Cyclic amine derivatives, pharmaceutical compositions and methods of treatment and prevention of diseases

 

(57) Abstract:

The invention relates to new cyclic amine derivatives of General formula I, where R1represents a phenyl group substituted by halogen atom,2represents C1- C8aliphatic acyl group or (C1- C4alkoxy)carbonyl group, R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy selected from the group comprising: mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, C1- C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from a number of protective groups, and the number of protective groups for the specified mercaptopropyl includes C1- C20alcoholnye group, C3- C20alkenone group and benzoline group, and the said cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5where R4represents a hydrogen atom, and R5represents a hydrogen atom, a C1- C4alkyl group, UB> - C4-alkyl)karbamoilnuyu group. Cyclic amine derivatives of formula I possess inhibitory effect on platelet aggregation or inhibiting effect on the development of arteriosclerosis and used to obtain drugs. Also describes a pharmaceutical composition based on compounds of the formula I for the prevention or treatment of embolism, the pharmaceutical composition based on compounds of the formula I for the prevention or treatment of thrombosis, the pharmaceutical composition based on compounds of the formula I for the prevention or treatment of arteriosclerosis, the method of prevention or treatment of embolism, the method of prevention or treatment of thrombosis, the method of prevention or treatment of arteriosclerosis. 7 C. and 20 C.p. f-crystals, 4 PL.

The present invention relates to a cyclic amine derivatives or its pharmaceutically acceptable salt, which has an excellent inhibitory effect on platelet aggregation inhibiting effect on the development of arteriosclerosis or etc., and which can be used as a therapeutic agent or a prophylactic agent against embolism, thrombosis or arteriosclerosis; to compositions for the prevention revnege ingredient; to use this compound for the production of pharmaceutical agents for the prevention or treatment of the above diseases; or to method of treating or preventing the above diseases, introducing a pharmacologically effective amount of the above compounds warm-blooded animal.

Background of the invention

Known cyclic amine derivatives having the effect, inhibiting platelet aggregation, or similar action, for example, is hydropyridine derived [see, for example, U.S. patent N 4051141, a patent application in Japan Kokai N Sho 59-27895 (ER) and a patent application in Japan Kokai N Hei 6-41139 (EP542411)].

Description of the invention

The authors of the present invention conducted studies of the pharmacological action of a cyclic amine derivatives for many years. As a result of these studies it was found that the specific cyclic amine derivatives have an excellent inhibitory effect on platelet aggregation inhibiting effect on the development of arteriosclerosis or similar (especially effect, inhibiting platelet aggregation), and therefore they can be used as therape the and or arteriosclerosis (especially against embolism or thrombosis), what is the purpose of the present invention.

The present invention relates to a cyclic amine derivatives or its pharmaceutically acceptable salt, which has an excellent inhibitory effect on platelet aggregation inhibiting effect on the development of arteriosclerosis or etc., and which can be used as a therapeutic agent or a prophylactic agent against embolism, thrombosis or arteriosclerosis; to compositions for the prevention or treatment of embolism, thrombosis or arteriosclerosis, containing the aforementioned compound as an effective ingredient; to the use of this compound for the production of pharmaceutical agents for the prevention or treatment of the above diseases; or to method of treating or preventing the above diseases, introducing a pharmacologically effective amount of the above compounds warm-blooded animal.

Cyclic amine derivatives of the present invention represented by the following formula:

< / BR>
In the above formula, R1represents a substituted or unsubstituted phenyl group (Deputy specified>alkyl group, a C1-C4alkoxygroup, fluoro-substituted C1-C4alkoxygroup, cyano or nitro-group);

R2represents a substituted or unsubstituted C1-C8aliphatic acyl group (Deputy of the specified group is a halogen atom, a hydroxyl group, a C1-C4alkoxygroup or cyano), substituted or unsubstituted benzoyloxy group (Deputy of the specified group is C1-C4alkyl group, a halogen atom or C1-C4alkoxygroup), or (C1-C4alkoxy) carbonyl group; and

R3is substituted 3-7-membered saturated cyclic amino group which may form a condensed ring [optional Deputy of the specified group is protected or unprotected mercaptopropyl or C1-C4alkyl group substituted by a protected or unprotected mercaptopropyl; and the specified cyclic amino group, furthermore preferably a substituted group of the formula =CR4R5(where R4and R5may be the same or different and each independently represents a hydrogen atom, a C1-C4alkyl group, the>C4alkyl)karbamoilnuyu group); and the protecting group of the specified mercaptopropyl is C1-C20alcoolica group, C3-C20alcoolica group, substituted or unsubstituted benzoline group (Deputy of the specified group is1-C4alkyl group, a halogen atom or C1-C4alkoxygroup), or (C1-C4alkoxy) carbonyl group].

C1-C4the alkyl group in the definition of substituents for substituted or unsubstituted phenyl group, R1is a straight or branched C1-C4alkyl group, such group may be, for example, methyl, ethyl, sawn, ISO-propyl, bucilina, second-bucilina, tert-bucilina or isobutylene group, of which preferred is a methyl or ethyl group, and particularly preferred is methyl group.

The halogen atom in the definition of substituents for substituted or unsubstituted phenyl group, R1may be, for example, fluorine atom, chlorine, bromine or iodine, of which preferred is a fluorine atom, chlorine or bromine and particularly preferred is a fluorine atom or chlorine.

Torsemide group, R1is a straight or branched fluoro-substituted C1-C4alkyl group, such group may be, for example, permetrina, deformational, triptoreline, 2-florachilena, 2-forproperty, 3-forproperty, 2-terbutalina, 3-terbutalina or 4-terbutalina group, of which preferred is deformational or triptorelin group, and particularly preferred is triptorelin group.

C1-C4alkoxygroup in the definition of substituents for substituted or unsubstituted phenyl group, R1is a straight or branched C1-C4alkoxygroup, which may be, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy or isobutoxy, of which preferred is methoxy or ethoxypropan, and particularly preferred is a methoxy group.

Fluoro-substituted C1-C4alkoxygroup in the definition of substituents for substituted or unsubstituted phenyl group, R1is a straight or branched fluoro-substituted C1-C4alkoxygroup, which may be, for example, formatosi, deformedarse, triptoreline, 2-floratone, 2nd, deformedarse or tripterocarpa and especially preferred is tripterocarpa.

The preferred substitute for substituted or unsubstituted phenyl group, R1is a methyl group, ethyl group, halogen atom, fluoro-substituted methyl group, a methoxy group, ethoxypropan, the fluoro-substituted methoxy group, cyano or nitro-group, of which more preferred are a fluorine atom, a chlorine atom, a bromine atom, triptorelin group, dipterocarp, tripterocarpa, cyano or nitro-group, and particularly preferred is a fluorine atom or chlorine.

The number of these substituents is preferably from 1 to 3, more preferably 1 or 2. The preferred position of the substituent is 2 or 4 and especially preferred position 2.

Aliphatic acyl group, substituted or unsubstituted1-C8aliphatic acyl group, R2is a straight or branched C1-C8alcoolica group, which may be, for example, formyl, acetyl, propylaniline, Butyrina, isobutylene, valerina, isovaleryl, bialoleka, hexanoyl, heptanoyl or octonaria group; or (C3-C7cycloalkyl) carbonyl group, such as Zakharchenya group, of which preferred is C2-C4alcoolica or (C3-C6cycloalkyl) carbonyl group, and more preferred is acetyl, propylaniline, isobutylene, cyclopropanecarbonyl or cyclobutanecarbonyl group.

Halogen atom, and C1-C4alkoxygroup, each of which is a surrogate for aliphatic acyl groups are the same as defined above for the substituents of the indicated phenyl group, and Deputy for the aliphatic acyl group is preferably a fluorine atom, chlorine atom, hydroxyl group, methoxy group, ethoxypropan or cyano, of which more preferred is a fluorine atom or a chlorine atom, and particularly preferred is a fluorine atom.

Specific examples of substituted aliphatic acyl group may be, for example, porcelina, deperately, trifluoracetyl, chlorocichla, trichloroethylene, bramaterra, educationa, 3-ferrominera, 3-chloropropionyl, 3-bromopropionyl, 3-iodopropynyl, 4-terbutalina, 4-chlorobutyryl, 5-forvilla, hydroxyazetidine, 3-hydroxypropiophenone, 4-hydroxybutyryl, ethoxyacetylene, 3-ethoxypropylamine, 4-ethoxymethylene, 5-ethoxyaniline, cyanoacetylene, 3-cyanopropyl, 4-cyanobacteria, 5-cyanovinylene, 2-portilloportilloanniea, 2,2-diverticulitisonline, 2-chlorocyclopropane, 2-bromocyclopropane, 2-portilloportilloanniea, 2-chlorcycloguanil, 2-portilloportilloanniea, 2-chlorocyclopentane, 2-forceclassiccontrolpanel, 2-chlorocyclohexanone, 2-hydroxycyclohexanecarboxylate, 2-hydroxycyclohexanecarboxylate, 2-hydroxycyclohexanecarboxylate, 2-hydroxycyclohexanecarboxylate, 2-methoxycyclohexanone, 2-methoxyisobutylisonitrile, 2-methoxycarbonylmethylene, 2-methoxycyclohexanone, 2-ethoxycyclohexanone, 2-amoxicillinonline, 2-amoxicillinwisconsin, 2-toxicologically, 2-cyanocobalamine, 2-cyanocobalamine, 2-cyanocobalamine and 2-cyanocyclohexyl group;

of which preferred are porcelina, deperately, trifluoracetyl, chlorocichla, 3-ferrominera, 3-chloropropionyl, hydroxyamine, 3-cyanopropyl, 2-portilloportilloanniea, 2,2-diverticulitisonline, 2-chlorocyclopropane, 2-portilloportilloanniea, 2-chlorcycloguanil, 2-portilloportilloanniea, 2-forceclassiccontrolpanel, 2-hydroxycyclohexanecarboxylate, 2-methoxycyclohexanone, 2-ethoxycyclohexanone and 2-cyanocobalamine group;

of which more preferred are porcelina, deperately, trifluoracetyl, chlorocichla, 3-ferrominera, 2-portilloportilloanniea, 2-chlorocyclopropane and 2-portilloportilloanniea group; and

most preferred are porcelina, deperately, trifluoracetyl, 3-ferrominera and 2-portilloportilloanniea group.

C1-C4alkyl group, a halogen atom, and C1-C4alkoxygroup in the definition of substituents for the substituted or unsubstituted bentilee group, R2are the same as defined above for the substituents mentioned phenyl groups. Deputy for bentilee group is preferably methyl group, ethyl group, fluorine atom, chlorine atom, methoxypolyethylene is a fluorine atom.

C1-C4alkoxides (C1-C4alkoxy) carbonyl group, R2is the same as it was defined for the substituents mentioned phenyl groups. Thus, it is preferable methoxycarbonyl or ethoxycarbonyl group, and more preferred is methoxycarbonyl group.

Examples of aminocyte substituted 3-7-membered saturated cyclic amino group which may form a condensed ring are circular C2-C8amino group which may have oxygen atom, nitrogen or sulfur, and these groups may be 1-aziridinyl, 1-azetidinone, 1-pyrrolidinyl, 1-piperidinyl 2N-hexahydroazepin-1-ilen, 7-azabicyclo[3.1.1]heptane-7-ilen, 8-azabicyclo [3.2.1.]Octan-8-ilen, 9-azabicyclo [3.3.1] nonan-9-ilen, 4-morpholinyl, 4-thiomorpholine or 4-piperazinilnom group, of which preferred are 1-azetidinone, 1-pyrrolidinyl, 1-piperidinyl, 7-azabicyclo[3.1.1]heptane-7-ilen, 8-azabicyclo[3.2.1.]Octan-8-ilen, 9-azabicyclo[3.3.1]nonan-9-ilen, 4-morpholinyl or 4-thiomorpholine group; more preferred are 1-azetidinone, 1-pyrrolidinyl, 1-piperidinyl, 8th 1-azetidinone, 1-pyrrolidinyl, 1-piperidinyl or 8-azabicyclo[3.2.1. ]octane-8-ilen group; and most preferred are 1-azetidinone, 1-piperidinyl or 8-azabicyclo[3.2.1.]Octan-8-ilen group.

C1-C4alkyl part mercaptoamines C1-C4alkyl group, which is Deputy 3-7-membered cyclic amino group represented by R3and C1-C4alkyl part is C1-C4alkyl group or a mono - or di-(C1-C4alkyl)carbamoyl group represented by R4or R5are the same as defined for the substituents of the indicated phenyl group; a (C1-C4alkoxy) carbonyl group represented by R4or R5that is the way it has been defined for the above2.

C1-C20alcoolica group, which is a protective group for mercaptopropyl, is a straight or branched1-C20alkanoyloxy group, and this group may be, for example,1-C8alcoolica group, examples of which are given above for R2or such a group can be nonantola, dekheila, Laurila, Mirandolina, p the>alcoolica group, more preferred is C1-C6alcoolica group, and most preferred is C2-C5alcoolica group.

Examples of C3-C20alkanoyloxy group, which is a protective group for mercaptopropyl, are straight or branched C3-C20alkenone groups, and such groups can be, for example, acrolina, metakaoline, 2-butenolide, 3-butenolide, 2-pentanolide, 3-pentanolide, 2-hexanamine, 3-hexanamine, 2-actinaria, 3-actinaria, 5-dodecanolide (especially CIS-form), palmarola, olaola or 11-ikastola (especially CIS-form), of which preferred are8-C20alkenone group, more preferred are C12-C20alkenone group, more preferred are C15-C20alkenone group, and most preferred are palmarola or olaola group.

Substituted or unsubstituted benzoline group and (C1-C4alkoxy) carbonyl group, each of which represents a protective group for mercaptopropyl, are as they were defined vyshyvat condensed ring, preferably is a 3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-1-azetidinone group, 3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-1-pyrrolidinyl group, 3 -, or 4- (protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-1-piperidinyl group, 4-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-3-(= CR4R5)-1-piperidinyl group [where R4and R5are the same or different and each independently represents a hydrogen atom, a C1-C4alkyl group, carboxypropyl, (C1-C4alkoxy) carbonyl group, karbamoilnuyu group or mono - or di-(C1-C4alkyl) karbamoilnuyu group] , or 8-Aza-3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl) bicyclo [3.2.1]octane-8-ilen group;

more preferred are 3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1 - azetidinone group, 3-(protected sludge is diseny or unprotected mercapto, or a protected or unprotected mercaptomethyl)-1 - piperidinyl group, 4-(protected or unprotected mercapto)- 3-(= CR4R5)-1-piperidinyl group [where R4and R5are the same or different and each independently represents a hydrogen atom, methyl group, ethyl group, carboxypropyl, methoxycarbonyl group, ethoxycarbonyl group, karbamoilnuyu group, methylcarbamoyl group, ethylcarbitol group, dimethylcarbamoyl group or diethylcarbamoyl group] or 8-Aza-C-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)bicyclo[3.2.1]octane-8-ilen group;

even more preferred are 3-(protected or unprotected mercapto)-1-azetidinone group, 3-(protected or unprotected mercapto)-1-pyrrolidinyl group, 3 -, or 4- (protected or unprotected mercapto)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(= CR4R5)-1 - piperidinyl group [where R4represents a hydrogen atom, and R5represents a hydrogen atom, methyl group, carboxypropyl, methoxycarbonyl group, ethoxycarbonyl group, karbamoilnuyu group, metolcarb]octane-8-ilen group;

and the most preferred are 3-(protected or unprotected mercapto)-1-azetidinone group, 4-(protected or unprotected mercapto)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(= CR4R5)-1-piperidinyl group [where R4represents a hydrogen atom, and R5is carboxypropyl, methoxycarbonyl group, ethoxycarbonyl group, karbamoilnuyu group, methylcarbamoyl group or dimethylcarbamoyl group] or 8-Aza-3-(protected or unprotected mercapto)bicyclo[3.2.1]octane-8-ilen group.

In the compound represented by formula (I), the carbon atom is linked to R1may be asymmetric carbon atom, and in this case, the specified connection can exist as optical isomers. These isomers and their mixtures are also included in the scope of the present invention. If the molecule of the compounds of formula (I) is a double bond, and/or cycloalkyl group or a cyclic amino group of these compounds there are two substituent, these compounds exist in the form of geometrical CIS-/TRANS-isomers. These isomers and their mixtures are also included in the scope of the present invention.

If R4and R5PR is whitesky acceptable salt by treatment with base. Examples of such salts can be inorganic salts, for example alkali metal salts, such as salts of sodium, potassium or lithium; salts of alkaline earth metals such as calcium salts or magnesium salts of metals such as aluminium salt, iron salt, zinc salt, copper salt, Nickel salt or a salt of cobalt; or ammonium salt; or salts of amines, such as organic salts such as salt tert-octylamine, salt dibenzylamine, salt of the research, salt of glucosamine, salt complex Olkiluoto phenylglycine ester, salt, Ethylenediamine salt, N-methylglucamine, salt of guanidine, salt diethylamine, salt, triethylamine salt of dicyclohexylamine, salt N,N'-dibenziletilendiaminom, salt chloroprocaine, salt of procaine, diethanolamine salt, a salt of N-benzylpenicillin, salt, piperazine salt of Tetramethylammonium or salt of Tris(hydroxymethyl) aminomethane, of which preferred are alkali metal salts (especially sodium or potassium salt).

Alternatively, the compound (I) can be easily transformed into its pharmaceutically acceptable salt by treatment with acid. Examples of such salts can be, for example, inorganic salts such as hydrochloride, sulfate, nitrate or phosphate; or salts of organic acids, sulfonate, econsultant, bansilalpet or p-toluensulfonate, of which preferred are the hydrochloride, sulfate, nitrate, oxalate, succinate, fumarate or methanesulfonate.

In addition, the hydrate of compound (I) or its salt is also included in the scope of the present invention.

