Imidazole derivatives, methods for their production, intermediate substances and pharmaceutical compositions based on derivatives of imidazole

 

(57) Abstract:

Imidazole derivatives of General formula I, where R1- H, alkoxy, 1,3-dioxolane, dioxane, phenyl, benzoyl or penalty, in which phenyl possibly substituted by hydroxy or C1-C4alkoxy; R2and R3the same or different, selected from halogen; carboxyethyl, free or esterified WITH1-C4by alkyl; formyl; alkyl, phenylthio, alkylthio, possibly substituted by one or more radicals selected from halogen atoms, hydroxy, C1-C4alkoxy, carboxy free or esterified, phenyl, possibly substituted by hydroxy or C1-C4alkoxy; Y is phenyl substituted by two radicals, forming together dioxol, one or more halogen atoms, possess antagonistic properties with respect to the endothelin receptors. 5 S. and 6 C.p. f-crystals.

The invention concerns new derivatives of imidazole, the method of their derivation, the new intermediate compounds and pharmaceutical compositions based on derivatives of imidazole.

More specifically, the present invention relates to compounds of formula (I)

< / BR>
in which R1is an atom in what arbonia, where the alkyl radical, linear or branched, contains not more than 6 carbon atoms, and aryl and alkyl in all the radicals, that is R1possibly substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, free carboxy radical, turned into salt, esterified or liderando, cyano, nitro, amino radical, possibly substituted by one or two identical or different alkyl radicals containing not more than 6 carbon atoms, cycloalkyl containing from 3 to 7 carbon atoms, alkyl, alkenyl and alkoxy containing not more than 6 carbon atoms, haloalkyl, alkylthio, haloalkylthio, haloalkoxy, phenoxy, funeralcare, carbamoyl, possibly substituted, acyl, acyloxy, tetrazolyl possibly turned into salt, and phenyl, possibly substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, alkyl and alkoxy containing not more than 4 carbon atoms, trifloromethyl, cyano, free carboxyl, converted into a salt or esterified, and tetrazolyl,

R2and R3identical or different, chosen from:

a) halogen atoms, radicals markai of radical P(O)(OR)2where R is a hydrogen atom, alkyl or phenyl,

b) the radicals R4and OR4where

or R4is the radical -(CH2)m1-S(O)m2-X-R10where m1 is an integer from 0 to 4, m2 is an integer from 0 to 2 and

or X-R10is an amino radical,

or X is a simple bond or radicals

NR11-; -NR11-CO-, -HR11-CO-O-, -NR11-CO-NR12and

- N=CR11-NR12-, a R10is alkyl, alkenyl or aryl, and these radicals possibly substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, cycloalkyl containing from 3 to 7 carbon atoms, the radicals alkyl, alkoxy, haloalkyl, alkylthio, haloalkylthio or a linear or branched, haloalkoxy radical containing not more than 6 carbon atoms, phenoxy, funeralcare radicals, carbamoyl possibly substituted, acyl, acyloxy, free carboxyl, converted into a salt or esterified, tetrazolyl, cyano, nitro, amino radical, possibly substituted by one or two identical or different alkyl radicals containing not more than 6 carbon atoms, and aryl, possibly substituted by one or is not more than 4 carbon atoms, trifloromethyl, free carboxyl, converted into a salt or esterified, and tetrazolyl, and R11and R12identical or different, are selected from a hydrogen atom and the values defined for R10,

or R4is a hydrogen atom; an alkyl, alkenyl, quinil and acyl, and these radicals, linear or branched and contain not more than 6 carbon atoms and may be interrupted by one or more heteroatoms selected from sulfur atoms, oxygen or nitrogen; amino radical or carbamoyl, possibly substituted by one or two alkyl or alkenylamine radicals, identical or different, containing not more than 6 carbon atoms, or a radical -(CH2)m1-S(O)m2-X-R10defined above; cycloalkyl containing from 3 to 6 carbon atoms, or aryl, and alkyl radicals, alkenyl and all aryl radicals representing R4can be substituted by one or more identical or different radicals chosen from:

- atoms of halogen,

is hydroxyl, mercapto, cyano, azido, nitro,

- SO3H, free carboxyl, turned into salt, esterified or liderando,

radicals of alkyl, alkenyl, alkoxy, radicals contain not more than 6 carbon atoms, and aryl, arylalkyl, arylalkyl, aaltio, aryloxy or Allakaket radicals, where the aryl possibly substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl, alkyl and alkoxy radicals containing not more than 6 carbon atoms, haloalkyl, alkylthio, haloalkylthio, haloalkoxy, carbamoyl, possibly substituted, acyl, acyloxy, free carboxyl, converted into a salt or esterified, cyano, nitro, amino radical, possibly substituted by one or more identical or different alkyl radicals containing not more than 6 carbon atoms, tetrazolyl, and phenyl, possibly substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, alkyl and alkoxy containing not more than 4 carbon atoms, trifloromethyl, free carboxyl, converted into a salt or esterified, and tetrazolyl,

radicals

< / BR>
< / BR>
where:

or R6and R7or R8and R9identical or different, chosen from:

is a hydrogen atom,

- amino acids

- alkyl and alkenyl containing not more than 6 carbon atoms and is possibly substituted by one or more identical or more to 6 carbon atoms,

- aryl, arylalkyl and arylalkyl, where the alkyl and alkenyl, linear or branched and contain not more than 6 carbon atoms, and these aryl, arylalkyl and arylalkyl radical possibly substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, nitro, cyano, alkyl radicals, alkenyl, haloalkyl, alkoxy and acyl, and these radicals contain not more than 6 carbon atoms, amino radical, possibly substituted by one or two identical or different alkyl radicals containing not more than 6 carbon atoms, free carboxyl, converted into a salt or esterified, aryl and arylalkyl, the latter two radicals may be substituted by one or more radicals selected from halogen atoms, hydroxyl radicals, trifloromethyl, nitro, cyano, free carboxyl, converted into a salt or esterified, and tetrazolyl,

- radical - (CH2)m1-S(O)m2-X-R10defined above,

or R6and R7or R8and R9form respectively with the nitrogen atom to which they relate, monocyclic radical containing 5, 6 or 7 links, or a radical consisting of condensed cycles the natives heteroatoms, selected from atoms of oxygen, nitrogen or sulfur and may be substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, nitro, cyano, alkyl radicals, alkenyl, haloalkyl, alkoxy and acyl, and these radicals contain not more than 6 carbon atoms, amino radical, possibly substituted by one or two identical or different alkyl radicals containing not more than 6 carbon atoms, radicals, carboxy free, turned into salt, esterified or liderando, aryl and arylalkyl, the latter two radicals may be substituted by one or more radicals, selected from halogen atoms, hydroxyl radicals, trifloromethyl, nitro, cyano, free carboxyl, converted into a salt or esterified, and tetrazolyl,

or R8and R9identical or different, are acyl, or one of them, R8or R9is carbamoyl, alkoxycarbonyl or benzyloxy-carbonyl and the other is chosen from the above values for R8and R9or R8and R9form together with the nitrogen atom to which they relate, phthalimido or succinimido radical,

Y is the radical Y1-B-Y2calov of dioxole and radicals, which can denote R3and R2,

B is a simple relationship between Y1and Y2or one of the divalent radicals: -CO-, -O-, -NH-CO-,

-CO-NH - or-O-(CH2)p- where p is 1, 2 or 3,

Y2has the following values:

or, regardless of the values of B and if Y2identical to or different from Y1, Y2chosen from the values defined for Y1,

or, if a is a simple bond, Y2is a hydrogen atom, a halogen atom, an alkoxy radical, cyano, carboxy or free carboxyterminal, turned into salt, esterified or emitirovannykh, tetrazolium, or the radical -(CH2)m1-S(O)m2-X-R10defined above, with compounds of formula (I) are presented in all possible forms of racemic isomers, enantiomers and diastereoisomers, as well as additive salts with inorganic or organic acid or with an inorganic or organic base.

In the compounds of formula (I) and forth:

- the term "linear or branched alkyl" means, preferably, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, and pentyl or hexyl, in particular isopentyl Anil, butenyl, in particular 1-butenyl, or pentenyl,

- the term "linear or branched quinil" means, preferably, ethinyl, propargyl, butynyl or pentenyl.

As alkyl radicals interrupted by one or more heteroatoms, one can cite, for example, methoxymethyl, methoxyethoxymethyl, propertyproxy, propylacetate, propitiate, methylthiomethyl,

the term "halogen atom" means, preferably, a chlorine atom, and also may mean a fluorine atom, bromine or iodine,

- the term "linear or branched alkoxy radical" means, preferably, methoxy , ethoxy, propoxy - or isopropoxy-radicals, and may also indicate a linear secondary or tertiary, butoxy radical,

the term "acyl" means, preferably, a radical, having from 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl or benzoyl, and pentanol, hexanol, acryloyl, crotonyl, or carbarnoyl,

- the term "acyloxy-radical" means, for example, radical, in which acyl has the above value, and means, preferably, formyloxy, atomic charges, propionyloxy, butyryloxy or benzoyloxy radical,

- the term "cycloalkyl" means, preferably, cycloplegia radicals, where alkyl is defined above values and substituted by one or more halogen atoms, such as bromacil, trifluoromethyl, triptorelin or pentaborate,

- the term "haloalkoxy-radical" means, preferably such radicals in which the alkoxy radical as defined above and substituted by one or more halogen atoms as defined above, for example, bromoethoxy, triptoreline, triptoreline or pentaborate radicals

- the term "dioxol" can mean either carboxylicacid radical containing up to 6 carbon atoms and 2 oxygen atoms, for example 1,3-dioxolane-2-yl, or dioxane, or carbocyclic cycle containing 2 oxygen atom connected with aryl Deputy, for example 1,3-benzodioxolyl,

the term "aryl" means a monocyclic unsaturated radical containing 5, 6 or 7 links, or a radical consisting of condensed cycles, carbocyclic or heterocyclic, and containing 8 to 14 links, while the heterocyclic radicals may contain one or more heteroatoms selected from oxygen atoms, nitrogen or sulfur and, if these heterocyclic radicals contain more than one heteroatom, the heteroatoms of these heterocyclic radicality, thienyl, such as 2-thienyl and 3-thienyl, furyl, such as 2-furyl, pyridyl, such as 2-pyridyl and 3-pyridyl, pyrimidinyl, pyrrolyl, thiazolyl, isothiazolin, pyrazolyl, triazolyl, tetrazolyl, translated in salt tetrazolyl, thiazolyl, thiadiazolyl, tetrazolyl, oxazolyl, oxadiazolyl, 3 - or 4-isoxazolyl; condensed heterocyclic group containing at least one heteroatom selected from sulfur, nitrogen or oxygen, for example benzothiazyl, such as 3 - benzothiazol, benzofuran, benzopyrrole, benzimidazolyl, benzoxazolyl, Tinetti, indolyl, indolinyl, chinolin or ethanolic, purinol,

- the term "arylalkyl" means radicals, which are, respectively, alkyl and aryl can have the values described above for these radicals; as examples of such arylalkyl you can specify benzyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, intermetal, thienylmethyl, such as 2-thienylmethyl, furylmethyl, such as furfuryl, pyridylmethyl, pyridylethyl, pyrimidinyl or pyrrolidinyl, while in the non-limiting list of the alkyl radicals may mean methyl, and ethyl, propyl or butyl, such as, for example, radicals of phenylalkyl, such as phenylethyl, phenylpropyl or phenylbutyl;

As an example, alkyl radicals, substituted aryl, you can lead, for example, the above-described arylalkyl.

As an example of alkenyl, substituted aryl, you can lead, for example, described above arylalkenes.

