in all the possible isomer forms, as well as the addition salts with acids and bases of the said products of formula (Ιβ).
These products possess useful pharmacological properties which justify their use as medicaments. such that one represents a hydrogen atom and the other is chosen from the radicals -ORg, -CO2R7 and -R^, in which radicals: R6 and R?, identical or different, represent a hydrogen atom 5 or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, R1T 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 branchedalkyloxy or alkenyloxy radicalshaving at most 5 carbon atoms, - aryl radicals optionally substituted by one or more radicals 15 chosen from halogen atoms, hydroxyl, trifluoro-methyl, 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: in which Ra and Rb, identical or different, are chosen from 25 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 35 radical, d) the radical: in which Ra and R^ have the meaning indicated above, or one at most of R1B, R2B' R3B an(* R5B rePresents a hydrogen atom, and theothers are chosen from the radicals -CH2-O-R1Q, -ORg, -CO2R7, -R^ and the radical -N in which Rg, R7, R1Q, Rn' Rc and Rg have the values indicated above, R4B represents a free, esterified or salified carboxy radical, 15 or a tetrazolyl radical, or a -(CH,)m-SO2-X-R12 radical in which m represents an integer from 0 to 4 and either (X-R12) represents NH2 or X represents a single bond, or the radicals -NH-, -NH-CO20 NH- or -NH-CO- and R12 represents an alkyl, alkenyl or aryl radical, these radicals being optionally substituted, the said products of formula (Ιβ) 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 (Ιβ). Notably a subject of the present invention is the products of formula (Ιβ), as defined above, in which: R represents a butyl or buten-l-yl radical, R2B and R5B are such that one of R2B and R5B represents a hydrogen atom and the other represents a radical -N in which Rc and Rd, identical or different, are chosen from 35 hydrogen atoms, alkyl or alkenyl radicals having 1 to 4 carbon atoms and phenyl radicals, all these radicals being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro or amino radicals, alkoxy radicals containing at most 4 carbon atoms, phenyl or benzyl radicals, free, salified or esterified carboxy radicals and tetrazolyl radicals, R1B represents an alkyl radical having at most 4 carbon atoms 5 optionally substituted by one or more radicals chosen from halogen atoms, the hydroxyl radical, methoxy, ethoxy radicals, free, salified or esterified carboxy radicals, amino, mono- or dialkylamino radicals and the phenyl radical, itself optionally substituted by one or more radicals chosen from halogen atoms, methoxy, trifluoromethyl, cyano radicals, free, salified or esterified carboxy radicals and tetrazolyl radicals, R3B is chosen from the radicals ORg and CO2R7 in which Rg and R7 represent a hydrogen atom or an alkyl or alkenyl radical containing at most 5 carbon atoms, R4B represents a free, esterified or salified carboxy radical or a tetrazolyl radical, or a -(CH2)p-SO2-Xd-R12d radical in which p represents the values 0 and 1, Xd represents the radicals -NH-, -NH-CO-NH-, -NH-CO- or a single bond and R12d rePresents a methyl, ethyl, propyl, vinyl, allyl, phenyl, benzyl, pyridyl, pirydylmethyl, pyridylethyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperydinyl, thiazolyl, alkylthiazolyl, tetrahydropyrannyl, methyltetrahydrofurannyl ; these radicals being optionally substituted by one or two radicals chosen among -(CH2)p-SO2~Zc-R14c as defined above and the alkyl and alkenyl radicals containing at most 4 carbon atoms optionally substituted ; all this radicals being optionally substituted by one or more selected from the halogen atoms, the hydroxy radical, alkyl, alkenyl and alkoxy radical containing at most 4 carbon atoms, trifluoromethyl, cyano, free, salified or esterified carboxy or tetrazolyl radical, the said products of formula (Ιβ) 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 (IB).
A particular subject of the present invention is the products of formula (Ιβ) corresponding to the formula (IA): in which: R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R1A' R2A' R3A and R5A are such that: either R1A, R2A' R3A and R5A are i^entical and represent a hydrogen atom, or R2A and R5A are such that one represents a hydrogen atom or a -CH2_O-R10 radical, in which Rg0 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 R1A and R3A are such that one represents a hydrogen atom and the other is chosen from the radicals -ORg, -CO2R7 and -Rll' in which radicals: Rg and R7, identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, Rgg 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 at most 5 carbon atoms, - the free, esterified or salified carboxy radical, - the radical: in which Ra and Rfa, identical or different, are chosen from 5 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 formyl radical, R4A represents a free, esterified or salified carboxy radical, a cyano radical, or a tetrazolyl radical, optionally salified, the said products of formula (IA) being in all the possible 15 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 (Ιβ) and (IA), as defined above and corresponding 2 0 to the formula (I) : (I) in which: R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R^, R2, R3 and R5 are such that: either Rg, R2, Rg and Rg are identical and represent a hydrogen atom, or R2 and Rg are such that one represents a hydrogen atom or a -CH2-O-R10 radical and the other represents a hydrogen atom, and Rg and Rg are such that: one represents a hydrogen atom and the other is chosen from the radicals -ORg, -CO2R? and -CH2-O-Rg, which radicals RgQ, Rg, R7 and Rg, identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, R4 represents a free, esterified or salified carboxy radical, the said products of formula (I) 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 (I).
In the products of formulae (Ιβ), (IA) and (I) 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 designates a vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, or 2-butenyl radical but can also represent a 1-pentenyl, 2pentenyl or also 3-pentenyl radical, - the term halogen atom preferably designates the bromine atom, but can also represent a fluorine, chlorine or iodine atom, - the alkyloxy and alkenyloxy radicals that can be represented by O"R10 and -O-Rg are formed for example with the alkyl and alkenyl radicals as defined above, for alkyloxy radicals there can be mentioned preferably 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 5 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 phenyl radical; among the heterocyclic monocyclic radicals, there can be mentioned, for example, the following radicals; thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, 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 phenanthryl radicals, among the radicals constituted by heterocyclic condensed rings there can be mentioned, for example, benzothienyl, naphtho[2,3-b]-thienyl, indany1, indeny1, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, the naphthyridinyl, imidazopyridyl, pyrimidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, betacarbolinyl, acridinyl, phenazinyl, phenothiazinyl, 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, nitrogen and oxygen, for example benzothienyl such as benzothien-3-yl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.
Such aryl radicals can be optionally substituted such as for example the N-substituted pyrrolyl radical, for example Nmethylpyrrolyl, 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 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, 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 -(CH2)m-SO2-X-R12 radical can represent for example the radicals in which (CH2)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 R12 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 substituted as is indicated above for these radicals.
There can be mentioned, for example and in a nonexhaustive manner, the following radicals: -SO2~NH2, -SO2-NHCH3, -SO2-NH-CF3, -SO2-NH-C6H5, -SO2-NH-CH2-C6H5.
The radical R preferably represents a propyl, 1-propenyl, butyl or 1-butenyl radical but can also represent an isopropyl, sec-butyl, tert-butyl and 2-butenyl radical.
The addition salts with mineral or organic acids and mineral or organic bases of the products of formulae (Ιβ), (IA) and (I) can be, for example, the salts formed with the 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 benzenesulphonlc and aryldisulphonic.
The salts formed with hydrochloric acid are notably preferred.
The carboxy radical or radicals of the products of formula (I) can be salified by mineral bases such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, Ν,Ν-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.
A particular subject of the invention is the products of formula (Ιβ) corresponding to formula (IA) as defined above, in which R represents a butyl or 1-butenyl radical and R1A represents a hydrogen atom or an alkyloxy radical, 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).
Among the products in which R1A represents a hydrogen atom, the preferred products are thus those in which R2A» R3A and R5A are identical and represent a hydrogen atom and those in which R2A or RgA represents a hydrogen atom, a hydroxy radical or an alkyloxy radical, and R3A represents a hydroxy or alkyloxy radical, or is chosen from the radicals 25 0Rg, -co2R? and -Rgg, in which radicals: Rg and R7, identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms.
Rgg 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, - the free, esterified or salified carboxy radical, - the radical: in which Ra and Rb, identical or different, are chosen from 5 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 formyl radical, and R4A represents a tetrazolyl radical or a carboxy radical, free, salified or esterified by an alkyl radical, the alkyl and alkyloxy radicals as defined above contain 1 to 5 carbon atoms.
Among the products in which R1A represents an alkyloxy radical, there can be mentioned for example the products in which R2A, r3A and R5A rePresent a hydrogen atom.
In the preferred products indicated above the alkyl and 20 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 25 products of formula (lA) as defined above, in which R represents a butyl radical and R1A, R2A, R3A and R5A 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 (IA)· A more particular subject of the invention is the products of formula (IA) as defined above, in which R represents a butyl radical, R1A, R2Aand R5a rePresent a hydrogen atom, and R3A is chosen from the radicals -ORg, -CO2R7 and -R13, in which radicals: Rg and R^, identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms.
R13 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: 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 radical, 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, R4A 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 or organic bases of the said products of formula (IA).
Notably a subject of the invention is the products of formula (XA) as defined above, in which R represents a butyl radical and R1A, R2A and R5A rePresent a hydrogen atom, and R3A represents 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 all the possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with the mineral or organic acids and mineral or organic bases of the said products of formula dA>.
