Derived thiazolidinone with widening collateral vessel activity, containing a pharmaceutical composition for the treatment or prophylaxis of angina and the way to obtain specified derivatives of thiazolidinone

 

(57) Abstract:

The proposed derivatives of thiazolidinone having the General formula I, where W represents a sulfur atom and X represents a group having the formula-N(R1)-; R1, R2, R3and R4represent each a hydrogen atom; R5is substituted cycloalkyl group having 3-8 carbon atoms, optionally containing a ring nitrogen atom substituted by a group having the formula-B-ONO2and, in addition, optionally substituted alkyl group having from 1 to 6 carbon atoms, where B represents a single bond or alkilinity group having from 1 to 6 carbon atoms; a represents a single bond or alkilinity group having from 1 to 6 carbon atoms or their pharmacologically acceptable salts. Proposed also a method of obtaining derivatives of thiazolidinone General formula I by the interaction of the compounds of formula II with the compound of the formula III. Pharmaceutical composition for treatment or prevention of angina. Derivatives of thiazolidinone have a vasodilator effect on the collateral vessels, not subject to first pass phase and give fewer side effects. 3 S. and 19 C.p. f-crystals, 1 PL.

Isoprenyl widening collateral vessel action and protivoskleroticheskim action and to therapeutic drug or a preventive drug against angina pectoris, containing them as active ingredient.

It is known that as a therapeutic drug for cardiovascular diseases, in particular through the toad, the most frequently used in the clinic nitroglycerin. However nitroglycerin easily subject first passing effect, and due to the pressure reduction has side effects such as headache, dizziness, tachycardia. For this reason, when breast toad would be desirable therapeutic drug, which is not affected by first passing phase and which produces fewer side effects.

It is known, for example, the following compound derived thiazolidinone with protivoskleroticheskim action (Japanese unexamined patent publication (COCA) N Hei 5-213910).

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These applicants in the years received a number of derivatives of nitrates and investigated their pharmacological action. In the present applicants have discovered that compounds of thiazolidinone with a certain Deputy, have excellent long-term relaxing effect on collateral vessel and a smaller ski of the drug against angina pectoris, that became the basis of the creation of the present invention.

Derived thiazolidinone of the present invention has the General formula:

< / BR>
In the above formula, W represents a sulfur atom or an oxygen atom, and X represents a group having the formula: -N(R1)-; or

X represents a sulfur atom or an oxygen atom, and W represents a group having the formula: -N(R1)-;

R1represents a hydrogen atom, a C1-C6alkyl group or a C1-C4alkyl group substituted by aryl;

R2and R3may be the same or different and each represent a hydrogen atom, a C1-C6alkyl group, a C1-C4alkyl group substituted by aryl, aryl group or optionally substituted 5 - or 6-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms (Deputy is C1-C6alkyl, halogen, amino or mono - or di-C1-C6alkylamino);

R4represents a hydrogen atom, a C1-C6alkyl group or a C1-C4alkyl group substituted by aryl;

R5is Sam is essentially a group, having the formula: -B-ONO2(where B represents a single bond or C1-C6alkylenes group) and optional C1-C6alkyl group];

A represents A single bond or C1-C6alkylenes group; and

specified aryl group represents C6-C10aryl group which may be optionally substituted (Deputy is C1-C6alkyl, C1-C6alkoxy, hydroxy, halogen, amino, mono - or di-C1-C6alkylamino or nitro)] .

C1-C6Alkyl groups for R1, R2, R3, R4and the like, alkyl or C1-C6alkoxygroup, C1-C6alkylamino group, etc. contained in the aryl or similar group include, for example, the group of methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl and hexyl, and preferably, C1-C4alkyl group, more preferably, C1-C2alkyl group, and particularly preferably a methyl group.

Aryl parts of C1-C4alkyl groups, substituted Allami, for R1, R2, R3and R4(the number of aryl substituents, and before honor is PPI, the corresponding C1-C6the alkyl groups mentioned above. C1-C4alkyl group, substituted aryl group include, for example, benzyl group, phenethyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, diphenylmethyl, 1-naphthylmethyl and 2-naphthylmethyl, preferably, the group phenyl- (C1-C4alkyl), more preferably benzyl or fenetylline group, and particularly preferably benzyl group.

C6-C10Aryl groups for R2and R3include, for example, phenyl group and naftalina group, preferably phenyl group.

Halogen as a substituent in the C6-C10aryl groups for R2and R3include, for example, fluorine atom, chlorine atom, bromine atom and iodine atom, preferably fluorine atom or chlorine atom.

Meanwhile, the substituent in the aryl group (the number of substituents, preferably from 1 to 3, more preferably from 1 to 2, and particularly preferably 1) includes, preferably, C1-C4alkyl group, a C1-C4alkoxy group, a hydroxy-group, halogen atom, amino group, mono - or di-C1-C4alkylamino or nitrogroup, more preferably C1the school is more preferable, methyl group, a methoxy group, a hydroxy-group, fluorine atom or chlorine atom, and particularly preferably a methyl group or a methoxy group.

5 - or 6 - membered aromatic heterocyclic ring containing 1 to 3 heteroatoms selected from the group comprising nitrogen atoms, oxygen atoms and sulfur atoms, for R2and R3can be optional kondensirovannoi with the benzene ring, and may include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, indolyl, chinosol and hintline, preferably furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazole or pyridyl, more preferably furyl, thienyl or pyridyl, and, particularly preferably, thienyl.

The substituent in the 5 - or 6-membered aromatic heterocyclic ring may include, preferably C1-C4alkyl group, halogen atom, amino group or mono - or di-C1-C4alkylamino, more preferably C1-C2alkyl group, a fluorine atom or a chlorine atom, and particularly preferably a methyl group.

Cycloalkyl part substituted C3-C8cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, aziridinyl, azetidin, pyrrolidinyl, piperidinyl, 2H-hexahydroazepin and octahedrally, preferably, C3-C6cycloalkyl group, the group pyrrolidinyl or group piperidinyl, more preferably, a group cyclopropyl, cyclopentyl or cyclohexyl, even more preferably, the group cyclopentyl or cyclohexyl group, and particularly preferably a cyclohexyl group.

