Derivatives thioformate or their pharmacologically acceptable salts

 

(57) Abstract:

Derivatives thioformate General formula I, where Y is a group of the formula-C(O)-, -CH(OH)-, Z is-CH2-; A substituted or unsubstituted, imidazopyridine; R1, R2, R3and R4is hydrogen or lower alkyl; or their pharmaceutically acceptable salts are excellent antihypertensives.

< / BR>
5 C.p. f-crystals, 1 table.

The present invention relates to a derived thioformate, useful as medicines.

Hypertension is known as the disease that causes complications such as stroke or heart disease, which occupy a high place in the list of causes of death in Japan, therefore conducted a variety of studies on prevention and treatment. System regulation of blood pressure is complex and therefore apply different types of antihypertensive drugs.

Such anti-hypertensive tools include diuretics, - blockers and ACE-inhibitors. However, diuretics cause undesirable effects in the form of hyperuricemia, acute diabetes, gout attacks and so on; - blockers - heart failure, bronchospasm, etc.; ACE-inhibitors - shortness of breath, slow deadlinereuters actions in particular heart disease, which hinders their application or makes it undesirable.

In Japan, the number of patients with abnormalities of the coronary vessels reached the same level as in Europe and America, as we move to the Western way of life, and it is assumed that there is a very significant number of patients with ischemic heart disease (such as angina pectoris (angina or myocardial infarction), including diseases caused by hypertension.

Although nitrite drugs and antagonists, and are used as preventive and therapeutic agents from angina, nitrite preparations have the disadvantage that they cause tolerance in patients and are accompanied by unwanted effect, such as methemoglobinemia or ocular hypertension, while blockers are the reason, as mentioned above, undesirable actions, such as heart failure or bronchospasm. Therefore, caution is required in using these drugs.

Meanwhile, the number of patients suffering from asthma for the last time was increased, presumably due to changes in eating habits or habitat deterioration, vyzvannogo is rest asthma was used - stimulants, methylxanthines, stabilizers fat cells and steroids. However, stimulants cause as undesirable actions arrhythmia, hypertension, headache, etc.; methylxanthines - gastrointestinal disorders or neuropathy; steroids - diabetes or osteoporosis. So, these drugs can sometimes cause serious side effects and therefore require caution in their use. Although the stabilizers of the fat cells do not cause any undesirable action, they have the disadvantages that their application for children and the elderly presents difficulties, since they can only be used as a dosage form for inhalation that they are not effective against severe asthma and that they can only be used as a preventive tool.

In such circumstances there is a need for the development of antihypertensive drugs or means of prevention and treatment of heart disease or asthma, which have different mechanisms of action and can easily be applied due to its safety and quality, superior quality preparations of the prior art.

The authors of the present invention conducted intensive research, studying sonoct by opening ATP-sensitive potassium channel and conducted research in order to find the connection, with this activity.

The result of these studies, the authors of the present invention have found that derivatives thioformate, which will be described below, can achieve the above goals. The present invention is made on the basis of this discovery.

Although derived thioformate having activity as drugs, are disclosed, for example, in Japanese patent publication N 59150/1990 and in Japanese patent applications laid NN 63260/1991, 289543/1990, 286659/1990, 211566/1989, 273/1990, 308275/1989 and 258760/1990, the compounds of the present invention differ from them in structure.

The essence of the invention.

The present invention relates to a derived thioformate represented by the following General formula (I) or its pharmacologically acceptable salt:

< / BR>
in which

Y denotes a group represented by formula-O-, a group represented by the formula (where n is zero or an integer from 1 to 2), a group represented by the formula

the group represented by the formula (where R5and R6may be the same or different and each denotes hydrogen, lower alkyl, lower alkoxy, cyano, cianelli may secure carboxyl may (optional) secure carboxylic igge R8denotes hydrogen, cyano, lower alkyl, possibly substituted arylalkyl, possibly substituted heteroaromatic may secure carboxyl or perhaps protected carboxyethyl), a group represented by the formula (where R9and R10may be the same or different and each denotes hydrogen, cyano, lower alkyl, possibly substituted arylalkyl, possibly substituted heteroaromatic may secure carboxyl, or perhaps protected carboxylic, or alternative R9and R10can denote, together with the nitrogen atom to which they are attached, a cyclic group), hydrogen, cyano, cianelli, lower alkyl, possibly substituted arylalkyl, possibly substituted heteroaromatic may secure carboxyl, or perhaps protected carboxyethyl), or a group represented by the formula {where R11and R12may be the same or different and each denotes hydrogen, lower alkyl, aryl, arylalkyl, cianelli, arylalkyl may secure carboxyethyl, a group represented by the formula -(CH2)s-O-R13[where R13denotes hydrogen, lower alkyl, possibly substituted arylalkyl, possibly substituted heteroaromatic, lower alkoxyalkyl, possibly substituted arylalkylamines, possibly substituted heteroarylboronic, possibly substituted arylsulfonyl, possibly substituted heteroarylboronic, alkylsulfonyl, possibly protected carboxylic, aminoalkyl, in which the amino may be substituted, or a group represented by the formula (where B represents sulfur, oxygen or a group represented by the formula =N-CN; and R16and R17may be the same or different and each denotes hydrogen, cyano, lower alkyl, possibly substituted aryl, possibly substituted heteroaryl, possibly substituted arylalkyl, or possibly substituted heteroaromatic, or alternative R16and R17can denote, together with the nitrogen atom to which they are attached, a cyclic group; and s is zero or an integer from 1 to 10], or a group represented by the formula [where R14and R15may be the same or different and each denotes hydrogen, lower alkyl, possibly substituted arylalkyl, possibly substituted heteroaromatic, lower alkoxyalkyl, acyl, carbarnoyl, allylcarbamate, possibly substituted arylcarbamoyl, possibly substituted arylalkylamines, possibly substituted arylsulfonyl, possibly substituted heteroallyl, the group represented by formula (where D represents sulfur, oxygen or a group represented by the formula = N-CN; and R18and R19may be the same or different and each denotes hydrogen, cyano, lower alkyl, possibly substituted aryl, possibly substituted heteroaryl, possibly substituted arylalkyl or possibly substituted heteroaromatic, or alternative R18and R19can denote, together with the nitrogen atom to which they are attached, a cyclic group), possibly protected carboxylic, or aminoalkyl, in which the amine part can be substituted, or alternatively R14and R15can denote, together with the nitrogen atom to which they are attached, a cyclic group; and t is zero or an integer from 1 to 10]};

Z denotes a group represented by formula-O-, a group represented by the formula (where m is zero or an integer from 1 to 2) or a group represented by the formula -(CH2)p- (where p is zero or an integer from 1 to 2);

A represents aryl, thienyl, furyl, benzofuranyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazolyl, isoxazolyl, isothiazolin, oxazolyl, benzimidazolyl, imidazopyridine, imidazopyridines, imidazopyrimidines, imidazopyridines, Deputy and the unsubstituted imidazolyl excluded when Y represents a group represented by formula-O - or-S - or when Z represents a group represented by formula-O - or-S-;

R1and R2may be the same or different and each denotes hydrogen, lower alkyl, possibly substituted arylalkyl, or possibly substituted heteroaromatic, or alternative R1and R2may together denote a benzene ring;

R3and R4may be the same or different and each denotes hydrogen, lower alkyl, cycloalkyl, lower alkoxy, hydroxyl, aryl, arylalkyl, heteroaryl, or heteroaromatic or alternative R3and R4can denote, together with the nitrogen atom to which they are attached, a cyclic group which may contain oxygen atom, nitrogen or sulfur.

Lower alkyl specified in the relation R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18and R19represents a linear or branched alkyl having from 1 to 8 carbon atoms, examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, propyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl and octyl. Among these groups, preferred methyl, ethyl, propyl and isopropyl, and most preferred methyl and ethyl.

Lower alkoxy, specified in respect of R3and R4represents a linear or branched alkoxy having from 1 to 8 carbon atoms, and its examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Deut. -butoxy, tert. -butoxy, 1 methylbutoxy, 2-methylbutoxy, 1,2-DIMETHYLPROPANE, hexyloxy. Among these groups, preferred methoxy, ethoxy, with the most preferred methoxy.

Cycloalkyl specified in the relation R3and R4is cycloalkyl having from 3 to 8 carbon atoms, preferably from 3 to 7 carbon atoms and most preferably 5 or 6 carbon atoms.

Aryl specified in the relation R3, R4, R11, R12, R14, R15, R16, R17, R18, R19and A, includes phenyl, nafti is, 4, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18and R19is the same as the group above. Alkyl group (i.e Allenova group), which is arylalkyl, is a group having from 1 to 6 carbon atoms.

Heteroaryl specified in the relation R3, R4, R16, R17, R18and R19is heteroaryl originating from a 5 - or 6-membered ring containing one or two heteroatoms selected from nitrogen atoms, sulfur and oxygen.

Heteroaryl group, which is heteroallyl specified in the relation R1, R2, R3, R4, R7, R8, R9, R10, R13, R14and R15is the same as the group above. Alkyl group (i.e Allenova chain), which is heteroallyl, is a group having from 1 to 6 carbon atoms.

Arylalkylamines specified in the relation R13, R14and R15is arylalkylamines derived from any of the above arylalkyl groups.

Heteroarylboronic specified in the relation R13, R14and R15is the 2">

Arylsulfonyl specified in the relation R13, R14and R15is arylsulfonyl derived from any of the above aryl groups.

Heteroarylboronic specified in the relation R13, R14and R15is heteroarylboronic derived from any of the above heteroaryl groups.

Alkylsulfonyl, specified in respect of R13, R14and R15is alkylsulfonyl derived from any of the above lower alkyl groups.

As indicated above, R14and R15can denote, together with the nitrogen atom to which they are attached, a cyclic group. A cyclic group include groups derived from piperidinol and pyrazolinones rings. The cyclic group may further contain oxygen atom, nitrogen or sulfur, and examples of such groups include groups derived from morpholino and pieperazinove rings. A cyclic group is not limited to these groups. Alternative R14and R15may jointly represent acyl group derived from a dicarboxylic acid, i.e., they can form kidney group together with a nitrogen atom.

Preferred examples of replace is ylthio, alkylsulfanyl, alkylsulfonyl, galijasevic lower alkyl, cyano, carboxyl possibly protected, aryl, possibly substituted, and heteroaryl, possibly substituted.

As indicated above, R5, R6, R8, R9and R10can each identify possible protected carboxyl, and the protective group suitable for this case, includes lower alkyl groups such as methyl, ethyl and t-butyl; phenylsilane lower alkyl group in which the phenyl group can be substituted, such as n-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenated lower alkyl groups such as 2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy-lower alkyl groups, such as pivaloyloxymethyl, acetoxymethyl, propionylacetate, butyraldoxime, valerolactone, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxymethyl and 2-pivaloyloxymethyl; the highest alkanoyloxy-lower alkyl groups, such as palmitoleate, heptadecanoyl and 1-palmitoleate; lower alkoxycarbonyl-lower alkyl groups, such as methoxycarbonylmethyl, 1-(butoxycarbonylamino)ethyl and 1-(isopropoxycarbonyl)ethyl; carboxy-lower alkyl grannie benzoyloxy-lower alkyl group, such as 4-glycidoxypropyl; (substituted dioxolan)-lower alkyl groups such as (5-methyl-2-oxo-1,3 - dioxolan-4-yl)methyl; cycloalkylation lower alkanoyloxy-lower alkyl groups such as 1-cyclohexanediacetic; and cycloalkylcarbonyl-lower alkyl groups such as 1-cyclohexyloxycarbonyloxy. Further, the carboxyl group can be protected in the form of various amides of the acids. In short, the protective group may be any group which can be removed by some in vivo with a free carboxyl group.

As indicated above, R8, R9, R10, R11, R12, R13, R14and R15can each represent possible protected carboxylic, and the protective group suitable for this case is the same as that described above with respect to possible protected carboxyl. Next, Allenova group being possibly protected carboxyethyl is a group derived from any of the above alkyl groups.

Although imidazolyl specified above with respect to A, may be of any preferred imidazolyl represented by the formula

< / BR>
(where R20and R21

Imidazopyridine specified in relation to A, can be imidazopyridine derived from any imidazopyridine, and its examples include

(1) group derived from imidazo/1,2-a/pyridine, such as imidazo/1,2-a/pyridine-2-yl, imidazo/1,2-a/pyridine-3-yl, imidazo/1,2-a/pyridine-5-yl, imidazo/1,2-a/pyridine-6-yl, imidazo/1,2-a/pyridine-7-yl, imidazo/1,2-a/pyridine-8-yl;

(2) groups derived from imidazo/1,5-a/pyridine, such as imidazo/1,5-a/pyridine-1-yl, imidazo/1,5-a/pyridine-3-yl, imidazo/1,5-a/pyridine-5-yl, imidazo/1,5-a/pyridine-6-yl, imidazo/1,5-a/pyridine-7-yl, imidazo/1,5-a/pyridine-8-yl;

(3) group derived from imidazo/4,5-b/pyridine, such as imidazo/4,5-b pyridine-1-yl, imidazo/4,5-b pyridine-2-yl, imidazo/4,5-b pyridine-3-yl, imidazo/4,5-b pyridine-5-yl, imidazo/4,5-b pyridine-6-yl, imidazo/4,5-b pyridine-7-yl;

(4) group derived from imidazo/4,5-c/pyridine, such as imidazo/4,5-c/pyridin-1-yl, imidazo/4,5-c/pyridin-2-yl, imidazo/4,5-c/pyridin-3-yl, imidazo/4,5-c/pyridin-4-yl, imidazo/4,5-c/pyridin-6-yl, imidazo/4,5-c/pyridin-7-yl.

Preferred examples of the substituent for milfoil, galijasevic lower alkyl, possibly substituted aryl, possibly substituted heteroaryl and possibly protected carboxyl.