Among the products which are a subject of the invention, there can be mentioned quite particularly: methyl 4(2-butyl-lH-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylate and its salts, 4·—[(2-butyl-lH-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylic acid and its salts, 2-butyl-l-[(2·-carboxy-biphenyl-4-yl)-methyl]-lH-benzimi10 dazole-7-carboxylic acid and its salts, 4'[2-buty1-7-(2-hydroxy ethyl)-lH-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylic acid and its salts, 4’-[(2-butyl-7-formyl-lH-benzimidazol-l-yl)-methyl]-biphenyl2-carboxylic acid and its salts, 2-butyl-l-[[2’-(lH-tetrazol-5-yl)-(1,11-biphenyl)-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid and its salts.
Also a subject of the invention is a preparation process for products of formula (Ιβ) as defined above, characterized in that: either a product of formula (ΐνβ): in which R has the meaning indicated above and R1B,, R2B· ’ R3B, and R5B, have the meanings indicated above for R1B, R2B, 30 R3B and R5B respectively in which the optional reactive functions are if desired protected by protective groups, is reacted with a compound of formula (νβ): in which Hal represents a halogen atom and R4B, has the meaning indicated above for R4B in which the optional reactive functions are, if desired, protected by protective groups, in order to obtain a product of formula (ΙΧβ): in which R, Rgg, / R2B'' R3B'? R5B' and indicated above, or a) a compound of formula (VIg): 4B' have the meanings in which R1B,, R2B’' R3B’ an5B' have the previous meanings, is reacted with the compound of formula (II): R-C-Rg(II) O in which Rg 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 (Χβ): in which R, R3B«» R2B*' R3B* and R5B’ have the Previous meanings, b) a compound of formula (VIg,): in which R1B,, R2Bi» R3B' an<1 R5B’ ^ave ttie Previous meanings, is reacted with the compound of formula (II) as defined above in order to obtain the product of formula (Χβ|): in which R1B»» r2b·' r3B·' 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 (Xg) is reacted with the compound of formula (Vg) as defined above, in order to obtain a product of formula (Xlg): •Ε 911950 in which R, R1B,, R2Bi/ R3B*' R5B’ and R4B' have the previous meanings, which is subjected to a selective reduction reaction of the nitro function, in order to obtain the product of formula (ΧΙΙβ): ^B’ in which R, R1B., R2B,, R3B'' R5B* and R4B' have the previous meanings, which is subjected to a cyclization reaction in order to obtain the products of formula (ΙΧβ) as defined above, or the compound of formula (VIB) is reacted with the compound of formula (VB) as defined above, in order to obtain a product of formula (VIIB): in which R1B,, R2B·' R3B·' R5B· and R4B* have the m®anings indicated above, which is subjected to a selective reduction reaction of the nitro radical in order to obtain a product of formula (Vlllg): in which R1B,, R2B,, R3B*' R5B’ and R4B* have the meanings indicated above, which is reacted with the product of formula (III) C ii (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 (ΙΧβ) as defined above, which product of formula (ΙΧβ), if desired and if necessary, is subjected to one or more of the following reactions, in any order: - 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 5 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, - an oxidation reaction of a hydroxyalkyl radical into an esterified carboxy radical, - 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 the possible racemic, enantiomeric and diastereoisomeric isomer forms.
In the preferred conditions for implementing the invention, the above process is carried out in the following manner: The reaction of the compound of formula (Vg) in which the halogen atom preferably represents a bromine atom on the anion of the imidazole of formula (IVg) 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 tetrahydrofuran.
The addition reaction of the compounds of formula (II) on the free amine function of the compounds of formula (VIg) or (VIg,) in order to obtain the products of formula (Χβ) or (Xg,) respectively can be carried out by simple heating to a temperature of about 120°C to 170°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 (VIg) or (VIB,).
The nitration reaction of the products of formula (Χβ|) in order to give the products of formula (Xg) 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°C.
The addition reaction of the compounds of formula (Vg) on the amide function of the compounds of formula (Χβ) in order to obtain the products of formula (Xlg) can be carried out at ambient temperature or by heating to a temperature of between 20°C and 150°C, preferably in the presence of an alkaline 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 formula (XIB) into an amino radical in order to obtain the products of formula (Xllg) 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 (IXg) 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 order to obtain the products of formula (Vllg) can be carried out in the same conditions as those described above for the addition of the compounds of formula (νβ) on the products of formula (ΐνβ).
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 such as for example tetrahydrofuran or dimethylformamide at a temperature of between 20°C and 200°C.
The compound of formula (III) can be, for example, when X represents NH, ethyl pentanimidoate and when X represents O, for example, valeric acid.
According to the values of R10,, R2B,, R3B· and R5B*' the products of formula (ΙΧβ) constitute or do not constitute the products of formula (Ιβ).
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.
The following non-exhaustive list of examples of 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 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.
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.
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 ΙΕ 91195ο 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 5 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 radical 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 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 (Ig) can be prepared by resolution of the racemics according to the usual methods known to a man skilled in the art. The salts formed with optically active bases can for example be used.
The compounds of formula (Ιβ) as defined above as well as their addition salts with acids have useful 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 (Ιβ) above, the said products of formula (IB) being in all the possible racemic or optically active 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 (Iq).
A subject of the invention is in particular, as 5 medicaments, the products of formula (Ιβ) as defined above in which R represents a butyl or 1-butenyl radical and Rgfi represents a hydrogen atom, and guite particularly the products of formula (Ιβ) as defined above in which R represents a butyl radical and RgB, R2B and R5B are identical and each represents a hydrogen atom and R3B 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, salified or esterified carboxy radicals, R4B represents a free, salified or esterified carboxy radical, an optionally 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 (Ιβ).
A more particular subject of the invention is, as medicaments, the following products of formula Methyl 4'-[(2-butyl-lH-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylate, 4’-[(2-buty1-lH-benzimidazol-1-yl)-methyl]-biphenyl-2carboxylic acid, 2-butyl-l-[[2'-carboxy biphenyl-4-yl]-methyl]-lH-benzimidazole-7-carboxylic acid, 4·-[[2-butyl-7-(2-hydroxy ethyl)-ΙΗ-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylic acid, 4'-[(2-butyl-7-formyl-lH-benzimidazol-l-yl)-methyl]-biphenyl35 2-carboxylic acid, 2-butyl-1-[[2'-(lH-tetrazol-5-yl)-(1,1'-biphenyl)-4-yl]methyl]-ΙΗ-benzimidazole-7-carboxylic acid, as well as their addition salts with pharmaceutically 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 10 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 preparations, ointments, creams, gels and aerosol 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, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agent, and preservatives.
The usual dosage, variable according to the product used, the patient treated and the affection in question, can be, for example, 1 to loo mg per day for an adult, by oral route.
The starting compounds of formulae (II), (III), (ΐνβ)ι (VB), (VIB) 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) 59, 178.
The other products of formula (IVg) can be prepared by the action of a compound of formula (III) as defined above with a product of formula (XIII): R.B' H2N h2n (XIII) in which R^g», R2B*' R3B· and R5B’ 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 (Vlllg).
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, by LONZA.
An example of the preparation of these compounds of formula (III) is given in J. Amer. Chem. Soc. (1942), 64. 1827.
A preparation process for the products of formula (νβ) as defined above can consist of subjecting methyl iodo-benzoate marketed for example by JANSSEN, to the action of iodotoluene, marketed for example by FLUKA, the reaction is carried out for example in the presence of powdered copper at a temperature of 100°C to 300°C, in order to obtain a product of formula (Vg,): 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 above, 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 (Vg) or (Vg,) or also some of the conversions of the R4B radical of the products of formula (ΙΧβ) can be found, for example, in the Patent US 4,880,804 or EP 0,253,310.
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 (VIg) can also be prepared, for 25 example, by the process described in: Canadian journal of chemistry, (1977), 55 (10), pp 1653-1657.
The products of formula (VIg,) which are aniline derivatives are commercially available such as for example 2,4-dimethoxy aniline from ALDRICH or can be prepared as we) 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 (Ig) the compounds of formulae (IVg), (Vllg), (Vlllg), (Xg) an (XgI )· In addition to the products described in the examplt 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 (IA) are such that R represents a butyl radical, R4A represents a carboxy radical and R1A, R2A» R3A ΙΑ l2A 5A 3A H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H ch2oh ch2oh ch2oh ch2oh ch2oh ch2oh ch2oh ch2oh ch2oh och3 och3 och3 och3 och3 och3 och3 och3 och3 Cl Cl Cl Cl Cl Cl Cl Cl Cl H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H OH COOMe ch3 Cl OH COOMe COOH ch3 Cl ch2oh ch2ci ch2-ch2-oh ch2-ch2-ci OH COOMe COOH ch3 Cl ch2oh CH2C1 CH2-CH2-OH CH2-CH2-C1 OH COOMe COOH ch3 Cl CH2OH ch2ci CH2-CH2-OH ch2-ch2-ci IR1A — R2A — rsa I R3A [ OH H H OH | OH H H COOMe | OH H H ch3 | OH H H Cl | OH H H ch2oh | OH H H ch2ci | OH H H CH2-CH2-OH I I_ OH _ H _ H CH2-CH2-C1 I I The following examples illustrate the invention without however limiting it.