Substituted C3-C8cycloalkyl group, which may optionally contain a nitrogen atom, may typically include, for example, group 1 - or 2-nitrosomethylurea, group 1 - or 2-(2-nitroxyethyl)cyclopropyl, group 1 - or 2-(3 - nitrosopropane)cyclopropyl, group 1 - or 2-(3-nitroxymethyl)cyclopropyl, group 2 - or 3-nitrosomethylethylamine, group 2 - or 3-nitroxylenes, group 2 - or 3 - nitrosomethylethylamine, group 2 - or 3-(2-nitroxyethyl)- cyclopentyl, group 2 - or 3-(3-nitrosopropane) cyclopentyl, group 2 - or 3-(4-nitroxymethyl)cyclopentyl, group 2-, 3-or 4 - nitrocyclohexane, group 2-, 3 - or 4-microclimatological, group 2-, 3 - or 4-(2-nitroxyethyl)- cyclohexyl group, 2-, 3 - or 4-(3-nitrosopropane)cyclohexyl group is methyl-1-pyrrolidin-2-yl, group 3-, 4 - or 5-(2 - nitroxyethyl)pyrrolidin-2-yl group, 3-, 4-or 5-(3 - nitrosopropane)pyrrolidin-2-yl group, 3-, 4 - or 5-(4 - nitroxymethyl)pyrrolidin-2-yl group, 3-, 4-, 5 - or 6 - nitrosopiperidine-2-yl group, 3-, 4-, 5 - or 6-nitrosomethylurea-2-yl group, 3-, 4-, 5 - or 6-nitroxymethyl-1 methylpiperidin-2-yl group, 5 - or 6-nitroxymethyl-piperidine-3-yl group, 5 - or 6-nitroxymethyl-1 methylpiperidin-3-yl group, 3-, 4-, 5 - or 6-(2-nitroxyethyl)- piperidine-2-yl group, 3-, 4-, 5 - or 6-(3-nitroxymethyl)- piperidine-2-yl group, 3-, 4-, 5 - or 6-(4-nitroxyethyl)- piperidine-2-yl, preferably, group 2-nitrosomethylurea, group 2 - or 3-nitroxylenes, group 2-or 3 - nitrosomethylethylamine, group 2 - or 3-(2-nitroxy - ethyl)cyclopentyl, group 2 - or 3-(3-nitroxymethyl)-cyclopentyl, group 2 - or 3-(4-nitroxymethyl)cyclopentyl, group 2-, 3 - or 4-nitrocyclohexane, group 2-, 3 - or 4 - microclimatological, group 2-, 3 - or 4-(2-nitroxy - ethyl) - cyclohexyl group, 2-, 3 - or 4-(3-nitroxymethyl)- cyclohexyl group, 2-, 3 - or 4-(4-nitroxymethyl)-cyclohexyl group, 3-, 4 - or 5-nitrosomethylurea-2-yl group, 3-, 4 - or 5-nitroxymethyl-1 methylpyrrolidine-2-yl group, 3-, 4-, 5 - or 6-nitrosomethylurea-2-yl group, 3-, 4-, 5 - or 6 - nitroxymethyl-1-mailpipe 3-, 4-, 5 - or 6-(2-nitroxyethyl) piperidine-2-yl group, 3-, 4-, 5 - or 6-(3-nitrosopropane) piperidine-2-yl group, 3-, 4-, 5 - or 6-(4-nitroxymethyl) piperidine-2-yl, more preferably, group 2 - or 3 - nitrosomethylethylamine, group 2 - or 3-(2 - nitroxyethyl)cyclopentyl, group 2 - or 3-(3-nitrosopropane)cyclopentyl, group 2 - or 3-(4-nitroxymethyl)-cyclopentyl, group 2-, 3 - or 4-nitrocyclohexane, group 2-, 3 - or 4 - microclimatological, group 2-, 3 - or 4-(2 - nitroxyethyl)cyclohexyl, 2-, 3 - or 4-(3 - nitrosopropane)cyclohexyl, 2-, 3 - or 4-(4 - nitroxyethyl)cyclohexyl group, 3-, 4-, 5 - or 6 - nitrosomethylurea-2-yl, or a group of 3-, 4-, 5 - or 6 - nitroxymethyl-1 methylpiperidin-2-yl, even more preferably, the group of 2 - or 3-microclimatological, group 2-, 3 - or 4 - nitrocyclohexane, group 2-, 3 - or 4-microclimatological, group 2-, 3 - or 4-(2-nitroxyethyl)- cyclohexyl group, 2-, 3 - or 4-(3-nitrosopropane)-cyclohexyl, or a group of 2-, 3 - or 4 - (4-nitroxymethyl)cyclo-hexyl, then, even more preferably, group 3-nitrosomethylethylamine, group 4-nitrocyclohexane, group 2-, 3 - or 4 - microclimatological, group 3 - or 4-(2 - nitroxyethyl)cyclohexyl group, a 3 - or 4-(3-nitrosopropane)cyclohexyl, or a group of 3 - or 4-(4-proxetil)-cyclohexyl, group 4-(3-nitrosopropane)cyclohexyl or a group of 4-(4 - nitroxyethyl)cyclohexyl, and most preferably a group 4 - microclimatological.

C1-C6alkylene groups A and B may include, for example, methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene and hexamethylene, preferably, C1-C4alkylenes group, more preferably, A is A methylene group or ethylene group and B is a methylene group, ethylene group, trimethylene group or tetramethylene group; and particularly preferably, A is A methylene group and B is a methylene group or ethylene group (particularly, methylene group).

Those compounds (I), which contain an acid group, such as phenol moiety may form salts with bases. Such salts may include, for example, salt with alkaline metal such as lithium, sodium or potassium, salts with alkaline earth metal such as barium or calcium; salts with another metal, such as magnesium or aluminum salt with an organic amine, such as dicyclohexylamine, and salt with basic amino acid such as lysine and arginine, and, preferably, a salt with alkaline metallome salts with acids. Such salts may include, for example, salt with inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid and carbonic acid, salt with carboxylic acid, such as acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid, malic acid and benzoic acid, a salt with a sulfonic acid, such as methanesulfonate acid, econsultancy acid, benzolsulfonat acid and toluensulfonate acid, and salt with acidic amino acid such as glutamic acid and aspartic acid, preferably salt with hydrochloric acid or carboxylic acid (in particular, salt with hydrochloric acid).

