SK594A3 - Method of preparation of sulfur imidazole derivatives and intermediates - Google Patents

Description

Technical field

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

where

R 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 of 3 to 7 carbon atoms, all of which are optionally substituted.

R ₉ and R ₉ , the same or different, are selected from the group consisting of a / hydrogen, halogen atoms, hydroxyl, mercapto, methyl, acyl, carboxy free, in salt or esterified, nitro, cyano and -PO 4 R 6 »Represents a hydrogen atom or an optionally substituted alkyl or phenyl radical.

b / the remainder "(^ Η ₂ ) πίη rS (0? _m 2-XR ₁ q, where it represents an integer from 0 to 4, ^ 2 Represents an integer from 0 to 2 and X represents a single bond or -NH-,

-NH-CO-, -NH-CO-O-, -N = CH-NR ₁₃ , -NH-CO-NH- and θ and R _3, same or different, represent a hydrogen atom, a linear or branched alkyl or alkenyl C 1 -C 6 -cycloalkyl, optionally substituted phenyl or benzyl, further pyridyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl, C 1-6 alkyl, an alkenyl, alkoxy or alkylthio group, wherein the sulfur atom is optionally mono- or dioxidated, each of which linear or branched and having up to 6 carbon atoms is optionally interrupted by one or more heteroatoms selected from the group consisting of sulfur, oxygen or nitrogen, and optionally substituted,

d.) a phenyl, benzyl radical and a phenylthio group, wherein the sulfur atom is optionally mono- or dioxidated, radicals which are optionally substituted,

R> R e _g / radicals -CO-N <'and N _{<7 from} y' R ₉ wherein ^the R Bucl. 3 R y or R _g and R _Q, same or different, are selected from

- a hydrogen atom,

- amino acids,

- alkyl and alkenyl radical having up to 6 carbon atoms, optionally substituted,

- phenyl, benzyl and phenethyl, optionally substituted,

the residue -fCH ₂ 7 _ml ^{with 0 0} m2 2 m 2 ^X 10 ^R 10 ' ^{as defined} above, or R 8 and R 8. or. R _g and R each forming with the nitrogen atom to which they are attached, a monocyclic radical containing 5, 6 or 7 ring atoms or a residue of the same or different fused rings with 8-14 ring atoms optionally containing one or more further pharmaceutical heteroatoms selected from oxygen, nitrogen and sulfur atoms optionally substituted by one or more radicals selected from halogen, hydroxyl, nitro, alkyl and alkoxy of up to 6 carbon atoms, amino optionally substituted by one or two of the same or different alkyl radicals having up to 6 carbon atoms and phenyl, or R _g and R, identical or different, represent an acyl radical, or one of R _g and R is carbamoyl, alkoxycarbonyl or benzyloxycarbonyl radical, or R _g and R ^ taken together with the atom the nitrogen to which they are attached, the phthalamido or succinimido moiety, f / the residue -SSR ₁₂ > where R ₂ ^is as defined for R ₂ or R 3 in para and a to e) except for amino and alkoxy, provided that at least one of R ₂ and R 2 is an optionally substituted alkoxy or - (CH ₂ ) _ml -S (O) _m 2 ^{"x" R} io ^st s ^SAIET defined meaning.

Rf. is selected from the residue "^^^ m1 ~ 0 ^{In light} zwitterionized defined meaning, halogen atoms, nitro * radical, radicals - (CH?) _m -COOR _{1 4,}

- (CH ₂ ) 1 -sCONHR ₄ , -CN, wherein m ₁ is as defined above, -SO ₂ NH-SO ₂ , -R ₁₄ , -NK-SO ₂ -R ₁₄ , -PO 2 R,

-NHsSCy-CF ₂ -SO ^, and "N = C (R ^) - N (0¾) _2, - (0¾) _{m1 -SO-4,}

-CO-NH-OR ₁₄ , -CO-NH-NH-SO ₂ CF, -CO-NK-SC-R ₄ -ch ₂ so ₂ nhco-r ₁₄ , -ch ₂ conh-so ₂ r _{1 4} , -nhso ₂ nhco-r * ₄

-NKC0NHS0 ₂ 7 R _14, -CONHSO ₂ NR ₁₄ R _15, -SO ₂ NHCONR ₁₄ R _15, -SO ₂ N (R _u) OR _15, -SO ₂ NHSO ₂ R _14, -SO ₂ NHPOfR _{14) 2,} - C0NHP0 (R ₁₄ ) ₂ , SO ₂ NHCN, -SO ₂ NHCOR ₁₄ , -SO ₂ NHSO ₂ NR ₁₄ R ₁ -SO ₂ NHSO ₂ NfGH ₂ CH ₂ ) ₂ Y, -NHSC 4 NHSO ₄ , -NHSC 4 NHPO ₂ ^ j, -NSSO ₂ R _14, 'DB _i4 COGO ₂ H, -S0 ₂ NHG0 ₂ R _4, wherein R .has higher above and R ₄ and R, the same aleboírôzne, are H, 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, wherein all alkyl, alkenyl, cycloalkyl, alkylthio, phenylthio, alkoxy, phenyl, benzyl radicals are optionally in

disubtituované; 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;

amine, mono and dialkylamino, carboxy, free, in salt or esterified, haloalkyl, alkylthio, haloalkythio, haloalkoxy, phenyl, pyridyl, benzyl, phenethyl, benzoyl, phenoxy, benzyloxy, phenythio, carbamoyl, acyl, acyloxy and tetrazolyl, all products of formula I are in all possible isomeric racemic, enantiomeric and diastereomeric forms, as well as addition salts of the products of formula I with mineral and organic acids or with mineral and inorganic bases, consisting of the compound of formula II

// (II) wherein R * ₁ , R * 2 ^and R * 3 are as defined above for R ₁ and R ₂ , respectively. R ^, resp. R 1, and where optionally reactive groups are optionally protected, is reacted with a compound of formula III

Xi \

X 2 (III) wherein Hal represents a halogen atom, B represents a boron atom and X ₁ , X ₂ are such that either X ₁ and X ₂ , the same or different, represent a hydroxyl alkyl or alkoxy radical of up to 6 carbon atoms, phenyl or phenoxy, or X - with X - form with the boron atom to which they are bound / in a cycle selected from the group consisting of:

wherein X 3 represents a hydrogen atom or up to 4 carbon atoms, to give the product of formula IV an alkyl radical

(IV) wherein R _1, R 2 ^{»R #} 3> ^X 1» ^{E X} 2 ^{and m} ^ ^{u reens wherein} the product of formula IV is reacted in the formula above, the product

R '4 (V) wherein X 1 represents a halogen atom, alkoxy, triflate or -O-SO 4 F and R 4 has the meaning given above for which optional functional groups are optionally protected, to give the product of formula I

which, if desired and necessary, undergoes one or more of the following reactions in any order:

a) removing protecting groups that may carry protected reactive groups, b) converting to a salt with a mineral or organic acid or base, c) esterification; d) saponification of the ester group, e / conversion of the cyano group to acid functionality, f / reduction of the carboxy group to an alcohol group, g / conversion of the alkoxy group to a hydroxyl group, h / oxidation of the sulfur-containing group to the corresponding sulfoxide or sulfonic acid groups i) converting a sulfoxide or sulfone group to the corresponding sulfoximine group,

j) / conversion of the nitrile residue to tetrazole, k / resolution of racemic forms into individual products,

1) conversion of the carboxyl radical to a carbamoyl radical, m / conversion of the carbamoyl radical to a nitrile radical, the products of the formula I thus obtained being in all possible isomeric racemic, enantiomeric and diastereomeric forms.

In the above-defined residue -ÍCHg) S θ where m is different from the L, a (CH _{2) m1} defined alkylene radical such as methylene, ethylene, n-propylene or n-butylene, and in particular when when m = 0, 1 or 2, the residue (CHg) represents a single bond, respectively. a methylene residue and an ethylene residue, respectively.

The values of ^ -S ^ θ-XI that can not exhaustive examples _{of the} mentioned radicals -S0 ₂ -NH-, -S-C-NH-CK ^.

-3Ο ₂ -ΝΗ-Ο? ₃ ,

-S0 _{of the} GH-NH-G, H 2 O 2

CHO-Soo-NH

-CH ₉ -SO ₂ -NH-C ₆ H ₅ , -5O ₉ -NK-CO-NH-CH ₃ , -NK-CO-NK-v -So-NH-CO-NH-CK. , C _r C

-SO-NH-CO-NH-G ^,

-Sd.-NH-CO-NH-D,

-S0 _the -NK-C0-NL-CF.,.

J 2 2 c j '2 wherein D represents phenyl, pyridine or pyrimidine

the remainder, -3O ₂ -MH-G0-NH-CH ₂ - ((JV-VSO ₂ -isS- = GO-1H-OH ₂ -CH ₂ -CH ₃ ,

-SO ₂ -NK-CO-NH-CH = GH-GH, -SO ₂ -xNH-CO-NH-CH ₂ -C = CH, wherein A and B, A 3 are the same or different are selected from the group consisting of a hydrogen atom, a phenyl, pyridyl and pyrimidyl radical,

-S 0 ₉ -NK-C 0-NH-GH _y -GK _?

-so ₂ -nh-co-nh-ce ₂ -ξ

N · • M '# _

-SO-NK-GO-NH-GH _{2 n} - &gt; ^X N = /, where n = 1 or 2

In the products of Formula 1 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 especially 1-outenyl or pentenyl,

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

examples of alkyl radicals interrupted by one or more heteroatoms include methoxymethyl, methoxyethoxymethyl, propythiopropyl, 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 formyl, acetyl, propionyl, butyryl or benzoyl, but also pentanoyl, hexynoyl, acryloyi, crotonoyl or carbamoyl,

the term amino substituted by one or two alkyl radicals refers preferably to radicals in which the alkyl radical or radicals are selected from the radicals as defined above, such as, for example, for a monoalkylamino radical methylamino or ethylamino or for dialkylamino, dimethylamino or further setylethylamino,

- 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 cycliopropyl, cycloethyl, cyclopentyl or cyclohexyl,

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

- 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, pyridimidinyl, pyridimidinyl, pyridimidinyl, pyridimidinyl thiadiazolyl, oxazolyl, furazanyl, pyrrolinyl, such as delta-2-pyrrolinyl, imidazolinyl, such as delta-2-indiazolinyl, pyrazolinyl, such as delta-β-pyrazolinyl, as well as isomers at the heteroatom position but heteroatoms which may have these residues contained, such as isothiazolyl or isoxazolyl,

the term fused-ring radical denotes saturated residues, for example 1-oxaspiro [4,5] decyl, tetrahydrooyran-2-spiroeyklohexyl, cyclohexanspiro-2 '- (tetrishydrofuran) or -1,10-daazaanth-4-yl, or unsaturated residues such as bensothienyl, naphtho [2,3-b] thienyl, indenyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, benzopyrrolidyl, benzimidasolyl, isoquinolyl, quinolyl, thiazolinyl, naphthyridinyl, quinolazolinyl ester, quinolazolinyl , carazolazolyl, t -carbinyl, acridinyl, isoeninyl, indolinyl, isoindolinyl, or further fused polycyclic systems consisting of heterocyclic monocycles as defined above, such as furo [2,3-b] pyrrole or thieno [ 2,3-b] furan,

the term haloalkyl radical 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 bromomethyl, trifluoromethyl, trifluoromethyl or further pentafluoroethyl,