Acyl specified above in relation to R5, R6, R13, R14and R15can be an acyl derived from any of the aliphatic saturated monocarboxylic, aliphatic saturated dicarboxylic, aliphatic unsaturated carboxylic saturated and unsaturated carbocyclic carboxylic, heterocyclic carboxylic, hydroxycarbonate, alkoxycarbonyl and any other carboxylic acids. Examples of acyl include lower alcoholnye groups, such as formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl and pivaloyl; aroline groups such as benzoyl, toluene and naphtol; and heteroaryl groups, such as furoyl, nicotinoyl and isonicotinoyl.

Cianelli above in relation to R11and R12is the alkyl group described above in which one of the hydrogen atoms included in the alkyl group is replaced by the cyano.

Arylalkyl above in relation to R11and R12is arylalkyl derived from any of the above lower alkyl group by replacing one of the hydrogen at the includes inorganic salts, such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, tartrate, methanesulfonate, bansilalpet and toluensulfonate; and salts of amino acids such as arginine, aspartate and glutamate.

Further, a derivative according to the present invention can form a salt of the metal such as sodium, potassium, calcium or magnesium. Pharmacologically acceptable salt in accordance with the present invention include those salts of metals.

Further, the derivatives in accordance with the present invention can be presented in the form of geometric or optical isomers, depending on the Deputy. The present invention includes these isomers.

The following describes typical methods of producing compounds in accordance with the present invention.

The method of obtaining 1.

The connection represented by the General formula (I) in which R3is hydrogen, a Y is a group represented by the formula can be obtained according to the following method:

< / BR>
where

R1, R2, R4, A and Z have the above meaning.

More specifically, the target compound (III) can be obtained by carrying out the reaction with the base.

The base includes alkali metal alkoxides, such as t-piperonyl potassium; alkali metal hydrides such as sodium hydride; and organolithium compounds such as n-utillity.

The solvent used in the above reaction represents preferably an ether, such as tetrahydrofuran, a polar aprotic solvent such as N,N-dimethylformamide, or a mixture thereof, although they may be any organic solvent inert under the conditions of this reaction.

The reaction temperature may range from -78oC to the temperature of reflux distilled solvent used.

The method of obtaining 2.

The connection represented by the General formula (I) in which Y is a group represented by the formula , can be obtained according to the following method:

< / BR>
where

R1, R2, R3, R4A and Z each have the above values.

More specifically, the target compound (VI) can be obtained by recovering the compound represented by the General formula (V) metal hydride complex or a metal hydride.

Metallovedenie complex includes sodium borohydride and aluminosilicate, and as a hydride IU the given reactions, represents preferably an alcohol, such as methanol, ether, such as tetrahydrofuran, or hydrocarbons, such as toluene, although they can be any organic solvent inert under the conditions of this reaction.

The reaction temperature may range from -78oC to approximately the 50oC.

Alternative compound represented by the General formula (VI) can be obtained by recovering the compound represented by the General formula (V) an aluminum alkoxide in an alcohol solvent. In this reaction, it is preferable to use isopropyl alcohol as a solvent and an alkoxide of aluminum as a reducing agent.

The reaction temperature may be in the range from room temperature to the temperature of reflux distilled solvent used.

The method of obtaining 3.

The connection represented by the General formula (I) in which Y is a group represented by the formula (where R1a3denotes the acyl) can be obtained according to the following method:

< / BR>
where

R1, R2, R3, R4, A, Z and R1a3everyone has the above values.

More specifically, the target compound (VII) can the General formula (VIII) or a reactive derivative of it, the usual way.

Alternative you can use the salt of the compounds (VIII) and turn it into a compound (VIII) in the reaction system.

The reactive derivative of the compound (VIII) includes galodamadruga and symmetric anhydrite acids. When the compound (VIII) is used in the form of the free alcohol, usually with him used condensing agent.

Preferred examples of the condensing means include diphenylphosphine, N-hydroxybenzotriazole, N-hydroxysuccinimide, ethylchloride, methansulfonate, 1,3-dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, diethylazodicarboxylate and dipyridamole.

Further, the above condensation can be carried out in the presence of a base in some cases. The base used in this case is preferably an organic base, such as diisopropylethylamine, triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline or 4-dimethylaminopyridine, or inorganic base such as potassium carbonate or sodium hydroxide, although they can be any base.

The solvent used in this reaction represents preferably an alcohol, such as orotan, polar aprotic solvent, such as ethyl acetate, N,N-dimethylformamide or acetonitrile or pyridine.

The reaction temperature may be in the range -20oC to the temperature of reflux distilled solvent used.

The method of obtaining 4.

The connection represented by the General formula (I) in which Y is a group represented by the formula can also be obtained in the following way:

(Stage 1)

< / BR>
where

R1, R2A and Z each have the above values, R22denotes lower alkyl or benzyl: and Q denotes a leaving or delete the group.

More specifically, the target compound (X) can be obtained by reaction of the compounds represented by the General formula (II), first with carbon disulfide and then with the compound represented by the General formula (IX) in the presence of a base.

Leaving the group specified in the relation Q is preferably a halogen or methansulfonate.

Preferred examples of the base include alkali metal alkoxides, such as t-piperonyl potassium; hydrides of alkali metals, such as sodium hydride; and organolithium compounds such as n-utillity.

Dissolve the aprotic solvent, such as N,N-dimethylformamide or a mixture thereof, although it may be any organic solvent inert under the reaction conditions.

(Phase 2)

< / BR>
where

R1, R2, R3, R4, R22A and Z each have the above values.

The target compound (XI) can be obtained by conducting the reaction of the compounds represented by the General formula (X) with the compound represented by the General formula (XII), usually in excess, in the presence or in the absence of a solvent and, if necessary, under pressure.

When in the above reaction is meant a solvent, the solvent is preferably an alcohol, such as ethanol, ether such as tetrahydrofuran, or hydrocarbons, such as toluene, although they can be any organic solvent inert under the reaction conditions.

The reaction temperature may be in the range from room temperature to the temperature of reflux distilled solvent.

It is useful to R22-SH, formed during the reaction, was captured in the form of heavy metal by adding, for example, mercury chloride in the reaction system.

The method of obtaining 5.

The connection represented by the General form
R1, R2, R3, R4, R7A and Z each have the above values.

More specifically, the target compound (XIV) can be obtained by condensation produced thioformate represented by the General formula (XI) with the compound represented by the General formula (XIII) or its salt accession acid (acidic additive salt) in the presence of a base.

The base is preferably a pyridine or an inorganic base such as sodium acetate.

The solvent used in the reaction is preferably an alcohol, such as methanol, pyridine or water, although they can be any organic solvent inert under the reaction conditions.

The reaction temperature may be between approximately 0oC to the temperature of reflux distilled solvent used.

The method of teaching 6.

The connection represented by the General formula (I) in which Y is a group represented by the formula can also be obtained in the following way

< / BR>
where

R1, R2, R3, R4, R7A and Z each have the above values.

More specifically, the target compound (XIV) can be obtained to the second formula (XIII), or its salt accession acid in the presence of Lewis acid.

The Lewis acid is preferably titanium tetrachloride.

The solvent used in the reaction preferably is a halide, an organic solvent, such as dichloromethane, although they can be any organic solvent inert under the reaction conditions.

The reaction temperature may be between approximately 0oC to the temperature of reflux distilled solvent used.

The way to obtain 7.

The connection represented by the General formula (I) in which Y is a group represented by the formula (where R15has the above meaning), can be obtained in the following way:

< / BR>
where

R1, R2, R3, R4, R15A and Z each have the above values.

More specifically, the target compound (XV) can be obtained by reduction of the derived thioformate (XIV)', obtained by method 6 in normal conditions.

This recovery can be carried out in the usual way, for example, a method using a metal hydride complex or catalytic hydrogenation.

MH comp is e, preferred is an ether, such as tetrahydrofuran, or an alcohol, such as methanol. Preferably, the reaction temperature was between approximately -20oC and approximately 50oC.

The catalytic hydrogenation can be carried out by using a conventional catalyst, such as platinum/carbon, platinum oxide, Raney Nickel or rhodium/alumina.

The solvent used in the catalytic hydrogenation, preferably is an alcohol, such as methanol, hydrocarbons such as toluene, an ether, such as tetrahydrofuran, N,N-dimethylformamide or ethyl acetate. Preferably, the reaction temperature was between 0oC and temperature of reflux distilled solvent used.

The method of obtaining 8.

The connection represented by the General formula (I) in which Y is a group represented by the formula

(where R5and R6each have the above values), can be obtained in the following way:

< / BR>
where

R1, R2, R3, R4, R5, R6A and Z each have the above meanings; R23is lower alkyl; R24represents phenyl; and Hal represents halogen.

Preferred examples of the base used in this reaction include hydrides of alkali metals, such as sodium hydride; organolithium compounds such as n-utility; and alkoxides of alkali metals, such as t-piperonyl potassium.

The solvent used in the reaction, preferably represents an ether, such as tetrahydrofuran, or a polar aprotic solvent such as N, N-dimethylformamide, although they can be any solvent inert under the reaction conditions.

The reaction temperature may be in the range of from about -78oC to the temperature of reflux distilled solvent used.

When at least one of R3and R4is hydrogen, it is sometimes desirable that tifernina group of the compound (XI) was protected with a compound represented by the General formula: R22-Q (where R22and Q each have the above values) before reaction with compound (XVII) or (XVIII).

The method of obtaining 9.

The connection represented by the General formula (I) in which Y is a group represented by the formula where R112accordingly, provided that the group represented by the formula (where R14and R15everyone has the stated values) and-OR13(where R13have the above values) excluded/, can be obtained in the following way:

< / BR>
where

R1, R2, R3, R4, R5, R6, R1a1,R1a2A and Z each have the above values.

More specifically, the target compound (XIX) can be obtained by catalytic hydrogenation of compounds represented by the General formula (XVI) under normal conditions.

The catalyst used in the hydrogenation process includes palladium/carbon, platinum oxide, Raney-Nickel and rhodium/alumina.

Preferred examples of the solvent used in the reaction include alcohols such as methanol, hydrocarbons such as toluene, ethers such as tetrahydrofuran, N,N-dimethylformamide and ethyl acetate.

The reaction temperature may be between approximately 0oC to the temperature of reflux distilled solvent used.

The method of obtaining 10.

The connection represented by the General formula (I) in which Y is a group represented by the formula (where n SUP>, A, Z, Q and n each have the above values.

More specifically, the target compound (XXI) can be obtained by reaction of the compounds represented by the General formula (XX), first with carbon disulfide and then with the compound represented by the General formula (IX) in the presence of a base.

This group indicated for Q preferably represents halogen or methansulfonate.

Preferred examples of the base include alkali metal alkoxides, such as t-piperonyl potassium, and dialkylamide alkali metal, such as diisopropylamide lithium.

The solvent used in the reaction, represents preferably an ether, such as tetrahydrofuran, which can be used together with hexamethylphosphoramide as co-solvent in some cases.

Preferably, the reaction temperature was between about -78oC and temperature of reflux distilled solvent used.

< / BR>
where

R1, R2, R3, R4, R22, A, Z and n each have the above values.

More specifically, the target compound (XXII) can be obtained by reaction of compound (XXI) obtained predpochtitelno is an alcohol, such as ethanol, ether such as tetrahydrofuran, or hydrocarbons, such as toluene, although they can be any organic solvent inert under the reaction conditions.

Preferably, the reaction temperature was between room temperature and the temperature of reflux distilled solvent used.

It is useful to R22-SH, formed during the reaction, was udeblivelse least in the form of salts of heavy metal by adding to the reaction system, for example, chloride of mercury.

The method of obtaining 11.

The connection represented by the General formula (I) having an asymmetrical carbon atom, can be obtained in the form of optically active substances in the following way:

< / BR>
where

R1, R2, R3, R4, A, Y, and Z each have the above values.

When derived thioformate represented by the General formula (I) have basic properties, optically active compound (I') can be obtained by reaction of a derivative with an optically active acid, such as dibenzoyltartaric acid, with the formation of diastereoisomeric acid mixture, the mixture exposure fractional crystallization from a suitable solvent with gaining the active compound (I') can also be obtained by reaction of a derivative thioformate, represented by the General formula (I) with an optically active reagent for optical separation (such as optically active hydrazine) with the formation of diastereoisomeric mixture, separation diastereoisomeric mixture using column chromatography or fractional crystallization to obtain pure diastereoisomer from optically active reagent.

Further, the optically active compound (I') can also be obtained directly by dividing the derived thioformate represented by the General formula (I), using chromatography using chiral columns.

Further, the optically active compound (I') can also be obtained by subjecting derived thioformate represented by the General formula (I), kinetic separation using asymmetric reducing agent and oxidizing the obtained diastereoisomeric product in the usual way.

The effect of the invention.

Below are examples of pharmacological experiments to illustrate the invention.

(1) Vasopeptidase activity in the sample of rat aorta.

Compounds according to the present invention was investigated on vasopeptidase activity with POM is from male SD rats, which has a weight of 250 - 400 g, and from the aorta were prepared spiral pattern. This spiral pattern is vertically suspended in Ogunwande, filled with a solution of Krebs-Hensleit at 30oC, through which was passed a gas mixture consisting of 95% oxygen and 5% carbon dioxide. The change in the voltage of the sample was measured as a result of isotopically under a load of 1 g

After the tension of the sample stabilized in bath was added 20 mm KCl. After the resulting tension stabilized in Organand cumulative added investigated the connection to determine the relaxation.

The magnitude of the relaxation, i.e., the activity to slow the occurrence of tension was determined by taking the tension that arises when adding KCl to 100% and calculating the value of the IC50. The values of the IC50defined this way, is shown in the table.

(2) the Activity in relation to potential (hidden) duration on the right ventricular papillary muscle of the Guinea pig.

Compounds according to the invention was investigated on the effect of activated potassium channel using the right ventricular papillary muscle of the Guinea pig.

Experimental method.

90) reflects the output current of potassium. Connection with the effect of activation of the potassium channel, can activate the opening of the potassium channel, reducing APD90(see Proc. Natl. Acad. Sci., USA, 85, 8360 - 8364 (1988)).

