SK494A3 - Method of preparation of sulfur imidazole derivatives and intermediates - Google Patents

Abstract

The subject of the invention is a process for the preparation of products of formula (I): <IMAGE> in which: R1 represents alkyl, alkenyl, alkynyl, alkylthio or cycloalkyl R2 and R3 represent in particular hydrogen, halogen, hydroxyl, mercapto, acyl, alkyl, alkenyl, alkoxy, alkylthio, phenyl, benzoyl, phenylthio, amino, carbamoyl, carboxyl, nitro, cyano or -(CH2)m1-S(O)m2-X-R10 with m1 representing 0 to 4 and m2 0 to 2 and X representing a single bond or -NH-, -NH-CO-, -NH-CO-O-, -N=CH-N-R13 or -NH-CO-NH- with R10 and R13 representing hydrogen, alkyl, alkenyl or carbo- or heterocycle, R4 represents in particular -(CH2)m1-S(O)m2-X-R10, -SO2NHCONR14 R15, -SO2NHSO2R14, -SO2NHCOR14, -SO2NHSO2NR14R15 or -SO2NHCO2R14 with R14 and R15 representing in particular hydrogen or alkyl.

Description

The present invention relates to a novel process for the preparation of sulfur imidazole derivatives and to novel intermediates obtained.

SUMMARY OF THE INVENTION

The present invention provides a novel process for the preparation of the products of formula I

(I) fcde ^- R ₁ represents alkyiový, alkenyl, alkynyl radical and "alkylthio, each of which may be linear or branched and containing up to 10 carbon atoms or a cycloalkyl radical having 3 to 7 carbon atoms, all of which moieties are optionally substituted by .

R, and R _? , the same or different, are selected from the group consisting of a / hydrogen, halogen atoms, hydroxyl, mercapto, formyl, acyl, carboxy, salt or esterified, nitro, cyano and -PO ₃ (R 7 ₂ ) R represents a hydrogen atom or an optionally substituted alkyl or phenyl radical.

b / -S (O) _{m 2} -XR ₁ q, where m ₁ is an integer from 0 to 4, jq ₂ is an integer from 0 to 2, and X is a single bond or -NH-,

-NK-CO-, -NH-CO-O-, -N = CH-NR _13, -NH-CO-NH- and _R] and R θ _13> the same or different, are H, linear or branched alkyl, or alkenyl radical of up to C 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, optionally substituted phenyl or benzyl, furthermore pyridyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl, methyltetrahydrofuranyl, , an alkenyl, alkoxy or alkylthio radical, wherein the sulfur atom is optionally mono- or dioxidated, each of which linear or branched and up to 6 carbon atoms is optionally interrupted by one or more heteroatoms selected from the group consisting of sulfur atoms, oxygen or nitrogen, and optionally substituted, d / phenyl, benzyl, and phenylthio, wherein the sulfur atom is. optionally mono- or dioxidized, radicals which are optionally substituted,

R

R 8e / -GO-N ⁴ and -N? Radicals

wherein • the Bucl R _R and R, or R _a and B_, the same I 6 7 8 9 'selected from

- a hydrogen atom,

J

-j amino acids,

an alkyl and alkenyl radical, even optionally substituted,

I i

-, phenyl, benzyl and phenethyl or different, having 6 carbon atoms, the radical optionally substituted,

- rest -fCK _? 7 _Ti , -SfO) _m2 -X-R ₁ θ, as defined above, • j Ί

R _o · 'always forms

9 'I? pi, ·, H 9 · p -j. '- ·' to which they are viasané monocyclic radical having 5, 6 or 7 ', and T ômámi'v "ring" B a s a t Rest of the formed identify V H ^- and le bo different fused ring having 3 to 14 carbon in the a ring optionally containing one or more additional heteroatoms selected from oxygen, nitrogen and sulfur atoms optionally substituted with one or more radicals selected from halogen, hydroxyl, nitro, alkyl and alkoxy of up to 6 carbon atoms, amino, optionally substituted with one or two identical or different alkyl radicals having from 6 to 6 carbon atoms and phenyl, or εθ and Rg, the same or different, represent an acyl radical or one of the radicals of the group "TDV ^r" r and r is carbamoyl, alkoxycarbonyl or benzyloxykarbony1-AC-ale'b'O'Rg'3 radical r ~ ± tvor'fas'po bčne with the nitrogen atom to which they are attached form a phthalimido radical and the succinimido, f / -SSR ₁₂ radical, wherein R ₂ ^m · ® as defined for R and R and the odstavcooh / and e / residues other than amino, and alkoxy, provided that at least one of R ^ and R ^ is an optionally · substituted alkoxy or a radical - (0¾) ^ - s (0 ^ J ^ q -XR ^the above defined meaning,

R 3 is selected from the group consisting of a residue

-XR ₁ θ as defined above, halogen atoms, nitro residue, residues - (0¾) _m1 -GOOR ₁ ,

- (CH _{2) m} CONHR _1-i - (0¾) _m -CH, wherein is as defined above, -302-1 -302 ^ ^^, -ΝΗ-302-R, -R ^ R,

-NHkSO ₂ -CF _3, and -SO ₂ -N = C _(R @) N (CH _{3) 2,} - (0¾) ^ '^ SO

-CO-NH-OB ₁₄ , -CO-NH-NH-SO ₂ -CF ₃ , -CO-NH-SO ₄ -CH ₂ -CH ₂ SO ₂ NHCO-R ₁₄ , -CH ₂ CONH-SO ₂ R ₁₄ , -nhsc ^ nhco-r ^

-NHCONHSO _2, t _{1 4,} -CONHSO ₂ NR ₁₄ R _{1 5,} -SO _{NHCOín-4 R] 5,} -SO ₂ N (R ₁₄₎ OR _15, -SO ₂ NHSO ₂ R _14, -SO ₂ NHPO (R ₁₄ ) ₂ , -CONHFO (R ₁₄ ) ₂ , 50 ₂ NHCN, -SO ₂ NHCOR ₁₄ , -SO ₂ NHSO ₂ NR ₁₄ R ₁ -SO ₂ NRSO ₂ NfCH ₂ CH _{2 12} Y, -NHSC 4 NHSO ₄ , -NHSO ₂ NHPO ₁ , ₂ , -NITO ₂ R ₁₄ , -NR ₄ CO ₃ O ₂ H, -SO ₂ NHCO ₂ R ₄ , where R 4. is as defined above and R ₄ and R 4 are the same or; differently represent a hydrogen atom, an alkyl radical of up to 6 carbon atoms or a cycloalkyl radical of 3 to 6 carbon atoms, optionally substituted, and Y represents an oxygen or sulfur atom, all of the alkyl, alkenyl, cycloalkyl, alkylthio, phenylthio, alkoxy, phenyl, benzyl optionally _e s »disubtituované. one or more, selected from the group consisting of halogen atoms, hydroxy, nitro, alkyl alkenyl and alkoxy of up to 4 carbon atoms, trifluoromethyl, cyano amino, mono and dialkylamino, carboxy, free, in salt or esterified, haloalkyl, alkylthio, haloalkythio, haloalkoxy, phenyl, pyridyl, benzyl, phenethyl, benzoyl, phenoxy, benzyloxy, phenylthio, corbamoyl, acyl, acyloxy and tetrazolyl, and wherein all products of formula I are in all possible isomeric racemic, enantiomeric and diastereomeric forms, the addition salts of the products of formula I with mineral and organic acids or with mineral and inorganic bases, comprising:

wherein Hal represents a halogen atom and R * vyššie above for R, in which optionally the reactants are optionally protected, is reacted with refraction to form a compound of formula B having the meaning given below: actively functional SCO

CB)

R'4

wherein R * ₄ is as defined above and which is agglomerated with the compound of formula II is left to re

H + N

CII)

wherein R is as defined above for R ^, in which optionally reactive groups are protected, to give the product of formula C

R '3 (G) wherein R and P 1 are as defined above, which is reacted with a compound of formula III

R 1 -CO-HaL (III) wherein R 1 has the meaning given above for R 1, in which optional reactive groups are protected and Hal represents a halogen atom to give the product of formula D

(CD) wherein R 1, R 1 and R 1 are as defined above, which are subjected to an addition reaction on the CK residue by means of a reagent capable of introducing the substituent R 2, wherein R is known above for R 1, in which reactive groups are optional protected to give the product of formula E

R 'i O

NH ₂

R 3

IE)

R '4 wherein R., R ^# 2> ^, and * 4 are as shall be optionally subjected to a substitution reaction Sea S to give the product of formula L Ný above, kt oxygen atom of the hole and i

where R *, »R 1, R *, and R *" are as defined above, then the product of formula S or the product of formula L is subjected to a cyclization reaction to give the product of formula I *

wherein p / p R * ₂ , R 1 and R 1 are as defined above, wherein the products of formulas D, E and L during the above process and products of formula I may be subjected, if any, if desired it is necessary to undergo one or more of the following reactions in any order:

a) esterification of the acid functional group, b) esterification of the ester group, c) conversion of the cyano group to the acid functionality, d / reduction of the carboxy group to an alcohol group, e / conversion of the alkoxy group to a hydroxyl group, f / ^z oxidation of the atcm group sulfur, to the corresponding sulfoxide or sulfone, g / conversion of the alcohol group or suifone to the corresponding aldehyde or acid group, h / conversion of the nitrile residue to tetrazole, i) conversion of the formyl residue to a carbamoyl residue, j) conversion of the carbamoyl residue to a nitrile residue, k / conversion of the remainder

- SO ₂ X, for the remainder -30 "-NH-C-NK-X", where X, _, X - and X, _n , the same as to II 1 UO Ί IU or different, represent a hydrogen atom, or an alkyl or alkenyl radical having up to 4 carbon atoms, optionally substituted, wherein the products of formula I * may be products of formula 1 or may be subjected, if desired and necessary, to one or more of the following reactions in any order to produce products of formula I:

a) removing the protecting groups carrying the protected reactive groups, b) converting to a salt with a mineral or organic acid or a base to form the corresponding salt, c / cleaving the racemic forms into the individual products, the products of formula I thus obtained are in all

-SO ₂ -NH-CO-NH-CH ₂ -CH ₂ isomeric racemic, enantiomeric and diastereomeric forms.

In the above defined moiety ies CH) _m1 --S fO ^ XR ^ _p-n where m is different from 0, a-CH _{2) m1} meaning an alkylene radical such as methylene, ethylene, n-propylene or n-butylene, and in particular when mj is Q, 1 or 2, the remainder of βθ ₂ ) represents a single bond, respectively. methylene residue, respectively. ethylene residue.