- the term "aryloxy-radical" means, preferably, the radicals in which the aryl as defined above, for example, phenoxy radical,

- the term "Allakaket-radical" means, preferably, the radicals in which the aryl and alkoxy radicals are as defined above, as, for example, benzyloxy, venlafaxi or phenylisopropyl,

- the term "aaltio-radical" means, preferably, the radicals in which the aryl means radicals, as defined above, such as, for example, phenylthio, pyridylthio or pyramidally, and the x alkyl is defined above, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, isopentyl or sagacity, possibly substituted as, for example, hydroxyethylthio or aminoacylation,

- the term "haloalkylthio" means, preferably, the radicals in which the alkyl such as defined above, substituted by one or more halogen atoms as defined above, as, for example, brometalia, triptoreline, triptoreline or pentaverate.

- the term "arylalkyl" or "alkylthio", substituted aryl, means, for example, benzylthio or venatici.

All radicals that may indicate or contain R1, R2, R3and R4defined above, the sulfur atoms can be neocolony as radicals, alkylthio, aaltio, cycloalkylation, for example, cyclohexylthio radical, or, on the contrary, oxidized to alkylsulfanyl, cycloalkylcarbonyl, arylsulfonyl, alkylsulfonyl, cycloalkylcarbonyl or arylsulfonyl:

- the terms "alkylsulfonyl" and "alkylsulfonyl" refers to radicals of alkylthio, in which the linear or branched alkyl may mean, for example, the values specified above for alkyl, and thio-moiety oxidized to sulfinil
- the term "arylsulfonyl" and "arylsulfonyl" means aaltio radicals in which the aryl may be, for example, the values specified above for aryl, and thio-moiety oxidized to sulfinil or sulfonyl, as, for example, the radicals phenyl - sulfinil or sulfonyl, pyridyl-sulfinil or sulfonyl, pyrimidyl-sulfinil or sulfonyl, imidazolyl-sulfinil or sulphonyl or N-methylimidazole-sulfinil or sulfonyl.

Carbarnoyl and amino radicals, which may indicate or contain one or more possible substituents of the radicals described in the compounds of formula (I), means a radical in which a nitrogen atom connected to two radicals, equal or different, selected from the hydrogen atom with obtaining amino radical; radicals of alkyl such as defined above, to obtain monoalkyl or dialkylamino radicals in which the linear or branched alkyl radicals contain from 1 to 6 carbon atoms, all these radicals possibly substituted, as described above and below.

Carbocyclic and heterocyclic radicals, which presents R6, R7, R8and R9can have the values defined above for these radicals and, in particular, to mean fenilina, piperazinil, and these radicals can be substituted by one or more radicals, such as defined above, as, for example, the radicals methylpiperazine, formatterproperties or benzylpiperazine.

If R6and R7on the one hand, R8and R9or R14and R15on the other hand, such as defined above to form together with the nitrogen atom to which they are linked, a heterocycle, then we are talking about such cycles, as, for example, pyrrolyl, imidazolyl, indolyl, indolinyl, purinol, pyrrolidinyl, piperidino, morpholino, piperazinil, imidazolidinyl, pyrazolidine, thiomorpholine, azepine; and these radicals can be optionally substituted by one or more radicals as defined above, and, in particular, by one or more radicals selected from chlorine atoms and fluorine radicals methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, benzoyl, methoxycarbonyl, ethoxycarbonyl, as, for example, in methylpiperazine, hermetiseerimine, ethylpiperazine, propyl-piperazinil, phenylpiperazine or benzylpiperazine: in the last two radicals, the radicals phenyl and benzyl can be substituted as described above in the aryl radicals, arylalkyl is te R6and R7on the one hand, and R8and R9on the other hand, respectively, with the nitrogen atom to which they are connected, may preferably rich heterocycle.

In addition, the compounds of formula I the radicals carbarnoyl or amino are those in which the substituents on the nitrogen atom, the same or different, may denote an aliphatic or cyclic chain, or may form with the nitrogen atom to which they are attached, a heterocycle described above for the radicals R6, R7, R8and R9.

Radical "amino possibly substituted" means then amino radical, possibly substituted by one or two alkyl radicals described above, as, for example, in the case of monoalkylamines that the radicals methylamino, ethylamino, isopropylamino, and in the case of dialkylamino this dimethylamino radicals, diethylamino or methylethylamine, and alkyl radicals can be substituted as indicated above and, for example, mean methoxymethyl, methoxyethyl, ethoxyethyl.

As a non-limiting example, the term "carbarnoyl, possibly substituted" means carbarnoyl, possibly substituted on the nitrogen atom by one or two alkyl radicals, possibly substituted the carbarnoyl, or N,N - dialkylamino, such as N,N-dimethylcarbamoyl, N, N - diethylcarbamoyl; N-(hydroxyalkyl)carbarnoyl, such as N- (hydroxymethyl)carbarnoyl, N-(hydroxyethyl)carbarnoyl, phenylcarbamoyl; pyridylcarbinol; benzylcarbamoyl; N-methyl-N - phenylcarbamoyl; pyridylmethylamine. In addition, as substituted alkyl radicals can also lead alkyl radicals, substituted by carbamoyl defined above, with the formation of carbamoylethyl, such as carbamoylmethyl or carbamoylethyl.

Amino radical can be alkoxycarbonyl radical, this radical, preferably, is tert.- butyloxycarbonyl-radical or benzyloxycarbonylamino radicals.

If m1 is 0,1,2,3 or 4, the radical -(CH2)m1- is a simple bond, methylene, ethylene, propylene, isopropylene or butylene.

Carboxy-radical(s) of compounds of formula (I) can be converted into a salt or esterified various well-known specialist groups chosen, for example, from:

- salt-forming compounds, inorganic bases, such as, for example, an equivalent of sodium, potassium, lithium, calcium, magnesium or ammonium or organic base is rice(hydroxymethyl)amino - methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methylglucamine,

- tarifitsiruemih compounds, alkyl radicals with the formation of alkoxycarbonyl groups, such as, for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, and these alkyl radicals can be substituted by radicals chosen, for example, from halogen atoms, hydroxyl radicals, alkoxy, acyl, acyloxy, alkylthio, amino or aryl, such as, for example, chloromethyl, hydroxypropyl, methoxymethyl, propionylacetate, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl.

Additive salts of inorganic or organic acids of the compounds of formula (I) can be, for example, salts formed from hydrochloric, pomodorini, iododecane, nitric, sulfuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, Glyoxylic, aspartic, ascorbic acid, allylmalonate acids such as, for example, methanesulfonate, econsultancy, propanesulfonic acid; alkyldiethanolamine acids such as, for example, mutandis alsultany acid, and originationtime acids.

When R2and R3are both sulfur-containing group, R2and R3the same or different, in the preferred compounds of the invention, these sulfur-containing groups do not necessarily have the same degree of oxidation.

The present invention also concerns the above-described compounds of formula (I) complying with formula (IA):

< / BR>
in which R1Ais a hydrogen atom, hydroxy-, alkoxy radical, a formyl, dioxolan, aryl, arylcarbamoyl, aaltio, alkylcarboxylic, where the alkyl, linear or branched, contains not more than 6 carbon atoms, and aryl and alkyl in all the radicals representing R1can be substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, alkoxy, alkylthio containing not more than 6 carbon atoms, acyl, carboxy free, turned into salt, esterified or liderando, radicals, cyano, nitro, amino, possibly substituted by one or two identical or different alkyl radicals containing not more than 6 carbon atoms, cycloalkyl containing from 3 to 7 carbon atoms, and phenyl, the alkyl and alkoxy, containing not more than 4 carbon atoms, trifloromethyl, free carboxyl, converted into a salt or esterified, cyano radical and tetrazolyl,

R2Aand R3Aidentical or different, chosen from:

a) halogen atoms, radicals, mercapto, acyl, free carboxyl, converted into a salt or esterified, nitro, cyano radicals,

b) the radicals R4aand-OR4awhere

or R4Ais the radical -(CH2)m3-S(O)m2-Xa-R10awhere

m3 is an integer from 0 to 1, m2 is an integer from 0 to 2 and

either Xa-R10ais an amino radical,

either Xais a simple bond or a radical-NH, -NHCO-, -NHCO-O-, -NHCO-NH - and-N= CH-NR11A-, and R10ais alkyl, alkenyl or aryl, and these radicals possibly substituted by one or more substituents selected from halogen atoms, hydroxyl radicals, alkyl and alkoxy containing not more than 4 carbon atoms, radicals of trifloromethyl, nitro, cyclohexyl, cyclopentyl, aryl, possibly substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, alkyl, alkoxy containing not more than 6 carbon atoms, tRNA, possibly substituted by one or two identical or different alkyl radicals containing not more than 4 carbon atoms, and R11Ais a hydrogen atom or has the meanings given for R10aor R4Ais a hydrogen atom; an alkyl, alkenyl and acyl, and these radicals, linear or branched and contain not more than 6 carbon atoms and may be interrupted by one or more heteroatoms selected from sulfur atoms, oxygen or nitrogen; aminosalicylate, possibly substituted by one or two alkyl radicals, identical or different, containing not more than 6 carbon atoms; cycloalkyl containing from 3 to 6 carbon atoms, or aryl, and alkyl, alkenyl and all aryl radicals representing R4can be substituted by one or more identical or different radicals chosen from:

- atoms of halogen,

is hydroxyl, mercapto, cyano, azido, nitro, SO3H, free carboxyl, turned into salt, esterified or liderando,

- alkyl, alkenyl, alkoxy, haloalkyl, alkylthio, acyl, acyloxy, atillio, haloalkylthio, haloalkoxy radicals, and these radicals contain not more than 6 carbon atoms, and aryl,many identical or different radicals, selected from halogen atoms, hydroxyl radicals, alkyl and alkoxy radicals containing not more than 6 carbon atoms, trifloromethyl, free carboxyl, converted into a salt or esterified radicals, cyano, nitro, amino, possibly substituted by one or two identical or different alkyl radicals containing not more than 4 carbon atoms, tetrazolyl, and phenyl, possibly substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, alkyl and alkoxy radicals containing not more than 4 carbon atoms, trifloromethyl, free carboxyl, converted into a salt or esterified,< / BR>
radicals

< / BR>
< / BR>
where, or R6Aand R7Aor R8Aand R9Aidentical or different, chosen from:

is a hydrogen atom,

is an alkyl radical containing not more than 4 carbon atoms and is possibly substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl or alkoxy radicals containing not more than 4 carbon atoms,

- aryl and arylalkyl, where alkyl radicals, linear or branched and contain not more than 4 carbon atoms, and aryl and arylalkyl can be the ANO, trifloromethyl, the radicals alkyl, alkoxy and acyl containing not more than 6 carbon atoms, amino radical, possibly substituted by one or two identical or different alkyl radicals containing not more than 4 carbon atoms, free carboxy radicals, converted into a salt or esterified, tetrazolyl and phenyl, possibly substituted by one or more radicals chosen from halogen atoms, hydroxyl, trifloromethyl, nitro, cyano, free carboxyl, converted into a salt or esterified, and tetrazolyl,

- radical -(CH2)m1-S(O)m2-X-R10defined above,

or R6Aand R7Aor R8Aand R9Aform respectively with the nitrogen atom to which they relate, monocyclic radical containing 5, 6 or 7 links, or a radical consisting of condensed cycles containing 8 to 14 links, and these radicals, identical or different, may contain one or more other heteroatoms chosen from oxygen atoms, nitrogen or sulfur and may be substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, nitro, cyano, trifloromethyl, the radicals alkyl, alkoxy and acyl containing skillname radicals, containing not more than 4 carbon atoms, free carboxyl, turned into salt, esterified or liderando, tetrazolyl, oxazolyl and phenyl, possibly substituted by one or more radicals chosen from halogen atoms, hydroxyl radicals, trifloromethyl, nitro, cyano, free carboxyl, converted into a salt or esterified, and tetrazolyl,

or R8Aand R9Aidentical or different, are acyl, or one of them, R8Aor R9Ais carbamoyl, alkoxycarbonyl or benzyloxycarbonyl, and the other is chosen from the above values for R8Aand R9Aor R8Aand R9Aform together with the nitrogen atom to which they relate, phthalimido or succinimido radical,

YAis the radical Y1A-B-Y2Awhere:

Y1Ais aryl, possibly substituted by one or more radicals chosen from the radicals of dioxole and radicals, which can mean R2Aand R3A,

B is a simple relationship between Y1Aand Y2Aor one of the divalent radicals: -CO-, -O-, -NH-CO-, -CO-NH - or-O-(CH2)p- where p is 1,2 or 3, Y2Ahas the following values:

or, outside zavisimyh for Y1A,

or, if a is a simple bond, Y2Ais a hydrogen atom, a halogen atom, an alkoxy radical, cyano, free carboxyla or carboxyterminal, turned into salt, esterified or emitirovannykh, tetrazolium or the radical -(CH2)m3-S(O)m2-Xa-R10adefined above, with compounds of formula (IA) are presented in all possible racemic forms, isomers, enantiomers and diastereoisomers, as well as additive salts with inorganic or organic acids or with inorganic or organic bases.