EXAMPLE 1¾ Methyl 4·-((2-butyl-lB-bansimidaiol-l-yl)-methyl)biphenyl-2-oerboxylate 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) §2, 178) in 3 cm3 of dimethylformamide is . . . 3 added to a suspension of 650 mg of sodium methylate in 5 cm of dimethylformamide cooled down to 0°C. 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 cm3 of dimethylformamide is added over 15 minutes.
Agitation is carried out for 4 hours at 40°C, the dimethylformamide is evaporated off and 50 cm3 of an aqueous solution of sodium bicarbonate is added. After extraction three times with 100 cm3 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 (1-1)). 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. = 155°C, 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^gHjyNjOjCl = 435.01 C Η Cl N 35 % calculated 71.79 6.25 8.15 6.44 % found 72.00 6.2 8.3 6.3 IR Spectrum (CHC13) Absorption complex 2800 ====> 2000 cm (of the type: ΞζΝ ® -H) Ο II -c-och3 c=c ON Aromatic 1723 ~ -i cm 1438 cm-1 1620 cm-1 1599 ^.-1 cm 1558 ^-1 cm 1510 cm-1 1488 _ -1 cm example 2: 4'-[(2-butyl-lH-benziMida8ol-l-yl)-methyl]bipheny1-2-carboxylic acid 0.8 cm3 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 of methanol. Agitation is carried out for 4 hours under reflux. The methanol is evaporated off, the resultant mixture is cooled down to +10°C and acidified to a pH of 5-6 with 2N hydrochloric acid, then agitated for 30 minutes at +10°C, separated, washed with water, dried at 80°C under reduced pressure. 400 mg of product is obtained, M.p. = 190°C, which is recrystallized twice from isopropanol in order to obtain 125 mg of the desired product. M.p. = 234°C.
Analysis for C25H24N2°2 = 384·48 C % calculated 78.10 % found 78.00 IR Spectrum (Nujol) C=O 1682 cm Aromatic + 1615 cm heteroaromatic H 6.29 6.3 N 7.28 7.2 1597 cm 1518 cm'1 PREPARATION 1: Methyl 4'-[N-[2-(methoxycarbonyl)-6-nitro30 phenyl]-N-(pentanoyl)-aminomethyl]-biphenyl-2-carboxylate STAGE A; 2-amino-3-nitro benzoic acid a) acetylation: 0.65 cm3 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 of acetic anhydride and the mixture is agitated for one hour at ambient temperature. 50 cm of water is added, followed by agitation for 15 minutes, separating, washing with water then with ether, and drying at 100°C under reduced pressure. 13.6 g of desired product is obtained.
M.p. - 156°C. b) oxidation: 13.4 g of the compound obtained above is added to a 5 suspension of 29.48 g of potassium permanganate and 21.44 g of magnesium sulphate m 1470 cm of water. The mixture is agitated for 3 hours at 100°C, allowed to return to ambient temperature, then cooled down to 0°C +5°C. The insoluble part is filtered off, 10 cm of concentrated hydrochloric acid (pH 2-3) is added to the filtrate which has been cooled down to 0°C +5°C. Extraction is carried out 4 times with 500 cm3 of ethyl acetate, the extracts are washed with water, dried, filtered and evaporated under reduced pressure. 16.1 g of product is obtained which is crystallized from ethyl ether in order to collect 12.1 g of the desired product. M.p. = 192°C. c) hydrolysis: g of the previously obtained product is agitated for 4 hours at 120°C with 75 cm3 of water with 5% concentrated hydrochloric acid, the mixture is allowed to return to ambient temperature, cooled down to 0°C +5°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 the desired product is obtained. M.p. = 210°C.
STAGE B: Methyl 2-amino-3-nitro benzoate A suspension of 1 g of the acid obtained in Stage A, 15 cm3 of methanol and 1.4 cm3 of 95-97% sulphuric acid is agitated under reflux for 48 hours. The methanol is evaporated off, 100 cm3 of water is added, alkalization is carried out by adding sodium bicarbonate, followed by extracting 3 times with 200 cm3 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°C.
STAGE C: Methyl 3-nitro-2-pentanamido benzoate 850 mg of product obtained in Stage B above and 5 cm of valeryl chloride are agitated under reflux for one hour. . · . . 3 After evaporation to dryness the residue is taken up in 80 cm of ethyl ether, treated with activated charcoal, filtered and 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°C.
An analytical sample was prepared by dissolution in 20 cm3 of isopropyl ether under reflux, filtration and concentration to 5 cm3. The medium is left at rest for 18 hours at ambient temperature, separated, and washed with isopropyl ether. 710 mg is obtained. M.p. = 60°C.
This 710 mg is dissolved in 25 cm3 of hot isopropyl ether, treated with activated charcoal, filtered, and concentrated to 10 cm . 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.
M.p. = 60°C.
Analysis forC13H16N C 2°5 = 280.27 H N % calculated 55.71 5.75 10.00 % found 55.8 5.38 9.9 20 IR Spectrum (CHClg) NH complex 3400 „ -1 cm (βΡ) 3330 cm-1 (max) C=0 complex 1730 -1 cm (ep) 1708 ^,-1 cm (max) 25 Aromatic Ί 1 + / 1608 - 1588 - 1499 cm Amide II \ NO- 1540 - 1360 cm-1 STAGE D: Methyl 4'-[N-[2-(methoxycarbonyl)-6-nitro phenyl]-N30 (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 5 cm3 of dimethylformamide. Agitation is carried out for 5 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 ο and the residue is taken up 3 times in 250 cm of ethyl acetate then washed 3 times with 50 cm3 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 (CHC13) C=O complex 1726 and 1670 cm-1 NO, 1538 and 1352 cm1 . -1 Aromatics 1600 and 1576 cm example 3¾ Methyl 2-butyl-l-[2·-(nethoxycarbcny1)-biphenyl-4yl]-methyl]-lH-benzimidazole-7-carboxylate 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 . . 3 ... preparation I 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 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 m 5 cm of ethyl acetate and 5 cm of isopropanol and a large excess of a solution of hydrochloric acid in ethyl acetate is added. The mixture is heated to 50°C for 5 minutes and left for 30 minutes at ambient temperature, the solvents are evaporated off and the residue is taken up 3 times in 3 cm3 of ethyl acetate. After separating and washing with ether, 640 mg of the desired product is obtained. M.p. = 160°C. 190 mg of the above product is recrystallized from isopropanol, M.p. = 160°C. Analysis for and 163 mg of the expected product is obtained C28H28N2°4' HC1 = 492*99 C H Cl N 35 % calculated 68.21 5.93 7.19 5.68 % found 67.8 5.8 7.3 5.5 IR Spectrum Absorption complex type 5.N®- •H 2380 cm1 C=O 1727 and 1721 cm EXAMPLE 4: 2-butyl-1-[(2·-carboxy biphenyl-4-yl)-methyl]-ihbensimidasole-7-carboxylic acid A solution of 440 mg of the product obtained in Example 3 . 3 3 3 with 10 cm of ethanol, 1 cm of water and 1 cm of caustic soda lye is agitated for one hour under reflux. The ethanol is evaporated off, the residue is dissolved in water (10 cm3) and the solution is acidified to pH 3-4 with acetic acid.
After separating, 360 mg of product is obtained, M.p. = 160°C, then at 250°c, 450 mg of product obtained as above is recrystaliized from 15 cm of methanol, 5 drops of acetic acid . and 5 cm of water. 370 mg of product is obtained, M.p. = 255°C, which is dissolved in 20 cm3 of methanol and io cm3 of methylene chloride under reflux. The solution is filtered, the methylene chloride is evaporated off and one drop of acetic acid and 5 cm3 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 C26H24N2°4 = 428.47 C H N % calculated 72.88 5.65 6.54 % found 73.0 5.6 6.5 IR Spectrum (nujol) General absorption OH/NH region C=O 1704 cm'1 NMR Spectrum (DMSO)CH3 0.88 (t) ch2 1.39 (m) ch2 1.76 (m) ch2-c= 2.87 (m) n-ch2- 5.90 (S)C6H4 6.88 (d,l) 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]-aminoaethyl]-biphenyl-2carboxylate STAGE A: 2-amino-3-nitrobenzyl alcohol cm3 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 +8°C, to a solution of 3.54 g of the product obtained in Stage B of Preparation 1 in 90 cm3 of tetrahydrofuran. The resultant mixture is agitated for 30 minutes then, 40 cm of tetrahydrofuran with 10% water is added over 15 minutes, with further agitation, then 10 cm3 of water is added and agitation is continued for 30 minutes at ambient temperature, 350 cm of methylene chloride with 10% 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 10 cm3 of isopropyl ether. 2.22 g of the desired product is obtained. M.p. = 110°C.
An analytical sample was obtained by recrystallizing 170 mg of the above product, hot and cold, from isopropyl ether. mg of pure product is collected. M.p. = 112°C.
