RU2067095C1 - Derivatives of benzimidazole or their additive salts with organic or mineral acids, or with mineral or organic bases, method of their synthesis and pharmaceutical composition based on thereof - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: derivatives of benzimidazole (I)

where R - alkyl, alkenyl, R₁B, R₂B, R₃B, R₄B and R₅B - hydrogen; R₂B and R₅B - hydrogen; R₁B and R₃B - one hydrogen and another - CO₂R₇ and -R₁; R₇ - hydrogen, alkyl or alkenyl; R₁ - hydrogen, hydroxyl, alkylated carboxyl, radical -

where Ra and Rb - hydrogen, alkyl or alkenyl. Method of synthesis of (I)

involves interaction of (II)

with (III)

obtaining (IV)

followed by removal of protecting groups. Pharmaceutical composition showing antagonistic action with regard to angiotensin II containing (I)

Description

 The invention relates to new benzimidazole derivatives, a process for their preparation, new intermediates obtained, their use as medicines and pharmaceutical compositions containing them.

где R прямолинейный или разветвленный радикал алкил или алкенил с 3 или 4 атомами углерода;
R_1B, R_2B, R_3B и R_5B такие, что:
либо R_1B, R_2В, R_3B и R_5B одинаковые и представляют атом водорода,
либо R_2B и R_5B такие, что один атом водорода и другой атом водорода или же радикал -CH₂-O-R₁₀, где R₁₀ атом водорода или прямолинейный или разветвленный радикал, алкил или алкенил с не больше, чем 5 атомов углерода, или же радикал

где R_c и R одинаковые или различные определенные ниже значения для R_a, и R_b и R_1B и R_3B такие, что когда один водород и другой выбирается среди радикалов -OR₆, -CO₂R₇ и -R₁₁, радикалов, в которых:
R₆ и R₇ одинаковые или различные атом водорода или прямолинейный или разветвленный радикал алкил, или алкенил с не больше, чем 5 атомов углерода,
R>₁₁ выбирается в группе, образованной:
a) радикалами алкил с не больше, чем 4 атома углерода, могущими быть замещенными одним или несколькими радикалами, выбираемыми среди:
атомов галогена,
могущих быть ацилированными радикалами гидроксил,
прямолинейных или разветвленных радикалов алкилокси или алкенилокси с не больше, чем 5 атомов углерода,
радикалов арил, могущих быть замещенными одним или несколькими радикалами, выбираемыми среди атомов галогена, радикала гидрокси, трифторметил, циано, нитро, амино, радикалов алкокси с не больше, чем 4 атомами углерода, фенил, бензил, свободный, превращенный в соль или в сложный эфир радикал карбокси и тетразолил,
свободного, превращенного в соль или в сложный эфир радикала карбокси;
радикала:

где R_a и R_b одинаковые или различные выбираются среди атомов водорода, радикалов алкил или алкенил с 1-4 атомами углерода и арила, причем все эти радикалы могут быть замещенными одним или несколькими радикалами, выбираемыми среди атомов галогена, или радикала гидроксид, трифторметил, циано, нитро, амино, радикалов алкокси с не больше, чем 4 атомами углерода, фенил, бензил, свободных, превращенных в соль или в сложный эфир радикала карбокси,
б) прямолинейными или разветвленными радикалами алкенил с 2-5 атомами углерода,
в) радикалами ацил с 2-7 атомами углерода и радикалом формил,
г) радикалом:

где R_a и R_b имеют указанное выше значение,
либо один из R_1B, R_2B, R_3B и R_5B атом водорода,
и другие выбираются среди радикалов -CH₂-O-R₁₀, -OR₆, -CO₂R₇, -R₁₁ и радикала

где R₆, R₇, R₁₀, R₁₁, R_c и R_d имеют указанное выше значение,
R_4B свободный, превращенный в соль или в сложный эфир радикал карбокси или радикал тетразолил,
или радикал -(CH₂)_m-SO₂-X-R₁₂, где m целое число от 0 до 4 и,
либо (X-R₁₂)-NH₂,
либо Х простая связь, или радикалы -NH-, -NH-CO-NH, или -NH-CO- и R₁₂ радикал алкил, алкенил или арил, причем эти радикалы могут быть замещенными,
данные продукты формулы (I_B) находятся во всех возможных изомерных видах рацемических, энантиомерных и диастереоизомерных, а также как и аддитивные соли с минеральными и органическими кислотами и минеральные и органические основания данных продуктов формулы (I_B).This invention aims at products of formula (I _B ):

where R is a straight or branched alkyl or alkenyl radical with 3 or 4 carbon atoms;
R _1B , R _2B , R _3B and R _{5B are} such that:
or R _1B , R _2B , R _3B and R _{5B are the} same and represent a hydrogen atom,
either R _2B and R _5B such that one hydrogen atom and another hydrogen atom or the radical —CH ₂ —OR ₁₀ , where R _{10 is} a hydrogen atom or a straight or branched radical, alkyl or alkenyl with no more than 5 carbon atoms, or same radical

where R _c and R are the same or different values defined below for R _a , and R _b and R _1B and R _{3B are} such that when one hydrogen and the other are selected from the radicals —OR ₆ , —CO ₂ R ₇ and —R ₁₁ , the radicals , in which:
R ₆ and R _{7 are the} same or different hydrogen atom or a straight or branched alkyl or alkenyl radical with no more than 5 carbon atoms,
R> ₁₁ is selected in the group formed by:
a) alkyl radicals with not more than 4 carbon atoms, which can be substituted by one or more radicals selected from:
halogen atoms
hydroxyl radicals that can be acylated,
straight or branched radicals of alkyloxy or alkenyloxy with no more than 5 carbon atoms,
aryl radicals, which can be substituted by one or more radicals selected from halogen atoms, hydroxy radicals, trifluoromethyl radicals, cyano, nitro radicals, amino radicals, alkoxy radicals with no more than 4 carbon atoms, phenyl, benzyl, free, converted into a salt or into a complex ether carboxy radical and tetrazolyl,
a free carboxy radical converted to a salt or an ester;
radical:

where R _a and R _{b are} identical or different among hydrogen atoms, alkyl or alkenyl radicals with 1-4 carbon and aryl atoms, all of these radicals can be substituted by one or more radicals selected from halogen atoms, or a hydroxide, trifluoromethyl radical, cyano, nitro, amino, alkoxy radicals with not more than 4 carbon atoms, phenyl, benzyl, free, converted into a salt or ester of a carboxy radical,
b) straight-chained or branched radicals alkenyl with 2-5 carbon atoms,
c) acyl radicals with 2-7 carbon atoms and a formyl radical,
g) radical:

where R _a and R _b have the above meaning,
either one of R _1B , R _2B , R _3B and R _{5B is} a hydrogen atom,
and others are selected from the radicals —CH ₂ —OR ₁₀ , —OR ₆ , —CO ₂ R ₇ , —R ₁₁ and the radical

where R ₆ , R ₇ , R ₁₀ , R ₁₁ , R _c and R _d have the above meaning,
R _{4B is a} free carboxy radical or tetrazolyl radical converted to a salt or an ester,
or the radical - (CH ₂ ) _m —SO ₂ —XR ₁₂ , where m is an integer from 0 to 4 and,
either (XR ₁₂ ) -NH ₂ ,
either X is a single bond or radicals —NH—, —NH — CO — NH, or —NH — CO— and R _{12 are} alkyl, alkenyl or aryl radicals, these radicals being optionally substituted,
these products of formula (I _B ) are in all possible isomeric forms of racemic, enantiomeric and diastereoisomeric, as well as additive salts with mineral and organic acids and mineral and organic bases of these products of formula (I _B ).

где R_c и R_d одинаковые или различные выбираются среди атомов водорода, радикалов алкил или алкенил с 1-4 атомами углерода и фенил, причем все эти радикалы могут быть замещенными одним или несколькими радикалами, выбираемыми среди атомов галогена, радикала гидроксил, трифторметил, циано, нитро, амино, радикалов алкокси с не более, чем 4 атома углерода, фенил, бензил, свободного, превращенного в соль или в сложный эфир радикала карбокси и тетразолил,
R_1B радикал алкил с не больше, чем 4 атомами углерода, могущего быть замещенным одним или несколькими радикалами, выбираемыми среди атомов галогена, радикала гидроксил, радикалов метокси, этокси, свободного, превращенного в соль или в сложный эфир радикала карбокси, амино, моно- или диалкиламино и самого радикала фенил, могущего быть замещенным одним или несколькими радикалами, выбираемыми среди атомов галогена, радикалов метокси, трифторметил, циано, свободного, превращенного в соль или в сложный эфир радикала карбокси и тетразолила,
R_3B выбирается среди радикалов OR₆ и CO₂R₇, где R₆ и R₇ атом водорода или радикал алкил или алкенил с не больше, чем 5 атомов углерода,
R_4B свободный, превращенный в соль или в сложный эфир радикал карбокси или радикал тетразолил,
или радикал -(CH₂)_p-SO₂-X_d-R₁₂, где p - значения 0-1,
X_d радикалы -NH-, -NH-CO-NH-, -NH-CO- или простая связь и R_12d радикал метил, этил, пропил, винил, аллил, фенил, бензил, пиридил, пиридилметил, пиридилэтил, нитропиридил, пиримидил, тетразолил, диазолил, пиперидинил, алкилпиперидинил, тиазолил, алкилтиазолил, тетрагидрофуранил, метилтетрагидрофуранил; амино или карбамоил, могущие быть замещенными одним или несколькими радикалами, выбираемыми среди радикалов -(СН₂)_p-SO₂-Z_c-R_14c, таких, как они определены выше, и радикалов алкил и алкенил с не больше, чем 4 атомами углерода, и могущими быть замещенными; причем все эти радикалы могут быть замещенными одним или несколькими радикалами, выбираемыми среди атомов галогена, радикала гидроксил, алкил и алкенил, алкокси с не больше, чем 4 атомами углерода, трифторметил, циано, свободного, превращенного в соль или сложный эфир радикала карбокси; причем эти продукты формулы (I_B) находятся во всех возможных изомерных видах рацемических, энантиомерных и диастереоизомерных, а также как и их аддитивные соли с минеральными или органическими кислотами и минеральные или органические основания этих продуктов формулы (I_B).In particular, this invention aims at products of formula (I _B ), as defined above, wherein:
where R is a butyl or buten-1-yl radical, R _2B and R _{5B are} such that one of R _2B and R _{5B is} a hydrogen atom and the other radical

where R _c and R _{d are the} same or different among hydrogen atoms, alkyl or alkenyl radicals with 1-4 carbon atoms and phenyl, all of these radicals can be substituted by one or more radicals selected from halogen atoms, hydroxyl radicals, trifluoromethyl radicals, cyano atoms , nitro, amino, alkoxy radicals with not more than 4 carbon atoms, phenyl, benzyl, free, carboxy and tetrazolyl radical converted into a salt or ester,
R _{1B is an} alkyl radical with no more than 4 carbon atoms, which can be substituted by one or more radicals selected from halogen atoms, hydroxyl radicals, methoxy radicals, ethoxy radicals, free carboxy, amino, mono radicals converted into a salt or ester radical or dialkylamino and the phenyl radical itself, which can be substituted by one or more radicals selected from halogen atoms, methoxy, trifluoromethyl, cyano, free radicals converted into a salt or ester of a carboxy and tetrazolyl radical,
R _3B is selected from the radicals OR ₆ and CO ₂ R ₇ , where R ₆ and R _{7 are} a hydrogen atom or an alkyl or alkenyl radical with no more than 5 carbon atoms,
R _{4B is a} free carboxy radical or tetrazolyl radical converted to a salt or an ester,
or the radical - (CH ₂ ) _p —SO ₂ —X _d —R ₁₂ , where p are 0-1,
X _d radicals -NH-, -NH-CO-NH-, -NH-CO- or a single bond and R _12d radical methyl, ethyl, propyl, vinyl, allyl, phenyl, benzyl, pyridyl, pyridylmethyl, pyridylethyl, nitropyridyl, pyrimidyl , tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl; amino or carbamoyl, which may be substituted by one or more radicals selected from among - (CH ₂ ) _p —SO ₂ —Z _c —R _14c radicals, as defined above, and alkyl and alkenyl radicals with no more than 4 atoms carbon, and which can be substituted; moreover, all of these radicals can be substituted by one or more radicals selected from halogen atoms, hydroxyl, alkyl and alkenyl, alkoxy radicals with not more than 4 carbon atoms, trifluoromethyl, cyano, free, carboxy radical converted into a salt or ester; moreover, these products of formula (I _B ) are found in all possible isomeric species of racemic, enantiomeric and diastereoisomeric ones, as well as their addition salts with mineral or organic acids and the mineral or organic bases of these products of formula (I _B ).

где R прямолинейный или разветвленный радикал алкил с 3 или 4 атомами углерода,
R_1A, R_2A, R_3A и R_5A такие, что:
либо R_1A, R_2A, 3_3A и R_5A идентичны и представляют атом водорода,
либо R_2A и R_5A такие, что один атом водорода или радикал -CH₂-O-R₁₀, где R₁₀ атом водорода или прямолинейный или разветвленный радикал алкил или алкенил с не больше, чем 5 атомов углерода, а другой атом водорода, и R_1A и R_3A такие, что один атом водорода и другой выбирается среди радикалов -OR₆, -CO₂R₇ и -R₁₁, радикалов, где:
R₆ и R₇ одинаковые или различные атом водорода или прямолинейный или разветвленный радикал алкил или алкенил с не больше, чем 5 атомов углерода,
R₁₁ выбирается в группе, образованной:
а) радикалами алкил с не больше, чем 4 атомами углерода, могущими быть замещенными одним или несколькими радикалами выбираемыми среди:
атомов галогена,
могущего быть ацилированным радикалом гидроксил,
прямолинейных или разветвленных радикалов алкокси или алкенилокси с не больше, чем 5 атомов углерода,
свободного, превращенного в соль или в сложный эфир радикала карбокси,
радикала:

где R_a и R_b одинаковые или различные выбираются среди атомов водорода, радикалов алкил или алкенил с 1-4 атомами, могущими быть замещенными атомом галогена или радикалом гидрокси,
б) прямолинейными или разветвленными радикалами алкенил с 2-5 атомами углерода,
в) радикалами ацил с 2-7 атомами углерода и радикалом формил,
R_4A свободный, превращенный в соль или в сложный эфир радикал карбокси, радикал циано или радикал тетразолил, могущий быть превращенным в соль, причем эти продукты формулы (I_A) находятся во всех возможных изомерных видах, рацемических, энансиометрических и диастереоизометрических, а также как и аддитивные соли с минеральными или органическими кислотами и минеральные или органические основания этих продуктов формулы (I_A).Especially, in particular, this invention aims at products of the formula (I _B ) corresponding to the formula (I _A ):

where R is a straight or branched alkyl radical with 3 or 4 carbon atoms,
R _1A , R _2A , R _3A and R _{5A are} such that:
or R _1A , R _2A , 3 _3A and R _{5A are} identical and represent a hydrogen atom,
or R _2A and R _5A such that one hydrogen atom or a radical —CH ₂ —OR ₁₀ , where R _{10 is} a hydrogen atom or a straight or branched alkyl or alkenyl radical with no more than 5 carbon atoms, and another hydrogen atom, and R _1A and R _{3A are} such that one hydrogen atom and the other is selected from the radicals —OR ₆ , —CO ₂ R ₇ and —R ₁₁ , radicals, where:
R ₆ and R _{7 are the} same or different hydrogen atom or a straight or branched alkyl or alkenyl radical with no more than 5 carbon atoms,
R ₁₁ is selected in the group formed by:
a) alkyl radicals with not more than 4 carbon atoms, which can be substituted by one or more radicals selected from:
halogen atoms
hydroxyl, which can be an acylated radical,
straight or branched alkoxy or alkenyloxy radicals with no more than 5 carbon atoms,
a free carboxy radical converted to a salt or an ester,
radical:

where R _a and R _{b are the} same or different, selected from hydrogen atoms, alkyl or alkenyl radicals with 1-4 atoms, which may be substituted by a halogen atom or a hydroxy radical,
b) straight-chained or branched radicals alkenyl with 2-5 carbon atoms,
c) acyl radicals with 2-7 carbon atoms and a formyl radical,
R _{4A is a} free, carboxy radical, a cyano radical or a tetrazolyl radical converted to a salt or an ester, which can be converted to a salt, these products of formula (I _A ) being in all possible isomeric forms, racemic, enansiometric and diastereoisometric, as well as and addition salts with mineral or organic acids and the mineral or organic bases of these products of formula (I _A ).