The meanings of θ include, but are not limited to, the radicals -SC 4 -N 1 · 4, -SO ₂ -NH-CH 2, -SO ₂ -NH-CF ₃ , -SO ₂ -NH-CgH ₅ , -SO ₂ " NH-CH ₂ -C ₆ h _5, -CH ₂ -SO ₂ -NH _2, -CH ₂ -SO ₂ -NH-g ₆ h _5, -SO _{2 -NH-cO-NH-CH3, -SO2} NH-CO-NH-C ₆ h _5, -SO ₂ -NE-GO-NH-GF _{3, -SO2} -NH-CO-NH-CH ₂ -C ₆ h _5, -SO ₂ -NH-CO -nh-d, wherein D is phenyl, pyridine or pyrimidine

C 1 radical, -S0 _{2 -NH-C0-NH-CH2} ^^^> - CVS0 ₂ »NB-G0" IFFI »a H ₂ CH ₂ CH _3,

-SO ₂ -NK-GO-NH-CH = CH-CH ₃ , -SO ₂ -NH-CO-NH-CH ₂ -C = CH, where A and B,

A B, the same or different, are selected from the group consisting of hydrogen, phenyl, pyridyl and pyrimidyl,

-so ₂ -nh-co-nh-ch ₂ N

-SO-NK-CO-NH- GH _O-en

N = /, where n = 1 or 2

In the products of formula I and in the following

the term linear or branched alkyl radical denotes preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl and tert. butyl, but may also be pentyl or hexyl, and in particular isopentyl and isohexyl,

- the term linear or branched alkenyl radical denotes preferably vinyl, allyl, 1-propenyl, butenyl and in particular 1-butenyl or pentenyl,

- the term linear or branched alkynyl radical preferably denotes linear or branched ethynyl, propynyl, butynil,

examples of alkyl radicals interrupted by one or more heteroatoms include methoxymethyl, methoxyethoxymethyl, propylthiopropyl, propyloxypropyl, propylthioethyl, methylthiomethyl,

- the term halogen atom preferably denotes a chlorine or bromine atom, but may also be a fluorine or iodine atom,

- the term linear or branched alkoxy preferably denotes methoxy, ethoxy, propoxy or isopropoxy, but may also mean linear, secondary or tertiary butoxy,

- the term acyl radical denotes preferably a radical having 1 to 6 carbon atoms, such as, for example, formyl, acetyl, propionyl, butyryl or benzoyl, but also pentanoyl, hexynoyl, acryloyl, crotonoyl or ksrbamoyl,

the term amino substituted by one or two alkyl radicals denotes preferably the radicals in which the alkyl radical or radicals are selected from the radicals defined above: for example, for a monoalkylamino radical a methylamino or ethylamino radical or, for example, for a dialkylamino, dimethylamino or other methylethylamino radical

- acyloxy refers to a radical in which the acyl radical is as defined above, and preferably means formyloxy, acetyloxy, propionyloxy, butyryloxy or benzyloxy,

- the term cycloalkyl radical preferably denotes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,

- the term monocyclic residue and the residue formed by fused rings refer to saturated or unsaturated residues,

the term monocyclic radical denotes saturated radicals, for example pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl, or unsaturated radicals, for example, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl thiadiazolyl, oxazolyl, furazanyl, pyrrolidinyl, such as delta-2-pyrrolinyl, imidazolinyl, such as delta-2-imidazolinyl, pyrazolinyl, such as delta-3-pyrazolinyl, as well as isomers at the heteroatom or heteroatoms position which may be contain such residues as isothiazolyl or isoxazolyl,

- condensed ring radical denotes saturated radicals, for example 1-oxaspirof4,5 decyl, tetrahydropyran-2-spirocyclohexyl, cyclohexanspiro-2 '- (tetrahydrofuran) or 1,10-daazaanth-4-yl, or unsaturated radicals, for example benzothienyl, naphtho [2,1-b-thienyl, indenyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, indazolyl, purinyl, quinolizinyl, benzopyrrolyl, benzimidazolyl. 3-carbolinyl, acridinyl, phenazinyl, indolinyl, isoindolinyl, or other condensed poly cyclic systems, consisting of heterocyclic monocycles as defined above, such as furol [2,3-b] pyrrole or lieno [2,3-b] furan "haloalkyl" preferably refers to radicals in which the alkyl radical is as defined above and is substituted by one or more halogen atoms as defined above, e.g. example, bromoethyl, trifluoromethyl, trifluoroethyl, or pentafluoroethyl 5alej.

the term alkylthio preferably denotes radicals in which the alkyl radical is as defined above, for example. methylthio or ethylthio,

- the haloalkylthio group preferably denotes radicals in which the alkyl radical is as defined above and is substituted by one or more halogen atoms as defined above, for example bromomethylthio, trifluoromethylthio, trifluoroethylthio or further pentafluoroethylthio,

- the haloalkoxy group preferably denotes radicals in which the alkoxy group is as defined above and is substituted by one or more halogen atoms as defined above, for example bromoethoxy, trifluoromethoxy, trifluoroethoxy or linear pentafluoroethoxy,

the term carbamoyl radical also denotes carbamoyl radicals, N-monosubstituted by a lower alkyl group such as N-methylcarbamoyl, N-ethylcarbamoyl, N, N-difluoro) and alkylcarbamoyl such as N, N-dimethylcarbamoyl, N, N-diethylcarbam , N- (lower hydroxyalkyl) caroamoyl, such as N-hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl, carbamoyl (lower) alkyl, such as carbamoylmethyl, carbamoylethyl,

the phenyl radical substituted with an alkylthio group represents, for example, a henzylthio group.

In the products of formula I and the following, the alkyl, alkenyl, cycloalyl and phenyl radicals which may be represented or carried by R _{@ 1} ^and the radicals mentioned above may be unsubstituted or substituted by one or more identical or different substituents with the same or different substituents. as defined above. R ³ can, for example, represent an alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl or arylsulfonyl group, but also a cycloalkylthio group such as cyclohexylthio,

14th

the terms alkylthio, alkylsulfinyl and alkylsulfonyl refer to radicals in which a linear or branched alkyl radical may have, for example, the meaning given above for alkyl radicals: these radicals then preferably represent methylthio, hydroxymethylthio, ethylthio, aminoethylthio, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, ethylsulfonyl may also be propylthio, isopropylthio, butylthio, sec-butylthio, tert. butylthio, isopentylthio or isohexylthio or the same radicals in which the thio group is oxidized to a sulfinyl or sulfonyl radical,

According to the meaning of m ₁ , and R θ in the rest of _m? -XR3 ₍₎ may ^and Rj also represent the following radicals: phenylthio, pyridylthio or pyrimidylthio, imidazolylthio, N-methylimidazolylthio, as well as radicals in which the thio group is oxidized to a sulfinyl or sulfonyl group such as phenylsulfinyl or phenylsulfonyl.

Examples of substituted alkyl radicals include those substituted by one or more phenyl radicals, for example benzyl, diphenylmethyl, triphenylmethyl, and pyridyl-substituted radicals, for example pyridylmethyl, and of course, in the non-exhaustive elimination of the radicals, the alkyl radical may also be ethyl, propyl or for example, in the ethylene residue.

Examples of substituted alkenyl radicals include those substituted with one or more phenyl or pyridyl radicals. as ... is mentioned above. The alkyl radical is replaced by an alkenyl radical, for example phenylvinyl or phenylallyl.

The above carbamoyl radicals and amino groups, and in particular:

remains

-CO-N a

R is a radical in which two radicals, identical or different, are selected from the group consisting of hydrogen to form an amino group, alkyl radicals as defined above to form a monoalkyl or dialkylamino group in which the linear or branched alkyl radicals contain 1; up to 6 carbon atoms, in particular methyl, ethyl, isopropyl, methoxymethyl, methoxyethyl and phenyl, benzyl or phenethyl, optionally substituted to form, for example, phenylamino or benzylamino groups.

Among the substituted carbamoyl radicals, N-mono (lower alkylcarbamoyl, for example N-methylcarbamoyl, N-ethylcarbamoyl, N, N-di (lower) alkylcarbamoyl, for example Ν, Ν-dimethylcarbamoyl) may be mentioned as substituted carbamoyl radical Ν-diethylcarbamoyl, N- (lower hydroxyalkyl) carbamoyl, for example N- (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl, lower carbamoylalkyl, for example carbamoylmethyl, carbamoylethyl, phenylcarhamoyl, pyridylcarbamyol, N-methyl-N-phenylcarhamoyl, pyridyl.

The term amino acid preferably denotes a residue derived from. one of the natural amino acids such as glycine, alanine, valine, leucine, isoieucin, phenylalanine, and in particular proline, or one of the other natural amino acids known to those skilled in the art.

Among the residues - {CH ₂ -X R J} which may be R 6,

R y, R g or R 6, especially -NH-SO ₂ -CH 4,

-NH-SO ₂ -CgH ₅ , -NH-SO ₂ -CF ₃ , -NH-CH ₂ -SO ₂ -NH-C ₆ H ₅ ,

-CO-NH-SO ₂ -C ₂ H ₅ , -CO-NH-SO ₂ -CH ₃ , -CO-NH-SO ₂ -CH ₂ -C ₆ H ₅ .

Keterocycle, which can form t Rg and R? or R 8 and R 8 is preferably saturated.

It may be optionally substituted with the aforementioned substituents, in particular one or more radicals selected from the group consisting of chlorine and fluorine atoms, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, benzoyl, methoxycarbonyl, ethoxycarbonyl: is; methylpiperazinyl, ethylpiperazinyl, propylpiperazinyl, phenylpiperazinyl or benzylpiperazinyl may be mentioned, for example: in the latter two residues, phenyl and benzyl may be substituted as described above, for example as chlorophenyl or trifluorophenyl.

^ Acyl -ové residues which can represent R _L and R, may in particular be selected from acetyl, propionyl, butyryl, pentanoyl and carbamoyl moiety.

When R 8 or R 6 is an alkoxycarbonyl radical, it is preferably tert. butyloxycarbonyl.

The carboxyl radicals of the products of formula (T) may be in the form of a salt or esterified with various groups known to the person skilled in the art, including, for example. :

as salt-forming compounds, mineral bases such as sodium, potassium, lithium, calcium, magnesium or ammonium salt, or organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, Ν, Ν- dimethylethanolamine, tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexamine, morpholine, benzylamine, procaine, lysine, arginine, histidine. N-methylglucamine.

as esterifying compounds, alkyl radicals to form alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these alkyl radicals being substituted by, for example, halogen, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl such as in the groups chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl.

The mineral or organic acid addition salts of the products of formula (I) may be, for example, salts formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoic, maleic acids. fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, with alkyl monosulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, with alkyidisulfonic acids, such as methanesulfonic acid / methanesulfonic acid, eisulfonic acid, eisulfonic acid, aryl monosulfonic acids such as benzenesulfonic acid and aryldisulfonic acids.

If the two radicals R ₂ and R represent a sulfur alkylthio "or phenylthio optionally oxidized, wherein R ₉ and R are the same or different, are the preferred products according to the invention particularly the products of formula I, in which the sulfur of the same oxidation state .

The preferred products of the invention are particularly the products of formula I wherein one of R ₂ and R ^ is above the sulfur, optionally oxidized, and the other of R @ ₂ and is preferably alkyl, alkoxy, carboxy, a free, salified or esterified or phenyl, optionally substituted with one or more substituents as defined above.

The useful products of the invention are particularly the products of formula I are wherein R ₂ is a sulfur radical.

and / or R1 may in particular represent alkylthio or alkenylthio radicals, optionally substituted by one or more radicals selected from the group consisting of formyl, hydroxyl, alkoxy, acyloxy, carboxy, free, in salt form or esterified, amino-substituted amino, carbamoyl, substituted carbamoyl, alkylthio, phenylthio, pyridinyl, pyrimidinyl, phenyl.