Analysis for C7HgN2O3 = 168.15 H % calculated % found C 50.00 49.8 4.80 4.8 N 16.66 16.5 IR Spectrum (CHC13) OH =C—NH 25 NH 3604 cm def 3498 - 3390 cm (F) -1 1624 cm _T complex Aromatic 1580 cm-1 STAGE B: 3-nitro-2-pentanamido benzyl pentanoate 1.5 g of the product obtained in Stage A and 15 cm3 of valeroyl chloride are agitated for 6 hours at ambient temperature. 80 cm3 of essence G (B.p.40-70°C) 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 ci7H24N2°5 = 336·38 NO, % calculated C 60.70 H 7.19 N 8.33 38 % found 60.7 7.3 8.4 IR Spectrum (CHClg) =C—NH 3426 cm-1 C=O 1734 and 1702 cm-1 5 Aromatics 'K°2 + 1610 - 1588 - 1538 - 1480 cm-1 Amide II ) STAGE C: Methyl 4·-[N-[[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 • · . 3 of 1.35 g of the product obtained in Stage B above in 13.5 cm 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 . . . 3 extraction 3 times with 50 cm 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 8-2). 2.05 g of the desired product is obtained, used as it is (Rf 0.20 (cyclohexane - ethyl acetate 8-2)). example 5i Methyl 4·-[[2-butyl-7-[(pentanoyloxy)-methyl]-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate hydrochloride The operation is carried out as in Example 3 starting with 2.05 g of the product obtained in Stage c of Preparation 2, using 1.025 g of palladium on activated charcoal then 20 cm3 of ethyl acetate saturated with hydrochloric acid gas. 1.8 g of desired product is obtained, M.p. = approx. 145°C. 300 mg of the above product is recrystallized fromisopropanol. 180 mg of product is collected, M.p. = 145°C.
Analysis for C32H36N2°4' c % calculated 69.99 % found 69.9 IR Spectrum (CHClg) Absorptions NH region HCI = 549.124 H Cl N 6.79 8.33 5.10 6.9 6.5 5.2 2000 - 2800 cm1 c=o Conjugated system + Aromatic 1726 cm"1 (F) complex 1624 - 1599 - 1568 - 1510 and 1498 cm"1 EXAMPLE ¢: 4 · - [[2-butyl-7-(hydroxymethyl)-lH-benzimidazol-1yl]-methyl]-biphenyl-2-carboxylic acid The operation is carried out as in Example 4, starting with 400 mg of the product obtained in Example 5. 290 mg of desired product is obtained (M.p. = 250°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°C.
Analysis for C26H26N2°3 = 414·51 C H % calculated 75.34 6.32 % found 75.2 6.3 IR Spectrum (CHC13) Absorptions OH/NH approx.
C=O Aromatic + Heterocycle NMR Spectrum (DMSO) 300 MHz N 6.76 6.8 3480 cm 1688 cm"1 1598 - 1518 cm CHι 3 0.87 ppm (t) 25 CH1 2 1.36 ppm (m) CHI 4 1.73 ppm (m) ch2 1.81 ppm (m)C6H4 —CH--O- 4.52 (s)C6H4 6.91 (d) 30 7.28 (d) the other aromatics approx. 7.08 (m) 2H - 7.32 1H approx. 7.54 (m) 2H - 7.70 (d) 1H - 5.50 EXAMPLE 7: Methyl 4·-[[2-butyl-7-(hydroxymethyl)-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate A solution of 823 mg of the product obtained in Example 5 in 8.2 cm3 of ethanol and 1.6 cm3 of 2N soda is agitated for 30 minutes. Then 10 cm of water is added, followed by separating and drying, and 600 mg of the expected product is Γ1 obtained (M.p. = 138°C) which is recrystallized from ethyl acetate then isopropanol, M.p. - 140°C.
Analysis for C27H28N2°3 - 428.51 C Η N % calculated 75.67 6.59 6.54 % found 75.8 6.5 6.5 IR Spectrum (CHC13) OH 3600 cm C=O 1722 cm' EXAMPLE 8: Methyl 4'-[[2-butyl-7-(chloromethyl,-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate hydrochloride . 3 . ..3 A solution of 1 cm of thionyl chloride m 5 cm of methylene chloride is added to a solution of 250 mg of the 15 product obtained in Example 7 in 25 cm 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. 20 Analysis forC27H28C1 2N2°2 = 483 .43 C H Cl % calculated 67.08 5.84 14.66 % found 67.0 5.9 14.4 IR Spectrum (CHC13) 25 C=O 1724 cm-1 EXAMPLE 9: 4 * -[[2-butyl-7-(chloromethyl) N .80 .9 yl]-methyl]-biphenyl-2-carboxylic acid . « . 3 350 mg of the product obtained in Example 6 in 5 cm of thionyl chloride is agitated for 2 hours at ambient temperature. After evaporation, about 5 g of ice then 20 cm3 of water are added and agitation is carried out overnight at ambient temperature. The water is decanted, the residue is taken up in 30 cm3 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 (9-1)). PREPARATION 3: Methyl 4·-[N-[2-nitro-6-[(2-pentanoyloxy,ethyl]-phenyl]-N-pentanoyl]-aainomethyl]-biphenyl-2IE 91195® carboxylat· STAGE A: 2-(2-pentanamido phenyl)-ethyl pentanoate The operation is carried out as in Stage B of Preparation starting with 5 cm3 of 2-amino phenethyl alcohol. 10.06 g 5 of expected product is obtained, M.p. = 59°C. 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°C.
Analysis forC18H27 N03 = 305.42 C H N % calculated 70.79 8.91 4.59 % found 70.9 9.2 4.6 IR Spectrum (chci3) 15 (3360 cm-1 II -C-NH ) η } 3430 cm-1 C=O 1684 cm x Amide II 1530 cm-1 -0-C- 1720 cm-1 STAGE B: 2-(3-nitro-2-pentanamido phenyl)-ethyl pentanoate 7.1 cm of acetic acid is added at a temperature of between 0° and +10°C to a solution of 9.1 g of the product obtained in Stage A above in 50 cm of acetic anhydride.
Agitation is carried out for 2 hours between 0° and 10°C, 150 ... cm 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 ci8H26N2°5 = 350,42 C H N 35 % calculated 61.7 7.48 7.99 % found 61.5 7.5 7.9 IR Spectrum I 3330 cm 1 I 3420 cm1 1725 cm1 1700 cm-1 1605 cm1 1583 cm1 1535 cm"1 1478 cm"1 (complex) 1348 cm1 II -C-NH C=O Aromatics + Amide II + 1st NO2 band 2nd NO2 band STAGE C: Methyl 4'-[N-[[2-nitro-6-[(2-pentanoyloxy)-ethyl]phenyl]-N-pentanoyl]-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 mg 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 3-7), 5.19 g of the desired product is obtained.
IR Spectrum (CHC13) (PE 580) ^C=O 1728 cm1 20 1666 cm1 — 1 CH, Of -C 3 \ OCH3 1438 cmN02 1534 „ -1 cm EXAMPLE 10:Methyl 4·-[[2-butyl-7-[2-(pentanoyloxy)-ethyl]-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate The operation is carried out as in Example 3 starting with 3.38 g of the product obtained in Stage C of Preparation 3, using 1.03 g of catalyst. After chromatography on silica (eluant: ethyl acetate - cyclohexane (3-7)), 2.42 g of the desired product is obtained.
IR Spectrum (CHC13) />0 1724 cm1 (F) Conjugated system 1599 cm1 + Aromatic 1520 cm1 EXAMPLE ll: Methyl 4’-[[2-butyl-7-(2-hydroxy ethyl)-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate . . . 3 2.42 g of the product obtained in Example 10 with 20 cm of methanol and 5.5 cm3 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 5 pressure. The residue is crystallized from ethyl acetate, and 1.59 g of desired product is obtained. M.p. = 139°C. An analytical sample was prepared by recrystallization of 110 mg of the above product from ethyl acetate and 79 mg of product is collected. M.p. = 139°C.
Analysis for C23H30N2°3 = 442.56 C % calculated 75.99 % found 75.8 IR Spectrum (CHClg) OH - 3615 + Associated 3550 ^C=O 1720 H 6.83 6.8 N 6.33 6.2 cm cm cm example 12: 4'-[[2-butyl-7-(2-hydroxy ethyl)-lH-benzimidazol1-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 11. 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. 1/2 C2H5OH = 451.574 Analysis for C27H28N2O3' C 74.48 74.15 % calculated % found IR Spectrum Absorption OH/NH region H 6.92 7.0 N 6.20 6.2 1680 cm 1592 cm 1512 cm _C=O Conjugated system + Aromatic NMR Spectrum (DMSO) 250 MHz 35 Presence of about 0.4 mol of ethanol CHi J CHi 2 CHI Z 0.87 (t) 1.37 (m) 1.73 (m) CH2 2.80 (t) feH5 CH1 2 2.88 (t) CH- 1 2 3.62 (t) OH n-ch2-c6h5 5.71 (S)C6H4 1 6.92 (d) 1 7.29 (d) the other aromatic H’s)6.96 (d) IH - 7.10 (t) IH 10 ^-7.34 (d) IH - 7.40 to 7.60 3H /7.70 (dd) IH mobile H 4.2 to 5.0 EXAMPLE 13: Methyl 4·-[[2-butyl-7-(2-chloro-ethyl)-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylate hydro15 chloride A mixture of 714 mg of the product obtained in Example 11 is agitated for 45 minutes at 80°C with 14 cm3 of thionyl chloride. After evaporation of the thionyl chloride, the . . . . 3 mixture is taken up 3 times with 20 cm of methylene chloride and evaporated to dryness each time. The final dry extract is crystallized from ethyl acetate. 733 mg of desired product is obtained, M.p. = 151°C. A microanalytical sample was obtained by two successive recrystallizations from an ether - ethyl acetate mixture (1-1). The purified product is obtained.