- 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 other pentafluoroethylthio,

- haloalkoxy 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 still pentafluoroethoxy,

the term carbamoyl radical also denotes carbamoyl radicals, N-monosubstituted by lower alkyl, such as _: N-methylcarbamoyl, N-ethylcarbamoyl, N, N-di (lower) alkylcarbamoyl, such as Ν, Ν-dimethylcarbamoyl, N, N- diethylcarbamoyl, an N- (lower, hydroxyalkyl) carbanoyl group such as N- (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl, carbamoyl (lower) and 1 alkyl such as carbamoylmethyl, carbamoylethyl,

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

In the products of formula Tav below, the alkyl, alkenyl, cycloalyl and phenyl radicals which may be or are R 1, R p, P and R 3 may have the meanings given above for these radicals and may be unsubstituted or substituted by one or more radicals. several identical or different substituents as defined above. P ₉ and R 6 may, for example, represent an alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl or arylsulfonyl group, but also a cycloalkylthio group such as cyclohexylthio,

the terms alkylthio, alkylsulphinyl 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, but may also be propylthio, isopropylthio, butylthio, tert-butylthio, tert-butyl. butylthio, isopentylthio or isohexylthio or the same radicals in which the thio group is oxidized to a sulphinyl or sulphonyl radical,

According to the meaning of m ^, and - (CH, “S (O) π2 ^- ^ ^ 1 0” 2 residues: phenylthio, pyridylthiolylthio, N-methylimidazolylthio, the thio group oxidized to the salt in the residue U and R ^ also represents these or Pyrimidylthio, imidazole as well as residues in which a finyl or suiphonyl group, such as phenylsinyl or phenylsulfonyl.

Examples of such compounds are those substituted with one residue, for example benzyl, and those substituted by pyridyl dylmethyl, with, of course, some or more phenyl ifenylmethyl, triphenyimethyl, and those, e.g. an alkyl or butyl radical, such as in the same meaning ethyl, may be a phenethylene radical.

Examples of substituted alkenyl include radicals substituted with one or phenyl or pyridyl radicals, such as the above, wherein the alkyl radical is replaced by aikenes com, e.g. phenyivinyl or phenylallyl.

The above-mentioned carbamoyl residues and amino groups are mainly mentioned.

and

means radicals in which two radicals, identical or different, are selected from the group consisting of hydrogen to form amino, alkyl radicals as defined above to form a monoalkyl or dialkylamino group in which they are linear. or branched alkyl radicals contain 1 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.

Among the substituted carbamoyl radicals, N-mono (lower alkylcarbamoyl, e.g., N-methylcarbamoyl, N-ethylcarbamoyl, N, N-di (lower) alkylcarbamoyl, e.g., Μ, Ν-dimethylcarbamoyl) may be mentioned as substituted carbamoyl. N- (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl, lower carbamoylalkyl, e.g. carbamoylmethyl, carbamoylethyl, phenylcarbamoyl, pyridylcarbamoyl, N-methylmethyl-N-phenyl, .

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

Among the residues - (CH ₂ ) _n -X-? _{1 Q} , which may represent R <,

Ηγ, R _g and R g, which may be mentioned in particular, radicals -NH-SC-CH ^ -NH-SO ₂ -C ₆ H _-NH-SO2 -GF _3, -NH-CH ₂ -SO ₂ -NH -g ₆ h ₅

-Π

O-NK-SO ₂ -C ₂ H ₅ , -co-nk-so ₂ -ch ₃ , -co-nk-so ₂ -ch ₉ -c ₅ h ₅

Heterocycle that may be formed by Rg and R? or R 8 and R ₈ , is preferably saturated.

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

The acyloxy moieties which may be selected, in particular, may be R _c and R _c ,

With an acetyl, propionyl, butyryl, pentancyl and carbamoyl radical.

When R _c or R _{c is an} alkoxycarbonyl radical, c is preferably tert. butyloxycarbonyl.

The carboxyl residues of the products of formula (I) may be in the form of a salt or esterified with various groups known to those 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) aminooneoane, ethanolamine, pyridine, picoline, dicyclohexamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine.

as esterifying compounds, alkyl radicals to form alkoxycarbonyl groups such as nontoxycartones 1, ethoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, these knife radicals being substituted by radicals selected from, 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, fumaric, succinic, tartaric, citric, glyoxyl, aspartic, ascorbic, with alkylmonosuifonic acids, such as methanesulfonic acid, ethanesulfonic acid, prooansulfonic acid, with slkyidisulfonic acids, such as methanedisulfonic acid, ethanedisulfonic acid, aryimonosuifonic acids, and aryimonosuifonic acids, such as methionosulfonic acid, such as benzenesulfonic acid.

If both residues and? represent a sulfur or a group aikyltio · phenylthio optionally oxidized, and wherein _the R 3, the same or different, are preferred: p> £ j ... ftdttktaini invention in particular the products of formula 1, in which the sulfur of the oxidation state of the same co lor oredovsetedsn from residues R _n and R predscs—

One preferred product of the present invention wherein the products of formula I 'is the above-mentioned sulfur group, optionally oxoic acid, and the other one of the radicals R @ 1. and R 1 is preferably alkyl, alkoxy, carboxy, free, in the form of a salt or esterified or phenyl, optionally substituted with one or more substituents as defined above.

Among the suitable products according to the invention are, in particular, products of formula 1, wherein R ₂ represents a sulfur residue.

In particular, R 2 and / or R 6 may represent alkylthio or alkenylthio radicals, optionally substituted with one or more radicals selected from the group consisting of formyl, hydroxyl, alkoxy, acyloxy, carboxy, free, in salt form or esterified, amino substituted with amino, carbamoyl , substituted carbamoyl, alkylthio, phenylthio, pyridinyl, pyrimidinesL, phenyl.

Among the substituents which may be carried by the radicals R ₉ and R 8, in particular the amino group and the carbamoyl may be substituted by one or two residues and the above-mentioned amino acids.

Substituted amino groups and carbamoyl radicals which can carry R R and R a radicals _. , may also formed hezeroeyklus, for example of the type described above.

R _a and R, it may in particular further represented alkylthio substituted by one or niexoikými naxogénu atoms such as chlorine and fluorine. It is possible to mention, for example, the remainder - S - From - - - -

_the heights r and R, may t3kto oredstavovat following the ^ radicals wherein n ^ n ^ n, identical or different, may have a value of 0 to 2: -SO-uH ^, -SO ^ ii, o-^ · mH , * Sf ~ S ”^ 4»

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

-S- (CH _2? CH = CH _{full-FCH 2) 4} -X ₉ wherein X is H, OH, cyclohexyl, pyridyl, phenyl, ERO, COOH, NH ₂ or

IN'

N í

rr

Residues R ^. and R 6 may also represent, in particular, the following radicals: -GOOH, -GO 1, X 1, X 2, -NH ₂ ,

-OMe, OEt, -GH = GH-COOH, tetrazolyl,

-C CCCH3> -CH 2 I.

COOMe

COOH COOII

C - CH 2 -

in all isomeric forms, cis-trans isomers

-CH-NH-C

I

COOH

\

0x5

NH-CH-COO-Xfe,

-NH-COO-X5, where Χς represents an alkyl or aryl radical,

Radicals _R2 and R can be in particular a radical

-CO-NHΝ '

The products of formula I, therefore, are in particular those wherein the ³ R 3 are as defined, and especially products in which R represents the above defined aikyitioskupinu, optionally substituted, or alkoxy, such as methoxy, a is carboxyl in aqueous form, in the form of a salt, ester or amide such as, in particular, -GOOH, -COO-methyl, -COo-ethyl, -CONH _2, or

N'-N h \ ^x

-CO-NII-v / N

N

I

H

The preferred all of cyano, and a defined meaning of R ₄ is a group, may be mentioned p _-tCH? ) _Ail -SOp-XR ₁ with t θ separately · radicals -S0 ₂ -NK-C0-NH -CH _the Redos

1-CO-NE-GH ₂ -GH _y

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

SD ^ SOB

fla>

where.

R 1 represents a linear or branched alkyl or alkenyl radical having up to 4 carbon atoms, ^R 2a ^{and K} 3a ^equally or differently are 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 radicals being linear or branched and containing up to 6 carbon atoms, phenyl, benzoyl, phenylthio, where the atom the sulfur is optionally mono- or dioxidated, all of which are optionally substituted with one or more of the same or different radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, cyano, nitro, formyl, alkyl and alkoxy

... with up to 4 carbon atoms, phenyl and carboxy group in salt form or esterified with (-CO-N) residues

and -N <

8a

R

7 wherein one of R _a, R _a, R _a and R _a, the same or different, are selected from H, amíno21 forms, and also their addition salts with mineral and organic acids or · mineral and organic bases consisting of in that the products of formulas II, III and IV in which R * ₁ , R * ₂ → R and R * 4 have the meanings given above for R @ 1 _and R @ 2 are respectively used for the preparation described above. R2 _and > R 6 ⁱⁿ which 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 &amp;

where

R, ^k 1b

3b

R

2b represents an alkyl radical of up to 4 carbon atoms, represents a hydrogen atom, formyl, acyloxy, optionally substituted alkyl or alkoxy or carboxy, free, in salt form or esterified with an alkyl radical, represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkyisulfonyl or alkylsulphinyl optionally such that, in all the radicals which R @ 1 and R @ 2 _b may represent, the alkyl radicals and alkoxy groups contain up to 6 carbon atoms and the phenyl radicals are optionally substituted by one

V v

- or by several radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, acyloxy, carboxy, free, in salt or esterified form, phenyl, pyridyl, tetrazolyl, alkyl and alkoxy of up to 4 carbon atoms and optionally substituted with alkoxy of up to 4 carbon atoms,

R _b is cyano, carboxy, a free, salified or esterified, radical -SO ₂ "X _b" R ob 'of which is, radicals -NH-, -NH-CO-, -NH-CO-O-, -N = CH-NR ₁ -j _b > -NH-CO-NH- or a single bond and ^R 10b ^and b * ^equally or differently represent hydrogen, methyl, ethyl, propyl, vinyl, allyl, pyridyl, phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuranyl, wherein said products of the formula are in all possible isomeric racemic, enantiomeric and diastereoisomeric salts, and also organic isomers, and also isichloroisomeric salts. mineral or organic bases, consisting in the fact that for their preparation as described above are used the products of formulas II, III and IV wherein R _1, R _2, ^ * 3 ^N * ⁴ mA TI values, the above ^ 4.b ' ^{in which reactions} resp. R ^ _b > respectively for R _1b resp. R _2b , active groups optionally protected.