The invention applies in particular to compounds of the above formula (I) complying with formula (IIN):

< / BR>
in which R1Bis a hydrogen atom, alkoxy radicals, dioxolan, phenyl, benzoyl, phenylthio, where phenyl optionally substituted by one or more radicals chosen from halogen atoms, hydroxyl, alkyl and alkoxy radicals containing not more than 4 carbon atoms, trifloromethyl, cyano, free carboxyl, converted into a salt or esterified, and tetrazolyl,

R2Band R3Bidentical or different, chosen from:

a) atoms of radikalov alkoxy and acyl, containing not more than 6 carbon atoms; nitro; cyano and benzoyl;

a) radicals R4Band-OR4Bwhere

or R4Bis the radical - (CH2)m3-S(O)m2-XB-R10B,

where m3 is an integer from 0 to 1, m2 is an integer from 0 to 2

either XB-R10Bis aminosalicylate,

either XBis a simple bond or a radical NH, -NHCO-, -NH-CO-O-, -NH-CO-NH - and-N=CH-NR11Band R10Bis stands, ethyl, propylene, vinyl, allyl, pyridium, phenyl, pyrimidinyl, tetrazolyl, thiazolyl, diazolinum, chinaillon or fullam, and these alkyl and alkeneamine radicals can be substituted by one or more substituents selected from halogen atoms, hydroxyl and alkoxy containing not more than 4 carbon atoms, radicals of trifloromethyl, nitro, cyclohexyl, cyclopentyl, pyridyl, pyrimidinyl, teinila, tetrazolyl and phenyl, all the phenyl radicals may be substituted by one or more radicals selected from halogen atoms, hydroxy radicals, alkoxy, containing not more than 4 carbon atoms, cyano and tetrazolyl, a R11Bis a hydrogen atom or has the values of R10B,

or R4Bis a hydrogen atom, or alkyl phenyl, pyridium, pyrimidinium, tetrazolium or imidazolium, and these radicals can be substituted by one or more identical or different radicals chosen from:

- atoms of halogen,

is hydroxyl, mercapto, atillio, trifloromethyl, triptoreline, triptoreline, cyano, azido, nitro, formyl, -SO3H, free carboxyl, turned into salt, esterified or liderando,

radicals of alkyl, alkylthio, acyl, acyloxy and alkoxy radicals containing not more than 6 carbon atoms, and phenyl, phenylthio, all these radicals can be substituted by one or more radicals chosen from halogen atoms, hydroxy radical, alkoxy radicals containing not more than 4 carbon atoms, free carboxyl, turned into salt, esterified or liderando, a nitro radical and a phenyl,

radical isoxazolyl, pyrrolidinyl, pyrrolidinylcarbonyl, pyridyl, pyrimidyl, thiazolyl, diazole, piperidinyl, tetrazolyl, tetrahydrofuranyl, all these radicals can be replaced by stands, ethyl or nitro radical,

radicals

< / BR>
< / BR>
where, or R6Band R7B, R8Band R9Bidentical or different, wdnm or more identical or different radicals, selected from halogen atoms, hydroxyl or alkoxy radicals containing not more than 4 carbon atoms, the radicals phenyl, benzyl, Venetia, azepine, piperidyl, research, pyrrolidinyl, piperazinil,

or R6Band R7Bon the one hand, and R8Band R9Bon the other hand, form respectively with the nitrogen atom to which they are attached, heterocyclic radical, these radicals are identical or different, chosen from imidazolyl, pyrrolyl, pyrrolidyl, pyrrolidinyl, pyridyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperazinil, phenylpiperazine, piperidyl, oxazolyl, morpholinyl and thiomorpholine, azepine, indolyl, and these radicals can be substituted by one or more identical or different radicals chosen from halogen atoms, hydroxyl radicals, nitro, cyano, acyl, trifloromethyl, alkyl and alkoxy, containing not more than 4 carbon atoms, free carboxyl, turned into salt, esterified or liderando, tetrazolyl, oxazolyl and phenyl,

YBis phenyl, possibly substituted by one or more radicals chosen from halogen atoms, radicals of dioxole, cyano, free carboxyl UB>-S(O)m2-XB-R10Bdefined above,

moreover, the compounds of formula (IB) are presented in all possible forms of racemic isomers, enantiomers and diastereoisomers, as well as additive salts with inorganic or organic acids or with inorganic or organic bases.

The invention applies in particular to compounds of the formula (I) corresponding to the above formula (IB), when one or both of the following conditions:

Y is phenyl, possibly substituted by two radicals, forming together dioxol, and possibly substituted by one or more radicals chosen from halogen atoms and alkoxy radicals, free carboxy or carboxyterminal, converted into a salt or esterified, or at least one of R2Band R3Bchoose from the following radicals:

-(CH2)m3-S(O)m2-XB-R10Bdefined above,

of alkyl, substituted free carboxylation, turned into salt, esterified or emitirovannykh,

- formyl,

- free carboxyl, turned into salt, esterified or liderando,

and aryl,

moreover, these soeriaatmadja, and also as additive salts with inorganic or organic acids or with inorganic or organic bases.

The radical -(CH2)m3-S(O)m2-XB-R10Bcan mean, in particular, radicals in which XB-R10Bis the following radicals:

-NH-CO-V-V4,

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where n3 is an integer from 0 to 3, V is a simple bond or a radical-NH - and-O - V1V2identical or different, are a hydrogen atom, a halogen atom, in particular chlorine or fluorine, and alkoxy radicals, in particular methoxy radical, and V4is a hydrogen atom or an alkyl or alkenyl radical, such as methyl, ethyl, propyl, butyl, vinyl or allyl.

The radical -(CH2)m3-S(O)m2-XB-R10Bas described above, can also as a non-limiting example to mean radicals:

-SO2-NH2,

-SO2-N=CH-N(CH3)2,

-SO2-NH-CO-CF3,

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
SO2-NH-CO-NH-nPr,

< / BR>
< / BR>
< / BR>
-SO2-NH-CO2H,

-SO2-NH-CO2Et,

-SO2-NH-CO2Pr,

-SO2-NH-CO2BU

< / BR>
1is a hydrogen atom, alkoxy radical, dioxolan, phenyl, benzoyl, phenylthio radical in which the phenyl may be substituted by hydroxy radicals or alkoxy radicals containing not more than 4 carbon atoms,

R2and R3identical or different, chosen from halogen atoms; the free carboxy radical, turned into

salt or esterified with an alkyl radical containing not more than 4 carbon atoms; formyl; and radicals tetrazolyl, phenyl, phenylthio, phenylsulfonyl, phenylsulfinyl, alkyl containing not more than 4 carbon atoms, alkylthio, alkylsulfonyl and alkylsulfonyl, all these radicals can be substituted by one or more radicals chosen from halogen atoms, hydroxy radicals, alkoxy containing not more than 4 carbon atoms, free carboxyl, converted into a salt or esterified, phenyl, possibly substituted by a hydroxy radical or alkoxy containing not more than 4 carbon atoms,

and Y is phenyl, possibly substituted by two radicals, forming together dioxol, and one or more atoms of halogen,

moreover, these compounds of formula (I) are presented in all possible racemic forms by isocitrate or with inorganic or organic bases.

The invention also concerns the compounds of formula (I) complying with formula (ID), in which:

R1is a hydrogen atom, 1,3-dioxolane, phenyl, benzoyl, phenylthio, in which phenyl may be substituted by a hydroxy radical or alkoxy containing not more than 4 carbon atoms,

R2is a halogen atom; alkylthio radical in which the alkyl radical, linear or branched, contains not more than 4 carbon atoms and may be substituted by phenyl which may itself be substituted by a alkoxy radical and a radical of phenylthio, where phenyl possibly substituted by alkoxyalkyl,

R3is formyl or free carboxylation, esterified, converted into a salt or emitirovannykh, and U is phenyl, possibly substituted by a halogen atom and two radicals, forming together dioxol,

moreover, these compounds of formula (I) are presented in all possible forms of racemic isomers, enantiomers and diastereoisomers, as well as additive salts with inorganic or organic acids or with inorganic or organic bases.

Among the compounds that are the subject of the invention include, inter alia, the following with the ol-5 - carboxaldehyde,

-4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl) -2-phenyl-1H-imidazole-5-carboxylic acid,

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-(((4-methoxy-phenyl) methyl)thio)-2-(phenylthio)-1H-imidazole-5-carboxylic acid,

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-(4-methoxy-phenyl)thio) -2-(phenylthio)-1H-imidazole-5-carboxylic acid,

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2,4-bis (4-methoxy-phenyl)thio)-1H-imidazole-5-carboxylic acid,

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-((3,4 - dimethoxy-phenyl)thio)-2-(1,3-dioxolane-2-yl)-1H-imidazole-5 - carboxylic acid,

as well as their extension salts of inorganic or organic acids or inorganic or organic bases.

The subject of the invention is also a method of obtaining compounds of the above formula (I), characterized in that:

or spend the reaction of the compound of formula (II):

< / BR>
where R'1has the values specified above for R1where possible reactive functions are optionally protected by protective groups, with a compound of formula (III):

< / BR>
where Gal is a halogen atom, and Y' have the values specified above for Y, where possible reactive functions are optionally protected by a protective group, to obtain a product of formula (> are galogenirovannyie to obtain the compounds of formula (IV2):

< / BR>
where R'1, Gal and Y' have the above meanings, or a compound of the formula (VIII):

< / BR>
where a Gal has the above values,

or injected into the reaction interaction with the above-described compound of the formula (III),

or protect the protective group P, to obtain a product of formula (IX):

< / BR>
where a Gal has the above values, and W is a or-CH2-Y', where Y' is defined above, or a group P, which is a protective group of a nitrogen atom, the compound obtained of the formula (IX) is subjected to the reaction of the exchange of the halogen-metal, then the reaction of interaction with an electrophilic compound of formula (X), (X'), (XI), (XII) or (XII'):

L1- CHO (X)

L1- CO - Cl (X')

(-S-L1)2(XI)

L1SO2-S-L'1(XII)

L1SO2-Cl (XII')

where L1and L'1identical or different, are alkyl, alkenyl or aryl, as defined above,

to obtain the compounds of formula (XIII):

< / BR>
where Gal and W have the above values, R1means aryl - or alkyl-carbonyl, aryl - or alkyl-hydroxymethyl or aaltio radical, where the aryl and alkyl radicals have indicated the compound of formula (IV2) or (XIII) is subjected to the reaction of the exchange of the halogen-metal with one of the halogen atoms, then the reaction of interaction with CO2or DMF or electrophilic compound of formula (Ya), (Yb), (Va), (VIb), (VIc):

(S-Z1)2(Va)

or

MeSO2SZ1(Vb)

or

< / BR>
or

< / BR>
or

< / BR>
where Z1is alkyl, alkenyl or aryl, possibly substituted, in which the possible reactive functions are optionally protected by a protective group, and ALK is an alkyl radical containing not more than 4 carbon atoms, to obtain, respectively, the compounds of formula (I1):