M.p. = 160°C.
Analysis for c28H3oN2°2C12 = 497.47 % calculated % found C 67.60 67.5 H 6.08 6.08 N .63 14.25 .6 Cl 14.2 IR Spectrum CHC13 Absorption type ® -H 1725 cm II -C-OCH3 Aromatic Heteroaromatic 1512 - 1496 cm’ example 14: 41-[[2-buty1-7-(2-chloro-ethyl)-lH-benzimidazol-1yl]-methyl]-biphenyl-2-carboxylic acid 500 mg of the product obtained in Example 13 is 1434 cm 1624 - 1600 - 1565 cm -1 introduced under agitation at ambient temperature into 35 ml of 36% hydrochloric acid. The mixture is refluxed for 2 hours 30 minutes, then evaporated.
After chromatography on silica (eluant: methanol 5 methylene chloride (1-9)), 479 mg of product is obtained, which is dissolved in 60 ml of a 50/50 mixture of water and methanol brought to a pH of approx. 10 with soda then neutralized to a pH of approx. 5 with acetic acid. The methanol is evaporated off, followed by separating, washing with ether and drying under reduced pressure at about 100°C. 310 mg of desired product is obtained. M.p. = 226°C.
Recrystallization is carried out three times from methanol and 112 mg of expected product is obtained. M.p. = 233°c.
IR Spectrum in NUJOL ^=o 1698 cm1 Aromatic 1597 cm-1 Heteroaromatic 1518 cm-1 NMR Spectrum (DMSO) 250 MHz ch3 0.90 (t)CH2 1.39 (m)CH2 1.77 (m) ch2-c 2.85 (t)C6H5-CH2- 3.18 (t) ci-ch2 3.64 (t) N-CH2-C6H5 5.64 (s)C6H4 6.92 (d) 7.29 (d) 7.05 (d) 1H - 7.13 (t) 1H - other aromatics 7.33 (d) 1H - 7.40 to 7.60 7.70 (dd) 1H EXAMPLE 15: Methyl 4·-[[2-butyl-7-formyl-lH-ben2imidazol-iyl]-methyl]-biphenyl-2-carboxylate hydrochloride 600 mg of the product obtained in Example 7 is dissolved . 3 . . m 60 cm of methylene chloride and 1.2 g of activated manganese dioxide is added. The mixture is agitated for 24 hours at ambient temperature, filtered and evaporated to dryness under reduced pressure, and 600 mg of the expected product is obtained in the form of a base.
Preparation of the hydrochloride 600 mg of the product obtained above is dissolved in 3 cm3 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°C.
IR Spectrum in CHClg C=O 1723 - 1706 cm"1 Aromatic 1618 - 1599 - 1563 - 1520 cm"1 Heterocycles 1498 cm"1 example 16¾ 4'-[(2-butyl-7-formyl-lH-ben«imidasol-l-yl)15 methyl]-biphanyl-2-carboxylic acid 600 mg of the product obtained in Example 15 is dissolved in 6 cm3 of ethanol, 0.8 cm3 of water and 0.8 cm3 of caustic soda lye and agitation is carried out for 2 hour 30 minutes at 50°C. The mixture is cooled down, 30 cm3 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°C under reduced pressure. 470 mg of product is obtained. M.p. = 225°C.
The product obtained above is dissolved in 30 cm3 of 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°C under reduced pressure. 360 mg of the expected product is obtained. M.p. = 230°C.
Analysis for C26H24N2°3 = 412,47 C H % calculated 75.7 5.87 % found 75.5 5.8 35 IR Spectrum C=O in Nujol 1690 cm"1 Aromatics 1600 - 1580 cm1 Heterocycle 1516 cm"1 NMR Spectrum (DMSO) 300 MHz CH| 3 0.88 (t) CH- 1 1.38 (m) CH- 1 1.75 (m) 5 CH1 2 2.88 (m) c=o J N-£H2-C6H5 6.05 (si)C6H4 6.93 (d) 7.25 (d) 10 7.31 (d) 1H - 7.42 (m) 2H the other aromatics 7.53 (td) IH - 7.69 (d) IH 7.83 (d) IH - 8.0 (d) IH mobile protons 10.08 and 12.75 example 17; 4’-[[2-butyl-7-[(dinethylamino)-methyl]-1H15 bensimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid dihydroohloride 360 mg of the product obtained in Example 9 is dissolved in 10 cm3 of dimethylamine at 33% in ethanol and agitation is carried out for 19 hours at ambient temperature. The mixture . . . 3 is evaporated, extracted 3 times with 20 cm of methylene chloride, washed twice with 15 cm of salt water, dried, filtered and evaporated under reduced pressure. 300 mg of the expected product is obtained in the form of a base.
Preparation of the dihvdrochloride The operation is carried out as in Example 15, by . . « 3 dissolving 300 mg of the product obtained above in 5 cm of isopropanol in the presence of an excess of ethyl acetate and hydrochloric acid. 110 mg of the expected product is obtained.
M.p. = 260°C.
Analysis for C28H3iN3°2' 2HC1 = = 514.47 Cl N C H % calculated 65.36 6.46 13.78 8.17 % found 65.3 6.5 13.8 8.0 IR Spectrum in Nujol C=O 1770 - 1680 cm" 1 Aromatics 1623 - 1597 cm •1 Heterocycles 1514 - 1495 cm" 1 NMR Spectrum (DMSO) 300 MHz H3 0.92 ppm (t) CH_ 1 1.44 (m) H2 1.83 (m) 9H2 3.24 (m) =C-CH~-N 1 2 4.38 (m) N-£H2-C6H5 5.98 (Si)C6H4 1 7.20 (d) 7.34 (d) 7.56 (d) 1H - 7.88 (d) 1H the other aromatics 7.75 (d) 1H - 7.55 (m) 2H 7.47 (t) 1H - approx. 7.37 masked 1H mobile protons 11.39 and 12.78 EXAMPLE 18: Methyl [2-butyl-l-[2 *-(methoxycarbonyl)-biphenyl15 4-yl]-methyl]-lH-benzimidazol-7-acetate hydrochloride a) Preparation of the f2-butvl-l-r2*-(methoxvcarbonvl)biphenvl-4-vl1-methyl1-lH-benzimidazol-7-acetic acid g of the product obtained in Example 11 is introduced . 3 3 into 10 cm of acetone and 1.5 cm of BOWERS reagent. The 20 mixture is agitated for one hour at ambient temperature, filtered, the filtrate is rinsed with methylene chloride, evaporated and the residue is taken up m 50 cm of water and cm of methanol, brought to pH 12 with IN soda, then acidified to pH 4-5 with acetic acid. After evaporation, . . . . . 3 extraction is carried out 3 times with 100 cm of methylene chloride, and the extracts are washed twice with 40 cm of water, dried, filtered and evaporated to dryness. 1.07 g of the expected product is obtained. b) Preparation of methyl Γ2-butvl-l-r2-(methoxvcarbonvl) 30 biphenvl-4-vl1-methyl1-lH-benzimidazol-7-acetate The product obtained above is dissolved in 10 cm3 of methylene chloride, then esterified with about 10 cm3 of diazomethane in methylene chloride, evaporated to dryness and 968 mg of product is collected which is chromatographed on silica (eluant: ethyl acetate - flugene (7-3)). 745 mg of the expected product is obtained in the form of the base. c) Preparation of the hydrochloride The operation is carried out as in Example 15, 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 ® -H approx. 2500 cm-1 2>0 C-OMe tl o 1725 - 1714 cm -1 1438 cm (F) Aromatics Heteroaromatics 1565 - 1512 - 1500 cm EXAMPLE 19: 2-butyl-l-[(2'-carboxy-biphenyl-4-yl)-methyl]-1Hbenzimidazol-7-acetic acid 745 mg of the product obtained in Example 18 is introduced at ambient temperature into 8 cm3 of ethanol and .... 1.6 cm 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 10 cm 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°C. Recrystallization is carried out from isopropanol then from methylethyl ketone. 184 mg of expected 1623 - 1599 cm product is obtained. M.p. = Analysis for C27H26N2 04 = 442 25 C H % calculated 73.29 5.92 % found 73.3 5.9 IR Spectrum Nujol OH/NH very associated general 30 C=0 1712 cm NMR Spectrum (DMSO) 300 MHz CH1 J 0.88 (t) CH1 2 1.38 (m) CH! 2 1.75 (m) 35 ch2-< 2.33 (t) c6h5-ch2-c= 3.62 (S) n-ch2-c6h5 5.65 (s) N 6.33 6.3 C6H4 the other aromatics 6.90 (d) 7.29 (d) 6.39 (d) 1H - 7.13 (t) 1H 7.34 (d) 2H - 7.43 (dd) 2H 7.54 (m) 2H - 7.71 (dd) 1H mobile H 12.75 EXAMPLE 20: 4 · - [[2-butyl-7-ethenyl-lH-benziaidazol-l-yl]methyl]-biphenyl-2-carboxylic acid 300 mg of the product of Example 13 is introduced at 10 ambient temperature into 3 cm3 of methanol, 0.6 cm3 of water and 0.6 cm of 32% soda.