Used male Guinea pigs, Hartley weight of from 300 to 500, the Guinea pigs were killed by exsanguination, papillary muscle were completely removed from her right ventricle and recorded in Ogunwande. The surface of the papillary muscles were washed with Tyrode solution at 36 0,5oC, through which was passed a mixture of oxygen/carbon dioxide. The resulting sample is stimulated by the application thereto of a rectangular wave pulse 1 Hz to record the action potential by the method of glass microelectrode.

After the action potential has stabilized, the sample was rinsed with Tyrode solution containing each of the investigated compounds, for 30 minutes to determine the curve dose-response.

Ratio (%) APD90detected at each concentration of tested compound in Tyrode solution to the initial APD90detected before the introduction of the compounds were calculated to determine the concentration of the compound (-log M), where APD90was reduced by 50% from Persia IC50.

(3) Hypotensive activity and activity to increase coronary blood flow have shot the dog with an open chest.

Compounds according to the present invention were tested for hypotensive activity and activity to increase coronary blood flow by using a shot of the dog with an open chest.

Experimental method.

Used adult hybrid dog. The dog opened the chest under inhalation anesthesia using enflurane/laughing gas. Set the sensor of the electromagnetic flowmeter in the envelope branch (ramus circumflexes) of the left coronary artery for determination of coronary blood flow. Blood pressure was determined by placing the probe tip pressure catheter in the aortic arch (arcus aortae).

Each test compound was administered intravenously at a dose of 3 mg/kg via a catheter inserted in the femoral vein.

Hypotensive activity and activity to increase coronary blood flow for each connection listed in the table as the change in blood pressure and coronary blood flow compared with those before the introduction of the connection.

Experimental method.

The systolic blood pressure of spontaneously hypertensive males rats (weight: 260 - 360 g), which were not fed for 12 hours, was determined bloodless method tail cuff. Every drug suspended in 0.5% aqueous solution of methylcellulose and was administered orally at a dose of 1 mg/kg Control rats given only the solvent.

Blood pressure in rats 2 hours after drug administration are shown in the table, and blood pressure before the introduction is taken as 100.

The experimental results.

The results of the above experimental examples from (1) to (13) shown in the table. Connection 1 - 13 are the following:

connection 1

(-)-1-(imidazo/1,2-a/pyridine-6-yl)-N-methyl-2-oxocyclohexanecarboxylic

connection 2

(-)-N-ethyl-1-(imidazo/1,2-a/pyridine-6-yl)-2-oxocyclohexanecarboxylic

connection 3

(-)-N-methyl-1-(2-methylimidazo/1,2-a/pyridine-6-yl)-2 - oxocyclohexanecarboxylic

connection 4

(-)-2-benzoyloxy-1-(imidazo/1,2-a/pyridine-6-yl)-2-N - methylcyclohexanecarboxylic

connection 5

2-benzyloxy-1-(imidazo/1,2-a/pyridine-6-yl)-N-methyl - cyclohexanecarboxylic

connection 6

anti-2-benzyloxy the/1,2-a/pyridine-6-yl)-N - methylcyclohexanecarboxylic

compound 8

2-(imidazo/1,2-a/pyridine-6-yl)-N-methyltetrahydrofuran-2 - carbothioamide-1-oxide

connection 9

2-benzoyloxy-N-methyl-1-(4-nitroimidazol-1-yl)cyclohexanecarboxylic

connection 10

2-benzyloxy-N-methyl-1-(4-nitroimidazol-1-yl)cyclohexanecarboxylic

connection 11

anti-2-benzylamino-N-methyl-1-(4-nitroimidazol-1 - yl)cyclohexanecarboxylic

connection 12

(-)-1-(2-triptoreline/1,2-a/pyridine-6-yl)-N-methyl-2 - oxocyclohexanecarboxylic

connection 13

(-)-2-(2-methylimidazo/1,2-a/pyridine-6-yl)-N-methyltetrahydrofuran-2 - carbothioamide-1-oxide

As can be seen from the results of pharmacological experiments, the compounds according to the present invention can be activated potassium channel smooth muscles, thereby relaxing blood smooth muscle and thereby manifesting the activity in increasing coronary blood flow and hypotensive activity. In accordance with this connection according to the present invention is effective as a means of opening of the potassium channel and due to this activity, they can be used as medicines.

Thus, the compounds according to the present invention is effective in the prevention and treatment the SNO present invention are less toxic and have a large margin of safety what makes them valuable in this sense.

The connection according to the present invention are introduced as a therapeutic and prophylactic agent in the above-mentioned diseases in the form of tablets, powder, granules, capsules, syrups or inhalations. Although the dose of the compound varies depending on the severity of the symptom, age and type of disease, a daily dose for an adult is from about 0.1 to 1000 mg, preferably from 1 to 500 mg, and can be entered in one or more doses per day.

When the connection according to the present invention is introduced in the form of injection, the dose is usually from 1 to 3000 μg/kg, preferably about 3 to 1000 μg/kg

Pharmaceutical preparations in accordance with the present invention are prepared using conventional media in the usual way.

More specifically, the solid preparation for oral administration in accordance with the present invention is prepared by adding to the active ingredient excipient and, if necessary, a binder, disintegrator, lubricants, coloring and/or modifying substances and forming the resulting mixture into tablets, coated tablets, granules, powder or capsule about what it crystalline cellulose and silicon dioxide; examples of the binder include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragakant, gelatine, shellac, hydroxypropylcellulose, hydroxymethylcellulose, calcium citrate, dextrin and pectin; examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica, and hydrogenated vegetable oil; examples of the coloring matter include permitted pharmaceutical additives, and examples of the modifying substances include cocoa powder, mint, aromatic powder, peppermint oil, borneol and powdered bark brown wood. Of course, tablets, granules can be suitably coated with sugar, gelatinous or similar substance, if necessary.

Injection solution in accordance with the present invention is prepared by adding, if necessary, to the active ingredient of the pH Adjuster, buffer, stabilizer and/or solubilizing agent and formulating the mixture into an injection for subcutaneous, intramuscular or intravenous injection in the usual way.

Example.

Below are described examples in accordance with the present invention, by preparative examples describing the preparation of drugs of source materials used in obtaining the target compounds according to the present invention.

In the following preparative examples and examples, Me represents methyl, Et is ethyl.

Preparative example 1.

2-(Imidazo/1,2-a/pyridine-6-yl)cyclohexanone

< / BR>
49,35 g of magnesium was added to 500 ml of tetrahydrofuran, and the mixture was bury 11,4 ml brometane at room temperature under stirring in nitrogen atmosphere to prepare Grignard reagent. The resulting reaction mixture was cooled with water and this reaction mixture for about one hour was added dropwise a solution of 100 g of 6-bromoimidazo/1,2-a/pyridine and 102 ml of brometane in 1 l of tetrahydrofuran. After the addition the mixture was heated under reflux for 30 minutes.

The resulting reaction mixture was cooled with ice, followed by adding dropwise the solution of 263 g of 2-methoxycyclohexanone in 200 ml of tetrahydrofuran. After the addition the mixture was stirred at room temperature for 3 hours.

The resulting reaction mixture was again cooled with ice, and was tempered by adding nsysu phase was washed with ethyl acetate, was podslushivaet concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent, obtaining of 122.5 g of brown oil.

To this oil portions were added 300 ml of concentrated sulfuric acid. The resulting mixture was shaken at room temperature rather vigorously, getting a brown solution, which took approximately 2 hours. The obtained brown solution was poured over ice and the resulting mixture was podslushivaet concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The obtained residue was purified chromatographic columns with silica gel /solvent: dichloromethane/methanol(50 : 1 - 30 : 1)/ and the obtained solid was thoroughly washed with ether, receiving 63,46 g the main compound in the form of powder color light ochre.

Further, the washing water was concentrated and purified chromatographic column with silica gel /solvent: dichloromethane/methanol (30 : 1)/. The obtained solid was washed with ether, receiving 6,83 g the main compound in the form of powder color light ochre. Thus, BP>H-NMR (400 MHz, CDCl3) : 1,76 - 1,12 (4H, m), 2,16 - of 2.28 (1H, m), 2,29 - of 2.38 (1H, m), 2,44 - 2,62 (2H, m) and 3.59 (1H, dd, J = 5,5, and 12.4 Hz), to 6.95 (1H, dd, J = 1,6, and 9.3 Hz), 7,52 (1H, dd, J = 0.5, and 1.3 Hz), EUR 7.57 (1H, d, J = 9.3 Hz), 7,60 (1H, d, J = 1.3 Hz), 7,94 (1H, dd, J = 0.5, and 1.3 Hz).

Preparative example 2.

2-(2-Methylimidazo/1,2-a/pyridine-6-yl)cyclohexanone

< / BR>
of 7.70 ml (0,103 mol) of ethylbromide was to bury suspension 32,08 g (1,32 mol) of metallic magnesium turnings in 350 ml of tetrahydrofuran in a nitrogen atmosphere. As soon as it was observed the formation of ethylacetamide, to the mixture was added dropwise a solution of 69,52 g (0,329 mol) of 6-bromo-2-methylimidazo-/1,2-a/pyridine and 66,0 ml (0,880 mol) of ethylbromide in 700 ml of tetrahydrofuran in the course of an hour with such speed, that lasted spontaneous soft deregulirovanie. After the addition the mixture was heated under reflux for 30 minutes and cooled with ice. To the reaction mixture solution was added RUB 171.1 g (of 1.34 mol) 2-methoxycyclohexanone in 150 ml of tetrahydrofuran for 30 minutes at such a rate that the temperature of the main mass of the mixture did not exceed 30oC. the resulting mixture was shaken at room temperature for 3 hours, cooled with ice and acidified by the addition of saturated aqueous solution of chloride of shumilkin) is, onselaciune concentrated aqueous ammonia and extracted with chloroform. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum.

To the obtained crude 2-methoxy-2-(2-methylimidazo-/1,2-a/-pyridine - 6-yl)cyclohexanone (73,7 g) was added in portions over 30 minutes, 200 ml of concentrated sulfuric acid, cooling the resulting mixture in a suitable manner in a water bath. The obtained reddish-purple liquid was stirred at room temperature for 16 hours.

The reaction mixture was poured on ice, cooling with ice. The resulting mixture was podslushivaet concentrated aqueous ammonia and was extracted with dichloromethane. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. The obtained residue (62.3 g) was purified chromatographically on a column of silica gel /solvent: dichloromethane/methanol (50 : 1)/, getting 51 g of a yellow crystal. The crystals are recrystallized from dichloromethane/ethyl acetate, getting 18,85 g the main compound in the form of colorless crystals. Further, the mother liquor (26.7 g) was poroshkovo e obtained 35,74 g specified in the title compound (yield: 48%).

So pl. (oC): 147 - 148.

1H-NMR (400 MHz, CDCl3) : 1,76 - of 2.08 (4H, m), 2,16 - of 2.24 (1H, m), 2,31 (1H, m) 2,44 (3H, d, J = 0.9 Hz), 2,46 - 2,60 (2H, m), of 3.57 (1H, DD, J = 12,4, a 5.4 Hz), make 6.90 (1H, DD, J = 9,3, 1,6 Hz), 7,27 (1H, Shir. C.), was 7.45 (1H, d, J = 9,2 Hz), to 7.84 (1H, DD, J = 1,6, and 0.8 Hz).

Preparative example 3.

2-(Imidazo/1,2-a/pyridine-6-yl)-2-((4-methoxybenzylthio)(methylimino) methyl)cyclohexanol

< / BR>
2.50 g of 2-Hydroxy-1-(imidazo/1,2-a/pyridine-6-yl)-N - methylcyclohexanecarboxylic (M-form) suspended in 45 ml of N,N-dimethylformamide followed by the addition of 1.32 g of anhydrous potassium carbonate and 1.29 ml of 4-methoxybenzylamine. The resulting mixture was stirred at room temperature for 10 hours.

The resulting reaction mixture was concentrated, then added water. The resulting mixture was filtered, receiving insoluble material. This material was washed with 50% aqueous ethanol and ether successively, receiving 3,19 g specified in the title compound as a slightly yellow powder (yield: 90%).

So pl. (oC): 203 - 206 (decomp.).

1H-NMR (400 MHz, CDCl3) : 1,36 is 1.70 (5H, m), 1,83 - 1,90 (1H, m), 2,59 of 2.68 (1H, m) to 3.33 (1H, d, J = 12.3 Hz), 3,55 (3H, m), and 3.72 (3H, in), 3.75 (1H, d, J = 12.3 Hz), 4,37 (1H, DDD, J = 2.7, and a 2.9, 10.1 Hz), 6,53 - to 6.57 (2H, m), of 6.68 - 6.73 x (2H, m), 7,49 - 7,56 (3H, m), to 7.61 (1H, m), a total of 8.74 (1H, Shir. with the (o) (methylimino)methyl)cyclohexane

< / BR>
1.04 g (2 Imidazo/1,2-a/pyridine-6-yl)-2-((4-methoxybenzylthio) (methylimino))methyl)cyclohexanol suspended in 25 ml of tetrahydrofuran. The resulting suspension was cooled to -60oC immediately followed by the addition of 300 mg of t-butoxide potassium. The resulting mixture was stirred at -60oC for 2.5 hours followed by the addition of 0.32 ml of benzylbromide. The temperature of the mixture was gradually raised to 0oC for about one hour, and the resulting mixture was stirred at 0oC for 2 hours, then added water. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The residue was purified chromatographically on a column of silica gel /solvent: dichloromethane/methanol (50:1)/, receiving 500 mg specified in the title compounds as a pale yellow oil (yield: 39%).

1H-NMR (400 MHz, CDCl3) : 1,14 of 1.28 (1H, m), 1,45 to 1.76 (3H, m), 1,88 - 2,02 (2H, m), 2,19 (1H, dt, J = 3,5, and 12.7 Hz), 3,35 (1H, d, J = 12.3 Hz), of 3.60 (3H, s), 3,70 (3H, s), and 3.72 (1H, d, J = 12.3 Hz), 4,07 (1H, d, J = 11.7 Hz), 4,35 (1H, Shir. C) to 4.41 (1H, d, J = 11.7 Hz), 6,51 - 6,56 (2H, m), 6,64 of 6.68 (2H, m), 6,83 (2H, DD, J = 1,5, and 8.4 Hz),? 7.04 baby mortality - 7,17 (4H, m), 7,46 (2H, t, J = 4.4 Hz), to 7.61 (1H, d, J = 1.3 Hz), 7,98 (1H, m).