< / BR>
or the compounds of formula (XIV)

< / BR>
in which R'1, R1, Gal, Y' and W have the abovementioned meanings and Z3is a carboxy radical, a formyl,

S-Z1defined above, or a radical R-O-ALK, where K is the radical

< / BR>
and ALK have the above values,

the compound obtained of the formula (I1or (XIV), when Z3is formyl or esterified carboxy radical, is subjected to the reaction of interaction with the compound of the formula (VII):

Z2-S-M (VII)

where S is a sulfur atom, is but substituted, in which the possible reactive functions are optionally protected by a protective group, to obtain, respectively, the compounds of formula (I2):

< / BR>
or the compounds of formula (XV):

< / BR>
in which R'1, R1, Y', Z2and W have the abovementioned meanings and Z4is formyl or esterified carboxy radical, the compound obtained of the formula (I2or (XV), when Z4is formyl, oxidised or reduced to, respectively, the compounds of formula (I3):

< / BR>
or the compounds of formula (I4):

< / BR>
where R'1, R1, Z2, Y' and W have the abovementioned meanings and Z5is the radical CH2OH or a carboxy radical, free or esterified linear or branched alkyl radical containing not more than 6 carbon atoms; the resulting compound of formula (XV) or (I4) when W is defined above by P, after the release of the blocked group P aminophenol, is subjected to a reaction between the above compound of formula (III) with a compound of formula (I5):

< / BR>
where R1and Y' have the above significance, and R2and R3independently from each other, about inania formula (XVI):

< / BR>
where R'1has the above values, a R'2and R'3are shown, respectively, for R2and R3where possible reactive functions are optionally protected by protective groups,

subjected to a reaction between the above compound of formula (III) with a compound of the formula (I'):

< / BR>
where R'1, R'2, R'3, Y' have the above values,

the compounds of formula (I1), (I2), (I3), (I4), (XIV), (XV), (I5) and (I') can be compounds of the formula (I) and distinguish them or to obtain other compounds of formula (I) is subjected, if desired and if necessary, one or more of the following conversion reactions, in any order:

a) esterification of the acid function,

b) saponification of essential functions to acid,

C) a reaction for the conversion of essential functions in the acyl,

g) a reaction for the conversion of the cyano function in acid,

d) a reaction for the conversion of the acid function in the amido function, then if necessary in thioamide function,

(e) the restoration of the carboxy function to an alcohol function,

g) a reaction for the conversion of alkoxy function in the hydroxy function or hydroxy-options) the conversion of formyl in carbarnoyl,

l) a reaction for the conversion of carbamoyl in nitrile,

m) the conversion of nitrile in tetrazolyl,

h) oxidation of alkylthio or aaltio group to a sulfoxide or sulfone, respectively,

a) the conversion of sulfide, sulfoxide or sulfone in the appropriate sulfoximine,

p) reaction conversion oxo-functions to thioxo function,

p) reaction for the conversion of the radical in the radical then, if necessary, again in the moiety , where L1defined above,

(C) a reaction for the conversion of the acid function into a function:

< / BR>
t) reaction conversion-keto-sulfoxide functions in-ketotifen function,

I) the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea,

f) removing the protective groups which can be protected reactive functions,

x) the formation of salts with inorganic or organic acid or base

C) reaction of the separation of racemic forms, with the compounds of formula (I) are presented in all possible racemic forms, isomers, enantiomers and diastereoisomers.

In a preferred method of carrying out the invention, the above-described way can the mA but it can also be a chlorine atom or iodine. The condensation reaction of imidazoles described above formulas (II), (VIII), (XVI), (XV) and (I4) (for compounds of formula (XV) and (I4) when W is the group P and after removal of the protective groups of the nitrogen atom) with a compound of formula (III) receiving, respectively, compounds of formula (IY1), (IX), when W is Y', and compounds of formula (I5) and (I'), this reaction can be carried out in a solvent such as, for example, dimethylformamide or dimethylacetamide, tetrahydrofuran, dimethoxyethane or dimethylsulfoxide at a temperature of the boiling point of the solvent under reflux or at room temperature, preferably with stirring; the reaction is carried out preferably in the presence of a base, such as, for example, sodium hydride or potassium or sodium carbonate or potassium, methylate, ethylate or tert-butyl sodium or potassium.

The reaction of halogenation of compounds of formula (IV1in the compound of formula (IV2) can be carried out under normal conditions and, in particular, bromirovanii using Ufa science BSI in CH2Cl2or with Br2in acetic acid.

Compounds of formula (IV2), (IX) and (XIII) can be Padberg, the mayor as n-utility or EtMgBr, in a solvent such as THF at a temperature about -78oC for utility and at room temperature for EtMgBr.

The carboxylation reaction with CO2and formirovaniya using DMF compounds of formula (IV3and (XIII) into compounds of formula (I1and (XIV) can be carried out in normal conditions, for example in THF at room temperature.

Z1and Z2identical or different, have the following meaning radicals alkyl, alkenyl or aryl, to Z1-S - and Z2-S - have the respective meanings indicated above for R2and R3in which the possible reactive functions are optionally protected by protective groups.

L1and L'1identical or different, are alkyl, alkenylamine or aryl radical, to R1had corresponding values selected from the values for R1in which the possible reactive functions are optionally protected by protective groups.

The reaction of interaction of the compounds of formula (IV2) or (XIII) with the compound of the formula (VIa) (VIBor (VIc) to obtain the corresponding compounds of formula (I1) and is alizatio in tetrahydrofuran at room temperature.

The reaction of interaction of the compounds of formula (IV2and (XIII) with compounds of the formula (Va) or (Vb) can be carried out in the usual conditions known to a specialist, i.e., for example, in tetrahydrofuran at room temperature.

The reaction of interaction of the compounds of formula (IX) with compounds of formula (X), (X'), (XI), (XII) and (XII') can be carried out in known for specialist conditions, i.e., for example, in THF at room temperature.

Amino-function compounds of formulas (XV) and (I4) protected group P, defined above, can be released under conditions known to the specialist, and, in particular, when P is a radical-CH2-O-(CH2)2-Si(CH3)3the hydrogen atom may be released in THF or in the presence of fluoride ion.

The saponification reaction can be carried out by conventional methods known to the expert, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of caustic soda or sodium hydroxide, or cesium carbonate.

Of reduction reaction, or oxidation of the compounds of formula (I2and (XV) respectively to compounds of formula (I3) and (I4could be made in the usual way 3, R3compounds of formula (I1), (I2), (I3), (I4), (I5), (XIV), (XV) and (I') can submit or not to submit a compound of formula (I) and can form compounds of formula (I) or may be converted into other compounds of formula (I) by one or more of the above reactions from a) to C).

Thus, different reaction functions, which may have some connection in the above reaction, may if necessary be protected: we are talking about, for example, free radicals hydroxyl, acyl, carboxy, or about amino, monoalkylamines radicals, which may be protected with appropriate protective groups.

The following is a non-limiting list of protective groups of the reaction functions:

- hydroxyl group may be protected, for example, alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,

the amino group may be protected, for example, acetyl, Triticum, benzyl, tert-butoxycarbonyl, phthalimido or other radicals known in the chemistry of peptides,

- acyl groups such as formyl, can be protected, for example, in videotel, or dietetically or atlanticocean,

acid functions of the above-described compounds can be optionally lidirovali primary or secondary amine, for example in methylene chloride in the presence of, for example, the hydrochloride of 1-ethyl-3- (dimethylaminopropyl)carbodiimide at room temperature,

acid functions can be protected, for example, in the form of esters formed with easily biodegradable esters, such as benzyl ester acid or tert-butyl acid or esters known in the chemistry of peptides.

The reaction, which, if desired, or if necessary, are compounds of formula (I1), (I2), (I3), (I4), (I5), (XIV), (XV) and (I') can be carried out, as described below.

a) the Above-described compounds may be optionally tarifitsirovana possible carboxy functions, the esterification reaction can be carried out by conventional methods known to the expert.

b) Possible reaction for the conversion of essential functions in the acid functions of the above-described compounds can be optionally carried out in the usual conditions known to the expert, in particular by acid or alkaline hydrolysis, vodorodnoi or sulfuric acid.

C) Reaction of the conversion of essential functions where E1can be alkyl or aryl radical, possibly substituted and protected acyl function , can be implemented in particular by the impact of a carbanion where E2E3and E4identical or different, are chosen from hydrogen atoms, alkyl radicals, alkylaryl, alkylsulfonate, arylsulfonate, alkylsulfonate, arylsulfonate, acyl, free carboxyl, turned into salt, esterified or liderando, and also radicals of alkyl, alkylthio and aryl, possibly substituted and protected as described above.

This reaction is carried out, in particular, as described in the experimental part, or by conventional methods known to the expert.

g) Possible cyano-functions of the above-described compounds can be converted to the acid function in the usual conditions known to a specialist, such as a double hydrolysis in an acid medium, for example in a mixture of sulfuric acid, glacial acetic acid and water, and all three components are taken, preferably, in equal shares, or in a mixture of sodium hydroxide, ethanol and water at boiling temperature under reflux.

d) Re the Oia first carboxylic acid under normal conditions, well-known specialist, and, for example, the influence of SOCl2then amidation described above, or by direct amidation of acid.

In particular, it is possible to get radical:

< / BR>
by conversion of the acid function into an acid chloride of the acid, in particular, the influence of SOCl2in a solvent such as, for example, toluene or benzene, followed by reaction with amine:

< / BR>
Thus obtained amide can be converted to thioamide, in particular, the influence of reagent Lawesson in toluene.

e) Possible free or esterified carboxy functions of the above compounds can be optionally restored to an alcohol function by the methods known to the expert: the possible esterified carboxy functions can be restored to an alcohol function well-known specialist methods, in particular using lithium hydride and aluminum in a solvent such as, for example, tetrahydrofuran or dioxane or ethyl ether.

Possible free carboxy functions of the above-described compounds can be optionally restored to an alcohol function, in particular, by using a boron hydride.

g) Possible alkoxy-funkcie functions in well-known specialist conditions, for example, using tribromide boron in a solvent such as, for example, methylene chloride, using bromhidrosis or pyridine hydrochloride or by using pomodorini or hydrochloric acid in water or triperoxonane acid at the boiling temperature under reflux.

and Possible alcohol functions described above products can be, if desired, converted into aldehyde or acid function by oxidation under normal conditions, known to the specialist, for example using manganese oxide, obtaining aldehydes or using Jones reagent with obtaining acids.

K) l) the conversion of formyl in carbarnoyl and carbamoyl in the nitrile is carried out, in particular, for R3and R4in the usual conditions known to the expert, for example, passing through ketonitriles and by displacing the amine (Chem.Comm./ 1971, S. 733).

m) Possible nitrile functions of the above-described compounds can be, if desired, converted into tetrazolyl in the usual conditions known to a specialist, such as cyclopentadiene metal azide such as sodium azide or azide trialkyl tin on the nitrile function, as described in the publication J. Organometallic Chemistry) 31,337 (1971) S. KOZIMA 7 & coll.

Getting sulfoxides functions can be facilitated by using equimolar mixture of compounds containing alkylthio or aaltio group, and reagent, such as, for example, percolate.

Obtaining a sulfonic function can be facilitated by use of a mixture of compounds containing alkylthio or aaltio group, with an excess of reagent, such as, in particular, percolate.

about Possible sulfide, sulfoxide or sulfonic functions of the above-described compounds can be optionally converted into a corresponding sulfoximine function in the usual conditions known to a specialist: the non-limiting examples of the preparation of compounds containing sulfoximine functions described below.

For example, to obtain compounds such as N- (arylsulfonyl)sulfoximine and, for example, when the aryl group represented by X' is toluene, sulfoximine can be obtained by the reaction of azide paratoluenesulfonyl in the publication by J. A. C. S., 95, S. C. 4287 (1973) JOHNSON C. R. & coll.