As the compounds of formula (I), which is an effective ingredient of the present invention, preferred are the following compounds:

(1) compounds where R1represents a substituted phenyl group (Deputy of the specified group is methyl, ethyl, halogen, fluoro-substituted methyl, methoxy, ethoxy, fluoro-substituted methoxy, cyano or nitro);

(2) compounds where R1represents a substituted phenyl group (Deputy of the specified group is fluorine, chlorine, bromine, trifluoromethyl, deformedarse, triptoreline, cyano or nitro);

(3) compounds, where R1represents a substituted phenyl group (Deputy of the specified group is fluorine or chlorine);

(4) compounds, where the number of substituents on the substituted phenyl group represented by R1is from 1 to 3;

(5) compounds, where the number of substituents on the substituted phenyl group represented by R1is 2 or 4;

(7) compounds, where R2represents a substituted or unsubstituted C2-C4alkanoyloxy or (C3-C6cycloalkyl) carbonyl group (Deputy of the specified group is fluorine, chlorine, hydroxyl, methoxy, ethoxy or cyano), substituted or unsubstituted benzoyloxy group (Deputy of the specified group is methyl, ethyl, fluorine, chlorine, methoxy or ethoxy) or (C1-C4alkoxy) carbonyl group;

(8) compounds, where R2represents C2-C4alkanoyl or (C3-C6cycloalkyl) carbonyl group, which is unsubstituted or substituted by fluorine or chlorine; benzoyloxy group, or (C1-C4alkoxy) carbonyl group;

(9) compounds, where R2represents acetyl, propionyl, isobutyryl, cyclopropanecarbonyl or cyclobutanecarbonyl group, where these groups are unsubstituted or substituted by fluorine, or methoxycarbonyl or ethoxycarbonyl group;

10) compounds, where R2is propionyloxy, cyclopropanecarbonyl, methoxycarbonyl or ethoxycarbonyl group;

(11) compounds, where R3represents a 3-(protected or the PPU, 3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-1-pyrrolidinyl group, 3 -, or 4-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-1-piperidinyl group, 4-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-3-(= CR4R5)-1-piperidinyloxy group or 8-Aza-3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl) bicyclo [3.2.1] octane-8-ilen group

R4and R5are the same or different and each independently represents a hydrogen atom, a C1-C4alkyl group, carboxypropyl, (C1-C4alkoxy) carbonyl group, karbamoilnuyu group or mono - or di-(C1-C4alkyl) karbamoilnuyu group, and

a protective group for mercaptopropyl is C1-C20alcoolica group, C3-C20alcoolica group, substituted or unsubstituted benzoline group (Deputy of the specified group is1-C4alkyl group, a halogen atom or C1-C4alkoxygroup) or (C1-C44R5)-1-piperidinyloxy group or 8-Aza-3- (protected or unprotected mercapto, or protected or unprotected mercaptomethyl) bicyclo[3.2.1]octane-8-ilen group

R4and R5are the same or different and each independently represents a hydrogen atom or a methyl, ethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl or diethylcarbamoyl group, and

a protective group for mercaptopropyl is C1-C20alcoolica group, C8-C20alcoolica group, substituted or unsubstituted benzoline group (Deputy of the specified group is methyl, ethyl, fluorine, chlorine, methoxy or ethoxy) or (C1-C4alkoxy) carbonyl group;

(13) compounds, where R3is 3-(semisylido group, 3 - or 4-(protected or unprotected mercapto)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(= CR4R5)-1 - piperidinyloxy) group or 8-Aza-3-(protected or unprotected mercapto) bicyclo[3.2.1]octane-8-ilen group

R4represents a hydrogen atom, a R5represents a hydrogen atom or a methyl, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl group and

a protective group for mercaptopropyl is C2-C6alcoolica, palmarola, olaola, benzoline, methoxycarbonyl or ethoxycarbonyl group, and

(14) compounds, where R3represents a 3-(protected or unprotected mercapto)-1-azetidinol group, 4-(protected or unprotected mercapto)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(= CR4R5)- 1-piperidinyloxy group or 8-Aza-3-(protected or unprotected mercapto) bicyclo[3.2.1]octane-8-ilen group

R4represents a hydrogen atom, a R5represents carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl group and

protective gropparello group,

R1preferably is such as defined in (1)-(3) and (4) to(6), R2preferably is such as defined in (7)-(10), a R3preferably is such as defined in (11)-(14).

As compounds represented by formula (I) may be used in any combination of 2-4 groups selected from the class including a group of (1) to(3), group (4)-(6), a group of (7)-(10) and a group of (11)-(14). Preferred examples of such combinations are:

(15) compounds, where R1represents a substituted phenyl group (Deputy of the specified group is methyl, ethyl, halogen, fluoro-substituted methyl, methoxy, ethoxy, fluoro-substituted methoxy, cyano or nitro),

the number of substituents on the substituted phenyl group represented by R1is 1-3,

R2represents a substituted or unsubstituted C2-C4alkanoyloxy or (C3-C6cycloalkyl) carbonyl group (Deputy of the specified group is fluorine, chlorine, hydroxyl, methoxy, ethoxy or cyano), substituted or unsubstituted benzoyloxy group (Deputy of the specified group is methyl, ethyl, fluorine, chlorine, methoxy or ethoxy) or (C1-C4alkoxy) carbonello the group is fluorine, chlorine, bromine, trifluoromethyl, deformedarse, triptoreline, cyano or nitro),

the number of substituents on the substituted phenyl group represented by R1is 1 or 2 and

R2represents C2-C4alkanoyloxy or (C3-C6cloacal) carbonyl group, which is unsubstituted or substituted by fluorine or chlorine, benzoyloxy group, or (C1-C4alkoxy) carbonyl group;

(17) compounds, where R1represents a substituted phenyl group (Deputy of the specified group is fluorine, chlorine, bromine, trifluoromethyl, deformedarse, triptoreline, cyano or nitro),

the position of the substituent on the substituted phenyl group represented by R1is position 2 or 4,

R2represents C2-C4alkanoyloxy or (C3-C6cycloalkyl) carbonyl group, which is unsubstituted or substituted by fluorine or chlorine, benzoyloxy group, or (C1-C4alkoxy) carbonyl group,

R3represents a 3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-1-azetidinol group, 3-(protected or unprotected mercapto, or protected the hydrated mercapto, or protected or unprotected mercapto-C1-C4alkyl)-1-piperidinyl group, 4-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl)-3-(=CR4R5)-1-piperidinyloxy group or 8-Aza-3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4alkyl) bicyclo[3.2.1]octane-8-ilen group

R4and R5are the same or different and each independently represents a hydrogen atom, a C1-C4alkyl group, carboxypropyl, (C1-C4alkoxy) carbonyl group, karbamoilnuyu group or mono - or di-(C1-C4alkyl) karbamoilnuyu group, and

a protective group for mercaptopropyl is C1-C20alcoolica group, C3-C20alcoolica group, substituted or unsubstituted benzoline group (Deputy of the specified group is1-C4alkyl group, a halogen atom or C1-C4alkoxygroup) or (C1-C4alkoxy) carbonyl group;

(18) compounds, where R1represents a substituted phenyl group (Deputy of the specified group is fluorine or chlorine),

SUP> represents acetyl, propionyl, isobutyryl, cyclopropanecarbonyl or cyclobutanecarbonyl group, where these groups are unsubstituted or substituted by fluorine, or methoxycarbonyl or ethoxycarbonyl group

R3represents a 3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-azetidinol group, 3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-pyrrolidinyl group, 3 -, or 4-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(=CR4R5)-1-piperidinyloxy group or 8-Aza-3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl) bicyclo[3.2.1] octane-8-ilen group

R4and R5are the same or different and each independently represents a hydrogen atom or a methyl, ethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl or diethylcarbamoyl group, and

a protective group for mercaptopropyl is C81-C4alkoxy) carbonyl group;

(19) compounds, where R1represents a substituted phenyl group (Deputy of the specified group is fluorine or chlorine),

the position of the substituent on the substituted phenyl group represented by R1is position 2 or 4,

R2is propionyloxy, cyclopropanecarbonyl, methoxycarbonyl or ethoxycarbonyl group

R3represents a 3-(protected or unprotected mercapto)-1-azetidinol group, 3-(protected or unprotected mercapto)-1-pyrrolidinyl group, 3 -, or 4-(protected or unprotected mercapto)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3 (=CR4R5)-1-piperidinyloxy group or 8-Aza-3-(protected or unprotected mercapto)bicyclo[3.2.1]octane-8-ilen group

R4represents a hydrogen atom, a R5represents a hydrogen atom or a methyl, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl group and

a protective group for mercaptopropyl is C2-C6alcoolica, palmarola, olaola, bantilan phenyl group (Deputy of the specified group is a fluorine atom or chlorine),

the position of the substituent on the substituted phenyl group represented by R1is position 2 or 4,

R2is propionyloxy, cyclopropanecarbonyl, methoxycarbonyl or ethoxycarbonyl group

R3represents a 3-(protected or unprotected mercapto)-1-azetidinol group, 4-(protected or unprotected mercapto)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(= CR4R5)-1-piperidinyloxy group or 8-Aza-3-(protected or unprotected mercapto)bicyclo[3.2.1] octane-8-ilen group

R4represents a hydrogen atom, a R5represents carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl group and

a protective group for mercaptopropyl is C2-C5alcoolica, benzoline, methoxycarbonyl or ethoxycarbonyl group.

The above compounds according to (15)-(20) are preferred.

As examples of compounds of formula (I) can serve the following specific preferred compounds are presented in Table 1 (see end of description).

The abbreviations given in Tablesetting

Bu: butyl

i-Bu: isobutyl

c-Bu: cyclobutyl

Bur: butyryl

i-Bur: isobutyryl

Et: ethyl

Hxn: hexanoyl

Lau: lauroyl

Me: methyl

Olo: oleoyl

Pal: Palmitoyl

Ph: phenyl

Pr: propyl

c-Pr: cyclopropyl

i-Pr: isopropyl

Pipd: 1-piperidinyl

Piv: pivaloyl

Prop: propionyl

Pyrd: 1-pyrrolidinyl

Stl: stearoyl

Val: Valerie.

In Table 1, preferred compounds are compounds NN 5, 10, 11 12, 15, 17, 20, 21, 26, 29, 36, 41, 42, 43, 46, 48, 50, 51, 52, 57, 60, 67, 72, 73, 74, 77, 79, 81, 82, 83, 86, 88, 91, 98, 103, 104, 105, 108, 110, 113, 114, 117, 119, 122, 129, 134, 135, 136, 139, 141, 144, 148, 150, 153, 160, 165, 166, 167, 170, 172, 174, 175, 181, 184, 191, 196, 197, 198, 201, 203, 205, 206, 207, 208, 210, 212, 215, 222, 227, 228, 229, 232, 234, 236, 237, 241, 243, 246, 250, 253, 258, 259, 260, 263, 265, 267, 268, 272, 274, 277, 284, 287, 289, 290, 291, 294, 296, 299, 305, 308, 312, 314, 317, 318, 320, 324, 327, 334, 336, 337, 339, 340, 342, 343, 346, 349, 356, 358, 360, 361, 362, 364, 368, 371, 380, 382, 383, 385, 390, 392, 393, 395, 400, 403,404, 407, 410, 413, 420, 422, 424, 425, 426, 428, 429, 432, 435, 444, 446, 447, 449, 454, 456, 457, 459, 462, 463, 464, 465, 466, 467, 468, 470, 471, 474, 477, 484, 486, 487, 489, 490, 492, 496, 499, 506, 508, 510, 511, 512, 514, 515, 518, 521, 528, 530, 532, 533, 535, 540, 542, 543, 545, 547, 548, 552, 553, 554, 555, 558, 560, 565, 568, 571, 574, 575, 584, 585, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 607, 608, 609, 610, 613, 616, 617, 618, 619, 620, 621, 622, 627, 628, 641, 642, 651, 652, 656, 657, 658, 659, 660, 661, 668, 669, 670, 675, 676, 688, 689, 708, 709, 713, 714, 716, 717, 723, 724, 728, 729, 735, 736, 751, 752, 761, 762, 768, 865, 866, 871, 872, 876, 883, 890, 891, 896, 897, 901, 902, 907, 908, 912, 922, 923, 928, 929, 930, 931, 936, 937, 944, 945, 949, 950, 951, 952, 956, 963, 964, 968, 969, 970, 971, 975, 979, 984, 986, 987, 992, 993, 997, 998, 1003, 1004, 1008, 1013, 1015, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1033, 1034, 1039, 1040, 1044, 1049, 1054, 1055, 1059, 1060, 1061, 1062, 1066, 1073, 1074, 1078, 1079, 1080, 1081, 1085, 1089, 1090, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1118, 1125, 1130, 1132, 1133, 1138, 1139, 1143, 1144, 1149, 1150, 1154, 1161, 1166, 1168, 1169, 1174, 1175, 1179, 1180, 1185, 1186, 1190, 1200, 1201, 1205, 1206, 1207, 1208, 1212, 1219, 1220, 1224, 1225, 1226, 1227, 1231, 1235, 1236, 1241, 1242, 1247, 1248, 1250, 1256, 1258, 1260, 1279, 1280, 1281, 1285, 1291, 1293, 1295, 1296, 1300, 1301, 1302, 1304, 1308, 1309, 1310, 1311, 1312, 1314, 1316 and 1318, more preferred are compounds NN 5, 10, 20, 26, 29, 36, 41, 51, 57, 60, 67, 74, 82, 88, 91, 98, 113, 119, 122, 129, 134, 141, 144, 150, 153, 160, 175, 181, 184, 191, 198, 203, 206, 212, 215, 222, 237, 243, 246, 253, 258, 268, 274, 277, 284, 299, 305, 308, 314, 317, 324, 336, 339, 346, 349, 358, 361, 368, 371, 380, 382, 383, 390, 392, 400, 403, 410, 413, 422, 425, 432, 435, 444, 446, 447, 449, 454, 456, 462, 464, 467, 471, 474, 477, 486, 489, 496, 499, 508, 511, 518, 521, 530, 532, 533, 540, 542, 543, 552, 553, 554, 555, 558, 565, 568, 574, 589, 590, 591, 594, 595, 597, 598, 600, 601, 602, 603, 608, 609, 610, 613, 616, 617, 619, 620, 621, 651, 656, 658, 668, 669, 675, 688, 716, 717, 723, 728, 735, 761, 768, 773, 780, 800, 802, 803, 806, 813, 816, 826, 828, 829, 832, 839, 841, 854, 860, 865, 890, 896, 901, 922, 930, 944, 951, 963, 986, 987, 992, 997, 1003, 1022, 1023, 1028, 1033, 1039, 1054, 1060, 1061, 1073, 1079, 1089, 1094, 1096, 1098, 1102, 1107, 1109, 1113, 1114, 1132, 1138, 1143, 1149, 1168, 1174, 1179, 1185, 1200, 1207, 1219, 1226, 1236, 1242, 1248, 1250, 1256, 1279, 1281, 1296, 1300, 1302, 1304, 1308, 1309, 1310, 1312 and 1316,

even more predpochtitel, 67, 474, 477, 486, 496, 508, 518, 530, 540, 552, 554, 589, 590, 591, 594, 595, 600, 601, 602, 608, 610, 616, 617, 619, 620, 621, 656, 658, 716, 717, 728, 761, 773, 800, 803, 826, 890, 1022, 1023, 1039, 1096, 1098, 1102, 1107, 1109, 1132, 1143, 1168, 1179, 1200, 1236, 1242, 1248, 1296, 1302, 1308, 1312 and 1316,

and the most preferred are the compounds:

Compound No. 82: 1-( -cyclopropanecarbonyl-2-terbisil)- 4-mercaptopyridine,

The compound N 88: 1-(2-fluoro- -methoxycarbonylbenzyl)-4 - mercaptopyridine,

The compound N 91: 1-(2-chloro - methoxycarbonylbenzyl)-4 - mercaptopyridine,

The compound N 422: 1-( -cyclopropanecarbonyl-2-terbisil)-3 - ethoxycarbonylmethylene-4-mercaptopyridine,

The compound N 435: 1-(2-chloro - methoxycarbonylbenzyl)-3 - ethoxycarbonylmethylene-4-mercaptopyridine,

The compound N 464: 1-( -cyclopropanecarbonyl-2-terbisil)- 3-carboxymethylamino-4-mercaptopyridine,

The compound N 477: 1-(2-chloro - methoxycarbonylbenzyl)-3 - carboxymethylamino-4-mercaptopyridine,

The compound N 486: 1-( -cyclopropanecarbonyl-2-terbisil)- 3-(N,N-dimethylcarbamoyl)methylidene-4-mercaptopyridine,

The compound N 508: 1-( -cyclopropanecarbonyl-2-terbisil)-3-(N - methylcarbamoyl)methylidene-4-mercaptopyridine,

The compound N 589: 4 acetylthio-1-( -cyclopropanecarbonyl-2-terbisil) piperidine,

The compound N 591: 4 butylthio-1-( - cyclopeptides,

The compound N 601: 4 benzylthio-1-( -cyclopropanecarbonyl-2-terbisil) piperidine,

The compound N 608: 4 acetylthio-1-(2-fluoro- - methoxycarbonylbenzyl) piperidine,

The compound N 620: 4 benzylthio-1-(2-fluoro- -methoxycarbonylbenzyl) piperidine,

The compound N 621: 4 acetylthio-1-(2-chloro - methoxycarbonylbenzyl) piperidine,

The compound N 800: 3-acetylthio-1-( - cyclopropanecarbonyl-2-terbisil)azetidin,

The compound N 1022: 4 acetylthio-1-( -cyclopropanecarbonyl-2-terbisil) -3-ethoxycarbonylmethylene,

The compound N 1039: 4 acetylthio-1-(2-chloro - methoxycarbonylbenzyl)-3 - ethoxycarbonylmethylene,

The compound N 1132: 4 acetylthio-1-( -cyclopropanecarbonyl-2 - terbisil)-3-(N,N-dimethylcarbamoyl) metiletilpiridin and

The compound N 1168: 4 acetylthio-1-( -cyclopropanecarbonyl-2 - terbisil)-3-(N-methylcarbamoyl) metiletilpiridin.

The compound of formula (I) of the present invention can be easily obtained in the following way:

How A

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In the above formula, R1, R2and R3are the same as defined above, R2a is the same as R2except that the hydroxyl group contained in R2was protected, R3new ring [optional Deputy of the specified group is a hydroxyl group or hydroxy-C1-C4the alkyl group and the cyclic amino group, furthermore preferably a substituted group of the formula =CR4aR5a (where R4a and R5a are the same as R4and R5respectively, except that they lack the carboxyl group)] , R3b is the same as R3a, except that a hydroxyl group, or hydroxycut contained in R3a, was converted into a halogen atom (preferably a chlorine atom or a bromine atom); C1-C4alkanesulfonyl (preferably by methanesulfonylaminoethyl), which may be substituted by halogen atom; or a substituted or unsubstituted benzolsulfonate (Deputy of the specified group is C1-C4alkyl, halogen, C1-C4alkoxy or nitro, of which preferred are methyl, chlorine, methoxy or nitro, and particularly preferred are p-methyl or p-nitro), R3c is the same as R3a, except that a hydroxyl group, or hydroxycut contained in R3a, was replaced by a group of formula-S-COR6(where R6is the same as defined below), R6represents C1

Examples of the protective group for hydroxyl group can be, for example, cyclic ether groups such as tetrahydropyranyl or tetrahydropyranyl group, methoxymethyl group, methoxyethoxymethyl group, a substituted or unsubstituted benzyl group (Deputy of the specified group is C1-C4alkyl, halogen, C1-C4alkoxy or nitro, of which preferred are methyl, chlorine, methoxy or nitro, and particularly preferred are p-chloro or p-methoxy), or a substituted or unsubstituted benzyloxycarbonyl group (substituents of the specified group are C1-C4alkyl, halogen, C1-C4alkoxy or nitro, of which preferred are methyl, chlorine, methoxy or nitro and the most preferred is p-chloro or p-methoxy), of which preferred are tetrahydropyranyl, methoxymethyl, benzyl, p-methoxybenzyl, p-chloraniline, benzyloxycarbonyl, p-methoxybenzylideneamino or p-chlorobenzenesulfonyl group, and most preferred are the gasoline Method A is a method of synthesis of Compound (I).