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

(Iu>

where it represents, an alkyl radical of up to 4 carbon atoms, R 1d represents a carboxy group free, in salt form or esterified. a linear or branched alkyl radical having up to 4 carbon atoms, formyl, acyloxy, an alkyl having up to 4 carbon atoms, optionally substituted by hydroxyl.

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

R _d is a radical -SO -NHg, -SO-NH-CO-OR ^

-SO _q -N = CH-NR _1. ^ S0 or _a NH-C0-NH-R. _n wherein R ,, _n, 2 and 13 d 2 from the ship _T ^ 1 ^ θ 13d ^Γ0νη3 or different, are selected from hydrogen, methyl, ethyl, n-propyl and propenyl, the said products of formula I, _d being in all possible isomeric racemic, enantiomeric and diasteroisomeric forms, as well as their addition salts with mineral and organic acids or with mineral and organic bases, characterized in that products of formulas II, III and IV in which R *, ^R * 2> ³ have the meanings given above for R _1d and R _1d , respectively. Rg ^, respectively. R ^, resp. In which the reactive functional groups are optionally protected.

Another object of the present invention is the above-mentioned process, wherein the starting product is a product of formula II wherein R @ 1 represents an alkyl radical of up to 4 carbon atoms, R @ 3 represents a carboxy group, free, in salt or esterified by linear or branched alkyl of up to 4 carbon atoms, formyl, acyloxy, alkyl of up to 4 carbon atoms, optionally substituted with hydroxyl, B. represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl or alkylsulfinyl, wherein the alkyl moiety contains, up to. 4 carbon atoms, and the reactive functions are optionally protected and a product of formula V, wherein R ^ is a radical -SO -NH ^ -, -SO _{2 -NH-CO-1QD,} -S0 ₂ -N = NR _1-GH or -SO-NH-CO-NH-R _to which R ₁ and R the same or different: _for .SU selected from hydrogen, methyl, ethyl, n-propyl and propenyl, in which reactive. the functional groups are optionally protected.

The present invention furthermore relates to a process according to the above-mentioned process, wherein the starting product is a product of formula II wherein R @ 1 is alkoxy or carboxy in the form of a salt or esterified and R @ ₂ is alkylthio or phenylthio; optionally oxidized in the form of a sulfoxide or sulfone, wherein the alkoxy, alkylthio and phenylthio radicals are optionally substituted by one or more radicals selected from the group consisting of atoms, halogen, alkyl or alkyl of up to 4 carbon atoms, trifluoromethyl, amino , mono- or dialkylamino, cyano, acyl, acyloxy or phenyl.

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-L, 2 * -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- (methylthyrr) -1H-imidazole-5-carboxylic acid,

- 4 * -C [2-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- [12'-carboxy- (1,1'-biphenyl) -4-yl] methyl] -4- (ethylthio) -1H-imidazole-5-carboxylic acid,

- 2-butjrl acid-1 - C [2-carboxy-* (i., 1 ^# -biphenyl) -4-yl7metyl] -4- (phenylsulfonyl) -1H-imidazole-5-carboxylic acid,

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

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

- ethyl 2-butyl 4- (methylthio) -1- ^[# £ 2 - ff ((propylamínojkarbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-methyl-YLJ 1J-1 H-imidazol-5 carboxylate,

- 2-Butyl-4- _{(methylthio>)} -1 - ££ * 2 - ((((propylamino) carbonyl) amino) sulfonyl) - (Ί, 1 &apos; -biphenyl) -4-yl Ij methyliodide 1H imidazole-5-carboxylic acid,

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

The invention furthermore relates in particular to the above-mentioned process for the preparation of the 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-imide az-5-carboxylate,

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

- dipotassium salt of 2-butyl-4- (methylthio) -1 - [[2

- ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole-5-carboxylic acid.

In preferred conditions for carrying out the invention, the product of formula III is such that Hal is preferably a bromine atom, but may also be a sulfur or iodine atom.

The reaction of the product of formula III with the product of formula II can be carried out in a solvent such as dimethylformamide, tetrahydrofuran, acetone, acetonitrile, dimethylpropylurea, dimethoxyethane or dimethylsulfoxide, at reflux of the solvent or at room temperature, preferably with stirring: such as sodium or potassium hydride, methylate, ethylate. or sodium or potassium tert-butylate, or preferably sodium, potassium or cesium carbonate.

Reaction of the thus obtained product of formula IV with a compound of formula V as defined above, wherein it represents preferably. the bromine, iodine or chlorine atom may be carried out in a solvent such as a mixture of toluene and ethanol, or further in dimethylformamide in the presence of a weak base such as sodium, potassium or cesium bicarbonate, preferably in the presence of a catalyst such as tetrakistriphenyl palladium osphine or a mixture of triphenylphosphine and palladium diacetate or tetrakistriphenylphosphine nickel.

Other catalysts include, for example, nickel, palladium, ruthenium or platinum complexes and preferably palladium complexes: bis (dibenzylideneacetone) Pd in the presence of PPh-, tris (dibenzylideneacetone) Pd, trans-benzyl (chloro-bis-triphenylphosphine) palladium, Pd OA OAc--trisfurylphosphine, Pd (OAc) 2 -triphenyl phosphine, tetrakis (triphenylphosphine) palladium, 1,4-bis (diphenylphosphino) butane Pd, CL, Sr or OAc, 1,3-bis (diphenylphosphino) propane Pd, Cl , Br or OAc, 1,2-bis (diphenylphosphino) ethane Pd, Cl, Br or OAc, 1,1-bis (diphenylphosphino) ferrocene Pd, Cl, Br or OAc.

In the reaction of the product of formula IV with the product of formula V, they are used. solvents. pre-degassed, for example by bubbling argon.

The various reactive functional groups which may carry some of the above-mentioned reactants may, if necessary, be protected: for example, hydroxyl, acyl, free carboxyl residues and poured amine and monoalkylamino, which may be protected by the respective protecting groups. .

Calculation of the various protecting groups available is possible; can be found, for example, in Patent 3F 2,499,995.

The following are non-exhaustive examples of the protection of reactive functional groups:

the hydroxyl group is. can be protected, for example, with alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, 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 with n-butyls in the form of cyclic or acyclic ketals such as dimethyl or diethyl ketal or ethylenedioxyketal,

acidic functions of the above products are possible if;

with.

if desired, amidify with a primary or secondary amine, for example in methylene chloride. in the presence of, for example, 1-ethyl-N-dimethylaminopropyl hydrochloride. carbodiimide at room temperature,

The acid functions can be further protected, for example, in

In the form of esters formed by readily cleavable esters, axo is the benzyl ester or the tert-butyl ester known in peptide chemistry,

The obtained products of formula I .aeubvV 'v 1, Λ p, Λ -s &

products of formula I.

in accordance with the well-known feature, they either form or do not form

If the products of Formula 1 do not represent the products of Formula I, the knife was, if necessary or desirable, subjected to the abovementioned reactions to give the products of Formula I.

Removal of protecting groups, such as those mentioned above, may be accomplished under conditions known to those skilled in the art, in particular by acid hydrolysis using an acid such as hydrochloric, benzenesulfonic

p-toluenesulfonate, formic or trifluoroacetic acid, or else by catalytic hydrogenation.

The phthalamido group may be cleaved with hydrazine.

If desired, the above products may be subjected to salt-forming reactions, for example with a mineral or organic acid, by conventional methods known to those skilled in the art.

The above product may, if desired, be subjected to a salt formation reaction with a mineral or organic base or esterification, if desired, to a carboxy group: these reactions may be carried out by conventional methods known to the person skilled in the art.

The possible conversion of the ester function to the acid function of the above products may, if desired, be carried out under conventional conditions known to the person skilled in the art, in particular by acid or alkaline hydrolysis, for example sodium or potassium hydroxide in an alcohol such as methanol or hydrochloric or sulfuric acid.

If desired, the cyano groups of the above products may, if desired, be converted to acidic function under conventional conditions known to the person skilled in the art, for example by double hydrolysis carried out in an acid medium such as a mixture of sulfuric acid, glacial acetic acid and water. parts or in a mixture of sodium hydroxide, ethanol and water at reflux.

The optional free or esterified carboxy groups in the above products may, if desired, be reduced by methods known to those skilled in the art to alcoholic function: in the case of esterified carboxy groups, lithium and aluminum hydride may be used in a solvent such as tetrahydrofuran or poured dioxane; etyláter.

v ^v

In particular, boron hydride may be used for the free carboxy groups.

optional alkoxy groups of the above products, led to the hydroxyl group known to one another, for example bro is, for example, methylene chloride, pyridine house or further an acid such as, in particular, methoxy, can be, if desired, hydrogenated in water or acetic acid under usual conditions, borohydride in the solvent, and hydrobromide or hydrochloride hydrobromide or chio refxux.

Optional sulfur-containing groups in the above products can, if desired, be converted into the corresponding sulfoxide or suiphone groups under conventional conditions known to the person skilled in the art, for example with perkysines such as peracetic acid or m-chloro benzoic acid, or ozone, oxone, sodium periodate in 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 reagents such as, in particular, peracid.

The sulfone function can be obtained by mixing a product containing an alkylthio or arylthio group with an excess of a reagent such as, in particular, a peracid.

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 those skilled in the art, such as manganese oxide treatment, to form aldehydes or an acid-leading Jones reagent.

The optional nitrile function of the above-described products may, if desired, be converted to tetrazole in common conditions known to those skilled in the art, such as cycloaddition of a metal azide, such as a alkyl alkynide, of the descent described to the nitrile group, as disclosed. article in J. Orgsnometallic Chemistry 33, 337> 971, lozozima, Ξ. and d.

Optionally, the optically active axupins in the products of formula I may be prepared by cleavage of the recemic mixtures by conventional methods known to those skilled in the art.

The products of formula I are known and are described in particular in European patent applications no. 0 465 3-63 and 0 pC3 162.

The products of formula 1 prepared by the above process, as well as their acid addition salts 3, have interesting pharmacological properties.

Thus, the products are endowed with angiotensin II receptor 2 antagonist properties, in particular, being inhibitors of the effects of angiotensin II, especially vasoconstrictive effect, and also a trophic effect at the level of myocytes.

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 the 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 primarily as medicaments in the treatment of arterial hypertension, cardiac insufficiency, endocrine deficiency and prevention of post-angioplastic restenosis.