где R прямолинейный или разветвленный радикал алкил или алкенил с 3 или 4 атомами углерода,
R₁, R₂, R₃ и R₅ такие, что:
либо R₁, R₂, R₃ и R₅ одинаковые и представляют атом водорода,
либо один из R₂ и R₅ атом водорода или радикал -CH₂-O-R₁₀ и другой атом водорода и R₁ и R₃ такие, что:
один атом водорода, а другой выбирается среди радикалов, -OR₆, -CO₂R₇ и -CH₂-O-R₈, а радикалы R₁₀, R₆, R₇ и R₈ одинаковые или различные атом водорода или прямолинейный или разветвленный радикал алкил или алкенил с не больше, чем 5 атомов углерода,
R₄ свободный, превращенный в соль или в сложный эфир радикал карбокси, причем данные продукты формулы (I), находятся во всех возможных изомерных видах рацемических, энантиомерных и диастереоизомерных, а также как и аддитивные соли с минеральными и органическими кислотами и минеральные и органические основания данных продуктов формулы (I).Thus, the present invention aims at products of formulas (I _B ) and (I _A ), as defined above and corresponding to formula (I):

where R is a straight or branched alkyl or alkenyl radical with 3 or 4 carbon atoms,
R ₁ , R ₂ , R ₃ and R _{5 are} such that:
or R ₁ , R ₂ , R ₃ and R _{5 are the} same and represent a hydrogen atom,
either one of R ₂ and R ₅ a hydrogen atom or a radical-CH ₂ -OR ₁₀ and the other hydrogen atom and R ₁ and R ₃ such that:
one hydrogen atom and the other selected among the radicals, —OR ₆ , —CO ₂ R ₇ and —CH ₂ —OR ₈ , and the radicals R ₁₀ , R ₆ , R ₇ and R _{8 are the} same or different hydrogen atom or a straight or branched radical alkyl or alkenyl with not more than 5 carbon atoms,
R _{4 is a} free carboxy radical converted into a salt or an ester, and these products of formula (I) are in all possible isomeric forms of racemic, enantiomeric and diastereoisomeric, as well as additive salts with mineral and organic acids and mineral and organic bases these products of formula (I).

In the products of formulas (I _B ), (I _A ) and (I) and in what follows:
the term straight or branched chain alkyl radical preferably refers to methyl, ethyl, propyl or isopropyl, butyl, isobutyl, secondary butyl or tert-butyl radicals, but may also mean a pentyl radical and, in particular, tertiary pentyl,
the term straight or branched alkenyl radical preferably means a vinyl, allyl, 1-propenyl radical; 2-propenyl, 1-butenyl, 2-butenyl, but may also be 1-pentenyl, 2-pentenyl or 3-pentenyl,
the term halogen atom preferably means a bromine atom, but may also mean a fluorine, chlorine or iodine atom,
alkyloxy and alkenyloxy radicals, which may be designated —OR ₁₀ and —OR ₆ , are formed, for example, with alkyl or alkenyl radicals as defined above,
for alkoxy radicals, preferably methoxy or ethoxy radicals can be given, but propoxy, isopropoxy, butoxy, secondary-butoxy, tertiary-butoxy or still pentoxy radicals can also be given,
for alkenyloxy radicals, it is preferable to give vinyloxy or propenyloxy radicals,
for ester radicals of carboxy radicals, it is preferable to give a group (alkyloxy or lower alkenyloxy carbonyl) such as methoxycarbonyl or ethoxycarbonyl, but also the radicals propoxycarbonyl, butoxycarbonyl, butenyloxycarbonyl, tert-butoxycarbonyl or else pentoxycarbonyl,
the term acyl radical preferably means a radical with no more than 7 carbon atoms, such as the formyl, acetyl, propionyl, butyryl or benzoyl radical, but the radicals valeryl, hexanoyl, acryloyl, crotonoyl or carbamoyl can also be used,
the term acyloxy radical preferably refers to groups containing acyl radicals, as defined above, and associated with an oxygen atom, such as acetoxy or benzoyloxy,
the term aryl radical refers to monocyclic radicals or radicals formed from fused rings, carbocyclic or heterocyclic, it being understood that heterocyclic radicals may contain one or more heteroatoms selected from oxygen, nitrogen or sulfur, and when these heterocyclic radicals contain more than one heteroatom , then the heteroatoms of these heterocycles can be the same or different.

The term monocyclic radical preferably means radicals that contain 5 or 6 chains, phenyl radical can be mentioned as a monocyclic carbocyclic radical;
among monocyclic heterocyclic radicals, for example, thienyl, furyl, pyrannyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrroinyl, such as delta, 2-pyrrolidino, 2-imidazolinyl, pyrazolinyl, such as delta 3-pyrazolinyl, as well as isomers at the position of the heteroatom or heteroatoms that may be present on these radicals, such as, for example, isothiazolyl or isoxazolyl radicals.

The term radical formed from condensed rings preferably refers to radicals that contain 8-14 chains:
among the radicals formed from carbocyclic fused rings, for example, naphthyl and phenanthryl radicals can be given,
among the radicals formed from heterocyclic fused rings, for example, benzothienyl, naphtho (2,3-b) thienyl, indanyl, indenyl, thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathianyl, indolisinyl, isoindolyl, indazolyl, purinyl, quinolinyl can be cited. isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, imidazopyridinyl, pyrimidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and indole polydinazinyl TED system formed of heterocyclic monocycles such as defined above, such as furo (2,3-b) pyrrole or thieno (2,3-b) furan.

 An example of such an aryl radical is 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; fused heterocyclic groups containing at least one heteroatom selected from sulfur, nitrogen and oxygen, for example benzothienyl, such as benzothienyl-3-yl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl or purinyl.

и

которые представляют радикал амино, могущий быть замещенным одним или двумя одинаковыми или различными радикалами, указывают, например, радикалы моноалкил и диалкиламино, где радикалы алкил могут принимать значения, указанные выше, такие как например, метил, этил, изопропил, бутил, изобутил, причем эти радикалы могут быть замещеными, как например, в гидроксиметил, гидроксиэтил, метоксиэтил, метоксиметил, или еще этоксиэтил, трифторметил, пентафторметил; радикал амино может также быть замещенным одним или двумя радикалами алкенил, таких как это определено выше и как например радикалы винил, аллил, 1-пропенил, 1-бутенил;
среди заместителей этих радикалов амино можно также привести радикалы арил и аралкил, как например радикалы фенил, бензил, фенетил, нафтил, индолил, индолинил, тиенил, фурил, пирролил, пиридил, пирролидинил, пиперидино, морфолино, пиперазинил, причем эти радикалы могут быть замещенными одним или несколькими радикалами, такими как это определено выше, как например в метилпиперазинил, фторметилпиперазинил, этилпиперазинил, пропилпиперазинил, фенилпиперазинил или бензилпиперазинил.Such aryl radicals may be substituted, for example, the N-substituted pyrrolyl radical, for example N-methylpyrrolyl, the substituted 3- or 4-isoxazolyl radical, for example 3-aryl-5-methylisoxazol-4-yl, wherein the aryl group may be, for example phenyl or halophenyl;
groups

and

which represent an amino radical which can be substituted by one or two identical or different radicals, indicate, for example, monoalkyl and dialkylamino radicals, where the alkyl radicals can be as defined above, such as, for example, methyl, ethyl, isopropyl, butyl, isobutyl, these radicals can be substituted, for example, in hydroxymethyl, hydroxyethyl, methoxyethyl, methoxymethyl, or else ethoxyethyl, trifluoromethyl, pentafluoromethyl; the amino radical may also be substituted with one or two alkenyl radicals, such as defined above and such as vinyl, allyl, 1-propenyl, 1-butenyl radicals;
among the substituents of these amino radicals, aryl and aralkyl radicals can also be cited, such as phenyl, benzyl, phenethyl, naphthyl, indolyl, indolinyl, thienyl, furyl, pyrrolyl, pyridyl, pyrrolidinyl, piperidino, morpholino, piperazinyl radicals, and these radicals may be substituted one or more radicals, as defined above, such as, for example, methylpiperazinyl, fluoromethylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl.

the radical - (CH ₂ ) _m —SO ₂ —XR ₁₂ may represent, for example, radicals where (CH ₂ ) _m represents the alkylene values of the alkyl radicals indicated above, for example, methylene, ethylene, n-propylene, isopropylene, isobutylene or tert -butylene and R ₁₂ may represent an alkyl radical selected from the values given above, or an aryl radical also selected from the above values for this radical, such as phenyl, biphenyl, naphthyl, tetrazolyl; the alkyl radical, which may be represented by the radical R ₁₂ , may be substituted by an aryl radical selected from the above values to form an aralkyl radical.

 These alkyl, aralkyl and aryl radicals may in turn be substituted as indicated above for these radicals.

For example, the radicals —SO ₂ —NH ₂ , —SO ₂ —NH — CH ₃ , —SO ₂ —NH — CF ₃ , —SO ₂ —NH — C ₆ H ₅ , —SO ₂ —NH, can also be cited. -CH ₂ -C ₆ H ₅ .

 The radical R is preferably a propyl, 1-propenyl, butyl or 1-butenyl radical, but may also be an isopropyl, sec-butyl, tert-butyl and 2-butenyl radical.

Additive salts with mineral or organic acids and mineral organic bases of the products of formula (I _B ), (I _A ) and (I) can be, for example, salts formed with hydrochloric acid, hydrogen bromide, hydrogen iodide, nitric acid, sulfuric, phosphoric , propionic, acetic, formic, benzoic, fumaric, succinic, tartaric, citric, oxalic, maleic, glyoxalic, aspartic, ascorbic acids, alkyl monosulfonic acids, such as, for example, methanesulfonic acid, ethanesulfonic acid propanesulfonic acid, lkilsulfokislotami such as e.g. metandisulfokislota, 1,2-ethanedisulfonic acid, arilmonokislotami such as benzenesulfonic acid and aryldisulfonic acids.

 In particular, salts formed with hydrochloric acid are preferred.

 The radical or radicals of the carboxy products of formula (I) can be converted into a salt with mineral bases, such as the equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium, or organic bases, such as, for example, methylamine, propylamine, trimethylamine, diethylamine , triethylamine, N, N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

In particular, the invention aims at products of formula (I _B ) corresponding to formula (I _A ), as defined above, wherein R is a butyl or 1-butenyl radical and R _{12 is} a hydrogen atom or an alkyloxy radical, these products are of formula (I _A ) are in all isomeric species (possible) of racemic, enantiometric and diastereoisomeric, as well as additive salts with mineral or organic acids and mineral or organic bases of these products of formula (I _A ).

Among the products where R _{1A is} a hydrogen atom, thus, preferred products are those where R _2A , R _3A and R _5A are the same hydrogen atom and those where R _2A or R _{5A are} hydrogen atom, hydroxy radical or alkyloxy radical, and R _3A a hydroxy alkoxy radical, or selected from —OR ₆ , —CO ₂ R ₇ and —R ₁₁ radicals, radicals wherein:
R ₆ and R _{7 are the} same or different hydrogen atom or a straight or branched alkyl or alkenyl radical with no more than 5 carbon atoms.

где R_a и R_b одинаковые или различные выбираются среди атомов водорода, радикалов алкил или алкенил с 1-4 атомами углерода, могущими быть замещенными атомом галогена или радикалом гидрокси,
б) прямолинейными или разветвленными радикалами алкенил с 2-5 атомами углерода,
в) радикалами ацил с 2-7 атомов углерода и радикалом формил, и
R_4A радикал тетразолил или свободный, превращенный в соль или в сложный эфир радикал карбокси (превращенный в сложный эфир радикалом алкил), радикалы алкил и алкокси, такие как они определены выше, содержат 1-5 атомов углерода.R ₁₁ is selected from the group formed by:
a) alkyl radicals with no more than 4 carbon atoms, which can be substituted by one or more radicals selected from radicals:
halogen atoms
hydroxy radical, which can be acylated,
straight or branched alkoxy or alkenyloxy radicals with no more than 5 carbon atoms,
free, converted to an ester or salt of a carboxy radical,
radical:

where R _a and R _{b are the} same or different, selected from hydrogen atoms, alkyl or alkenyl radicals with 1-4 carbon atoms, which may be substituted by a halogen atom or a hydroxy radical,
b) straight-chained or branched radicals alkenyl with 2-5 carbon atoms,
c) acyl radicals with 2-7 carbon atoms and a formyl radical, and
R _{4A is a} tetrazolyl radical or a free carboxy radical converted into a salt or ester (an alkyl radical is transformed into an ester), alkyl and alkoxy radicals, as defined above, contain 1-5 carbon atoms.

Among the products where R _{1A is an} alkyloxy radical, for example, products where R _2A , R _3A and R _{5A are} hydrogen atoms can be mentioned.

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

A particularly subject of the invention are products of formula (I _A ), such as defined above, where R is a butyl radical and R _1A , R _2A , R _3A and R _{5A are} hydrogen atoms, and the products of this formula (I _A ) are in all possible isomeric forms , racemic, enantiometric and diastereoisometric, as well as additive salts with mineral and organic acids and mineral and organic bases of these products of formula (I _A ).

In particular, the subject of the invention is the products of formula (I _A ) as defined above, wherein R is a butyl radical, R _1A , R _2A and R _{5A are} hydrogen atoms and R _3A is selected from the radicals —OR ₆ , —CO ₂ R ₇ and -R ₁₁ radicals in which:
R ₆ and R _{7 are the} same or different hydrogen atom or a straight or branched alkyl or alkenyl radical with no more than 5 carbon atoms.