Among the substituents which may carry radicals ^θ , in particular, the amino group and the carbamoyl may be substituted by one or two residues and the above-mentioned amino acids.

The substituted amino and carbamoyl which may have radicals R ₂ and R may also form a heterocycle, such as the type described above.

R _? and R 1 may furthermore in particular represent alkylthio groups substituted by one or more halogen atoms such as chlorine and fluorine. The možné.uviest e.g., -S-radicals CFP -S-CHF _2, -S-CH ₂ F, -S-CF ₂ CHF _2, -S-CF ₂ -ckfci.

The radicals R ₂ and R may represent the following ₀ takf radicals., N, n ^ n _2, and the same: different, have .môžu note hrs 0-2: -SO-CHP -SO ^ ,. -S-CHy, -Sf -SfGH ^ _q2 -X ₄ ,

ABOUT

-S- (CH _{2) n} -X _{4-S-CH 2) n 1} -NH-FCH _{2) n 2} -X _4, -S-CH = CH- (CH _{2) n} -X _4,

-S- (CH ₂ ) _{n 1} -CH = CH-fCHP _{n 2} -X 4, wherein X 4 represents H, OH, cyclohexyl, pyridyl, phenyl, CHO, COCH, KH _2, ^or

The residues R ^{8 m} ®žu also represented in particular the following radicals: -COO-, -CO ₂ X ^, ^ -SX, _-NH2, -C? N, OMe, OEt, -CH = CH-COOH, tetrazolyl,

-C »CCCH ₃ ) -1

COOMe

-C - C - Cl 2 I 1

COOH COOII

in all isomeric forms, cis-trans isomers,

-CH-NH-C

COOH

OXS

NH-CH 2 -COO-X S.

-NH-COO-X5, wherein X1 represents an alkyl or aryl radical.

Residues R? and can especially represented the rest of the \\

The products of formula I are thus particularly the products wherein R ₂ and R are as defined, and especially products in which R ₂ is alkylthio as defined herein: radical, optionally substituted, or alkoxy, e.g., methoxy, and R represents a carboxy group in free form, in the form of a salt, ester or amide, such as, in particular, -COOH, -COO-methyl, -COO-ethyl, -COJIE4 or

N-N

-CO-NIIH l

H

The preferred meanings of R which may be mentioned in particular, a cyano group, a - _{(CH2) m-X--SOg} Rjθ the above defined meaning, and especially £ 'radicals _{-SO2 -NE-NK-CO-CH2-CH} = CH ₂ , -SO ₂ -NH-CO-NH-CH ₂ -CH ₂ GH ₃ , -SO ₂ -N-CO-NH-CH ₂ 'CE ₂ -CH ₃ ,

K *

-SO ₂ -NH-CO-NH-CH ₂ -CH ₂ -SO ₂ -NH-CO-NH-CH ₂ -

In particular, the present invention relates to the above process for the preparation of products of formula I corresponding to formula I _g

where

R1 represents a linear or branched alkyl or ¹ alkenyl radical of up to 4 carbon atoms,

R _2a and R j _{and the} same or different are selected from the group consisting of o / hydrogen, raercapto, formyl, carboxy in salt or esterified form, halogen atoms, hydroxy, cyano, nitro, acyl, b / alkyl, olkenyl, alkoxy, alkylthio, wherein the sulfur atom is optionally mono- or dioxidated, the radicals being linear or branched and containing up to 6 carbon atoms, phenyl, benzoyl, phenylthio, wherein the sulfur atom is optionally mono- or dioxidated, all of which radicals being optionally substituted with one or several of the same or different radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro, formyl, alkyl and alkoxy of up to 4 carbon atoms, phenyl and carboxy, either in salt form or esterified. N <

8a

7o

R _o '9a where bud Rg _a , R? _and, R _a and R, identical or different, are selected from H, amíno22 acid alkyl which eye radicals containing up to 6 carbon atoms, phenyl, benzyl and phenethyl, or R <, and R ~, and R _a and R -. in each case, together with the oak atom 7θ Qa and 9a, they form a heterocyclic radical, the same or different radicals being selected from the group consisting of limidazolyl: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyridyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrosinyl, piperazinyl, phenylpiperazinyl, piperidyl, oxazolyl, morpholyl, morpholinyl and thiomorpholinyl, asenine, indolyl, the radicals optionally substituted by one or more equals or different radicals selected from the group consisting of halogen atoms, hydroxyl, nitro, alkyl and alkoxy containing up to 6 atoms carbon and phenyl,

R _a is cyano, carboxy vacant, salified or esterified, a - (CH _{O? -50-R-X} ,,, .where 'KPKA 1 ua' p = 0 or 1, X _a radical - NH-, -NH-CO-, -NH-CO-O-, -N = CH-WR _{1 Me,} -NH-CO-NH or a bond, and the spirit of _1UA R and ^{R in the} same ring or different, are H , linear or branched alkyl or alkenyl containing up to 6 carbon atoms, optionally substituted, pyridyl, phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl, the alkyl and alkenyl radicals being alkyl and alkenyl substituted with one or more radicals selected from the group consisting of halogen atoms, hydroxyl, nitro, alkyl, alkenyl and alkoxy of up to 4 carbon atoms, trifluoromethyl, cyano, amino, mono- and dialkylamino, carboxy, in the form of salts or esterified, phenyl, tetrazolyl, said prod the compounds of formula I are in all possible isomeric racemic, enantiomeric and diastereoisomeric forms as well as their addition salts with mineral and organic acids or mineral and organic bases, by using the products of formulas II, III and IV for the preparation described above, In which ,

R * 2 ^{and m9 are} as defined above for R 1 _and > respectively.

R _2a , resp. R | _and wherein the reactive functional groups are optionally protected.

In particular, the present invention relates to the above process for the preparation of products of formula I corresponding to formula I

CI b>

wherein R, 1b

3b

2b represents an alkyl radical of up to 4 carbon atoms, represents a hydrogen, formyl, acyloxy, optionally substituted alkyl or alkoxy or carboxy group, free, in salt or esterified with an alkyl radical, represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl or alkylsulfinyl optionally substituted such that in all the radicals which R @ 1 and R @ 2b may represent alkyl radicals and alkoxy groups of up to 6 carbon atoms and the phenyl radicals are optionally substituted by one or more radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, acyl, carbonyl, free, in salt or esterified form, phenyl, pyridyl, tetrazolyl, alkyl of alkoxy of up to 4 carbon atoms and optionally substituted with alkoxy of up to 4 carbon atoms,

4b represents cyano, carboxy, in the form of a salt or esterified, -SO ₂ -X _b -R k where X _b is -NH-, -NH-CO-, -NH-CO-O-, -N = CH-NR _13b, -NH-CO-NII or a single bond and ^R 10b ^and ijb ^ ^'like θΐθβο different, are H, methyl, ethyl, propyl, vinyl, allyl, pyridyl, phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkyipiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofurans1, said products of formula ₍ Ib) being in all possible isomeric racemic, enantiomeric diastereoisomeric forms as well as their acidic or mineral salts and their mineral and organic addition salts; consisting in the fact that for their preparation as described above are used the products of formulas II, III and IV stated above wherein R _1, R _2, ^and Π j ^H 4 ⁿ '° Wow defined for R _lb respectively. R _2b resp. R _jb , resp. R _4b , active groups optionally protected.

in which there are reactions

Another object of the present invention is to provide a process for the preparation of products of formula I corresponding to formula I

where

R 1d represents an alkyl radical of up to 4 carbon atoms, R jj represents a carboxy group in the form of a salt or esterified with a linear or branched alkyl radical of up to 4 carbon atoms, formyl, acyloxy, alkyl of up to 4 carbon atoms optionally substituted with hydroxy.

R _2d represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl, or alkylsulfinyl, wherein the alkyl moiety contains up to 4 carbon atoms,

R ^ _d represents the radical -SOg-NHI, -SOg-NH-CO-OR ^ _Qd ,

-SO. -N = CH-MR ₁ ,, -S0 or _a NH-C0-NH-R ,, _in which R, _n. and ά 1 Ju _Λ 2 10 d _of 10 d ^R 1JD ^{mother) k} or different, are selected from hydrogen, methyl, ethyl, n-propyl and propenyl, the said products of formula I, _d being in all possible isomeric racemiekých, enontiomerných a diaster The various forms and also addition salts thereof with mineral and organic acids or mineral and organic bases, characterized in that products of formulas II, III and IV in which R *, R * 2 are used for their preparation as described above, are used. ⁰ have the meanings given above for R _1d and R _1d , respectively. Rjj, respectively. ^rGS P · ^{3 in} which the reactive functional groups are optionally protected.

In particular, the present invention relates to the above process, wherein the starting product is a product of formula a, wherein R * ₁ represents the radical -SC 1 -NI 4 -SO ₂ -NH-CO-O-R _10d , -SO 2 ₂ -14 = 011-1? _Jd or -SC? -NH-CO-NH-R, _Qd wherein R? _D and the ^same or different are selected from hydrogen, methyl, ethyl, n-propyl and propenyl, wherein the reactive ion groups are optionally protected, the product of formula II wherein R is a carboxy group free, in the form of a salt or esified with a linear or branched alkyl radical of up to 4 carbon atoms, formyl, acyloxy or alkyl of up to 4 carbon atoms optionally substituted with a hydroxyl radical; the product of formula III, wherein R ₁ is aikyiový radical having up to 4 carbon atoms, and an agent able to introduce a substituent R 2> ^ ÚE R 2 ^Ρ Γ θ ^ ³ ^ ^{3ν 'α 3θ} phenylthio, phenylsulfonyl 1, fenylsuifinyl, alkylthio, alkylsulfonyl or alkylsulfinyl, wherein the alkyl moiety contains up to 4 carbon atoms and reactive groups are optionally protected.

In particular, the present invention provides a method of using the product of formula (A) wherein R 'is a residue

- SO.

N 'product of formula II, wherein R * 1 represents an alkoxy or carboxy group, free, in salt form or esterified, the product of formula III, wherein R * ₁ represents an alkyl of up to 4 carbon atoms, and an agent capable of introducing a substituent R 1'; wherein R ₉ represents an alkylthio or phenylthio group, optionally oxidized in the form of a sulfoxide or sulfone, wherein the alkoxy, alkylthio and phenylthio groups are optionally substituted by one or more radicals selected from halogen atoms, alkyl radicals or alkoxy groups having up to 4 carbon atoms , trifluoromethyl, amino, mono or dialkylamino, cyano, phenyl, hydroxy, carboxy free or esterified, acyl, and acyloxy groups.

The present invention also provides the above process, consisting in that a compound of formula A ₁

wherein Kal is a halogen atom, reacted with an oxidizing agent to form a compound of formula 3

CHO

which is then reacted with a compound of formula II

Π M ij ⁴ⁱ 2 (II)

where. 3 * 3 is as defined above, with the formation of the product of formula. G 1

wherein it is as defined above, which is reacted with a compound of formula III

Rj-GO-Kal (III) wherein R and Kal are as defined above to give the product of formula D.