It can also be used in the treatment of certain gastrointestinal and gynecological disorders, and in particular for the relaxing effect at the delohy level 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 either the buccal, rectal, parenteral or topical routes for topical application to the skin or mucous membranes.

These compositions can be solid or liquid and can be found in all pharmaceutical forms commonly used in human medicine, such as ointments;

And for the "* byčajné tablet _(or drsžé, capsules, suppositories, talons, ointments, creams, gels and aerosol preparations: prior of vujú the usual methods. The active ingredient may be formulated in carriers conventionally used in these pharmaceutical compositions such as talc, gum gum, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty bases of animal or vegetable origin, para-derivative derivatives, glycols, various coating agents, dispersing or emulsifying agents, preservatives.

The usual dosage, varying according to the product to be 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 II are known and can be prepared, for example, according to European ostent EF 158 950.

In particular, the starting products of formula (II) may be prepared by a sposoo consisting of formula (IIa) and reduction.

HO - C = N (R 1, where R * 2 is as defined above) is treated with a reducing agent to give the corresponding amine of formula II.

wherein H is as defined above which is treated with a compound of formula II.

R, -C (Hal) II- ^L-

O is as defined above to give the product of formula (I ')

- 33 .0 = N

G - NHGH '

Wherein R 1 and H 2 are as defined above, which are reacted with compounds of formula II

R @ ₃ -YH < ^T - ^T e>

wherein R * is as defined above and Y represents a sulfur or oxygen atom to give the product of formula II

NH, me onroo:

(11J

R 1 and Y have the same meaning as above, which is followed by elimination reaction to produce t, x, y.

of formula n, kt;

Then, if several of the following responses are needed in the academic class, it is necessary to have one or more ooros:

a) cleavage of the unreacted reactive functional groups, groups which can be protected by reaction with a mineral or some organic acid or base to form the corresponding salt, c) esterification of the acid function, d) saponification of the ester function to an acid function, conversion of the cyano group to an acid function g / reaction of conversion of an alkoxy group to a hydroxyl function, h / oxidation of a group containing a sulfur atom to the corresponding sulfoxide or sulfone function, i) oxidative alcohol functions to an aldehyde or esph / acid function, j / conversion of the nitrile function ns tetrasol function, k (resolution), racemic forms to the individual isomers, 1 / conversion of the carboxy group to a carbamoyl residue, m / conversion of the carbamoyl residue to a nitric residue, the products of formula II thus obtained are in all possible isomeric, racemic, enantiomeric and diastereoisomeric forms.

Under preferred conditions for carrying out the invention, the above process is carried out in the following manner:

- reduction of formula ΖΖ _Λ to give a compound of formula ³ ,

II can be carried out by conventional methods known to those skilled in the art, such as, for example, aluminum amalgam, prepared under conventional conditions, such as the action of mercury chloride on aluminum; the reaction is carried out in a solvent such as, for example, ice-cold tetrahydrofuran or toluene, preferably at a temperature of? 0 ° C;

- the addition of the product of formula IZ ', wherein W represents a bromine atom or preferably a chlorine atom, to the amine of formula ZZ ^ may be carried out by methods known to the person skilled in the art, for example in the presence of a base such as pyridine or triethylamine; the reaction is preferably carried out: at a temperature of about P G. It is also possible to obtain a compound of formula ZZ by subjecting the compound of formula ZZ to axially;

and the acylation in the presence of anhydride, such as acetic anhydride, butyric acid or valeric anhydride, by hydrogenation in the presence of tune or zinc or other sodium dithionate.

- addition of a sulfur derivative of formula ZZ to an amide of formula ZZ

O is accomplished, for example, by dissolving the amide of formula ZZ _H in a solvent, e.g., in an alcohol such as ethanol or methanol, and thereafter. by sequential addition of a base such as triethylamine and compounds of formula ZZ preferably with stirring and at room temperature, e - ··

the cyclization reaction of the compound of formula 11 may be carried out in a solvent such as, for example, dichloromethane, dichloroethane or chloroform; the reaction may be carried out, for example, in the presence of phosphorus pentachloride, previously dissolved in dichloromethane, at a temperature of about -75 ° C in the presence of a base such as pyridine or dimethylaminopyridine; the reaction can be carried out with stirring at room temperature.

The product of formula II thus obtained may be subjected to one or more reactions which may be carried out under the same conditions as those described above for the products of formula ca I.

The compound of formula II may be, for example, ethyl isonitrone and cyanoacetate, which may be present, for example, in the form of a commercial product of LANCASTSR under the designation S93C.

The compound of formula III as defined above may be obtained by reacting the compound in equilibrium with its trimeric form of formula 71

B C OH> 2

t.ol-S

I o

FROM 1 \ 1 / WITH and 1 tol

Table

I o

(71) where

B is as defined above and tol represents a tertiary moiety with an appropriate alcohol, such as methanol, ethanol, or butanol, or with a mole such as propanediol, ethylene glycol or dimethylpropanedio, to give a compound of formula VIIa.

(III) wherein 3, X 1 and X ₉ are as defined above, which are reacted with a halogenating agent to give the product of formula III.

A process for the preparation of the product of formula (I) above is obtained by obtaining a product of formula (IV) by reacting a compound of formula (VI) with a halogenating agent mentioned in H, H. SNYDER et al.

1953 to give a compound of formula: P, o

u. Ann. Jnem. boe, neha. with its trimeric form of the formula

Hal lial

Lol-S'I

ABOUT

Tol-S-Hal

I

ABOUT

I t-ol I

Ha 1 where S and toi are as defined above 2 Hal represents, a halogen atom, preferably a bromine atom, this compound of formula VI * is reacted with a compound of formula II to give a product of formula IV, then the synthesis is continued

co ₂ v

SCH ·

SCH

co ₂ in the process to form the product of formula I _o

These reactions can be carried out under the above conditions and as described in the Examples.

As mentioned above, the process for preparing the products of formula I can be carried out by reacting the product of formula II

where P. * ₁ , R * _o and R * are as defined above, the duct of formula ITT corresponds to formula III _and or o ·

Hal

wherein Kal and b are as defined above to form an oroduct of formula 17 corresponding to formula IV

where H ', H'j, r'j the product of formula and B are as defined above, then IV _o is reacted with a compound of formula V

Hal

R 1 - (wherein J 1 and R 2 are as defined above).

an example of such a preparation of the product of formula (I) above is given in Example 1.

In the above process, it is possible to react the product of formula (11) with a product of formula (III) corresponding to formula (III).

wherein Kal and rto are as defined above to give the product of formula IV corresponding to the pattern

R2 '

R '3

(IV J axes of products R, R ₉ , R 8 are as described above, then the product of formula IV or IV * is reacted with the above product of formula V

An example of such a preparation of the product of formula (1) above is given in Example 2.

Such a product of formula I may, if necessary and if desired, be subjected to various reactions to form the other products of formula I mentioned above, in particular saponification. Also, products of formula IV and, for example, products of formula IV _g , IV & They can also be subjected to various reactions to form other products of formula IV.

The invention furthermore relates to novel industrial products and, in particular, to intermediates necessary for the preparation of the products of the formula I, for the benefit of the above formulas IV and V.

Some of the products of formula III are also novel and therefore form the subject of the invention.

In particular, as new industrial products, the invention relates to the following products:

2-iodobenzenesulfonamide

2. 2-Iodo-N - [(propylamino) carbonyl] benzenesulfonamide

4.a 2- [4- (Bromomethyl> phenyl) -5,5-dimethyl-1,3,2-dioxaborolan

4b 2- [4- (Bromomethyl) phenyl] -1,3,2-dioxaborolane ethyl 1 - [(4-boronophenyl) methyl] -2-butyl-4- (methylthio) -1K-imidazole-5-carboxylate

6a Ethyl-2-butyl-1- [4- (5,5-dimethyl-1,3,2-dioxaborolan-2-yl) phenylmethyl] -4- (methylthio) -1H-imidazole-5 6b Ethyl 2-butyl-1- [4- (1,3,2-dioxaborolan-2-yl) phenylmethyl] - (methylthio) -1H-imidazole-5-carboxylate (7-4) ( (4 - ((2-butyl-4- (hiethylthio) ') - 5' - (ethoxycarbonyl) -1H-imidazol-1-yl - ((methyl) phenyl) - ((2,2 '- (methylimino) -bis (ethanolato) () - (2 -) - N, 0,0 * -bor

8-Ethyl 2-butyl-1 - ((4- (1,3,2-benzodioxaborol-2-yl) phenyl) methyl) -4- (methylthio-1H-imidazole-5-carboxylate) 9a Ethyl 2-butyl-1- ((4- (4,4,5,5-1-trimethyl-1,3,2-dioxolaborolan-2-yl) phenyl) methyl) -4- (methylthio) -1H-imidazole-5-carboxylate

9b Ethyl 2-butyl-1 - ((4- (1,3,2-dioxolaborolan-2-yl) phenyl) methyl) -4- (methylthio) -1H-imidazole-5-carboxylate.

These products correspond to the following formulas 1 to 9:

in

SCHco ₂ v

5CH ₃

BU \

B co ₂ v

 «ΆώαύΟΒώ & αΛββίααι

where. Z and W, identical or different, represent a hydrogen atom or ^one alkyl radical, in particular methyl or ethyl, and the above-mentioned. products 4, 6 and 9 are designated 4a, 6a and 9a when Z is methyl and 4b, 6b and 9b when Z is hydrogen.

Methods for preparing the above compounds and some of their homologues are set forth in the experimental section.

An example of an embodiment of the invention

Examples of preparation of the products of formula I are given for the purpose of illustrating the invention but do not limit its scope.

CJ

Preparation 1: 2-Iodobenzenesulfonamide (Product 1)

60 g of χ-aminobenzenesulphonamide and 25 ml of sulfuric acid (36 µl) were heated to 60 ° C. 20 g of ice are added and a solution of 1.45 g of sodium nitrite in 4 ml of water is added at 0-5 ° C. The mixture was stirred for 3 hours. at a temperature lower than 10 ° C, then a solution of 3.75 g of potassium potassium in 25 ml of water is added at 5 to 0 ° C.

The mixture is stirred for 1.9 hours and 50 ml of water are added, filtered and washed with water, then the residue is taken up in 50 ml of ethyl acetate, washed with 0.2N sodium thiosulfate solution, then with water, concentrated to give 4 g of the expected oroduct.

Analytical results:

Melting point 197-196

IP fnujoi;

3367, 3255, 1562 cm ^-1

4 *

11 NMP Mass Spectrum: GDGi _{

5.17 fbs, NHp), 7.23 and 7.52 (td, aromatic salts, 2H), 6.08 (i, aromatics, 2H).

with 3.20

263 «—MWMIMBS

- 45 Preparation of 2 t 2-Iodo-N - [(propylamino) carbonyl benzenesulfonamide (Product 2)

4 g of iodobenzenesulfonamide and 40 ml of acetone are mixed. 3.92 g of potassium carbonate are added. The mixture is brought to reflux, 1.46 ml of n-propyl isocyanate is added and the mixture is maintained for 2 hours. na reŕiuxe. It is concentrated, 200 ml of water are added, then 2N hydrochloric acid solution is added to the pH of 3 with cooling of the reaction mixture to about 0 to 5 ° C. Recrystallization from acetone-isopropyl ether gives 4.9 g of the expected product.