In connection with (I) a carbon atom that is attached to R2and R3the carbon atom to which is attached a group having the formula: - CON(R4)-A-R5(where R4, R5and A have the same values as defined above), and the carbon atom contained in R5may be asymmetric carbon atoms, and isomers on the basis of such carbon atoms are also included in the compounds of the present invention. Next, the Roadster is Lena above), and each isomer or a mixture thereof are also included in the compound of the present invention (preferably, a TRANS form), and moreover the hydrate of compound (I) or its salt is also included in the compound of the present invention.

The compound having the above General formula (I) may, preferably, include:

(1) a compound in which W is a sulfur atom or an oxygen atom and X is a group having the formula-NR1-; or X is a sulfur atom and W is a group having the formula-NR1-;

(2) a compound in which W is a sulfur atom or an oxygen atom and X is a group having the formula-NR1-;

(3) a compound in which W is a sulfur atom and X is a group having the formula-NR1-;

(4) the compound in which R1is a hydrogen atom, a C1-C4alkyl group, benzyl group or fenetylline group;

(5) the compound in which R1is a hydrogen atom, methyl group or benzyl group;

(6) the compound in which R1is a hydrogen atom;

(7) a compound in which R2and R3may be the same or different, and each denote a hydrogen atom, a C1-C4alkalisation C1-C4the alkyl, C1-C4alkoxy, hydroxy, halogen or nitro), naphthylmethyl group, phenyl group (the phenyl group may be optionally substituted C1-C4the alkyl, C1-C4alkoxy, hydroxy, halogen or nitro), naftalina group, or furyl group, thienyl, pyridyl, oxazolyl, thiazolyl, isoxazolyl or isothiazole, which may be optionally substituted C1-C2the alkyl, fluorine or chlorine;

(8) the compound in which R2and R3may be the same or different, and each represents a hydrogen atom, methyl group, ethyl group, benzyl group which may be optionally substituted with stands, methoxy, hydroxy, fluorine or chlorine, fenetylline group which may be optionally substituted with stands, methoxy, hydroxy, fluorine or chlorine, phenyl group which may be optionally substituted with stands, methoxy, hydroxy, fluorine or chlorine, follow group, thienyl group or pyridyloxy group;

(9) a compound in which R2is a hydrogen atom, methyl group, ethyl group, benzyl group which may be optionally substituted with stands, methoxy or hydroxy, or Venelin is a hydrogen atom, or R2and R3are methyl group;

(10) the compound in which R2is a hydrogen atom, methyl group, benzyl group which may be optionally substituted by stands or methoxy, or phenyl group, and R3is a hydrogen atom, or R2and R3are methyl groups;

(11) a compound in which R2is a hydrogen atom, methyl group or benzyl group, and R3is a hydrogen atom;

(12) a compound in which R2is a hydrogen atom, and R3is a hydrogen atom;

(13) the compound in which R4is a hydrogen atom, a C1-C4alkyl group, benzyl group or fenetylline group;

(14) the compound in which R4is a hydrogen atom, methyl group or benzyl group;

(15) the compound in which R4is a hydrogen atom;

(16) the compound in which R5is substituted C3-C6cycloalkyl group; pyrrolidinyl group or piperidinyl group [Deputy essentially is a group having the formula: -B-ONO2(where B represents a single bond, methylene group, ethylene grunge, in which R5is substituted cyclopropenes group, cyclopentyloxy group or tsiklogeksilnogo group [Deputy essentially is a group having the formula: -B-ONO2(where B represents methylene group, ethylene group, trimethylene group or tetramethylene group)];

(18) the compound in which R5is substituted cyclopentyloxy group, tsiklogeksilnogo group [Deputy is a group having the formula: -B-ONO2(where B represents methylene group, ethylene group, trimethylene group or tetramethylene group)];

(19) the compound in which R5is a group of 2 - or 3 - nitrosomethylethylamine, group 2 - or 3-(2 - nitroxyethyl)cyclopentyl, group 2 - or 3-(3 - nitrosopropane)cyclopentyl, group 2 - or 3-(4 - nitroxymethyl)cyclopentyl, group 2, 3 - or 4 - nitrocyclohexane, group 2-, 3 - or 4 - microclimatological, group 2-, 3 - or 4-(2 - nitroxyethyl)cyclohexyl, 2-, 3 - or 4-(3 - nitrosopropane)cyclohexyl group, 2-, 3 - or 4-(4 - nitroxyethyl)cyclohexyl group, 3-, 4-, 5 - or 6 - nitrosomethylurea-2-yl or a group of 3-, 4-, 5 - or 6 - nitroxymethyl-1 methylpiperidin-2-yl;

(20) the compound in which R5is a group of 2-hexyl, group 2-, 3 - or 4-(2 - nitroxyethyl)cyclohexyl, 2-, 3 - or 4-(3 - nitrosopropane)cyclohexyl, 2-, 3 - or 4-(4 - nitroxyethyl) cyclohexyl;

(21) the compound in which R5is a group or a 3 - nitrosomethylethylamine, group 4 - nitrocyclohexane, group 2-, 3 - or 4 - microclimatological, group 3 - or 4-(2 - nitroxyethyl)cyclohexyl group, a 3 - or 4-(3 - nitrosopropane)cyclohexyl, or a group of 3 - or 4-(4 - nitroxyethyl) cyclohexyl;

(22) the compound in which R5is a group of 3 - or 4 - microclimatological, group 4-(2 - nitroxyethyl) cyclohexyl group, 4-(3-nitrosopropane) cyclohexyl, or a group of 4-(4-nitroxyethyl)cyclohexyl;

(23) the compound in which R5is a group of 4 - microclimatological;

(24) a compound in which A is A single bond or C1-C2alkalinous group;

(25) a compound in which A is A methylene group or ethylene group; and

(26) a compound in which A is A methylene group.