Preparative example 5.

oC and stirred under nitrogen atmosphere followed by the addition of 6.9 ml of a 1.6 M solution of n-utility in hexane. The resulting mixture was stirred for one hour, then added immediately to 1.5 ml of N,N-dimethylformamide. After an hour the temperature of the mixture was raised to room temperature, and the resulting mixture was stirred for 30 minutes.

Added ice water to the mixture, and the resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled in vacuum to remove solvent. Added ether to the resulting residue, and the resulting mixture was filtered, receiving insoluble material. Thus, there was obtained 0,43 g specified in the title compound as light brown powder. Next, the filtrate was concentrated and the obtained residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (50 : 1)/ getting to 0.47 g specified in the procurement compound as a pale yellow solid. Thus they received a total of 0.90 g of target compound (yield: 62%).

So pl. (oC): 151 - 153,5.

1H-NMR (400 MHz, CDCl3) : 7,66 (1H, DD, J = 1,6, and 9.3 Hz), 7,71 (1H, d, J = 9.3 Hz), 7,74 (1H, DD, J = 0,9, 1.3 Idasa/1,2-a/pyridine-6-yl)methanol

< / BR>
0,90 g 6 imidazo/1,2-a/pyridinecarboxamide obtained in preparative example 5, was dissolved in 20 ml of methanol. The resulting solution was stirred under cooling with ice, and then thereto was added 90 mg of sodium borohydride. The resulting mixture was stirred for 50 minutes followed by the addition of water. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The obtained residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (30 : 1 to 10 : 1)/, getting 0.52 g specified in the procurement connections in the form of slightly orange-yellow solid (yield: 57%).

So pl. (oC): 106 - 107.

1H-NMR (400 MHz, CDCl3) : 4,69 (2H, d, J = 0.9 Hz), 7,12 (1H, DD, J = 1,6, and 9.3 Hz), to 7.50 (1H, d, J = 9.3 Hz), 7,52 (1H, DD, J = 0.5, and 1.3 Hz), 7,58 (1H, d, J = 1.3 Hz), 8,10 (1H, DDD, J = 0,5 0,9, 1,6 Hz).

Preparative example 7.

6-((4-Chlorobutyl)thiomethyl)imidazo/1,2-a/pyridine

< / BR>
11,23 g (imidazo/1,2-a/pyridine-6-yl)methanol obtained in preparative example 6, was dissolved in 170 ml of chloroform, and then was added dropwise to 11.1 ml of thionyl chloride at room temperature under stirring. An hour later, drove the solvent. So abrazolasa was added to the mixture, containing 40 ml of methanol and 40 ml of ethanol, and then adding 6,92 g of thiourea. The resulting mixture was heated under reflux for 4 hours, cooled, allowing it to stand, and distilled to remove solvent. Thus obtained crude S-((imidazo/1,2-a/pyridine - 6-yl)methylisothiazoline-dihydrochloride in the form of a light brown powder.

This powder was dissolved in 40 ml of water followed by the addition of 15.2 ml of 10 N. aqueous sodium hydroxide solution. The resulting mixture was heated under reflux for 2 hours and cooled in ice. To the mixture was sequentially added to 9.1 ml of 10 N. aqueous sodium hydroxide solution, and 11.4 ml of 1-bromo-4-chlorobutane and 40 ml of ethanol. The resulting mixture was stirred at room temperature for 2 hours.

To the mixture was added water, and then extracted with ethyl acetate. The organic phase was extracted with dilute hydrochloric acid. The aqueous phase was podslushivaet potassium carbonate and was extracted again with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The obtained residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (50 : 1)/, 1
H-NMR (400 MHz, CDCl3) : 1,70 - to 1.79 (2H, m), 1,82 - 1,90 (2H, m), 2,46 (2H, t, J = 7,1 Hz), 3,53 (2H, t, J = 6.2 Hz), of 3.69 (2H, d, J = 0.4 Hz), 7,20 (1H, DD), J = 1,6, and 9.3 Hz), 7,54 (1H, DD), J = 0.5, and 1.1 Hz), to 7.59 (1H, d , J = 9.3 Hz), a 7.62 (1H, d, J = 1.1 Hz), with 8.05 (1H, DDD., J = 0,4, 0,5, 1,6 Hz).

Preparative example 8.

6-((-Chlorobutyl)sulfanilyl)imidazo/1,2-a/pyridine

< / BR>
to 11.79 g of 6-((4-chlorobutyl)thiomethyl)imidazo/1,2-a/pyridine, obtained in preparative example 7, was dissolved in 160 ml of dichloromethane. The resulting solution was cooled with ice and then adding to 7.99 g of m-chloroperbenzoic acid for about 40 minutes. The resulting mixture was stirred. After 30 minutes, thereto was added 0.4 g of m-chloroperbenzoic acid. The resulting mixture was further stirred for one hour, and then thereto was added an aqueous solution of sodium thiosulfate. The resulting mixture was vigorously stirred at room temperature for 30 minutes and was extracted with chloroform. The organic phase was washed with an aqueous solution of potassium carbonate, dried over anhydrous magnesium sulfate and distilled to remove solvent. The obtained residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (30 : 1 to 10 : 1)/ receiving of 9.51 g specified in the title compound ,7 Hz), to 3.58 (2H, t, J = 6.0 Hz), a 3.87 (1H, d, J = 13,4 Hz), 3,98 (1H, d, J = 13,4 Hz), 7,07 (1H, DD, J = 1,6, 9,2 Hz), 7,60 (1H, DD, J = 0.7 and 1.2 Hz), to 7.64 (1H, d, J = 9,2 Hz), 7,66 (1H, d, J = 1.2 Hz), 8,19 (1H, DD, J = 0.7 and 1.6 Hz).

Preparative example 9.

2-(Imidazo/1,2-a/pyridine-6-yl)tetrahydrothiopyran 1-oxide

< / BR>
8,68 g t butoxide potassium was added to 80 ml of a mixture /4:1 (vol./vol.)/ of tetrahydrofuran and hexamethylphosphoric triamide followed by cooling with ice. To the mixture was added dropwise a solution of 9.51 g of 6-((4-chlorobutyl)-sulfanilyl)imidazo/1,2-a/pyridine, obtained in preparative example 8, 30 ml of a mixture /4:1 (vol./vol.)/ of tetrahydrofuran and hexamethylphosphoric triamide. The resulting mixture was stirred for one hour, after which it was added ice-cold water. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The resulting oil was utverjdali, allowing it to stand, followed by the addition of ether. The resulting mixture was filtered, receiving of 5.84 g specified in the connection header in the form of a dark cream-colored powder (yield: 71%). NMR spectroscopic analysis of the powder revealed that the powder is a mixture containing two diastereomers in the ratio of approximately ,56 - to 7.67 (3H, m), 8.17 - a 8,19 (1H, m).

Preparative example 10.

2-(4-Nitroimidazol-1-yl)cyclohexanone

< / BR>
84,0 ml (0,736 mol) 2-chlorocyclohexanone and 92,54 g (0,670 mol) of potassium carbonate was added to the suspension 75,16 g (0.665 mol) 4-intorimidazole in 1 ml of acetonitrile. The resulting mixture was heated under reflux for 18 hours and cooled, allowing it to stand, and then thereto was added water. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. The obtained residue was poroshkovo with ethyl acetate, getting 86,46 g specified in the title compound as a pale brown powder (yield: 62%).

So pl. (oC): 122 - 123.

1H-NMR (400 MHz, CDCl3) / : is 1.81 (1H, square so, J = 13,4, and 3.8 Hz), was 1.94 (1H, m), 2,12 (1H, square D. J = 12,8, 3,4 Hz) to 2.18 (1H, m), and 2.27 (1H, m), 2,53 (1H, TDD. , J = 13,8, 6,2, 0.7 Hz), 2,60 (1H, m), 2,70 (1H, fellow of Queen., J = 13,9 and 2.2 Hz), the 4.90 (1H, DD), J = 13,0, 5.7 Hz), 7,42 (1H, d, J = 1.6 Hz), to 7.77 (1H, d, J = 1.6 Hz).

Preparative example 11.

2-(4-Nitroimidazol-1-yl)cyclohexanol

< / BR>
40,0 ml (395 mmol) of cyclohexanone and 86,37 g (625 mmol) of potassium carbonate was added to the suspension 50,08 g (443 mmol) 4-nitrome the th and 20 hours, getting yellowish-brown suspension. This suspension was cooled, allowing it to stand, and was filtered to remove insoluble substances. The filtrate was concentrated in vacuum. Added water to the obtained residue to form a crystalline precipitate. The crystalline precipitate was removed by filtration and washed with water. The resulting crude crystal was dissolved in chloroform, and the resulting solution was washed with a saturated aqueous solution of common salt. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuum. During concentration began to precipitate crystals. The crystals were removed by filtration, getting 53,26 g specified in the title compounds as colorless crystals. Next, the filtrate was recrystallized from dichloromethane/isopropyl ether, receiving 5,14 g of target compound in the form of light brown crystals. Thus, the total received 58,30 g of target compound (yield: 70%).

So pl. (oC): 150 - 151.

1H-NMR (400 MHz, CDCl3) : 1,36 - and 1.54 (3H, m) of 1.76 (1H, m), 1,84 - to 1.98 (2H, m), 2,12 - of 2.26 (2H, m), 3,18 (1H, d, J = 4, 2 Hz), disappeared when adding D2O, 3,71 (1H, m, when added D2O, etc. J = 9,9, 4.5 Hz), with 3.79 (1H, DDD, J = 12,3, 9,5 to 3.8 Hz), 4,47 (1H, d, J = 1.6 Hz), 7,79 (1H, d, J = 1.6 Hz).

is slingload in 250 ml of dichloromethane was cooled in a bath of dry ice and methanol. In the above solution for 10 minutes was added dropwise a solution of 27.0 ml (380 mmol) of dimethyl sulfoxide in 90 ml of dichloromethane with such speed that the temperature of the mass of the solution was maintained in the range from -60 to -50oC. the resulting mixture was further stirred for 4 minutes, getting a colourless solution. In the colorless solution was added dropwise a solution of 31,92 g (151 mmol) of 2-(4-nitroimidazol-1-yl)cyclohexanol obtained in preparative example 11, a mixture containing 240 ml of dichloromethane and 30 ml of dimethyl sulfoxide, within 7 minutes with such a speed that the temperature of the main weight did not exceed -50oC. the resulting mixture was further stirred for 15 minutes. In the mixture for 7 minutes was bury 80,0 ml (570 mmol) of triethylamine with such speed that the temperature of the main weight did not exceed -50oC. the resulting mixture was further stirred for 7 minutes and then cleaned the bath of dry ice and methanol. After 30 minutes the temperature of the main mass was reached +10oC. To the resulting mixture were added saturated aqueous solution of acid sodium carbonate, and the mixture was left to stand for separation liquid-liquid. The organic phase was concentrated in vacuo phase was combined with an ethyl acetate solution, previously obtained. The resulting mixture was washed with a saturated aqueous solution of common salt. The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuum, getting to 33.9 g of crude crystals. The crude crystals are recrystallized from dichloromethane/ethyl acetate, getting 26,53 g of target compound in the form of colorless crystal. Further, the mother liquor was recrystallized from dichloromethane/diisopropyl ether, receiving 2,52 g of target compound in the form of light yellowish-brown crystals. So, just got 29,05 g of target compound (yield: 92%).

Preparative example 13.

2-((4-Methoxybenzylthio)(methylimino)methyl)-2-(4-nitroimidazol - 1-yl)cyclohexanol

< / BR>
to 21.7 ml (160 mmol) of 4-methoxybenzylamine and 32,94 g (238 mmol) of potassium carbonate were added to a solution of 45,23 g (159 mmol) of 2-hydroxy-N-methyl-1-(4-nitroimidazol-1-yl)cyclohexylcarbodiimide (L-form) obtained in example 17, in 300 ml of N,N-dimethylformamide. The resulting mixture was stirred at room temperature for 17 hours, getting a tan suspension. To this suspension was added water and salt, and the resulting mixture was extracted with ethyl acetate. The organic phase was washed nasyshennoy balance (65,5 g) was recrystallized from dichloromethane/ethyl acetate, getting 42,78 g specified in the connection header in the form of light yellowish-brown crystals (yield: 66%).

So pl. (oC): 135 - 136.

1H-NMR (400 MHz, CDCl3) : of 1.28 to 1.48 (3H, m), and 1.56 to 1.76 (3H, m), 1,90 (1H, m), 2.63 in (1H, m), 3,44 (1H, d, J = 12,5 Hz) to 3.58 (3H, s), 3,74 (1H, d, J = 12,5 Hz), of 3.77 (3H, s), to 4.38 (1H, dt, J = 11,0, 3.1 GHz with the addition of D2O, DD, J = 11,3, 3.6 Hz), 4,78 (1H, Shir.with. disappeared when adding D2O) 6,74 (2H, d, J = 8.6 Hz), 6,85 (2H, d, J = 8.6 Hz), to 7.99 (1H, d, J = 1.6 Hz), of 8.27 (1H, d, D = 1,6 Hz).

Preparative example 14.