Analytical results:

Melting point 2 · 1-212 ~ C TP (nujol) _β 1

3.066, 3366, 1715, 1565, 1539 cm

4H-mass spectrum M 366 JblH. --J

0.82 (t J - ϊ, ϊ, CH - 1 _t 3 H), 1.4p (m, CH 2, 2H), 3.14 (m, CH 3, 2H), 6.39 (t, C ONE) , 1H), 7.29 (dt, J = 11'6, boronates J, 7.54 (td, J = S, 15, boronates), 8.13 (m, boronates), 7.59 (s, SC (1H, 1H).

Preparation of the products 5a, 6'o, 7, 5, 9a and 9b described in U.S. Pat

in the experimental part, it can be schematically represented as follows:

 fiiiÉfnhťWťťťifirŕŕi

tn o

H 'Y

<30

CD

O o λλ

(0 (J * vi * y ^ \ _y in ^ O-O * cz>

H

Ύ

and

S3 = o o u

Vi O y = ^ vh> O ‘

SCHEME

33 o o

vi

H

Ύ

(0

UD

I

OJ p

o o (. U

H 2 · * Y

οΥΆ oooeeiiafiadttEäfe ^.

- 47 Preparation J Ethyl 1 - ((4-boronophenyl) methyl) -2-butyl-4- (methylthio) -1H-imidazole-p-carboxylate (Product 5)

Method 1:

To a mixture of 0.434 g of ethyl 2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate, 5 ml of dimethylformamide and 0.552 g of potassium carbonate is added 0.423 g of acid

4-bromomethylphenylboronic acid (prepared by the method of Snyder et al., JACS 30, 335 (1955)). After 43 hrs. After stirring at room temperature, the reaction mixture was poured into ice water. After stirring for 15 minutes, the mixture is filtered, washed with water and recrystallized from a mixture of cyclohexar and isopropyl ether to give 0.450 g of the expected product.

Method 2:

To a mixture of 9.44 g of ethyl 2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate, 62 ml of anhydrous dimethyiformamide and 10.75 g of potassium carbonate is added a solution of 11 g of 2 '- (4- ( bromomethylphenyl) -1,3,2-dioxabrocrolan in 56 ml dimethylformamide. After 43 hours of stirring, the ori teoiote temperature the reaction mixture was poured into ice science and acidified to pH 2 with hydrochloric ohlo- dt '27 ^1! I 'r *'! ^- -? ---— - .-- 'o -, washes through the water, and dries and gets the net

10.45 .g of expected product.

M.p. 159-170 ° C

IR (aujol) _ 1 £ C <1 0 1 'S - C 1 J rvm • “-D f i t V i>„ · ✓ f ·, · · J- w Ja

Mass spectrum 1074 (trimeric form)

NMR: 3DCl _?

Monemer mixture and trimer doubling - 3 / 4-1 / 4 signals 0.37 and 0., 36 (t GHp JH), 1.32 (m, GH ₂ , 2H), 1.30 (t, 50 ₂ CH ₉₎ CHjh), 1.64 (m, GH _2, 2H), 2,6.0 (m, GH _2, 2H), 2, and O1 2,5j (s, SCH, 3H), 4.25 (q doubled. GO (2H, 2H, 2H, 2H), 5.5 and 5.60 (s,

Annotation PV

Title of the invention

A novel process for the preparation of sulfur derivatives of imidazole and novel intermediates

Products of formula I wherein R 1, R 1, R 1 and R ₄ are as defined in the claims are prepared by reacting a compound of formula II wherein R * ₁ , R * ₂ and R * are as defined in the claims. claims, so. * z wherein Hal is a halogen atom with X, and

Also in the claims, where R is of the formulas

T3 P 7, up, - 3 » ^A ] Claims, which

IN.

The compound of formula III has the meaning given to the compound of formula IV, the meaning given in the reaction with the compound

The products have: angiotensin activity and angiotensin activity

inhibition of ovarian constriction myocytes.

receptors of action.

- 76 Formulas for annotation C I,

II

III, IV, V)

Xz /

CIII) <V>

μβμβββ.

43 N-Cl 2 -Ph, 2H), 7.00 and 7.63 (bd, aromatics, 2H), 7.1 L and 8.12 (bd, aromatics, 2H), 4.93. (m, broad - 0.2H, mobile).

Preparation 4: Ethyl 2-butyl-1- [4- (1,3,2-dioxaborolsn-2-yl) phenylmethyl] -4- (methylthio) -1H-imidazole-5'-carboxylate. (Product 6b)

For 4 hours A mixture of 1,292 g of ethyl-1 - Ĺ (4-boronophenyl) methyl] -2-ethyl acetate is stirred at reflux to remove the water formed.

-butyl-4 '(methylthio) -1H-imidazole-5-carboxylate, obtained in 3', according to Preparation 3, 25 cm @ 3 of toluene and 0.710 cm @ 3 of 1,3-propanediol. The mixture is evaporated under reduced pressure, the residue is crystallized by treatment with heat and cold from heptane, filtered, washed to give 1.12 g of the desired product.

NIvIR: CDCl ₃ (250 MHz) ppm

0.36 (t, 3K): 1H ₃ nBu, 1.30 (m, 23) -1.60 (m, 2H) -2.5S (t, 2H); CH? nBu; 1.23 (t, 3H) -4.23 (q, 2H): -OOOEt, 2.01 (m, 2H): _0-CH2-CH -eh _{7 7} -0, 4.14 (t , 4kJ: _{-0-CH2-CH-CH 9 of} -0-, 2.55 (s, 3H): 'SCH _3, 5? 52 (s, 2H): Ar-CK ^ -imidizol "6.94 and 7.63 (22, 4H): aromatics.

Example 5 Ethyl 2-butyl-1- [4- (5,5-dimethyl-1,3,2-dan-2-yl) phenylmethyl] -4- (methylthio) -1H-5-carboxylate ( 6a) aoxa o or o211US 2 Οχ ”

Proceed to Preparation 4 using 2 - 0 mg ethyl-L - (4-boronophenyl) methyl) -2-butyl. 1- (methylthio) -1H-imidazole-5-carboxylate and 70 mg of 2,2 &apos; -dimethyl-β, 3-propanol are obtained to give 200 mg of a fasted product.

Preparation of (T-4) - ((4 - ((2-Butyl-4- (methylthio) -5- (eshoxycarbonyl) -1H-imidazol-1-yl) methyl) phenyl) -) ((2,2 - ( methylimino) -bis (ethanolato) - (2-) -N, 0,04-bor (product 7)

AAAI síifiSíiiiáaižaátasaiSíÄi £ £ £ ŕiÄíiaŕití iiÄ5iidiidÍii5ŕa ^ ^^ áÄäciÄíto

Proceed according to Preparation 4 using 2 g of ethyl 1- [f (4-boronophenyl) methyl] -2-butyl-4- (methylthio) -1H-imidazole.

5-carboxylate, 30 cm @ 3 of cyclohexyne and 10 cm @ 3 of ethyl acetate, and 0.61 cm @ 3 of N-methyldiethanolamine, when dissolved hot. After concentration, 2.17 g of the desired product is obtained.

NMR: CH 2 Cl 2 (250MHz? Ppm)

0.35 (t, 3H): CH <nBu; 1.3 (t, 3H of CH ?: COOEt, 1.3 (m, 2H) -1.62 (q, 2H ?: CK at position ₂ J and CH ₂ at position 2 nBu, 2.30 (s, 3 H 2, -N ⁺ -CH 3, 2.60 (s, 2H and T, 2H 2: S-CH 2 and CH ₂ at position 1 nBu, 2 , and J 98, 20 (m, 4 H) 4.15 (m, 4 H) .CH ₂ -3T.

4.27 (q, 2H), CH 2 of COOEt, 5.50 (s, 2H): N-CH ₂ -imidazole.

6.9 and 7.5 (2d, 4H) aromatics.

Preparation 7: ethyl-2-butyl-1 - ((4- (1,3,2-beinzodicosborol-2-yl) phenyl) methyl) -4- (methylthio) -1H-imide az-5-carboxylate (oroduct 3)

Preparation 4 was carried out using 1 g of ethyl 1-1 (4-boronophenyl) methyl) -2-methyl-4- (methylthio) -1H-imidazole-5-carboxylate and 0.233 g of cechechol. 16 g of the sought-after product are obtained. product.

2 DIR: CDCl ₃ (200 MHz) ppm 0.37 (t, 3H): CH-, nBu, 1.35 (m, 2H): 2¾ (m, 2K) γ-α and O 2 O 7 5 5 v. '- J ·.-.- jolone 3 n cu,

OO · (i., Ir.);

Lohe

-. ·). .- »tt.-T ₉ τρσι λ qc ii_u,. (-> u - / - - ¹ - '- ^ ₂ -ι-, p, 2H''9 position 1' nBu, 1, _J · _L t, 3E), CE 2 in CO ₂ - £ t, 4.25 (q, 2H): CE, [nu] OH, 2, & 3 (s, j, -); p, c (· =, 2u): oenzyl, 7.1 and 3.05 (2d): aromatics, 7, 15 and 7.3: catechol.

Preparation 8: Ethyl-2-butyl-1 - ((4- (4,4,5, p-tetramethyl-1,3,2-dioxa-borol-2-yl) phenyl) methyl) -4- (methylthio) a &lt; B &gt;

··. · .; _? · · Ζ ^^

- 50-1H-imidazole-5-carboxylate (product '9a)

Preparation 4 proceeds: starting with 0.5 g of ethyl 1- (4-boronophenyl) methyl] -2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate using 0.189 g of pinacol. 0.511 g of the product sought is obtained.

NMR: GDC1 ₃ (250 MHz) ppm 0.87 (t, 3H) i. CK ₃ nBu, 1.33 (m, 2H): CK ₂ v position 3 nBu, 1, 63 (m, 2H): _CH2 in position 2 NSU, 2.53 (t, 2H); gh ₂ in po- Lohe 1 nBu, 1.33 (s, 12HJ: 4 GE4-G-, 1.23) (T, 3H): Fin!?> · You 2 ** J 4.23 (q, 2Hj: CO ₂ St, 2.61 (s, 3E): S-GH 4, 5.52 (with) : N-GH _? Ar. 6.37 and 7.73 (2d, 4H): aromatics.