Another method used is that the process N-tesislerinin obtained from sulfide by reaction with, for example, chloramine T, oxidant such as sodium hypochlorite, in terms of the transfer phase, as described, for example, in the publication J.Org, Chem., 49, pp. 2282 (984) K. AKUTAGAWA & coll.

p) Reaction conversion oxo function in thioxo function can be carried out, in particular, by using a reagent Lawesson under these conditions.

p) Reaction conversion of the radical in the radical can in particular be carried out using manganese oxide in dioxane.

The reverse reaction is the conversion of the radical in the radical can be carried out, in particular, by using borgert sodium in ethanol.

C) the Reaction conversion of the acid function in tetraallyloxyethane can be carried out, for example, by first converting the acid function in chlorhydric acid, as described above, then the reaction of Cu-CN, a well-known specialist normal conditions, with the obtained acid chloride acid, thereby obtaining a radical which can be converted into the radical:

< / BR>
for example, the reaction of the compound Sn(Bu)3Nmay be carried out by bromirovanii in the alpha-position keto-sulfoxide, for example, using NBS in, for example, methylene chloride, followed by reaction of PUMMERER in a mixture triperoxonane acid and methylene chloride or mixtures of sulfuric acid and dioxane.

In particular, as described above in PP) - t), you can perform the following sequence of reactions:

< / BR>
compounds in which R'1and Y' have the above significance, and R is alkyl or aryl, possibly substituted, as described above.

d) Reaction of the conversion of carbamate into urea and, in particular, sulfonylamino in the sulfonylurea may be implemented, for example, at the boiling temperature of the solvent under reflux, for example, in toluene, in the presence of adequate Amin.

f) removing the protective groups, such as described above may be carried out in the usual conditions known to the expert, in particular by acid hydrolysis carried out such an acid, such as hydrochloric, benzolsulfonat or para-toluensulfonate, formic or triperoxonane acid, or by catalytic hydrogenation.

Phthalimido group can be removed using hydrazine.

A list of the different used protective groups described, for example, in PA what omashu inorganic or organic acids or inorganic or organic base according to the usual methods, well-known specialist.

C) the Possible optically active forms of the above products can be obtained by separation of the racemate according to conventional methods known to the expert.

The above reactions are illustrated in the following examples of the preparation.

The compounds of formula I and their additive salts with acids have valuable pharmacological properties.

The above compounds of formula (I) have antagonistic properties against endothelin receptors and are therefore, in particular, inhibitors of the effects of endothelin, in particular, inhibitors vasoconstrictor and hypertensive actions induced by endothelin. It is noted, especially, anti-ischemic effect, while the vasoconstrictor effect of endothelin disappears.

The compounds of formula I are capable to resist to the stimulating effect of endothelin on the level of all types of cells, in particular cells, smooth muscle, nerve and bone cells.

These properties justify their use in therapy, and the invention concerns the use as medicaments the above compounds of formula (I), and these compounds of formula (I) is present in all uditing salts with inorganic or organic acids or with inorganic or organic bases.

The invention relates, particularly, use as drugs of compounds of formula (IA) and (IB), and these compounds of formula (IA) and (IB) are presented in all possible isomeric racemic or optically active forms, as well as pharmaceutically acceptable additive salts with inorganic or organic acids or with inorganic or organic bases.

The invention relates, particularly, use as drugs of compounds of formula (Ic), and these compounds of formula (Ic) are presented in all possible isomeric racemic or optically active forms, as well as pharmaceutically acceptable additive salts with inorganic or organic acids or with inorganic or organic bases.

The invention relates, particularly, use as drugs of compounds of formula (ID), and these compounds of formula (ID) are presented in all possible isomeric racemic or optically active forms, as well as pharmaceutically acceptable additive salts with inorganic or organic acids or with inorganic or organicann above compounds of formula (I), in particular, the following:

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-(((4-methoxyphenyl) methyl)thio)-2-(phenylthio)-1H-imidazol-5-carboxaldehyde,

-4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl) -2-phenyl-1H-imidazole-5-carboxylic acid,

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-(((4-methoxyphenyl)methyl) thio)-2-(phenylthio)-1H-imidazole-5-carboxylic acid,

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- (4-methoxy-phenyl)thio)-2-(phenylthio)-1H-imidazole-5-carboxylic acid,

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2,4-bis(4 - methoxyphenyl)thio)-1H-imidazole-5-carboxylic acid,

-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-((3,4-acid) thio)-2-(1,3-dioxolane-2-yl)-1H-imidazole-5-carboxylic acid,

and their pharmaceutically acceptable additive salts with inorganic or organic acids or with inorganic or organic bases.

The drugs that are the subject of the present invention can find application, for example, in the treatment of all vascular spasms, cerebral post-hemorrhagic States, spasms of the coronary arteries, peripheral vascular, and renal failure. These medicines can also be used for the treatment of myocardial infarction, cardiovascular nedostatocnost the hypertension, in particular pulmonary hypertension, as well as for the treatment of asthma.

The drugs that are the subject of the present invention may also find application in the treatment of osteoporosis, prostatic hyperplasia and to protect nerve cells.

The invention also concerns pharmaceutical compositions containing as active principle at least one of the above medicines.

These pharmaceutical compositions may be administered orally, rectally, parenterally or locally for application to the skin and mucous membranes, or for intravenous or intramuscular injection.

These compositions can be solid or liquid and can be presented in all the pharmaceutical forms commonly used in medicine, for example simple tablets or coated tablets, gelatin capsules, granules, suppositories, injectable solutions, ointments, creams, gels and aerosols; they are prepared by conventional methods. The active principle can be put into eccipienti commonly used in pharmaceutical compositions, such as talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous media, animal or vegetable fats, paraffin is tx2">

Prescribed dosage of the drug depends on the connection from the patient and the type of disease and may be, for example, 1-300 mg / day for an adult in oral introduction, and 1-100 mg / day when administered intravenously.

Some of the initial compounds of formulas (II) and (XVI) are known and can be obtained, for example according to European patent EP 0168950.

Other starting compound of formulas (II) and (XVI) are available on sale, as, for example, the compound of formula II: 2-phenylimidazol manufactured by Aldrich.

Examples of compounds of the formula (XVI), available on the market, are given in the patents EP 0465368 and EP 0503162.

In addition, some compounds of formulae (II) and (XVI) can be obtained from compounds of formula (II), if, for example, these compounds can undergo one or more reactions, as described in paragraphs a) - C) above, carried out in the above-described conditions.

Some compounds of formula (XVI) can also be obtained by monohalogenated the compounds of formula II, described above, to obtain compounds of formula (P1):

< / BR>
in which R'1and P have the values specified above for the compounds of formula (II), the compound obtained is subjected to the interaction of the compound according to well-known specialist methods in particular, using the same type of reaction, which is described above for converting compounds of formula (XIII) to a compound of formula (XIV).

The initial compounds of the formula (VIII) can also be found on the market, in particular 2,4,5-tribromoimidazole manufactured by Aldrich, or they can be obtained according to known methods.

The initial products of formula (Ya), (Yb), (VIa), (VIb), (VIc) are commercially available, in particular the products of formula (Vaor (XI), such as:

- sec-butyl disulfide,

- ethyl disulfide,

- isopropyl disulfide,

- methyl disulphide,

- benzyl disulfide,

- phenyl disulphide,

- propyl disulfide,

the compounds of formula (Vbor (XII), such as:

- methylmethanesulfonate,

- vinylbenzenesulfonic,

the compounds of formula (VIasuch as:

- methylchloroform,

- benzylchloride,

- isobutylphthalate,

- ethylchloride,

- N-propylchloride,

the compounds of formula (VIbsuch as:

- dimethylcarbonate,

- diethylcarbamyl,

the compounds of formula (VIcsuch as:

di-tert-butylacetate,

- diethyloxalate,

- dimethyloxalate.

July (X), as

- benzaldehyde or butanal

or the compounds of formula (X'), such as:

- benzoyl - or butyryl chloride,

or the compounds of formula (XII'):

- methylchloride,

- taillored.

The way some of the compounds of the formula (III) are described in particular in European patent EP 0465368.

Examples of preparing compounds of the formula (III) is also described in the literature, in particular in the patent US 4,880,804 or in the journal Chemistry and Industry, 7 september 1987, HOWARD and COLQUHOUN c.c. 612-617.

Thus, the compound of formula (III), in particular, 6 - chloropiperonyl, manufactured by a company Jansen.

The object of the present invention are new industrial products of formula (IV1), (IV2), (XIII), (XIV) and (XV) in which Y' is phenyl, possibly substituted by one or more radicals chosen from halogen atoms and dioxolane radicals, where possible reactive functions are optionally protected by protective groups.

The object of the present invention is, in particular, the use of compounds of the above formula (I) to obtain pharmaceutical compositions intended for the treatment of diseases caused by abnormal stimulation of endothelin receptors.

ISi, intended for the treatment of hypertension caused by endothelin.

The invention in particular relates to the use of compounds of formula (I) to obtain pharmaceutical compositions intended for the treatment of all vascular spasms and cerebral post-haemorrhagic conditions and

renal insufficiency.

The invention in particular relates to the use of compounds of formula (I) to obtain pharmaceutical compositions intended for the treatment of myocardial infarction and prevention of post-angioplasticheskih restenosis.

The following non-limiting examples illustrate the present invention.

EXAMPLE 1

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl) -2-(phenylthio)-1H-imidazol-5-carboxaldehyde

STAGE 1:

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2,4,5-(tribrom)-1H - imidazol

25 g of 2,4,5-tribromoimidazole introduced into 500 ml of dimethylformamide and added 4.3 g of sodium hydride. Stirred for 10 min at room temperature. Then add in the reaction medium of 18.4 g of 6-chloropiperonyl, then 25 g of sodium iodide and stirred for 15 min at room temperature.

Reaction medium was poured into 3 l of water, centrifuged, abundantly p is CLASS="ptx2">

Dried and extracted to 31.5 g of the target product (solid cream color).

Melting point = 225oC

IR CHCl3(cm-1)

No = C-NH

Aromatic heterocycle 1624-1506-1497-1485

STAGE 2:

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4,5 - dibromo-2-(phenylthio)-1H-imidazol

to 4.73 g obtained in stage 1 of the product injected into 100 ml of a mixture of methylene chloride/sulphuric ether (20/80), was added dropwise 3.5 ml of ethylbromide magnesium: is stirred for 30 min at room temperature.

Then in the reaction medium was added 2.9 g vinylbenzenesulfonic. Stirred for 2 hours at room temperature.

Conduct the hydrolysis medium, adding dilute hydrochloric acid, then extracted with ethyl acetate, washed copiously with water and dried, remove the solid cream color, then clear, sagusa in 50 ml of ethanol. So get at 3.35 g of the target product.

So pl. = 165oC.

IR CHCl3(cm-1)

Aromatic heterocycle 1585-1509-1484

Microanalysis

calculated, %: C to 40.6; H 2,2; N 5,57; S 6,37; Br 31,8; Cl 7,05;

received, %: C 40,7; H 2,1; N 5,4; S 6,4; Br 31,4; Cl 6,8.

STAGE 3:

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)marihuana, was added dropwise to 9.3 ml of ethylbromide magnesium. Stirred for 30 min at room temperature.

Then in the reaction medium was added 5 equivalents of dimethylformamide.

Stirred for 2 hours at room temperature.

Conduct the hydrolysis medium, adding dilute hydrochloric acid, then extracted with ethyl acetate, washed copiously with water and dried, remove the solid brown color, which is purified by chromatography on silica with methylene chloride as eluant. So, get 5 g of the target product (the So-square = 155oC), 500 mg which is recrystallized from 25 ml of ethanol: after centrifugation and drying, Recuperat 420 mg of the target product (solid white). (So pl. = 155oC).