2-Benzyloxy-1-((4-methoxybenzylthio)(methylimino)methyl)- 1-(4-nitroimidazol-1-yl)cyclohexane

< / BR>
The solution 42,76 g (106 mmol) of 2-((4-methoxybenzylthio)(methylimino)methyl - 2-(4-nitroimidazol-1-yl)cyclohexanol obtained in preparative example 13, in 300 ml of tetrahydrofuran was added dropwise to a suspension 5,13 g (60% dispersion in mineral oil, 128 mmol) of sodium hydride in 60 ml of tetrahydrofuran under nitrogen atmosphere at room temperature for 20 minutes. The resulting mixture was further stirred at 50oC for 10 minutes followed by the addition of 13.2 ml (111 mmol) of benzylbromide at 50oC. the resulting mixture was stirred at 50oC for one hour and then under reflux distilled by heating for 20 extragonadal with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. The obtained residue (55.8 g) was purified by chromatography on a column of silica gel /solvent: benzene/acetone (25 : 1 to 5 : 1)/, getting 6,15 g specified in the title compound as a brown oil (yield: 12%).

1H-NMR (400 MHz, CDCl3) : 1,28 - 1,49 (2H, m), 1,49 is 1.60 (1H, m), 1.60 - to of 1.78 (2H, m), at 1.91 (1H, m), 2,19 (1H, DDD, J = 12,8, 8,8, 2,9 Hz), 2,39 (1H, m) to 3.58 (3H, s) and 3.59 (1H, d, J = and 19.4 Hz), 3,76 (1H, d, J = and 19.4 Hz), of 3.77 (3H, s), 4,24 (1H, d, J = 11.4 in Hz), the 4.29 (1H, DD, J = 6,9, 2,5 Hz), a 4.53 (1H, d, J = 11.4 in Hz) of 6.75 (2H, d, J = 8,8 Hz) 6,91 (2H, d, J = 8,8 Hz), was 7.08 (2H, DD, J = 7,5, 1.8 Hz), 7,22 - to 7.32 (3H, m), to 7.61 (1H, d, J = 1.1 Hz), of 7.69 (1H, d, J = 1.1 Hz).

Preparative example 15.

2-(2-(Triptoreline/1,2-a/-pyridine-6-yl)-cyclohexanone

< / BR>
of 6.9 g of magnesium was added to 120 ml of tetrahydrofuran, and the resulting mixture was stirred in nitrogen atmosphere. To the resulting mixture was added 1.6 ml of brometane dropwise at room temperature to obtain a Grignard reagent. To the above reaction mixture was bury solution of 18.9 g of 6-bromo-2-triptoreline/1,2-a/pyridine and 14.4 ml of brometane in 120 ml of tetrahydrofuran. Upon completion of the addition the mixture was heated ml of 2-methoxycyclohexene. The resulting mixture was stirred at room temperature for 3 hours and cooled again with ice, followed by adding a saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent to obtain a brown oil.

To this oil portions was added 70 ml of concentrated sulfuric acid. The resulting mixture was stirred at room temperature for 2 hours and poured into ice. The resulting mixture was podslushivaet concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The residue was purified by chromatography on a column of silica gel /solvent: n-hexane/ethyl acetate (2 : 1 to 1 : 1)/ and the obtained solid was washed with ether, receiving 10,18 g specified in the title compound as a slightly yellow powder (yield: 51%).

So pl. (oC): KZT 166.5 - 169.

1H-NMR (400 MHz, CDCl3) : 1,76 - 2,03 (3H, m) 2,07 (1H, m), 2,24 (1H, m), 2,35 (1H, m), 2,46 - 2,62 (2H, m), 3,62 (1H, DD, J = 5,3, and 12.4 Hz), to 7.09 (1H, DD, J = 1.6 Hz, 9.3 Hz), a 7.62 (1H, d, J = 9.3 Hz), 7,82 (1H, m), 7,98 (1H, m).

Preparative example hagedoorn and 0.3 g of iodine, and 18 ml of brometane was added to the obtained mixture to obtain a Grignard reagent. To the above reaction mixture was slowly added dropwise a solution of 170,5 g of 6-bromo-2-methylimidazo/1,2-a/pyridine and 162 ml of brometane in 500 ml of tetrahydrofuran. By the end of the addition the mixture was heated under reflux for 30 minutes and then cooled with ice. Formaldehyde was generated by heating the container containing 242 g of paraformaldehyde, 200oC and introduced into the reaction mixture using a stream of nitrogen. After 30 minutes, to the resulting mixture was added diluted hydrochloric acid, and the resulting mixture was filtered to remove insoluble substances. The filtrate was podslushivaet concentrated aqueous ammonia and extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (30:1 to 10:1)/, getting 120 g of target compound as a pale yellow solid (yield: 91,9%).

So pl. (oC): 136 - 137

1H-NMR (400 MHz, CDCl3) : 1,8 (1H, W), 2,43 (3H, d, J = 0.9 Hz), of 4.66 (2H, s), 7,06 (1H, DD, J = 1,6 Hz and 9.2 Hz), 7,27 (1H, s), 7,39 (1H,pyridine

< / BR>
to 6.80 g of 2-methylimidazo/1,2-a/pyridine-6-methanol, obtained in preparative example 16, was dissolved in 90 ml of chloroform, and then was added dropwise to the obtained solution of 6.1 ml of thionyl chloride with stirring at room temperature. After two hours the solvent drove away. Received crude 6-hermetic-2-methylimidazo/1,2-a/pyridine hydrochloride as a brown oil.

The oil was dissolved in a mixture containing 40 ml of methanol and 40 ml of ethanol, followed by addition of 3.8 g of thiourea. The resulting mixture was heated under reflux for 3.5 hours and then cooled, allowing it to stand. The resulting mixture was distilled to remove the solvent to give crude S-((2-methylimidazo/1,2-a/pyridine - 6-yl)methyl)sociosocio-dihydrochloride in the form of a bright orange-yellow amorphous substance.

This substance was added 40 ml of water and 8.4 ml of 10 N. aqueous sodium hydroxide solution. The resulting mixture was heated under reflux for one hour and cooled in ice followed by the addition of 5.8 ml of 10 N. aqueous sodium hydroxide solution, 5.0 ml of 1-bromo-4-colorbutton and 2.2 ml of ethanol, in that order. The resulting mixture was stirred at room temperature for 2 hours, then to her DOB is aristolochioides acid. The aqueous phase was podslushivaet potassium carbonate and was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (from 100 : 1 to 50 : 1)/ receiving of 4.95 g specified in the procurement compound as a yellow oil (yield: 44%).

1H-NMR (400 MHz, CDCl3) / : 1,69 - to 1.79 (2H, m), 1,81 - 1,89 (2H, m), of 2.45 (3H, d, J = 0.9 Hz), 2,50 (2H, t, J = 7,1 Hz), 3,53 (2H, t, J = 7,1 Hz) to 3.67 (2H, s), 7,14 (1H, DD, J = 1,8 Hz, 9.3 Hz), 7,29 (1H, s), 7,47 (1H, d, J = 9.3 Hz), of 7.95 (1H, m).

Preparative example 18.

6-((4-Chlorobutyl)sulfanilyl)-2-methylimidazo/1,2-a/-pyridine

< / BR>
of 4.95 g of 6-((4-chlorobutyl)thiomethyl)-2-methylimidazo/1,2-a/-pyridine obtained in preparative example 17, was dissolved in 50 ml of dichloromethane, followed by cooling the resulting solution with ice. In the resulting solution was added dropwise over 20 minutes a solution 3,18 g of m-chloroperbenzoic acid in 20 ml of dichloromethane. After one hour the resulting mixture was added 0.16 g of m-chloroperbenzoic acid. The resulting mixture was additionally stirred for 30 minutes, and then thereto was added an aqueous solution of sodium thiosulfate. The resulting mixture was vigorously premesis the i.i.d. mixture was extracted with dichloromethane. The organic phase was dried over anhydrous potassium carbonate and distilled to remove solvent. The residue was purified by chromatography on a column of silica gel /solvent: dichromate/ methanol (50 : 1 to 30 : 1)/, getting 4,18 g specified in the title compounds as a pale pink solid (yield: 79 %).

1H-NMR (400 MHz, CDCl3) : 1,83 - 2,03 (4H, m), 2,46 (3H, d, J = 0.9 Hz), to 2.66 (2H, m), of 3.57 (2H, m), 3,86 (1H, d, J = 13,6 Hz), of 3.96 (1H, d, J = 13,6 Hz), 7,02 (1H, DD, J = 1,8 Hz, 9.3 Hz), 7,35 (1H, m), 7,52 (1H, d, J = 9.3 Hz), 8,08 (1H, m).

Example 1.

1-(Imidazo/1,2-a/pyridine-6-yl)-N-methyl-2-oxo-cyclohexanecarboxylic

< / BR>
13,00 g 2-(imidazo/1,2-a/pyridine-6-yl)cyclohexanone obtained in preparative example 1, suspended in 200 ml of anhydrous tetrahydrofuran followed by the addition 7.50 g t butoxide potassium while cooling with ice. The resulting mixture was stirred for one hour. To the mixture was added a solution 4,88 g of methyl isocyanate in 10 ml of tetrahydrofuran, followed by adding 20 ml of N, N-dimethylformamide. The resulting mixture was stirred at room temperature for 45 minutes and was poured into a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and perelistat, receiving of 12.53 g specified in the title compound as a slightly yellow powder (yield: 72%).

So pl. (oC): 241 - 243 (decomp.).

1H-NMR (400 MHz, CDCl3) : 1,74 - to 1.86 (1H, m), 1,88 is 1.96 (2H, m), 1,98 - of 2.09 (1H, m), 2,30 - of 2.64 (2H, m), and 2.79 (2H, t, J = 6.2 Hz), 3,18 (3H, d, J = 4,8 Hz), 7,01 (1H, DD, J = 2,0, 9.7 Hz), 7,52 - EUR 7.57 (2H, m), a 7.62 (1H, d, J = 1.1 Hz), with 8.05 (1H, DD, J = 0,9, 2.0 Hz), 8,96 (1H, Shir.).

Example 2.

(-)-1-(Imidazo/1,2-a/pyridine-6-yl)-N-methyl-2-oxo - cyclohexanecarboxylic

< / BR>
the ceiling of 5.60 g of 1-(imidazo/1,2-a/pyridine-6-yl)-N-methyl-2 - oxocyclohexanecarboxylate obtained in example 1, suspended in 130 ml of a mixture of acetone and water /3 : 1 (vol./vol.)/ with the subsequent addition of a solution 7,34 g monohydrate (+)-Dibenzoyl-D-tartaric acid in 20 ml of a mixture of water with acetone /3 : 1 (vol./about. )/. The resulting mixture was stirred at room temperature for 30 minutes to obtain a precipitate. The precipitate was removed by filtration and washed with acetone, receiving of 5.85 g of white powder. The powder was dissolved in 100 ml of a mixture of ethanol and water /5 : 1 (vol./vol.)/ when heated. To the resulting solution was added water up until the solution became turbid. The resulting mixture was left to stand at room temperature to produce a precipitate. This precipitate was removed by filtration. Received 3.33 g of white needle-like acicular crystals, which was recrystallized again from 150 ml of ethanol-water /3 : 5 (vol./vol.)/, receiving 2.15 g of white needle-shaped crystals. The crystals were added to dilute aqueous ammonia, and the resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove the solvent, obtaining a crystalline residue. This crystalline residue was recrystallized from acetonitrile, getting 0.32g specified in the connection header in the form of lamellar crystals (yield: 6%).

Optical purity of this product, certain high-performance liquid chromatography using a chiral column was 100%.

Characteristics of high-performance liquid chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel chemical industries, Ltd.) (250 mm x 4.6 mm EXT. dia.).

Solvent: n-hexane/2-propanol /3 : 2 (vol./vol.)/.

Flow rate: 1.0 ml/min

Detection: UV-detector (254 nm).

Holding time: 10,2 min (retention time racemic modification was 7.8 and 10.2 minutes)

So pl. (oC): 225 - 227 (decomp.).

1H-NMR (400 MHz, CDCl3) : 1,74 - 1,86 (54 (1H, d, J = 0,9, 1.3 Hz), a 7.62 (1H, d, J = 1.3 Hz), of 8.04 (1H, d, J = 0,9, 2.0 Hz), 8,94 - 9,03 (1H, sir.).

Specific rotation: is 236o(C = 1.0, methanol).

Example 3.

-Ethyl-1-(imidazo/1,2-a/pyridine-6-yl)-2-oxocyclohexanecarboxylic

< / BR>
to 5.00 g (23,4 mmol) 2-(imidazo/1,2-a/pyridine-6-yl)cyclohexanone obtained in preparative example 1 was dissolved in 50 ml of dry tetrahydrofuran. The resulting solution was cooled to 0oC, and then added to it t-piperonyl potassium. The resulting mixture was stirred for 30 minutes, followed by slow addition dropwise of a solution of 2.45 g of N-utilizationof in 5 ml of the resulting mixture. The temperature of the mixture was gradually raised to room, and the resultant mixture was left over night to mix with obtaining a crystalline precipitate. This crystalline precipitate was separated by filtration and washed with ethyl acetate, receiving 4.8 g of the target compound as white crystals (yield: 72%).

So pl. (oC): 176 (decomp.).

1H-NMR (400 MHz, CDCl3) : of 1.24 (3H, t, J = 7,3 Hz), 1,74 is 2.10 (4H, m), 2,50 - 2,62 (2H, m), 2,70 - 2,84 (2H, m), 3,59 is 3.76 (2H, m), 7,01 (1H, DD, J = 1.9 Hz, 9.6 Hz), 7,50 - 7,58 (2H, m), a 7.62 (1H, d, J = 1.3 Hz), 8,05 - 8,08 (1H, m), is 8.75 (1H, Shir.S.).

Example 4.

(-)-N-Ethyl-1-(imidazo/1,2-a/pyridine-6-
1,43 g racemic modification, prepared in example 3 and of 2.06 g of (+)-Dibenzoyl-D-tartaric acid monohydrate was dissolved in 10 ml of a mixture of water and acetone (3:1) when heated. The resulting solution was slowly cooled, obtaining 1.5 g of a crystalline precipitate. This precipitate was removed by filtration, and was again dissolved in 7 ml of a mixture of water and acetone (3:1) and recrystallized from her with obtaining 1.0 g of crystals. These crystals were dissolved in aqueous sodium bicarbonate solution, and the resulting solution was extracted with chloroform, getting free connection. This compound was recrystallized from ethyl acetate, getting 210 mg of the target compound.