где R_a и R_b одинаковые или различные выбираются среди атомов водорода, радикалов алкил или алкенил с 1-4 атомами углерода, могущими быть замещенными атомом галогена или радикалом гидрокси,
б) прямолинейных или разветвленных радикалов алкенил с 2-5 атомами углерода,
в) радикалов ацил с 2-7 атомами углерода и радикала формил, причем R_4A имеет значение, указанное выше, и данные продукты формулы (I_A) находятся во всех возможных изомерных видах, рацемических, энантиометрических и диастереоизомерных, а также как и аддитивные соли с минеральными кислотами или органическими кислотами и минеральные или органические основания данных продуктов формулы (I_A).R ₁₁ is selected in the group formed by:
a) alkyl radicals with not more than 4 carbon atoms, which can be substituted by one or more radicals selected from:
halogen atoms
hydroxy radical, which can be acylated,
straight or branched alkoxy or alkenyloxy radicals with no more than 5 carbon atoms,
free carboxy radicals converted to a salt or an ester,
radical:

where R _a and R _{b are the} same or different, selected from hydrogen atoms, alkyl or alkenyl radicals with 1-4 carbon atoms, which may be substituted by a halogen atom or a hydroxy radical,
b) straight or branched alkenyl radicals with 2-5 carbon atoms,
c) acyl radicals with 2-7 carbon atoms and a formyl radical, with R _4A having the meaning indicated above, and these products of formula (I _A ) are in all possible isomeric forms, racemic, enantiometric and diastereoisomeric, as well as additive salts with mineral acids or organic acids; and mineral or organic bases of these products of formula (I _A ).

In particular, the invention aims at products of formula (I _A ), as defined above, wherein R is a butyl radical and R _1A , R _2A and R _{5A are} hydrogen atoms and R _{3A is} free or ester radical is converted to a carboxy radical by the action of an alkyl radical with no more than 4 carbon atoms; formed; alkyl or alkenyl with no more than 4 carbon atoms; moreover, the alkyl radical may be substituted by one or more radicals selected from halogen atoms, hydroxy radicals, acyloxy radicals, amino radicals that can be substituted by one or more radicals alkyl with no more than 4 carbon atoms; moreover, these products of formula (I _A ) are in all isomeric species of racemic, enantiomeric and diastereoisomeric, as well as additive salts with mineral or organic acids and mineral or organic bases of these products of formula (I _A ).

Among the products that are the subject of the invention, it is especially possible to cite: 4'- // 2-butyl 1H-benzimidazol-1-yl / methyl / diphenyl-2-carboxylic acid methyl ester and its salt,
4'- // 2-butyl 1H-benzimidazol-1-yl / methyl / diphenyl-2-carboxylic acid and its salts,
2-butyl 1- // 2'-carboxy diphenyl-4-yl / methyl / 1H-benzimidazole-7-carboxylic acid and its salts,
-4'- // 2-butyl 7- / 2-hydroxy ethyl / 1H-benzimidazol-1-yl / methyl / diphenyl-2-carboxylic acid and its salts,
-4'- // 2-butyl 7-formyl 1H-benzimidazol-1-yl / methyl / diphenyl 2-carboxylic acid and its salts,
2-butyl 1- // 2 '- / 1H-tetrazol-5-yl // 1,1'-diphenyl / 4-yl / methyl / 1H-benzimidazole-7-carboxylic acid and its salts.

где R имеет упомянутое выше значение и R_1B', R_2B', R_3B' и R_5B' имеют значения, указанные выше для R_1B, R_2B, R_3B и R_5B, где возможные реактивные функции, по желанию, защищены защищающими группировками, подвергают взаимодействию с соединением формулы (V_B):

где На1 атом галогена и R_4B' имеет значение, указанное для R_4B, где возможные реактивные функции, по желанию, защищены защитительными группировками, для получения продукта формулы (IX_B):

где R, R_1B', R_2B', R_3B', R_5B' и R_4B' имеют вышеуказанные значения,
либо соединение формулы (VI_B):

где R_1B', R_2B', R_3B' и R_5B' имеют предыдущее значение, подвергают взаимодействию с продуктом формулы (II):

(11)
где R₉ радикал гидрокси, алкокси или атом галогена и R имеет указанное выше значение, для получения продукта формулы (X_B):

где R, R_1B', R_2B', R_3B' и R_5B' имеют предыдущее значение,
б) соединение формулы (VI_B'):

где R_1B', R_2B', R_3B' и R_5B' имеют предыдущее значение, подвергают взаимодействию с соединением формулы (II), такой как она определена выше, для получения продукта формулы (X_B'):

где R_1B', R_2B', R_3B', R_5B' и R имеют предыдущее значение, который подвергают реакции нитрования, чтобы получить соединение формулы (X_B), такой как она определена выше, продукт формулы (X_B), который подвергают взаимодействию с соединением формулы (V_B), такой как она определена выше, чтобы получить продукт формулы (XI_B):

где R, R_1B', R_2B', R_3B', R_5B' и R_4B' имеют упомянутое выше значение, который подвергают реакции выборного восстановления функции нитро, для получения продукта формулы (XII_B):

где R, R_1B', R_2B', R_5B' и R_4B' имеют уже упомянутое значение, который подвергают реакции циклизации для получения продуктов формулы (IX_B), такой как она определена выше,
либо соединение формулы (VI_B) подвергают взаимодействию с соединением формулы (V_B), такой как она определена выше, для получения продукта формулы (VII_B):

где R_1B', R_2B', R_3B', R_5B' и R_4B' имеют значения, указанные выше, который подвергают реакции селективного восстановления радикала нитро для получения продукта формулы (VIII_B):

где R_1B', R_2B', R_3B', R_5B' и R_4B' имеют указанные значения, который подвергают взаимодействию с продуктом формулы (III):

(III)
где Х атом кислорода или радикал NH, R₉ и R имеют уже указанное значение, для получения после циклизации продукта формулы (IX_B), такой как она определена выше, продукт формулы (IX_B), который по желанию и при необходимости подвергают одной или нескольким следующим реакциям в каком-либо порядке:
удаление возможных защитительных группировок,
реакция превращения в соль действием минеральной или органической кислоты или минерального или органического основания, чтобы получить соответствующую соль,
реакция превращения в сложный эфир или в соль функции кислоты,
реакция кислого гидролиза или щелочного гидролиза эфирной функции в функцию кислоты,
реакция превращения радикала алкилокси в радикал гидрокси,
реакция превращения радикала галоалкила в радикал алкилен,
реакция замещения атома галогена радикалом амино,
реакция замещения радикала гидрокси атомом галогена,
реакция восстановления превращенного в сложный эфир радикала карбокси в радикал гидроксиалкил,
реакция окисления радикала гидроксиалкил в превращенный в сложный эфир радикал карбокси,
реакция окисления радикала гидроксиметил в радикал формил,
реакция раздвоения рацемических видов в раздвоенные продукты,
реакция превращения свободной, превращенной в сложный эфир или в соль функции карбокси в радикал тетразолил,
причем таким образом полученные продукты формулы (I_B) находятся во всех возможных изомерных видах рацемических, энансиомерных и диастереоизомерных.The invention also has the aim of a method for producing products of formula (I _B ), as defined above, characterized in that:
or a product of formula (IV _B ):

where R has the above meaning and R _{1B '} , R _2B' , R _{3B '} and R _5B' have the meanings indicated above for R _1B , R _2B , R _3B and R _5B , where possible reactive functions are, if desired, protected by moieties are reacted with a compound of formula (V _B ):

where H1 is a halogen atom and R _{4B ′} has the meaning indicated for R _4B , where possible reactive functions are, if desired, protected by protecting groups, to obtain a product of formula (IX _B ):

where R, R _{1B '} , R _2B' , R _{3B '} , R _5B' and R _{4B '} have the above meanings,
or a compound of formula (VI _B ):

where R _{1B '} , R _2B' , R _{3B '} and R _5B' have the previous meaning, are subjected to interaction with the product of the formula (II):

(eleven)
where R _{9 is a} hydroxy, alkoxy or halogen atom and R is as defined above to obtain a product of formula (X _B ):

where R, R _{1B '} , R _2B' , R _{3B '} and R _5B' have the previous meaning,
b) the compound of formula (VI _{B '} ):

where R _{1B '} , R _2B' , R _{3B '} and R _5B' have the previous meaning, are reacted with a compound of formula (II), as defined above, to obtain a product of formula (X _{B '} ):

where R _{1B '} , R _2B' , R _{3B '} , R _5B' and R have the previous meaning, which is subjected to nitration reaction to obtain a compound of formula (X _B ), as defined above, a product of formula (X _B ), which reacting with a compound of formula (V _B ), as defined above, to obtain a product of formula (XI _B ):

where R, R _{1B '} , R _2B' , R _{3B '} , R _5B' and R _{4B '} have the above meaning, which is subjected to the reaction of selective restoration of the function of nitro, to obtain a product of formula (XII _B ):

where R, R _{1B '} , R _2B' , R _{5B '} and R _4B' have the aforementioned meaning, which are subjected to a cyclization reaction to obtain products of formula (IX _B ), as defined above,
or a compound of formula (VI _B ) is reacted with a compound of formula (V _B ), as defined above, to produce a product of formula (VII _B ):

where R _{1B '} , R _2B' , R _{3B '} , R _5B' and R _{4B '} have the meanings indicated above, which are subjected to the reaction of selective reduction of the nitro radical to obtain a product of formula (VIII _B ):

where R _{1B '} , R _2B' , R _{3B '} , R _5B' and R _{4B '} have the indicated meanings, which are reacted with a product of the formula (III):

(III)
where X is an oxygen atom or an NH, R ₉ and R radical as already indicated, to obtain, after cyclization, a product of formula (IX _B ), as defined above, a product of formula (IX _B ), which, if desired, is subjected to one or the following few reactions in any order:
removal of possible defensive groups,
a salt conversion reaction by the action of a mineral or organic acid or a mineral or organic base to obtain the corresponding salt,
the conversion reaction to an ester or a salt of an acid function,
the reaction of acid hydrolysis or alkaline hydrolysis of an ester function to an acid function,
the reaction of conversion of an alkyloxy radical to a hydroxy radical,
the reaction of conversion of a haloalkyl radical to an alkylene radical,
substitution reaction of a halogen atom with an amino radical,
substitution reaction of a hydroxy radical with a halogen atom,
a reaction for reducing a carboxy radical to an ester radical to a hydroxyalkyl radical,
the oxidation reaction of a hydroxyalkyl radical to a carboxy radical converted into an ester,
the oxidation reaction of the hydroxymethyl radical to the formyl radical,
reaction of bifurcation of racemic species into bifurcated products,
the reaction of the conversion of a free carboxy function converted into an ester or salt into a tetrazolyl radical,
moreover, the thus obtained products of the formula (I _B ) are in all possible isomeric species of racemic, enansiomeric and diastereoisomeric.

 In the preferred conditions for carrying out the invention, the above method is as follows.

The reaction of a compound of formula (V _B ), where the halogen atom is preferably a bromine atom, to an imidazole anion of formula (IV _B ), obtained, for example, by the action of an alkaline agent such as sodium or potassium hydride, or else 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 reaction of the additive of the compounds of formula (II) to the free function of the amine of the compounds of formula (VI _B ) or (VI _{B '} ) to respectively obtain products of the formula (X _B ) or (X _B' ) can be carried out by simple heating at a temperature of about 120- 170 ^o C; the compound of formula (II) can be, for example, valerianic acid, then used preferably in excess with respect to the compound of formula (VI _B ) or (VI _{B '} ).

The nitration reaction of the products (X _{B '} ) to give products of the formula (X _B ) can be carried out, for example, in the presence of nitric acid, in a solvent such as acetic anhydride and acetic acid at 0-10 ^° C.

The additive reaction of compounds of formula (V _B ) to the function of the amide of compounds of formula (X _B ) to produce products of formula (XI _B ) can be carried out at room temperature or by heating at 20-150 ^° C., preferably in the presence of an alkaline substance such as for example, triethylamine, sodium hydroxide, sodium methylate or ethylate or else sodium hydride in a solvent, such as, for example, tetrahydrofuran or dimethylformamide.

The reduction of the nitro radical of products of formula (XI _B ) to an amino radical to produce products of formula (XII _B ) can be carried out by conventional methods known to those skilled in the art, in particular by hydrogenation (catalytic) in the presence of palladium hydroxide in a solvent such as, for example, ethanol, or zinc in a solvent, such as, for example, acetic acid in the presence of sodium acetate, or else sodium borohydride.

The cyclization reaction of the products of formula (XII _B ) to obtain products of the formula (IX _B ) can be carried out by simple heating or in the presence of a catalyst, such as, for example, thionyl chloride, phosphorus pentachloride, or else phosphoric anhydride in a solvent, such as, for example tetrahydrofuran or dimethylformamide.

An additive reaction of compounds of formula (V _B ) to the free function of amino compounds of formula (VI _B ) to produce products of formula (VII _B ) can be carried out under the same conditions as those described above for adding compounds of formula (V _B ) to products formulas (IV _B ).

The reduction of the nitro radical of the products of formula (VII _B ) to the amino radical to obtain the products of the formula (VIII _B ) can be carried out by conventional methods known to those skilled in the art, in particular under the same conditions as those described above for the reduction of the nitro radical products of the formula (XI _B ).

The additive reaction of the compounds of formula (III) to the free radical amine of the products of formula (VIII _B ), followed by cyclization of the products thus obtained, can be carried out under various reaction conditions, which are known to those skilled in the art, preferably in an organic solvent, such as, for example, tetrahydrofuran or dimethylformamide at 20 200 ^o C.

 The compound of formula (III) can be, for example, when X-NH, ethyl pentanimido acid and when X-O, for example, valerianic acid.

Depending on the values of R _{1B '} , R _2B' , R _{3B '} , and R _5B', products of formula (IX _B ) form or do not form products of formula (I _B ).

 The various reactive functions that may be present on some of the compounds defined above may, if necessary, be protected: for example, the hydroxy radical or the carboxy free radical, which can be protected by easily removable suitable protecting groups.

The following list, not limiting examples of reactive function protection, is given below:
hydroxy radicals may be protected, for example, by trimethylsilyl, methoxymethyl or tetrahydropyranyl radicals,
carboxy groups can be protected, for example, in the form of esters formed with readily cleavable esters, such as benzyl or tert-butyl esters or esters known in peptide chemistry.

 Removal of the protecting groups can be carried out under ordinary conditions familiar to those skilled in the art, in particular acid hydrolysis, using hydrochloric acid, benzenesulfonic acid, paratoluenesulfonic acid, formic acid or trifluoroacetic acid.

 The list of various protective groups that can be used is given, for example, in patent FP 2499995.

 The products described above, if desired, can be the target of salt conversion reactions using mineral or organic acid for this, in accordance with conventional methods known to those skilled in the art.

 The possible conversion of the functions of the ester into the acid function of the products described above can, if desired, be carried out under ordinary conditions known to those skilled in the art, in particular by acid hydrolysis with hydrochloric or sulfuric acids, or else alkaline hydrolysis, for example, with sodium hydroxide or caustic potassium in alcohol, such as methanol.

 The possible functions of alkyloxy, in particular the methoxy of the products described above, can, if desired, be converted to the function of an alcohol under ordinary conditions known to those skilled in the art, such as using boron tribromide in a solvent, such as methylene chloride, using hydrobromide or pyridine hydrochloride or else using hydrogen bromide or hydrochloric acid in water or acetic acid with reflux.

 The possible conversion of the haloalkyl radical to the alkylene radical of the products described above can be carried out, if desired, under ordinary conditions known to those skilled in the art, in particular by saponification and dehalogenation, for example, in the presence of aqueous sodium hydroxide in an alcohol, such as methanol.

 A possible reaction of replacing a halogen atom with a radical of the amino product described above can, if desired, be carried out under ordinary conditions known to those skilled in the art, in particular by treating the halogenated compound with an aminated derivative, such as dimethylamine at room temperature in a solvent such as alcohol, for example ethanol or methanol.

 The reaction of replacing a radical with a hydroxy by a halogen atom can be performed under ordinary conditions known to those skilled in the art, such as, for example, thionyl chloride chlorination.