The mixture is agitated for one hour under reflux. The methanol is evaporated off, 5 cm3 of water is added, followed by neutralizing to pH 5-6 with acetic acid, separating, washing with water and drying at 100°C under reduced pressure 228 mg of expected product is obtained. M.p. = 228°C. 474 mg of product obtained as above is recrystallized from methylethylketone then from isopropanol, and 278 mg of desired product is collected. M.p. = 238°C.
Analysis for C27H26N2°2 = 410·52 H 6.38 6.5 N 6.82 6.9 C % calculated 79.00 % found 79.2 IR Spectrum Nujol OH/NH very associated general absorption >c=o 1678 cm-1 Conjugated system 1599 cm-1 + 1589 cm-1 Aromatic 1514 cm1 NMR Spectrum (DMSO) 300 MHz CH, ι J 0.87 (t) ?H2 1.37 (m) CH, 1 1.72 (m) CH2-C 2.81 (t) ch,=c—c,hr- -2 ι D □ 5.27 (dd, J = 1.5 and 11) ii 5.62 (dd, J = 1.5 and 17) ch2-ch-c6h5 7.08 (dd, J = 11 and 17) n-ch2-c6h5- 5.64 the other aromatic H's mobile H's C6H4 6.97 (d) 7.31 (d) 7.10 to 7.25 (m) 2H - 7.31 (m) 1H 7.42 (td) 1H - 7.57 (m) 2H 7.63 (dd) 1H 12.77 ( 1H) EXAMPLE 21: Methyl 4'-[2-butyl-7-(2-dimethylamino)-ethyl]biphenyl-2-carboxylate 1.05 g of product obtained in Example 13 is introduced 10 under agitation at ambient temperature into 25 cm3 of dimethylamine at 33% in ethanol.
The mixture is maintained for 16 hours at 80°C, then evaporated under reduced pressure at 60°C, extracted 3 times . 3 with 60 cm of methylene chloride, the extracts are washed 3 15 times with 20 cm of water, dried and evaporated to dryness.
After chromatography on silica, (eluant: methanol methylene chloride (1-9)), 789 mg of the expected product is obtained. CCM: Rf 0.37 (eluant: methylene chloride - methanol (9-1)).
EXAMPLE 22: 4·-[[2-butyl-7-[2-(dimethylamino)-ethyl]-1Hbenzimidazol-l-yl]-methyl]-biphenyl-2-carboxylic acid dihydrochloride 789 mg of the product obtained in Example 21 is introduced at ambient temperature into 15 cm3 of ethanol and 1.3 cm3 of 32% soda.
The mixture is agitated for one hour at 85°C, evaporated, the residue is taken up in 10 cm3 of water, acidified to pH 5 with acetic acid, and extracted 3 times with 60 cm3 of methylene chloride; the extracts are washed twice with 10 cm of water, dried, filtered and evaporated to dryness. • . . 3 The resultant product is dissolved in 5 cm of methylethylketone, 5 cm3 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 separated out, washed with methylethylketone and dried at 60°C under reduced pressure. After recrystallization from acetonitrile, 429 mg of the expected product is obtained.
M.p. = 218°C.
Analysis for ^29Η33Ν3°2' 2HC1 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 N 7.95 8.2 O A 1708 ^-1 cm 1690 „-l cm Aromatic 1625 cm-1 10 + 1598 „ -i cm Heteroaromatic 1569 cm"1 1510 cm-1 NMR Spectrum (DMSO) 250 MHz CH~ I 0.91 (t) CH- 1 1.42 (m) 15 CHO 1 * 1.82 (m) CH2-C c6h5-ch2-ch2-n 3.09 (m) 2H and =C-CH2-CH2 '3.26 (m) 4H n-ch2-c6h5 6.04 (si) 20C6H4 7.23 (d) 2H 7.34 (d) 2H 7.80 (d) 1H - 7.74 the other aromatic H’ s 7.56 (m) 2H - 7.44 7.30 (masked) 1H 25 the N-CH3's 2.65 (si) mobile H’s 11.38 EXAMPLE 23: Methvl 2- butyl-l-[2 '-cyano-(1,1’ methyl]-lH-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 cm of tetrahydrofuran, 280 mg of palladium at 18% on activated charcoal is added and the reaction medium is hydrogenated for 30 minutes (absorption 160 cm3 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°C under reduced pressure. 450 mg of crude product is recovered which is recrystallizedfrom isopropyl ether. M.p. = 90°C. Analysis for ci3Hi8N2°3r 250·29 C H % calculated 62.38 7.25 % found 62.4 7.4 IR Spectrum (CHC13) =C-NH N 11.19 11.1 C=O 3420 cm 1698 cm 1680 cm 3340 cm Max.
Ep.
Aromatic NH2 def. 1620, 1601, 1580, 1514 cm Amide II STAGE B; Methyl 4'-[N-[[2-(methoxycarbonyl)-6-aminophenyl]-npentanoyl]-aminomethyl-biphenyl-2-carboxylate 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 3 . cm of dimethylformamide, and the mixture is agitated for 15 minutes, then 300 mg of 4'-(bromomethyl)-biphenyl-2-nitrile is added and agitation is carried out for 15 minutes at ambient temperature. The solvent is evaporated off, 60 cm3 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 silica (eluant: flugene - ethyl acetate (7-3)) then crystallized from isopropyl ether then from ethyl ether. 125 mg of expected product is obtained. M.p. = 80°C then 145°C. Analysis for C27H27N3O3, 441.51 C H % calculated 73.45 6.16 % found 73.4 6.2 IR Spectrum (CHC13) =C-NH2 3496 cm-1 3395 —C=N 2226 cm-1 -C=O 1722 - 1656 cm Aromatics 1613 cm"1 1597 NH- def. 1588 cm1 1515 N 9.52 9.2 —1 Γ1 .-1 STAGE C: Methyl 2-butyl-l-[2’-cyano-(1,1’-biphenyl)-4-yl)methyl]-lH-benzimidazol-7-carboxylate hydrochloride 730 mg of product obtained as in Stage B is dissolved in 3 cm of a solution of hydrochloric acid m ethyl acetate and 5 agitation is carried out for 10 minutes at 50°C. The solvent is evaporated off, the residue is taken up in a mixture of methylethylketone and ether, followed by separating and drying at 80°C 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°C.
Analysis forC27H25N3O2, HCl 459.96 C Η N Cl % calculated 70.50 5.70 9.14 7.71 % found 70.6 5.8 9.2 7.8 IR Spectrum (chci3) -co2ch3 1723 cm-1 1436 cm1 -Csn 2226 cm-1 1620 cm-1 1598 cm-1 1564 cm1 1496 cm-1 Complex absorptions max. to about 2450 cm-1 of the type sN +-H aromatics Heteroaromatics EXAMPLE 24: Methyl 2-butyl-l-[2'-(lH-tetrazol-5-yl)-(l,l·biphenyl)-4-yl)-methyl]-lH-benzimidazol-7-carboxylate a) 10 cm of a saturated aqueous solution of sodium bicarbonate is added to a suspension containing 650 mg of the hydrochloride prepared in Example 23 in 50 cm of water, the mixture is 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 base is collected. b) The 600 mg of above product is dissolved in 6 cm3 of xylene and 511 mg of trimethyltin azide is added. After agitation for 23 hours at 115-120°C, a further 205 mg of azide is added and heating is continued for 24 hours. The xylene is . .... evaporated off, 30 cm of water is added, agitation is carried out for 15 minutes, 10 cm3 of methanol is added, followed by extraction with methylene chloride; the extracts are dried and evaporated to dryness under reduced pressure. g of crude product is obtained which is chromatographed on silica (eluant: methylene chloride - methanol (91)) then the residue is crystallized from ether. 470 mg of expected product is obtained. M.p. = 165°C.
EXAMPLE 25: 2-butyl-l-((2·-(lH-tstrazol-5-yl)-(1,1·biphenyl)-4-yl)-methyl]-lH-benzimidazol-7-carboxylic acid 470 mg of product obtained in Example 24 in solution in 12 cm3 of ethanol is agitated for 2 hours under reflux in the presence of 3 cm of N soda, the ethanol is evaporated off, 10 , 3 , cm of water is added, then drop by drop 0.8 cm 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 reduced pressure. 420 mg of crude product is collected which is dissolved m 10 cm of a methanol - methylethylketone mixture (1-1), the solution is . 3 . filtered, concentrated to 5 cm , one drop of acetic acid is . ,.. added then 5 cm of water is added, crystallization is started and left at +4°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. 210-220°C.