Moreover, the combination of compounds randomly selected from a group comprising(1)-(3), (4)-(6), (7)-(12), (13)- (15), (16)-(23) and (24)-(26) is also preferred, and include, for example, such that predstavleniya the formula: -NR1-; or X is a sulfur atom and W is a group having the formula-NR1-;

R1is a hydrogen atom, a C1-C4alkyl group, benzyl group or fenetylline group;

R2and R3may be the same or different and are each a hydrogen atom, a C1-C4alkyl group, a C1-C4alkyl group, substituted phenyl (the phenyl may be optionally substituted C1-C4the alkyl, C1-C4alkoxy, hydroxy, halogen or nitro), naphthylmethyl group, phenyl group (the phenyl may be optionally substituted C1-C4the alkyl, C1-C4alkoxy, hydroxy, halogen or nitro), naftilos group or furyl group, thienyl, pyridyl, oxazolyl, thiazolyl, isoxazolyl or thiazolyl, which can be optionally locked C1-C2the alkyl, fluorine or chlorine;

R4is a hydrogen atom, a C1-C4alkyl group, benzyl group or fenetylline group;

R5is substituted C3-C6cycloalkyl group, pyrrolidinyl group or piperidinyl group [Deputy essentially is a group having the formula: -B-ONO2is metilenovuju group) and optional methyl group]; and

A is A single bond or C1-C2alkalinous group;

(28) the compound in which W is a sulfur atom or an oxygen atom and X is a group having the formula-NR1-;

R1is a hydrogen atom, methyl group or benzyl group;

R2and R3may be the same or different and are each a hydrogen atom, methyl group, ethyl group, benzyl group which may be optionally substituted with stands, methoxy, hydroxy, fluorine or chlorine), fenetylline group which may be optionally substituted with stands, methoxy, hydroxy, fluorine or chlorine, phenyl group which may be optionally substituted with stands, methoxy, hydroxy, fluorine or chlorine, or shriley group, thienyl group or peredelnoj group;

R4is a hydrogen atom, methyl group or benzyl group;

R5is substituted C3-C6cycloalkyl group, pyrrolidinyl group or piperidinyl group [Deputy essentially is a group having the formula: -B-ONO2(where B represents a single bond, methylene group, ethylene what is a single bond or C1-C2alkalinous group;

(29) the compound in which W is a sulfur atom and X is a group having the formula-NR1-;

R1is a hydrogen atom, methyl group or benzyl group;

R2and R3may be the same or different and are each a hydrogen atom, methyl group, ethyl group, benzyl group which may be optionally substituted with stands, methoxy, hydroxy, fluorine or chlorine, fenetylline group which may be optionally substituted with stands, methoxy, hydroxy, fluorine or chlorine, phenyl group, which may be optional sameena the stands, methoxy, hydroxy, fluorine or chlorine, or shriley group, thienyl group or peredelnoj group;

R4is a hydrogen atom, methyl group or benzyl group;

R5is substituted C3-C6cycloalkyl group, pyrrolidinyl group or piperidinyl group [Deputy essentially is a group having the formula: -B-ONO2(where B represents a single bond, methylene group, ethylene group, trimethylene group or tetramethylene group) and, optionally, a methyl group is ω W is a sulfur atom and X is a group, having the formula-NR1-;

R1is a hydrogen atom, methyl group or benzyl group;

R2is a hydrogen atom, methyl group, ethyl group, benzyl group which may be optionally substituted with stands, methoxy or hidroxil or phenyl group which may be optionally substituted by stands or methoxy or thienyl group, and R3is a hydrogen atom, or R2and R3are methyl group;

R4is a hydrogen atom, methyl group or benzyl group;

R5is substituted cyclopropenes group, cyclopentyloxy group or tsiklogeksilnogo group [Deputy is a group having the formula: -B-ONO2(where B represents methylene group, ethylene group, trimethylene group or tetramethylene group)]; and

A is A single bond or C1-C2alkalinous group;

(31) the compound in which W is a sulfur atom and X is a group having the formula-NR1-;

R1is a hydrogen atom, methyl group or benzyl group;

R2is a hydrogen atom, methyl group, benzyl group, which is odorata, or R2and R3are methyl group;

R4is a hydrogen atom, methyl group or benzyl group;

R5is substituted cyclopentyloxy group or tsiklogeksilnogo group [Deputy is a group having the formula: -B-ONO2(where B represents methylene group, ethylene group, trimethylene group or tetramethylene group)]; and

A is A single bond or C1-C2alkalinous group;

(32) the compound in which W is a sulfur atom and X is a group having the formula-NR1-;

R1is a hydrogen atom, methyl group or benzyl group;

R2is a hydrogen atom, methyl group or benzyl group;

R3is a hydrogen atom;

R4is a hydrogen atom, methyl group or benzyl group;

R5is a group of 2 - or 3-nitrosomethylethylamine, group 2 - or 3-(2-nitroxyethyl)cyclopentyl, group 2 - or 3-(3 - nitrosopropane)cyclopentyl, group 2 - or 3-(4 - nitroxymethyl)cyclopentyl, group 2-, 3 - or 4-nitroxy - cyclohexyl group, 2-, 3 - or 4-microclimatological, group 2-, 3 - or 4-(2-nitroxyethyl)cyclohexyl, graphicdocumentproperties-2-yl or a group of 3-, 4-, 5 - or 6 - nitroxymethyl-1 methylpiperidin-2-yl; and

A is A single bond or C1-C2alkalinous group;

(33) the compound in which W is a sulfur atom and X is a group having the formula-NR1-;

R1is a hydrogen atom;

R2is a hydrogen atom, methyl group or benzyl group;

R3is a hydrogen atom;

R4is a hydrogen atom;

R5is a group of 2 - or 3-nitrosomethylethylamine, 2-, 3 - or 4-nitrocyclohexane, group 2-, 3 - or 4 - microclimatological, group 2-, 3 - or 4-(2-nitroxyethyl)cyclohexyl, 2-, 3 - or 4-(3-nitroxymethyl)- cyclohexyl, or a group of 2-, 3 - or 4-(4-nitroxymethyl)- cyclohexyl; and

A is A methylene group or ethylene group; (34) the compound in which W is a sulfur atom, and X is a group having the formula-NR1-;

R1is a hydrogen atom;

R2is a hydrogen atom, methyl group or benzyl group;

R3is a hydrogen atom;

R4is a hydrogen atom;

R5is a group of 3-nitrosomethylethylamine, group 4-nitrocyclohexane, group 2-, 3 - or 4-nitroxyl or group 2, 3 - or 4-(4-nitroxymethyl)-cyclohexyl; and

A is A methylene group or ethylene group;

(35) the compound in which W is a sulfur atom and X is a group having the formula-NR1-;

R1is a hydrogen atom;

R2is a hydrogen atom;

R3is a hydrogen atom;

R4is a hydrogen atom;

R5is a group of 3 - or 4-microclimatological, group 4-(2-nitroxyethyl)cyclohexyl group, 4-(3 - nitrosopropane)cyclohexyl or a group of 4-(4-nitroxymethyl)- cyclohexyl; and

A is A methylene group; and

(36) the compound in which W is a sulfur atom and X is a group having the formula-NR1-;

R1is a hydrogen atom;

R2is a hydrogen atom;

R3is a hydrogen atom;

R4is a hydrogen atom;

R5is a group of 4-microclimatological; and

A is a methylene group; and

Preferred compounds having the General formula (I), can be specifically illustrated in the table. 1 and 2 (see the end of the description). Compounds shown in table. 1 and 2, have the structural formula (I-1) and (I-2), respectively.