R * i O

CN

C 3,)

R '3

wherein R 3 and R ^# are as defined above, which BUA. undergoes an addition reaction on the remainder of the CN using the above reagent capable of introducing the substituent R * ₂ to give the product of formula (E).

optionally a sulfur atom

R'2 3 R * ₃ are as defined above, which undergo a substitution reaction of an oxygen atom to form a product of formula L,

wherein R p R _p and R have the meaning given above which, if necessary or desired, is converted to the product of formula L ₂

where R p R g ³ R j are as defined above, then the product of formula E ₁ , J p or L? undergo a cyclization reaction to give the product of formula or I ' ₂

R2 '

N or

ϋ where S * 2 ^and having I * are optionally converted or the product of formula above and the product of formula to the above product of formula K is subjected to an addition reaction to the residue with ₂ ♦ to give the product of formula D ₉

wherein R * ^ and R * ^ are as defined above, which is subjected to the above addition reaction to produce a product of formula

F '

N H;

wherein R * j, R * ²³ are as defined above, which is cyclized to produce the above product

I 'is subjected to the formula

In particular, the present invention further relates to the above process for the preparation of products of formula I corresponding to the following formulas:

- 2-butyl-1-t2C-carboxy (1,1'-biphenyl-4-yl) methyl-4- (phenylthio) -1H-imidazole-5-carboxylic acid,

- 2-butyl-1 - [[2'-carboxy- (1,1'-biphenyl-4-ylmethyl) -4- (methylthio) -1H-imidazole-5-carboxylic acid,

- 4'-Er2-butyl-4- (ethylthio) -5- (hydroxymethyl) -1H-imidazol-1-yl] methyl- (1,1'-biphenyl) -2-carboxylic acid,

- 2-butyl-1- (2'-carboxy- (1,1'-biphenyl) -4-ylmethyl) -4- (ethylsulfonyl) -1H-imidazole-5-carboxylic acid,

- 2-butyl-1 - [[2'-carboxy- (1,1-biphenyl) -4-yl] methyl] -4- (ethylsulfinyl) -1H-imidazole-5-carboxylic acid,

- 2-butyl-1 - [(2'-carboxy- (1,1'-biphenyl) 4-yl) methyl] -4- (ethylthio) -1H-imidazole-5-carboxylic acid,

- 2-butyl-1 - C [2'-carboxy- (1,1'-biphenyl) -4-yl] methyl] -4- (phenyisulfonyl) -1H-imidazole-5-carboxylic acid,

- 2-butyl-1 - [[2'-carboxy- (1,1'-biphenyl) -4-ylmethyl] -4- (phenyisulfinyl) -1H-imidazole-5-carboxylic acid,

2-butyl-1- [2'-tetrazolyl- (1,1'-biphenyl) -4-yl] methyl] -4- (methylthio) -1H-imidazole-5-carboxylic acid.

v v

In particular, the present invention relates to the above process for the preparation of products of the formula I corresponding to the following formulas:

- ethyl-2-butyl-4- (methylthio) -1 - [[2 * - ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole- 5-carboxylate,

2-butyl-4- (methylthio) -1- [E2 '- ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole-5- carboxylic acid,

- dipotassium salt of 2-butyl-4- (methylthio) -1- [t 2 '- ((((propylaminocarbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl) methyl} -1 H -imidazole-5-carboxylic acid i.

3.4

In the product of formula A, Hal is preferably b: o, but may also be chlorine or

The reaction of the compound of formula B with compound II is accomplished by reductive amination. performed in

Under preferred conditions for carrying out the invention, the product of formula B may be prepared by oxidizing the halide of formula A, for example, with hexamethylartetramine in 50% acetic acid or N-oxide-N-methylmorpholine in a solvent such as me. for example dichloromethane, dichloroethane or toluene.

iodine atom.

two stages possible:

The first compound of the amine of the oroduct B is added by adding the product of formula II to the aldehyde group of the product of formula B in a solvent such as dichloromethane, dichloroethane or tetrahydrofuran, preferably under acid catalysis, for example in the presence of amberlyst H ⁺ or acetic acid.

The second step represents the imine with a reducing agent such as NaBH (OAc) 2 (prepared in advance with acetic acid).

the reduction of the resultant is, for example, NaBH4 CN or sodium borohydride

The product of formula C is preferably butyryl chloride or valers to the product of the formula acylating agent, for example halide k

D converts acids, such as their amide, in the presence of carbonate or triethylamine in tone, tetrahydrofuran, sodium or potassium, pyridine solvents, such as acediehiormethane or dichloroethane.

The product of formula (D) is converted to the product of formula (B) by addition of the radical R *? to cyano; this amidation may be carried out in a solvent such as an alcohol such as methanol or ethanol, or by reacting the compound R 1 -SH with a cyano group in a solvent such as toluene, tetrahydrofuran or dichloroethane.

In the case where R * sí represents a sulfur-containing radical, the reaction of the product of formula D to give the corresponding product of formula Ξ is thioamidation, carried out by the action of a compound of formula R ^ q-SH, or a branched alkyl radical having up to 4 carbon atoms or a phenyl radical; these residues are optionally substituted as described above.

The thioamidation may be carried out, for example, by bubbling a compound of the above formula R 6 -OC with a solvent such as an alcohol such as ethanol or methanol, or with dichloromethane, toluene, tetrahydrofuran in the presence of a base such as triethylamine.

Thioamidation may be so

R ^ SMa or θδΚ at the same as ore R. _n SH.

i for lesions reaxised with a range of conditions:

Substitution reaction for the formation of the product of formula L of the oxygen atom with a sulfur atom at v

can be realized, for example, with Lawesson's reagent.

c and i is a foot realized either _Λ I napríklad for example of amberlys-'tu H

Reaction cyclization of the product of formula h to the product by formula catalysis using tosylic acid or sulfuric acid in a solvent such as toluene, ethyl acetate, dichloromethane, dichloroethane or with pentachioride in pyridine or dimethylaminopyridine, or poured in dimethylsulfone.

The various reactive functional groups which may carry some of the aforementioned reactants may, if necessary, be protected: for example, hydroxyl, acyl, free carboxyl radicals, and furthermore amino and monoalkylamino, which may be protected by appropriate protecting groups.

The calculation of the various protecting groups used can be found, for example, in Patent 3F 2,499,995.

Here are some non-exhaustive examples of protecting reactive functional groups:

hydroxyl groups can be protected, for example, with alkyl radicals such as tert. butyl, trimethylsilyl, tert. butyl-dimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,

amino groups can be protected, for example, with acetyl, trityl, benzyl, tert. butoxycarbonyl, phthalimido or other residues known in peptide chemistry,

-acyl groups such as formyl can be protected, for example, in the form of cyclic or acyclic ketalases such as dimethyl or diethyiketal or ethylenedioxyketsl,

- the acidic functions of the above products can, if desired, be amidified with a primary or secondary amine, for example in methylene chloride in the presence of, for example, 1-ethyl-3 'hydrochloride (dimethylamino-propylcarbodiimide at room temperature),

the acidic functions can be further protected, for example, in the form of esters formed with ester-cleavable strands. known in the art of peptides.

Like the products of formula I, the products of formulas D and E may be subjected to the above process in the above process.

And the various reactions mentioned above, and in particular those relating to the above-mentioned substituent

Thus, the product of formula E ₁ may be converted to the product Ej as described above to convert the product to the product Dj before proceeding with the synthesis.

The products of the above formulas i '1' ff or or T _{2 obtained} ^, depending on the meaning, of the substituents R, R 2, R 4 and R 4 then either form or do not form the products of formula I.

The reactions to which the products of formulas D, E and I * above may be subjected may, if necessary, be carried out as follows:

a) The products described above may, if desired on optional carboxy groups, be subjected to mineral or organic base salting reactions or esterifications, such reactions may be carried out by conventional methods known to those skilled in the art.

b) if desired, the conversion of the ester groups to the acid functional group can, if desired, be carried out under conventional conditions known to the person skilled in the art, in particular by acidic or alkaline hydrolysis, for example sodium or potassium hydroxide in an alcohol such as methanol or poured hydrochloric acid; sulfuric acid.

c) Optional cyano groups of the above products can, if desired, be converted to an acid functional group under conventional conditions known to the person skilled in the art, for example by double hydrolysis, carried out in an acidic medium, for example a mixture of sulfuric acid, glacial acetic acid and water. its three components are preferably in equal proportions or further in a mixture of sodium hydroxide, ethanol and water at reflux.

d) Optional free or esterified carboxy groups of the above prodrugs can, if desired, be reduced to alcoholic function by methods known to the person skilled in the art; in the case of an esterified carboxy group, it is possible in particular to use lithium and aluminum hydride in a solvent such as tetrahydrofuran or further dioxane or ethyl ether. In particular, boron hydride can be used for the free carboxy groups.

e) Optional alkoxy groups, in particular methoxy, of the above products may, if desired, be converted to hydroxyl function under conventional conditions known to those skilled in the art, for example boron tribromide in a solvent such as methylene chloride, hydrobromide or hydrochloride pyridine or further hydrobromic or hydrochloric acid in water or acetic acid at reflux.

f) The optional sulfur-containing groups of the products described above can, if desired, be converted into the corresponding sulfoxide or sulfone functions under conventional conditions known to the person skilled in the art, such as by peracids, for example peracetic acid or m-chloroperbenzoic acid or ozone. sodium periodate in a solvent such as methylene chloride or dioxane at room temperature. The sulfoxide function can be obtained by equimolar mixing of a product containing an alkylthio or arylthio group and a reagent such as, in particular, a peracid. The sulfone function can be obtained by mixing the product containing an alkylthio or arylthio group with an excess of a reagent such as, in particular, a peracid.

g) The optional alcohol groups of the above-described products can, if desired, be converted to an aldehyde or acid function by oxidation under conventional conditions known to the person skilled in the art, such as manganese oxide, to form aldehydes or an acid-mediated Jones reagent. The optional nitrile functions of the above-described products may, if desired, be converted to tetrazole under conventional conditions known to the skilled person, such as by cycloaddition of a metal azide such as trialkyltin azide to a nitrile group as described in the procedure described in J. Organometallic Chemistry 33, 337 (1971) by Kozima, S. et al.

i) The reaction of converting the formyl residue to a carbamoyl residue and the carbamoyl residue to a nitrile residue is carried out under conventional conditions known to those skilled in the art.

The products of formula I are further optionally subjected to the following reactions:

deprotection under conditions known to the person skilled in the art, in particular by acid hydrolysis using an acid such as hydrochloric, bensenesulfonic or p-toluenesulfonic acid, formic or trifluoroacetic acid or further by catalytic hydrogenation. The phthalimido group may be foamed with hydrazine,

- the conversion to the salt is carried out with a mineral or organic acid according to conventional methods known to the person skilled in the art,

the resolution of the racemic mixtures to obtain optically active forms of the products of formula I is carried out by conventional methods known to the person skilled in the art.

The products of formula I are known 3 are described in European patent applications no. 0 465 368 and C 503 162.