Stage A1 is the stage of synthesis of the compounds of formula (III) and implemented by the interaction of the compounds of formula (II) with a halogenation agent, or sulfonylureas agent.

Examples of the halogenation agent used at this stage may be, for example, thionylchloride, such as thionyl chloride or thienylboronic; trihalogen phosphorus, such as trichloride phosphorus or tribromide phosphorus; pentachloride phosphorus, such as pentachloride phosphorus or pentabromide phosphorus; oxychloride phosphorus, such as phosphorus oxychloride or oxybromide phosphorus; or three (phenyl, unsubstituted or substituted C1-C4by alkyl) phosphine-operaterrassen, such as triphenylphosphine-carbon tetrachloride, trailerteen-carbon tetrachloride or triphenylphosphine-tetrabromoethane, of which preferred are thionyl chloride, trichloride phosphorus, tribromide phosphorus, pentachloride phosphorus, triphenylphosphine-carbon tetrachloride, trailerteen-carbon tetrachloride or triphenylphosphine-tetrabromoethane and most preferred are thionyl chloride, triphenylphosphine-carbon tetrachloride or triphenylphosphine-tetrabromoethane.

Examples sulfonylurea agents used at this stage, can be alkanesulfonyl anhydrides, which may be substituted with halogen; and benzosulphochloride, which may be substituted; preferred are C1-C4alkanesulfonyl, which may be substituted by fluorine;1-C4alkanesulfonyl; C1-C4alkanesulfonyl anhydrides, which may be substituted by fluorine; benzosulphochloride, which may be substituted; or benzosulfimide, which may be substituted; more preferred are C1-C2alkanesulfonyl, triftormetilfullerenov, C1-C2alkanesulfonyl anhydrides, triftormetilfullerenov anhydride, benzosulphochloride, toluensulfonate or nitrobenzenesulfonamide; and most preferred are methansulfonate, triftormetilfullerenov, benzosulphochloride or p-toluensulfonate.

The compound (II) and halogenation agent is subjected to interaction in the presence or absence (preferably in the presence of inert solvent. The nature of the inert solvent used at this stage, does not have any particular limitation, provided that it has no adverse effect on new hydrocarbon, such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane; simple ether, such as diethyl ether, tetrahydrofuran or dioxane; a ketone, such as acetone or methyl ethyl ketone; a nitrile such as acetonitrile; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoric; sulfoxide such as dimethylsulfoxide, or mixtures thereof, with the preferred are ethers or halogenated hydrocarbons.

Although the reaction temperature depends on the nature of the starting compound (II), halogenation agent and solvent, however, it usually ranges from -10oC to 200oC (preferably from 0oC to 100oC). The reaction time depends on the reaction temperature and so on, but it usually takes from 30 minutes to 24 hours (preferably from 1 hour to 12 hours).

The compound (II) and sulfonyloxy agent is subjected to interaction in an inert solvent in the presence and in the absence (preferably in the presence) of the Foundation. In this reaction can be used inert solvents, similar inert solvents used in the reaction between Compound (II) and halogenation agent.

Preferred p is as lithium hydroxide, sodium hydroxide or potassium hydroxide; a carbonate of an alkali metal such as lithium carbonate, sodium carbonate or potassium carbonate; bicarbonate of an alkali metal such as sodium bicarbonate or potassium bicarbonate; alkali metal alkoxide such as lithium methoxide, sodium methoxide, ethoxide or sodium tert-piperonyl potassium; or an organic amine, such as triethylamine, tributylamine, N-methylmorpholine, pyridine, 4-dimethylamino-pyridine, picoline, lutidine, kallidin, 1,5-diazabicyclo[4.3.0]-5-nonen or 1,8-diazabicyclo[5.4.0] -7-undecene, of which more preferred are the alkali metal carbonates or organic amines, and particularly preferred are sodium carbonate, potassium carbonate, triethylamine, tributylamine, pyridine or lutidine. When organic amines are used in liquid form, they can be used in large excess amounts as a base, and as a solvent.

The reaction temperature depends on the nature of the starting compound (II), sulfonylurea agent and solvent, but it usually ranges from -10oC to 100oC (preferably from 0oC to 50oC). The reaction time depends on the reaction temperature and so forth, but obicnnii from the reaction mixture in each reaction receive the target connection in the standard way. For example, if necessary, the target compound can be obtained by filtering off nerastvorimogo substances, if any, followed by distillation of solvent under reduced pressure; or by removal of the solvent under reduced pressure, adding to the residue water, extraction is not miscible with water with an organic solvent such as ethyl acetate, and drying with anhydrous magnesium sulfate or so on, followed by distillation of the solvent. If necessary, can be effected by an additional purification by standard means, such as recrystallization or column chromatography.

Stage A2 is the stage of synthesis of the compounds of formula (Ia), and is accomplished by interaction of the Compound (III) with the compound of the formula (IV) in an inert solvent.

The nature of the inert solvent used at this stage, does not have any particular limitation, provided that it has no adverse influence on the reaction, and such a solvent can be, for example, a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; a ketone, such as acetone or methyl ethyl ketone; esters such as ethyl acetate or butyl acetate; alcohol, so the sludge; amide such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoramide; sulfoxide such as dimethyl sulfoxide; or mixtures thereof, with the preferred are amides or sulfoxidov.

The reaction temperature depends on the nature of the starting compound (III), starting compound (IV) and solvent, but usually it ranges from 0oC to 200oC (preferably from 20oC to 150oC). The reaction time depends on the reaction temperature and so on, but it usually takes from 30 minutes to 24 hours (preferably from 1 hour to 12 hours).

After completion of the reaction from the reaction mixture in each reaction receive the target connection in the standard way. For example, if necessary, the target compound can be obtained by filtering off insoluble materials, if any, followed by distillation of solvent under reduced pressure; or by removal of the solvent under reduced pressure, adding to the residue water, extraction is not miscible with water with an organic solvent such as ethyl acetate, drying with anhydrous magnesium sulfate or so on, followed by distillation of the solvent. If necessary, it can be done CLASS="ptx2">

Stage A3 stage is carried out in the case, if necessary, and this stage includes:

Reaction: the reaction of transformation of the group-S-COR6(where R6is as it was defined above) contained in the3c, mercaptopropyl;

Reaction (b): the reaction of acylation of mercaptopropyl formed in Reaction (a);

Reaction (c): the reaction of removing the protective group of hydroxyl group contained in R2a;

Reaction (d): the reaction of transformation alkoxycarbonyl groups contained in R3c, carboxypropyl; and

Reaction (e): the reaction of isomerization of CIS/TRANS-shape having a double bond and is contained in R3c.

If necessary, the order of these stages can be changed.

Reaction (a):

The reaction of transformation of the group-S-COR6(where R6is as it was defined above) in mercaptopropyl in Reaction (a) is carried out by hydrolysis of the corresponding compounds with acid or alkali (preferably acid) or by decomposition by the addition of alcohol. This reaction is carried out in accordance with well known methods of organic synthesis. In that case, if the hydrolysis of Khujand the Yu group, or a cyclic ether group, which is one of the protective groups of the hydroxyl group contained in R2a, and if the hydrolysis is carried out using alkali, in the process of hydrolysis alkoxycarbonyl group contained in R3c, is transformed into carboxypropyl.

Examples of acids which may be used in this reaction are, for example, inorganic acids such as hydrogen chloride, nitric acid, hydrochloric acid or sulfuric acid, or organic acids such as acetic acid, triperoxonane acid, methanesulfonate acid or p-toluensulfonate acid, of which preferred are hydrogen chloride, hydrochloric acid, sulfuric acid or triperoxonane acid, and particularly preferred are a hydrogen chloride or hydrochloric acid.

Examples of alkali, which can be used in this reaction are, for example, alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide; a carbonate of an alkali metal such as sodium carbonate or potassium carbonate, or a bicarbonate of an alkali metal such as sodium bicarbonate or potassium bicarbonate, of which preferred are the hydroxides of alkali metal who meet any specific restrictions, provided that it has no adverse influence on the reaction, and such a solvent can be, for example, hydrocarbons, such as hexane, benzene or toluene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane; simple ether, such as diethyl ether, tetrahydrofuran or dioxane; a ketone, such as acetone or methyl ethyl ketone; an alcohol such as methanol, ethanol, propyl alcohol, isopropyl alcohol or butyl alcohol; carboxylic acid such as formic acid, acetic acid, propionic acid or butane acid; water, or a mixture thereof; in the case of hydrolysis with acid, the preferred solvents are alcohol, carboxylic acid, water or mixtures thereof; and in case of carrying out the hydrolysis using a base, the preferred solvents are alcohol or water.

The reaction temperature depends on the nature of the parent compound (Ia), base and solvent, but it usually ranges from -10oC to 70oC (preferably from 0oC to 50oC).

The reaction time depends on the reaction temperature and so on, but it usually takes from 30 minutes to 48 hours (predpochtite the t target connection in the standard way. For example, if necessary, the target compound can be obtained by filtering off insoluble materials, if any, neutralization of the reaction mixture if the reaction mixture is acidic or basic, with subsequent distillation of the solvent under reduced pressure, or by removal of the solvent under reduced pressure, adding to the residue water, extraction is not miscible with water with an organic solvent such as ethyl acetate, drying with anhydrous magnesium sulfate or so on, followed by distillation of the solvent. If necessary, can be effected by an additional purification by standard means, such as recrystallization or column chromatography.

Reaction (b)

This acylation reaction of mercaptopropyl in Reaction (b) is implemented by interaction of the corresponding connection allermuir agent in an inert solvent in the presence or in the absence (preferably in the presence) of the Foundation. This reaction is carried out in a manner analogous to the method described for the reaction of sulfonylurea on stage A1, except that in this reaction instead sulfonylurea agent use the following allerease agent.<, 2-C20alkanolamine, mixed anhydrides of formic and acetic acids, anhydrides C2-C20alkenylboronic acid, C3-C20alkanolamine, anhydrides C3-C20alkenylboronic acid, substituted or unsubstituted benzoylchloride, substituted or unsubstituted anhydrides of benzoic acid or C1-C4alkylhalogenide, of which preferred are C2-C20alcoholclone or bromides, mixed anhydrides of formic and acetic acids, anhydrides C2-C20alkenylboronic acid, C3-C20alcoolilor or bromide, anhydrides C3-C20alkenylboronic acid, a substituted or an unsubstituted benzoyl chloride or bromide, substituted or unsubstituted anhydrides of benzoic acid or C1-C4alcolhol or Bracamonte; more preferred are C2-C20alcoholclone, mixed anhydrides of formic and acetic acids, anhydrides C2-C6alkenylboronic acid, C3-C20albanology, a substituted or an unsubstituted benzoyl chloride or C1-C4alkylchlorosilanes; and especially preferred are C2-C20alny or an unsubstituted benzoyl chloride or C1-C4alkylchlorosilanes.

Reaction (c)

The reaction for removing the protective group of hydroxyl group contained in R2a, in the Reaction (c) depends on the nature of the protective group and the reaction is carried out by a method well known to experts in the field of chemistry organic synthesis.

In that case, if the protective group of hydroxyl group is substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxycarbonyl group, the removal of this group is implemented by interaction of the corresponding compounds with hydrogen (usually under the pressure of 1-10 atmospheres, preferably 1-3 atmospheres) in an inert solvent (preferably in an alcohol, such as methanol, ethanol or isopropanol; in simple ether, such as diethyl ether, tetrahydrofuran or dioxane; aromatic hydrocarbons, such as toluene, benzene or xylene; aliphatic hydrocarbon such as hexane or cyclohexane; ether complex, such as ethyl acetate or butyl acetate; fatty acid, such as acetic acid, or in mixtures of the above organic solvent and water) in the presence of catalytic hydrogenating catalyst (preferably is of that palladium-barium or similar).

The reaction temperature is usually from 0oC to 100oC (preferably from 20oC to 80oC). The reaction time depends on the reaction temperature and so on , but it usually takes from 30 minutes to 48 hours (preferably from 1 hour to 24 hours).

In that case, if the protective group of hydroxyl group is methoxymethyl group, methoxyethoxymethyl group or a cyclic ether group, then its removal is carried out, for example, by reaction with acid (for example, with an inorganic acid such as hydrogen chloride, nitric acid, hydrochloric acid or sulfuric acid; organic acid such as acetic acid, triperoxonane acid, methanesulfonate acid or p-toluensulfonate acid; or a Lewis acid such as boron TRIFLUORIDE, of which preferred is an inorganic or organic acid, and more preferred is hydrochloric acid, sulfuric acid or triperoxonane acid) in an inert solvent (hydrocarbon, such as hexane or benzene; halogenated hydrocarbon, such as methylene chloride, chloroform or carbon tetrachloride; complex ester such as ethyl acetate; ketone such is Il, tetrahydrofuran or dioxane; or a mixture of the above solvent and water, of which preferred are ester, a simple ether or halogenated hydrocarbon).

The reaction temperature is usually from -10oC to 100oC (preferably from -5oC to 50oC). The reaction time depends on the reaction temperature and so on , but it usually takes from 5 minutes to 48 hours (preferably from 30 minutes to 10 hours).

Alternatively, the protective group of hydroxyl group can be selectively removed by changing the nature of the protective group for hydroxyl group and choice of reaction conditions, which allows to distinguish this reaction from the reaction conversion group of the formula-S-COR6(where R6was defined above), present in R3c, mercaptopropyl, or reaction conversion alkoxycarbonyl groups present in R3c, in the carboxyl group.

After completion of the reaction from the reaction mixture in each reaction receive the target connection in the standard way. For example, if necessary, the target compound can be obtained by neutralizing the reaction mixture, if necessary, filtering off insoluble weechat, washing with water and subsequent removal of the solvent. If necessary, the thus obtained target compound can be further purified by standard means, such as recrystallization, pereosazhdeniya or column chromatography.

Reaction (d)

The reaction conversion alkoxycarbonyl groups present in R3c, carboxypropyl in the Reaction (d) is carried out in a manner analogous to the method described for the reaction of transformation group of the formula-S-COR6(where R6is as it was defined above) in mercaptopropyl in Reaction (a). Alternatively, alkoxycarbonyl group R3c can be hydrolyzed and separated from the R2a through reaction with a strong acid (e.g. concentrated hydrochloric acid, concentrated sulfuric acid, concentrated nitric acid or etc.) in an inert solvent (for example, aliphatic carboxylic acid, such as acetic acid).

Reaction (e)

This reaction of isomerization of CIS/TRANS-forms a double bond present in R3c, in the Reaction (e) is carried out by irradiation with light of the appropriate compound in an inert solvent in the presence or in the absence (Preta, is a mercury lamp, low pressure (from 20 W to 100 W, preferably 32 W), and as a sensitizer used benzophenone, fluorenone or anthraquinone.

This reaction can also be carried out by adding organic sulfur compounds such as dimethyl disulfide, diatinguished or diphenyldisulfide to stimulate reactions and/or suppression of side reactions.

The nature of the inert solvent used at this stage, does not have any particular limitation, provided that it has no adverse influence on the reaction, and such a solvent can be, for example, a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; an ester such as ethyl acetate or butyl acetate; an alcohol such as methanol, ethanol, propyl alcohol, isopropyl alcohol or butyl alcohol; nitrile such as acetonitrile; an amide such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or hexamethylphosphoramide; sulfoxide such as dimethyl sulfoxide; or mixtures thereof; preferred are alcohols or NITRILES.

The reaction temperature depends on the nature of the parent compound and the light source, but usually it kostnoi temperature or so p. , but it usually takes from 5 minutes to 8 hours (preferably from 10 minutes to 3 hours).

After completion of the reaction from the reaction mixture in each reaction receive the target connection in the standard way. For example, the target compound can be obtained, if necessary, by filtering off insoluble materials, if any, followed by distillation of solvent under reduced pressure, or by removal of the solvent under reduced pressure, adding to the residue water, extraction is not miscible with water with an organic solvent such as ethyl acetate, drying with anhydrous magnesium sulfate or so on, followed by distillation of the solvent. If necessary, can be effected by an additional purification by standard means, such as recrystallization or column chromatography.

The compound (I) can be converted into its pharmaceutically acceptable salt by treatment with acid in a standard way. For example, this salt can be obtained by reaction with the corresponding acid at room temperature over a period of time from 5 minutes to 1 hour in an inert solvent (preferably in simple ether, such as diet is torode, such as methylene chloride or chloroform) followed by distillation of solvent under reduced pressure.

The original compound (II) of the present invention can be easily obtained in accordance with the following methods:

Method B

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The method C

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Method D

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In the above formulas, R1, R2a, R3a, R4a and R5a are the same as defined above, R7represents a protective group for amino group removed in acidic conditions, R8represents a protective group for the amino group to be deleted in reducing conditions, Y represents a halogen atom (preferably chlorine atom or bromine), m = 0-3 and n = 1 or 2.

A protective group for amino group removed in acidic conditions, R7may be, for example, triticina group or tert-butoxycarbonyl group, and the protecting group for the amino group to be deleted in reducing conditions, R8may be, for example, substituted or unsubstituted benzyl group, or a substituted or unsubstituted benzyloxycarbonyl group similar to the above protective group for hydroxyl group, of which the preferred anilina or p-chlorobenzenesulfonyl group, and particularly preferred is benzyl or p-methoxybenzyl group.

Method B is a method of synthesis of Compound (II).