Optical purity of this product was determined using high performance liquid chromatography using a chiral column was 100%.

Characteristics of high-performance liquid chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel chemical industries. Ltd.) (250 mm x 4.6 mm EXT. dia.).

Solvent: n-hexane/2-propanol/diethylamine (60:300:1).

Flow rate: 0.5 ml/min

Detection: UV-detector (254 nm).

Holding time: 16,7 min (retention time racemic (C = 1.0, ethanol).

Example 5.

N-Methyl-1-(2-methylimidazo/1,2-a/pyridine-6-yl)-2 - oxocyclohexanecarboxylic

< / BR>
In nitrogen atmosphere, the solution 35,79 g (of) 0.157 mol) of 2-(2-methylimidazo/1,2-a/pyridine-6-yl)cyclohexanone prepared in preparative example 2, in 550 ml of tetrahydrofuran was cooled with ice, and then thereto was added 19,55 g (0,174 mol) t-butoxide potassium. The obtained yellow solution was stirred under ice cooling for one hour, and then thereto was added a solution of 11.8 ml (0,173 mol) of methyl isocyanate in 50 ml of tetrahydrofuran and 60 ml of N,N-dimethylformamide, in that order. The resulting reaction mixture was stirred under ice cooling for one hour followed by the addition of saturated aqueous solution of ammonium chloride. The resulting mixture was extracted with chloroform. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. During concentration began to precipitate crystals. The crystals were isolated by filtration. Received 37,09 g of the target compound as colorless crystals. Next, uterine fluid (14.5 g) was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (100:3)/ and paracrystal. Thus, they received a total of 40.3 g of target compound (yield: 85%).

So pl. (oC): 217 - 220 (decomp.).

1H-NMR (400 MHz, dimethylsulfoxide-d6) / : 1,58 - to 1.82 (3H, m), 1,88 - 2,02 (1H, m), 2,22 (1H, m), 2,31 (3H, d, J = 0.7 Hz), 2,40 (1H, dt, J = 13,6, 3.5 Hz), of 3.00 (1H, m), 3,01 (3H, d, J = 4.4 Hz), 3,13 (1H, DDD, J = 13,6, 11,5, 6.4 Hz), 7,16 (1H, DD, J = 9,5, 1,8 Hz), 7,32 (1H, d, J = 9.5 Hz), 9,67 (1H, W), 8,24 (1H, DD, J = 2.0 a, and 0.9 Hz), 9,80 (1H, Shir.d, J = 4.4 Hz).

Example 6.

(-)-N-Methyl-1-(2-methylimidazo/1,2-a/pyridine-6-yl)-2 - oxocyclohexanecarboxylic

< / BR>
The solution 20,26 g (53.8 mmol) of (+)-Dibenzoyl-D-tartaric acid monohydrate in 110 ml of a mixture of acetone and water (4:1) was added to a solution 16,21 g (53.8 mmol) of ()-N-methyl-1-(2-methylimidazo/1,2-a/ pyridine-6-yl)-2-oxocyclohexanecarboxylate prepared in example 5, in 900 ml of a mixture of acetone and water (4:1). The resulting mixture was left to stand at room temperature for 2 hours, obtaining (+)-N-methyl-1-(2 - methylimidazo/1,2-a/pyridine-6-yl)-2-oxocyclohexanecarboxylic (+)-Dibenzoyl-D-tartaric acid in the form of colorless prismatic crystals. Crystals (14.6 g, 95% or higher) was filtered.

The filtrate was concentrated in vacuo and the resulting residue was dissolved in 900 ml of a mixture of ethanol and water (9:1) under conditions of reflux distilled. The resulting solution was left to stand is in 900 ml of a mixture of ethanol and water (9:1) under conditions of reflux distilled. The resulting solution was cooled, allowing it to stand for 2 hours, and received a colorless needle crystals. These crystals were isolated by filtration. Thus, received a 14.17 g (98%) of (-)-N-methyl-1-(2-methylimidazo/1,2-a/pyridine-6-yl)-2 - oxocyclohexanecarboxylate (+)-Dibenzoyl-D-tartaric acid.

To a suspension of a 14.17 g (21.5 mmol) of the salt prepared above in 200 ml of water was added 100 ml of 1 N. aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 5 minutes, getting a colourless solution, which was extracted with chloroform. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. During concentration began precipitation of crystals. The resulting crystals were removed by filtration. Thus, it was received with 5.22 g of the target compound as colorless crystals (yield: 32%, optical purity: 99%).

The optical output was determined using high performance liquid chromatography using a chiral column.

Characteristics of liquid chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel Ke is column temperature: room temperature.

Flow rate: 1 ml/min

Detection: UV-detector (254 nm).

Retention time: 16 min (retention times of racemic modifications were 14 and 16 minutes).

So pl. (oC): 219 - 222 (decomp.).

1H-NMR (400 MHz, CDCl3) : to 1.79 (1H, m), 1,90 (2H, Quint, J = 6.4 Hz), from 2.00 (1H, m), 2,43 (3H, d, J = 0.9 Hz), to 2.55 (2H, m), 2,80 (2H, m), and 3.16 (3H, d, J = 4,8 Hz), of 6.96 (1H, DD, J = a 9.5, 2.0 Hz), 7,30 (1H, Shir.C) the 7.43 (1H, Shir.d, J = 9.5 Hz), of 7.96 (1H, DD, J = 2.0 a, and 0.9 Hz), 8,98 (1H, Shir.C).

Specific rotation: -218o(C = 1,09, methanol).

Example 7.

(+)-N-Methyl-1-(2-methylimidazo/1,2-a/pyridine-6-yl)-2 - oxacyclobutane

< / BR>
A suspension of 14.6 g (22,1 mmol) of (+)-N-methyl-1-(2-methylimidazo/1,2-a/ pyridine-6-yl)-2-oxocyclohexanecarboxylate (+)-Dibenzoyl-D-tartaric acid, filtered in example 6, in 1 l of a mixture of methanol and water (9:1) was heated under reflux for 30 minutes and cooled, allowing to stand for 90 minutes. The resulting suspension was filtered, obtaining crystals.

To a suspension 12,02 g (18.2 mmol) of the obtained salt in 200 ml of water was added 100 ml of 1 N. aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 5 minutes, getting a colourless solution, which was extracted with chloroform. About the Oia and concentrated in vacuum. During concentration began to precipitate crystals. Formed in this way, the crystals were removed by filtration. Received 4,30 g of the target compound as colorless crystals (yield: 27%, optical purity: 99%).

Optical purity was determined by high performance liquid chromatography using a chiral column.

Characteristics of liquid chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel chemical industries, Ltd.) (250 mm x 4.6 mm EXT. dia.).

Eluent: n-hexane/2-propanol /4:1 (vol./vol.)/.

The column temperature: room temperature.

Flow rate: 1 ml/min

Detection: UV-detector (254 nm).

Holding time: 14 min (retention times of racemic modifications were 14 and 16 minutes).

So pl. (oC): 219 - 222 (decomp.).

1H-NMR (400 MHz, CDCl3) : of 1.78 (1H, m), at 1.91 (2H, Quint, J = 6.3 Hz), from 2.00 (1H, m), 2,43 (3H, d, J = 0.7 Hz), of 2.56 (2H, m), 2,80 (2H, m), and 3.16 (3H, d, J = 4.6 Hz), of 6.96 (1H, DD, J = 9,4, 1.9 Hz), 7,30 (1H, Shir.C), 7,42 (1H, Shir.d, J = 9.5 Hz), of 7.96 (1H, DD, J = 2.0 a, and 0.9 Hz), of 9.00 (1H, Shir.C).

Specific rotation: 227 iso(C = of 1.03, methanol).

Example 8.

2-Hydroxy-1-(imil-2 - oxocyclohexanecarboxylate, obtained in example 1, suspended in 280 ml of methanol. The resulting suspension was cooled with ice, followed by addition of 1.27 g of bergerat sodium. The resulting mixture was stirred for 30 minutes.

The reaction mixture was analyzed using thin-layer chromatography on silica gel /developer: benzene/ethyl acetate/methanol (10 : 10 : 1)/, it was found that the reaction product consists of nizkoposhibnogo of diastereoisomer (L-form) as a secondary component and a highly polar diastereoisomer of (M-form) as a main component.

To the reaction mixture was added water, and the resulting mixture was filtered for separation of insoluble material. Thus, there was obtained 15,12 g of target compound in the form of a pure diastereoisomer in the form of a pale yellow powder (yield: 62%).

So pl. (oC): 231 - 233 (decomp.).

1H-NMR (400 MHz, dimethylsulfoxide-d6) : 1,27 - of 1.41 (3H, m), 1,52 - 1,71 (2H, m), 1,92 is 2.01 (1H, m), 2,16 - of 2.26 (1H, m), 2,47 - of 2.56 (1H, m), 2,92 (3H, d, J = 4.4 Hz), 4,59 - and 4.68 (1H, m), 4,88 is equal to 4.97 (1H, m), 7,32 (1H, DD, J = 1,8, 9.5 Hz), 7,44 (1H, d, J = 9.5 Hz), 7,51 (1H, d, J = 1.3 Hz), 7,95 (1H, m), 8,63 (1H, m), of 9.21 - 9.28 are (1H, m).

Example 9.

2-Benzoyloxy-1-(imidazo/1,2-a/pyridine-6-yl)-N-methyl - cyclohexanecarboxylic

< / BR>
500 which was spencervale in 5 ml of N, N-dimethylformamide, followed by addition of 470 mg of benzoic anhydride, of 0.29 ml of triethylamine and catalytic amounts of 4-dimethylaminopyridine. The resulting mixture was stirred at room temperature for 2 hours, and then thereto was added water. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove solvent. The residue was purified and distilled to remove solvent. The residue was purified chromatographic column with silica gel /solvent: dichloromethane/methanol (30 : 1)/, and the obtained solid substance was recrystallized from a mixture of chloroform/ether, receiving 40 mg of target compound as a white powder (yield: 6%).

So pl. (oC): 273 - 274 (decomp.).

1H-NMR (400 MHz, CDCl3) : 1,38 to 1.76 (4H, m), 1,90 - 2,02 (1H, m), 2,35 is 2.51 (2H, m), 2,69 - 2,78 (1H, m), 3.04 from (3H, d, J = 4,8 Hz), to 6.19 (1H, DD, J = 3,5, 8,8 Hz), 7,31 (1H, DD, J = 1,8, 9.5 Hz), 7,35 - 7,45 (3H, m), 7,50 - 7,56 (2H, m), 7,60 (1H, m), 7,46 (1H, d, J = 1.1 Hz), 7,81 - 7,86 (2H, m), 8,59 (1H, m).

Example 10.

(-)-2-Hydroxy-1-(imidazo/1,2-a/pyridine-6-yl)-N - methylcyclohexanecarboxylic (M-form)

< / BR>
A suspension of 1.00 g of (-)-1-imidazo/1,2-a/pyridine-6-yl)-N-methyl-2 - oxocyclopent 53 mg sodium borohydride. The resulting mixture was stirred for 30 minutes.

The reaction mixture was analyzed using thin-layer chromatography on silica gel /developer: benzene/ethyl acetate/methanol (10 : 10 : 1)/, it was found that the reaction product consisted of nizkoposhibnogo of diastereoisomer (L-form) as a secondary component and a highly polar diastereoisomer of (M-form) as the main component.

In the reaction mixture was added water and the resulting mixture was filtered to extract the insoluble material. Thus, it was received and 0.61 g of target compound in the form of a pure diastereoisomer in the form of a white powder (yield: 60%).

So pl. (oC): 244 - 246 (decomp.).

1H-NMR (400 MHz, dimethylsulfoxide-d6) : 1,26 - of 1.40 (3H, m), 1,52 - 1,72 (2H, m), 1.93 and - 2,02 (1H, m), 2,15 was 2.25 (1H, m), 2,47 is 2.55 (1H, m), 2,92 (3H, d, J = 4.4 Hz), 4,60 - of 4.66 (1H, m), 4,88 - 4,94 (1H, m), 7,32 (1H, DD, J = 1,8, 9.5 Hz), 7,44 (1H, d, J = 9.5 Hz), 7,51 (1H, d, J = 1.3 Hz), of 7.96 (1H, m), 8,63 (1H, m), 9,20 - of 9.30 (1H, m).

Specific rotation: -44o(C = 0,68, N,N-dimethylformamide).

Example 11.

(-)-2-Benzoyloxy-1-(imidazo/1,2-a/pyridine-6-yl)-N - methylcyclohexanecarboxylic

< / BR>
400 mg of (-)-2-Hydroxy-1-(imidazo/1,2-a/pyridine-6-yl)- methylcyclohexanecarboxylic (M-form), the floor is 380 mg of benzoic anhydride and catalytic amounts of 4-pyrrolidinedione. The resulting mixture was stirred at room temperature for 2 hours, and then thereto was added a saturated solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove solvent. The residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (50 : 1 to 30 : 1)/ and the obtained solid was recrystallized from dichloromethane/ether, receiving 380 mg specified in the connection header in the form of needle crystals (yield: 69%).

Optical purity of the above product was 98% and was determined by high-performance liquid chromatography using a chiral column.

Characteristics of high-performance liquid chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel chemical industries, Ltd.) (250 mm x 4.6 mm EXT. dia.).

Solvent: n-hexane/2-propanol /4 : 1 (vol./vol.)/.

Flow rate: 0.5 ml/min

Detection: UV-detector (254 nm).

Holding time: 11.2 min (retention times is SUP>H-NMR (400 MHz, CDCl3) : 1,39 - is 1.51 (1H, m), and 1.56 to 1.76 (3H, m), 1,91 is 2.01 (1H, m), 2,35 is 2.51 (2H, m), 2,70 - 2,78 (1H, m), 3,05 (3H, d, J = 4.6 Hz), to 6.19 (1H, DD, J = 3,5, 8.6 Hz), 7,34 (1H, DD, J = 1,8, 9.5 Hz), of 7.36 - 7,41 (2H, m), 7,42 - of 7.48 (1H, m), 7,50 - 7,56 (2H, m), 7,58 (1H, m), 7,63 (1H, d, J = 1.3 Hz), 7,82 - 7,86 (2H, m), 8,55 (1H, m).