IR CHCl3(cm-1)

C=O 1669

Aromatic substance + Heteroatom 1627-1580-1505-1485

Microanalysis

calculated, %: C 47,9; H to 2.67; N 6,2; S 7,09; Br 17,68; Cl 7,84;

received, %: C 47,9; H 2,6; N 6,1; S 7,2; Br 17,7; Cl 7,7.

EXAMPLE 2

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-(((4 - methoxyphenyl)methyl)thio)-2-(phenylthio)1H-imidazole - 5 - carboxaldehyde

620 mg of 50% sodium hydride in oil is introduced into 50 ml tetrahydrofurane.

Then enter in the received tilt 3.8 g of the product of example 1 dissolved in 25 ml of tetrahydrofuran. Stirred under these conditions for 2 h 30 min

Reaction medium was then poured 0.1 N sodium hydroxide, extracted with ethyl acetate, rinsed with water, then dried and Recuperat brown resin, which is purified by chromatography on silica, as eluent, methylene chloride/cyclohexane (80/20), then methylene chloride + 20% ethyl acetate.

Collect 2 faction: 1,97 g of the target product (Pf=135oC) and 1.98 g of the second product, which is obtained in the same conditions: 1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2,4-bis(((4-methoxyphenyl) methyl)thio)-1H-imidazol-5-carboxaldehyde

ANALYSIS OF THE PRODUCT A

IR CHCl3(cm-1)

C=O 1660

Incense + a Heterocycle 1611-1580-1513 - 1505-1485

Microanalysis

calculated, %: C 59,47; H is 4.03; N 5,33; S 12,21; Cl 6,75;

received, %: C 59,2; H 3,8; N 5,2; S 12,0; Cl 6,7.

ANALYSIS OF THE PRODUCT B

IR CHCl3(cm-1)

The absence of S-phenyl

C=O 1655

Incense + a Heterocycle 1612-1585-1512-1508-1485

EXAMPLE 3

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl) -1H-imidazol-5-carboxaldehyde

STAGE 1:

1-((6-chloro-1,3-benzodioxol-5-yl)Matilda 1 product introduced in 300 ml of a mixture of methylene chloride/sulphuric ether (60/40), was added dropwise to 4.6 ml of ethylbromide magnesium, then stirred for 30 min at room temperature, then the reaction medium was added 100 ml of ice water.

After acidification, extraction, washing, and then drying, Recuperat at 3.35 g of the target product (homogeneous solid cream color) (Pf 150oC).

IR CHCl3(cm-1)

A heterocycle + aromatic substance 1626-1508-1484

STAGE 2:

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl) -1H-imidazol-5-carboxaldehyde

Act as in stage 3 of example 1, but originate from 900 mg obtained in stage 1 product, introduced in 10 ml of tetrahydrofuran, and added dropwise 1.7 ml ethyl magnesium bromide. Stirred for 15 min at room temperature.

Then in the resulting reaction medium was added 0.9 ml, i.e., 5 equivalents of dimethylformamide. Stirred for 2 hours at room temperature.

After hydrolysis of the environment by adding dilute hydrochloric acid, extraction, washing and drying remove solid cream color, which is then purified by chromatography on silica, as IR CHCl3(cm-1)

C=O 1670

Aromatic substance + Heteroatom 1625-1510-1485

EXAMPLE 4

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-(((4-methoxyphenyl) methyl)thio)-1H-imidazol-5-carboxaldehyde

Act as in example 2, but originate from 90 mg of 50% sodium hydride in oil in 10 ml of tetrahydrofuran and added slowly 0,26 ml 4-methoxybenzonitrile.

Then enter in the received tilt 580 mg of the product of example 3, dissolved in 5 ml of tetrahydrofuran, stirred under these conditions for 2 hours and 30 minutes Acting as in example 2, Recuperat brown resin, which is purified by chromatography on silica, as eluant methylene chloride/ethyl acetate (95/5), and receive 400 mg of the product, purified by recrystallization in 20 ml of ethanol (Pf=160oC).

IR CHCl3(cm-1)

C=O 1664

Incense + a Heterocycle 1610-1584-1513-1506-1483

Microanalysis

calculated, %: C 57,62; H 4,11; N Of 6.71; S 7,69; Cl 8,5;

received, %: C 57,2; H 4,0; N 6,7; S 7,7; Cl 8,7.

EXAMPLE 5

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)- 2-phenyl-1H-imidazole-5-carboxylic acid

STAGE 1:

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2-phenyl-1H-imidazol

1.44 g of 2-phenylimidazole dissolved in 30 ml of dimethylformamide, dorsatum add 2,05 g of 6-chloro-piperonylic and leave overnight at room temperature. Dimethylformamide is evaporated, add 50 ml of saturated ammonium chloride and extracted 3 times with 70 ml of methylene chloride, dried, evaporated and chromatographic on silica with ethyl acetate as eluant. Thus, the gain of 2.8 g of the target product, Pf=163oC.

STAGE 2:

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4,5 - dibromo-2-phenyl-1H-imidazol

2.8 g obtained in stage 1 of the product is dissolved in 50 ml of methylene chloride, then add small portions of 3.6 ml of N-bromosuccinimide and leave overnight at room temperature. The organic phase is then washed 1H sodium hydroxide, then with a saturated solution of sodium chloride, dried, evaporated and Recuperat of 3.3 g of the target product, after thickening in the air. Pf= 173oC.

STAGE 3:

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2 - phenyl-1H-imidazole-5-carboxylic acid

In the solution of 706 mg, obtained in stage 2 of the product in 15 ml of anhydrous tetrahydrofuran, was added dropwise at room temperature to 750 μl of a solution of ethylbromide magnesium in ether, leave for 30 min at room temperature, and then passed through a solution of an excess of CO2within 30 minutes Gidrolizovat with saturated ammonium chloride, then padcal the Ute residue in methylene chloride to obtain 310 ml of the target product, Pf=215oC.

EXAMPLE 6

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl) -2-phenyl-1H-imidazol-5-carboxaldehyde

In a solution of 3.7 g obtained in stage 2 of example 5 product in 80 ml of anhydrous tetrahydrofuran was added dropwise at room temperature with 5.2 ml of 3N ethylbromide magnesium in ether, leave for 20 min at room temperature, and then injected 5 ml of anhydrous dimethylformamide and leave for another 2 h at room temperature. Hydrolyzing with saturated ammonium chloride and extracted with ethyl acetate. Dried, evaporated, condensed ether the solid residue to obtain 2.5 g of the target product, Pf=148oC.

EXAMPLE 7:

1-((6-chloro-1,3-benzodioxol-5-yl)methyl) -4-(((4-methoxyphenyl)methyl)thio)-2-phenyl-1H-imidazol-5 - carboxaldehyde

Act as in example 2, using as starting compound of example 6.

In a solution of 635 μl parameterstyle in 50 ml of dimethylformamide add 250 mg of 50% sodium hydride in oil, leave for 15 min at room temperature, add 1.7 ml of the product of example 6, then left for 4 hours at room temperature and evaporated dimethylformamide. Absorb the remainder of 1N sodium hydroxide and extracted with methylene chloride. Organicstyle.com (2/8). Obtain 1.31 g of the target product, Pf=120oC.

EXAMPLE 8

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- (((4-methoxyphenyl)methyl)thio)-2-phenyl-1H-imidazol-5-methyl carboxylate

Carry out the operations of example 9, but using the compound of example 7.

Into a solution of 600 mg of the product of example 7 in methylene chloride consistently add 30 ml of methanol, 120 μl of acetic acid, 2.25 g of manganese oxide and 300 mg of sodium cyanide. Stirred at room temperature for 96 hours, filtered off, washed with ethyl acetate and evaporated. Obtain 410 mg of the target product, Pf=158oC.

EXAMPLE 9

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-(((4 - methoxyphenyl)methyl)thio)-2-(phenylthio)-1H-imidazol-5 - methylcarbamoyl

970 mg of the product of example 2 is introduced into a mixture of methylene chloride and methanol (25 ml/100 ml) and then added successively 5 g of manganese oxide, 500 mg of sodium cyanide and 200 μl of acetic acid. Stirred for 72 hours at room temperature.

Centrifuged, washed with methylene chloride, then concentrated in vacuo.

The crude product is purified high-speed transmission through silica with methylene chloride as eluant.

Obtain 910 mg of a crude target Pro 815 mg of the target product (solid white) (Pf=130oC).

IR CHCl3(cm-1)

Ester 1699 1436

Incense + a Heterocycle 1610-1584-1513-1505-1483

Microanalysis

calculated, %: C 58,4; H 4,17; N 5,04; S 11,55; Cl 6,38;

received, %: C 58,5; H 4,1; N 4,9; S 11,4; Cl 6,6.

EXAMPLE 10

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- (((4-methoxyphenyl)methyl)-thio)-2-(phenylthio)-1H-imidazole-5 - carboxylic acid

500 mg obtained in example 9 the product is introduced into a mixture of ethanol and tetrahydrofuran (15 ml/20 ml) and add 15 ml of 2N sodium hydroxide. Stirred for 48 hours at room temperature.

The reaction medium is acidified by adding 2N hydrochloric acid and then extracted with ethyl acetate, rinsed with water, then dried, Recuperat 340 mg of the residue in a creamy white color, which is purified by chromatography on silica, as eluant ethyl acetate/methylene chloride (50/50).

Purify by recrystallization in 20 ml of ethanol and, after centrifugation and drying obtain 180 mg of the target product (solid white) (Pf=180oC).

IR CHCl3(cm-1)

-OH 3510

-C=O 1659 1704

Conjugated system 1610-1580-1513-1505-1483

Microanalysis

calculated, %: C 57,7; H 3,91; N 5,18; S 11,85; Cl 6,55;

Act as in example 9, but come from 1 g of the product of example 4 in a mixture of methylene chloride and methanol (20 ml/50 ml) and consistently add 6 g of manganese oxide, 750 mg of sodium cyanide and 400 µl of acetic acid. Stirred for 48 hours at room temperature.

Operating as in example 9, to obtain 700 mg of the target product, Pf=123oC.

IR CHCl3(cm-1)

Ester 1700

Incense + a Heterocycle 1611-1580-1513-1505-1483

EXAMPLE 12

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-(((4 - methoxyphenyl)methyl)thio)-1H-imidazole-5-carboxylic acid

Act as in example 10, but extend from 600 mg of the product of example 11 in a mixture of ethanol and tetrahydrofuran (25 ml/30 ml) and add 50 ml of N sodium hydroxide.

Stirred for 48 hours at room temperature.

Acting as in example 10, to obtain 310 mg of the target product (Pf= 195oC).

IR NUIOL (cm-1)

The total area of the absorption OH/NH

-C=O 1690

Incense + a Heterocycle 1610-1583-1513-1508-1488

Microanalysis

calculated, %: C of 55.5; H 3,95; N 6,47; S To 7.4; Cl 8,2;

received, %: C a 55.4; H 3,7; 6,5 N; S 7,3; Cl 8,2.

EXAMPLE 13

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- ((4-methoxyphenyl)-thio)-2-(phenylthio ml of tetrahydrofuran, then added to 1.4 ml of 4-methoxy-bentolila. Stirred for 15 min at room temperature.

Then enter to the thiol solution of 3.7 g of the product of example 1 in 50 ml of tetrahydrofuran. Stirred under these conditions for 1 h 30 min

Acting as in example 2, collect 2 fractions: to 3.02 g of the target product and 600 mg of the product of example 16.

IR CHCl3(cm-1)

C=O 1663

Incense + a heterocycle 1593-1580-1570 - 1505-1494-1484, of which S-f-OCH3< / BR>
Example 14

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- ((4-methoxyphenyl)thio)-2-(phenylthio)-1H-imidazol-5 - methylcarbamoyl

Act as in example 9, but come from 1 g of the product of example 13 in a mixture of methylene chloride and methanol (20 ml/100 ml) and then added successively 5 g of manganese oxide, 500 mg of sodium cyanide and 300 μl of acetic acid.

Stirred for 24 hours at room temperature.

Operating as in example 9, to obtain 820 mg of the target product (Pf=140oC).