Preparation 9: Ethyl 2-butyl - ((4- (1,3,2-dioxabrolol-2-yl) phenyl) methyl) -4- (methylthio) -1H-imidazole-7-carboxylate (Product 9b)

Preparation 4 proceeds: starting with 0.2 g of ethyl 1 - [(4-boronophenyl) mexyl] -2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate using 39 mg of ethylene glycol . Obtains an oroduct.

to 0.2 'g of the expected

NMR: GDC1-, (250MHz) ppm

0.9 (t, 3?): GH nSu, 1.35 (m, 2H): GE ₉ at 3 nBu position, 65 (m, 2H): GH ₉ at 2 nBu position, 2.6 j " (t, 2H): 7E ₉ at position 1 nEu, 1.3θ '(ΐ. JH): GC ₉ 2t, 4.25 (q, 2H): G0 ₉ Zt, 2.5J (s, 3H): 3 -GHj, 5.60 (s, 2H): Ar-GH ₉ -imidazole, 4.45 (s, 4 H): CH2, O, 7.92 9 7, s (2 i) woaéty.

'ioraví

2-bromo-N - [(propylamino) carbonyl] benzo; amide

5 g of 2-bromobenzanesulfonamide in 150 car acetone are heated to reflux, 17.5 g of potassium carbonate are added, followed by 6.6 cnP of N-propylisocyanate, and the mixture is stirred for 2.5 hours.

- 51 to reflux, cooled to ³ C and D adjusted to pH 5 to give 18.35 g of the expected product (m.p. 218-219 DEG C.) NMR: ppm GDC1

0.84 (t, 3H): CK ₃ , 1.45 (m, 2H, 3.07 (q, 2K), GH ₂ , 6.08, (1, 1H): NH, 7.5 (m, 2H), 7.71 (fdd, 1H), 8.25 (d, 1H): aromatics, 10.00 (L, 1H): NH.

Example 1

Dipotassium salt of 2-Bury-4H- (methylthio) -1- [2 '£ t (((. Propylaaíno) carbonyl) amino) sulfonyl) -1, 1 ^# -biphenyl-4-methyliodide YLJ · H-imidazole -5-carboxylic acid itupene A: 2- C (4-bromomethyl) phenyl] -5,5-dimethyl-1,3,2-dioxaborolane hr. is heated to reflux to remove the resulting water j. 4 g of 4-methylphenylboronic acid or its

Of the trimeric form and 2.6 g of 2,2-dimethylpropane-1,3-diol in 50 cm @ 3 of cyclohexane. 4.45 g of M-bromosuccinimide and 100 mg of azobisoisoutyronitrile are added. The mixture is maintained for 4 hours. Luxe cut, cooled, filtered, washed with cyclohexane and a mortar oroduct, Teciota rotating 1 and 0 &lt; 0 &gt; G.

; nsma se

NH: GDG1: om

1.01 (s, 6 H): _OH? -G, 3.75 (s, 4 H): GH-CH, 4.52 (s, 2H): ₀ 3 r OH, 6.95 (d, 2 E \ 7.72 (d, 2H) aromatics.

step S: ethyl-2-butyl-1- [4- (5,5-dimethyl-S, 3,2-dioxaborolan-2-yl) phenylmethyl] -4- (mesylthio) -1H-imidazole-6-one; carboxylate min. A mixture of ethyl 2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate, 65 cm @ 3 of dimethylformamide and 3.75 g is stirred.

«gaggwtp

potassium carbonate, then 3 g of the product prepared in Step A in solution in 32 cm @ 3 of dimethylformamide are added. The mixture was stirred at room temperature for 48 hours. It flows. _Q. After trituration with cyclohexane-ethyl acetate (8: 2), 5.67 g of the desired product is obtained (m.p. 145-146 ° C).

NMR: GDCl-1 ppm

0.86 (t, 3H): GH 3 nBu, 1.29 (t, 3H): GH ₃ in G ₂ O ₂ , 1.34 fm, 2H), 1.62 (m, 2H 2, 2.60 ( d, 2H): GH ₂ in nBu, 2.61 (s, 3H): S-GHp 4.23 (q, 2H ?: CK ₂ in G ₂ Et, 5.52 (s, 2H): QR? benzyl 6.36 (d, 2H) and 7.71 (d, 2H): aromatics.

Step G: ethyl-2-butyl-4K- (methylthio) -1 - [[2 (((((propylamino) carbonylamino) sulfonyl) -1,11- (biphenyl) -4-yl) methyl) -1H -imideszole-5-carboxylate was heated at reflux for 1 hour with a mixture of 62 mg of 2-bromo-1 H- (propylamino) carbonyl] -benzenesulfonamide, obtained overnight at 10.4 cm @ 3 of toluene, 0.193 cm @ 2 of 2N sodium carbonate solution in water. tezrakis mg (triphenyl phosphine) palladium, 1.5 cm @ of ethanol, 55.5 mg of the product of step 3, and 0.4 ^cc of toluene.

A small amount of toluene was added and the mixture was acidified to β2.2K with hydrochloric acid. It is extracted with methylene chloride, washed with water, dried, evaporated to dryness to give 65 mg of product which is c-iromatographed on silica gel with toluene-dioxane-acetic acid (95: 4: 1) to give 75 mg of lane. product (m.p. '32 ° C).

T.

i - JUU

NMR: GDG1, ppm

0.72 (t, 3H): GH-, nBu; 1.67 (m, 2H): _GH? , 5.03 (q, 2H ?:

-Q | -'I W «,

7.64 (t), 7.53 (t), 8.12 (d): aromatics.

Δ ₉ -λΉ, 6.01 (s, 1K): 30 _q NH, 6.11 (t, 1H): CONH, 7.25 (d),

^? J <

Step D: Dipotassium salt of 2-butyl-4H- (methylthio) -1-CC2 '- ((((propylamino) carbonyl) amino-sulfonyl) -1,11- (' oiphenyl) -4-ylmethyl) -1K imidazole-5-carboxylic acid

To a solution of 2 g of the product obtained according to Step G in cm @ 3 of ethanol was added at 0 DEG C., 2 cm @ 3 of a 6N potassium hydroxide solution. The mixture was allowed to warm to room temperature.

"3

After 72 hours, the precipitate was filtered off and washed with 4 ^{L of} ethanol and then with 4 mL of ethyl acetate. After drying, 2.04 g of the product sought is obtained:

mp > 260 ° C

Analysis for ^C 26 ^H 30 ^K 2 ^N 4 ° 5 ^S 2 ^: Calculated ^: C, 50.5; C, 50.5; C, 4.9 found

H, 9.02; N, 10.33; N, 9.0; 10.3

WITH,

Q

Example 2a

Dipotassium salt of 2-butyl-4H- (methylthio) -1 - [[2'-f (((propylamino-carbonyl) amino) sulfonyl) -1,4-biphenyl) -4-yl] methyl-1H-imidazole-5-yl -carboxylove j

C - * -, m.p. A: 2- (4-Broamethylphenyl) -1,3,2-dioxaborolan

It works as in stucco & oriad 1; barring

21.06 g of 4-metyifenylborcncvej using a 17 cm trimethylene and 250 ^cc of cyclohexyl, 44o mg of azobisisobutyronitrile and 32.03 g of N-oromsukciáimidu.Získa jl is the product '(m.p. 108-109 DEG C.).

.r behold.

ΝΜΉ: (GDG1 <) ppm

2.05 (m, 2Hb centrally _with GH, and 14 (t, 4H) 5-0-GH ,, 4.49 (s, 2H): GH ₂ -3R, 7.27 (d, 2H), and 7.7 * (d, 2K): aromatics.

Step 3 ': Ethyl 2-butyl-1- [4- (1,1,2-dioxaborolan-2-yl) phenylmethyl] -4-methylthio) -1H-imidazole-5-carboxylate for 20 minutes 22 ° C heats a mixture of 34.5 g of ethyl 2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate, 59 h of potassium carbonate, 3.32 g of tetrabutylammonium bromide and 312 cnP of acetone. 33.6 g of the product obtained in Step A are then added. The mixture is stirred for 24 hours, filtered and concentrated to dryness under reduced pressure. After crystallization by heat and cold in 59 cm @ 3 of ethanol, 20.1 g of the desired product (m.p. 120-121 DEG C.) are obtained.

NMR: (GDC1) ppm

0.86 (t, 3H): GH-J, 1.28 feet, 3H): GH CO, Et, 1.30 (m, 2H): GH _2, 1.60 (m, 2H): GH ₂ , 2.53 (t, 2HJ CH ₂ -C = N, 2.55 (s, J H) s-GH ,, 2.04 (m, 2H): CH central ₉ 4.11 feet, 4H? : 50-CH?

4.23 (t, 2HJ: GH ₂ in CO ₂ 3t, 5.52 (b, 2HJ: GH ₂ -N, δ, 94 2H) and 7.63 (d, 2H): aromatics.

Step G: ethyl-2-tert-yl-4H- (methylthio) -1- [t5 '- ((((propylamino) carbonyl) amino) sulfonyl) -1,1 * - (biphenyl) -4-yl - methyl 1-1H-imidazole-5-carboxylate - a mixture of 14 mg of the product obtained after about 1 cm @ 3 of toluene;

2N sodium carbonate solution,

17,3 mg gaivinoxyium, mixed 15

12.9 mg triphenylphosphine and 5.5 mg palladium acetate. The mixture is stirred for 15 minutes and a solution of 400 mg of the product prepared in step 3 in 1.3 cm of toluene and 5.3 cm is added.

I, ~ m y *: ·:

refiuxe.

irisdení ethanol. the mixture is missed 24 night.

énorn and acidified by the addition of 1.47 ^j 2Z1 acid, the mixture was extracted with methylene chloride, dried 3 evaporated in vacuo to dryness. The residue is chromatographed on silica gel, eluting with 75: 25: 5 cyclophiexane / n-chlorobutane / iopropylaikohoi) to give 0.25 g of the desired product, identical to the product obtained in Step G of Example 1.

W »« i «i> rii> n <H> aicftiiaiiMaeiiŕ» aeiaaitfŕaagBiiiagä8BBÍŕs ^^

- 55 Step D: Dipotassium salt of 2-outyl-4H- (methylthio) -1- CC 2 ((((propylamino) carbonyl) amino) sulfooyl) -1,1 *

- (Biphenyl) -4-yl] methyl-1H-imide-3Zole-5-carboxylic acid

The procedure is as in Step 1 of Example 1.

Example 2b

Dipotassium sol. 2-butyl-4H-methylthio) -1-ff 2 * - ((((propylamino) carbonyl) amino) sulfonyl) -1,1- (biphenyl) -4-yl] methyl] -1H-imidazole-5- carboxylic acid

The procedure is as follows: 12.9 mg triphenylphosphine phosphinopropane. In step C of Example 2, with step D of Example 1, the compound 49, which is used in the formation, is used

2s; in step d, 1 mg of 1, 1'-bisdiphenylmg of the product prepared is treated as indicated in the product.