 The chlorinated derivative may optionally be substituted with an aminated derivative, such as, for example, dimethylamine.

 The reaction of reducing a carboxy radical converted into an ester to a hydroxyalkyl radical is carried out under ordinary conditions known to the skilled person, for example, by the action of lithium aluminum hydrate, diisobutyl aluminum hydride or other reducing agents known to the skilled person.

 The oxidation reaction of the hydroxyalkyl radical to an ester converted to a carboxy radical can be carried out under ordinary conditions known to those skilled in the art, such as an oxidizing mixture such as BOVERS reagent, followed by conversion to an ester, for example disomethane.

 The oxidation of the hydroxymethyl radical to the formyl radical can be carried out under ordinary conditions known to those skilled in the art, such as, for example, the action of activated manganese dioxide in methylene chloride.

Possible optically active forms of the products of formula (I _B ) can be obtained by resolving the racemates by conventional methods known to those skilled in the art. For example, salts formed with optically active bases may be used.

The compounds of formula (I _B ), such as those defined above, as well as their acid addition salts, exhibit interesting pharmacological properties.

 The products have antagonistic properties with respect to the angiotensin II receptor and, in particular, are inhibitors of the effects of angiotensin II, and especially the vasoconstrictor effect and also the trophic effect at the level of myocytes.

These properties justify their use in therapy, and the invention also aims, as drugs, products such as those defined by formula (I _B ), and these products of formula (I _B ) are in all possible isomeric forms, racemic or optically active, as well as their addition salts with mineral or organic acids and mineral or organic bases, pharmaceutically acceptable, of these products of formula (I _B ).

Particularly, the subject of the invention is, as medicines, the products of formula (I _B ), as defined above, where R is a butyl or 1-butenyl radical and R _{1B is} a hydrogen atom, and in particular the products of formula (I _B ), as defined above, where R is butyl and R _1B , R _2B and R _{5B are the} same and each hydrogen atom and R _{3B is} a hydrogen atom, a carboxy free radical, or an alkyl radical transformed into an ester with no more than 4 carbon atoms; formyl, alkyl or alkenyl with not more than 4 carbon atoms; alkyl substituted with one or more radicals selected from halogen atoms, hydroxyl, acyloxy, amino radicals, which can be substituted with one or two radicals with no more than 4 carbon atoms, and a free carboxy radical converted into a salt or ester, R _{4B is a} free carboxy, cyano or tetrazolyl radical converted to a salt or ester, which can be converted to a salt, as well as addition salts with pharmaceutically acceptable mineral or organic acids and are pharmaceutically acceptable mineral or organic bases of these products of formula (I _B ).

In particular, the invention aims, as medicines, the following products of formula (I _B ):
4'- / (2-butyl 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester,
4'- / / 2-butyl 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid,
2-butyl 1- / / 2'-carboxy biphenyl-4-yl / methyl / 1H-benzimidazole-7-carboxylic acid, 4'- / / 2-butyl 7- / 2-hydroxy ethyl / 1H-benzimidazole-1- sludge / methyl / biphenyl-2-carboxylic acid,
4'- / (2-butyl 7-formyl 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid,
2-butyl 1- / / 2 '- / 1H-tetrazol-5-yl / / 1,1'-biphenyl / 4-yl / methyl / 1H-benzimidazole-7-carboxylic acid,
as well as their addition salts with pharmaceutically acceptable mineral or organic acids and organic or organic bases.

 The drugs that are the subject of the invention can be used in the treatment of high blood pressure, heart disease, kidney failure and for the prevention of postangioplasty restenosis.

 They can also be used in the treatment of certain gastrointestinal disorders, gynecological disorders and, in particular, because of their relaxing effect at the level of the uterus.

 The invention extends to pharmaceutical formulations containing, as an active principle, at least one of the drugs, such as those defined above.

 These pharmaceutical formulations may be administered by mouth, rectally, parenterally or topically, by topical application to the skin and mucous membranes.

 These formulations can be liquid or solid and can be found in all pharmaceutical forms commonly used in human medicine, such as tablets, dragees, jelly, granules, suppositories, injectable preparations, ointments, creams, gels and aerosol preparations; these preparations are prepared in the usual way. The active principle can be mixed with excipients commonly used in these pharmaceutical formulations, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, animal or vegetable fats, paraffin derivatives, glycols, various wetting agents, dispersants , emulsifiers and preservatives.

 The usual posology, which varies depending on the product used, the patient being treated and the disease itself, can be, for example, from 1 to 100 mg per day for an adult, by mouth.

The starting products of formulas (II), (III), (IV _B ), (V _B ), (VI _B ) and (VI _{B '} ) can be purchased commercially or can be obtained by conventional methods known to those skilled in the art.

The preparation of certain compounds of formula (IV _B ) is described in: J. Americ. Chrm. Soc. (1937) 59, 178.

где R_1B', R_2B', R_3B' и R_5B' имеют указанное выше значение.Other products of formula (IV _B ) can be prepared by the action of a compound of formula (III), as defined above, on a product of formula (XIII):

where R _{1B '} , R _2B' , R _{3B '} and R _5B' have the above meaning.

The conditions of fulfillment are the same as those indicated above for the effect of the products of the formula (III) on the products of the formula (VIII _B ).

 Some products of formula (XIII) can be found in trade, such as, for example, 3,4-diamino-benzoic acid methyl ester manufactured, for example.

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

 Among the compounds of formulas (II) and (III) is, for example, ethyl pentanimido acid, which can be obtained, for example, by the action of gaseous hydrochloric acid in ethanol on valeronitrile, produced, for example.

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

превращенный в сложный эфир радикал карбокси которого, может, по желанию, быть освобожден от радикала алкил известными классическими способами, известными специалистам или указанными выше, например, кислым или щелочным гидролизом, который можно подвергнуть реакции бромирования на радикал метил, классическими способами, известными специалистам, например, действием N-бромсукцинимида в тетрахлорметане.A method of obtaining products of formula (V _B ), as defined above, may consist in the fact that methyl iodobenzoic acid, produced, for example, JANSSEN, is exposed to iodotoluene, produced, for example, FLUKA, the reaction is carried out, for example, in the presence of powder copper at 100 300 ^o C, to obtain a product of the formula (V _{B '} ):

a carboxy radical transformed into an ester, which, if desired, can be freed from the alkyl radical by known classical methods known to the skilled person or as mentioned above, for example by acid or alkaline hydrolysis, which can be subjected to a bromination reaction to a methyl radical by classical methods known to those skilled in the art, for example, the action of N-bromosuccinimide in carbon tetrachloride.

The preparation of certain compounds of formula (V _B ) or (V _{B ′} ) or some other conversion of the R _4B radical of the products of formula (IX _B ) can be found, for example, in US Pat. No. 4,880,804 or EP 0253310.

The compound of formula (VI _B ) may, for example, be orthonitroaniline as a product manufactured by OCB.

The products of formula (VI _B ) can also be obtained, for example, by the method described in Canadian Journal of Chemistry (1977), 55 (10), p. 1653-1657.

The products of formula (VI _{B '} ), which are derivatives of aniline, can be found in trade, such as, for example, 2,4-dimethoxy aniline manufactured by ALDRICH, or can be obtained, as indicated, for example, in the following references: BEILSTEIN Volume XII , 3-application, p. 1662; BEILSTEIN Volume XIII, 3-Appendix, p. 2128.

Finally, this invention is intended as new industrial products and, in particular, as intermediate products necessary to obtain products of formula (I _B ), compounds of formulas (IV _B ), (VII _B ), (VIII _B ), (X _B ) and (X _{B '} ).

In addition to the products described in the examples, which illustrate the invention but do not limit it, the following products comprise products that can be obtained in the framework of the present invention: these products of formula (I _A ) are such that R is butyl, R _{4A is} carboxy and R _1A , R _2A , R _3A and R _5A have the meanings indicated in the following table. one.

 The following examples illustrate the invention but do not limit it.

 Example 1: 4'- [/ 2-Butyl 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester hydrochloride.

To a suspension of 650 mg of sodium methylate in 5 cm ^{3 of} dimethylformamide, cooled to 0 ^° C., a solution of 2 g of 2-butyl 1H-benzimidazole (prepared by WO POOL, HJ HARWOOD and AW RALSTON J. Americ. Chem. Soc. (1937) was added. 59, 178) in 3 cm ^{3 of} dimethylformamide. Stirred for 15 minutes, allowing the temperature to rise to room temperature. In 15 min, a solution of 3.6 g of 4 ′ - / bromomethyl / biphenyl-2-carboxylic acid methyl ester (prepared according to EP 0253310) in 5 cm ^{3 of} dimethylformamide is added.

It is stirred for 4 hours at 40 ^° C., dimethylformamide is evaporated and 50 cm ^{3 of an} aqueous sodium bicarbonate solution are added. It is extracted 3 times, each time using 100 cm ^{3 of} ethyl acetate, washed with water, dried, filtered and evaporated to dryness. The residue was chromatographed (4.6 g) on silica (eluant: ethyl acetate, cyclohexane (1-1)). 1.8 g of the expected product are obtained in the form of a base.

Conversion to salt:
To a solution of 500 mg of the base obtained above in isopropanol, a solution of ethyl acetate in hydrochloric acid was added to pH acid. Ethyl acetate was evaporated, the product was crystallized in isopropanol, filtered off with suction, washed with isopropanol and dried under reduced pressure at 100 ^° C. 350 mg of hydrochloride was obtained, mp. 155 ^o C, which are recrystallized twice in isopropanol. Thus, 230 mg of the expected product is obtained in the form of hydrochloride. Mp 155-160 ^o C.

Analysis for C ₂₆ H ₂₇ N ₂ O ₂ Cl 435.01
Calculated, C 71.79; H 6.25; Cl 8.15; N, 6.44.

 Found, C, 72.00; H 6.2; Cl 8.3; N, 6.3.

H)

Пример 2: 4'- / /2-бутил 1Н-бензимидазол-1-ил/метил/бифенил-2-карбоновая кислота.I.K. spectrum: (CHCl ₃ )
Complex absorption of 2800 ___ → 2000 cm ^-1 (type:

H)

Example 2: 4'- [/ 2-butyl 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid.

To a solution of 500 mg of the ester obtained in Example 1 as a base in 8 cm ^{3 of} methanol is added 0.8 cm ³ 2N. caustic soda. Stirred for 4 hours and 30 minutes with reflux. Methanol is evaporated, cooled to 10 ^° C. and acidified to pH 5-6 with 2N. hydrochloric acid solution, stirred for 30 min at 10 ^o C, suctioned off, washed with water, dried at 80 ^o C under reduced pressure. 400 mg of product Tm are obtained. 190 ^o C, which are recrystallized twice in isopropanol to obtain 125 mg of the target product. Mp 234 ^o C.

Analysis for C ₂₅ H ₂₄ N ₂ O ₂ 384.48
Calculated, C 78.10; H 6.29; N, 7.28.

 Found, C, 78.00; H 6.3; N, 7.2.

Приготовление 1: Метиловый эфир 4'-/N-/2-/метоксикарбонил/ 6-нитро фенил/N-/пентаноил/аминометил/ бифенил-2-карбоновой кислоты.I.K. spectrum (liquid paraffin)
C = O 1682 cm ^-1

Preparation 1: 4 '- / N- / 2- / methoxycarbonyl / 6-nitrophenyl / N- / pentanoyl / aminomethyl / biphenyl-2-carboxylic acid methyl ester.

Stage A: 2-amino 3-nitro-benzoic acid
a) Acetylation:
To a suspension cooled to 10 ^° C., 12 g of 2-amino 3-nitro-toluene and 14.4 cm ^{3 of} acetic anhydride, 0.65 cm ^{3 of} concentrated sulfuric acid are added, stirred for 1 h at room temperature, 50 cm ^{3 of} water are added, stirred for 15 minutes, suctioned off, washed with water and then with ether, dried at 100 ^o C under reduced pressure. 13.6 g of the expected product are obtained. Mp 156 ^o C.

b) Oxidation:
To a suspension of 29.48 g of potassium permanganate, 21.44 g of magnesium sulfate in 1470 cm ^{3 of} water, 13.4 g of the compound obtained above are added. Stirred for 3 hours at 100 ^° C, allowed to cool to room temperature, cooled to 0-5 ^° C, insoluble matter was filtered off, 10 cm ^{3 of} concentrated hydrochloric acid was added to the filtrate cooled to 0-5 ^° C (pH 2-3) . It is extracted 4 times, each time with 500 cm ³ ethyl acetate, washed with water, dried, filtered and evaporated under reduced pressure. 16.1 g of product are obtained, which crystallize in ethyl ether to obtain 12.1 g of the expected product. Mp 192 ^o C.

c) Hydrolysis:
12 g of the product obtained above are stirred for 4 hours at 120 ^° C. with 75 cm ^{3 of} water containing 5% concentrated hydrochloric acid, allowed to drop to room temperature, cooled to 0-5 ^° C., stirred for 1 hour at this temperature, suctioned off, washed with water and then with ether, dried at 100 ^o C under reduced pressure. 8.8 g of the expected product are obtained. Mp 210 ^o C.

Stage B: 2-amino 3-nitro-benzoic acid methyl ester
A suspension of 1 g of the acid obtained in stage A, 15 cm ^{3 of} methanol and 1.4 cm ^{3 of} 95-97% sulfuric acid is stirred for 48 hours with reflux. Methanol is distilled off, 100 cm ^{3 of} water are added, alkalinized with sodium bicarbonate, extracted 3 times, using 200 cm ^{3 of} methylene chloride each time, washed with water, dried, filtered and evaporated under reduced pressure. 1 g of the expected product is obtained. Mp 96 ^o C.

Stage B: 3-nitro 2-pentanamido benzoic acid methyl ester
Stirred for 1 h with reflux 850 mg of the product obtained above in stage B and 5 cm ^{3 of} valeryl chloride. It is evaporated to dryness and the residue taken up in 80 cm ^{3 of} ethyl ether, treated with activated carbon, filtered off and evaporated under reduced pressure. Obtain 1.3 g of the product, which is crystallized in a mixture of isopropyl ether and pentane, collect 1 g of the target product. Mp 58 ^o C.

An analytical sample was prepared by dissolving in 20 cm ^{3 of} isopropyl ether with reflux, filtering and concentrating to 50 cm ³ . Leave alone for 18 hours at room temperature, suction, washed with isopropyl ether. 710 mg is obtained. Mp 60 ^o C.

These 710 mg are dissolved in 25 cm ^{3 of} isopropyl ether in hot form, treated with activated carbon, filtered off, concentrated to 10 cm ³ . Leave alone at room temperature for 1 h, sucked off, washed with isopropyl ether. Get 380 mg of the target product. Mp 60 ^o C.

Analysis for C ₁₃ H ₁₆ N ₂ O ₅ 280.27
Calculated, C 55.71; H 5.75; N, 10.00.

 Found, C 55.8; H 5.38; N, 9.9.