Specific rotation: -238o(C = 0.5, methanol).

Example 12.

2-Benzyloxy-1-(imidazo/1,2-a/pyridine-6-yl)-N - methylcyclohexanecarboxylic

< / BR>
500 mg of 2-benzyloxy-1-(imidazo/1,2-a/pyridine-6-yl)-1-((4 - methoxybenzylthio)(methylimino)methyl)cyclohexane, prepared in preparative example 4, was dissolved in 5 ml of dichloromethane followed by the addition of 1 ml of anisole. The resulting mixture was cooled with ice, followed by a gradual addition of 5 ml triperoxonane acid. The resulting mixture was stirred one hour, then to it was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate and distilled to remove solvent. The obtained residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (50: 1)/. The resulting oil was led out of the ether and the resulting crystals were removed by filtration. Thus, there were obtained 300 mg Clevo, CDCl3) : 0,98 - 1,11 (1H, m), 1,43 is 1.60 (2H, m), 1,71 of - 1.83 (2H, m), 2,14 - 2,22 (1H, m), 2,38 is 2.46 (1H, m), 2.63 in (1H, dt, J = 3.3, which is 13.5 Hz), 3,03 (3H, d, J = 4,8 Hz), 4,32 (1H, DD, J = 4,4, 11.7 Hz), 4,43 (1H, d, J = 11.2 Hz), 4,71 (1H, d, J = 11.2 Hz), 7,21 (1H, DD, J = 1,8, 9.5 Hz), 7,24 and 7.36 (5H, m), 7,54 (1H, W), at 7.55 (1H, DD, J = 0,9, 1.3 Hz), 7,58 (1H, d, J = 9.5 Hz), 7,63 (1H, d, J = 1.3 Hz), 8,80 (1H, DD, J = 0,9, 1.8 Hz).

Example 13.

Anti-2-benzylamino-1-(imidazo/1,2-a/pyridine-6-yl)-N - methylcyclohexanecarboxylic

< / BR>
600 mg of 1-(imidazo/1,2-a/pyridine-6-yl)-N-methyl-2-oxohexanoate prepared in example 1 was dissolved in 5 ml of pyridine followed by the addition of 730 mg of O-benzylhydroxylamine-hydrochloride. The resulting mixture was stirred at 80oC in nitrogen atmosphere for 13 hours, and then thereto was added an aqueous solution of potassium carbonate. The resulting mixture was extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The obtained residue was purified chromatographically on a column of silica gel /solvent: dichloromethane/methanol (from 100:1 to 50:1)/, and the oil obtained was led out of the ether. The resulting crystals were removed by filtration. Thus received 610 mg of the target compound as a white similar to ribbon crystals (yield: 74%).

(2H, m), 3,05 (3H, d, J=4.9 Hz), is 5.06 (2H, s) 6,91 (1H, DD, J = 1,8, 9.5 Hz), 7,25 - 7,30 (2H, m), 7,32 - 7,44 (5H, m), EUR 7.57 (1H, d, J = 1.3 Hz), 7,80 (1H, DD, J = 0,9, 1.8 Hz), 8,24 (1H, Shir. ).

Example 14.

2 Benzylamino-1-(imidazo/1,2-a/pyridine-6-yl)-N-methyl - cyclohexanecarboxylic

< / BR>
1.50 g of 1-(imida/1,2-a/pyridine-6-yl)-N-methyl-2 - oxocyclohexanecarboxylate prepared in example 1, and 2.35 g benzylamine was dissolved in 20 ml of dichloromethane. The resulting solution was cooled to 0oC.

In vyshepredstavlennyh solution was slowly bury 5.5 ml of solution (1 mmol/ml) TiCl4in dichloromethane, and the temperature of the mixture was raised to room temperature. The resulting mixture was stirred for 2 hours, followed by addition of an aqueous solution of sodium bicarbonate. The resulting mixture was filtered through celite to remove insoluble particles. The filtrate was extracted three times with chloroform. The combined organic phases were dried over sodium sulfate and distilled in vacuum to remove solvent to obtain oil. Oil as such (without purification) was dissolved in 10 ml of a mixture of dichloromethane with methanol (1:1) followed by the addition of 350 mg of NaBH3CN at room temperature. To the resulting solution were added acetic acid to bring the pH to nutria. The resulting mixture was extracted three times with chloroform. The combined organic phases were dried over sodium sulfate and distilled in vacuum to remove the solvent, obtaining oil. This oil was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (50:1)/, getting 950 mg of target compound (yield: 45%).

1H-NMR (400 MHz, CDCl3) : to 1.19 and 1.33 (1H, m), USD 1.43 - of 1.78 (4H, m), is 2.05 and 2.13 (1H, m), 2,37 - of 2.56 (2H, m), 3,70 (3H, d, J = 4 Hz), 3,55 (1H, DD, J = 4 Hz, 12 Hz), to 3.64 (1H, d, J = 12 Hz), 3,90 (1H, d, J = 12 Hz), 7,22 - 7,31 (4H, m), 7,31 - 7,38 (2H, m), 7,52 - EUR 7.57 (2H, m), to 7.61 (1H, d, J = 1,61 Hz), to 8.70 (1H, Shir.C.), 8,98 (1H, s).

Example 15.

2-(Imidazo/1,2-a/pyridine-6-yl)-N-methyltetrahydrofuran-2 - carbothioamide 1-oxide

< / BR>
3.00 g of 2-(imidazo/1,2-a/pyridine-6-yl)-tetrahydrothiopyran 1-oxide, prepared in preparative example 9, suspended in 40 ml of a mixture of tetrahydrofuran with hexamethylphosphoric triamide /4:1 (vol./vol.)/. The resulting suspension was cooled with ice and then adding 1,58 g t butoxide potassium. The resulting mixture was stirred one hour, then to bury 1.5 ml carbon disulphide. The resulting mixture was stirred 30 minutes and then to bury 2.4 ml under the conditions. The resulting mixture was stirred at room temperature for 1.5 charaiveti water and saturated aqueous sodium chloride, was dried over anhydrous magnesium sulfate and distilled to remove solvent.

The obtained red oil was dissolved in 10 ml of methanol was then added to a solution of 10 ml of 40% solution of methylamine in methanol. The resulting mixture was stirred at room temperature for 1.5 hours and concentrated. The residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (20 : 1 to 10 : 1)/ and was led from ethyl acetate, receiving 160 mg of target compound in the form of a slightly yellow powder (yield: 4%).

So pl. (oC): $ 235 (decomp.).

1H-NMR (400 MHz, CDCl3) : 1,56 - of 1.84 (3H, m), 2,09 was 2.25 (2H, m), 2,65 is 2.75 (1H, m), 3,01 - is 3.08 (1H, m), or 3.28 (3H, d, J = 4,8 Hz), 3,92 - a 4.03 (1H, m), 6,94 - 7,00 (1H, m), 7,17 - 7,22 (1H, m), 7,42 (1H, m), 7,54 (1H, d, J = 1.3 Hz), 8,08 (1H, m), 9,74 - 9,83 (1H, Shir).

Example 16.

N-Methyl-1-(4-nitroimidazol-1-yl)-2-oxocyclohexanecarboxylic

< / BR>
In nitrogen atmosphere, the suspension 76,40 g (0,365 mol) of 2-(4-nitroimidazol-1-yl)-cyclohexanone, prepared in preparative example 10, in 1.2 l of tetrahydrofuran was cooled with ice and then adding 45,16 g (0,402 mol) t-butoxide potassium. The obtained reddish-purple reaction mixture was stirred under ice cooling for one hour pad in this order. The reaction mixture was stirred once, while its temperature was raised to room. To the resulting mixture was sequentially added a saturated aqueous solution of ammonium chloride and water, followed by extraction with chloroform. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue was poroshkovo chloroform, getting 46,93 g specified in the title compound as light brown powder. The mother liquid was concentrated in vacuo and the residue was poroshkovo chloroform again, receiving becomes 9.97 g of target compound as a pale brown powder. Further, the mother liquor was concentrated in vacuo and the residue was poroshkovo with ethyl acetate, getting 3,24 g of target compound as a brown powder. Thus, it was obtained only 60,14 g of target compound (yield: 58%).

So pl. (oC): 205 - 208 (decomp.).

1H-NMR (400 MHz, dimethylsulfoxide-d6) :/ 1,58 - of 1.78 (2H, m) to 1.86 (1H, m) to 1.98 (1H, m), 2,50 - 2,62 (2H, m), of 3.07 (3H, d, J = 3.5 Hz), is 3.08 - 3,18 (2H, m), 7,79 (1H, d, J = 1.6 Hz), of 8.25 (1H, d, J = 1.6 Hz), 10,48 (1H, Shir.C).

Example 17.

2-Hydroxy-N-methyl-1-(4-nitroimidazol-1-yl)-cyclohexylcarbodiimide (L-form)

< / BR>
Suspend 160 ml of methanol was cooled with ice. To the resulting suspension portions over 3 minutes added 2,68 g (70,8 mmol) sodium borohydride in such a way that the temperature of the main weight does not exceed 10oC. the resulting mixture was stirred under ice cooling for 30 minutes followed by the addition of saturated aqueous solution of ammonium chloride and water, in that order. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The resulting organic phase was analyzed by chromatography on a column of silica gel /developer: benzene/ethyl acetate (1:2)/, it was found that the product of this stage consists of nizkoposhibnogo of diastereoisomer (L-form, Rf: 0,41) and highly polar diastereoisomer of (M-form, Rf: 0,29) in the ratio 2: 1. The organic phase was concentrated. During concentration began falling crystals. Formed in this way, the crystals were removed by filtration. Thus was obtained target compound in the form of a diastereoisomer in the form of pale yellow crystal (yield: 50%).

So pl. (oC): 198 - 201 (decomp.).

1H-NMR (400 MHz, dimethylsulfoxide-d6) : of 1.06 (1H, m), of 1.28 to 1.48 (2H, m), Casali adding D2O) to 8.12 (1H, d, J = 1.1 Hz), 8,54 (1H, d, J = 1.1 Hz), 9,48 (1H, Shir.S., disappeared when adding D2O).

Example 18.

2-Benzoyloxy-N-methyl-1-(4-nitroimidazol-1-yl)-cyclohexanecarboxylic

< / BR>
To a suspension of 4.99 g (17.5 mmol) of 2-hydroxy-N-methyl-1-(4 - nitroimidazol-1-yl)cyclohexylcarbodiimide (L-form), prepared in example 17, in 50 ml of dichloromethane was added to 2.7 ml (to 19.4 mmol) of triethylamine, to 4.38 g (to 19.4 mmol) of benzoic anhydride and 215 mg (1.8 mmol) of N,N-dimethylaminopyridine. The resulting mixture was stirred at room temperature for 14 hours, getting orange solution, and then thereto was added a saturated solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic phase was washed successively with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue (7.5 g) was purified chromatographically on a column of silica gel /solvent: dichloromethane/acetone (20:1 to 5:1)/ and recrystallized from dichloromethane/diisopropyl ether, receiving a 3.15 g of the target compound as pale yellow crystals (yield: 46%).

So pl. (oC): 209 - 210.

1H-NMR (400 MHz, CDCl3) : 1,32 (1H, m), 1.56 to a 1.88 (4H, m), 2,34 (1H) - Rev., J = 7,7 Hz), to 7.59 (1H, t, J = 7.5 Hz), of 7.75 (1H, Shir. C), 7,89 (2H, d, J = 7.9 Hz), 7,95 (1H, d, J = 1.3 Hz), 8,21 (1H, d, J = 1.3 Hz).

Example 19.

2-Benzyloxy-N-methyl-1-(4-nitroimidazol-1-yl)-cyclohexylcarbodiimide

< / BR>
6,15 g (12.4 mmol) of 2-benzyloxy-1-((4-methoxybenzylthio)(methyl)- 1-(4-nitroimidazol-1-yl)cyclohexane, prepared in preparative example 14, was dissolved in 25 ml triperoxonane acid while cooling with ice, followed by adding 5 ml of anisole. The resulting mixture was stirred at 0oC for 10 minutes, getting a dark brown solution, which was poured into a mixture containing an aqueous solution of sodium bicarbonate and ice. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue (8,02 g) was purified by chromatography on a column of silica gel /solvent: dichloromethane/acetone (40:1)/ and recrystallized from dichloromethane/diisopropyl ether, receiving of 3.14 g of the target compound as colorless crystals (yield: 67%).

So pl. (oC): 165 - 166.

1H-NMR (400 MHz, CDCl3) : 0,98 (1H, square so, J = 13,5, 3,4 Hz) to 1.38 (1H, square D. , J = 12,6, and 3.7 Hz), 1,50 (1H, square so J = 12,9, and 3.7 Hz), to 1.70 (1H, m) of 1.76 (1H, m),7 (1H, d, J = 10,8 Hz), 7,22 (2H, DD, J = 7,6, 1.7 Hz), 7,28 and 7.36 (3H, m), the 7.65 (1H, Shir.C.), 7,88 (1H, d, J = 1.6 Hz), 8,10 (1H, d, J = 1.6 Hz).

Example 20.

Anti-2-benzylamino-N-methyl-1-(4-nitroimidazol-1 - yl)cyclohexanecarboxylic

< / BR>
To a suspension of the 6.06 g (21.5 mmol) of N-methyl-1-(4-nitroimidazol-1-yl)- 2-oxocyclohexanecarboxylate prepared in example 16 in 50 ml of pyridine was added to 10.01 g (62,7 mmol) O-benzylhydroxylamine - hydrochloride. The resulting mixture was stirred under heating at 100oC for 19 hours and cooled, allowing it to stand. To the resulting mixture were added saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuum. The residue (12.9 g) was purified chromatographically on a column of silica gel /solvent: dichloromethane/acetone (30:1 to 5:1)/ and recrystallized from dichloromethane/ethyl acetate, receiving of 2.27 g of the target compound as colorless crystals (yield: 275 g).