The products of formula I, prepared as described above, as well as their acid addition salts, have interesting pharmacokinetic properties.

In particular, they are antagonists of the angiotensin T1 voc receptor and are therefore primarily inhibitors of the angiotensin T1 activity, particularly of the vasoconstrictive effect as well as of the trophic effect at the myocyte level.

These properties justify the use of the products of formula I prepared as described above in therapy as medicaments, said products of formula I being in all possible isomeric racemic or optically active forms, or addition salts of products of formula I with pharmaceutically acceptable mineral or organic acids.

The products of formula I, prepared as described above, as well as their addition salts with pharmaceutically acceptable mineral or organic acids, can be used, in particular, as medicaments in the treatment of arterial hypertension, cardiac insufficiency, renal insufficiency and prevention of post-angioplastic restenosis.

They may also be used in the treatment of certain gastrointestinal and gynecological disorders, and in particular for uterine-relaxing activity in the form of pharmaceutical compositions containing, as an active ingredient, at least one medicament as defined above.

These pharmaceutical compositions may be administered by buccal, rectal, parenteral or topical administration to the skin or mucosa.

These compositions may be solid or liquid, and commonly used in human medicine, such as ordinary table eco ara. · * »M o m-» ♦ r, -.4. v ™, capsules, granules, lace, injectables, gels and aerosol formulations; they are prepared by conventional methods. The active ingredient may be formulated in a formulation commonly used in these pharmaceutical compositions, such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicle, fatty bases of animal or vegetable origin, paraffinic derivatives, glycols or emulsifiers, preservative preservatives, dispersants.

The usual dosage, varying according to the product of the subject being treated and the type of attack, may be, for example, 1 to 100 mg per day in an adult, by oral route.

Some of the starting products of formula A are known and can be prepared, for example, according to European patent EP 0 503 162.

The products of formula 011 are commercially elongated or can be prepared according to European patent application EP 0 465 368.

The products of formula III are commercially available or can be readily prepared from an acid or a suitable derivative.

As novel industrial products, the subject of the invention are the compounds of formula vd,, D, d,, D ₂ , i, ώf, iu ® hp <

An example of an embodiment of the invention

In order to illustrate the invention, examples are given to illustrate the invention but do not limit its scope.

Example 1

Didraseine 2-butyl-4- (methylthio) -1 - [[2 - ((((propylamino) carbonyl) amino) auifonyl) -1,1'-biphenyl-4-yl] methyl] -1H-imidazole 5-carboxylic

Stuoen Ä

N- (dimethylamino) methylene] -4'-formyl- (1,1'-biphenyl-2-sulfonamide)

10 g of NL (dimethylamino) methylene] -4 ^z -bromomethyl- (1,1 ^z -biphenyl) -2-sulfonamide, S, 14 g of hexamethylenetetramine, 80 ml of 50% acetic acid are mentioned. The mixture was stirred for 1 hour. pr: 120 G. After the addition of 220 ml of water, the reaction mixture is neutralized with saturated sodium bicarbonate solution, extracted with dichloromethane, dried and evaporated to give 7.99 g of the expected product.

MS MH ⁺ 317

NMR (CDCl3)

2.71 and 2.77 (2S, 6H.

N <~ ^h ₃

7.17 s, K = GE-U, 7.15

7-91 (system AB, 6H. Aromatics), 10.11 (CEO. 1H)

Step B: Amino-cyano-ethyl acetate mono (4-methylbenzenesulfonate)

50 g of (B) cyano hydroxyimino) ethyl acetate in 440 ml of water and 340 ml of sodium hydrogen sulphate solution are introduced, 150 g of hydrogen sulphate are added and the mixture is stirred for about

350 ° G for about 30 min. The solution was saturated with sodium chloride, extracted with styrene chloride and dried. The residue was taken up in ether: 44 g was added. p-toluenesulfonic acid in 110 ml of ethanol, 740 ml of ether, the solvents are removed and recovered. 35 g of the expected product. Melting point 125-130 ° G.

Step G: Style-cyano-CCD * - CLI (dimethylamino) methylene amine sulfonyl] - (1,1-biphenyl) -4-ylmethyl] amino

A solution of 13 g of amino-cyano-ethyl acetate mono (4-methyl-benzene).

sulfonate}, obtained in step 3, 1 g of amberlyst 15 (HJ and 12o3 g of the product prepared in step A, in dichloromethane is stirred at reflux for about 7 hours. This solution is cooled and added to a slurry containing 3 µg. g of sodium borohydride, 14.2 ml of glacial acetic acid and 60 ml of dichloroethane or 10 '

The zisxanes are stirred for about 18 hours. 200 ml of water are added, and the precipitate obtained is filtered off. The organic phase is washed with water, dried and concentrated under reduced pressure.

After purification by chromatography on silica gel with dichloromethane / ethyl acetate 85: 150, 9 g of the expected product is obtained in the form of an oil.

TLC (dichloromethane / ethyl acetate 85:15) = 0.20

IR (CHCl3)

3340 (-ΙΊΗ-) 1753 (0 = 0) 1628 (N = CE-N 2 · 1344, 1148 (SO ₂ )).

NMR (ODC1 _7?

1.37 (t, J = 7, CO ₂ CH ₂ CH), 2.75 and 2.79 (2S, dimethylamine),

2.21 (mobile NE), 3.94 and 4.06 (NOH ₂ -O =, AS? System, 4.35 (q J = 7, GO ₂ GH ₂ CH ₇ )), 4.35 (connected N-CH-C »N) , 7.14 (s, N = CH-N);

7.22 (dd, 1H, aromatic), 7.51 (m, 2H, aromatics), 7.39 ( ^with rare chasuble).

Supen O: ethyl-cyano-trans [2 - [(dimethylasino) methylene] amino} sulfonyl] - (1,1'-biphenyl) -4-yl] methyl] (1-oxopentyl) amino] scetate

To a solution of 11.1 g of ethyl-cyano-CCl2 * - [[(dimethylamino) methylene] amino] sulfonyl] -1,11-biphenyl) -4-yl] methyl amino-3-acetate, prepared in Step C, in 200 ml of dry acetone g K _{o 3} and 3.33 ml of valeryl chloride. After the mixture ς

stir 20 hr. at room temperature, the solution is filtered and dried. Purify by chromatography on. dichloromethane / ethyl acetate 85:15. 11.6 g of a white solid are obtained

Rf (dichloromethane / ethyl acetate)

35:15) = 0.24

Step E: ethyl-3-amino-2-βΠ 2 [[[((dimethylamino) methylene] amino] sulfonyl] - (1,1'-biphenyl) -4-yl] methyl] - (1-oxopentyl) amino-1-methylthio) 2-enoate

250 mg of ethyl-cyano-Cl 2 ^from -CCC (dimethylamino) methylene-amino-sulfonyl] - (1,1'-biphenyl) -4-yl] -methyl- (1-oxopentyl-amine-acetate), prepared in step D, 2.5 ml of ethanol are introduced. and 7 ml of diethylamine, cooled to -5 [deg.] C. and bubbled with methanethiol for 10 min, stirred for 1 h at -5 [deg.] C., allowed to warm to room temperature and stirred for 48 h. Nitrogen was bubbled at room temperature, then the solvents were removed under reduced pressure, after chromatography on silica gel (eluent: dichloromethane / ethyl acetate 80:20?), 0.91 g of the expected product was obtained.

Step F Ethyl 2-butyl-4- (methylthio) -l - EL2 * -CĽC s dimethylamino) methylene] amínojsulfonyl] - ^{(1,1-out-biphenyl)} -4-METHYL-1 H YLJ-imidazol-5 "carboxylate

50 mg of ethyl-3-amino-2-chloro-CLC (dimethylamino-methylene) amino sulfonyl-3- (1,1'-biphenyl) -4-yl] methyl] - (1-thiopentyl) amino-3- (methylthio) are reported. -2-2-propeonate, prepared in step 53. 500 µl toluene and a catalytic amount of amberlyst 15. Heat at reflux for 20 hours, filter the amberlyst, wash the mixture, remove the solvents under reduced pressure to obtain 0.20 g of the expected product.

Step G ethyl-1-butyl-4- (methylthio-1-CC2-thiamino) sulfonyl} - (1,1'-biphenyl> -4-yl) -methyl] -1H-imidazole-5-carboxylate

43.5 g of ethyl 2-butyl-4- (methylthio) -1-2 * CCC (dimethylsulfonyl) - (1,1'-diphenyl) -4-yl-methylamino] amino-1H-1H-1 H is maintained at reflux. -imidazole 5-carboxylate obtained in step F, in 800 ml of methanol, 400 ml of concentrated acid / hydrochloric acid. The methanol is evaporated, the remaining phase is adjusted to pH 5-6 by addition of 6N sodium hydroxide. Is it extracted three times with ether f400 ml? , dried over Na ₂ SO 4 and then the solvent is evaporated. 37.5% of crude product is obtained. It is triturated in a mixture of 50 ml of ethanol + 500 ml of isopropyl ether, then filtered. 31.4 g of the expected product are obtained. Mp 127-129 ° C.

Step H: ethyl 2-butyl-4- (methylthio) -1-C 2 - [[C (propylamino) carbonyl] amino] sulfonyl] - (1,1-biphenyl) -4-yl] methyl 1 H -imidazole-5-carboxylate

At reflux 2 hours. maintains a solution of 10 g of ethyl 2-butyl-4- (methylthio) -1- [E2 [1,1'-amino sulfonyl] - (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole-5-carboxylate in an inert atmosphere prepared in Step G, 5.6 g of potassium carbonate (previously crushed and dried under reduced pressure at 100 ° C) in 70 ml of ethylene glycol dimethyl ether. After 1 hour 4 ml of n-propyl isocyanate is added and heating is continued for 30 min. The mixture was allowed to cool to room temperature, then the solvent was evaporated. To the remainder ss is added ml of water and then with:

The mixture is treated with 5 to 6 by slowly adding 1N hydrochloric acid. The product crystallizes. It is recrystallized from 50 ml of ethyl acetate to give 10.1 g of the expected product.

Didr - 2- (δ-2-butyl-4- (methylthio) -1 [CC (propylamino) carbonyl] amino sulfonyl) biphenyl) -4-ylimidyl-1H-imidazole-5-carboxylic acid

The

-CCl (for a solution of 2 g ethyl-2-butyl-4- (methylthio) opylamino) carbonyl-amino-sulfonyl- (>

1-CĹ2'1 ^of biphenyl) -446

1-Methyl] -1R-imidazole-5-carboxylate, prepared according to Step H, in 40 mL of ethanol was added 2.3 mL of 6N potassium hydroxide solution at 0 ° C. The mixture was allowed to warm to room temperature. After 72 hours, the precipitate is filtered off and washed with 4 ml of ethanol and then with 4 ml of ethyl acetate. After drying, 2.04 g of the desired product is obtained. Melting point = 260 DEG C. Analysis calculated: 50.30% G, 4.37% H, 9.02% N, 10.33% S, found 50.5% C 4.9% H, 9.0 % N, 10.3% S.