<
Bu butyl ...

Buc... cyclobutyl

Bz ... benzil

Et -- ethyl

Fur ... furyl

Hxc... cyclohexyl

Me methyl ...

Np ... naphthyl

Ph ... fenil

Pip ... piperidinyl

Pnc... cyclopentyl

Prc... cyclopropyl

Pyr ... pyridyl

Pyrr ... pyrrolidinyl

Then ... Teenel

Thiz ... thiazolyl

In table. 1 and 2 predpochtite. connections are:

Connection N 1-1, 1-5, 1-6, 1-8, 1-9, 1-14, 1-17, 1-29, 1- 30, 1- 32, 1-36, 1-37, 1-39, 1-40, 1-45, 1-48, 1-59, 1-60, 1-61, 1-64, 1- 65, 1-69, 1-70, 1-72, 1-78, 1-81, 1-92, 1-93, 1-94, 1-96, 1-97, 1- 99, 1-101, 1-103, 1-105, 1-124, 1-128, 1-129, 1-130, 1- 138, 1-169, 1-170, 1-178, 1-189, 1-190, 1-198, 1-207, 1-210, 1- 213, 1-216, 1-219, 1-243, 1-245, 1-247, 1-249, 1-251, 1-282, 1-295, 1-309, 1- 315, 1-346, 1-349, 1-351, 1-353, 1-355, 1-374, 1- 388, 1-419, 1- 439, 1-457, 1-460, 1-463, 1-466, 1-469, 1-493, 1- 495, 1-497, 1- 499, 1-501, 1-513, 1-525, 1-537, 1-549, 1-561, 1- 573, 1-585, 1- 597, 1-609, 1-621, 1-633, 1-645, 1-657, 1-669, 1- 681, 1-693, 1- 705, 1-717, 1-729, 1-741, 1-753, 1-765, 1-777, 1- 789, 1-801, 1- 813, 1-825, 1-837, 1-849, 1-861, 1-873, 1-885, 1- 888, 1-891, 1- 894, 1-897, 1-900, 1-903, 1-906, 1-909, 1-912, 1- 915, 1-921, 1-924, 1-927, 1-930, 1-1224, 2-1, 2-32, 2-36, 2-45, 2-59, 2-60, 2-61, 2-65, 2-96, 2-99, 2-101, 2-105, 2-124, 2-138, 2-169, 2-189, 2-207, 2-210, 2-213, 2-216, 2-243, 2-245, 2-247, 2- 249, 2-251, 2-282, 2-315, 2-346, 2-349, 2-351, 2-353, 2-355, 2-374, 2-388, 2-419, 2-439, 2-457, 2-460, 2-463, 2-466, 2-469, 2-493, 2-495, 2-497, 2-499, 2-501, 2-513, 2-525, 2-537, 2-549, 2-561, 2-573, 2- 585, 2-597, 2-609, 2-621, 2-633, 2-645, 2-657, 2-669, 2-681, 2- 693, 2-705, 2-717, 2-729, 2-741, 2-753, 2-765, 2-777, 2-789, 2- 801, 2-813, 2-825, 2-837, 2-849, 2-861, 2-873, 2-885, 2-888, 2- 891, 2-894, 2-897, 2-900, 2-903, 2-906, 2-909, 2-9 1-39, 1- 45, 1-48, 1-59, 1-60, 1-61, 1-64, 1-65, 1-69, 1-70, 1-72. 1- 78, 1-81, 1-92, 1-93, 1-94, 1-96, 1-97, 1-99, 1-101, 1-103, 1-105, 1-124, 1-128, 1-129, 1-130, 1-138, 1-169, 1-170, 1-178, 1-189, 1-190, 1-198, 1-207, 1-210, 1-213, 1-216, 1-219, 1-243, 1-245, 1- 247, 1-249, 1-251, 1-282, 1-295, 1-309, 1-315, 1-346, 1-349, 1- 351, 1-353, 1-419, 1-439, 1-501, 1-513, 1-525, 1-573, 1-585, 1- 621, 1-633, 1-681, 1-729, 1-753, 1-777, 1-900, 1-924, 1-1224, 2-1, 2-32, 2-36, 2-45, 2-59, 2-60, 2-61, 2-65, 2-99 and 2-169.

Particularly preferred compounds are:

Connection 1-32 N: N-(4-nitrosomethylethylamine)-2 - oxothiazolidine-4-ylcarbonyl,

Connection 1-36 N: N-(4 - nitrosomethylethylamine)-5 - methyl-2-oxothiazolidine-4 - ylcarbonyl,

The compound N 1-39: N-(4 - nitrosomethylethylamine)-2-oxo-5-(2-thienyl)thiazolidin-4 - ylcarbonyl,

The compound N 1-45: N-(4 - nitrosomethylethylamine)-5-(4-methoxyphenyl)- 2-oxothiazolidine-4-ylcarbonyl,

The compound N 1-59: N-(4 - nitrosomethylethylamine)-5-benzyl-2-oxothiazolidine-4 - ylcarbonyl,

Connection 1-60 N: N-(4 - nitrosomethylethylamine)-5-(4 - methylbenzyl)-2 - oxothiazolidine-4-ylcarbonyl,

Compound 1-61 N: N-(4 - nitrosomethylethylamine)-5-(4-methoxybenzyl)-2 - oxothiazolidine-4-ylcarbonyl,

Compound 1-65 N: N-[2-(4 - microclimatological)ethyl)-2-oxothiazolidine-4-ylcarbonyl,

The compound N 1-69: N-[2-(4-nitrosomethylethylamine-oxo-5-(2-thienyl) thiazolidin-4-ylcarbonyl,

Compound 1-78 N: N-[2-(4 - microclimatological)ethyl)]-5-(4-methoxyphenyl)-2 - oxothiazolidine-4-ylcarbonyl,