IR CHCl3(cm-1)

Ester 1704

Incense + a Heterocycle 1593-1575-1505-1494-1483

EXAMPLE 15

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-((4 - methoxyphenyl)thio)-2-(phenylthio)-1H-imidazole-5-carboxylic sour is hydrofuran (20 ml/30 ml) and add 20 ml of 1N sodium hydroxide.

Stirred for 4 hours 30 min at room temperature.

Acting as in example 10, to obtain 550 mg of the target product (Pf= 170oC).

IR CHCl3(cm-1)

complex-HE/NH

C=O 1686

Aromatic substance + Conjugated system 1592-1573-1503-1493

Microanalysis

calculated, %: C to 57.0; H 3,63; N 5.3; S 12,16; Cl 6,72;

received, %: C 56,8; H 3,4; N 5.3; S 11,8; Cl 6,8.

EXAMPLE 16

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)- 2,4 - bis((4-methoxyphenyl)thio)-1H-imidazol-5-carboxaldehyde

The product of example 16 (600 mg) are obtained in accordance with example 13, above.

IR CHCl3(cm-1)

C=O 1663

Incense + a Heterocycle 1593-1575-1505-1495-1484, of which S-f-OCH3< / BR>
EXAMPLE 17

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)- 2,4-bis-((4-methoxyphenyl)thio)-1H-imidazol-5-methyl-carboxyla

Act as in example 9, but come from 470 mg of the product of example 16 in a mixture of methylene chloride and methanol (10 ml/50 ml) and then added sequentially 2.5 g of manganese oxide, 250 mg of sodium cyanide and 200 μl of acetic acid. Stirred for 24 hours at room temperature.

Operating as in example 9, to obtain 315 mg of the target product (Pf=130oC).

IR CHCl3<
1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2,4 - bis-((4-methoxyphenyl)thio)-1H-imidazole-5-carboxylic acid

Act as in example 10, but come from 280 mg) obtained in example 17 product in a mixture of ethanol and tetrahydrofuran (20 ml/20 ml) and add 20 ml of 1N sodium hydroxide. Stirred for 5 hours at room temperature.

In example 10, obtain 240 mg of the target product (Pf=110oC).

IR NUIOL (cm-1)

Aromatic substance + Heteroatom 1593-1573-1505-1489

Microanalysis

calculated, %: C 56,06; H 3,8; N 5,02; S 11,5; Cl 6,36;

received, %: C 55,7; H 3,8; N 4,7; S 11,2; Cl 6,5.

EXAMPLE 19

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-5- (hydroxymethyl)-4-(4-methoxyphenyl)thio)-2-(phenylthio)-1H - imidazol

820 mg of the product of example 13 is introduced into 50 ml of ethanol and add 60 mg of sodium borohydride.

Stirred for 30 minutes at room temperature.

Add 0.5 ml of acetic acid, and then 50 ml of ice water.

After 10 minutes stirring, centrifuged, washed in water, dried and extract 700 mg of crude product which is purified by recrystallization in 20 ml of isopropanol, centrifuged and washed with 20 ml of ethanol.

Get 410 ml of the target product (Pf=146o
Microanalysis

calculated, %: C 58,5; H 4,13; N 5,46; S 6,91; Cl 12,5;

received, %: C 56,2; H 4,0; 5,4 N; S 7,0; Cl 12,3.

EXAMPLE 20

1-((-6-chloro-1,3-benzodioxol-5-yl)methyl)-4- ((4-methoxyphenyl)thio)-2-phenyl-1H-imidazol-5-carboxaldehyde

Act as in example 2, using 4 g of the product of example 6, 640 mg of 50% sodium hydride in oil, 1,64 mg 4-methoxythiophene, and thus receive the of 4.05 g of the target product (Pf=116oC).

EXAMPLE 21

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- ((4-methoxyphenyl)thio)-2-phenyl-1H-imidazol-5-methylcarbamoyl

Act according to example 9 using 2 g of the product of example 20, 10 g of manganese oxide, 1 g of sodium cyanide, 200 ml methanol, 40 ml of methylene chloride and 600 μl of acetic acid, and obtain 1.64 g of the target product (Pf=161oC).

EXAMPLE 22

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4-((4 - methoxyphenyl)thio)-2-phenyl-1H-imidazole-5-carboxylic acid

Act according to example 10, using 1 g of the product of example 21, 25 ml of 1N sodium hydroxide, 25 ml of ethanol and 50 ml of tetrahydrofuran. Thus, getting 629 mg of the target product (Pf=190oC).

EXAMPLE 23

2-benzoyl-1-((6-chloro-1,3-benzodioxol-5-yl) methyl)-4-((4-methoxyphenyl)thio)-1H-imidazol-5-methyl - carboxylate

STAGE 1:

1-((6-chloro-1,3-benzodiox is received in stage 1 of example 1 product in a mixture of methylene chloride/sulphuric ether (100 ml/350 ml), and added dropwise to 7.3 ml ethylbromide magnesium. Stirred for 20 min at room temperature.

Then in the resulting reaction medium was added 10 ml of benzaldehyde.

Stirred for 2 hours at room temperature.

Acting as in stage 2 of example 1, get 5.34 g of the target product.

IR CHCl3(cm-1)

-OH 3603 + the total absorption

Aromatic substance + heteroatom 1627-1603-1505-1484

STAGE 2:

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2- -hydroxy-(phenylmethyl))1H-imidazole-5 - carboxaldehyde

Acting as in stage 3 of example 1, but using 5.3g obtained above in stage 1 of the product in 100 ml of tetrahydrofuran, was added dropwise 11 ml ethylbromide magnesium. Stirred for 15 min at room temperature.

Then in the resulting reaction medium was added 5 ml of dimethylformamide. Stirred for 2 hours at room temperature.

Acting as in stage 3 of example 1, get 2,067 target product.

IR CHCl3(cm-1)

C=O 1674

-OH 3596 complex

Incense + a Heterocycle 1628-1602-1505-1485

STAGE 3:

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-2 - (hydroxy-(phenylmethyl))-4-((4-methoxy who rija in oil in 50 ml of tetrahydrofuran, slowly add 1 ml of 4-methoxy-bentolila. Stirred for 15 min at room temperature.

Then in the resulting tiolet add a solution of 2.6 g of the product obtained above in stage 2, in 25 ml of tetrahydrofuran. Stirred for 2 hours under the same conditions.

Acting as in stage 2, obtain 2.15 g of the target product.

IR CHCl3(cm-1)

C=O 1667

-OH 3598 associated

Incense + a Heterocycle 1593-1574-1505-1494-1484

STAGE 4:

2-benzoyl-1-((6-chloro-1,3-benzodioxol-5-yl) methyl)-4-((4-methoxyphenyl)thio)-1H-imidazol-5-methylcarbamoyl

Operating as in example 9, but using of 2.15 mg of product obtained in stage 3, 200 ml of methanol, add sequentially 11 g of manganese oxide, 1.1 g of sodium cyanide and 700 μl of acetic acid.

Stirred for 48 hours at room temperature.

Operating as in example 9, the gain of 1.32 g of the target product (Pf=166oC).

IR CHCl3(cm-1)

No OH

C=O 1716-1653

Incense + a Heterocycle 1597-1579-1508-1495

EXAMPLE 24

2-benzoyl-1-((6-chloro-1,3-benzodioxol-5-yl) methyl)-4-((4-methoxyphenyl)thio)-1H-imidazol-5-methyl - carboxylic acid

Apply to ml 1N sodium hydroxide.

Stirred for 48 hours at room temperature.

Acting as in example 10, to obtain 385 mg of the target product (Pf= 210oC).

IR NUIOL (cm-1)

The total area of the absorption OH/NH

-C=O 1679-1652

Incense + a Heterocycle 1590-1572-1503-1485

Microanalysis

calculated, %: C 59,71; H 3,66; N 5,35; S 6,13; Cl 6,77;

received, %: C to 59.4; H 3,7; N 5,2; S 6,0; Cl 7,0.

EXAMPLE 25

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- (((4-methoxyphenyl)methyl)thio)-2-phenyl-1H-imidazol-5 - methylcarbamoyl acid

Act as in example 10, but using the product of example 8.

To a solution of 740 mg of the product of example 8 in a mixture of tetrahydrofuran and ethyl acetate (50 ml/50 ml) is added 30 ml of 2N caustic soda and leave for 96 h at room temperature. Is evaporated, remove the residue with 30 ml of water, acidified with 1N hydrochloric acid and filtered.

So, get 440 mg of the target product (Pf=190oC).

EXAMPLE 26

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- ((3,4-acid)thio-2-dioxolane-2-yl)-1H-imidazol-5 - carboxaldehyde

STAGE A:

1-((6-chloro-1,3-benzodioxol-5-yl) methyl)-4,5-(dibromo)-2-(1,3-dioxolane-2-yl)-1H-imidazol

In a solution of 20 g of the product, poluchennogo and stirred for 20 min at room temperature. Add 200 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried and the solvent is evaporated. The obtained intermediate aldehyde absorb in 200 ml of toluene, add 20 ml of ethylene glycol and heated under reflux for 16 hours. Evaporate the solvent, extract the residue with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, washed with water, dried and the solvent is evaporated under reduced pressure. The remainder is condensed in isopropyl ether, filtered off, dried under reduced pressure and obtain 13.5 g of the target product. Pf=188oC.

STAGE B:

4-bromo-1-((6-chloro-1,3-benzodioxol-5-yl) methyl)-2-(1,3-dioxolane-2-yl) 1H-imidazole-5-carboxaldehyde

10 g obtained in stage A product is introduced into 200 ml of tetrahydrofuran, was added dropwise 10 ml of a 3M solution of ethylbromide magnesium in ether. Stirred for 20 min at room temperature. Then in the resulting reaction medium was added 10 ml of dimethylformamide and stirred for 2 hours at room temperature. Conduct the hydrolysis medium, adding 200 ml of diluted hydrochloric acid, then extracted with ethyl acetate, washed with water, is the product.

STAGE C:

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- ((3,4-acid)thio-2-dioxolane-2-yl) 1H-imidazole-5 - carboxaldehyde

Enter 1.1 g of sodium hydride to 3.15 ml of a solution of 3,4 - dimethoxyphenol in 200 ml of dimethylformamide and stirred for 20 minutes at room temperature. Add 7.6 g obtained at the stage In the product, stirred for 16 hours at room temperature, the solvent is evaporated under reduced pressure, distilling the residue 200 ml of a saturated aqueous solution of ammonium chloride and extracted with dichloromethane. The organic phase is dried, the solvent is evaporated, condensed residue with isopropyl ether, filtered and gain of 5.2 g of the target product. Pf-149oC.

EXAMPLE 27

1-((6-chloro-1,3-benzodioxol-5-yl)methyl)-4- ((3,4-acid)thio-2-dioxolane-2-yl) 1H-imidazole-5 - methylcarbamoyl

Enter a solution of 5.05 g of the product of example 26 in a mixture of methylene chloride and methanol (100 ml/500 ml), add successively 22 g of manganese oxide, 2.2 g of sodium cyanide and 1.5 ml of acetic acid, then stirred for 72 hours at room temperature. Filtered off, washed with water the organic phase is dried, the solvent is evaporated and after chromatography on dioxide Kremer)-4- ((3,4-acid)thio)-2-(1,3-dioxolane-2-yl) 1H-imidazole - 5-carboxylic acid

Enter 1 g of the product of example 27 in 100 ml of ethanol and add 50 ml of 2N sodium hydroxide. Stirred for 16 hours at room temperature, the solvent is evaporated under reduced pressure, remove the residue with a mixture of water with ice, acidified with 2N hydrochloric acid, extracted with ethyl acetate, dried and the solvent is evaporated under reduced pressure. Obtain 650 mg of the target product. So pl. = 155oC.