Example 2

Dipotassium salt of 2-butyl-4- (methylthio) -1-C 2 -

- LCt (propylamino) carbonyl] amino] sulfonyl] - (1,1'-biphenyl) -4-ylmethyl] -1H-imidazole-5-carboxylic acid ethyl-cyano- (CC2'-CCl) dimethyl- amino / methylene-amino-sulfonyl] - (1, 1 &apos; -biphenyl) -4-yl] metylJamínojacetat

I

2 g of the amino-cyano-ethyl acetate mono (4-methylbenzyl-sulfonate) obtained in step B of Example i are mixed with 9 g of N-dimethylamino-methylene] -4 * -formyl- (1,1'-biphenyl) -2 -suif ónsmidu ,. prepared in step a of Example 1, and stirred for 3 hours. in dichloromethane at 35 ° C, then 0.396 g of sodium cyanotetrahydroborate is added and the solution is left under stirring at room temperature for 18 hours. The reaction mixture was filtered, washed with water and evaporated. After chromatography on silica gel (dichloromethane / ethyl acetate 35:15 J), 770 mg of the expected product is obtained, identical to the product of Step G of Example 1.

2) Then proceed as in the process obtained here in Step G of Example 1, and obtain as expected product ice 1 with a substitute. the above-mentioned products are potassium dipotassium salt

2-butyl-4- (methylthio) -1-CC2 propylamino) carbonylamino amino sulfonyl-1- ⁽ 1,1'-biphenyl) -4-ylmethyl] -1H-imidazole-p-carboxylic acid.

Example 3

2-Butyl-4- (methylthio) -1-CC2 dipotassium salt ^of - ECC (propylamino) carbonyl-amino] -sulfonyl-1- (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole-5- carboxylic acid

Stage A.: ethyl-CCC2 ^from - (aminosulfonyl) - (1,1'-biphenyl) -4-yl] methyl] - (1-oxopentyl) amino] cyanoacetate

1.0 g of ethyl-cyano-CCCl2 (1H) (diethylamino) methylene-amino-sulfonyl] - (1,1'-biphenyl-4-ylmethyl) - (1-oxopentyl) aminoacetate, prepared in Step D of Example 1, at 20 ml of ethylene glycol dimethyl ester with 10 ml of concentrated hydrochloric acid is stirred for 30 minutes at 100 DEG C. After cooling to room temperature, the pH of the solution is adjusted to pH = by addition of 6N sodium hydroxide.

The organic phase is washed with water saturated with sodium chloride and dried. P.reči /h< mainnt 9R J .: 1) sure c hr or ifiou feluer.t

Step o Preparation of ethyl-cyano-CC 2 - [[L (propylamino) carbonyl] amino sulfonyl] - (1,1'-biphenyl) -4-oxopentyl) amino acetic acid (1'-methyl) - (letyl-f [[2 ^z - (Aminosulfonyl) - (ixopentyl) amino aneacetyl, ^z- biphenyl) -4-yl.

Stir with 2 V · 1.48 ml of n-propyl isocyanate for 2 + / 2 hours. at reflux in 180 ml acetone. After cooling, 2N hydrochloric acid was added to the solution. The residue is dissolved in an aqueous mixture of dichloromethane. Extraction with dichloromethane, drying and removal of solvent under reduced pressure recrystallized from ethyl acetate to give 6.6 g of the expected product (white solid).

FU (SiO ₂ , ethyl acetate) - 0.48

Melting point 131-133 ° G.

Step C: ethyl-3-may-2- (Cl 2 -CCC (propylamino) carbonyl) amino] sulfonyl] - (1,1'-biphenyl) -4-ylmethyl] - (1-oxo-pentyl) amino-4 '- (methylthio) - 2-propenoate

2.4 ml trie thiol · OH and oc that the rez t 40 ° rt dy · Po z lika about le (e

feed me tan The following spoke: after 10 bar on the of photographs on the It is called S, 0 g

Solution 8.5 g. ethyl-cyano-CCl2 - [E (propylamino) carbonyl] amino-4-sulfonyl] - (1,1'-biphenyl) -4-ylmethyl-1- (1-oxopentyl) amino acetate, prepared in step 8 above, and

2.4 ml of triethylamine in 100 ml of dichloromethane is saturated with methanedioion and cooled to -20 G. The temperature is allowed to rise and the solution is maintained for 48 hours. under nitrogen pressure 1 After concentration, the residue is purified by chromatography (dichloromethane / MeOH 20: 1).

of the expected product.

R f (SiO _2, dichloromethane / MeOH 20: 1) = 0.39

Step D: ethyl-2-butyl-4- (methylthio) -1 - [(2- (propyl) amino) carbonyl] amino] sulfonyl] -1- (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole-5- carboxylate

180 mg of phosphorus pentachloride was suspended in 16 ml of dichloromethane to give 230 mg of dimethylaminopyridine in solution in 10 ml of anhydrous dichloromethane and stirred for a further 10 min. At -78 ° C a solution of 500 mg of ethyl-J-amino-2-fluoro-C (propylamino) carbonyl-amino-sulfonyl] - (1,1'-biphenyl) -4-yl] methyl- (1-oxo) is added. (pentyl) atmosphere of argon sulphuromethane. After cooling to -78 ° C

G Sč- o:

of amino-3- (methylthio) -2-propenoate prepared in Step C above in 25 ml of dichloromethane and stirred for 13 hours.

or room temperature. The precipitate was filtered off, washed with water and dried. Chromatography on silica gel (eluent: dichloromethane / MeOH 20: 1) gave 330 mg of crude product, which was recrystallized from ethyl acetate / n-heptane to give 270 mg of a white solid.

R f _{(SiO y} acetate / n-heptane 4: 1) 0.42 + ^Heat? rotating 127-129 ° C.

Step E: 2-butyl-4 - ( 'Methylthio) ^-1-LLC2, - [[£ (propylamino) carbonyl] amino] sulfonylamino] - (1,1' -biphenyl) - 4-yl] methyl -1H-imidazole-5-carboxylic acid

Solution 1 30 mg ethyl-2-butyl-4- (methylthio) -1-LC2- [C (propylamino) carbonyl] amino] sulfonyl] - (1,1'-biphenyl) -4-yl] methyl 1-K-imidazole-5-carboxylate in 10 mL of methanol and 3.1 mL of 2N sodium hydroxide was stirred for 1 h. at room temperature. The methanol was evaporated and the remaining aqueous solution was acidified to pH = 6 by the addition of 2 H hydrochloric acid. The precipitate was filtered off, washed with water and dried under reduced pressure. 1 and 5 mg of the expected product are obtained.

Melting point 109-111 ° G.

1?

tuner. and

-ĹĹ2 '- [CĹ (- (,, 1'-bif

2-butyl-4-methylthio) -1-propylamino) carbonyl] amino] sulfonyl] enyl-4-yl] methyl] -1H-imidazole-5-carboxylic acid salt , amino) carbonyl] am

-4- (methylthio) -1- (2'-sulfonyl) -1- (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole-5-carboxylic acid, prepared in Step C above, using an aqueous solution potassium hydroxide as described in Example 1 yields the expected product.

Example 4

Dipotassium salt of 2-butyl-4-fmetyltio) -l - CC2 * III (propylamino) carbonyl] aminol sulphonic onylj - (i, 1 ^# biphenyl.) - 4-yl] Mstyle] -lH-imidazol-5-carboxylic acid j / Ethyl-cyano-CC 2 ^# - [[[(dimethylamino) methylene] amino] sulfonyl] - (1,1'-biphenyl) -4-yl] methyl] - (1-oxopentyl amino acetate)

200 mg ethyl-3-amino-2-cff2 [[[(propylaminocarbonyl) amino sulfonyl] - (11-biphenyl) -4-yl] methyl] - (1-oxopentyl) amino-3-methylthio) -2-propeno The ester prepared in Step C of Example 3 was dissolved in 5 ml of ethylene glycol disethylether and 1 ml of concentrated sulfuric acid was added at room temperature. After 1 hour with stirring, water is added while cooling in an ice bath. Extract with dichloromethane. the organic phases are washed, dried and the solvent is evaporated off under reduced pressure. ISO mg of crude product is obtained, which is recrystallized from ethyl acetate to give 140 mg of the expected product.

Melting point 130-132 ° G.

2/7 of the synthesis is continued as in Example J, replacing the product prepared in Step D of Example 3 with the above product to give the expected product.

Example 5

e.for> 1-2-butyl-4- (methylthio) ^-1 - [[2 - [[[(propylamino) carbonyl] amino] sulfonyl] - (>1'-biphenyl / -4-yl) methyl] -hh -imidazole-5-carboxyethyl

Grade A

-cyano- [ΐ [2 '- [[C (propylamino) carbonyl] amino-sulfonyl) - (1,1'-biphenyl) -4-yl] -methyl] -aminoacetate

Ecrztok 2 g formyl- (l ' -biphenyl) -2- [2-IX ^of (propylamino) karbonyij aminoJsulfonyluj, prepared as in step A of Example 1 from the corresponding sulfonamide derivative and 1.83 g etylkyanoamínoscetatu, prepared according to European Patent Application 0 465 368, in 40 ml of dichloromethane is stirred for 6 hours. at 35 ° FG. This solution was added to a suspension containing 11.55 mmol of sodium borohydride, 2 ml. glacial acetic acid and 30 ml of dichloromethane, at a temperature of + 10 ° C. The solution thus obtained is stirred for 16 hours. Water is added, the organic phase is extracted, washed and dried, evaporated under reduced pressure of the solvent and subjected to silica gel chromatography (eluent: dichloromethane / MeOH 30: 1). 1.8 g of the expected product are obtained.

Rc. (SiO ₉ , dichloromethane / MeOH 20: 1) = C. 39

Step S: ethyl-cyano- [C 2 H 2 -CCl (propyl amino) carbonyl] amino sulfonyl] - (1,1'-biphenyl) -4-ylmethyl-1- (1-oxooentyl) amino acetate, 7 g of ethyl-cyano-C12-22 ^/ -CCC (propylamino) carbonyl-3-aminosulfonyl] - (1,1'-biphenyl) -4-ylmethyl] amino amino acetate, prepared in step A above, is dissolved in 50 ml of acetone and added with 0.79 g of acetone. potassium carbonate and 0.45 ml of chloride chloride, and the mixture thus obtained is stirred at room temperature for 6 hours. The insoluble matter is filtered off and the filtrate is evaporated to dryness; Purification by chromatography: dichloromethane / ethyl acetate 4: 1? yield 295 mg of the expected product.

(3I0 _about, dichiórmetan. / E tylscetát 4: 1? »0.30

The synthesis is continued according to steps C, D, Ξ and F of Example 3 to give the expected product.