Ίν »» * ´ / · Ί example 3

2-ethyl-2-cutyl-4H-phenylamino) -: - [C2 '- (t-propylamino) carbonyl) amino) sulfonyl) -1,1- (biphenyl-4-ylmethyl) -1J-1

imidazole-p-carboxylate

It is studied as in Stage C of Example 1 using

0.0524 g of the 2-iodo-1-propoxycarbonylbenzenesulfonamide obtained according to Preparation 2 and 109 mg of the product prepared by Preparation 4 gave the expected product.

Example 4

Ethyl-2-butyl-4H- (methylthio) -1 - [['(1') - ((((propylamino) - 56 carbonyl) amino) suifonyl) -1,1- (biphenyl-4-ylmethyl) -1H Inidazole-5-carboxylate.

Example 2 with oouz;

Proceed as in step mg of 2-iodo-N-propylaminocaroonylsulfonamide and 1.2 g of the product prepared in Preparation 5 to give 905 g of the desired product.

Example 5

Ethyl-2-butyl-4H- (methylthio) -1-Cl 2 - (((((propylamino) carbonyl) amino) sulfonyl) -1,1- (biphenyl) -4-yl) methyl] -1

imidazole-5-carboxylate and in the spup;

of Example 1

of 442 rv, · - · v- »» ^u oy * 264 mg r \ H i: IN 152 mg <'o p O

administration o, avv.m and 313: 0 53 03 k

EXAMPLE 6-1-2-ο-γ1-ΐΗ-β-β-111ο} -ΐ-fC2 '- (((((propylamino). -Carbonylamino) -sulfones J -1,1- (benyl) 1-yl) meoyl) PROCEDURE in,>> vf f ·: - * f X 1 · - * w kZ

Liυ Li x.

- 'V ^- »Λ -r. *>»> · VS ”' ¹ -Ί

-. · J-U. z, v .y η - ».»> ο ·: ττ ~ o fcX. ' - C ‘lorsvy

Ä 7. ΐ 15> '7 QU QU QU ľ--.U <

* Example 7

Styyl-2'-butyl-4E- (methylthio) -1-phenyl - ((((propylamino) F7 carbonyl) amino) sulfonyl) -1,1 '- (biphenyl) -4-yl] ethyl-1H imidazole-5-carboxylate

The procedure is as in Example o; starting with 1 g of the product obtained in Preparation j and 528 mg of 2-iodo-N-C (propylamino) -carbonyl] benzenesulfonamide prepared according to Preparation 2 to obtain 71 mg of the desired product.

Example 8

Stvl-2-butyl-4H- (methylthio-1-CL2 '- ((((propylamino) carbonyl) amino) sulfonyl) -1,1 * - (biphenyl-4-yl) methyl} -1H-imidazole -p-carboxylate

Progresses. as in Step 1 of Example 2, using instead of the product obtained according to Step B of Example 2, 432.5 o the product prepared in Preparation 7 's, 121 ns of the expected oroduct is obtained.

Styl-2-butyl L-4 ', :-( methylthio) -1- ['2' - (<(propylamino) carbonyl) amino) sulfonyl} -1 '- (bi-ethyl) -s-yl tulle J - i:

imidazole-p-carboxylate

The procedure of Example 2 was followed using, instead of the product obtained in Example 2, Step B, 387 mg of the product prepared in Preparation 9 to give 22 '. mg of expected product.

Styl-2-butyl-dH- (non-methylthioyl-1- [*2 * - ((((propylamino)) instead of the product obtained according to step Ξ of Example 2, 440 mg of the product prepared in Preparation 8 to give 172 mg of the expected product.

Example 1 i

Pharmaceutical composition

Tablets of the following composition were prepared: Example 1 p? m>:

r * a per p :) + and a - * ň * ·.

u L - V .. .A (carrier in particular: Lactose, talc, starch, stearate stearate; --s n s «« «« «« «« « - n ** / Λ y o oi * u co n r ', fr c c «** r * · on

-1Λ.0 -t * - e ...-.- J) - - ..4. ‘- - · £ —Ι.τ ·. -Í λ T ii ii ii / Cy Cy ú ú ú

According to the invention, it is said to precede all compounds

Claims (9)