I.K. spectrum (CHCl ₃ )
Complex NH 3400 cm ^-1 (shoulder) 3330 cm ^-1 (max)
Complex C = C 1730 cm ^-1 (shoulder) 1708 cm ^-1 (max)
Aromatic compound 1608-1588-1499 cm ^-1
Amid 11
NO ₂ 1540-1360 cm ^-1
Stage D: 4 '- / N- / 2- / methoxycarbonyl / 6-nitrophenyl / N- / pentanoyl / aminomethyl / biphenyl-2-carboxylic acid methyl ester
To a solution of 1 g of the product obtained in the above step B in 5 cm ^{3 of} dimethylformamide, 170 mg of 50% sodium hydride in oil are added. Stirred for another 5 min after the completion of hydrogen evolution, and then added 1.09 g of methyl 4 ′ - / bromomethyl / biphenyl-2-carboxylic acid (Preparation of EP 00253310), stirred for 1 h at room temperature. The solvent is evaporated and the residue is taken up in 250 cm ³ three times ethyl acetate, and then washed 3 times with 50 cm ³ water, dried, filtered and evaporated under reduced pressure. 2 g of product are obtained, which is chromatographed on silica (eluant: methylene chloride-methanol 99-1). 1.6 g of the expected product is collected.

I.K. spectrum (CHCl ₃ )
Complex C = O 1726 and 1670 cm ^-1
NO ₂ 1538 and 1352 cm ^-1
Aromatic compounds 1600 and 1576 cm ^-1
Example 3: 2-Butyl 1- / 2'-methoxycarbonyl / biphenyl-4-yl / methyl 1H-benzimidazole-7-carboxylic acid methyl ester hydrochloride
a) Hydrogenation:
To a solution of 730 mg of the product obtained in stage D, preparation 1, in 15 cm ^{3 of} tetrahydrofuran, 365 mg of 18% palladium on activated carbon are added, stirred for 1 h 30 min in a hydrogen atmosphere (109 cm ^{3 of} hydrogen are absorbed), the catalyst is filtered off, rinsed methylene chloride and evaporated to dryness under reduced pressure, get 730 mg of the product.

b) Cyclization:
730 mg of the above product are dissolved in 5 cm ^{3 of} ethyl acetate and 5 cm ^{3 of} isopropanol and a slight excess of a solution of hydrochloric acid in ethyl acetate is added. Heated for 5 minutes at 50 ^° C. and left for 30 minutes at room temperature, the solvents were distilled off and the residue was taken up three times in 3 cm ^{3 of} ethyl acetate. Sucked off, washed with ether. Get 640 mg of the target product. Mp 160 ^o C.

190 mg of the above product are recrystallized in isopropanol to obtain 163 mg of the expected product. Mp 160 ^o C.

Analysis for C ₂₈ H ₂₈ N ₂ O ₄ , HCl 492.99
Calculated, C 68.21; H 5.93; Cl 7.19; N, 5.68.

 Found C 67.8; H 5.8; Cl 7.3; N 5.5.

2380 см^-1
C=O 1727 и 1721 см^-1
Пример 4: 2-бутил 1- / /2'-карбокси бифенил-4-ил / метил / 1Н-бензимидазол-7-карбоновая кислота
Перемешивают 1 ч с рефлюксом раствор 440 мг продукта, полученного в примере 3, с 10 см³ этанола, 1 см³ воды, 1 см³ едкого натра. Отгоняют этанол, растворяют остаток в воде (10 см³) и подкисляют до pН 3-4 при помощи уксусной кислоты. После отсасывания получают 360 мг продукта. Тпл. 160^oC, а затем 250^oC, перекристаллизуют 450 мг полученного выше продукта в 15 см³ метанола, 5 капель уксусной кислоты и 5 см³ воды. Получают 370 мг продукта, Тпл. 255^oC, которые растворяют в 20 см³ метанола и 10 см³ хлористого метилена с рефлюксом, фильтруют, отгоняют хлористый метилен и прибавляют 1 каплю уксусной кислоты и 5 см³ воды. После одной ночи при комнатной температуре отсасывают и получают 330 мг продукта. Тпл. 255^oC.I.K. range
Type absorption complex

2380 cm ^-1
C = O 1727 & 1721 cm ^-1
Example 4: 2-butyl 1- / (2'-carboxy biphenyl-4-yl / methyl / 1H-benzimidazole-7-carboxylic acid
A solution of 440 mg of the product obtained in Example 3 is stirred for 1 h with reflux with 10 cm ^{3 of} ethanol, 1 cm ^{3 of} water, 1 cm ^{3 of} sodium hydroxide. Ethanol is distilled off, the residue is dissolved in water (10 cm ³ ) and acidified to pH 3-4 with acetic acid. After suction, 360 mg of product is obtained. Mp 160 ^o C, and then 250 ^o C, 450 mg of the product obtained above are recrystallized in 15 cm ^{3 of} methanol, 5 drops of acetic acid and 5 cm ^{3 of} water. Get 370 mg of product, mp. 255 ^o C, which are dissolved in 20 cm ^{3 of} methanol and 10 cm ^{3 of} methylene chloride with reflux, filtered, distilled off methylene chloride and add 1 drop of acetic acid and 5 cm ^{3 of} water. After one night at room temperature, it is suctioned off and 330 mg of product is obtained. Mp 255 ^o C.

Analysis for C ₂₆ H ₂₄ N ₂ O ₄ 428.47
Calculated, C 72.88; H 5.65; N, 6.54.

 Found, C 73.0; H 5.6; N, 6.5.

N-CH₂ 5,90 (s)
C₆H₄ 6,88 (d,1) 7,23 (d,1)
7 других Н ароматических соединений 7,20 до 7,90 (м)
Подвижные Н 12,95 (м)
Приготовление 2: Метиловый эфир 4'/N/ /2-нитро 6- / /пентаноилокси/метил/фенил/N-пентаноил/аминометил/бифенил-2-карбоновой кислоты
Стадия А: 2-амино 3-нитробензиловый спирт
К раствору 3,54 г продукта, полученного в стадии Б приготовления 1, в 90 см³ тетрагидрофурана прибавляют в 1 ч 30 мин и при 7 8^oC, 50 см³ гидрида диизобутилалюминия (в растворе 1,0 М в гексане). Перемешивают 30 мин, а затем прибавляют в течение 15 мин 40 см³ тетрагидрофурана, содержащего 10% воды, перемешивают а затем прибавляют 10 см³ воды и перемешивают 30 мин при комнатной температуре, прибавляют 350 см³ хлористого метилена, содержащего 10% метанола, перемешивают 15 мин, фильтруют и упаривают досуха под уменьшенным давлением. 3,3 г полученного остатка кристаллизуют в 10 см³ изопропилового эфира. Получают 2,22 г целевого продукта. Тпл. 110^oC.I.K. spectrum (liquid paraffin)
Total absorption region OH / NH
C = O 1704 cm ^-1
NMR spectrum / Dimethyl sulfoxide /

N-CH ₂ 5.90 (s)
C ₆ H ₄ 6.88 (d, 1) 7.23 (d, 1)
7 other N aromatic compounds 7.20 to 7.90 (m)
Movable N 12.95 (m)
Preparation 2: 4 '/ N / / 2-nitro 6- / pentanoyloxy / methyl / phenyl / N-pentanoyl / aminomethyl / biphenyl-2-carboxylic acid methyl ester
Stage A: 2-amino 3-nitrobenzyl alcohol
To a solution of 3.54 g of the product obtained in stage B of preparation 1 in 90 cm ^{3 of} tetrahydrofuran is added in 1 h 30 min and at 7 8 ^° C, 50 cm ³ of diisobutyl aluminum hydride (in a solution of 1.0 M in hexane). Stirred for 30 minutes and then added over 15 minutes 40 cm ^{3 of} tetrahydrofuran containing 10% water, stirred and then added 10 cm ^{3 of} water and stirred for 30 minutes at room temperature, added 350 cm ^{3 of} methylene chloride containing 10% methanol, stirred 15 min, filtered and evaporated to dryness under reduced pressure. 3.3 g of the obtained residue are crystallized in 10 cm ^{3 of} isopropyl ether. 2.22 g of the expected product is obtained. Mp 110 ^o C.

An analytical sample was obtained by recrystallizing 170 mg of the product obtained above with heat and cold in isopropyl ether. 80 mg of pure product is collected. Mp 112 ^o C.

Analysis for C ₇ H ₈ N ₂ O ₃ 168.15
Calculated, C 50.00; H 4.80; N, 16.66.

 Found C, 49.8; H 4.8; N, 16.5.

I.K. spectrum (CHCl ₃ )
OH 3604 cm ^-1 C-NH ₂ 3498-3390 cm ^-1
NH ₂ (def.) 1624 cm ^-1 (F)
NO ₂ 1520-1345 cm ^-1 complex
Aromatic compound 1580 cm ^-1
Stage B: 3-nitro 2-pentanamido benzyl ester of pentanoic acid
Stirred for 6 hours at room temperature, 1.5 g of the product obtained in stage A and 15 cm ³ of valeroil chloride. Add 80 cm ³ essences G (bp. 40-70 ^o C), sucked off and get 2.55 g of the target product. Mp 82 ^° C. After crystallization of 110 mg of the product obtained above in isopropyl ether, 72 mg of product is collected. Mp 84 ^o C.

Analysis for C ₁₇ H ₂₄ N ₂ O ₅ 336.38
Calculated, C 60.70; H 7.19; N, 8.33.

 Found, C, 60.7; H 7.3; N, 8.4.

I.K. spectrum (CHCl ₃ ) C-NH 3426 cm ^-1
C = O 1734 and 1702 cm ^{= 1}
Aromatic compounds
NO ₂ 1610-1588-1538-1480 cm ^-1
Amid 11
Stage B: 4 '- / N- [/ 2-nitro 6- / pentanoyloxy / methyl / phenyl / N-pentanoyl / aminomethyl / biphenyl-2-carboxylic acid methyl ester
To a solution of 1.35 g of the product obtained in Step B above in 13.5 cm ^{3 of} dimethyl formamide, 240 mg of 50% sodium hydride in oil are added, stirred for 15 minutes, and then 1.35 g of 4 '- / methyl ester are added. bromomethyl / biphenyl-2-carboxylic acid (preparation according to EP 00253310), stirred for 30 minutes at room temperature, extracted 3 times with 50 cm ^{3 of} methylene chloride, washed with water, dried, filtered and evaporated to dryness under reduced pressure. The residue was chromatographed (2.7 g) on silica (eluant: cyclohexane ethyl acetate 8-2). Obtain 2.05 g of the target product, used in this form (Rf 0.20 (cyclohexane-ethyl ether of acetic acid 8-2)).

Example 5: 4 '- / (2-butyl 7- / / pentanoyloxy / methyl) 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester hydrochloride
They act as in example 3, starting from 2.05 g of the product obtained in stage B of preparation 2, using 1.025 g of palladium on activated carbon, and then 20 cm ^{3 of} ethyl acetate, saturated with hydrochloric gaseous acid. Obtain 1.8 g of the target product TPL. 145 ^o C.

300 mg of the product obtained above is recrystallized in isopropanol. 180 mg of product are collected, mp. 145 ^o C.

Analysis for C ₆₉ H ₃₆ N ₂ O ₄ , HCl 549.124
Calculated, C 69.99; H 6.79; Cl 8.33; N, 5.10.

 Found C, 69.9; H 6.9; Cl 6.5; N, 5.2.

Пример 6: 4'- / /2-бутил 7-/гидроксиметил/ 1Н-бензимидазол-1-ил/метил/бифенил-2-карбоновая кислота
Действуют как в примере 4, исходя из 400 мг полученного в примере 5 продукта. Получают 290 мг целевого продукта (Тпл. 250^oC), которые перекристаллизуют в водном этаноле, в слегка уксусной среде, а затем в одном этаноле, чтобы собрать 207 мг целевого продукта. Тпл. 250^oC.I.K. spectrum (CHCl ₃ )
Absorption, NH2000-2800 cm ^-1
C = O 1726 cm ^-1 (F) (complex)

Example 6: 4'- / (2-butyl 7- / hydroxymethyl) 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid
Act as in example 4, based on 400 mg obtained in example 5 product. 290 mg of the expected product (mp. 250 ^° C.) is obtained, which are recrystallized in aqueous ethanol, in a slightly vinegar medium and then in ethanol alone to collect 207 mg of the expected product. Mp 250 ^o C.

Analysis for C ₂₆ H ₂₆ N ₂ O ₃ 414.51
Calculated, C 75.34; H 6.32; N, 6.76.

 Found C 75.2; H 6.3; N, 6.8.

ЯМР спектр (диметилсульфоксид) 300 МГц

Пример 7: Метиловый эфир 4'-/ /2-бутил 7-/гидроксиметил/1Н-бензимидазол-1-ил/метил/бифенил-2-карбоновой кислоты
Перемешивают 30 мин раствор 823 мг полученного в примере 5 продукта в 8,2 см³ этанола и 1,6 см³ 2н. раствора едкого натра. Затем прибавляют 10 см³ воды, отсасывают и сушат, получают 600 мг целевого продукта (Тпл. 138^oC), которые перекристаллизуют в этиловом эфире уксусной кислоты, а затем в изопропаноле. Тпл. 140^oC.I.K. spectrum (CHCl ₃ )
Absorption OH / NH 3480 cm ^-1
C = O 1688 cm ^-1

NMR spectrum (dimethyl sulfoxide) 300 MHz

Example 7: 4 '- / (2-butyl 7- / hydroxymethyl) 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester
The solution is mixed for 30 minutes with a solution of 823 mg of the product obtained in Example 5 in 8.2 cm ^{3 of} ethanol and 1.6 cm ^{3 of} 2N. caustic soda solution. Then, 10 cm ^{3 of} water are added, suctioned off and dried, and 600 mg of the expected product are obtained (mp. 138 ^° C.), which are recrystallized in ethyl acetate, and then in isopropanol. Mp 140 ^o C.

Analysis for C ₂₇ H ₂₈ N ₂ O ₃ 428.51
Calculated, C 75.67; H 6.59; N, 6.54.

 Found C 75.8; H 6.5; N, 6.5.

I.K. spectrum (CHCl ₃ )
OH 3600 cm ^-1
C = O 1722 cm ^-1
Example 8: 4 '- / (2-butyl 7- / chloromethyl) 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester hydrochloride
To a solution of 250 mg of the product obtained in Example 7, in 25 cm ^{3 of} methylene chloride, a solution of 1 cm ^{3 of} thionyl chloride in 5 cm ^{3 of} methylene chloride is added and stirred for 15 minutes. It is evaporated to dryness and the residue is crystallized in a mixture of ethyl acetate and ether. 250 mg of the expected product is obtained. Mp 150 ^o C.

Analysis for C ₂₇ H ₂₈ Cl ₂ N ₂ O ₂ 483.43
Calculated, C 67.08; H 5.84; Cl 14.66; N, 5.80.

 Found, C, 67.0; H 5.9; Cl 14.4; N, 5.9.

I.K. spectrum (CHCl ₃ )
C = O 1724 cm ^-1
Example 9: 4 '- / / 2-butyl 7- / chloromethyl / 1H-benzimidazol-1-yl / methyl biphenyl-2-carboxylic acid
350 mg of the product obtained in Example 6 are stirred in 5 cm ^{3 of} thionyl chloride for 2 hours at room temperature. Evaporate, add about 5 g of ice, and then 20 cm ^{3 of} water and mix at night at room temperature. Water is decanted, taken up in 30 cm ^{3 of} methylene chloride, dried, filtered and evaporated to dryness under reduced pressure.

 360 mg of the expected product is obtained in the form of an oil. CCM Rf 0.40 (methylene chloride-methanol (9-1)).

 Preparation 3: 4 '- / N- [2-nitro 6- / / 2-pentanoyloxy / ethyl / phenyl / N-pentanoyl / aminomethyl / biphenyl-2-carboxylic acid methyl ester.