So pl. (oC): 175 - 177.

1H-NMR (400 MHz, CDCl2) : was 1.58 to 1.76 (3H, m) of 1.84 (1H, m), 2,39 (1H, DDD, J = 14,1, 8,4, 3.5 Hz), 2.49 USD (1H, DDD, J = 15,6, 8,3, 5.0 Hz), 2,73 (1H, m), of 2.92 (1H, m), to 3.02 (3H, the EP 21.

1-(2-Triptoreline/1,2-a/pyridine-6-yl)-R-methyl-2 - oxocyclohexanecarboxylic

< / BR>
To a suspension of 6.0 g of 2-(2-triptoreline/1,2-a/pyridine - 6-yl)cyclohexanone prepared in preparative example 15, in 70 ml of tetrahydrofuran were added under ice cooling 2,63 g t butoxide potassium. The resulting mixture was stirred for one hour, followed by a solution of 1.7 g methylisothiocyanate in 5 ml of tetrahydrofuran. Then to the mixture was added 7 ml of N,N-dimethylformamide. After one hour the reaction mixture was poured into a saturated aqueous solution of chloride of ammonia and then extracted with chloroform. The organic phase was dried over anhydrous magnesium sulfate and distilled to remove solvent. The residue was purified by chromatography on a column of silica gel /solvent: dichloromethane/methanol (50 : 1)/, and the obtained solid was washed with ether, receiving of 5.99 g of the target compound as a white powder (yield: 79%).

So square (0oC): 116 - 120.

1H-NMR (400 MHz, CDCl2) :/ 1,76 - 2,12 (4H, m), of 2.51 2.63 in (2H, m), 2,69 (1H, m), of 2.81 (1H, m), 3,18 (3H, d, J = 4,8 Hz), to 7.15 (1H, DD, J = 2,0, 9.7 Hz), to 7.61 (1H, d, J = 9.7 Hz), 7,86 (1H, s), 8,08 (1H, m), 8,79 (1H, Shir.).

Example 22.

(-)-1-(2-Triptoreline/1,2-a/pyridine-6-yl)-N-methyl-2 - oxocyclohexyl in example 21, was subjected to preparative chromatography using an optically active column for optical separation.

Characteristics of preparative chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel chemical industries, Ltd.), (250 mm x 20 mm EXT. dia.).

Solvent: n-hexane/2-propanol (3 : 1 (vol./vol.)).

Flow rate: 6 ml/min

Detection: UV-detector (254 nm).

The peak for preparative purposes: a later peak between the two peaks.

The solid substance obtained by preparative chromatography, recrystallized from n-hexane/ethyl acetate, obtaining the target compound as white crystals.

Optical purity of this product was determined using high performance liquid chromatography using a chiral column, was 99%.

Characteristics of high-performance liquid chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel chemical industries, Ltd.), (250 mm x 4.6 mm EXT. dia.).

Solvent: n-hexane/2-propanol (3 : 1 (vol./vol.)).

Flow rate: 1.0 ml/min

Detec who were 12.8 and 20.0 minutes).

So pl. (oC): 184 - 186.

Specific rotation: -229o(C = 1,02, methanol).

Example 23.

2-(2-Methylimidazo/1,2-a/pyridine-6-yl)-N - methyltetrahydrofuran-2-carbothioamide 1-oxide

< / BR>
3,86 g t butoxide potassium was dissolved in 30 ml of a mixture (1 : 1 (vol./about.)) of tetrahydrofuran and hexamethylphosphoric triamide. The resulting solution was cooled with ice, followed by adding dropwise the solution 3,68 g of 6-((4-chlorobutyl)sulfanilyl)-2 - methylimidazo/1,2-a/pyridine, prepared in preparative example 18, 30 ml of a mixture (1 : 1 (vol./about.)) of tetrahydrofuran and hexamethylphosphoric triamide. After 1.5 hours the mixture was bury of 3.45 ml of carbon disulfide, followed by stirring the resulting mixture at +10oC. After 1.5 hours the mixture was bury 3,57 ml under the conditions, and the resulting mixture was stirred at room temperature for 1.5 hours and poured into ice-cold water. The resulting mixture was extracted with ethyl acetate. The organic phase is washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and distilled to remove the solvent, obtaining a brown solid.

This solid substance was dissolved in 10 ml of methanol, was added in rastenii one hour and distilled to remove solvent. The residue was purified chromatographically on a column of silica gel /solvent: dichloromethane/methanol (20 : 1)/, and the obtained solid was washed with ether, receiving 160 mg of the target compound as a white powder (yield: 3%).

So pl. (oC): 227 - 231.

1H-NMR (400 MHz, CDCl2) : 1,55 - of 1.81 (3H, m), 2,08 - of 2.24 (2H, m), 2,42 (3H, d, J = 0.7 Hz), 2,71 (1H, m), 3.04 from (1H, m), 3,23 (3H, d, J = 4,8 Hz), 3,88 (1H, m) 6,91 (1H, d, J = 9.5 Hz), 7,03 (1H, DD, J = 2.0 Hz, 9.5 Hz), 7,24 (1H, s), 8,29 (1H, s), 9,39 (1H, Shir.).

Example 24.

(-)-2-(2-Methylimidazo/1,2-a/pyridine-6-yl)-N-methyltetrahydrofuran - 2-carbothioamide 1-oxide

< / BR>
2-(2-Methylimidazo/1,2-a/pyridine-6-yl)-N-methyltetrahydrofuran - 2-carbothioamide 1-oxide prepared in example 20 was subjected to preparative chromatography using an optically active column for optical separation.

Characteristics of preparative chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel chemical industries, Ltd.), (750 mm x 50 mm EXT. dia.).

Solvent: n-hexane/2-propanol/diethylamine (750 : 250 : 1).

Flow rate: 100 ml/min

Detection: UV-detector (254 nm).

The peak for preparative purposes: more later ciali chromatography on a column of silica gel /solvent: dichloromethane/methanol (10 : 1)/ and recrystallized from aqueous ethanol, receiving the target compound in the form of white crystals.

Optical purity of this product was determined using high performance liquid chromatography using a chiral column was 100%.

Characteristics of high-performance liquid chromatography.

Column: Chiracel (registered trademark) (product of the company Daicel chemical industries, Ltd.), (250 mm x 4.6 mm EXT. dia.).

Solvent: n-hexane/2-propanol/diethylamine (750 : 250 : 1).

Flow rate: 0.7 ml/min

Detection: UV-detector (254 nm).

Holding time: 19,4 min (retention times of racemic modifications were 14.5 and is 19.4 minutes).

So pl. (oC): 219 - 223 (decomp.).

Specific rotation: -352o(C = 1,02, methanol).

1. Derivatives thioformate General formula I

< / BR>
in which y represents a group of formula:

CH(OH),

< / BR>
< / BR>
Z represents-CH2-;

A is unsubstituted or substituted imidazopyridine;

R1, R2, R3and R4independently represent hydrogen or lower alkyl,

or their pharmacologically acceptable salts.

2. Derivatives thioformate under item 1, in which they.

3. Derivatives thioformate under item 1, in which the optionally substituted imidazopyridine group is a

imidazo [1,2-a] pyridyloxy group selected from the group consisting of imidazo [1,2-a] pyridine-2-yl, imidazo [1,2-a] -pyridine-3-yl, imidazo [1,2-a] pyridine-5-yl, imidazo [1,2-a] pyridine-6-yl, imidazo [1,2-a] pyridin-7-yl, imidazo [1,2-a] pyridine-8-yl;

imidazo-[1,5-a] pyridyloxy group selected from the group consisting of imidazo [1,5-a] pyridine-1-yl, imidazo [1,5-a] -pyridine-3-yl, imidazo [1,5-a] pyridin-5-yl, imidazo [1,5-a]-pyridine-6-yl, imidazo [1,5-a] pyridin-7-yl, and imidazo [1,2-a] pyridine-8-yl;

imidazo-[4,5-b] pyridyloxy group selected from the group consisting of imidazo [4,5-b] pyridine-1-yl, imidazo [4,5-b] pyridine-2-yl, imidazo [4,5-b] pyridine-3-yl, imidazo [4,5-b] pyridine-5-yl, imidazo [4,5-b] pyridine-6-yl, imidazo-[4,5-b] pyridin-7-yl; or

imidazo-[4,5-c] pyridyloxy group selected from the group consisting of imidazo [4,5-c] pyridin-1-yl, imidazo [4,5-c] -pyridine-2-yl, imidazo [4,5-c] pyridine-3-yl, imidazo [4,5-c]-pyridine-4-yl, imidazo [4,5-c] pyridine-6-yl, and imidazo-[4,5-c] pyridine-7-Il,

or their pharmacologically acceptable salts.

4. Derivatives thioformate under item 1, in which Y is CH(OH)-, Z is-CH2-, Rwho Ridel, or their pharmacologically acceptable salts.

5. Derivatives thioformate under item 1 or its pharmacologically acceptable salt, having the ability to activate the exit of potassium ions through the canaliculi.

6. Derivatives thioformate under item 1 or their pharmaceutically acceptable salts having anti-hypertensive activity.

 

Same patents:

The invention relates to pyrazolopyrimidines General formula I and their pharmaceutically acceptable salts, where A is the group NR1R2or CR'1R'2R11, R1- H or C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, F, CL and others, or C2-C6alkenyl; or C2-C6-quinil; R2-C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, C1-C6-alkoxy and others; or C2-C6alkenyl or2-C6-quinil, or furanyl; and (C1-C4-alkylene)phenyl which may be substituted by 1 to 3 substituents: CL, F, C1-C4-alkyl, and one Deputy:1-C6-alkoxy, CF3, NO2, NH2; or (C1-C4-alkylen) hetaryl where hetaryl - thienyl, possibly substituted by CL, benzothiazyl, pyridyl, chinoline, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrrolidinyl, 1-benzylpiperidine, tetrahydropyranyl; or (C1-C4-alkylen)cyclopropyl; or NR1R2form hetaryl selected from the group consisting of pyrrolidyl, possibly substituted benzyl, pyrrolidinyl, possibly substituted by benzyl or HE, the IIR>-C6-alkyl; R3is hydrogen, C1-C6-alkyl, O-(C1-C6alkyl), S(C1-C4- alkyl); R4- C1-C6- alkyl, or S(O)n(C1-C6)-alkyl, where n= 0-2, R5- 2,4,6-substituted phenyl CL, C1-C6-alkyl, CF3; R11-N., HE, or COO- (C1-C2alkyl), provided that the group CR'1R'2R11not an alkyl straight chain; and when R3is N, then R4isn't C1-C6the alkyl

The invention relates to pharmaceutical compositions for the treatment of inflammatory diseases, for example asthma, arthritis and allergies; fear; depression; fatigue syndrome; headache; pain; cancer; irritable bowel syndrome, including Crohn's disease, mucous colitis and symptoms of irritation of the colon; deregulation of the immune system; infections caused by human immunodeficiency virus (HIV); neurovirology diseases, such as Alzheimer's disease; gastrointestinal diseases; disorders of appetite, such as anorexia nervous system; stress caused by bleeding; symptoms of drug and alcohol withdrawal symptoms; addiction to the excessive use of drugs; stress-induced psychotic States and problems of fertilization, containing the above compound of formula I is effective for the treatment of these diseases the number and pharmaceutically acceptable carrier

-aminocarbonyl acids possessing antiarrhythmic and antifibrillatory activity" target="_blank">

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to new derivatives of pyrazolo/4,3-d/pyrimidine-7-it formula I, where R1- H, CH3C2H5, R2- CH3CH2OH, CH2OCH3or n - C3H7, R3- C2H5CH2= CH - CH2, R4together with the nitrogen atom to which it is attached is 4-(R5)-piperidino - or 4-N (R6)-piperazino group, R5- H, N(CH3)2, CONH2, R6- H, CH3i - C3H7CH2CH2OH, CSNH2C(NH)NHCH3or C(NH)S CH3and their pharmaceutically acceptable salts, pharmaceutical compositions showing inhibitory activity against cyclic guanosin-31,51-monophosphatase (CGMP), which contains 1-400 mg per single dose of the compounds of formula (I) in a mixture with a pharmaceutically acceptable diluent or carrier; the method of treatment or prevention of conditions caused by the activity of CGMP, the essence of which consists in assigning to the person an effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or above compositions

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds

The invention relates to new chemical substances possessing valuable pharmacological properties, in particular a derivative of benzimidazole of General formula I

< / BR>
where

R1is alkyl with 1 to 3 carbon atoms,

R2- oxazol-4-yl, thiazol-4-yl, unsubstituted or substituted in position 2 by alkyl with 1-6 carbon atoms or phenyl, imidazol-4-yl unsubstituted or substituted in position 2 by alkyl with 1-6 carbon atoms or phenyl, and imidazol-4-yl in position 1 substituted by alkyl with 1 to 7 carbon atoms, in which position 1, 2, 3, 4, 5, 6 or 7 may be replaced by alkoxycarbonyl or aminocarbonyl, alkyl with 2 to 4 carbon atoms, which is in position 2, 3 or 4 substituted by hydroxyl, alkoxyl, alkoxyalkyl, dialkylamino, pyrrolidino, piperidino or morpholino,

R3is alkyl with 2 to 4 carbon atoms, alkoxyl, alkylthio, each with 2 or 3 carbon atoms in the alkyl part, cyclopropyl or cyclobutyl and

R4- translated in vivo in carboxyl group, carboxyl, cyano, 1H-tetrazolyl, 1-triphenylmethyl-tetrazolyl or 2-triphenylmethyl-tetrazolyl,

their salts, particularly for pharmaceutical use the physiologically case

The invention relates to medicine and AIDS for the treatment of elevated intraocular pressure and/or glaucoma

The invention relates to the field of medicine and is intended for the treatment of various fungal infections of the skin and mucous membranes, increases the efficiency of releasing the drug reduces allergenic and sensitizing effect

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

Up!