Stage B1 is the stage of synthesis of Compound (II) and includes the interaction of the compounds of formula (V) with the compound of the formula (VI) at 0oC-200oC (preferably at 20oC-150oC) within 1-24 hours (preferably for 2 to 15 hours) in an inert solvent (preferably in amide, such as N,N-dimethylacetamide, N,N-dimethylformamide, N is an organic or hexamethylphosphoramide, or a sulfoxide such as dimethylsulfoxide) in the presence or in the absence of a base (preferably in the presence of a carbonate of an alkali metal such as sodium carbonate or potassium carbonate).

Appropriate aminopropane can be obtained by hydrolysis of Compound (II) having as R3alkoxycarbonyl group, in a manner analogous to the method described for the reaction of (d) above the stage A3 of Method A, the result of which receive a corresponding carboxypropanoyl, which is subjected to interaction with C1-C4alkylaminocarbonyl, such as methylcarbonate, ethylchloride, ethylbromide, propylparaben, butylparaben or isobutylparaben, way is dtweedie active ester derivative, which is then subjected to the interaction with ammonia or mono - or di-(C1-C4alkyl) amine at -10oC-100oC (preferably at 10oC-50oC) for 1-24 hours, preferably 2-10 hours) in an inert solvent (preferably in a halogenated hydrocarbon, such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane).

Method C is a method of synthesis of Compound (Va), that is, the starting compound (V) in method B, with Deputy represented by the formula = CR4aR5a (where R4a and R5a are the same as defined above).

Stage C1 is a stage of synthesis of the compounds represented by formula (VIII), and includes the interaction of the compounds represented by formula (VII), with titillation, such as Fritillaria or trailered; with tert-butoxycarbonylamino, such as tert-butoxycarbonyl or tert-butoxycarbonylamino; or with di-tert-BUTYLCARBAMATE at 0oC-150oC (preferably at 20oC-100oC) within 1-24 hours (preferably for 2-10 hours) in an inert solvent (preferably in a halogenated hydrocarbon, such as dichlorocarbanilide or hexamethylphosphoramide; or sulfoxide, such as dimethylsulfoxide) in the presence or in the absence of a base (preferably in the presence of a carbonate of an alkali metal such as lithium carbonate, sodium carbonate or potassium carbonate).

Stage C2 represents a stage of synthesis of the compounds represented by formula (X), and includes the interaction of the compound (VIII) with di(C1-C4alkyl) amine or a 3-6-membered cyclic amine (preferably dimethylamine, diethylamine, pyrrolidine, piperidine or morpholine, and particularly preferably pyrrolidine, piperidine or morpholine) at 60oC-200oC (preferably at 80oC-150o) during the period of time from 30 minutes to 15 hours (preferably for 1-10 hours) in an inert solvent (preferably in an aromatic hydrocarbon such as benzene, toluene or xylene), which is azeotropic dehydration with formation of the corresponding engineprovides; and then it engineprovides subjected to interaction with the compound of the formula (IX) at 60oC-200oC (preferably at 80oC-150oC) during the period of time from 30 minutes to 10 hours (preferably 1-5 hours) necesse which is azeotropic dehydration.

Stage C3 is a stage of synthesis of the compounds of formula (XI) and includes the interaction of the compound (X) with a reducing agent (preferably with borhydride compound, such as sodium borohydride or Lamborgini sodium) at 0oC-100oC (preferably at the 5oC-50oC) for from 10 minutes to 6 hours (preferably for from 30 minutes to 3 hours) in an inert solvent (preferably in an alcohol, such as methanol or ethanol).

Stage C4 represents the stage of synthesis of the Compound (Va), and this stage is carried out by removal of the protective group of the amino group of Compound (XI). This stage is carried out in a manner analogous to the method described for Reaction (c) at the Stage A3 of Method A, in order to remove the protective group for hydroxyl group in acidic conditions.

Method D is an alternative method of synthesis of Intermediate compound (X) Method C.

Stage D1 represents a stage of synthesis of the compounds of formula (VIIIa). The compound (VII) and substituted or unsubstituted benzylamine or substituted or unsubstituted benzyloxycarbonylglycine (preferably chloride) is treated with a method similar to that described in Stage C1 Method C.1
-C4alkyl) amine or a 3-6-membered cyclic amine (preferably dimethylamine, diethylamine, pyrrolidine, piperidine or morpholine, and particularly preferably pyrrolidine, piperidine or morpholine), conducted by the method similar to that described in the first part of Stage C2 Method C, to obtain the corresponding engineprovides; and interaction thus obtained engineprovides with the compound of the formula (IX) at -10oC-100oC (preferably at 10oC-50oC) within 1-24 hours (preferably for 2 to 20 hours) in an inert solvent (preferably in a halogenated hydrocarbon, such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane) in the presence of an acid catalyst, preferably a Lewis acid such as a complex of boron TRIFLUORIDE-ether, aluminum chloride, titanium tetrachloride or tin tetrachloride is used).

Stage D3 is a stage of synthesis of the compounds of formula (VIII), and this stage is carried out by removal of the protective group of the amino group of Compound (XII). This stage is carried out in a manner analogous to the method described in Reaction (C) Stage A3 of Method A, for the removal of the protective group of the hydroxyl XIV), and this stage is carried out by protecting the amino group of Compound (XIII). This stage is carried out in a manner analogous to the method described in Stage C1 Method C.

Stage D5 represents a stage of synthesis of the Compound (X), and it includes sulfonylurea Compound (XIV) by the method similar to that described in Stage A1 of Method A, and the interaction obtained sulfonylacetonitrile with a base (preferably an organic amine, such as triethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, 1,5-diazabicyclo[4.3.0] -5-nonen or 1,8-diazabicyclo[5.4.0]-7 - undecene) at -10oC-100oC (preferably at 10oC-50oC) during the period of time from 30 minutes to 10 hours (preferably 1-5 hours) in an inert solvent (preferably in a halogenated hydrocarbon, such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane).

After completion of the reaction from the reaction mixture in each reaction receive the target connection in the standard way. For example, the target compound can be obtained by filtering off insoluble materials, if any, neutralize, if necessary, the reaction mixture in the case, if it is kiiiinda pressure, add to the residue water, extraction is not miscible with water with an organic solvent such as ethyl acetate, drying with anhydrous magnesium sulfate or etc., and subsequent removal of the solvent. If necessary, can be effected by an additional purification by standard means, such as recrystallization or column chromatography.

The original compound (VI) is known, or it can be obtained by a known method [for example described in the patent application of Japan Kokai N Sho 59-27895 (EP 99802) or in the patent application of Japan Kokai N Hei 6-41139 (EP 542411)]. The original compound (V) is known, or it can be obtained by a known method [for example, J. Org. Chem., 37, 3953 (1972)].

The compound of formula (I) of the present invention has excellent inhibitory effect on platelet aggregation or inhibiting effect on the development of arteriosclerosis and has low toxicity, and therefore it can be used as a therapeutic agent or a prophylactic agent against thrombosis, embolism or arteriosclerosis.

The best embodiments of the present invention

In more detail, the present invention is described in the following Primera to keep in mind these examples should not be construed as limiting the scope of the present invention.

Example 1

Hydrochloride of 1-( -cyclopropanecarbonyl-2 - terbisil)-4-mercaptopyridine (the above Compound No. 82)

(a) 4-Acetylthio-1-( -cyclopropanecarbonyl-2-terbisil) piperidine (described above the Compound N 589)

In 50 ml of dichloromethane was dissolved 8.0 g (of 28.9 mmol) 1 - cyclopropanecarbonyl-2 - terbisil)-4-hydroxypiperidine, and then add of 2.92 g (of 28.9 mmol) of triethylamine. To the resulting mixture under ice cooling are added dropwise a solution of 3.31 g (of 28.9 mmol) methanesulfonanilide in 10 ml of dichloromethane and then stirred at room temperature for 1 hour. The solvent is distilled off under reduced pressure. To the residue is added ethyl acetate and precipitated thus the triethylamine hydrochloride is filtered off. The filtrate is concentrated by evaporation under reduced pressure, resulting in a gain of crude 1-( -cyclopropanecarbonyl-2-terbisil)-4 - methylsulfonylmethane. To the crude product add 50 ml of dimethyl sulfoxide (DMSO) and 19.8 g (170 mmol) of thioacetate potassium and the resulting mixture is stirred for 4 hours at 50oC. After addition of water the mixture extragere the residue is subjected to column chromatography on silica gel (eluting solvent: toluene/ethyl acetate = 19/1) to obtain the reddish-brown oil. The oil obtained is crystallized from hexane and obtain 3.6 g of the target compound as light brown crystals (yield: 37%).

Melting point: 78-80oC

The NMR spectrum (CDCl3, ) : 0,79-of 0.87 (2H, m), 0,98 of-1.04 (2H, m), 1,66 and 1.80 (2H, m), 1,90-2,00 (2H, m), 2,16-2,22 (2H, m), of 2.28 (3H, s), 2,32 to 2.35 (1H, m), 2,70-2,78 (1H, m), 2,80-is 2.88 (1H, m), 3,38-3,47 (1H, m), to 4.62 (1H, s), 7,08-7,38 (4H, m);

Mass spectrum (CI, m/z): 336 (M++1);

IR spectrum (KBr.maxcm-1): 1689.

(b) Hydrochloride of 1-( -cyclopropanecarbonyl-2-terbisil)- 4-mercaptopyridine

In 50 ml of ethanol was dissolved 2.00 g (5,97 mmol) 4-acetylthio-1-( -cyclopropanecarbonyl-2-terbisil) piperidine. This solution is blown into the appropriate amount of gaseous hydrogen chloride and the resulting solution was left overnight at room temperature. The solvent is distilled off under reduced pressure. The residue is crystallized from diethyl ether and receive 1,95 g of target compound in the form of slightly brownish crystals (yield: 99%).

Melting point: 135-140oC;

Elemental analysis for C16H20FNOS HCl 1/4 H2O:

calculated: C 57,48; H 6,48; N 4,19;

found: C 57,33; H to 6.43; N 4,15;

Mass spectrum (CI, m/z): 294 (M++1).

Example 2

Hydrochloride of 1-(2-chloro - mitarbeiterin) piperidine (described above the compound N 621)

The reaction is carried out in the manner described in Example 1 (a), except that instead of 1-( -cyclopropanecarbonyl-2 - terbisil)-4-hydroxypiperidine using 1-(2-chloro - methoxycarbonylbenzyl)-4-hydroxypiperidine, resulting in a gain of the target compound in the form of a reddish-brown oil with a yield of 37%.

The NMR spectrum (CDCl3, ): 1,60-1,80 (2H, m), 1.85 to a 2.00 (2H, m), 2,10-of 2.25 (1H, m), is 2.30 (3H, s), 2,32-2,48 (1H, m), 2,55 is 2.75 (1H, m), 2,80-2,90 (1H, m), 3,40-of 3.60 (1H, m), 3,70 (3H, s), 4,70 (1H, s), 7,20-the 7.65 (4H, m);

Mass spectrum (CI, m/z): 342 (M++1)

(b) Hydrochloride of 1-(2-chloro - methoxycarbonylbenzyl)-4 - mercaptopyridine

The reaction is carried out in the manner described in Example 1 (b), except that instead of 4-acetylthio-1- ( - cyclopropanecarbonyl-2-terbisil)piperidine using 4-acetylthio-1-(2-chloro - methoxycarbonylbenzyl) piperidine and get the target compound in the form of light brown crystals with a quantitative yield.

Melting point: 134-140oC;

Mass spectrum (CI, m/z): 300 (M++1)

Example 3

Hydrochloride of 1-(2-fluoro- - methoxycarbonylbenzyl)-4-mercaptopyridine (the above compound No. 88)

(a) 4-Acetylthio-1-(2-fluoro- - methoxycarbonylbenzyl)piperidine (described above the compound N 608)

Reactionsin)-4-hydroxypiperidine using 1-(2-fluoro- -methoxycarbonylbenzyl)-4-hydroxypiperidine, in the result, get the target compound as a pale yellow solid (amorphous) substances with the release of 45.6%.

The NMR spectrum (CDCl3, ) : 1,65-of 1.78 (2H, m), 1,88 of 1.99 (2H, m), 2,20-of 2.33 (4H, m), 2,39 (1H, t, J=9.6 Hz), 2,75-of 2.86 (2H, m), 3,40-3,50 (1H, m), 3,71 (3H, s), a 4.53 (1H, s),? 7.04 baby mortality-7,49 (4H, m);

Mass spectrum (CI, m/z): 326 (M++1).

(b) Hydrochloride of 1-(2-fluoro- -methoxycarbonylbenzyl)-4 - mercaptopyridine

The method described in Example 1 (b), except that instead of 4-acetylthio-1-( -cyclopropanecarbonyl-2-terbisil) piperidine using 4-Acetylthio-1-(2-fluoro- -methoxycarbonylbenzyl) piperidine, get the target compound as a pale yellow solid (amorphous) substances with access to 97.1%.

The NMR spectrum (CDCl3, ): 1,70-of 2.24 (3H, m), 2,47-3,13 (3,5 H, m), 3,21-3,36 (0.5 H, m), 3,38-3,72 (2,5 H, m), 3,83, 3,84 (total 3H, each s), 3,92-was 4.02 (0.5 H, m), to 5.21, 5,24 (total 1H, each s), 7,20-to 7.93 (4H, m), 12,91-13,34 (1H, m);

Mass spectrum (CI, m/z): 284 (M++1).

Example 4

3 Acetylthio-1-( -cyclopropanecarbonyl-2 - terbisil)piperidine (described above the compound N 716)

The reaction is carried out in the manner described in Example 1(a), except that instead of 1-( -cyclopropanecarbonyl-2 - terbisil)-4-hydroxypiperidine using 1- ( -cyclopropanecarbonyl-2-terbisil)-3-hydroxyprop the

The NMR spectrum (CDCl3, ): 0,75-0,95 (2H, m), 1,00-1,10 (2H, m), 1,45 by 1.68 (1H, m), 1,72-of 1.85 (2H, m), 1,90 was 2.25 (2H, m), 2,30, 2,32 (total 3H, each s), 2,35-2,48 (1H, m), 2,80-to 3.02 (2H, m), 3,05 is 3.15 (1H, m), 3,16-3,30 (1H, m), 5,12 (1H, C), 7,05 was 7.45 (4H, m);

Mass spectrum (CI, m/z): 336 (M++1)

Example 5

Hydrochloride of 1-( -cyclopropanecarbonyl-2 - terbisil)-3-mercaptopyridine (the above compound No. 20)

(a) 3-Acetylthio-1-( -cyclopropanecarbonyl-2-terbisil) pyrrolidin (the above compound N 552)

The reaction is carried out in the manner described in Example 1 (a), except that instead of 1-( -cyclopropanecarbonyl-2 - terbisil)-4-hydroxypiperidine using 1-( - cyclopropanecarbonyl-2-terbisil)-3-hydroxypyrrolidine, resulting in a gain of the target compound as a brown oil in 51% yield.

The NMR spectrum (CDCl3, ): 0,78-0,85 (2H, m), 0,97-1,02 (2H, m), 1,75-of 1.78 (1H, m), 2,09-to 2.15 (1H, m), of 2.28 (3H, s), 2,32-3,39 (1H, m), 2,48-2,61 (2H, m), 2,72 is 2.80 (1H, m), 2,97-3,10 (1H, m), 3,91-of 3.97 (1H, m), 4,63, 4,65 (total 1 H, each s), 7,06-of 7.48 (4H, m);

Mass spectrum (CI, m/z): 321 (M++1);

IR spectrum (liquid membranemaxcm-1): 1692.

(b) Hydrochloride of 1- ( -cyclopropanecarbonyl-2-terbisil)- 3-mercaptopyridine

The reaction is carried out in the manner described in Example 1 (b), except that instead of 4-ACET the ZIL)pyrrolidin, in the result, get the target compound as a pale brown solid (amorphous) yield 74%.

Mass spectrum (CI, m/z): 280 (M++1);

IR spectrum (KBr,maxcm-1): 1710.

Example 6

Hydrochloride of 1-( -cyclopropanecarbonyl-2 - terbisil)-3-mercaptopyridine (the above compound N 206)

(a) 3-Acetylthio-1-( -cyclopropanecarbonyl-2-terbisil) azetidin (the above compound N 800)

The reaction is carried out in the manner described in Example 1(a), except that instead of 1-( -cyclopropanecarbonyl-2 - terbisil)-4-hydroxypiperidine using 1- - cyclopropanecarbonyl-2-terbisil)-3-hydroxyazetidine, resulting in getting the target compound in the form of light yellow crystals with a yield of 54%.

Melting point: 49-52oC;

The NMR spectrum (CDCl3, ): 0,74-of 0.87 (2H, m), 0,94-a 1.01 (2H, m), 1,92-to 1.98 (1H, m), of 2.28 (3H, s), 3,06-3,19 (2H, m), 3,62 (1H, DD, J=7,3, 7.9 Hz), 3,91 (1H, DD, J=7,3, 7.9 Hz), 4,13-is 4.21 (1H, m), to 4.62 (1H, s), 7,07-7,42 (4H, m);< / BR>
Mass spectrum (CI, m/z): 308 (M++1);

IR spectrum (KBr,maxcm-1): 1695.

(b) Hydrochloride of 1-( -cyclopropanecarbonyl-2-terbisil) -3-mercaptopyridine

The reaction is carried out in the manner described in Example 1 (b), except that instead of 4-acetensil)azetidin and obtain the target compound as white solid (amorphous) substance with a yield of 83%.

Mass spectrum (CI, m/z): 266 (M++1);

IR spectrum (KBr,maxcm-1): 1709;

Elemental analysis for C14H16FNOS HCl 1/2H2O

calculated: C 54,10; H of 5.84; N 4,51;

found: C 53,95; H of 5.68; N 4,45.

Example 7

Hydrochloride of 1-( -cyclopropanecarbonyl-2-terbisil)- 4-mercaptopyrimidine (the above compound No. 113)

(a) 4-Acetyltributyl-1-( -cyclopropanecarbonyl-2-terbisil) piperidine (described above the compound N 656)

The reaction is carried out in the manner described in Example 1(a), except that instead of 1-( -cyclopropanecarbonyl-2 - terbisil)-4-hydroxypiperidine using 1- -cyclopropanecarbonyl-2 - terbisil)-4-hydroxyethylpiperazine, resulting in a gain of the target compound as a brown oil in 51% yield.

The NMR spectrum (CDCl3, ): 0,78-0,88 (2H, m), 0,92-1,08 (2H, m), 1,28 of 1.50 (3H, m), 1,65-1,90 (3H, m), 2.05 is-to 2.15 (1H, m), 2,20-of 2.30 (1H, m), is 2.30 (3H, s), 2,80 (2H, d, J=7 Hz), 2,82-to 2.85 (1H, m), 2,98-to 3.02 (1H, m), 4,58 (1H, s), 7,05 was 7.45 (4H, m);

Mass spectrum (CI, m/z): 350 (M++1).