Analysis for C2gH24 NgO2, 452.50 C H N % calculated 69.01 5.35 18.57 25 % found 68.7 5.3 18.3 IR Spectrum Complex absorption OH/NH region C=0 1700 cm"1 Aromatic 1609 cm"1 1598 cm"1 30 Heteroaromatic 1515 cm-1 1488 cm"1 example 26: pharmaceutical composition Tablets were prepared corresponding to the following 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 27: pharmaceutical composition 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 - Test on the angiotensin 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 50 mM buffer pH 7.4, the grinding is followed by 3 centrifugations at 30,000 g for 15 minutes, the deposits being taken up in between in the Tris buffer pH 7.4.
The last deposits are put in suspension in an incubation buffer (Tris 20 mM, NaCl 135 mM, KCl 10 mM, glucose mM, MgCl2 10 mM phenylmethylsulphonyl fluoride 0.3 mM, bacitracin 0.1 mM, bis(trimethylsilyl) acetamide 0.2%).
The aliguoted fractions of 2 ml are divided into . 1 2 5 hemolysis tubes and τ angiotensin II (25,000 DPM per tube) and the product to be studied are added. (The product . . —5 is first tested at 3 x 10 M three times). When the tested product displaces by more than 50% the radioactivity linked specifically to the receptor, it is tested again according to 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 10-5M (in triplicate). The medium is incubated at 25°C 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 (IC5Q), that is as the concentration of studied product, expressed in nM, necessary to displace 50% of the specific radioactivity fixed Results: on the receptor studied ι 1 | Product of Example | I I 1 ICg0 in nanomoles | I 1 1 1 2 I 1 911 | 1 4 | 52 | 1 12 I 105 | 1 16 1 99 | 1 19 1 207 | 1 6 | 1_L 270 | 1 - 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 - KCl 4.7 - MgS04 1.2 - KH2PO4 1.2 - NaHCO-j 25 glucose 11.1 - CaCl2 2.5), the medium is maintained at 37°C and oxygenated with an 02 (95%), C02 (5%) 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 bath (1.10-6M).
At the end of the rest period angiotensin II (Ciba hypertensin) 3.10"®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 between two stimulations by angiotensin. The compound to be studied is introduced into the bath 15 minutes before a new stimulation by angiotensin. From increasing concentrations of the molecule being applied, an IC5Q (concentration which produces a 50% inhibition of the response to angiotensin) can be calculated, this being expressed in nanomoles. Results: — Product of Example -, IC50 in nanomoles | I4 1 9.5 | 16 45 | 2 looo | 1 - 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 (50 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 bilateral section of the pneumogastric nerves is carried out.
The rat is then demedullated.
After a sufficient period of stabilization, the study of the antagonism of the molecules vis- -vis angiotensin II (Hypertensin, CIBA) is approached in the following manner: - Three consecutive injections of angiotensin II (0.75 micrograms/kg) spaced 15 minutes apart permits a reproducible and stable pressure response to be obtained.
- 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 pressure effects of angiotensin II administered on its own. The dose which inhibits the studied effect by 50% is thus determined (IDgo).
Each animal is considered to be its own control.
Results: I- Product of Example "I-1 | ID50 in mg/kg | I I 4 1 1 1 0*3 1 12 1 1-77 I I 16 1 1.97 | 1 1

Claims (16)

1. ) Products of formula (Ι β ): Ρ R in which:
2. -butyl-l-[[2'-(lH-tetrazol-5-yl)-(1,1'-biphenyl)-4-yl]methyl]-lH-benzimidazole-7-carboxylic acid and its salts.
3. ) Products of formula (Ι β ) as defined in claims 1 and 2 and corresponding to formula (I A ): in which: R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, r 1A' R 2A' R 3A and R 5A are such that:
4. '-[(2-butyl-7-formyl-lH-benzimidazol-l-yl)-methyl]-biphenyl30 2-carboxylic acid and its salts, 4·—[(2-butyl-lH-benzimidazol-l-yl)-methyl]-biphenyl-2carboxylic acid and its salts, 25 2-butyl-l-[(2’-carboxy-biphenyl-4-yl)-methyl]-lH-benzimidazole-7-carboxylic acid and its salts, 4 1 -[[2-butyl-7-(2-hydroxy ethyl)-ΙΗ-benzimidazol-l-yl]methyl]-biphenyl-2-carboxylic acid and its salts,
5. 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 10 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, 5 formula (I A ). 5 bases of the said products of formula (I A ). 5) Products of formula (I A ) as defined in claim 3 in which R represents a butyl or 1-butenyl radical and R 1A represents a IE 91195° hydrogen atom or an alkyloxy radical, the said products of formula (I&) 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 5 4) Products of formulae (Ι β ) and (I A ), as defined in claims 1 to 3 corresponding to formula (I): in which: R represents a linear or branched alkyl or alkenyl radical 20 containing 3 or 4 carbon atoms, R ir R 2 , R 3 and Rg are such that: either R x , R 2 , R 3 and Rg are identical and represent a hydrogen atom, or R 2 and Rg are such that one represents a hydrogen atom or a 25 -CH 2 -O-R 10 radical and the other represents a hydrogen atom, and R 3 and R 3 are such that: one represents a hydrogen atom and the other is chosen from the radicals -OR g , -CO 2 R 7 and -CH 2 ~O-Rg, which radicals R 10 , R 6 , R ? and Rg, identical or different, represent a hydrogen 30 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 (I) being in all the possible racemic, enantiomeric and diastereoisomeric isomer forms, as 35 well as the addition salts with mineral or organic acids and mineral or organic bases of the said products of formula (I). 5 either R 1A , R 2A' R 3A and R 5A are identical and represent a hydrogen atom, or R 2A and R 5A are such that one represents a hydrogen atom or a -CH 2 ~O-R 10 radical, in which R 10 represents a hydrogen atom or or a linear or branched alkyl or alkenyl radical containing 5 or a -(CH 2 ) m -SO 2 -X-R 12 radical in which m represents an integer from 0 to 4 and either (X-R 12 ) represents NH 2 or X represents a single bond, or the radicals -NH-, -NH-CONH- or -NH-CO- and R 12 represents an alkyl, alkenyl or aryl 5 - aryl radicals optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, trifluoro-methyl, cyano, nitro, amino radicals, alkoxy radicals containing at most 4 carbon atoms, phenyl, benzyl radicals, free, salified or esterified carboxy radicals and tetrazolyl radicals,
6. ) Products of formula (I A ) as defined in claim 3 in which R represents a butyl radical and *1A' R 2A' R 3A and R gA represent a hydrogen atom, the said products of formula (I A ) being in all the possible racemic, enantiomeric and diastereoisomeric
7. ) Products of formula (I A ) as defined in claim 3, in which R represents a butyl radical, R 1A , R 2A' an ^ R 5A re P resent a
8. ) Products of formula (I&) as defined in claims 1 to 4, in which R represents a butyl radical and R 1A , R 2A and R 5A represent a hydrogen atom, and R 3A represents a hydrogen atom, a carboxy radical, free or esterified by an alkyl radical
9. ) Methyl 4(2-butyl-lH-benzimidazol-l-yl)-methyl]biphenyl-2-carboxylate and its salts,
10. Which is subjected to a nitration reaction in order to obtain the compound of formula (Χ β ) as defined above, which product of formula (Χ β ) is reacted with the compound of formula (ν β ) as defined above, in order to obtain a product of formula (ΧΙ β ): (XI B ) in which R, R 1B i, r 2b»' R 3B*' R 5B' and R 4B' have the P revious meanings, which is subjected to a selective reduction reaction of the nitro function, in order to obtain the product of formula (XII B ): in which R, R 1B ·» R 2B i» R 3B' r R 5B' and R 4B' have the previous meanings, which is subjected to a cyclization reaction in order to obtain the products of formula (IX B ) as defined above, or the compound of formula (VI B ) is reacted with the compound of formula (V B ) as defined above, in order to obtain a product in which R 1B ,, R 2B i , R 3B ,/ R 5B* a ^ d R 4B' have the meanings reduction reaction of indicated above, which is subjected to a 20 the nitro radical into an amino radical in order to obtain a product of formula (Vlllg): in which R^ B ,, R 2B*' R 3B’' R 5B* and R 4B’ have the mean i n g s 35 indicated above, which is reacted with the product of formula (HI): R-C-R q II 9 X (III) in which X represents an oxygen atom or an NH radical, R g and R have the meaning indicated above, in order to obtain after cyclization a product of formula (IXg) as defined above, which product of formula (IX B ), if desired and if necessary, 10 in which R 1B ,, R 2B i» R 3B’ and R 5B* have the previous meanings, is reacted with the compound of formula (II): r -C- r 9 (II) in which R g represents a hydroxy or alkyloxy radical or a 15 halogen atom and R has the meaning indicated above, in order to obtain the product of formula (X B ): in which R, R 1B·» R 2B'' R 3B’ and R 5B* have the previous 25 meanings, b) a compound of formula (VIg,): in which R^g,, R 2B i, R 3B* and R 5B' have tlie previous meanings, 35 is reacted with the compound of formula (II) as defined above in order to obtain the product of formula (Χ β| ): in which R 1B ,, R 2B ·/ R 3B*' R 5B' 5111(1 R have the meanings indicated previously, 10) Preparation process for products of formula (Ι β ) as defined in claim 1, characterized in that: 35 either a product of formula (IV&): IE 91*|950 < IV B> in which R has the meaning indicated in claim 1 and R^ B ,, R 2QI , R 3B i and R 5B , have the meanings indicated in claim 1 for 10 R 1B' R 2B' R 3B and R 5B respectively in which the optional reactive functions are if desired protected by protective groups, is reacted with a compound of formula (V B ): 20 in which Hal represents a halogen atom and R 4B , has the meaning indicated in claim 1 for R 4B in which the optional reactive functions are, if desired, protected by protective groups, in order to obtain a product of formula (ΙΧ β ): in which R, R 1B i, R 2B ·/ R 3B·' R 5B’ and R 4B' have the mea nings indicated above, < vi b) 10 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, hydroxyl radicals, acyloxy radicals, amino radicals optionally substituted by one or two 10 isomer forms, as well as the addition salts with mineral or organic acids and mineral or organic bases of the said products of formula (I A ). 10 at most 5 carbon atoms, and the other represents a hydrogen atom, and R 1A and R 3A are such that one represents a hydrogen atom and the other is chosen from the radicals -ORg, -CO 2 R 7 and -R^, in which radicals: Rg and R ? , identical or different, represent a hydrogen atom 10 propyl, vinyl, allyl, phenyl, benzyl, pyridyl, pirydylmethyl, pyridylethyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperydinyl, thiazolyl, alkylthiazolyl, tetrahydropyrannyl, methyltetrahydrofurannyl ; these radicals being optionally substituted by one or two radicals chosen 10 radical, these radicals being optionally substituted, the said products of formula (Ι β ) 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 (I B ). 10 - the free, esterified or salified carboxy radical, - the radical:
11. ) As medicaments, the products of formula (Ι β ) as defined in claim 1 or 2, the said products of formula (Ι β ) being in all the possible racemic, enantiomeric and diastereoisomeric 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 (Ι β ).