Example 6

Dipotassium salt of 2-butyl-4- (methylthio) -1 - [C2 * - ((((propylsmino) carbonyl] amino] sulfonyl) - (1,1'-biphenyl)

-4-ylmethyl-1H-imidazole-p-carboxylic acid Π-L

Step A: ethyl-J-amino-2 - [[[2 '- [[[(propylsmino) carbonyl] amino] sulfonyl] - (1,1'-biphenyl) -4-yl] methyl} - (1-thiopentyl) amino- 3-methylthio) -2-propenoate

Ethyl 3-amino-2 - [[[2-ECC-propylamino) carbonyl] amino sulfonyl] - (1,1'-biphenyl) -4-ynyl] - (1-oxopentyl) amino-i- ( of methyl thio) -2-propeonate, prepared in Stepwesson's reagent in 1 C ml of anhydrous Example J, and 342 mg of ethylene glycol diethyl ether at pressure, and the residue

Pη P V * T Π Ω 3 r r) P Γ A - rooms. The solution is concentrated under reduced pressure into dichloromethane / water (i: i). ro ex; washing with water, drying and removal of solvents, the remaining ointments are purified to give 506 mg of the expected product.

fSiOj ethylscetate / n-heptane

4th

Step B ethyl-2-dutyl-4- (methylthio) -1- [2'-C [(propyl) carbonyl] amino] sulfonyl] - (1,1'-biphenyl) -yl] methyl-1H-inidazole-5- carboxylate

A solution of 1-O mg of ethyl 3-anino-2- [C [2 propylamino] carbonyl] amino] sulfonyl] - (1,1'-biphenyl) -4-ylmethyl] -C-thiopentyl) amino-3- (methylthio) - The 2-propeonate prepared in step a., 58 [mu] l of dimethylsulfone in 5 ml of dichloromethane is stirred at reflux for 15 hours. After cooling to room temperature, the solution was washed with saturated sodium chloride solution and evaporated to dryness under reduced pressure. After chromatography on silica gel: ethyl acetate / n-hept 2: 1, 35 mg of the expected product is obtained.

The synthesis was continued as in S and F of Example 3 to give the expected product.

Claims (9)