(b) Hydrochloride of 1-( -cyclopropanecarbonyl-2 - terbisil)-4-mercaptopyrimidine

The reaction is carried out in the manner described in Example 1 (b), except that instead of 4-acetylthio-1-( - cyclopropanecarbonyl-2-terbisil)piperidine ispoveda-brown crystals with a yield of 88%.

Melting point: 150-155oC;

Mass spectrum (CI, m/z): 308 (M++1);

Elemental analysis for C17H20FNOS HCl 1/4H2O

calculated: C 58,61; H to 6.80; N WAS 4.02;

found: C 58,70; H 6,85; N 3,98.

Example 8

Hydrochloride of 1-( -cyclopropanecarbonyl-2 - terbisil)-3-mercaptopyrimidine (the above compound N 175)

(a) 3-Acetylcoumarin-1-( -cyclopropanecarbonyl-2-terbisil) piperidine (described above the compound N 761)

The reaction is carried out in the manner described in Example 1(a), except that instead of 1-( -cyclopropanecarbonyl-2-terbisil)- 4-hydroxypiperidine using 1-( -cyclopropanecarbonyl-2 - terbisil)-3-hydroxyethylpiperazine, resulting in a gain of the target compound as a brown oil with a yield of 75%.

The NMR spectrum (CDCl3, ): 0,81-0,88 (2H, m), 0,94-of 1.07 (3H, m), 1.56 to a 1.96 (6H, m), 2,13-2,16 (0.5 H, m), 2,29 (1,5 H, s), 2,32 (1,5 H, s), 2,67-2,70 (0.5 H, m), 2.77-to only 2.91 (4H, m), 4,58 (0.5 H, s), 4,59 (0.5 H, s), 7,06-7,17 (2H, m), 7,27-7,38 (2H, m);

Mass spectrum (CI, m/z): 350 (M++1);

IR spectrum (liquid membranemaxcm-1): 1695.

(b) Hydrochloride of 1-( -cyclopropanecarbonyl-2-terbisil) -3-mercaptopyrimidine

The reaction is carried out in the manner described in Example 1 (b), except that instead of 4-acetylphenyl) piperidine, in the result, get the target compound as a pale brown solid (amorphous) of a substance with a yield of 75%.

Mass spectrum (CI, m/z): 308 (M++1);

IR spectrum (KBr.maxcm-1): 1712, 2504.

Example 9

Hydrochloride 8- ( -cyclopropanecarbonyl-2-terbisil)-3-mercapto-8 - azabicyclo[3.2.1] octane (the above compound N 268)

(a) 3-Acetylthio-8-( cyclopropanecarbonyl-2-terbisil) -8-azabicyclo

[3.2.1] octane (the above compound N 826)

The reaction is carried out in the manner described in Example 1 (a), except that instead of 1-( -cyclopropanecarbonyl-2 - terbisil)-4-hydroxypiperidine use the isomer A-1 (the Compound of Preparative example 8) 8-( -cyclopropanecarbonyl-2 - terbisil)-3-hydroxy-8-azabicyclo[3.2.1] octane, resulting in a gain of the target compound (isomer A-2) in the form of white crystals with a yield of 23.7%. Similarly, using isomer B-1 (the Compound of Preparative example 8) get another isomer (isomer B-2) target compound as a pale yellow solid (amorphous) substance with a yield of 12.4%. When high-performance liquid chromatography (column: TSK-GEL ODS-80TM, mobile phase: acetonitrile/11 mm KH2PO4= 70/30, flow rate: 1.0 ml/min, is 2">

Isomer A-2:

Melting point: 113-114oC;

The NMR spectrum (CDCl3, ): 0,75-1,01 (4H, m), 1,67-2,17 (8H, m) to 2.29 (3H, s), 2,42-2,48 (1H, m), 3,09-3,14 (1H, m), 3,24-3,30 (1H, m), 3,71-3,81 (1H, m) and 4.65 (1H, s), 7.03 is-7,72 (4H, m);

Mass spectrum (CI, m/z): 362 (M++1)

Isomer B-2

The NMR spectrum (CDCl3, ): 0,76-1,01 (4H, m), 1,60 (1H, d, J=14,0 Hz), 1,70 (1H, d, J= 14,0 Hz), 1,84-2,04 (3H, m), 2.05 is-2,17 (1H, m) to 2.29 (3H, s), 2,39-of 2.50 (2H, m), 2,50-of 2.58 (1H, m), 3,03-3,10 (1H, m), 3,21-3,29 (1H, m), to 3.99 (1H, t, J=7.2 Hz), to 4.62 (1H, s), 7.03 is-7,73 (4H, m);

Mass spectrum (CI, m/z): 362 (M++1)

(b) Hydrochloride of 8-( -cyclopropanecarbonyl-2-terbisil)-3 - mercapto-8-azabicyclo[3.2.1]octane

The reaction is carried out in the manner described in Example 1 (b), except that instead of 4-acetylthio-1-( - cyclopropanecarbonyl-2-terbisil)piperidine use the isomers of A-2 and B-2 3-Acetylthio-8-( -cyclopropanecarbonyl-2-terbisil)-8-azabicyclo[3.2.1] octane of Example 9 (a) and obtain isomers A-3 and B-3 target connection outputs 61.1% and 99.2 percent, respectively. When high-performance liquid chromatography isomers A-3 and B-3 show the retention time of 10.0 minutes and 9.3 min, respectively (as measured under conditions analogous to Example 9 (a)).

Isomer A-3

Appearance: light yellow crystals;

Melting point: 181-185oC;

The NMR spectrum (CDClof 3.57 (1H, C), 12,40-12,71 (1H, m);

Mass spectrum (CI, m/z): 320 (M++1)

Isomer B-3

Appearance: a light grey solid (amorphous);

The NMR spectrum (CDCl3, ): 0,84-0,93 (1H, m), 0,95-1,05 (1H, m), 1,15-1,32 (2H, m), 1,72-2,05 (3H, m), 2.00 in a 2.45 (2H, m), 2,55-to 2.65 (1H, m), was 2.76-of 2.86 (1H, m), 3,55 (1H, s), 3,70-of 3.80 (3H, m) to 4.23 (1H, s), a total of 5.21 (1H, s), 7,19 is 7.50 (4H, m), 8,50-8,58 (1H, m), to 12.28-12,47 (1H, m);

Mass spectrum (CI, m/z): 320 (M++1);

Example 10

Hydrochloride (E)-1-( -cyclopropanecarbonyl - 2-terbisil)-3-ethoxycarbonylmethylene-4-mercaptopyridine (the above compound N 422)

(a) to (E)-4-Acetylthio-1-( - cyclopropanecarbonyl-2-terbisil)-3 - ethoxycarbonylmethylene (the above compound N 1022)

In 50 ml of anhydrous methylene chloride was dissolved 3.28 g (9.1 mmol) 1-( -cyclopropanecarbonyl-2-terbisil)-3 - ethoxycarbonylmethylene-4-hydroxypiperidine, and then add of 6.02 g (18.2 mmol) tetrabromomethane at room temperature. To the resulting mixture in one portion add 2,62 g (9.9 mmol)of triphenylphosphine and the mixture was stirred at room temperature for one hour. After concentrating the reaction mixture, the residue is purified by chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 19/1), resulting in a gain of 2.00 g (yield: 52,1%) 4-b is ASS="ptx2">

The NMR spectrum (CDCl3, ): of 0.75 to 0.88 (2H, m), 0,97-1,11 (2H, m), 1,22, 1,25 (total 3H, each t, J= 6,8 Hz, J=7,3 Hz), 2,05-of 3.00 (6H, m), 4,11, 4,13 (total 2H, each q, J=6,8 Hz, J=7,3 Hz), 4,45, 4,60 (total 1H, each d, J= 13,6 Hz, J= 14.1 Hz), 4,77, 4,78 (total 1H, each s), 5,90 (1H, s), 7,05-the 7.43 (4H, m);

Mass spectrum (CI, m/z): 424 (M++1).

To 30 ml of anhydrous ethanol is added 2.14 g (to 18.7 mmol) thioacetate potassium and 1.98 g (4.7 mmol) of 4-bromo-1-( -cyclopropanecarbonyl-2-terbisil)-3 - ethoxycarbonylpyrimidine, which was obtained as described above, and then stirred at room temperature for 1 hour, and then for 5 hours at 50oC. the Reaction mixture was filtered to remove precipitated salt, and then concentrated. The residue is purified by chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 19/1), resulting in a gain of 0.95 g (yield: 48,2%) target compound as a pale yellow oil.

The NMR spectrum (CDCl3, ): 0,78-of 0.90 (2H, m), 0,99-1,10 (2H, m), 1,22, 1,25 (total 3H, each t, J=6,8 Hz, J=7,3 Hz), 1,82-of 1.94 (1H, m), 2,13-of 2.28 (2H, m), 2,30, 2,31 (total 3H, each s), 2,35-2,90 (3H, m), 3,40 (1H, Shir. C), 4,11, 4,13 (total 2H, each square, J=6,8 Hz, J=7,3 Hz), 4,25-and 4.40 (1H, m), 4.75 in, 4,77 (total 1H, each s), to 5.93 (1H, s), 7,08-7,38 (4H, m);

Mass spectrum (CI, m/z): 420 (M++1), 350.

(b) Hydrochloride (E)-Aut way described in Example 1 (b), with the use of 0.57 g (1.3 mmol) of (E)-4-acetylthio-1-( -cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylpyrimidine and obtain 0.52 g (yield: 92%) of target compound in the form of light yellowish white crystals.

Melting point: 120-125oC;

The NMR spectrum (CDCl3, ): 0,80-0,93 (1H, m), 0,94 was 1.06 (1H, m) of 1.23 (3H, t, J=7,3 Hz), 1.70 to of 2.20 (5H, m), 2,80-3,06, 3,11-3,39 (total 1H, each m), 3,45-of 3.80 (1H, m), 3,90-of 4.25 (2H, m), 4,20 (2H, q, J=7,3 Hz), 4,58, of 5.05 (total 1H, each m), 5,49 (1H, s), and 6.25 (1H, s), 7,15-8,10 (4H, m).

Mass spectrum (CI, m/z): 378 (M++1), 308;

IR spectrum (KBr,maxcm-1): 1712.

Example 11

Hydrochloride (E)-1-( -cyclopropanecarbonyl-2-terbisil)-3 - carboxymethylamino-4-mercaptopyridine (the above compound N 464)

In a mixed solvent of 15 ml of acetic acid and 10 ml of concentrated hydrochloric acid dissolved 0,44 g (1.1 mmol) of (E)-1-( -cyclopropanecarbonyl-2-terbisil)-3 - ethoxycarbonylmethylene-4-mercaptopyridine and the resulting solution is kept for 12 days at room temperature in the dark. The reaction mixture is concentrated to dryness, and then crystallized from ethyl ether. The crystals are collected by filtration, purified by chromatography on a column of silica gel (aluigi bright yellowish-white crystals.

Melting point: 109-111oC;

The NMR spectrum (CDCl3, ): of 0.74 to 0.92 (1H, m), and 1.00-to 1.14 (1H, m), of 1.62 and 1.75 (1H, m), 1,76-1,90 (1H, m), 1,94-of 2.08 (2H, m), 2,20-2,39 (1H, m), 2,50-2,70 (2H, m,), 2,90-3,03, 3,08-3,18 ( total 1H, each m), 3,41-of 3.80 (3H, m), 4,11-to 4.28 (1H, m), 4,90, 5,03 (total 1H, each d, J=17.6 Hz), 5,98, 6,12 (total 1H, each s), 7,10-of 7.55 (4H, m);

Mass spectrum (CI, m/z): 350 (M++1), 280;

IR spectrum (KBr,maxcm-1): 1712.

Example 12

Triptorelin (Z)-1-( -cyclopropanecarbonyl-2-terbisil)-3 - carboxymethylamino-4-mercaptopyridine (the above compound N 464)

60 ml (1:1) mixed solvent of methanol and acetonitrile are dissolved 0.50 g (1.3 mmol) of the hydrochloride of (E)-1-( -cyclopropanecarbonyl-2-terbisil)-3 - carboxymethylamino-4-mercaptopyridine and 0.05 ml of dimethyl disulfide, and then subjected to light irradiation for 90 minutes under cooling with the use of a mercury low pressure lamp 32 watt. After completion of the reaction, the reaction mixture was concentrated by evaporation under reduced pressure. The residue is subjected to high performance liquid chromatography (column: TSK-GEL ODS-8-TS, mobile phase: acetonitrile/water = 3/7 (containing 0,016% triperoxonane acid; room temperature)), resulting in getting the target compound in the form of two GeoStereo. the retention time of isomer A and isomer B with high-performance liquid chromatography (column: Intersil ODS-2, mobile phase: a mixture of acetonitrile/water = 20/80 (containing 0,02% triperoxonane acid), temperature: 27oC; flow rate: 1.5 ml/min) is 16.5 minutes and 18.5 minutes, respectively.

Isomer A

NMR spectrum (CD3CN ): 0,80-1,10 (4H, m), 1,82-1,89 (1H, m), 1,92-2,02 (1H, m), 2.26 and is 2.46 (2H, m), 3,11-3,29 (2H, m), of 3.46 (1H, d, J=13,6 Hz), 3,81 (1H, d, J=14,2 Hz), 5,26 (1H, s) 5,38 (1H, s), 5,73 (1H, s), 7,27-to 7.59 (4H, m);

Mass spectrum (CI, m/z): 350 (M++1), 280

Isomer B

NMR spectrum (CD3CN : 0,80-1,11 (4H, m), 1,79-of 1.88 (1H, m), 1,95-2,04 (1H, m), 2,28 is 2.43 (2H, m), 2,86-a 3.01 (1H, m), 3,03-of 3.12 (1H, m), 3,52 (1H, d, J= 12,8 Hz), a 3.87 (1H, d, J=12,8 Hz), 5,24 (1H, s), from 5.29 (1H, s), of 5.68 (1H, C), 7,25-7,56 (4H, m);

Mass spectrum (CI, m/z): 350 (M++1), 280.

Example 13

(E)-4-Acetylthio-1-(2-chloro - methoxycarbonylbenzyl)- 3-ethoxycarbonylmethylene (the above compound N 1039)

The reaction is carried out in the manner described in Example 10 (a), except that instead of (E)-1-( -cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylmethylene-4 - hydroxypiperidine using (E)-1-(2-chloro - methoxycarbonylbenzyl)-3-ethoxycarbonylmethylene-4 - hydroxypiperidine, resulting in getting the target compound in the form of bright red is 2 (1H, m), 2,15-of 2.30 (1H, m), 2,32 (3H, s), 2,52-to 2.85 (2H, m), 3,48 (0.5 H, d, J=a 13.9 Hz), 3,60 (0.5 H, d, J=a 13.9 Hz), 3,71, and 3.72 (total 3H, each s), 4,05-4,14 (2,5 H, m), 4,25 (0.5 H, d, J=a 13.9 Hz), or 4.31-of 4.44 (1H, m), a 4.83, 4,85 (total 1H, each s), 5,96 (1H, s), 7,15-of 7.70 (4H, m);

Mass spectrum (CI, m/z): 426 (M++1).

Example 14

Hydrochloride (E)-1-(2-chloro - methoxycarbonylbenzyl)-3 - carboxymethylamino-4-mercaptopyridine (the above compound N 477)

The reaction is carried out by the method described in Example 11, except that instead of hydrochloride of (E)-1-( -cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylmethylene - 4-mercaptopyridine using (E)-4-acetylthio-1-(2-chloro - methoxycarbonylbenzyl)-3-ethoxycarbonylmethylene and obtain the target compound as a light brown oil with a yield of 32.9%.

Melting point: 122-130oC;

The NMR spectrum (CDCl3, ): 1,90-of 2.05 (2H, m), 2,70-and 2.83 (1H, m), 3,49-of 3.60 (1H, m), 3,80, 3,82 (total 3H, each s), 3.95 to as 4.02 (1H, m), 4,08-to 4.15 (1H, m), 4,70-4,78 (1H, m), 5,52 (1H, s), 6,51 (1H, s), 7,35-of 7.60 (4H, m), 8,03-of 8.15 (1H, m);< / BR>
Mass spectrum (CI, m/z): 338 (M++1-18(H2O))

Specified in the header of the connection process as in Example 12, resulting in getting the Z isomer is specified in the connection header.

Example 15

Hydrochloride (E)-1-( -cyclopropanecarbonyl-2 - terbisil)-3-(chloropicrine-2 - terbisil)-3-(N,N-dimethylcarbamoyl) metiletilpiridin (the above compound N 1132)

The reaction is carried out in the manner described in Example 10 (a), except that instead of (E)-1-( - cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylmethylene-4 - hydroxypiperidine using (E)-1-( -cyclopropanecarbonyl-2 - terbisil)-4-hydroxy-3-(N,N-dimethylcarbamoyl)metiletilpiridin, resulting in a gain of the target compound as a light brown oil with a yield of 24.9 percent.

The NMR spectrum (CDCl3, ): 0,76-of 0.91 (2H, m), 0,95 (PI)-1.09 (2H, m), 1.70 to was 1.94 (2H, m), 2,15-of 2.50 (5H, m), 2,70-3,30 (8H, m), 3,55-of 3.80 (1H, m), 4,28-and 4.40 (1H, m), 4,68, 4,75 (total 1H, each s), 6,14 (1H, s), 7,05-7,80 (4H, m);

Mass spectrum (CI, m/z): 419 (M++1).

(b) Hydrochloride (E)-1-( -cyclopropanecarbonyl-2 - terbisil)-3-(N,N-dimethylcarbamoyl)methylidene-4-mercaptopyridine

The reaction is carried out in the manner described in Example 1 (b), except that instead of (E)-4-acetylthio-1-( cyclopropanecarbonyl-2-terbisil) -3-ethoxycarbonylpyrimidine using (E)-4-Acetylthio-1-( -cyclopropanecarbonyl-2-terbisil)-3- (N,N-dimethylcarbamoyl)metiletilpiridin, resulting in getting the target compound in the form of light brown crystals with access 79,1%.