Compound 1-92 N: N-[2-(4 - microclimatological)ethyl)]- 5-benzyl-2-oxothiazolidine-4 - ylcarbonyl,

Compound 1-93 N: N-[2-(4 - microclimatological)ethyl)]-5-(4-methylbenzyl)-2 - oxothiazolidine-4-ylcarbonyl,

Compound 1-94 N: N-[2-(4 - microclimatological)ethyl)]-5-(4-methoxybenzyl)-2 - oxothiazolidine-4-ylcarbonyl,

The compound N 1-169: N-[4-(2 - nitroxyethyl)cyclohexylmethyl]-2 - oxothiazolidine-4-ylcarbonyl,

The compound N 1-207: N-[2-[4- (3-nitroxymethyl)-cyclohexyl]ethyl]-2-oxothiazolidine-4 - ylcarbonyl,

The compound N 1-900: N-[4-(3 - nitrosopropane)cyclohexylmethyl]-2-oxothiazolidine-4 - ylcarbonyl,

The compound N 1-1224: N-[4-(4-nitroxyethyl)cyclohexyl-methyl] -2-oxothiazolidine-4-ylcarbonyl,

The compound N 2-32: N-(4 - nitrosomethylethylamine)-2-oxothiazolidine-5-ylcarbonyl,

The compound N 2-36: N-(4-nitrosomethylethylamine)-4-methyl-2 - oxothiazolidine-5-ylcarbonyl,

The compound N 2-45: N-(4 - nitrosomethylethylamine)-4-(4-methoxyphenyl) -2 - oxothiazolidine-5-ylcarbonyl,

The compound N 2-59: N- (4-nitrosomethylethylamine)-4-benzyl-2-oxothiazolidine-5 - ylcarbonyl, and

The compound N 2-61: N-(4 - nitrosomethylethylamine)-4-(4-methoxybenzyl)-2 - oxothiazolidine-5-ylcarbonyl.

The compound having General formula (I) according to the present invention can be easily obtained according to the following methods.

How A

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In the above formulas, W, X, R2, R3, R4, R5and A have the meanings mentioned above, and Wa, Ha, R2a, R3a, R4a and R5a, each represent the same values as W, X, R2, R3, R4and R5accordingly, except that the amino group or aminogroups (-NH-) in each group may be optionally protected (preferably, a protected amino group or aminogroups), and R5b represents a substituted C3-C6cycloalkyl group, optionally containing a nitrogen atom [the Deputy is, essentially, a group having the formula: -B-OH (where B has the same meaning indicated above and preferably C1-C6alkyl group (aminogroup in the group may be protected)].

The protective group for amino group or aminogroup is not limited particularly, because it is commonly used in the field of synthetic organic chemistry, and includes, for example, tert-butyl is B>1-C6the alkyl, C1-C6alkoxy or halogen, such as benzyl, methylbenzyl, methoxybenzyl, tormentil and chlorbenzyl, benzyloxycarbonyloxy group which may be optionally protected C1-C6the alkyl, C1-C6alkoxy or halogen, such as benzyloxycarbonyl, methylbenzyloxycarbonyl, methoxybenzeneboronic, forantimicrobial and chlorobenzenesulfonyl or halogenoacetyl group such as chloroacetyl, bromoacetyl and iodoacetyl, preferably, tert-boutelou group, tert - butoxycarbonyl group, p-methoxybenzyl group, p - methoxybenzylideneamino group, chloroacetyl group, bromatology group or educationnow group, more preferably tert-butoxycarbonyl group, p - methoxybenzylideneamino group and, particularly preferably, tert-butoxycarbonyl group.

Method a is a method of obtaining the compound (I).

Stage A1 is the stage of obtaining compounds having General formula (I), and it is conducted by reacting the compounds having General formula (II) or its reactive derivative (acid halides, mixed acid anhydrides or active is o enable increases acids, such as hydrochloride, nitrates and sulphates) in an inert solvent, and removing the protective group such as amino group, and so on, the compounds formed.

The interaction of the compound (II) with compound (III) is conducted, for example, halogenosilanes method, mixed-anhydrite method, method with active esters or by the condensation method.

Halogenosilanes method is carried out by reacting the compound (II) with a halogenation agent (e.g. thionyl chloride, oxalicacid, pentachloride phosphorus, and the like) to produce gelegenheid acid, and then by the interaction of gelegenheid acid with compound (III) or its acid salt additive in an inert solvent in the presence or absence of a base.

Used here, the base can include, for example, organic amines such as triethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate, and preferably organic amines.

Used here, the inert solvent is not ogranichivaetsya, benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers such as ether, tetrahydrofuran and dioxane; ketones, such as acetone; amides such as N,N - dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide; and sulfoxidov, such as dimethylsulfoxide, and, preferably, hydrocarbons, halogenated hydrocarbons, ethers or amides.

The reaction temperature varies depending on the starting compounds (II) and (III) the type of solvent, etc., and the reaction temperature, for engagement halogenation agent with compound (II), and for the interaction of gelegenheid acid with compound (III) is usually from -20oC to 150oC. Preferably, the temperature for the first interaction is between -10oC to 50oC, and the temperature for the latter interaction is 0oC to 100oC. the reaction Time varies depending on the reaction temperature, etc. and the reaction time for both interactions is usually from 15 minutes to 24 hours (preferably from 30 minutes to 16 hours).

Method, mixed acid anhydride is carried out by interaction of the C< 10 aristotelia with compound (II) to obtain a mixed acid anhydride and then by reacting the mixed acid anhydride with the compound (III) or its acid salt additive.

The reaction to obtain a mixed acid anhydride is carried out by interaction of the C1-C6alkylaminocarbonyl, such as methylcarbonate, ethylchloride, isobutylparaben and Eximgarant (preferably ethylchloride or isobutylparaben), di - C1-C6alkylthiophenes acid, such dimethylthiophosphory acid, diethylthiophosphoryl acid and vexillifera acid (preferably, diethylthiophosphoryl acid), or di-C6-C10aristotelia, such as diphenylphosphoryl, di(p - nitrophenyl)phosphorylated and diafiltrate (preferably diphenylphosphoryl), with compound (II), preferably in an inert solvent in the presence of a base.

Used here, the base and inert solvent are similar to those used by galogenangidridy method.

The reaction temperature varies depending on the starting compound (II), the type of solvent, etc. , iatse depending on the reaction temperature, and so p. , and usually ranges from 15 minutes to 24 hours (preferably from 30 minutes to 16 hours).