12. ) As medicaments, the products of formulae (I A ) and (I) as 5 defined in one any of claims 3 to 9, as well as addition salts with pharmaceutically acceptable mineral or organic acids and mineral or organic bases of the said products of formulae (l A ) and (I).
13. ) The pharmaceutical compositions containing as active 10 ingredient, at least one of the medicaments as defined in anyone of claims 11 and 12.
14. ) As new industrial products, the compounds of formulae (IV B ), (VII B ), (VIII B ), (X B ) and (Χ β ,).
15. ) A process for preparing a compound of formulae (Ig) and (1^) as defined in claims 1 to 3, or formula (I) as defined in claim 4, substantially as described herein by way of example. 15 - 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 20 radical, - a substitution reaction of a hydroxy radical by a halogen atom, - a reduction reaction of an esterified carboxy radical into a hydroxyalkyl radical, 25 - an oxidation reaction of a hydroxyalkyl radical into an esterified carboxy radical, - an oxidation reaction of a hydroxymethyl radical into aformyl radical, - a resolution reaction of the racemic forms into resolved 30 products, - a conversion reaction of a free, salified or esterified carboxy function, into a tetrazolyl radical, the said products of formula (Ι β ) thus obtained being in all the possible racemic, enantiomeric and diastereoisomeric 35 isomer forms. 15 alkyl radicals containing at most 4 carbon atoms and free, salified or esterified carboxy radicals, the said products of formula (I A ) 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 20 bases of the said products of formula (I A ). 15 hydrogen atom, and R 3A is chosen from the radicals -ORg, CO 2 R 7 and -R 1X , in which radicals: R 6 and R ? , identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, 20 Rgg 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, 25 - linear or branched alkyloxy or alkenyloxy radicals having at most 5 carbon atoms, - the free, esterified or salified carboxy radical, - the radical: 30 - N in which R a and R b , 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 35 radical, b) linear or branched alkenyl radicals having 2 to 5 carbon atoms, c) acyl radicals having 2 to 7 carbon atoms and the formyl |£ «11950 radical, the said products of formula (I A ) 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 15 or a linear or branched alkyl or alkenyl radical containing at 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: 20 - halogen atoms, - the optionally acylated hydroxyl radical, - linear or branched alkyloxy or alkenyloxy radicals having at most 5 carbon atoms, - the free, esterified or salified carboxy radical, 25 - the radical: -N in which R a and R b , identical or different, are chosen from 30 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, 35 c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, R 4A represents a free, esterified or salified carboxy radical, a cyano radical, or a tetrazolyl radical, optionally salified, the said products of formula (I A ) 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 (I A ). 15 among -(CH 2 )p-SO 2 -Z c -R 14c as defined above and the alkyl and alkenyl radicals containing at most 4 carbon atoms optionally substituted ; all this radicals being optionally substituted by one or more selected from the halogen atoms, the hydroxy radical, alkyl, alkenyl and alkoxy radical containing at most 20 4 carbon atoms, trifluoromethyl, cyano, free, salified or esterified carboxy or tetrazolyl radical, the said products of formula (Ι β ) 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 25 bases of the said products of formula (Ig)· 15 2) Products of formula (Ι β ), as defined in claim 1, in which: R represents a butyl or buten-l-yl radical, R 2B and R gB are such that one of R 2B and R gB represents a hydrogen atom and the other a radical in which R c and R d , identical or different, are chosen from hydrogen atoms, alkyl or alkenyl radicals having 1 to 4 carbon 25 atoms and phenyl radicals, all these radicals being optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro or amino radicals, alkoxy radicals containing at most 4 carbon atoms, phenyl or benzyl radicals, free, salified or esterified carboxy 30 radicals and tetrazolyl radicals, Rjb represents an alkyl radical having at most 4 carbon atoms optionally substituted by one or more radicals chosen from halogen atoms, the hydroxyl radical, methoxy, ethoxy radicals, free, salified or esterified carboxy radicals, amino, mono- or 35 dialkylamino radicals and the phenyl radical, Itself optionally substituted by one or more radicals chosen from halogen atoms, methoxy, trifluoromethyl, cyano radicals, free, salified or esterified carboxy radicals and tetrazolyl radicals, R 3B is chosen from the radicals OR g and CO 2 R ? in which R g and R ? represent a hydrogen atom or an alkyl or alkenyl radical containing at most 5 carbon atoms, 5 R 4B re P resen ts a free, esterified or salified carboxy radical or a tetrazolyl radical, or a -(CH 2 )p-SO 2 -X d -R 12d radical in which p represents the values 0 and 1, X d represents the radicals -NH-, -NH-CO-NH-, -NH-CO- or a single bond and R 12 d re P resents a methyl, ethyl, 15 in which R a and R fa , 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 20 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, 25 c) acyl radicals having 2 to 7 carbon atoms and the formyl radical, d) the radical: in which R a and R b have the meaning indicated above, or one at most of Rg B , R 2B , R 3B and R 5B re P resents a hydrogen atom, and the others are chosen from the radicals -CH 2 -O-R 10 , 35 -ORg, -CO 2 R 7 , -Rgg and the radical c R. IE 91195® in which R g , R ? , R 10 , R 11# R c and R d have the values indicated above, R 4B represents a free, esterified or salified carboxy radical, or a tetrazolyl radical, 15 R represents a linear or branched alkyl or alkenyl radical containing 3 or 4 carbon atoms, R 1B' R 2B' R 3B and R 5B are suc ^ that: either Rj B , R 2B , R 3B and R 5B are identical and represent a hydrogen atom, 20 or R 2B and R 5B are such that one represents a hydrogen atom and the other represents a hydrogen atom or a -CH 2 -O-R 1Q radical, in which R 1Q represents a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at most 5 carbon atoms, or one of R 2B and R 5B represent the radical in which R c and R^, identical or different, represents the values defined hereafter for R_ and R. and R-, n and R, n are a o IB 3B 30 such that one represents a hydrogen atom and the other is chosen from the radicals -OR g , “ CO 2 R 7 and -R 11' ln whlch radicals: R 6 and R ? , identical or different, represent a hydrogen atom or a linear or branched alkyl or alkenyl radical containing at 35 most 5 carbon atoms, R^ 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 branchedalkyloxy or alkenyloxy radicalshaving at most 5 carbon atoms,
16. ) Products of a process according to claim 10 or claim 15.
IE195091A 1990-06-08 1991-06-07 New benzimidazole derivatives, their preparation process,¹the new intermediates obtained, their use as medicaments and¹the pharmaceutical compositions containing them IE911950A1 (en)

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FR909007135A FR2663028B1 (en) 1990-06-08 1990-06-08 NOVEL BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR909015811A FR2670489B1 (en) 1990-12-18 1990-12-18 NOVEL BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
FR9103778A FR2674523A1 (en) 1991-03-28 1991-03-28 New benzimidazole derivatives, process for their preparation, the new intermediates obtained, their application as medicaments and the pharmaceutical compositions containing them

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US5616599A (en) * 1991-02-21 1997-04-01 Sankyo Company, Limited Angiotensin II antagosist 1-biphenylmethylimidazole compounds and their therapeutic use
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US5753672A (en) * 1994-04-19 1998-05-19 Tanabe Seiyaku Co., Ltd. Imidazopyridine derivatives and process for preparing the same
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