Melting point: 106-111oC;

The NMR spectrum (CDCl3, ): 0,75-of 1.55 (4H, m), 1,60-2,50 (4H, m), 2,75-to 3.35 (7H, m), 3,40-4,80 (4H, m), 5,5 is EP 16

Hydrochloride (E)-1-( -cyclopropanecarbonyl-2 - terbisil)-3-(N-methylcarbamoyl)methylidene-4-mercaptopyridine (the above compound N 508)

(a) to (E)-4-Acetylthio-1-( -cyclopropanecarbonyl-2-terbisil)-3- (N-methylcarbamoyl)metiletilpiridin (above connection N1168)

The reaction is carried out in the manner described in Example 10 (a), except that instead of (E)-1-( -cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylmethylene-4 - hydroxypiperidine using (E)-1-( -cyclopropanecarbonyl-2-terbisil)- 4-hydroxy-3-(N-methylcarbamoyl)metiletilpiridin and get the target compound in the form of light yellow crystals with a yield of 13.5%.

The NMR spectrum (CDCl3, ): of 0.75 to 0.98 (2H, m), 0,98 is 1.13 (2H, 2m), 1,50-1,72 (1H, m), 1,72-1,90 (1H, m), 1.91 a-2,10 (1H, m), 2,10-of 2.45 (5H, m), 2,55 was 3.05 (5H, m), 3,05-to 3.35 (1H, m), 3,85-4,10 (1H, m), 4.26 deaths, 4,28 (total 1H, each s), 4,79, a 4.83 (total 1H, each s), 5,90 (1H, s), equal to 6.05 (1H, Shir. C), 7,05 is 7.50 (4H, m);

Mass spectrum (Cl, m/z): 405 (M++1).

(b) Hydrochloride (E)-1-( -cyclopropanecarbonyl-2-terbisil)-3- (N-methylcarbamoyl)methylidene-4-mercaptopyridine

The reaction is carried out in the manner described in Example 1 (b), except that instead of (E)-4-acetylthio-1-( - cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylpyrimidine using (E)-4-acetylene compound as light-brown crystals with a yield of 42.5%.

Melting point: 133-141oC;

The NMR spectrum (CDCl3, ): 0,80-of 1.15 (2H, m), 1,13-of 1.40 (2H, m), 1.60-to of 2.08 (5H, m), 2,50 was 3.05 (3H, m), 3,06-4,50 (5H, m), 5,41, 5,42 (total 1H, each s), 6,09, 6,18 (total 1H, each s), 7,15-7,98 (4H, m), 8,61, 8,81 (total 1H, each Shire. C) to 12.9 (1H, Shir. C);

Mass spectrum (CI, m/z): 363 (M++1).

Example 17

Hydrochloride of 1-( -cyclopropanecarbonyl-2-terbisil)-3-ethylidene-4 - mercaptopyridine (the above compound N 336)

(a) 4-Acetylthio-1-( -cyclopropanecarbonyl-2 - terbisil)-3-ethylidenebicyclo (the above compound N 890)

The reaction is carried out in the manner described in Example 1 (a), except that instead of 1-( -cyclopropanecarbonyl-2- (tormentil)-4-hydroxypiperidine using 1-( - cyclopropanecarbonyl-2-terbisil)-3-ethylidene-4-hydroxypiperidine, resulting in a gain of the target compound as a brown oil with a yield of 44.0%.

The NMR spectrum (CDCl3, ): 0,80-0,89 (2H, m), 0,93 was 1.06 (2H, m), 1,37-of 1.39 (3H, m), 2,08-of 2.23 (2H, m), 2,24-of 2.26 (1H, m), and 2.27 (1,5 H, s), 2,28 (1,5 H, s), 2,41-to 2.67 (2H, m), 2,89-3,13 (2H, m), 4,00-a 4.03 (1H, m), 4,69 (0.5 H, s), 4,70 (0.5 H, s), of 5.75 (1H, Shir. C), 7,07-to 7.18 (2H, m), 7,28-7,33 (1H, m), 7,43-7,47 (1H, m);

Mass spectrum (CI, m/z): 362 (M++1).

(b) Hydrochloride of 1-( -cyclopropanecarbonyl-2-terbisil)-3-ethylidene-4 - mercaptopyridine

The reaction is carried out is nil)piperidine using 3-acetylthio-1-(-cyclopropanecarbonyl-2 - terbisil)-3-ethylidenebicyclo, in the result, get the target compound as a pale brown solid (amorphous) substances with the release 85,0%.

Mass spectrum (CI, m/z): 320 (M++1);

IR spectrum (KBr,maxcm-1): 1713, 2424.

Example 18

4 Butylthio-1-( -cyclopropanecarbonyl-2-terbisil) piperidine (described above the compound N 591)

In 5 ml of dichloromethane was dissolved 0.50 g (1.5 mmol) of the hydrochloride of 1-( -cyclopropanecarbonyl-2-terbisil)-4 - mercaptopyridine, and then add 0.3 g (3 mmol) of triethylamine. To the resulting mixture under ice cooling are added dropwise a solution of 0.16 g (1.5 mmol) of butyrylcholine in 1 ml of dichloromethane and the resulting mixture is stirred for 1 hour at room temperature. To the reaction mixture are added water and extracted with dichloromethane. The extract is dried over anhydrous sodium sulfate. The solvent is concentrated by evaporation under reduced pressure and the residue is subjected to chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 30/1), resulting in a gain of 0.32 g (yield: 58%) of target compound as white crystals.

Melting point: 97-98oC;

The NMR spectrum (CDCl3, ): 0,76 is 0.86 (2H, m) of 0.91 (3H, t, J=7,3 Hz), 0,95-of 1.03 (2H, m), 1.60-to to 1.79 (4H, m), 1,88-to 1.98 (2H, (CI, m/z): 364 (M++1);

IR spectrum (KBr.maxcm-1): 1685.

Examples 19-24

The reaction is carried out by the method described in Example 18, except that instead of butyrylcholine use different halides or anhydrides of acids, resulting in a receive connection Examples 19-24.

Example 19

1-( -Cyclopropanecarbonyl-2-terbisil)-4 - Jaloliddin (the above compound N 594)

Used gelegenheid or acid anhydride: pivaloyloxy;

Yield: 72%;

Appearance: light brown crystals;

Melting point: 88-89oC;

The NMR spectrum (CDCl3, ): 0,72-of 0.90 (2H, m), 0,92-1,08 (2H, m) of 1.20 (9H, s), 1.60-to is 1.82 (2H, m), 1,83 is 2.00 (2H, m), 2,08 - of 2.38 (3H, m), 2,70-2,90 (2H, m), 3,28-of 3.42 (1H, m), to 4.62 (1H, s), 7,06 and 7.36 (4H, m);

Mass spectrum (CI, m/z): 378 (M++1);

IR spectrum (KBr,maxcm-1): 1677.

Example 20

1-( -Cyclopropanecarbonyl-2-terbisil)-4-exaniination (the above compound No. 595)

Used gelegenheid or acid anhydride: hexanoate;

Yield: 56%;

Appearance: white crystals;

Melting point: 64-65oC;

The NMR spectrum (CDCl3, ) : 0,79-0,84 (2H, m) to 0.88 (3H, t, J=7,3 Hz), 0,95-1,05 (2H, m), of 1.26 to 1.31 (4H, m), 1.60-to to 1.83 (4H, m), 1.85 to 2,02 (2H, m), 2,12-of 2.27 (2H, m),R> IR spectrum (KBr, maxcm-1): 1690.

Example 21

1-( -cyclopropanecarbonyl-2-terbisil)-4 - palmitoylcarnitine (the above compound N 597)

Used gelegenheid or acid anhydride: palmitoylated;

Yield: 73%;

Appearance: white crystals;

Melting point: 71-72oC;

The NMR spectrum (CDCl3, ): 0,77-0,84 (2H, m) to 0.88 (3H, t, J=6.8 Hz), 0,94 was 1.06 (2H, m), 1,11-1,34 (24H, m), 1,55-to 1.82 (4H, m), 1,87 is 2.00 (2H, m), 2,10-of 2.23 (2H, m), 2,27-of 2.38 (1H, m), 2,48 (2H, t, J=7,6 Hz), 2,70-2,89 (2H, m), 3,39-to 3.49 (1H, m), to 4.62 (1H, s), 7,07-7,37 (4H, m);

Mass spectrum (CI, m/z): 532 (M++1).

Example 22

1-( - Cyclopropanecarbonyl-2-terbisil)-4-stearoylethanolamine (the above compound N 598)

Used gelegenheid or acid anhydride: stearolic;

Yield: 60.1% of

Appearance: white crystals;

Melting point: 74-75oC;

The NMR spectrum (CDCl3, ): 0,77-0,85 (2H, m) to 0.88 (3H, t, J=7,1 Hz), 0,94 was 1.06 (2H, m), 1,14-1,34 (28H, m), 1,55-of 1.85 (4H, m), 1,88 is 2.00 (2H, m), 2,09-of 2.24 (2H, m), 2.26 and-of 2.38 (1H, m), 2,48 (2H, t, J=7,3 Hz), 2,70-2,90 (2H, m), 3,39-to 3.49 (1H, m), 4,63 (1H, s), 7,07 and 7.36 (4H, m);

Mass spectrum (CI, m/z): 560 (M++1).

Example 23

1-( -Cyclopropanecarbonyl-2-terbisil)-4 - levityheaven (the above compound N 600)

Used gelegenheid or anhydride sour the Mr spectrum (CDCl3, ) : 0,77-0,85 (2H, m) to 0.88 (3H, t, J=6.8 Hz), 0,94-of 1.07 (2H, m), 1.18 to 1,38 (20H, m), 1.56 to to 1.82 (4H, m), 1,88-2,07 (6H, m), 2,10-of 2.23 (2H, m), 2,27-of 2.38 (1H, m), 2,48 (2H, t, J=7.2 Hz), 2,70-2,89 (2H, m), 3,39-to 3.49 (1H, m), 4,63 (1H, s), 5,27-5,42 (2H, m), 7,07-7,37 (4H, m);

Mass spectrum (CI, m/z): 558 (M++1).

Example 24

4 Benzylthio-1-( -cyclopropanecarbonyl-2-terbisil)piperidine (described above the compound N 601)

Used gelegenheid or acid anhydride: benzoyl chloride;

Output: 39,9%;

Appearance: white crystals;

Melting point: 55-59oC;

The NMR spectrum (CDCl3, ): 0,78 to 0.92 (2H, m), 0,96 by 1.12 (2H, m), 1.70 to a 2.00 (2H, m), 2.00 in to 2.15 (2H, m), 2,15 of-2.32 (2H, m), 2,32 is 2.51 (1H, m), 2,74 are 2.98 (2H, m), 3,59-3,74 (1H, m), of 4.67 (1H, s), 7,12-7,93 (9H, m);

Mass spectrum (CI, m/z): 398 (M++1).

Examples 25-28

Compounds of Examples 25-28 receive the same manner as described in Example 18, except that instead of hydrochloride of 1-( -cyclopropanecarbonyl-2-terbisil)-4 - mercaptopyridine using the hydrochloride of 1-(2-fluoro- - methoxycarbonylbenzyl)-4-mercaptopyridine, and instead of butyrylcholine use different halides or acid anhydrides.

Example 25

1-(2-Fluoro- -methoxycarbonylbenzyl)-4 - palmitoylcarnitine (the above compound N 616)

Used gelegenheid or acid anhydride: palaestra (CDCl3, ): to 0.88 (3H, t, J=6.8 Hz), 1,14-1,34 (24H, m), 1,55-of 1.78 (4H, m), 1,87 is 2.00 (2H, m), 2,22 at 2.45 (2H, m), 2.49 USD (2H, t, J=7.5 Hz), 2,72-2,87 (2H, m), 3,39-3,50 (1H, m), 3,70 (3H, s), a 4.53 (1H, s), ? 7.04 baby mortality-7,49 (4H, m);

Mass spectrum (CI, m/z): 522 (M++1).

Example 26

1-(2-Fluoro- -methoxycarbonylbenzyl)-4-stearoylethanolamine (the above compound N 617)

Used gelegenheid or acid anhydride: stearolic.

Output: 56.4 per cent;

Appearance: white crystals;

Melting point: 50-52oC;

The NMR spectrum (CDCl3, ) : to 0.88 (3H, t, J=6.8 Hz), 1,15-1,35 (28H, m), 1,57-of 1.81 (4H, m), 1,86 of 1.99 (2H, m), 2,23 at 2.45 (2H, m), 2.49 USD (2H, t, J=7,6 Hz), 2,74-is 2.88 (2H, m), 3,40-3,50 (1H, m), 3,71 (3H, s), a 4.53 (1H, s), ? 7.04 baby mortality-of 7.48 (4H, m)

Mass spectrum (CI, m/z): 550 (M++1).

Example 27

1-(2-Fluoro- -methoxycarbonylbenzyl)-4-levityheaven (the above compound N 619)

Used gelegenheid or acid anhydride: reoiled.

Output: 70,4%;

Appearance: light yellow oil;

The NMR spectrum (CDCl3, ): to 0.88 (3H, t, J=6.8 Hz), 1,15-1,38 (20H, m), 1,58 and 1.80 (4H, m), 1,88-of 2.09 (6H, m), 2,22 at 2.45 (2H, m), 2.49 USD (2H, t, J=7,6 Hz), 2,74-to 2.85 (2H, m), 3,39-to 3.49 (1H, m), 3,70 (3H, s), a 4.53 (1H, s), 5,27-5,42 (2H, m),? 7.04 baby mortality-7,49 (4H, m);

Mass spectrum (CI, m/z): 548 (M++1).

Example 28

4 Benzylthio-1-(2-fluoro- - methoxycarbonylbenzyl)piperidine (described above the compound N 620)

And the lo;

The NMR spectrum (CDCl3, ): 1,75 is 1.91 (2H, m), 1,99 is 2.10 (2H, m), 2,34 (1H, t, J=9.6 Hz), a 2.45 (1H, t, J=9.6 Hz,), 2,81-only 2.91 (2H, m), 3,62-3,70 (1H, m), and 3.72 (3H, s), 4,56 (1H, s), 7,05-7,94 (9H, m);

Mass spectrum (CI, m/z): 388 (M++1).

Preparative example 1

1-( -Cyclopropanecarbonyl-2-terbisil)-4 - hydroxypiperidine

In 30 ml of dimethylformamide (DMF) was dissolved 3.13 g (31 mmol) of 4-hydroxypiperidine, and then add 7,94 g (31 mmol) cyclopropanecarbonyl-2-ftorangidridy and 4.7 g (34 mmol) of potassium carbonate. The resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture are added water and then extracted with toluene. The obtained organic layer is dried with anhydrous sodium sulfate. The solvent is concentrated by evaporation under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluting solvent: chloroform/methanol = 19/1), resulting in a gain of 8.00 g of the target compound as a brown oil (yield: 93%).

The NMR spectrum (CDCl3, ): 0,79-of 0.87 (2H, m), 0,98 of-1.04 (2H, m), 1,50-1,72 (2H, m), 1,82-to 1.98 (2H, m), 2,02-to 2.15 (1H, m), 2,18-of 2.30 (2H, m), 2,70-2,90 (2H, m), 3,60-3,74 (1H, m), to 4.62 (1H, s), 7,05 was 7.45 (4H, m);

Mass spectrum (CI, m/z): 278 (M++1).

Preparative example 2

1-(2-Chloro - methoxycarbonylbenzyl)-4-hydroximino-cyclopropanecarbonyl-2 - ftorangidridy use of 2-chloro - methoxycarbonylmethylene and get the target compound in the form of a colourless oil with a yield of 95%.

The NMR spectrum (CDCl3, ): 1,55-1,70 (2H, m), 1,80-2,00 (2H, m), 2,22 at 2.45 (2H, m), 2,65-2,82 (1H, m), 2,83 are 2.98 (1H, m), 3,70 (3H, s), 3.72 points-of 3.80 (1H, m), 4,70 (1H, s), 7,20-of 7.70 (4H, m);

Mass spectrum (CI, m/z): 284 (M++1).

Preparative example 3

1-( -Cyclopropanecarbonyl-2-terbisil)-3-hydroxypiperidine

The reaction is carried out by the method described in Preparative example 1, except that instead of 4-hydroxypiperidine use 3-hydroxypiperidine and obtain the target compound as a brown oil, mainly with quantitative yield.

The NMR spectrum (CDCl3, ): 0,75-0,95 (2H, m), 1,00-1,10 (2H, m), 1,45 by 1.68 (3H, m), 1,72-of 1.95 (1H, m), 2,02-of 2.20 (1H, m), 2,30-2,70 (4H, m), 3,80-are 3.90 (1H, m), 4.72 in (1H, s), 7,05 was 7.45 (4H, m);

Mass spectrum (CI, m/z): 278 (M++1).

Preparative example 4

1-( -Cyclopropanecarbonyl-2-terbisil)-3-hydroxypyrrolidine

The reaction is carried out by the method described in Preparative example 1, except that instead of 4-hydroxypiperidine use 3-hydroxypyrrolidine, resulting in a gain of the target compound as a yellow oil with a yield of 97%.

The NMR spectrum (CDCl3, ): 0,79-of 0.90 (2H, m), 1,00-of 1.03 (2H, m), 1,70-1,90 (1H, m), 2,02-of 2.20 (2H, m), 2,41-is 3.08 (5H, m), 4,28-and 4.40 (1H, m), 4,71, 4,72 (total 1H, each s), 7,07-7,46 (4H, m).

Mass spectrum (CI, m/z): 264 (M++1). the s carry out the method, described in Preparative example 1, except that instead of 4-hydroxypiperidine use 3-hydroxyazetidine, resulting in getting the target compound in the form of white crystals with a yield of 66%.

The NMR spectrum (CDCl3, ): 0,69-0,88 (2H, m), 0,90-of 1.07 (2H, m), 1,87 is 1.96 (1H, m), 2,94-3,03 (2H, m), 3,17 (1H, Shir. C) 3,44 (1H, DD, J=6,1, 6,7 Hz), 3,83 (1H, DD, J= 6,7, and 7.3 Hz), 4,45-a 4.53 (1H, m), to 4.62 (1H, s), 7,07-7,38 (4H, m);

Mass spectrum (CI ,m/z: 250 (M++1).

Preparative example 6

1-( -Cyclopropanecarbonyl-2-terbisil)-4-hydroxyethylpiperazine

The reaction is carried out by the method described in Preparative example 1, except that instead of 4-hydroxypiperidine use 4-hydroxyethylpiperazine, resulting in a gain of the target compound as a brown oil, mainly with quantitative yield.

The NMR spectrum (CDCl3, ): 0,75-0,90 (2H, m), 0,92-1,08 (2H, m), 1,28 of 1.50 (3H, m) of 1.65 and 1.80 (2H, m), 1.85 to 1,95 (1H, m), 2.05 is-to 2.18 (1H, m), 2,19-of 2.30 (1H, m), 2,80-2,90 (1H, m), 3.00 and-3,10 (1H, m), 3,50 (2H, d, J=6 Hz), to 4.62 (1H, C), 7,05 was 7.45 (4H, m);

Mass spectrum (CI, m/z): 292 (M++1).