The interaction of the mixed anhydride with the compound (III) or its acid salt additive is preferably carried out in an inert solvent in the presence or in the absence of base. Used here, the base and inert solvent are similar to those used by halogenosilanes method.

The reaction temperature varies depending on the starting compound (III), the type of solvent, etc. and is usually from -20oC to 100oC (preferably from -10oC to 50oC). The reaction time varies depending on the reaction temperature, etc. and usually ranges from 15 minutes to 24 hours (preferably from 30 minutes to 16 hours).

In this way, in the case where the used dialkylanilines acid or directorrelated, the compound (II) and the compound (III) may be subjected to the direct interaction in the presence of a base.

Method with an active complex ether is carried out by reacting the compound (II) with active etherification agent (for example, N - hydroxy, such as N-hydroxysuccinimide, N - hydroxybenzotriazole, etc. in prawnego of ester and by interaction of ester with compound (III) or its acid salt additive.

The reaction of the active complex ester is preferably carried out in an inert solvent, and used here, the inert solvent is similar to that used by halogenosilanes method.

Since the reaction temperature varies depending on the starting compounds (II) and (III) the type of solvent, etc. in the reaction of the active esterification it is usually from -20oC to 50oC (preferably from -10oC to 30oC), and the interaction of the active hard ether derivative with the compound (III) it is usually from -20oC to 50oC (preferably from -10oC to 30oC). The reaction time varies depending on the reaction temperature, etc. and the reaction time for both reactions is usually from 15 to 24 hours (preferably from 30 minutes to 16 hours).

The condensation method is carried out by reacting the compound (II) and compound (III), or their acid additive salts directly in the presence of a condensing agent (for example, dicyclohexylcarbodiimide, carbonyldiimidazole hydrochloride and 1-(N,N-dimethylaminopropyl)-3-ethylcarbodiimide).

This reaction is carried out similarly to the reaction of active complex acii on the way, usually used in the field of synthetic organic chemistry.

When the protective group is tert-butilkoi group, tert-butoxycarbonyl group, methoxybenzyl group or methoxybenzylideneamino group, it is removed by reacting the corresponding compound with an acid (e.g. a mineral acid such as hydrochloric acid, sulfuric acid and nitric acid, an organic acid such as acetic acid, triperoxonane acid, methanesulfonate acid and p-toluensulfonate acid, preferably hydrochloric acid) in an inert solvent (for example, a simple ether such as ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, or aromatic hydrocarbon, such as benzene, toluene and xylene, preferably, ether) at 0oC to 50oC (preferably at about room temperature for from 30 minutes to 5 hours (preferably from 1 hour to 2 hours).

Meanwhile, in the case where the protective group is halogenoacetyl group, it is removed by reacting the corresponding compound with thiourea in an inert solvent (e.g. the nutrient, amide) at 0oC to 50oC (preferably at room temperature) for from 30 minutes to 5 hours (preferably from 1 hour to 2 hours).

Moreover, when the protective group is a benzyl group which may be optionally substituted, or benzylcarbamoyl group which may be optionally substituted, it is removed by reacting the corresponding compounds with hydrogen (pressure, preferably from 1 to 3 ATM.) in an inert solvent (for example, a simple ether such as ether, tetrahydrofuran and dioxane, in alcohol, such as methanol and ethanol (preferably alcohol) in the presence of catalytic reduction catalyst (e.g. palladium on charcoal, platinum oxide) at 0oC to 50oC (preferably at about room temperature for from 30 minutes to 10 hours (preferably from 1 hour to 5 hours).

After completion of the reaction, the desired compound in each reaction is recovered from the reaction mixture by conventional methods, for example, by collecting the precipitated crystals by filtration, after undissolved particles are removed by filtration, if necessary; or by removing undissolved particles by fnai mixture, extraction of water-immiscible organic solvent, such as ethyl acetate, drying of the organic layer and evaporation of solvent extracted. If necessary, the resulting compound can be further purified by conventional methods, such as recrystallization and chromatography on the column.

Method B is a method of obtaining the compound (I).

Stage B1 is the stage of obtaining compounds having General formula (V) by reacting the compound (II) or its reactive derivative (gelegenheid, mixed anhydride or active ester) with a compound having General formula (IV), or its acid salt additive in an inert solvent. This stage is carried out, for example, halogenosilanes method, mixed-anhydrite method, method with an active complex air or condensation method, similar to the first stage A1 of method A.

Stage B2 is the stage of obtaining compounds having General formula (I) and it is conducted by reacting the compounds having General formula (V), with nitrous agent in the absence of solvent or in an inert solvent and removal of the protective group, such as aminogroup Amadou nitric acid, tetrafluoroboric of microcolony, thionyl chloride nitric acid, toniutto acid and tetrafluoroboric nitronium, and preferably, fuming nitric acid, tetrafluoroboric of microcolony or thionyl chloride-nitric acid.

Used here, the inert solvent is not limited particularly, because it does not affect the reaction, and may include, for example, hydrocarbons such as hexane, cyclohexane, benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride, ethers such as ether, tetrahydrofuran and dioxane, ketones, such as acetone, NITRILES, such as acetonitrile, amides such as N,N - dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoramide, and sulfoxidov, such as dimethylsulfoxide, preferably, halogenated hydrocarbons, ethers, NITRILES or amides, and particularly preferred NITRILES.

The reaction temperature varies depending on the starting compound (V), type nitrouse agent, etc. and usually ranges from 20oC to 50oC (preferably about room temperature). The reaction time varies depending on the reaction temperature, etc. and usually astavrou removed after completion of the above reaction in the same way, at the last stage A1 method A.

After completion of the reaction, the desired compound in each reaction is recovered from the reaction mixture by conventional means. For example, the desired compound can be obtained by collecting the precipitated crystals by filtration; or by neutralization, if necessary, removal of the solvent, adding water to the reaction mixture, extraction of water-immiscible organic solvent, such as ethyl acetate, drying of the organic layer and evaporation extracting solvent. If necessary, the resulting compound can be further purified by conventional methods such as recrystallization and chromatography on the column.