Stage A: 2- / 2-pentanamido phenyl / ethyl pentanoic acid
They act as in stage B of preparation 2, starting from 5 cm ^{3 of} 2-amino phenethyl alcohol. Obtain 10.06 g of the target product, mp. 59 ^o C. An analytical sample was prepared using 2 successive recrystallizations in essence G per 1.1 g of product, and 610 mg of pure product was obtained. Mp 62 ^o C.

Analysis for C ₁₈ H ₂₇ NO ₃ 305.42
Calculated, C 70.79; H 8.91; N, 4.59.

 Found, C, 70.9; H 9.2; N, 4.6.

1684 см^-1
Амид 11 1530 см^-1

1720 см^-1
Стадия Б: 2-/3-нитро 2-пентанамидо фенил/ этиловый эфир пентановой кислоты
При 0^oC 10^oC прибавляют 7,1 см³ уксусной кислоты к раствору 9,1 г продукта, полученного выше в стадии А, в 50 см³ уксусного ангидрида. Перемешивают 2 ч между 0^oC 10^oC. Прибавляют 150 cм³ воды, отсасывают, промывают водой. Получают 9,90 г продукта, которые хроматографируют на двуокиси кремния (элюант: этиловый эфир уксусной кислоты-циклогексан 30-70), получают 5,89 г целевого продукта. Тпл. 117^oC.I.K. spectrum (CHCl ₃ )

1684 cm ^-1
Amide 11 1530 cm ^-1

1720 cm ^-1
Stage B: 2- / 3-nitro 2-pentanamido phenyl / ethyl pentanoic acid
At 0 ^° C. 10 ^° C. 7.1 cm ^{3 of} acetic acid are added to a solution of 9.1 g of the product obtained in Step A above in 50 cm ^{3 of} acetic anhydride. The mixture is stirred for 2 hours between 0 ^° C. 10 ^° C. 150 cm ^{3 of} water are added, suctioned off, washed with water. 9.90 g of product is obtained, which is chromatographed on silica (eluant: ethyl acetate-cyclohexane 30-70), 5.89 g of expected product is obtained. Mp 117 ^o C.

Recrystallize 859 mg of the product obtained above in isopropyl ether, and then in ether, collect 494 mg of the target product. Mp 120 ^o C.

Analysis for C ₁₈ H ₂₆ N ₂ O ₅ 350.42
Calculate C 61.7; H 7.48; N, 7.99.

 Found C 61.5; H 7.5; N, 7.9.

2-ая полоса NO₂ 1348 см^-1
Стадия В: Метиловый эфир 4'-/N/ /2-нитро 6-/ /2-пентаноилокси/этил/фенил/N-пентаноил/аминометил/бифенил-2-карбоновой кислоты
Действуют, как в стадии В приготовления 2, исходя из 3,5 г продукта, полученного выше в стадии Б, употребляя 480 мг 50%-ного гидрида натрия в масле и 3,05 г метилового эфира 4'-/бромметил/ бифенил-2-карбоновой кислоты (приготовление ЕП 0253310). После хроматографии на двуокиси кремния (элюант: этиловый эфир уксусной кислоты циклогексан 3-7) получают 5,19 г целевого продукта.I.K. range

2nd strip of NO ₂ 1348 cm ^-1
Stage B: 4 '- / N / / 2-nitro 6- / / 2-pentanoyloxy / ethyl / phenyl / N-pentanoyl / aminomethyl / biphenyl-2-carboxylic acid methyl ester
They act as in stage B of preparation 2, starting from 3.5 g of the product obtained above in stage B, using 480 mg of 50% sodium hydride in oil and 3.05 g of 4 '- / bromomethyl / biphenyl-2 methyl ester -carboxylic acid (preparation of EP 0253310). After chromatography on silica (eluant: ethyl acetate, cyclohexane 3-7), 5.19 g of the expected product are obtained.

1438 см^-1
NO₂ 1534 cм^-1
Пример 10: Метиловый эфир 4'- / /2-бутил 7/2-/пентаноилокси/этил/ 1Н-бензимидазол-1-ил/метил/бифенил-2-карбоновой кислоты
Действуют, как в примере 3, исходя из 3,38 г продукта, полученного в стадии В приготовления 3, употребляя 1,03 г катализатора. После хроматографии на двуокиси кремния (элюант: этиловый эфир уксусной кислоты циклогексан 3-7) получают 2,42 г целевого продукта.I.K. spectrum (CHCl ₃ ) / PE 580 /

1438 cm ^-1
NO ₂ 1534 cm ^-1
Example 10: 4'- / (2-butyl 7 / 2- / pentanoyloxy / ethyl / 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester
Act, as in example 3, based on 3.38 g of the product obtained in stage B of preparation 3, using 1.03 g of catalyst. After chromatography on silica (eluant: ethyl acetate, cyclohexane 3-7), 2.42 g of the expected product are obtained.

1724 см^-1
Cопряженная система 1599 см^-1
+ Ароматическое соединение 1520 см^-1
Пример 11: Метиловый эфир 4'-/ /2-бутил 7-/2-гидрокси этил/ 1H-бензимидазол-1-ил/метил/бифенил-2-карбоновой кислоты
При комнатной температуре перемешивают 30 мин 2,42 г полученного в примере 10 продукта с 20 см³ метанола и 5,5 см³ 1н. раствора едкого натра. Отгоняют метанол, экстрагируют хлористым метиленом, промывают водой и упаривают досуха под уменьшенным давлением. Остаток кристаллизуется в этиловом эфире уксусной кислоты, получают 1,59 г целевого продукта. Тпл. 139^oC.I.K. spectrum (CHCl ₃ )

1724 cm ^-1
Coupled system 1599 cm ^-1
+ Aromatic compound 1520 cm ^-1
Example 11: 4 '- / (2-butyl 7- / 2-hydroxy ethyl / 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester
At room temperature, 2.42 g of the product obtained in Example 10 are mixed with 20 cm ^{3 of} methanol and 5.5 cm ³ 1N for 30 minutes. caustic soda solution. Methanol is distilled off, extracted with methylene chloride, washed with water and evaporated to dryness under reduced pressure. The residue crystallizes in ethyl acetate, to obtain 1.59 g of the target product. Mp 139 ^o C.

An analytical sample was obtained by recrystallization of 110 mg of the product obtained above in ethyl acetate, 79 mg of product was collected. Mp 139 ^o C.

Analysis for C ₂₃ H ₃₀ N ₂ O ₃ 442.56
Calculated, C 75.99; H 6.83; N, 6.33.

 Found C 75.8; H 6.8; N, 6.2.

1720 см^-1
Пример 12: 4'-/ /2-бутил 7-/2-гидрокси этил/ 1Н-бензимидазол-1-ил/метил/бифенил-2-карбоновая кислота
Действуют как в примере 4, исходя из 400 мг продукта, полученного в примере 11. Получают 371 мг целевого продукта, Тпл. 174^oC. Продукт перекристаллизуется два раза в этаноле, собирают 96 мг целевого продукта. Тпл. 175^oC.I.K. spectrum (CHCl ₃ )
OH 3615 cm ^-1
+ associated 3350 cm ^-1

1720 cm ^-1
Example 12: 4 '- / / 2-butyl 7- / 2-hydroxy ethyl / 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid
Act as in example 4, based on 400 mg of the product obtained in example 11. Receive 371 mg of the target product, mp. 174 ^o C. The product is recrystallized twice in ethanol, collect 96 mg of the target product. Mp 175 ^o C.

Analysis for C ₂₇ H ₂₈ N ₂ O ₃ , 1/2 C ₂ H ₅ OH 451.574
Calculated, C 74.48; H 6.92; N, 6.20.

 Found, C, 74.15; H 7.0; N, 6.2.

Подвижной Н 4,2 до 5,0
Пример 13: Хлоргидрат метилового эфира 4'-/ /2-бутил 7-/2-хлорэтил/ 1Н-бензимидазол-1-ил/метил/бифенил-2-карбоновой кислоты
45 мин перемешивают при 80^oC смесь 714 мг продукта, полученного в примере 11 с 14 см³ хлористого тионила. После выпаривания хлористого тионила смесь забирается три раза с 20 см³ хлористого метилена и упаривается досуха каждый раз. Сухой экстракт кристаллизуется в этиловом эфире уксусной кислоты. Получают 733 мг целевого продукта. Тпл. 151^oC.I.K. range
Absorption, OH / NH
C = O 1680 cm ^-1
Paired system 1592 cm ^-1
+ Aromatic compound 1512 cm ^-1
NMR spectrum (dimethyl sulfoxide) 250 MHz
The presence of about 0.4 mol of ethanol

Mobile N 4.2 to 5.0
Example 13: 4 '- / / 2-butyl 7- / 2-chloroethyl / 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester hydrochloride
A mixture of 714 mg of the product obtained in Example 11 with 14 cm ^{3 of} thionyl chloride was stirred at 80 ^° C. for 45 minutes. After evaporation of thionyl chloride, the mixture is taken three times with 20 cm ^{3 of} methylene chloride and evaporated to dryness each time. The dry extract crystallizes in ethyl acetate. 733 mg of expected product is obtained. Mp 151 ^o C.

A microanalytical sample was prepared by two successive recrystallizations in an ether-ethyl acetate mixture of acetic acid (1-1). A purified product is obtained. Mp 160 ^o C.

Analysis for C ₂₈ H ₃₀ N ₂ O ₂ Cl ₂ 497.47
Calculated, C 67.60; H 6.06; N, 5.63; Cl 14.25.

 Found, C, 67.5; H 6.08; N, 5.6; Cl 14.2.

1725 см^-1 1434 см^-1
Ароматическое соединение 1624-1600-1565 см^-1
Гетеро ароматическое соединение 1512-1496 см^-1
Пример 14: 4'-/ /2-бутил 7-/2-хлор этил/ 1Н-бензимидазол-1-ил/метил/бифенил-2-карбоновая кислота
При перемешивании и при комнатной температуре вводят 500 мг полученного в примере 13 продукта в 35 мл 36%-ного раствора соляной кислоты. Нагревают с рефлюксом 2 ч 30 мин, а затем выпаривают.I.K. spectrum of CHCl ₃
Absorption type

1725 cm ^-1 1434 cm ^-1
Aromatic compound 1624-1600-1565 cm ^-1
Hetero aromatic compound 1512-1496 cm ^-1
Example 14: 4 '- / / 2-butyl 7- / 2-chloroethyl / 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid
With stirring and at room temperature, 500 mg of the product obtained in Example 13 are introduced in 35 ml of a 36% hydrochloric acid solution. Heated with reflux for 2 hours 30 minutes, and then evaporated.

Chromatograph on silica (eluant: methanol-methylene chloride (1-9)) and obtain 479 mg of product, which is dissolved in 60 ml of a 50/50 mixture of water-methanol, adjusted to pH ≈ 10 with sodium hydroxide and then neutralized to pH 5 with acetic acid. Methanol is distilled off, filtered off with suction, washed with ether and dried under reduced pressure at about 100 ^° C. 310 mg of expected product is obtained. Mp 226 ^o C.

Recrystallized three times in methanol to give 112 mg of the expected product. Mp 233 ^o C.

 I.K. spectrum in liquid paraffin.

1698 см^-1
Ароматическое соединение 1597 см^-1
Гетероароматическое соединение 1518 см^-1
ЯМР спектр (Диметилсульфоксид) 259 МГц

N-CH₂-C₆H₅ 5,64 (s)

Пример 15: Хлоргидрат метилового эфира 4'-/ /2-бутил-7-формил 1Н-бензимидазол-1-ил/метил/бифенил-2-карбоновой кислоты
600 мг полученного в примере 7 продукта растворяют в 60 см³ хлористого метилена и прибавляют 1,2 г двуокиси марганца (активированного). Перемешивают 24 ч при комнатной температуре, фильтруют и упаривают досуха под уменьшенным давлением, получают 600 мг целевого продукта в виде основания.

1698 cm ^-1
Aromatic compound 1597 cm ^-1
Heteroaromatic compound 1518 cm ^-1
NMR spectrum (dimethyl sulfoxide) 259 MHz

N-CH ₂ -C ₆ H ₅ 5.64 (s)

Example 15: 4 '- / (2-butyl-7-formyl 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid methyl ester hydrochloride
600 mg of the product obtained in Example 7 are dissolved in 60 cm ^{3 of} methylene chloride and 1.2 g of manganese dioxide (activated) is added. Stirred for 24 hours at room temperature, filtered and evaporated to dryness under reduced pressure to obtain 600 mg of the expected product as a base.

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

It is suctioned off, washed with ether and dried at 80 ^° C. under reduced pressure.

610 mg of the desired hydrochloride are obtained. Mp 145 ^o C.

I.K. spectrum in CHCl ₃
C = O 1723-1706 cm ^-1
Aromatic compound 1618-1599-1563-1520 cm ^-1
Heterocycles 1498 cm ^-1
Example 16: 4'- // 2-butyl 7-formyl 1H-benzimidazole-1-methyl / biphenyl-2-carboxylic acid
600 mg of the product obtained in Example 15 are dissolved in 6 cm ^{3 of} ethanol, 0.8 cm ^{3 of} water and 0.8 cm ^{3 of} sodium liquor and stirred for 2 hours and 30 minutes at 50 ^° C. Cool, add 30 cm ^{3 of} water and acetic acid to pH 4-5.

It is stirred for 30 minutes at room temperature, suctioned off, washed with water and dried at 90 ^° C. under reduced pressure. 470 mg of product is obtained. Mp 225 ^o C.

The product obtained above is dissolved in 30 cm ^{3 of} methanol with reflux, filtered, concentrated and crystallized at room temperature. It is suctioned off, washed with methanol and dried at 90 ^° C. under reduced pressure. 360 mg of expected product is obtained. Mp 230 ^o C.

Analysis for C ₂₆ H ₂₄ N ₂ O ₃ 412.47
Calculated, C 75.7; H 5.87; N, 6.79.

 Found, C 75.5; H 5.8; N, 6.7.

Подвижные протоны 10,08 и 12,75
Пример 17: Дихлоргидрат 4'- // 2-бутил 7- // диметиламино/метил/1H-бензимидазол-1-ил/метил/бифенил-2-карбоновой кислоты
360 мг полученного выше продукта в примере 9 растворяют в 10 см³ диметиламина (33% -ного) в этаноле и перемешивают 19 ч при комнатной температуре. Выпаривают, экстрагируют 3 раза с 20 см³ хлористого метила, промывают 2 раза с 15 см³ соляной воды, сушат, фильтруют и упаривают под уменьшенным давлением. Получают 300 мг целевого продукта в виде основания.I.K. spectrum in liquid paraffin
C = O 1690 cm ^-1
Aromatic compounds 1600-1580 cm ^-1
Heterocycle 1516 cm ^-1
NMR spectrum / Dimethyl sulfoxide / 300 MHz

Mobile protons 10.08 and 12.75
Example 17: Dichlorohydrate 4'- // 2-butyl 7- // dimethylamino / methyl / 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid
360 mg of the product obtained above in Example 9 was dissolved in 10 cm ^{3 of} dimethylamine (33%) in ethanol and stirred for 19 hours at room temperature. It is evaporated, extracted 3 times with 20 cm ^{3 of} methyl chloride, washed 2 times with 15 cm ^{3 of} hydrochloric water, dried, filtered and evaporated under reduced pressure. 300 mg of the expected product are obtained in the form of a base.