Preparative example 7

1- ( -Cyclopropanecarbonyl-2-terbisil)-3-hydroxyethylpiperazine

The reaction is carried out by the method described in Preparative example 1, except that instead of 4-gaveta-yellow oil, mainly with quantitative yield.

The NMR spectrum (CDCl3, ): 0,79 is 0.86 (2H, m), 0,95-1,05 (2H, m), 1,16-of 1.23 (1H, m), 1,52-of 1.85 (4H, m), 2,09 is 2.33 (4H, m), 2,56-by 2.73 (2H, m), 3,56-3,70 (2H, m), 4,60 (0.5 H, s), 4,66 (0.5 H, s), 7,05-to 7.18 (2H, m), 7,25-7,41 (2H, m);< / BR>
Mass spectrum (CI, m/z): 292 (M++1).

Preparative example 8

8-( -cyclopropanecarbonyl-2-terbisil)-3-hydroxy-8-azabicyclo [3.2.1] octane

The reaction is carried out by the method described in Preparative example 1, except that instead of 4-hydroxy-piperidine use the 3-hydroxy-8-azabicyclo [3.2.1]octane (mixture of Exo-and endo-isomers). After separation by chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 100/3) receive two isomers of the target compounds, namely, isomer A-1 and isomer B-1 outputs of 45.2% and 24.6% respectively. When high-performance liquid chromatography (column: TSK-GEL ODS-80TM, mobile phase: acetonitrile/12 mm KH2PO4= 45/55; temperature: 35oC; flow rate: 1.0 ml/min) retention time of isomer A-1 and isomer B-1 is 4.0 minutes and 4.3 minutes, respectively.

Isomer A-1:

Appearance: light yellow solid;

The NMR spectrum (CDCl3, ): 0,68 was 1.06 (4H, m) of 1.35 (1H, s) of 1.62 (1H, d, J= a 13.9 Hz), 1,72 (1H, d, J=a 13.9 Hz), 1,82 of-2.32 (6H, m), 2,39-of 2.54 (1H, m), 3,05 (1H, s), 3,22 the yellow oil;

The NMR spectrum (CDCl3, ): 0,68-1,08 (4H, m), 1,25 (1H, s), 1,46 to 2.35 (8H, m), 2,38-of 2.54 (1H, m), 3,18 (1H, s), 3,26 (1H, s), 3,89-of 4.05 (1H, m), 4.72 in (1H, s), of 6.96-of 7.95 (4H, m);

Mass spectrum (CI, m/z): 304 (M++1).

Preparative example 9

(E)-1-( -cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylmethylene - 4-hydroxypiperidine

(a) 3-Ethoxycarbonylmethylene-1-triphenylmethyl-4-piperidone

To a solution of 10.6 g (of 65.1 mmol) of the hydrochloride monohydrate of 4-piperidone and 20.0 g (198 mmol) of triethylamine in 150 ml of dimethylformamide, with stirring at 60oC, portions add to 18.1 g (of 65.1 mmol) chlorotriphenylmethane, and then stirred for further 5 hours at the same temperature. After cooling, the precipitated thus the triethylamine hydrochloride is filtered off and the filtrate is concentrated by evaporation under reduced pressure. To the residue add 150 ml of water and the resulting mixture is extracted with 300 ml of ethyl acetate. The organic layer was washed with saturated saline solution and then dried with anhydrous magnesium sulfate. The solvent is concentrated by evaporation under reduced pressure, resulting in a gain 23,0 g (yield: 98,3%) 1-triphenylmethyl-4-piperidone.

The solution 23,0 g of the obtained product and 4.63 g (65,0 mmol) pyrrolidine in 300 ml of benzene is subjected to azeotropic digid To the residue add solution 6,63 g (65,0 mmol) of acylglycerol (type polymer) in 50 ml of benzene, and then again subjected to azeotropic dehydration for 90 minutes when heated and refluxed. After cooling immediately add 200 ml of water for washing residue. The organic layer was dried with magnesium sulfate. The solvent is concentrated by evaporation under reduced pressure and the residue purified via chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 19/1), resulting in a gain of 16.6 g (yield: 60,2%) target compound as a pale yellow oil.

The NMR spectrum (CDCl3, ): to 1.15 (3H, t, J=6.3 Hz), 2.57 m) of 2.68 (2H, m), 2,72-of 2.81 (2H, m), 3,61-with 3.79 (2H, m), 4,08 (2H, q, J=6.3 Hz), 6,55 (1H, s), 7,15-of 7.60 (15H, m);

Mass spectrum (CI, m/z): 426 (M++1).

(b) (E)-1-( -Cyclopropanecarbonyl-2-terbisil)-3 - ethoxycarbonylmethylene-4-hydroxypiperidine

To a solution of 16.6 g (39,1 mmol) 3-ethoxycarbonylmethylene-1-triphenylmethyl-4-piperidone in 150 ml of methanol under ice cooling are added in several portions 1.48 g (39,1 mmol) of sodium borohydride, and then stirred at room temperature for 1 hour. After concentrating the reaction mixture by evaporation under reduced pressure, add 50 ml of water and 150 ml ethyl acetate for extraction of the concentrate. The organic layer is washed with Nani and get to 16.8 g (yield: 100%) 3-ethoxycarbonylmethylene-4-hydroxypiperidine in the form of a brown oil.

To the obtained product, add 200 ml of tetrahydrofuran and 6,70 g (of 35.2 mmol) monohydrate para-toluensulfonate acid, and then stirred at 50oC for 1 hour. After completion of the reaction the solvent is distilled off under reduced pressure. The obtained solid is washed with toluene and obtain 10.8 g (yield: 86.6 per cent) para-toluensulfonate 3-ethoxycarbonylmethylene-4-hydroxypiperidine.

The obtained product is dissolved in 80 ml of dimethylformamide, and then add to 7.84 g (30,5 mmol) cyclopropanecarbonyl-2 - ftorangidridy and 9,27 g (67,0 mmol) of potassium carbonate. The resulting mixture was stirred for 1 hour at room temperature and for 3 hours at 50oC. After completion of the reaction, to the reaction mixture is added 150 ml of water and the resulting mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried with anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 9/1 ~ 4/1), resulting in getting the target connection (7,63 g; output: 69,3%) as a pale yellow oil.

The NMR spectrum (CDCl3, ): 0,74-0,88 (2H, m), 0,97-1,10 (2H, m), 4,46, 4,58 (total 1H, each d, J=13,6 Hz, J=14.1 Hz), 4,77, 4,78 (total 1H, each s) to 6.00 (1H, s), 7,05-the 7.43 (4H, m);

Mass spectrum (CI, m/z): 362 (M++1), 292.

Preparative example 10

(E)-1-(2-Chloro - methoxycarbonylbenzyl)-3-ethoxycarbonylmethylene - 4-hydroxypiperidine

The reaction is carried out by the method described in Preparative example 9 (b), except that instead of cyclopropanecarbonyl-2-ftorangidridy use of 2-chloro - methoxycarbonylbenzyl, resulting in a gain of the target compound as a yellow oil output to 62.1%.

The NMR spectrum (CDCl3, ): 1,10-of 1.35 (3H, m), 1.70 to 1,89 (1H, m), 1,92-2,10 (1H, m), 2,41-to 2.74 (2H, m), 2,82-2,96 (1H, m), 3,14 (0.5 H, d, J=a 13.9 Hz), 3,21 (0.5 H, d, J=a 13.9 Hz), 3,70, 3,71 (total 3H, each s), 4,00-4,22 (2H, m) to 4.52 (0.5 H, d, J=a 13.9 Hz), br4.61 (0.5 H, d, J=a 13.9 Hz), 4,82, 4,87 (total 1H, each s), 5,99, 6,01 (total 1H, each s), and 7.1 to 7.7 (4H, m);

Mass spectrum (CI, m/z): 368 (M++1).

Preparative example 11

1-( -Cyclopropanecarbonyl-2-terbisil)-3-(N, N - dimethylcarbamoyl)methylidene-4-hydroxypiperidine

In a mixture of 75 ml of concentrated hydrochloric acid and 180 ml of acetic acid are dissolved 9,72 g (26.9 mmol) 1-( -cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylmethylene-4 - hydroxypiperidine and the resulting solution was left for 7 days at room temperature the e silica gel (eluting solvent: chloroform/methanol = 100/3 ~ 2/1), resulting in a gain of 5.11 g (yield: 57%) 1-( -cyclopropanecarbonyl-2-terbisil)-3 - carboxymethylamino-4-hydroxypiperidine.

To the obtained product, add 50 ml of methylene chloride and 3.25 g (32,2 mol) of triethylamine. The resulting mixture is cooled to -5oC ~ 0oC, and then added dropwise 1.66 g of 15.3 mmol) atilglukuronida. The temperature of the reaction mixture is again brought to room temperature and at this temperature the mixture is stirred for 30 minutes. After cooling the reaction mixture to 10oC added to 1.25 g of 15.3 mmol) of dimethylamine hydrochloride, and then 1.54 g of 15.3 mmol) of triethylamine. The resulting mixture is stirred for 5 hours at room temperature. Then for the Department methylenchloride layer add a mixture of methylene chloride and water. Separated thus the layer is dried with anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The residue is purified by chromatography on a column of silica gel (eluting solvent: chloroform/methanol = 10,3), resulting in a gain of 3.65 g (yield: 64.4 per cent) of target compound as a pale yellow oil.

The NMR spectrum (CDCl3, ): 0,75-0,90 (2H, m), 0,93 was 1.06 (2H, m), 1,62 of-1.83 (1H, m), 1.85 to-2,10 (1H, m), 2,10 at 2.59 (2H, m), 2,75 (0.5 H, d, J=a 13.9 Hz), who nd 1H, each s), 6,13 (1H, s), 7,00-of 7.48 (4H, m);

Mass spectrum (CI, m/z): 361 (M++1).

Preparative example 12

1-( -cyclopropanecarbonyl-2-terbisil)-3-(N-methylcarbamoyl) methylidene-4-hydroxypiperidine

The reaction is carried out by the method described in Preparative example 11, except that instead of dimethylamine hydrochloride use of methylamine hydrochloride and obtain the target compound as a white solid with a yield of 55.1 per cent.

The NMR spectrum (CDCl3, ): 0,72-0,93 (2H, m), 0,94-1,12 (2H, m), 1,65-of 1.85 (1H, m), 1.85 to a 2.12 (2H, m), 2,15-2,34 (0.5 H, m), 2,4-of 2.68 (1H, m), 2,70-3,00 (4,5 H, m), 3.95 to 4,20 (2H, m), 4,79 (0.5 H, s) 4,85 (0.5 H, s), 5,96 (0.5 H, s), 5,97 (0.5 H, s), 6,60 (0.5 H, Shir. C) 6,83 (0.5 H, Shir. C), 7,05 was 7.45 (4H, m);

Mass spectrum (CI, m/z): 347 (M++1).

Preparative example 13

1-( -Cyclopropanecarbonyl-2-terbisil)-3-ethylidene-4-hydroxypiperidine

(a) 1-(tert-Butoxycarbonyl)-3-ethylidene-4-piperidone

A solution of 10.0 g (52,9 mmol) 1-benzyl-4-piperidone and 4.61 in (52,9 mmol) of the research in 100 ml of toluene is subjected to azeotropic dehydration for 5 hours when heated and refluxed using a water separator.

After completion of the reaction the solvent is distilled off under reduced pressure, resulting in a gain of 13.7 g of 1-benzyl-4-is inflorida cooled to -40oC in argon atmosphere, and then added dropwise to 5.3 ml (43 mmol) of the complex of boron TRIFLUORIDE-ether and 7,44 g (28.8 mmol) of 1-benzyl-4-morpholino-1,2,5,6-tetrahydropyridine obtained above. After completion of adding dropwise, the temperature is gradually increased and the reaction mixture is left overnight at room temperature. After adding water to terminate the reaction, the reaction mixture is extracted with methylene chloride. The organic layer was washed with saturated salt solution, dried with anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The residue is subjected to chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 4/1), resulting in a gain 4.68 g (yield: 69,7%) 1-benzyl-3-(1-hydroxyethyl)-4-piperidone in the form of a yellowish-brown oil.

The NMR spectrum (CDCl3, ): 1,11-to 1.14 (3H, d, J= 6 Hz), 2,35-2,95 (7H, m), 3,54-3,70 (2H, m), as 4.02-4,22 (1H, m), 7,28 and 7.36 (5H, m).

In 100 ml of ethanol is dissolved 4.68 g (20 mmol) obtained 1-benzyl-3-(1-hydroxyethyl)-4-piperidone. To the resulting solution was added 0.5 g of 5% palladium-on-charcoal, and then stirred at 60oC for 8 hours in an atmosphere of hydrogen gas. After completion of the reaction, palladium-on-coal removed by filtration through Celestino oil in quantitative yield.

The resulting product was dissolved in 20 ml of methylene chloride and the resulting solution was added 20 ml of 15% aqueous potassium carbonate solution. Then added with stirring 4.6 g (21 mmol) of di-tert-BUTYLCARBAMATE and the resulting mixture is stirred for further 3 hours at room temperature. After completion of the reaction, the reaction mixture is extracted with methylene chloride. The organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. The residue obtained after concentration by evaporation under reduced pressure, subjected to chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 4/1), resulting in a gain of 1.86 g (yield: 38.3 per cent) of 1-(tert-butoxycarbonyl)-3-(1-hydroxyethyl)-4-piperidone in the form of a colorless oil.

The NMR spectrum (CDCl3, ): 1,21 (1,5 H, d, J=7 Hz), 1,25 (1,5 H, d, J=6 Hz), of 1.50 (9H, s), 2.40 a-2,49 (3H, m), 2,98-is 3.08 (0.5 H, m), 3,26-to 3.33 (1H, m), 3,40-3,90 (2,5 H, m), 3.95 to 3,98 (0.5 H, m), 4,08-4,28 (1,5 H, m);

Mass spectrum (CI, m/z): 188, 144.

To a solution of 1.86 g (7.6 mmol) of the obtained 1-(tert-butoxycarbonyl)-3-(1-hydroxyethyl)-4 - piperidone in 20 ml of methylene chloride add 0,77 g (7.6 mmol) of triethylamine. To the resulting mixture under ice cooling 0.88 g (7.6 mmol) of methanesulfonamide, and then peremeshivayte ethyl acetate and precipitated thus the solid is filtered off, and then concentrated by evaporation under reduced pressure. Then the concentrate was dissolved in 20 ml of chloroform. To the resulting solution was added at room temperature of 1.16 g (7.6 mmol) of 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), and then stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mixture was concentrated by evaporation under reduced pressure and the residue is subjected to chromatography on a column of silica gel (eluting solvent: toluene/ethyl acetate = 19/1), resulting in a gain of 1.32 g (yield: 77.2 percent) of target compound as a colourless oil.

The NMR spectrum (CDCl3, ): for 1.49 (9H, s), of 1.80 (3H, d, J=7 Hz), of 2.54 (2H, t, J=6 Hz), 3,71 (2H, t, J=6 Hz), 4,35 (2H, Shir. C) 6,86 (1H, Shir. kV);

Mass spectrum (CI, m/z): 170.

1-( -Cyclopropanecarbonyl-2-terbisil)-3-ethylidene-4 - hydroxypiperidine

To a solution of 1.32 g (5.9 mmol) of 1-(tert-butoxycarbonyl)-3 - ethylidene-4-piperidone in 10 ml of methanol is added under ice cooling 2,19 g (5.9 mmol) of 7-hydrate of cerium chloride, and then added to 0.22 g (5.9 mmol) of sodium borohydride. The resulting mixture was stirred for 1 hour at room temperature. After removal of the solvent by distillation under reduced pressure, to the residue water is added, and then Nia under reduced pressure. The residue is subjected to chromatography on a column of silica gel (eluting solvent: chloroform), resulting in a gain of 1.33 g of 1-(tert-butoxycarbonyl)-3-ethylidene-4 - hydroxypiperidine in the form of a colorless oil in quantitative yield.

The NMR spectrum (CDCl3, ): of 1.46 (9H, s), 1,60 was 1.69 (1H, m), 1,71 (3H, d, J= 7 Hz), 1,80-1,90 (1H, m), 3,50-the 3.65 (2H, m), Android 4.04 (1H, Shir. C) to 4.23 (1H, Shir. t) 5,54 (1H, q, J=7 Hz);

Mass spectrum (Cl, m/z): 172, 154.

In 20 ml of methylene chloride is dissolved 1.51 g (6.7 mmol) of 1-(tert-butoxycarbonyl)-3-ethylidene-4-hydroxypiperidine. To the obtained solution under cooling with ice, add 5 ml triperoxonane acid, and then stirred at room temperature for 2 hours. To the reaction mixture while cooling with ice add 11 ml of triethylamine and 1.70 g (6.7 mmol) cyclopropanecarbonyl-2-ftorangidridy, and then stirred at room temperature for 2 hours. The solvent is distilled off under reduced pressure. To the residue is added ethyl acetate and precipitated thus the solid is filtered off. Then the filtrate is concentrated by evaporation under reduced pressure. The residue is subjected to chromatography on a column of silica gel (eluting solvent: chloroform/methanol = 100/1), resulting in a floor, ,96-1,06 (2H, m) of 1.23 (3H, d, J=6 Hz), 2,20-of 2.27 (3H, m), 2.40 a-by 2.73 (2H, m), 2,98-3,17 (2H, m), 4,17-4,19 (1H, m), 4,73 (0.5 H, s), 4,74 (0.5 H, s), 5,73 (1H, Shir. C) 7,08-to 7.18 (2H, m), 7,28-7,33 (1H, m), 7,41-of 7.48 (1H, m);

Mass spectrum (Cl, m/z): 304 (M++1).

Preparative example 14

1-(2-Fluoro- -methoxycarbonylbenzyl)-4-hydroxypiperidine

The method described in Preparative example 1, except that instead of cyclopropanecarbonyl-2-ftorangidridy use 2-fluoro- -methoxycarbonylbenzyl, get the target compound in the form of a colourless oil with a yield of 91.7%.

The NMR spectrum (CDCl3, ): 1,54-of 1.74 (2H, m), 1,83-of 1.97 (2H, m), 2,16 to 2.35 (2H, m), 2,73-is 2.88 (2H, m), 3,55-of 3.78 (1H, m), 3,70 (3H, s), a 4.53 (1H, s), 7,02-7,53 (4H, m);

Mass spectrum (Cl, m/z): 268 (M++1).