EXAMPLE 29

Prepare tablets of the following composition:

The compound of example 10 to 50 mg

Excipient for tablet 200 mg

(excipient: lactose, talc, starch, magnesium stearate)

THE RESULTS OF PHARMACOLOGICAL STUDIES

Research activity on the endothelin receptor Into

Prepare a membrane preparation from cells of the occipital area of the cerebral cortex and cerebellum of rats. The fabric is crushed in POSITRON e in buffer solution 50 mm Tris pH 7,4.

After keeping for 30 minutes at 25oC water bath (C. B.) the homogenate was centrifuged at a speed of 30,000 g for 15 minutes (2 centrifugation with intermediate absorption sludge buffer solution pH 7,4).

Sediments suspended in incubation buffer solution (Tris 25 mm, pastaigaties 2 ml portion was placed in a test tube for hemolysis and enter 125I Endothelin (approximately 5000 dpm/tube) and study the product. (The product is first tested three times on 310-5M). When tested product displaces more than 50% of the radioactivity specifically bound to the receptor, it is again tested at seven concentrations to determine the concentration that inhibits 50% of the radioactivity specifically bound to the receptor. Thus, to determine the concentration inhibiting 50%.

Nonspecific relationship is determined by adding 10-6M endothelin (three times). Spend incubation at 25oC for 60 minutes, incubated in a water bath at 0oC for 5 minutes, filtered under slight pressure, washed in a buffer solution of Tris 7.4 and count the radioactivity using a scintillation counter Triton.

The result is expressed as a concentration of 50% inhibition (C150), i.e. the concentration of test product (nm) required to offset 50% of the specific radioactivity of the test receptor.

Result:

The product of example B Receptor endothelin C150 (nm)

10 - 420

15 - 110

18 - 88

Research activity on the endothelin receptor-A

Prepare a membrane preparation from to the e standing for 30 minutes at 25oC (C. B.) the homogenate was centrifuged at a speed of 30,000 g for 15 minutes (2 centrifugation with intermediate absorption sludge buffer solution Tris pH 7,4).

Sediments suspended in incubation buffer solution (Tris 25 mm, pepstatin A 5 μg/ml, Aprotinin 3 μg/ml, 0.1 mm PMSF, 3 mm EDTA, 1 mm EGTA, pH 7,4).

Aliquot 2 ml portion was placed in a test tube for hemolysis and add125I Endothelin (approximately 5000 dpm /tube) and tested product. (The product is first tested three times 10-5M). When tested product displaces more than 50% of the radioactivity specifically bound to the receptor, it is again tested at seven concentrations to determine the concentration that inhibits 50% of the radioactivity specifically bound to the receptor. Thus, to determine the concentration inhibiting 50%.

Nonspecific relationship is determined by adding 10-6M endothelin (three times). Spend incubation at 25oC for 60 minutes, incubated in a water bath at 0oC for 5 minutes, filtered under reduced pressure, washed in a buffer solution of Tris 7.4 and count the radioactivity using a scintillation counter Triton.

The result of the expression of 50% of the specific radioactivity of the test receptor.

Result:

The product of example B Receptor endothelin C150 (nm)

10 - 167

15 - 170

18 - 230)

1. Imidazole derivatives of General formula I

< / BR>
in which R1is a hydrogen atom, an alkoxy radical, 1,3-dioxolane, dioxane, phenyl, benzoyl or phenylthio, in which phenyl may be substituted by hydroxy or alkoxyalkyl containing not more than 4 carbon atoms;

R2and R3identical or different, chosen from halogen atoms; carboxyethyl, free or esterified by alkyl containing not more than 4 carbon atoms; formyl; alkyl radicals, phenylthio, alkylthio, which can be substituted by one or more radicals selected from halogen atoms, hydroxy radicals, alkoxy containing not more than 4 carbon atoms, carboxy free or esterified, and phenyl, which itself can be substituted by a hydroxy radical or alkoxy containing not more than 4 carbon atoms;

Y represents phenyl, substituted with two radicals, forming together dioxol; one or more halogen atoms.

2. The compounds of formula I on p. 1, wherein R1means a hydrogen atom, a radical of 1,3-dioxolane, phenyl, benzoyl or phenylthio, in which the radical f the em halogen atom, radical, alkylthio, in which the alkyl radical, straight or branched, containing not more than 4 carbon atoms may be substituted by a phenyl radical which may itself be substituted by alkoxyalkyl, or phenylthiomethyl, in which the phenyl radical can be substituted by alkoxyalkyl; R3means formyl or carboxyl, free or esterified, and Y represents phenyl substituted by a halogen atom and two radicals form together a radical dioxol.

3. The compounds of formula I on p. 1, representing the following connections:

1-[(6-chloro-1,3-benzodioxol-5-yl)] -4-{ [(4-methoxyphenyl)methyl] thio}-2-(phenylthio)-1H-imidazol-5-carboxaldehyde;

4-bromo-1-[(6-chloro-1,3-benzodioxol-5-yl)methyl] -2-phenyl-1H-imidazole-5-carboxylic acid;

1-[(6-chloro-1,3-benzodioxol-5-yl)methyl] -4-{ [(4-methoxyphenyl)methyl]thio} -2-(phenylthio)-1H-imidazole-5-carboxylic acid;

1-[(6-chloro-1,3-benzodioxol-5-yl)methyl] -4-[(4-methoxyphenyl)thio] -2-(phenylthio)-1H-imidazole-5-carboxylic acid;

1-[(6-chloro-1,3-benzodioxol-5-yl)methyl] -2,4-bis(4-(methoxyphenyl)thio)-1H-imidazole-5-carboxylic acid;

1-[(6-chloro-1,3-benzodioxol-5-yl)methyl] -4-[(3,4-acid)thio]-2-(1,3-dioxolane-2-yl)-1H-imidazole-5-carboxylic acid.

4. The compounds of formula I of the ski or organic bases, having antagonistic properties with respect to the endothelin receptors.

5. The compounds of formula I on p. 2 or 3 or their pharmaceutically acceptable salts with inorganic or organic acids or with inorganic or organic bases, which has antagonistic properties with respect to the endothelin receptors.

6. The compounds of formula I on p. 1 or their pharmaceutically acceptable salts with inorganic or organic acids or with inorganic or organic bases, representing the active principle to obtain pharmaceutical compositions for the treatment of diseases caused by abnormal stimulation of endothelin receptors.

7. Connection on p. 6, which represents the active principle to obtain pharmaceutical compositions intended for the treatment of hypertension induced by endothelin, and any vascular spasm and States after a brain hemorrhage, renal failure, myocardial infarction and prevention postangioplasty of restenosis.

8. The method of obtaining compounds of formula I, described in paragraph 1, namely, that interact the compounds of formula II

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where is imeni protective groups

with the compound of the formula III

< / BR>
where Hal is a halogen atom;

Y' has the values listed in paragraph 1 to Y', where possible reactive functions are optionally protected by protective groups,

to obtain the compounds of formula IV1< / BR>
< / BR>
where R1'and Y' have the above values,

the compound obtained of the formula (IV1) are galogenirovannyie to obtain the compounds of formula (IV2)

< / BR>
where R1'Hal' and Y ' have the above values,

the compound obtained of the formula IV2subjected to the reaction of the exchange of the halogen-metal with one of the halogen atoms, then the reaction of interaction with CO2or DMF) to obtain the compounds of formula I1< / BR>
< / BR>
in which R'1Hal, Y' have the above meaning;

Z3is carboxylation, formyl or a radical-O-alk, in which K is the radical

< / BR>
alk has the values listed above,

the compound obtained of the formula I1in which Z3is formyl or esterified by carboxylation, is subjected to the reaction of interaction with the compound of the formula VII

Z2- S - M,

where S is a sulfur atom;

M is a metal, such as sodium or potassium;
< / BR>
< / BR>
in which R'1, Y' and Z2have the above values;

Z4is formyl or esterified by carboxyla, and when Z4is formyl, its oxidized or reduced to the compounds of formula I3< / BR>
< / BR>
where R'1, Y' and Z2have the above values,

Z5radical, CH2OH or carboxylation, free or esterified by alkyl, linear or branched, containing not more than 4 carbon atoms;

the compounds of formula (I1), (I2), (I3or are compounds of the formula I or to obtain other compounds of formula I to be subjected, if desired and if necessary, one or more of the following conversion reactions, in any order:

a) esterification of the acid function,

b) saponification of essential functions to acid,

C) a reaction for the conversion of Sinopoli in acid,

g) recovering carboxyphenyl to an alcohol function,

d) a reaction for the conversion of alkoxyphenyl in hydroxypoly, or hydroxypoly in alkoxyphenyl,

e) oxidation of the alcohol function to aldehyde or acid function.

9. The method of obtaining compounds of formula I, described lead in the interaction with the compound of the formula III

< / BR>
where Y' has a value specified for Y in p. 1;

Hal has the above values,

to obtain the compounds of formula IX

< / BR>
where Hal and Y' have the above values,

which is subjected to the reaction of the exchange of the halogen-metal, then the reaction of interaction with an electrophilic compound of formula

L1SO2-S-L'1,

where L1and L'1the same or different and are phenyl which may be substituted by a hydroxy radical or alkoxy containing not more than 4 carbon atoms,

obtaining the compounds of formula XIII

< / BR>
where Hal and Y' have the above meanings;

R1- phenyl, benzoyl, or phenylthiomethyl, in which phenyl may be substituted by a hydroxy radical or alkoxy containing not more than 4 carbon atoms,

which is then subjected to the reaction of the exchange of the halogen-metal with one of the halogen atoms, with the subsequent reaction of interaction with CO2or DMF) to obtain the compounds of formula XIV

< / BR>
where R1Hal, Y' have the above meanings;

Z3- formyl or esterified carboxylation,

which is subjected to interaction with the compound of the formula VII

Z2-S-M

where S is a sulfur atom, M is a metal, to obtain the compounds of formula XV

< / BR>
where R1, Y', Z2have the above values;

Z4- formyl or esterified carboxylation,

the resulting compound of formula XV, when Z4- formyl or esterified carboxylation, oxidised or reduced to the compounds of formula I4in which Z5is CH2OH or carboxylation, free or esterified by alkyl, linear or branched, containing not more than 4 carbon atoms; the compounds of formula I4, I5, XIV, XV or are compounds of the formula I or to obtain other compounds of formula I to be subjected, if desired and if necessary, one or more of the following conversion reactions, in any order:

a) esterification of the acid function,

b) saponification of essential functions to acid,

C) a reaction for the conversion of Sinopoli in acid,

g) recovering carboxyphenyl to an alcohol function,

d) a reaction for the conversion of alkoxyphenyl in hydroxypoly, or hydroxypoly in alkoxyphenyl,

e) oxidation of the alcohol function to aldehyde or acid function.

10. Pharmaceutical composition having antagonistically properties against CLASS="ptx2">

11. The compounds of formula IV1IV2, XIII, XIV and XV

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
in which Y' is phenyl, possibly substituted by one or more radicals chosen from halogen atoms or dioxole, where possible reactive functions are optionally protected by protective groups as intermediates in the synthesis of compounds of formula I.

 

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-(5'-nitro-2'-furyl)vinyl]-6,7,8,9 - tetrahydropyrimido[4,5-b] quinoline-4-one and 1-metalorganic-2- [-(5'-nitro-2'-furyl)vinyl]-7,8-dihydro-6n-pyrimido[4 ,5-b] -pyrindine-4-one, exhibiting antimicrobial activity" target="_blank">

The invention relates to the field of organic chemistry, a class pyrimido[4,5-b] quinoline, pyrimido[4,5 - b]pyrindine, namely to new biologically active 1-phenyl-2- [-(5'-nitro-2'-furyl)vinyl]-6,7,8,9-tetrahydropyrimido[4,5-b]quinoline-4-ONU(I)I1-metalorganic-2-[-(5'-nitro-2'-furyl)vinyl]-7,8-dihydro-6H-pyrimido[4,5-b]pyrindine-4-ONU (II), formula

< / BR>
< / BR>
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< / BR>
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