Preparation of Dichlorohydrate
Act as in example 15, dissolving 300 mg of the product obtained above in 5 cm ^{3 of} isopropanol in the presence of an excess of ethyl acetate and hydrochloric acid.

Obtain 110 mg of the target product. Mp 260 ^o C.

Analysis for C ₂₈ H ₃₁ N ₃ O ₂ , 2HCl 514.47
Calculated, C 65.36; H 6.46; Cl 13.78; N, 8.17.

 Found C 65.3; H 6.5; Cl 13.8; N, 8.0.

Подвижные протоны 11,39 и 12,78
Пример 18: Хлоргидрат метилового эфира /2-бутил 1-/2'-/метоксикарбонил/бифенил-4-ил/1H-бензимидазол-7-уксусной кислоты
a) Приготовление /2-бутил 1-/2'-метоксикарбонил/ бифенил-4-ил/метил/1H-бензимидазол-7-уксусной кислоты
1 г продукта, полученного в примере 11, вводят в 10 см³ ацетона и 1,5 см³ реактива БОВЕРС. Перемешивают 1 ч при комнатной температуре, отфильтровывают, прополаскивают хлористым метиленом, упаривают и забирают в 50 см³ воды и 50 см³ метанола, доводят pН до 12, употребляя 1н. раствор едкого натра, а затем подкисляют до pН 4-5 уксусной кислотой. Выпаривают, экстрагируют 3 раза 100 см³ хлористого метилена, промывают 2 раза с 40 см³ воды, сушат, фильтруют и упаривают досуха.I.K. spectrum in liquid paraffin
C = 0 1770-1680 cm ^-1
Aromatic compounds 1623-1597 cm ^-1
Heterocycles 1514-1495 cm ^-1
NMR spectrum (dimetisulfoxide) 300 MHz

Mobile protons 11.39 and 12.78
Example 18: Methyl ester hydrochloride / 2-butyl 1- / 2 '- / methoxycarbonyl / biphenyl-4-yl / 1H-benzimidazole-7-acetic acid
a) Preparation of / 2-Butyl 1- / 2'-methoxycarbonyl / biphenyl-4-yl / methyl / 1H-benzimidazole-7-acetic acid
1 g of the product obtained in example 11 is introduced into 10 cm ^{3 of} acetone and 1.5 cm ^{3 of} BOVERS reagent. Stirred for 1 h at room temperature, filtered off, rinsed with methylene chloride, evaporated and taken up in 50 cm ^{3 of} water and 50 cm ^{3 of} methanol, adjusted pH to 12 with 1N. sodium hydroxide solution, and then acidified to pH 4-5 with acetic acid. It is evaporated, extracted 3 times with 100 cm ^{3 of} methylene chloride, washed 2 times with 40 cm ^{3 of} water, dried, filtered and evaporated to dryness.

 Obtain 1.07 g of the target product.

b) Preparation of methyl ester / 2-butyl 1- / 2-methoxycarbonyl / biphenyl-4-yl / methyl / 1H-benzimidazole-7-acetic acid
The product obtained above is dissolved in 10 cm ^{3 of} methylene chloride and then converted to ester with about 10 cm ^{3 of} diazomethane in methylene chloride, evaporated to dryness and 968 mg of product are collected, which are chromatographed on silica (eluant: ethyl acetate - flugen 7-3).

 745 mg of the expected product is obtained in the form of a base.

c) Preparation of hydrochloride
Act as in example 15, based on 303 mg of the product obtained above, in a mixture of ethyl acetate and hydrochloric acid.

Obtain 280 mg of the desired hydrochloride. Mp 128 ^o C.

 I.K. spectrum in chloroform.

1725-1714 см^-1

1438 см^-1 /F/
Ароматические соединения 1623-1599 см^-1
Гетероароматические соединения 1565-1512-1500 см^-1
Пример 19: 2-бутил 1- // 2'-карбокси бифенил-4-ил/метил/ 1H-бензимидазол-7-уксусная кислота
При комнатной температуре вводят 745 мг полученного в примере 18 продукта в 8 см³ этанола и 1,6 см³ 32%-ного едкого натра и перемешивают 1 ч с рефлюксом этанола. Выпаривают забирают в 10 см³ подкисленной воды до pН 5 при помощи уксусной кислоты, отсасывают, промывают водой и сушат под уменьшенным давлением при 80^oC. Получают 516 мг целевого продукта. Тпл. 161^oC. Перекристаллизуют в изопропаноле, а затем в метилэтилкетоне. Получают 184 мг целевого продукта. Тпл. 220^oC.Absorption type

1725-1714 cm ^-1

1438 cm ^-1 / F /
Aromatic compounds 1623-1599 cm ^-1
Heteroaromatic compounds 1565-1512-1500 cm ^-1
Example 19: 2-butyl 1- // 2'-carboxy biphenyl-4-yl / methyl / 1H-benzimidazole-7-acetic acid
At room temperature, 745 mg of the product obtained in Example 18 are introduced into 8 cm ^{3 of} ethanol and 1.6 cm ^{3 of} 32% sodium hydroxide and stirred for 1 hour with ethanol reflux. Evaporated, pick up in 10 cm ^{3 of} acidified water to pH 5 with acetic acid, suction off, washed with water and dried under reduced pressure at 80 ^° C. 516 mg of the expected product are obtained. Mp 161 ^o C. Recrystallized in isopropanol, and then in methyl ethyl ketone. 184 mg of the expected product is obtained. Mp 220 ^o C.

Analysis for C ₂₇ H ₂₆ N ₂ O ₄ 442.52
Calculated, C 73.29; H 5.92; N, 6.33.

C₆H₄ 6,0/d/ 7,29 /d/ 6,39 /d/ 1H 7,13 /т/ 1H
Другие ароматические соединения 7,34 /d/ 2H 7,43 /dd/ 2H 7,54 /м/ 2H 7,71 /dd/ 1H
Подвижной Н 12,75
Пример 20: 4'- // 2-бутил 7-этенил 1Н-бензимидиазол-1-ил/ метил/бифенил-2-карбоновая кислота
При комнатной температуре вводят 300 мг продукта примера 13 в 3 см³ метанола, 0,6 см₃ воды и 0,6 см³ 32%-ного раствора едкого натра.Found
OH / N Total absorption very associated
C = O 1712 cm ^-1
NMR spectrum / Dimethyl sulfoxide / 300 MHz

C ₆ H ₄ 6.0 / d / 7.29 / d / 6.39 / d / 1H 7.13 / t / 1H
Other aromatic compounds 7.34 / d / 2H 7.43 / dd / 2H 7.54 / m / 2H 7.71 / dd / 1H
Movable H 12.75
Example 20: 4'- // 2-butyl 7-ethenyl 1H-benzimidiazol-1-yl / methyl / biphenyl-2-carboxylic acid
At room temperature, 300 mg of the product of Example 13 are introduced into 3 cm ^{3 of} methanol, 0.6 cm _{3 of} water and 0.6 cm ^{3 of a} 32% sodium hydroxide solution.

Stirred for 1 h with reflux. Methanol is distilled off, 5 cm ^{3 of} water are added, neutralized to pH 5-6 with acetic acid, suctioned off, washed with water and dried at 100 ^° C under reduced pressure. 228 mg of the expected product is obtained. Mp 228 ^o C.

Recrystallize 474 mg of the product obtained as the one obtained above in methyl ethyl acetone and then in isopropanol, collect 278 mg of the desired product. Mp 238 ^o C.

Analysis for C ₂₇ H ₂₆ N ₂ O ₂ 410.52
Calculated, C 79.00; H 6.38; N, 6.82.

 Found, C, 79.2; H 6.5; N, 6.9.

1678 см^-1
Сопряженная система 1599 см^-1 1589 см^-1
+
Ароматическое соединение 1514 см¹
ЯМР спектр /Диметилсульфоксид/ 300 МГц

Подвижные H 12,77 /<1H/
Пример 21: Метиловый эфир 4'-/2-бутил-7-/2-диметиламино/этил/бифенил-2-карбоновой кислоты
При перемешивании и при комнатной температуре вводят 1,05 г полученного в примере 13 продукта в 25 см³ 33%-ного диметиламина в этаноле.I.K. spectrum of petroleum jelly
OH / NH Total Absorption Very Associated

1678 cm ^-1
Paired system 1599 cm ^-1 1589 cm ^-1
+
Aromatic compound 1514 cm ¹
NMR spectrum / Dimethyl sulfoxide / 300 MHz

Movable H 12.77 / <1H /
Example 21: 4 '- / 2-Butyl-7- / 2-dimethylamino / ethyl / biphenyl-2-carboxylic acid methyl ester
With stirring and at room temperature, 1.05 g of the product obtained in Example 13 are introduced in 25 cm ^{3 of} 33% dimethylamine in ethanol.

It is held for 16 hours at 80 ^o C. Evaporated under reduced pressure at 60 ^o C, extracted 3 times, using 60 cm ^{3 of} methylene chloride each time, washed with water 3 times, using 20 cm ^{3 of} water each time, dried and evaporated to dryness.

 After chromatography on silica (eluant: methanol methylene chloride 1-9), 789 mg of the expected product are obtained.

 XTC P 0.37 (eluant: methylene chloride methanol 9-1).

Example 22: Dichlorohydrate 4 '- // 2-butyl 7- / 2- / dimethylamino / ethyl / 1H-benzimidazol-1-yl / methyl / biphenyl-2-carboxylic acid
At room temperature, 789 mg of the product obtained in Example 21 are introduced into 15 cm ^{3 of} ethanol and 1.3 cm ^{3 of a} 32% sodium hydroxide solution.

Stirred for 1 h at 85 ^o C. Evaporated, taken in 10 cm ^{3 of} water, acidified to pH 5 with acetic acid. It is extracted 3 times with 60 cm ^{3 of} methylene chloride each time, washed 2 times with 10 cm ^{3 of} water each time, dried, filtered and evaporated to dryness.

It is dissolved in 5 cm ^{3 of} methyl ethyl ketone, 5 cm ^{3 of a} mixture of ethyl acetate and hydrochloric acid are added and allowed to crystallize at room temperature, and then they are suctioned off, washed with methyl ethyl ketone and dried at 60 ^° C. under reduced pressure. Recrystallized in acetonitrile to give 429 mg of the expected product. Mp 218 ^o C.

Analysis for C ₂₉ H ₃₃ N ₃ O ₂ , 2HCl
Calculated, C 65.9; H 6.67; Cl 13.42; N, 7.95.

 Found C 65.7; H 6.6; Cl 13.1; N, 8.2.

Гетероароматическое соединение 1510 см^-1
ЯМР спектр /Диметилсульфоксид/ 250 МГц

N-CH₂-C₆H₅ 6,04 /sl/

N-CH₃ 2,65 /sl/
Подвижные Н 11,38
Пример 23: Хлоргидрат метилового эфира 2-бутил 1-/2'-циано/1,1'-бифенил/ 4-ил метил/ 1Н-бензимидазол-7-карбоновой кислоты
Стадия A: Метиловый эфир 3-амино 2-пентанамидо бензойной кислоты
560 мг продукта, полученного в стадии В приготовления 1, растворяют в 12 см³ в 12 см³ тетрагидрофурана, прибавляют 280 мг 18%-ного палладия на активированном угле и гидрогенизируют реакционную среду 30 мин (поглощение 160 см³ водорода). Перемешивают еще 10 мин, отфильтровывают, отгоняют растворитель под уменьшенным давлением, забирают остаток изопропиловым эфиром, отсасывают и сушат при 80^oC под уменьшенным давлением. Собирают 450 мг сырого продукта, которые перекристаллизуют в изопропиловом эфире. Тпл. 90^oC.IR spectrum: Vaseline oil
OH / NH Total Absorption Very Associated

Heteroaromatic compound 1510 cm ^-1
NMR spectrum / Dimethyl sulfoxide / 250 MHz

N-CH ₂ -C ₆ H ₅ 6.04 / sl /

N-CH ₃ 2.65 / sl /
Movable H 11.38
Example 23: 2-Butyl 1- / 2'-cyano / 1,1'-biphenyl / 4-yl methyl / 1H-benzimidazole-7-carboxylic acid methyl ester hydrochloride
Stage A: 3-amino 2-pentanamido benzoic acid methyl ester
560 mg of the product obtained in stage B of preparation 1 is dissolved in 12 cm ³ in 12 cm ^{3 of} tetrahydrofuran, 280 mg of 18% palladium on activated carbon are added and the reaction medium is hydrogenated for 30 minutes (absorption of 160 cm ^{3 of} hydrogen). It is stirred for another 10 minutes, filtered off, the solvent is distilled off under reduced pressure, the residue is taken up with isopropyl ether, filtered off with suction and dried at 80 ^° C. under reduced pressure. 450 mg of crude product is collected which is recrystallized in isopropyl ether. Mp 90 ^o C.

Analysis for C ₁₃ H ₁₈ N ₂ O ₃ , 250.29
Calculated, C 62.38; H 7.25; N, 11.19.

 Found, C, 62.4; H 7.4; N, 11.1.

Стадия Б: Метиловый эфир 4'-/N // 2-/метоксикарбонил/ 6-аминофенил/ н-пентаноил/ аминометил бифенил 2-карбоновой кислоты
К раствору 250 мг полученного выше продукта в стадии А в 2 см³ диметилформамида прибавляют 52 мг 50%-ного раствора гидрида натрия в масле, перемешивают 15 мин, а затем прибавляют 300 мг 4'-/бромметил/ бифенил-2-нитрила и перемешивают 15 мин при комнатной температуре. Отгоняют растворитель, прибавляют 60 см³ воды, экстрагируют хлористым метиленом, промывают водой, сушат и упаривают досуха под уменьшенным давлением. Собирают 600 мг целевого продукта в сыром виде, которые хроматографируют на двуокиси кремния (элюант: флюген этиловый эфир уксусной кислоты 7-3), а затем кристаллизуют в изопропиловом эфире, а затем в этиловом эфире.I.K. spectrum / CHCl ₃ / C-NH 3420 cm ^-1 3340 cm ^-1
C = O 1698 cm ^-1 max. 1680 cm ^-1 (shoulder)

Stage B: Methyl 4 '- / N // 2- / methoxycarbonyl / 6-aminophenyl / n-pentanoyl / aminomethyl biphenyl 2-carboxylic acid
To a solution of 250 mg of the product obtained above in stage A in 2 cm ^{3 of} dimethylformamide, 52 mg of a 50% sodium hydride solution in oil are added, stirred for 15 minutes, and then 300 mg of 4 '- / bromomethyl / biphenyl-2-nitrile are added and stirred 15 min at room temperature. The solvent is distilled off, 60 cm ^{3 of} water are added, it is extracted with methylene chloride, washed with water, dried and evaporated to dryness under reduced pressure. 600 mg of the expected product are collected in crude form, which are chromatographed on silica (eluant: flugen ethyl acetate 7-3), and then crystallized in isopropyl ether and then in ethyl ether.

125 mg of expected product is obtained. Mp 80 ^o C and then 145 ^o C.

Analysis for C ₂₇ H ₂₇ N ₃ O ₃ , 441.51
Calculated, C 73.45; H 6.16; N, 9.52.

 Found, C, 73.4; H 6.2; N, 9.2.