Test 1

The duration of bleeding in mice

In this experiment, we used a group of 10 mice male ICR (Charles River Japan Inc. ). The test compound suspended in 5% solution of Arabian gum, oral animals were injected for 3 days (48, 24 and 4 hours before the start of the experiment). Each mouse was placed in the vivarium and the tail did cross section at a distance of 5 mm from its tip, and the tail (2 cm) was immersed in a salt solution, heated at 37oC. the Period of bleeding was defined as the time interval is 5 minutes was recorded as 5 minutes (300 seconds). The results were expressed as the ratio of the period of bleeding for the group treated with the test compound, to the period of bleeding for a group, not treated (control) test connection, in which mice were treated with 5% solution of Arabian gum. The results are presented in Table 2 (see end of description).

Test 2

Anagrelidesee activity in rats

In this experiment, we used a group of 4 female mice of SD (Charles River Japan Inc. ). The test compound suspended in 5% solution of Arabian gum, oral was administered to rats for 4 days before the start of the experiment. Control rats were injected with 5% solution of Arabian gum. Platelet aggregation was measured by the method of P. Lumley & P. P. A. Humphrey (J. Pharmacol. Methods, 6, 153-166 (1981)), which was slightly modified. Blood (5,4 ml) was taken from the abdominal aorta shot in rats using 3.8% of% of (wt. /about.) solution of sodium citrate (0.6 ml) as anticoagulant. An aliquot treated with citrate blood (1.2 ml) was added into a cuvette and stirred (1000 rpm) at 37oC. After two minutes the blood (0.3 ml) were taken from the cell and using auto Hematology analyzer (S-4000, Toa lyo Denshi) was measured by the number of platelets, which is considered as the number of platelets before and is on to induce platelet aggregation. Two minutes after addition of ADP or after 4 minutes after the addition of collagen from the cell took the blood (0.3 ml) and measured the number of platelets, which is considered as the number of platelets after aggregation. Platelet aggregation (%) was determined by the following equation:

100 x (number of platelets before aggregation - the number of platelets after aggregation)/number of platelets before aggregation.

Anagrelidesee action of the tested compounds was determined by comparison of platelet aggregation in rats treated with the test compound, with platelet aggregation in rats (which did not enter the test connection). The results are presented in Table 3 (see below).

Test 3

Anagrelidesee effect on human platelets

Platelet aggregation was measured using an automatic device for measuring platelets (RAM-8C, Mebanix) according to method G. V. R. Born (Nature, 194, 927-929 (1962)), which was slightly modified. Blood was taken from the anterior cubital vein of healthy volunteers for 2 weeks did not take any medicines with the use of 3.8% sodium citrate as anticoagulant (1/9 volume of blood). Platelet-rich plasma (PRP) was obtained by centrr) was obtained by further centrifugation of the remaining blood at 2000 x g for 10 minutes at room temperature. The number of platelets in PRP was measured using an automatic hematological analyzer (K-1000, Toa Iyo Denshi) and brought up to number 3 x 108ml using PPP. PRP obtained as described above was used for the experiment on platelet aggregation. PRP (0,24 ml) was added to the cuvette and the cuvette was placed in aggregometer for counting platelets. After pre-incubation for 1.5 minutes at 37oC in the cuvette to initiate platelet aggregation, was added 0.01 ml of 0.25 mm ADP. Monitoring of platelet aggregation was carried out for 10 minutes.

Anagrelidesee action of the test compounds were expressed as inhibition (%) aggregation assessed by comparing the aggregation of platelets, obtained by processing the test compound with the aggregation of platelets obtained for the control (without addition of the test compounds). The results are presented in Table 4 (see the end of the description).

Composition 1

Hard capsules

The compound (50 mg) of Example 12 in powder form, 128,7 mg lactose 70 mg of cellulose and 1.3 mg of magnesium stearate are mixed, and then sieved through a sieve of 60 mesh. The obtained powder fill 250 mg gelatin capsules No. 3, resulting in receive medication in the form of kaktuz, 25 mg of cellulose and 1 mg of magnesium stearate are mixed and then pressed into tablets in a tablet press machine, resulting in receive tablets of 200 mg each. If necessary, the tablets may be coated with sugar.

Industrial application

The compound of formula (I) of the present invention has excellent inhibitory effect on platelet aggregation or inhibiting effect on the development of arteriosclerosis (especially effect, inhibiting platelet aggregation and has a low toxicity, and therefore it can be used as a therapeutic agent or prophylactic agent (particularly a therapeutic agent against embolism, thrombosis or arteriosclerosis (especially against embolism or thrombosis).

In that case, if the compound (I) of the present invention or its pharmaceutically acceptable salt is used as a therapeutic agent or a prophylactic agent against the above diseases, it (she) can be entered (a) orally in the form of tablets, capsules, granules, powders or syrups, or not oral, in the form of injections or suppositories, both separately and in mixture with an appropriate pharmaceutical additive, takaracho in a known manner with the use of additives. Examples of such additives may include fillers (for example, organic fillers, such as derivatives of sugars, such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, a-starch or dextrin; cellulose derivatives such as crystalline cellulose; Arabian gum; dextran; or pullulan; or inorganic fillers, such as silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or alumosilicate magnesium; phosphate salts such as calcium phosphate; carbonates such as calcium carbonate; and sulfate salts, for example, the calcium sulfate); oil (for example, stearic acid, metallic stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL-leucine; laurilsulfate, such as sodium lauryl sulfate or lauryl sulfate, magnesium; silicic acids such as silicic acid anhydride or silicic acid hydrate; or vysheukazanoj, polyvinylpyrrolidone, macrogol or the above-mentioned fillers); disintegrating agents (for example, cellulose derivatives such as hydroxypropylcellulose with a low degree of substitution, carboxymethyl cellulose, calcium carboxymethyl cellulose or sodium carboxymethyl cellulose with internal cross connections; or chemically modified starches or cellulose, such as sodium salt carboxymethylated starch, carboxymethoxy starch or structured polyvinylpyrrolidone); emulsifying agents (for example, colloidal clay, such as bentonite or beeswax; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationogenic surfactant, such as benzalkonium chloride; or nonionic surfactants such as Elgiloy the polyoxyethylene ether, ester of polyoxyethylenesorbitan and fatty acids or esters of sucrose and fatty acids), stabilisers (for example, peroxybenzoate, such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenethyl alcohol; chlorite is Runova acid); taste or sarahpalinusa additives (for example, commonly used sweetening agents, podnikatel or flavors); and thinners.

The dose of a compound of the present invention may vary depending on the symptoms and age of the patient. When administered orally the number of single dose for adults is at least 1 mg, preferably 10 mg) and as a maximum, 1000 mg (preferably 500 mg), and intravenous amount of a single dose is at least 0.5 mg (preferably 5 mg) and as a maximum, 500 mg, preferably 250 mg). This dose can be entered from one to six times a day depending on symptoms.

1. Cyclic amine derivatives having the following formula I, or its pharmaceutically acceptable salt:

< / BR>
where R1represents a phenyl group substituted by a halogen atom;

R2represents C1-C8aliphatic acyl group or (C1-C4-alkoxy) carbonyl group;

R3represents a 3 - to 7-membered saturated cyclic amino group which may form a condensed ring, where the specified cyclic amino group substituted by the Deputy, select the protective groups, defined below; and1-C4alkyl group, substituted mercaptopropyl, which can be unprotected or protected by a group selected from protective groups defined below; and an optional protective group for the specified mercaptopropyl selected from the group including C1-C20alcoholnye group, C3-C20alkenone group and benzoline group; the cyclic amino group, furthermore preferably a substituted group of the formula = CR4R5where R4represents a hydrogen atom, a R5represents a hydrogen atom, a C1-C4alkyl group, carboxypropyl, (C1-C4-alkoxy) carbonyl group, karbamoilnuyu group or mono - or di-(C1-C4-alkyl) karbamoilnuyu group.

2. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R1represents a substituted phenyl group (Deputy of the specified group is fluorine, chlorine or bromine).

3. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R1represents a substituted phenyl group (Deputy of the specified group is fluorine or chlorine).

4. Cyclic amino which Noah group, presents R1is position 2 or 4.

5. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R2is: C2-C4alkanoyloxy, (C3-C6-cycloalkyl)carbonyl group, or (C1-C4)alkoxy) carbonyl group.

6. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R2represents acetyl, propionyl, isobutyryl, cyclopropanecarbonyl, cyclobutanecarbonyl, or methoxycarbonyl, or ethoxycarbonyl group.

7. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R2is propionyloxy, cyclopropanecarbonyl, methoxycarbonyl or ethoxycarbonyl group.

8. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R3is: 3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4-alkyl)-1-azetidinol group; 3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4-alkyl)-1-pyrrolidinyloxy group; 3 - or 4-(protected or unprotected is diseny or unprotected mercapto, or protected or unprotected mercapto-C1-C4-alkyl)-3-(= CR4R5)-1-piperidinyloxy group, where R4represents a hydrogen atom and R5represents a hydrogen atom, a C1-C4alkyl group, carboxypropyl, (C1-C4-alkoxy) carbonyl group, karbamoilnuyu group or mono - or di-(C1-C4-alkyl)karbamoilnuyu group, or 8-Aza-3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4-alkyl)bicyclo[3.2.1] octane-8-strong group, and an optional protective group for mercaptopropyl selected from the group including C1-C20alcoholnye group, C3-C20alkenone group and benzoline group.

9. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R3is: 3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-azetidinol group, 3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-pyrrolidinyl group, 3 -, or 4- (protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(=CR4R5)-1-piperid the ing, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl or diethylcarbamoyl group, or 8-Aza-3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)bicyclo[3.2.1] octane-8-strong group, and an optional protective group for the specified mercaptopropyl selected from the group including C1-C20alcoholnye group, C8-C20alkenone group and benzoline group.

10. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R3is: 3-(protected or unprotected mercapto)-1-azetidinol group, 3-(protected or unprotected mercapto)-1-pyrrolidinyl group, 3 - or 4-(protected or unprotected mercapto)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(=CR4R5)-1-piperidinyloxy group, where R4represents a hydrogen atom, a R5represents a hydrogen atom or a methyl, carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl group, or 8-Aza-3-(protected or unprotected mercapto)bicyclo[3.2.1]octane-8-strong group, and neoba the ilen, Palmitoyl, aeolou and benzoyloxy group.

11. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R3is: 3-(protected or unprotected mercapto)-1-azetidinol group, 4-(protected or unprotected mercapto)-1-piperidinyl group, 4-(protected or unprotected mercapto)-3-(=CR4R5)-1-piperidinyloxy group, where R4represents a hydrogen atom, and R5represents carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl group, or 8-Aza-3-(protected or unprotected mercapto)bicyclo[3.2.1] octane-8-ilen group, an optional protective group for the specified mercaptopropyl selected from the group including C2-C5alkanoyloxy or benzoyloxy group.

12. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R1represents a phenyl group substituted by halogen atom,2represents C2-C4alkanoyloxy, (C3-C6-cycloalkyl)carbonyl group, or (C1-C4-alkoxy) carbonyl group.

13. Cyclic amine derivatives or pharmaceutically priemlemaya fluorine, chlorine and bromine; R2represents C2-C4alkanoyloxy, (C3-C6-cycloalkyl)carbonyl group, or (C1-C4alkoxy) carbonyl group.

14. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R1represents a phenyl group substituted in position 2 or 4 Deputy, selected from the group comprising fluorine, chlorine and bromine; R2represents C2-C4alkanoyloxy, (C3-C6-cycloalkyl) carbonyl group, or (C1-C4alkoxy) carbonyl group, and R3represents a 3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4-alkyl) -1-azetidinol group; 3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4-alkyl)-1-pyrrolidinyloxy group; 3 - or 4-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4-alkyl)-1-piperidinyl group; a 4- (protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4-alkyl)-3-(= CR4R5)-1-piperidinyloxy group, where R4represents a hydrogen atom and R5represents the atom karbamoilnuyu group or mono - or di-(C1-C4-alkyl) karbamoilnuyu group, or 8-Aza-3-(protected or unprotected mercapto, or protected or unprotected mercapto-C1-C4- alkyl) bicyclo[3.2.1] octane-8-strong group, and an optional protective group for the specified mercaptopropyl selected from the group including C1-C20alcoholnye group, C3-C20alkenone group and benzoline group.

15. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R1represents a phenyl group substituted in position 2 or 4 fluorine atom or chlorine, R2represents acetyl, propionyl, isobutyryl, cyclopropanecarbonyl, cyclobutanecarbonyl group, methoxycarbonyl or ethoxycarbonyl group, R3represents a 3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-azetidinol group; 3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-pyrrolidinyloxy group; 3 - or 4- (protected or unprotected mercapto, or protected or unprotected mercaptomethyl)-1-piperidinyl group; a 4-(protected or unprotected mercapto)-3-(=CR4R5)-1-piperidinyloxy g is carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl, ethylcarbitol, dimethylcarbamoyl or diethylcarbamoyl group, or 8-Aza-3-(protected or unprotected mercapto, or protected or unprotected mercaptomethyl)bicyclo[3.2.1]octane-8-strong group, and an optional protective group for the specified mercaptopropyl selected from the group including1-C20alcoholnye group, C8-C20alkenone group and benzoline group.

16. Cyclic amine derivatives or pharmaceutically acceptable salt p. 1, where R1represents a phenyl group substituted in position 2 or 4 fluorine atom or chlorine; R2is propionyloxy, cyclopropanecarbonyl, methoxycarbonyl or ethoxycarbonyl group, and R3represents a 3-(protected or unprotected mercapto)-1-azetidinol group; 3-(protected or unprotected mercapto)-1-pyrrolidinyloxy group; 3 - or 4-(protected or unprotected mercapto)-1-piperidinyl group; a 4-(protected or unprotected mercapto)-3-(=CR4R5)-1-piperidinyloxy group, where R4represents a hydrogen atom, and R5represents a hydrogen atom or a methyl, carboxy, IU the or 8-Aza-3-(protected or unprotected mercapto)bicyclo[3.2.1] octane-8-ilen group, and optional protective group for the specified mercaptopropyl selected from the group including2-C6alkanoyloxy, Palmitoyl, aeolou and benzoyloxy group.

17. Cyclic amine derivatives or pharmaceutically acceptable salts under item 1, where R1represents a phenyl group substituted in position 2 or 4 fluorine atom or chlorine; R2is propionyloxy, cyclopropanecarbonyl, methoxycarbonyl or ethoxycarbonyl group, and R3represents a 3-(protected or unprotected mercapto)-1-azetidinol group; a 4-(protected or unprotected mercapto)-1-piperidinyl group; a 4-(protected or unprotected mercapto)-3-(=CR4R5)-1-piperidinyloxy group, where R4represents a hydrogen atom, and R5represents carboxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl, methylcarbamoyl or dimethylcarbamoyl group, or 8-Aza-3-(protected or unprotected mercapto)bicyclo[3.2.1] octane-8-ilen group, an optional protective group for the specified mercaptopropyl selected from the group including C2-C5alkanoyloxy and benzoyloxy group.

18. Cyclic amine derivatives under item 1, selected from the GRU is capturedin, 1-(2-chloro-methoxycarbonylbenzyl)-4-mercaptopyridine, 1-(-cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylmethylene-4-mercaptopyridine, 1-(2-chloro-methoxycarbonylbenzyl)-3-ethoxycarbonylmethylene-4-mercaptopyridine, 1-(-cyclopropanecarbonyl-2-terbisil)-3-carboxymethylamino-4-mercaptopyridine, 1-(2-chloro-methoxycarbonylbenzyl)-3-carboxymethylamino-4-mercaptopyridine, 1-(-cyclopropanecarbonyl-2-terbisil)-3-(N, N-dimethylcarbamoyl)methylidene-4-mercaptopyridine, 1-(-cyclopropanecarbonyl-2-terbisil)-3-(N-methylcarbamoyl)methylidene-4-mercaptopyridine, 4-acetylthio-1-(-cyclopropanecarbonyl-2-terbisil)piperidine, 4-butylthio-1-(-cyclopropanecarbonyl-2-terbisil)piperidine, 1-(-cyclopropanecarbonyl-2-terbisil)-4-Jaloliddin, 4 benzylthio-1-(-cyclopropanecarbonyl-2-terbisil)piperidine, 4-acetylthio-1-(2-fluoro-methoxycarbonylbenzyl)piperidine, 4-benzylthio-l-(2-fluoro-methoxycarbonylbenzyl)piperidine, 4-acetylthio-1-(2-chloro-methoxycarbonylbenzyl)piperidine, 3-acetylthio-1-(-cyclopropanecarbonyl-2-terbisil)azetidin, 4-acetylthio-1-(-cyclopropanecarbonyl-2-terbisil)-3-ethoxycarbonylmethylene, 4 acetylthio-l-(2-chloro-methoxycarbonylbenzyl)-3-ethoxycarbonylmethylene, 4-acetylthio-l-(-cyclopropanecarbonyl-2-forbesi the l)metiletilpiridin; or their pharmaceutically acceptable salts.

19. Composition for prevention or treatment of embolism, which contains as an effective ingredient a cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18.

20. Composition for prevention or treatment of thrombosis, which contains as an effective ingredient a cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18.

21. Composition for prevention or treatment of arteriosclerosis, which contains as an effective ingredient a cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18.

22. Cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18 used to obtain a pharmaceutical preparation for the prevention and treatment of embolism.

23. Cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18 used to obtain a pharmaceutical preparation for the prevention and treatment of thrombosis.

24. Cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18, use is 25. The method of prevention or treatment of embolism involving the introduction of a pharmacologically effective amount of a cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18 warm-blooded animal.

26. The method of prevention or treatment of thrombosis, including the introduction of a pharmacologically effective amount of a cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18 warm-blooded animal.

27. The method of prevention or treatment of arteriosclerosis involving the introduction of a pharmacologically effective amount of a cyclic amine derivatives or pharmaceutically acceptable salt according to any one of paragraphs.1 - 18 warm-blooded animal.

 

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< / BR>
where R(1) phenyl which may be substituted by 1-2 methyl groups and/or chlorine,

R(2) and R(3) may be the same or different and are H, stands or stands, and

n number 3 and 4

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)6-cyano-3,4-dihydro-2,2 - dimethyl-trans - 4-(2-oxo-1-pyrrolidinyl) -2h-1-benzopyran-3-ol" target="_blank">

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The invention relates to new cyclic imino-derivatives of General formula

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X5link

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