PATENT CLAIMS A process for the preparation of products of formula I wherein R 1 represents an alkyl, alkenyl, alkynyl or alkylthio group, each of which is linear or branched and contains up to 10 carbon atoms or a cycloalkyl radical having 1 to 7 carbon atoms, all of which are optionally substituted. and R 6, the same or different, are selected from the group consisting of a / hydrogen, halogen atoms, hydroxyl, mercapto, formyl, acyl, carboxy free, salt or csterified, nitro, cyano and -PO 4 R 6 R 6 radicals; wherein R represents a hydrogen atom or an optionally substituted alkyl or phenyl radical. b / rest. yS (O? _m 2 -XR ₁₀ , where m is an integer from 0 to 4,? 2 is an integer from 0 to 2, and X is a single bond or -NH-, -NH-CO-, -NH-CO-O-, -N = CH-NR, -NH-CO-NH- and R and R ₁ , same or different, represent a hydrogen atom, a linear or branched alkyl or alkenyl group radical of up to 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, but not tetrahydrofuran 1 , (c) an alkyl, aleknyl, alkoxy or alkylthio group, wherein the sulfur atom is optionally mono- or dioxidized, each of which linear or branched with up to 6 carbon atoms is optionally interrupted by one or more heteroatoms selected from the group consisting of sulfur, oxygen or nitrogen atoms, and optionally substituted, d / phenyl, benzyl, and phenylthio, wherein the sulfur atom is optionally mono- or dioxidated, radicals which are optionally substituted, ^R 6 ^{λ R} 8 < e &gt; -CO-N < _z and -N ^< _f R ₇ 'R,' wherein bucL Rg and Ry or Rg and 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, - - rest -fCH _{2 in1} ^ S ~ ^(/ O) _m2 --X ~ q R _1, as defined above, or R and R. or R 8 and R 8 each form, with the nitrogen atom to which they are attached, a monocyclic radical having 5-, 6 or 7 ring atoms or a radical formed by the same or different condensed rings having 8 to 1'4 'ring atoms optionally containing one or a plurality of other 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, omino optionally substituted with one or two of the same or with different alkyl radicals having up to 6 carbon atoms and phenyl, or εθ and R 6, the same or different, represent an acyl radical or one of the substituents R 8 and R 6 represents a carbamoyl, aoxycarbonyl or benzyloxycarbonyl radical or R 8 together with a nitrogen atom to which they are bound, the phthalamido or succinimido moiety, f / moiety -S-SR ₁₂ > k de R ₁₂ has the meaning given for R ₂ or R in paragraphs a / to e) except amino and alkoxy radicals, provided that at least one of R ₂ and R 6 is. an optionally substituted alkoxy group or a - _(CH2) -S- (OQ ^{in the} Y ^{and G} ^ ^e defined meaning. Rf. is selected from the group consisting of the remainder - ^ ³ y m1 meaning as defined above, halogen atoms, nitro radical, the radicals - _(CH2 ^ -CUUR, - (CH _O). -CONHR. ., - (CH _{O) 5} CN where m. the aforementioned cmi 14 has the meaning, -SC 1 -NH-SC 3 -R 1, -NH-SC 3 -R 3, -PO 3 R 3, -NH 2 O 3 -CF 3 with _m) -SO ₃ R ₄ , -CO-NH-OR ₁₄ , -CO-NH-MH-SO ₂ -CF, -CO-NH-SO ₂ -R ₁₄ -CH ₂ SO ₂ NHCO-R ₁₄ , -CH ₂ CONH-SO ₂ R ₁ . ₄ , -NHSO ₅ NHCO-R 6 -NHCONHSO ^ t, _4, -CONHSO ₂ NR ₁₄ R _15, -SO ₂ NHCONR ₁₄ R _15, -SO ₂ N (R ₁₄₎ 'or _15, -SO ₂ NHSO ₂ R _{i4, -SO2} nhpo (r ₁₄ ) ₂ , ' -CO 2 (R ₁₄ ) ₂ , 50 ₂ NHCN, -SO ₂ NHCOR ₁₄ , -SO ₂ NHSO ₂ NR ₁₄ R ₁ -SO ₂ miSO ₂ N (CH ₂ CH ₂ ) ₂ Y, -NH ₅ O ₂ NHSO ₂ R ₁₄ , -NHSO ₂ NHPO (R ₁₄ ) ₂ , -NHSO ₂ R ₁₄ , -NR ₁₄ COCO ₂ H, -SO ₂ NHCO ₂ R ₁₄ , wherein R 11 'is as defined above and R ₁₄ and R 16 are the same, or: various, are 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 radicals , alkoxy, phenyl, benzyl are optionally in disubstituted by one or more selected products Z in Z 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, free, in salt or esterified, haloalkyl, alkylthio, haloalkylthio, haloalkoxy, phenyl, pyridyl, benzyl, phenethyl, benzoyl, phenoxy, benzyloxy, phenylthio, carbamoyl, acyl, acyloxy and tetrazolyl, and wherein all products of formula I are in all possible isomeric racemic, enantiomeric and diastereomeric forms as well as addition salts of products of formula I with mineral and organic acids or with mineral and inorganic bases, characterized in that with the compound of formula II wherein R * ₁ , R * ₉ and R 6 are as defined above for R ₁ and R ₂ , respectively. R ₂ , resp. R, and where optionally reactive groups are optionally protected, react with a compound of formula III \ 64 \ (III) wherein Hal represents a halogen atom, B represents a boron atom, and X p X ₂ are such that either moiety and X ₂ , same or different, represent a hydroxyl alkyl or alkoxy radical of up to 6 carbon atoms, phenyl or phenoxy, or X 2 s X ₂ forms with the boron atom to which they are attached a cycle selected from the group consisting of B. B rZ Z / \ / t // i Where it represents a hydrogen atom or an alkyl radical of up to 4 carbon atoms, to give a product of the formula IV wherein R * j, R * 2, ^ * 3 ' ^X p ^{and E πιει} ϋ6 as defined above, then leaving the product of formula IV is reacted with the product of formula V Wherein R represents a halogen atom, an alkoxy, a triflate or -O-SO 4 F and R * 4 has the meaning given above for where optional functional groups are optionally protected, to form from the product of formula (I) which, if desired and necessary, undergoes one or more of the following reactions in any order: a) removing the protecting groups which may not protect the protected reactive groups, b) converting to a salt with a mineral or organic acid or base, c) esterifying the acid functional group, d / esterifying the ester group, e / converting the cyano group into acid functional groups, f) reduction of the carboxy group to an alcohol group, g / conversion of the alkoxy group to a hydroxyl group, h / oxidation of the sulfur-containing group to the corresponding group. i) converting a sulfoxide or sulfone group to i ......... the corresponding suifoxiinin group, j. / conversion of the nitrile residue to tetrazole, k / resolution of racemic forms into individual products, 1) conversion of the carboxyl radical to a carbamoyl radical, m / conversion of the carbamoyl radical to a nitrile radical, wherein the products of formula I thus obtained are in all possible ways. The isomeric racemic, enantiomeric and diastereoisomeric forms. A process according to claim 1 for the preparation of products of formula I corresponding to formula I wherein R is a linear or branched alkyl, or ^{a 1,} the alkenyl radical having up to 4 carbon atoms, R _a and R, identical or different, are selected from the group comprising ~ I '-ups and / or hydrogen, mercapto, formyl, carboxy free salified or esterified, halogen, hydroxyl, cyano, nitro, acyl, b / alkyl alkenyl, alkoxy, alkylthio, where the sulfur atom is optionally mono- or dioxidized, these radicals being linear or branched and containing up to 6 carbon atoms, phenyl, benzoyl, phenylthio, wherein the sulfur atom .......... is optionally mono- or dioxidised; 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 and alkoxy of up to 4 carbon atoms, phenyl and carboxy, free in salt form or esterified consisting of halogen, hydroxyl, nitro, alkyl, alkenyl, and alkoxy having up to 4 carbon atoms, trifluoromethyl, cyano, of _the amino, mono and dialkylamino, carboxy free time, salified or esterified, phenyl, tetrazolyl, said products of formula I being in all possible isomeric racemic, enantiomeric and diasteroisomeric forms as well as their addition salts with mineral and organic acids or mineral and organic bases. in that the products of formulas II are used for the preparation described above. III and IV, in which r ' ₁ , R * 2, R and R 4 have the meanings given above for R 1 _and R 2, respectively. R _2a , resp. R _8g 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 1 ^ <Ib> where R 11 represents an alkyl radical of up to 4 carbon atoms, represents a hydrogen atom, formyl, acyloxy, optionally substituted alkyl or alkoxy or a carboxy group, free, in salt form or esterified with an alkyl radical, R 1b represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl or alkylsulfinyl, optionally substituted, so that, in all residues that R 2 may represent R _1b , contain alkyl radicals and alkoxy groups of up to 6 carbon atoms, and the phenyl radicals are optionally substituted with one radical or a few radicals selected from the group consisting of halogen atoms, hydroxyl, trifluoromethyl, acyloxy, carbocycle free, in salt or esterified form, phenyl, pyridyl, tetrazolyl, alkyl and alkoxy of up to 4 carbon atoms and optionally substituted by alkoxy of up to 4 carbon atoms, represents cyano, carboxy, free, in the form of a salt or esterified, the radical -SO ₂ -X _b "K ₁ ob 'where X _b represents the residues -NH-, -NH-CD-, -NH-CO-O-, - N-CH-N-R p ^, -NH-CO-NH or a single bond and R ₁ ob ^and _b, identical or different, are H, rnetyl, ethyl, propyl, vinyl, allyl, pyridyl, phenyl, benzyl, nitropyridyl, pyrimidyl, tetrazolyl, diazolyl, piperidinyl, alkylpiperidinyl, thiazolyl, alkylthiazolyl, tetrahydrofuranyl, methyltetrahydrofuronyl, said products of the formula being in all possible isomeric racemic, enantiomeric and diastereoisomeric forms and also their addition salts and their addition salts acids or with mineral or organic bases, characterized in that the products of formulas II, III and IV in which R @ 1, r @ ₂ , r @ 1 and H @ ₄ have the meanings given above are used for their preparation as described above. for R _1b resp. R _2b , resp. R _4b in which the reactive functional groups are optionally protected. The method of claim 1 for preparing products of formula I corresponding to formula I wherein R1 represents an alkyl radical of up to 4 carbon atoms, R1 represents a carboxy group 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 carbon atoms, optionally substituted. hydroxyl. R ₂ j is a phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylsulfonyl, or alkylsulfinyl, in which the alkyl portion contains up to 4 carbon atoms, R 8g represents the radical -SC 4 -NI 4, -SO ₂ NH-CO-OR 4, N ^ -SO-NR II, ,, -S0 or _a NH-C0-NH-R _{1 n} ,, wherein R 'and J d 2 1 2 LOD _of 10 d R _3d , same or different, are selected from hydrogen, methyl, ethyl, n-propyl and propenyl, said products of formula (1) being in all possible isomeric racemic, enontiomeric and diosteroisomeric forms and their addition salts with mineral and organic acids or with mineral and organic bases, characterized in that products of formulas II, III and IV are used for their preparation as described above, in which R *, R ^Z, P, R * j have the meanings given above for R 6, respectively. R ₂ ^{res res} P · R _{7 <} p resp. In which the reactive functional groups are optionally protected. zt V 5. The method of claim 1, characterized in that the starting material ako- using the product of formula II, wherein R ₁ is an alkyl radical having up to 4 carbon atoms, R ₃ is carboxyl, the free, salified or esterified by a linear or branched olkylovým C1-4 radical, formyl, acyloxy, alkyl of up to 4 carbon atoms, optionally substituted by a hydroxyl radical, R1. represents phenylthio, phenylsulfonyl, phenylsulfinyl, alkylthio, alkylisulfonyl or alkylsulfinyl, wherein the alkyl moiety contains up to 4 carbon atoms and the reactive functional groups are optionally protected and the product. of formula V wherein R 1 is -SO ₂ -NH ₂ , -SO ₂ -NH-CO-OR _10d , -30 ₂ -N = CII-NR _1d, or -SO 2 NH-CO-NH-R, _Qd AX wherein R 4 Q _d and R _{3d 3 are the} same or different, are selected from hydrogen, methyl, ethyl, n-propyl and propenyl, wherein the reactive functional groups are optionally protected. 6 '. The process according to claim 1, wherein the starting product is a product of formula II wherein R * is alkoxy or carboxy free, in salt form or esterified and ar is alkylthio or phenylthio, optionally oxidized in the form of sulfoxide or sulfone, these being the alkoxy, alkylthio and phenylthio radicals are optionally substituted with one or more. radicals selected from the group consisting of halogen atoms, alkyl or alkoxy of up to 4 carbon atoms, trifluoromethyl, amino, mono- or dialkylamino, cyano, acyl, acyloxy or phenyl. The process according to claim 1 for the preparation of the compounds of formula I corresponding to the formulas 1: 2-butyl-1-x2-carboxy (1,1'-biphenyl-4-yl) -methyl-4- (phenylthio) -1H- imidozol-5-carboxylic acid, - 2-butyl-1 - [[2'-carboxy - (- 1,1'-biphenyl) -4-ylmethyl] -4-methylthio) -1H-imidazole-5-carboxylic acid, - 4 -C [2-butyl-4- (ethylthio) -5- (hydroxymethyl) -1H-imidazol-1-yl] methyl] - (1,1'-biphenyl) -2-carboxylic acid, - 2-butyl-1 - C (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-indidazole-5-carboxylic acid, - 2-butyl-1 - ((2'-carboxy- (1,1'-biphenyl-4-yl) butyl) -4- (ethylthio) -1H-imidazole-5-carboxylic acid, - 2-butyl-1 - ((2'-carboxy- (1,1'-biphenyl) -4-yloxy) methyl] -4- (phenylsulfonyl) -1H-imidazole-5-carboxylic acid, - 2-butyl-1 - ([2-carboxy- (1,1-biphenyl) -4-yl} methyl) -4- (phenylsulfinyl) -1H-imidazole-5-carboxylic acid, - 2-butyl-1 ((2'-tetrazolyl- (1,1-biphenyl) -4-ylmethyl) -4- (methylthio) -1H-imidazole-5-carboxylic acid, - ethyl-2-butyl-4- (methylthio) -1- (2 (((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl) methyl) -1 H -imidazole -5 ^- carboxylate, - 2-butyl-4- (methylthio) -1 - ([2 '- ((((propylamino} carbonyl) amino) sulfonyl)) - (1,1-biphenyl) -4-yl] methyl] -1H- imidazole-5-carboxylic, - 2-butyl-4- (methylthio) -1 - [(2'-propylamino) carbonyl) amino) sulfonyl} - (1'-1-biphenyl) -4-ylmethyl] -1H-imidazole-5-didraseine salt -carboxy ej. about. The process according to claim 1 for preparing the products of formula I corresponding to the formulas - ethyl-2-butyl-4- (methylthio) -1-C [2'- ((((propylamino) carbonyl) amino) sulfonyl) - (1,1-biphenyl) -4-yl] methyl] -1H-imidazole-5 carboxylate, 2-butyl-4- (methylthio) -1 - [(2 '- ((((propylamino) carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl) methyl] -1H- imidazol-5 'carboxylic acid, - didraseine salt of 2-butyl-4- (methylthio) -1 - ((2 - ((((propylamino-carbonyl) amino) sulfonyl) - (1,1'-biphenyl) -4-yl] methyl] -1H-imidazole-5-carboxylic acid. 9. New industrial products consisting of compounds of formulas IV. and in. 10. New. industrial products, which are 1. 2-jódbenzénsulfonsmid 2 2-Iodo-N - [(propylamino) carbonyl] benzenesulfonamide 4a 2- [4- (bromomethyl; phenyl) -5,5-dimethyl-1,3,2-dioxaborolan 4b 2- [4- (bromomethyl) phenyl] -1,3,2-dioxaborolan 5 ethyl-1- [ (4-Boronophenyl) methyl] -2-butyl-4- (methylthio) -1H-imidazole-5-carboxylate 6a Ethyl 2-butyl-1- [4- (5,5-dimethyl-1,3-dioxaborolan-2-yl) phenylmethyl] -4-methylthio-1 H -imidazole-5-carboxylate 6b Ethyl 2-butyl-1- [4- (1,3,2-dioxaborolan-2-yl) phenylmethyl] - (methylthio) -1H-imidozole-5-corboxylate 7 (T-4) ((4 - ((2-butyl-4- (methylthio) -5- (ethoxycarbonyl) -1Himidazol-1-yl) - ((methyl) phenyl)) - ((2,2 '- ( methylimino) bis (ethanoate)) (2 -) - N, 0,0'-bor 8-Ethyl 2-butyl-1 - ((4- (1,3,2-benzodioxaborol-2-yl) phenyl) methyl) -4- (methylthio) -1H-imidazole-5-carboxylate 9a Ethyl-2-butyl-1 - ((4- (4,5,5,5-tetramethyl-1,3,2-dioxolaborolan-2-yl) phenyl) methyl) -4- (methylthio) -1Hi .midazol-5-carboxylate 9b Ethyl 2-butyl-1 - ((4- (1,3,2-dioxolaborolan-2-yl) phenyl) methyl) -4-methylthio) -1H-imidasol-5-corboxylate.