Стадия В: Хлоргидрат метилового эфира 2-бутил 1-/2'-циано -/1,1'-бифенил/ 4-ил/ метил/ 1Н-бензимидазол-7-карбоновой кислоты
730 мг полученного как в стадии Б продукта растворяют в 10 см³ раствора соляной кислоты в этиловом эфире уксусной кислоты и перемешивают 10 мин при 50^oC. Отгоняют растворитель, забирают остаток в смесь метилэтилкетон-эфир. Отсасывают и сушат при 80^oC под уменьшенным давлением. Получают 715 мг сырого продукта, которые перекристаллизуют в этиловом эфире уксусной кислоты, а затем в смеси метилэтилкетон эфир. Собирают 270 мг целевого продукта. Тпл. 140^oC.I.K. spectrum / CHCl ₃ / C-NH ₂ 3496 cm ^-1 3395 cm ^-1
-C≡N 2226 cm ^-1
-C = O 1722-1656 cm ^-1

Stage B: 2-Butyl 1- / 2'-cyano - / 1,1'-biphenyl / 4-yl / methyl / 1H-benzimidazole-7-carboxylic acid methyl ester hydrochloride
730 mg of the product obtained in Step B are dissolved in 10 cm ³ of a hydrochloric acid solution in ethyl acetate and stirred for 10 minutes at 50 ^° C. The solvent is distilled off, the residue is taken up in methyl ethyl ketone-ether mixture. It is suctioned off and dried at 80 ^° C. under reduced pressure. 715 mg of crude product is obtained, which are recrystallized in ethyl acetate, and then in a mixture of methyl ethyl ketone ether. 270 mg of the expected product is collected. Mp 140 ^o C.

Analysis for C ₂₇ H ₂₅ N ₃ O ₂ , HCl 459.96
Calculated, C 70.50; H 5.70; N, 9.14; Cl 7.71.

 Found, C, 70.6; H 5.8; N, 9.2; Cl 7.8.

Пример 24: Метиловый эфир 2-бутил 1-/2'-/1H-тетразол-5-ил/ /1,1'-бифенил/ 4-ил/ метил/ 1Н-бензимидазол-7-карбоновой кислоты
a) 10 см³ насыщенного водного раствора бикарбоната натрия прибавляют к суспензии, состоящей из 650 мг хлоргидрата, полученного в примере 23, в 50 см³ воды, перемешивают 10 мин, экстрагируют хлористым метиленом с 2% метанола, промывают водой, сушат и отгоняют растворитель под уменьшенным давлением. Собирают 600 мг основания.I.K. spectrum / CHCl ₃ /
-CO ₂ CH ₃ 1723 cm ^-1 1436 cm ^-1
-C ≡ N 2226 cm ^-1
Maximum complex absorption about 2450 cm ^-1 type

Example 24: 2-Butyl 1- / 2 '- / 1H-tetrazol-5-yl / / 1,1'-biphenyl / 4-yl / methyl / 1H-benzimidazole-7-carboxylic acid methyl ester
a) 10 cm ^{3 of a} saturated aqueous solution of sodium bicarbonate is added to a suspension of 650 mg of the hydrochloride obtained in Example 23 in 50 cm ^{3 of} water, stirred for 10 minutes, extracted with methylene chloride with 2% methanol, washed with water, dried and the solvent is distilled off under reduced pressure. 600 mg of base are collected.

b) 600 mg of the product obtained above are dissolved in 6 cm ^{3 of} xylene and 511 mg of trimethyltin azide are added. Stirred for 23 hours at 115-120 ^o C, add another 205 mg of azide and continue heating for 24 hours. Xylene is distilled off, 30 cm ^{3 of} water are added, stirred for 15 minutes, 10 cm ^{3 of} methanol is added, extracted with methylene chloride, dried and evaporated to dryness under reduced pressure.

1 g of crude product is obtained, which is chromatographed on silica (eluant: methylene chloride methanol 9-1), and then the residue is crystallized in ether. Obtain 470 mg of pure target product. Mp 165 ^o C.

Example 25: 2-butyl 1- // 2 '- / 1H-tetrazol-5-yl // 1,1'-biphenyl / 4-yl / methyl / 1H-benzimidazole-7-carboxylic acid
Stirred for 2 hours with reflux 470 mg of the product obtained in Example 24, in a solution in 12 cm ^{3 of} ethanol in the presence of 3 cm ³ 1N. sodium hydroxide solution, ethanol is distilled off, 10 cm ^{3 of} water are added, and then a drop of 0.8 cm ^{3 of} acetic acid is added dropwise. It is stirred for 2 hours at room temperature, suctioned off, washed with water and dried at 80 ^° C. under reduced pressure. 420 mg of crude product is collected, which is dissolved in 10 cm ^{3 of} a methanol-methyl ethyl ketone mixture (1-1), filtered off, concentrated to 5 cm ³ , 1 drop of acetic acid is added and then 5 cm ^{3 of} water are added, the crystallization is allowed to stand, left for 16 hours at 4 ^° C., washed with water and dried at 90 ^° C. under reduced pressure. After recrystallization in ethyl acetate, 310 mg of the expected product are obtained. Mp ≈ 210-220 ^o C.

Analysis for C ₂₆ H ₂₄ N ₆ O ₂ , 452.50
Calculated, C 69.01; H 5.35; N, 18.57.

 Found, C, 68.7; H 5.3; N, 18.3.

Пример 26: Фармацевтический состав
Были приготовлены таблетки, отвечающие следующей формуле:
Продукт примера 2 10 мг
Эксципиент для одной законченной таблетки в 100 мг
(Деталь эксципиента: лактоза, тальк, крахмал, стеарат магния).IR spectrum
Complex absorption region OH / NH
C = O 1700 cm ^-1

Example 26: Pharmaceutical Composition
Tablets were prepared according to the following formula:
The product of example 2 10 mg
Excipient for one finished 100 mg tablet
(Excipient Detail: Lactose, Talc, Starch, Magnesium Stearate).

Example 27: Pharmaceutical Composition
Tablets were prepared according to the following formula:
The product of example 25 10 mg
Excipient for one tablet finished in 100 mg
(Excipient Detail: Lactose, Talc, Starch, Magnesium Stearate).

Pharmacological results
1 Experience on the angiotensin receptor 11.

 Use fresh membrane preparation obtained from rat liver. The tissue is ground with a polytron in a Tris buffer solution of 50 mM pH 7.4, and after grinding, 3 centrifuges are made at 30,000 g 15 'with intermediate collection of sediments in Tris pH 7.4 buffer solution.

The last precipitates are introduced into the suspension in an incubation buffer solution (Tris 20 mM, aCl 135 mM, KCl 10 mM, glucose 5 mM, M Cl ₂ 10 mM, phenyl methyl sulfonyl fluoride 0.63 mM, bacitracin 0.1 mM, bis / trimethylsilyl / acetamide 0.2%).

Aliquots of 2 ml are distributed in hemolysis tubes and ¹²⁵ 1 angiotensin 11/25000 PDM / tube / and the product under study are added. (The product is first tasted at 3 • 10 ^-5 M in three). When the test product moves specifically more than 50% bound reactivity to the receptor, then it is re-examined over a range of 7 concentrations to determine the concentration that inhibits 50% bound radioactivity specifically to the receptor. Thus, a 50% inhibitory concentration is determined.

A non-specific relationship is determined by the addition of the product of the standard, or the product of example 94 of European patent 0253310 at 10 ^-5 (three). Incubated at 25 ^° C for 150 minutes, placed in a water bath at 0 ^° C for 5 minutes, filtered under vacuum, rinsed with Tris pH 7.4 buffer solution and counted for radioactivity in the presence of a Triton scintillator.

The results are expressed directly in inhibitory concentration of 50% (Cl ₅₀ ), i.e. in the concentration of the studied product, expressed in NM, necessary to move 50% of specific radioactivity fixed to the studied receptor.

 The results are shown in table. 2.

 2 Identification of the antagonistic activity of angiotensin 11 in the selected portal vein.

The portal vein was isolated on Wistar male rats (about 350 g) (IFFA Credo Franc) after cervical dislocation and rapidly introduced into saline (see below) at room temperature. A ring of about 1 mm was introduced into the bath for the selected organ, containing 20 ml of the following physiological solution, composition in mM: NaCl 118.3 KCl 4.7 MgSO ₄ 1.2 - KH ₂ PO ₄ 1.2 NaHCO ₃ 25 glucose 11, 1 CaCl ₂ 2.5), the medium being maintained at 37 ^° C and oxygenated with a mixture of O ₂ 95% CO ₂ 5%. The prescribed initial stress was 1 g, the rings were left alone for 60-90 minutes. To avoid spontaneous contraction, verapamil is added to the incubation bath (1 • 10 ^-6 M).

At the end of the rest time, angiotensin 11 Siba hypertensin (3 • 10 ^-8 M) is added to the incubation bath and the drug is left in contact for 1 min. This operation is performed every 30 minutes, and the tissue is washed 3 or 4 times between two angiotensin stimulations. The studied product is introduced into the bath for 15 minutes before new stimulation with angiotensin. When increasing concentrations of the molecule are applicable, then Cl ₅₀ (a concentration that inhibits 50% of the response to angiotensin) can be calculated, the latter being expressed in nanomoles.

 The results are shown in table. 3.

 3 Sample of antagonistic activity of angiotensin 11 in a demodulated rat.

 Male Sprague-Dawley rats (250-350) were anesthetized by intraperitoneal injection of sodium pentobarbital (50 mg / kg), diastolic blood pressure is recorded due to a heparinized catheter (PE50) inserted into the animal's left carotid artery and connected to a pressure calculator (Gould, Pressure Processor ) by means of a pressure sensor.

 A catheter is inserted into the right jugular vein of the animal to allow injection of the studied molecules.

 The animal is placed on auxiliary breathing. A section of the vagus nerves is made. Then the rat is demodulated.

At the end of a sufficient stabilization period, the study of molecules with respect to angiotensin 11 (Hypertensin, CIBA) begins as follows:
1 Three consecutive injections of angiotensin 11 (0.75 micrograms / kg) with an interval of 15 minutes provide a reproducible and stable response.

 2 While maintaining a frequency of 15 minutes for administration of angiotensin 11, molecules (0.01-10 mg / kg) are injected 5 minutes before angiotensin 11.

The effects of presses of angiotensin 11 in the presence of an antagonist are expressed in the effects of presses administered only by angiotensin. A inhibitory dose of 50% of the studied effect is thus determined (D1 ₅₀ ).

 Each animal is considered as its own control sample.

 The results are presented in table. 4. TTT1 TTT2

Claims (3)

1. Derivatives of benzimidazole of General formula I

where R is alkyl or alkenyl, linear or branched, containing 3 or 4 carbon atoms;
R _1b , R _2b , R _3b and R _5b are such that either they are all identical and represent hydrogen, or R _2b and R _{5b are} hydrogen, R _1b and R _{3b are} one hydrogen and the other is selected from the radicals -CO ₂ R ₇ and R ₁₁ , where R _{7 is} hydrogen or alkyl or alkenyl, linear or branched, containing more than 5 carbon atoms, R _{11 is} selected from the group formed by alkyl containing no more than 4 carbon atoms, which may be substituted by one or more radicals selected from hydrogen atoms, hydroxyl, optionally alkylated carboxy radical, free, esterified or converted to salt radical

where R _a and R _b are identical or different and are selected from hydrogen atoms, alkyl or alkenyl radicals having 1 to 4 carbon atoms; alkenyl, linear or branched, having 2 to 5 carbon atoms; acyl having 2 7 carbon atoms, or formyl, or not more than one of R _1b , R _2b , R _3b and R _5b hydrogen, the rest are selected from radicals -CH ₂ -OR ₁₀ where R ₁₀ acyl containing 2 7 carbon atoms ;
R _{4b is a} carboxy radical, free, esterified or converted into a salt, or tetrazolyl, wherein said products of formula I _b are in racemic enantiomeric and diastereoisomeric forms,
or their additive salts of compounds with organic or mineral acids or with mineral or organic bases. 2. A method of obtaining benzimidazole derivatives of General formula I

where R is straight or branched alkyl or alkenyl with 3 or 4 carbon atoms;
R _1b , R _2b , R _3b and R _{4b are} such that either they are all the same and represent hydrogen, or from R _2b and R _5b one is hydrogen and the other is hydrogen or a radical —CH ₂ —OR ₁₀ , where R _{10 is} hydrogen, or straight or branched alkyl, or alkenyl with more than 5 carbon atoms, or the radical

where R _e and R _d are the same or different values defined below for R _a and R _b such that one is hydrogen and the other is selected from the radicals —OR ₆ , —CO ₂ R ₇ and R ₁₁ , where R ₆ and R ₇ identical or different, hydrogen or a straight or branched chain radical, alkyl or alkynyl with no more than 5 carbon atoms, R ₁₁ selected from the group formed by alkyl containing no more than 4 carbon atoms, which may be substituted by one or more radicals selected from among halogen atoms a hydroxyl radical that can be acylated, straight or branched alkoxy or alkenyloxy radicals containing not more than 5 carbon atoms, aryl radicals, which may be substituted by one or more radicals selected from halogen atoms, hydroxyl radicals, trifluoromethyl, cyano, nitro, amino, alkoxy radicals, with not more than 4 carbon atoms , phenyl, benzyl, free, carboxy or tetrazolyl converted into a salt or ester, free, carboxy radical or radical converted into a salt or ester, radical

where R _a and R _{b are the} same or different and are selected among hydrogen atoms, alkyl or alkenyl radicals with 1 to 4 carbon atoms and aryl, all of these radicals can be substituted by one or more radicals selected from halogen or radical atoms, hydroxyl, trifluoromethyl, cyano , nitro, amino, alkoxy radicals with not more than 4 carbon atoms, phenyl, benzyl, a free, salt or ester radical of a carboxy radical, straight or branched radicals alkenyl with 2 5 carbon atoms, acyl radicals with 2 7 carbon atoms and Adikaev formyl radical

where R _a and R _b have the indicated meaning,
or no more than one of R _1c , R _2c , R _3c and R _5c — hydrogen and the others are selected from the radicals —CH ₂ —OR ₁₀ , OR ₆ —CO ₂ R ₇ , —R ₁₁ and the radical

where R ₆ , R ₇ , R ₁₀ , R ₁₁ , R _c and R _d have the indicated meanings;
R _{4c is a} free carboxy radical or tetrazolyl radical or a radical converted into a salt or an ester
- (CH ₂ ) _m —SO ₂ —XR ₁₂ ,
where m is an integer from 0 to 4;
or either (XR ₁₂ ) -NH or X is a single bond,
or radicals —NH—, NH — CO — N, or —NH — CO—;
R _{12 is an} alkyl, alkenyl or aryl radical, and these radicals may be substituted,
their racemates, enantiomers or diastereoisomers, or their addition salts with mineral or organic acids, or mineral or organic bases, characterized in that the compound of general formula II

where R has the indicated meanings;
R _1c , R _2c , R _3c have the indicated meanings for R _1c , R _2c , R _3c and R _5c ,
while their functional groups are protected, are reacted with a compound of the general formula III

where Hal is halogen;
R _{4c ′} has the indicated meanings,
to obtain compounds of General formula IV

where R has the indicated meanings;
R _1c , R _2c , R _3c , R _4c and R _5c have the indicated meanings for R _1c , R _2c , R _3c , R _4c , R _5c ,
where possible reactive functions are protected by protecting groups, followed by deprotection.  3. A pharmaceutical composition having an antagonistic effect on angiotensin II, containing a benzimidazole derivative as an active principle and a pharmaceutically acceptable carrier, wherein it contains a compound of general formula I in an effective amount as a derivative. Priority on points:
12/18/90 according to paragraphs 1 and 3;
03/28/91 under item 2.

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