PATENT A process for the preparation of products of formula I wherein R1 represents an alkyl, alkenyl, alkynyl or alkylthio radical, each of which is linear or branched and contains up to 10 carbon atoms or a cycloalkyl radical having from 1 to 7 carbon atoms, all of which are optionally substituted. R ₂ and R 1, the same or different, are selected from the group consisting of a / hydrogen, halogen atoms, hydroxyl, mercapto, formyl, acyl, carboxy, salt or esterified, nitro, cyano and -FG 4 (R? ₂ wherein R represents a hydrogen atom or an optionally substituted alkyl or phenyl radical. b / - (CH ₂ ) _m p S (O) _in pXR ₁ θ, where it represents an integer from 0 to 4, Jn ₂ represents an integer from 0 to 2 and X. represents a single bond or -NH- residues, -NH-CO-, -KH- GO-O-, = GH-II-j NR _1, -NH-CO-NH- and _{R] θ} and R j, identical or different, are H, a linear or a branched alkyl or alkenyl radical of up to 6 carbon atoms, cycloalkyl of 3 to 6 atoms. . carbon, optionally substituted phenyl or benzyl, furthermore pyridyl, nitropyridyl, pyrimidyl, tetrazolyl, palzolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuran, not the itetrahydrofuran 1, cis / alkyl, aleknyl, alkoxy or alkylthio group, optionally mono- or dioxidated, each of these radicals, linear or branched with up to 6 carbon atoms, optionally interrupted by one or more heteroatoms selected from the group consisting of sulfur, oxygen or nitrogen atoms, and optionally substituted; (phenyl, benzyl radical and phenylthio group, where the sulfur atom is optionally mono- or dioxidized, radicals which are optionally substituted, ^Π 6 ' ^R 8' and - the radicals -CO-N <'and -N ^< _f r ₇ ^of r) where either. Rg. and Ry or Rg of Rg, the same or different, are selected from the group consisting of - a hydrogen atom, - amino acids, - alkyl and alkenyl radical having up to 6 carbon atoms, optionally substituted, - phenyl, benzyl and phenethyl, optionally substituted, - radical "~ f ⁵ f O) _m ^X 2 'and ^R 0'^{of; £} * ^inov0n characterized above or R x and R y. or R 8 and R 8 each form with the nitrogen to which they are attached a monocyclic radical having 5, 6 or 7 ring atoms or a radical of the same or different fused rings of 8 to 14 ring atoms optionally containing one or more other heteroatoms, selected from oxygen, nitrogen and sulfur atoms which are optionally substituted by one or more radicals selected from the group consisting of halogen atoms, hydroxyl, nitro, alkyl and alkoxy of up to 6 carbon atoms, an omino group optionally substituted by one or two identical or different alkyl radicals up to 6 carbon atoms and phenyl, or R and R, identical or different, represent an acyl radical, or one of the substituents R and R is carbamoyl, alkoxycarbonyl or benzyloxycarbonyl radical and R _Q and R form together with the nitrogen to which they are bound, phthalamido or succinimido residue, f / -SSR ₁₂ residue, k de R ₁₂ is as defined for R ₂ or R 1 in paragraphs a / e to e) except for the amino and alkoxy residues, provided that at least one of R ₂ and R 6 is. optionally substituted alkoxy or a radical, -S- (O) n -XR 1, as defined above. per ml m2 1U R ₄ is selected from radical ^"(CH2 ^ m1" ^with (* ° ^ πι2 ^{Χ Κ} 1 0 ^{5 in} zwitterionized defined meaning, halogen atoms, a nitro radical, radicals - _{(CH2) m1-4 -CUUR>} - (¾) _m pCONHR ₁ - ('CH ₂ ) _ml -CN, where defined above, -SO ₂ -NH-SO ₂ -R ₁₄ , -NH-SC 4 -R 4, -PO 4 R 4, -NHjSO ₂ 'CF ₃ and -50 ₂ -Ν = σ (Η ₁₃ ) -Ν (0Η ₃ ) ₂ , - (¾) _m r ^SO 3 ^R 1 4, -CO-NH-OR ₁₄ , -CO-NH-NH-SO ₂ -CF, -CO-NH-SO ₄ -CH ₂ SO ₂ NHCO-R ₁₄ , -CH ₂ CONH-SO ₂ R ₁₄ , -NHSO ₂ NHCO-r ₄ -NHCONHSO ₂ .TR _{1 4,} -CONHSO ₂ NR ₁₄ R _{1 5,} -SO ₂ NHCONR ₄ R _{1 1 5} - ₂ ^p ° N (R ₄₎ R ₁₅ °, -SO ₂ R ₂ nhsg _i4, -5Ο ₂ ΝΗΡΟ (Ή ₁₄ ) ₂ , -COŇIIPO (R ₁₄ ) ₂ , 5O ₂ NHCN, -SO ₂ NHCOR ₁₄ , -SO ₂ NHSO ₂ NR ₁₄ R ₁ -SO ₂ NI ₁ SO ₂ N (CH ₂ CH ₂ ) ₂ Y, -NHSO ₂ NHSO ₂ R ₁₄ , -NHS0 ₂ NHPOŕR _{14) 2,} -NHSO ₂ R _14, -NR ₁₄ CO3O ₂ H, -S0 ₂ NHC0 ₂ R _14, wherein R .Me as defined above and R ₄ and R, -, and the same: different is hydrogen, alkyl of up to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, optionally substituted, and Y is oxygen or sulfur, all alkyl, alkenyl, cycloalkyl, alkylthio, phenylthio, alkoxy, phenyl, benzyl are optionally in substituted with one or more radicals selected from the group consisting of halogen atoms, hydroxyl, nitro, alkyl, alkenyl and alkoxy of up to 4 atoms, carbon, trifluoromethyl, cyano, amino, mono and dialkylamino, carboxy, free, in the form of a salt or est. erified, haloalkyl, alkylthio, haloalkythio, haloalkoxy, phenyl, pyridyl, benzyl, phenethyl, benzoyl, phenoxy, benzyioxy, phenylthio, carbamoyl, acyl, acyloxy and tetrazolyl, and wherein all products of formula I are in all possible isomeric racemic, enantiomeric and diastereomeric and diastereomeric and the addition salts of the products of formula I with mineral and organic acids or with mineral and inorganic bases, characterized in ^{that 30 is a} compound of formula A wherein lial represents a halogen atom and R is as defined above. - 56 above for Rp in which optionally reactive functional groups are optionally protected, is reacted with an oxidizing agent to form a compound of formula B CHO Wherein R is as defined above and which is then reacted with a compound of formula TT H _? N CN R, j (CII) wherein it has the above meaning for R p in which optionally reactive groups are optionally protected to give the product of formula C Nile CN < R 10 (C) where and R are as defined above, which are reacted with a compound of formula III R-CO-Hal. (III) wherein R * j has the meaning given above for Rp in which optional reactive groups are optionally protected and Hal represents a halogen atom to give the product V2orca D R 't n \ O C P R CN wherein R ° 3 R 4 are as defined hereinbefore, which is subjected to addition reaction on the CN radical agent schopnoho passed by R wherein R is as defined above for _R? wherein the optional reactive groups are protected from the formation of the product of formula (E) R '1 O I NNH ₂ R'3 (E) wherein R '. , R ^# 2, R 'a is optionally subjected R ' 4 are as defined above, which substituted reaction of the kycyclic atom and t. sír.v mm to give the product of formula I, wherein R *. [, R 2 ^'R * j ^q are as defined above, the product of formula E or the product of formula L is subjected cyklizae, the reaction thereof to form the product of formula I wherein R 'p r' ₂ , R ' ₃ and r' ₄ products of formulas D, E and are as defined above, wherein I, in the course of the above process and products of formula I urine, was desired or necessary, one or in any order: subjected, if any, to these reactions and / esterification of the acid functional group, b) saponification of the ester group, c / conversion of the cyano group to an acid functionality, d / reduction of the carboxy group to an alcohol group, e / conversion of the alkoxy group to a hydroxy group, f / ^z oxidation of the sulfur-containing group to the corresponding suifoxide. or suifone, g / conversion of the alcohol or sulfone to the corresponding aldehyde or acid group, h / conversion of the nitrile residue to tetrazole, i / conversion of the formyl residue to a carbamoyl residue, j / conversion of the carbamoyl residue to a nitrile residue, k / conversion of a residue - with ₂ - ⁸ for the rest of -30 _? -IIH-C-NH-X ₁ θ, wherein X g, X a ^ _Χ 1θ, the same or different 0, represent a hydrogen atom or an alkyl or alkenyl radical with n up to 4 carbon atoms, optionally substituted, said products of formula I 'may represent the products of formula I may be subjected, if desired and necessary, to one or more reactions in any order to produce products of formula I: a) removing the protecting groups carrying the protected reactive groups, b) converting to a salt with a mineral or organic acid or a base to form the corresponding salt, c / cleaving the racemic forms into the individual products, the products of formula I thus obtained are in all possible ways isomeric racemic, enantiomeric, and disstereoisomeric forms. 2. Soosob used for the preparation of the n-products of the formula I corresponding to the formula wherein where R _1a represents a linear or branched alkyl or alkenyl radical having up to 4 carbon atoms, ^R 2a ^{and R j being the same} or different, selected from the group consisting of a / hydrogen, mercapto, formyl, carboxy, free in salt or esterified, halogen atoms , hydroxyl, cyano, nitro, acyl, b / alkyl, alkenyl, alkoxy, alkylthio, wherein the sulfur atom is optionally mono- or dioxidized, these residues being linear or branched and containing up to 6 carbon atoms, phenyl, benzoyl, phenylthio, wherein the sulfur atom is optionally mono- or dioxidated, all of which are optionally substituted by one or more of the same or different radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro, formyl, alkyl-alkoxy and up to 4 carbon atoms, phenyl and carboxy, free in the form of a salt, or esterified cis -CO-III radicals and -N < 8a R. 7a 9 wherein one of R <R ', R "and R ,, which may be identical or different, from 6 a' 7 '8 ^ in' _t selected from H, D _L omínontrane acid, alkyl radicals that contain up to 6 carbon atoms, phenyl, benzyl and phenethyl, or on the one hand R 1 and R 2 and on the other. C £ J ci t 01 * X cJ V S G. y 5 £ C Oľ. The heterocyclic radical is identical to or different from the group consisting of imidazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyridyl, piperidinyl, pyrimidinyl, pyridazinyl. pyrazinyl, piperazinyl, phenylpiperazinyl, piperidyl, oxazolyl, morpholyl, morpholinyl, and thio 64 morpholinyl, azepine, indolyl, each of which is optionally substituted with one or more radicals selected from the group consisting of halogen, hydroxyl, nitro, alkyl and alkoxy containing up to 6 carbon atoms and phenyl, R _a is cyano, carboxy, a free, salified or esterified, a - (CH _{2 P-X, and} -SO ₂ -R _1OA, wherein p is 0 or 1, _Χ θ is the radical -NH-, -NH -CO-, -NH-CO-O-, -I ₎ '1 = CH-NR ₁₃ θ, -NH-CO-NH- or a single bond and R _10a θ ^R 10' the ^same or different, represent a hydrogen atom , linear or branched alkyl or n-alkenyl containing up to 6 carbon atoms, optionally substituted, pyridyl, phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl, the alkyl and alkenyl radicals being alkyl and alkenyl; substituted with one or more radicals selected from the group consisting of halogen atoms, hydroxyl, nitro, alkyl, alkenyl and alkoxy containing up to 4 carbon atoms, trifluoromethyl, cyano, amino, mono- and dialkylamino, carboxy, free, in salt or esterified, phenyl, tetrazolyl, said the products of formula (I) are in all possible isomeric racemic, enantiomeric and diasteric forms as well as their addition salts with mineral and organic acids or mineral and organic bases, characterized in that products of formulas a, III, III and an agent are used for the preparation of claim introducing the remainder R, the scavenger ve, the meanings of which are given above for R, i and i, respectively. _And wherein the reactive functional groups are optionally protected. · 'I' respectively -o -ja R ₄ 2s> ^res P · ^R j _a > A process according to claim 1 for the preparation of products of formula I corresponding to the formula wherein R 1b represents an alkyl radical of up to 4 carbon atoms, R _1b represents a hydrogen atom, formyl, acyloxy, optionally substituted alkyl or alkoxy or carboxy, in the form of a salt or esterified with an alkyl radical, R _2b is phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl or alkylsulfinyl, optionally substituted, so that in all radicals which R _2b and R _1b may contain, the alkyl radicals and alkoxy groups contain up to 6 carbon atoms and the phenyl radicals are optionally substituted with one or a few radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, acyloxy, carboxy, free, in salt or esterified form, phenyl, pyridyl, tetrazolyl, alkyl of alkoxy of up to 4 carbon atoms and optionally substituted with alkoxy of up to 4 carbon atoms, 4b represents the cyano, carboxy, a free, salified or esterified, radical -5ϋ ₂ -Χ -Η ^ _{1 Q b,} wherein R _b is a residue NH-, -NH-Cu, CU-NH-O-, -N = CH-NR j _b, -NH-CO-NH or a single bond, and Q R _b and R _b, equal ^to or different, are H, methyl, ethyl, propyl, vinyl, allyl, pyridyl, phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkyipiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl, wherein said products of formula (I) are in all possible isomeric racemic, enantiomeric and diastereoisomeric salts and also their mineral and their organic forms or with mineral or organic bases, characterized in that products of formulas A, II, III and reagents capable of introducing the radical R * ₂ in which R *, R / R * ₃ are used for their preparation according to claim 1 and R 'have the meanings given above for R _1b and R _1b , respectively. R _9fe , resp. R ^^, respectively. R 6 in which the reactive functional groups are optionally protected. A process according to claim 1 for the preparation of products of formula I corresponding to formula I _x wherein H represents an alkyl radical of up to 4 carbon atoms, R _Jd represents a carboxy group, free, in the form of a salt or an esterified linear or branched alkyl radical of up to 4 carbon atoms, formyl, acyloxy, alkyl of up to 4 atoms, optionally substituted hydroxyl. R _2d represents phenylthio, phenylsulfonyl, phenyisulfinyl, alkylthio, alkylsulfonyl, or alkylsulfinyl wherein the alkyl radical contains up to 4 carbon atoms, the radical is -SO 4 -NH 4, -SO 4 -NH-CO-Q-R 3 _Qd , -SO 4. rhdľH-NR. _3d or -SO ₂ -NH-G0-NH-R, _Qa , wherein R _10d and the same or different are selected from hydrogen, methyl, ethyl, n-propyl and propenyl, wherein the products of formula I _and are in all of the possible isomeric racemic, en and nitrous mineral and diastereoisomeric addition salts with mineral and / or with mineral and organic bases, the products of formulas A, II, III and the reagent capable of introducing the radical R @ 1 are used for their preparation by the method of broth 1; in which R ^, R * ₂ , R ₃ and R 6 have the meanings given above for R _{1a and} R _2a , respectively. R _2a , resp. R ₃ £, resp. In which the reactive functional groups are optionally protected. forms, as well as ganic acids, characterized by A process according to claim 1, characterized in that a product of formula A is used wherein R 1 represents a residue -SO "KKN» * -S-C-NH-GO-O-I ',, -S0 _the TA-N = NR *. or 2 2 '2' On '2' ja -SO2-NK-CO-NH-R8Q _d , wherein R6 ₍ - and _{R8 and the} same or different are selected from hydrogen, methyl, ethyl, n-propyl with propenyl, wherein the reactive functional groups are optionally protected , the product of formula II, wherein R @ 1 represents a carboxy group, free, in the form of a salt or esterified with a linear or branched alkyl radical of up to 4 carbon atoms, tert-butyl, acyloxy or alkyl of up to 4 carbon atoms optionally substituted with a hydroxyl radical; R is aikyiový radical having up to 4 carbon atoms, and an agent able to introduce the substituent R _0, wherein R ₂ represents a phenylthio, phenylsulphonyl, fenylsulfinyi, alkylthio, alkylsulfonyl or alkylsulfinyl, in which aikyiový radical having up to 4 carbon atoms and the reactive groups are optionally protected . A process according to claim 1, characterized in that a product of formula A is used, wherein R * 3 is a residue of the product of formula II, wherein R * ₃ is alkoxy or carboxy, free, in salt or esterified, product of formula III, R ^ is an alkyl having up to 4 carbon atoms and a reagent capable, introducing * R * _2> ^ of ^ R is alkylthio or phenylthio optionally oxidized in the form of sulfoxide or sulfone, the alkoxy, alkylthio and the phenylthio are optionally substituted with one or more radicals selected from halogen atoms, alkyl radicals or alkoxy groups of up to 4 carbon atoms, trifluoromethyl, amino, mono- or dialkylamino, cyano, phenyl, hydroxyl, carboxymethyl, in the form of a salt or esterified, acyl and acyloxy. A process according to claim 1 wherein the compound of formula (A) is: CA,) where. Hal represents a halogen atom, reacted. with an oxidizing agent to give a compound of formula B 1 CHO which is then reacted with a compound of formula II h ₉ n. m) where it is as defined above, to produce a product in gentian G ^c ? where. R * 1 is as defined above, which is reacted with a compound of formula III wherein R * ₁ and K a are of the formula wherein R, I shall give the above-mentioned meaning to J, About the origin of the product CD ₄ ) has a well-known belief, which succes the addition reaction to the remaining Ur <by the above euv »-> ⁱⁿ * bind the sucstztuent R 11 · ----» to the formation of the product of formula ... il SO2-N Where R and / or sulfur R @ ₁ and R @ 2 are as hereinbefore defined, undergoing a substitution reaction of an atom of the formula L to form an oructed product of formula L @ _1, which is referred to as R @ ₃ . R, R _o 2 R I, U,> 3, to produce a product of the formula: s, is as defined above, sweat; or subjected to cyclization; i s *. . i Pi SO2-NH y »ο I - J *: C d 9 P. In the case of formula r * 9 with kc it * ₉ , or if the remainder of the above meaning is reduced to the above-mentioned product of formula D, the product is subjected to the product of the formula - ¹ - - duct of formula P, \ r> Q P poarobi eykl T1, -, -, - with - O. As defined above, the formation of the product of the above formula is exemplified A process according to claim 1 for the preparation of compounds of formula I corresponding to the formulas - 2-butyl-1- (C2-carboxy (1,1'-biphenyl-4-yl) methyl) -4- (phenylthio) -1H-imidazole-5-carboxylic acid, - 2-butyl-1 - [[2'-carboxy- (1,1'-biphenyl) -4-ylmethyl] -4- (non-butylthio) -1H-imidazole-5-carboxylic acid, 4 - [[2-butyl-4- (ethylthio) -5-hydroxymethyl) -1H-imidazol-1-yl] methyl] - (1,1'-biphenyl) -2-carboxylic acid, 2-butyl-1- [ (2 ^of -carboxy- (1,1'-biphenyl) -4-ylmethyl) -4- (ethylsulfonyl) -1H-imidazole-5-carboxylic acid, - 2-butyl-1 - [[2'-carboxy- (1,1'-biphenyl) -4-yl] methyl] -4- (ethylsulfinyl) -1H-imidazole-5-carboxylic acid, - 2-butyl-1- [C2'-carboxy- (1,1'-biphenyl) -4-yl] methyl] -4- (ethylthio) -1H-imidazole-5-carboxylic acid, - 2-butyl-1 - C [2'-carboxy- (1,1'-biphenyl) -4-yl] methyl] -4- (phenylsulfonyl) -1H-imidozole-5-carboxylic acid, - 2-butyl-1-L [2'-carboxy- (1,1'-biphenyl) -4-ylmethyl] -4- (phenyisulfinyl) -1H-imidazole-5-carboxylic acid, 2-butyl-1 (E, 2'-tetrazolyl- (1,1'-biphenyl) -4-yl) methyl] -4- (methylthio) -1H-imidazole-5-carboxylic acid. The gposob according to claim 1 for the preparation of products of the formula I corresponding to the formulas - ethyl-2-butyl-4- (methylthio) -1 - [[2 * - (1 ((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl] methyl] -1H- imidazole-5-carboxylate, 2-butyl-4- (methylthio) -1- [12 ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl) methyl] -1H-imidazole-5 carboxylic acid, - dipotassium salt of 2-butyl-4- (methylthio) -1- [t 2 '(((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl) methyl 1 H-imirtazole-1'-carboxylic acid; I0. New industrial products, formulas rs, u, u,, u ₉ , -,