The original compound (II) is known or can be easily obtained according to known methods [e.g., Aust. J. Chem., 21, 1891 (1968), J. Chem. Soc., 4614 (1958), NIHON YAKUGAKU ZASSHI (Japanese Journal of Pharmacy), 73, 949, (1953), Chemische, Berichte, 91, 160 (1958), CALLED NIHON ZASSHI (Japanese Journal pf Chemistru), 82, 1075 (1961) or Japanese unexamined Patent publication N (KOKAI) Hei-5-213910].

Starting compound (III) and (IV) are known or easily obtained according to known methods [for example, J. Chem. Soc. Perkin. Trans. , 1, 1770 (1979), Tetrahedron Lett., 4285 (1970), Heterocycles, 34, 739 (1 the following ways:

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In the above formulas, R4a, a and B have the same values as defined above; R6represents a hydrogen atom or aminosidine group; R7represents a hydrogen atom, a C1-C6alkyl group or a C1-C6alkanoyloxy group (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or group hexanoyl, preferably the acetyl group, propionyl, butyryl or isobutyryl, and especially preferably a group isobutyryl); R7a represents a hydrogen atom or a C1-C6alkyl group; R8is carbamoyl group, or cyano; R9represents cyano or a group having the formula: - CH(CO2R7a)2(where R7a has the same significance as defined above); R10is hydroxyamino group (for example, 5 - or 6 - membered cyclic ether group such as 2 - tetrahydrofuryl, 2-tetrahydropyranyl, 4-methoxy-2 - tetrahydropyranyl and 2-tetrahydropyranyl, three-C1-C4alkylsilane group, such as trimethylsilyl, triethylsilyl and tert-butyldimethylsilyl, benzyl group which may be optionally substituted C1-C6lebenthal, benzylcarbamoyl group which may be optionally substituted C1-C6the alkyl, C1-C6alkoxy or halogen, such as benzyloxycarbonyl, methylbenzyloxycarbonyl, methoxybenzeneboronic, forantimicrobial and chlorobenzenesulfonyl and, preferably, group 2-tetrahydropyranyl, tert-butyldimethylsilyl or p-methoxybenzenesulfonyl); R11represents a cyano or sidegroup; Aa represents a single bond or C1-C5alkylenes group; Ba represents a single bond or C1-C4alkylenes group; a group having the formula:

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represents C3-C8cycloalkenyl group containing, optionally, a nitrogen atom, which may be optionally protected, and which is optionally substituted C1-C6alkyl group; Y represents a halogen atom (preferably chlorine atom or bromine atom), C1-C6alkylsulfonates (preferably, methanesulfonamido or econsultancy group), or arylsulfonate (preferably benzazolyl group or toluensulfonyl); p is 0 or 1; and q is 2 or 3.

Method C is a method obtained C3-C8cycloalkyl group containing, optionally, a nitrogen atom, which optionally can be protected (Deputy is, essentially, a group having the formula: -Ba-CH2TNA2(where Ba has the same meaning as defined above and preferably C1-C6alkyl group).

Stage C1 is the stage of obtaining compounds having General formula (IV) and it is conducted by reacting aminocarbonyl acid having the General formula (VI), with a regenerating agent (preferably, borhydride derivative, such as sodium borohydride and portionality sodium, and alumohydride derivative, such as lithium aluminum hydride) in an inert solvent (preferably, in a simple ether such as ether and tetrahydrofuran) at 0oC to 50oC (preferably at about room temperature) for 30 minutes to 10 hours (preferably from 1 hour to 5 hours). Meanwhile, amino group, etc. in the compound (IV), where R6is a hydrogen atom, can also be protected by reacting the compound with tert - butyl chloride, tert-butoxycarbonylamino, tert - butoxycarbonylamino, benzylchloride, which may be optionally protected C1-C61-C6the alkyl, C1-C6alkoxy or halogen, halide, such as chloracetamide, bromoacetamide and iodotetrachloride, or bicarbonates, such as di-tert-BUTYLCARBAMATE, dibenzyldithiocarbamate and di(C1-C6alkyl, C1-C6alkoxy or halogenmethyl)dicarbonate in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, or alcohols, such as methanol and ethanol) in the presence or in the absence of a base (preferably, amines such as triethylamine and pyridine) at 0oC to 50oC (preferably at about room temperature for from 30 minutes to 10 hours (preferably from 1 hour to 5 hours).

Stage C2 is the stage of obtaining compound (IlIa) and it is conducted by nitration of compounds (IVa) and, if necessary, by removal of the protective group, such as for amino group, etc. This stage spend like stage B2 of the above method B. meanwhile, in the reaction of removing the protective group, such as for amino groups, and so on, the protective group can be removed selectively by choosing the reaction conditions depending on the type of the protective group.

Method D is another way to get connected is/SUP>a, R6and A have the same values as defined above) is an aminomethyl group.

Stage D1 is the stage of obtaining compounds having General formula (IVb) and it is conducted by reacting compounds having the General formula (VII) with a regenerating agent (e.g., preferably borhydride derivative, such as sodium borohydride and borlangemal sodium, or aluminohydrides derivative, such as sociallyengaged) in an inert solvent (preferably, a simple ether such as ether and tetrahydrofuran) at 0oC to 150oC (preferably, from 30oC to 100oC) for from 15 minutes to 10 hours (preferably from 30 minutes to 5 hours). Meanwhile, the compound (IVb) can be obtained by catalytic reduction of the product from step A1 above method A.

Method E is a method of obtaining compound (Via), which corresponds to the compound (VI), in which a group having the formula: -Ba-CO2R7I (where R7and Ba have the same values as defined above) is a group having the formula: -VA- (CH2)pCO2R7(where R7, Ba and p have the same values as defined above). Stage E1 stage is polucheniyami, such as thionyl chloride, trichloride phosphorus, tribrominated phosphorus oxychloride phosphorus, methansulfonate, acanaloniidae, benzosulphochloride, benzosulfimide and p-toluensulfonate or sulfonic anhydrides, such as methanesulfonyl anhydride, econsultancy anhydride, benzosulfimide anhydride and p-toluensulfonyl anhydride in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, or a halogenated hydrocarbon such as methylene chloride and chloroform) in the presence or absence of a base (preferably, amines such as triethylamine and pyridine) at 0oC to 50oC (preferably at about room temperature for from 30 minutes to 10 hours (preferably from 1 hour to 5 hours). Meanwhile, the corresponding halide can also be obtained by reacting the obtained sulfonate derived from a halide of an alkali metal such as sodium bromide and sodium iodide, in an inert solvent (preferably, ketones, such as acetone, or amides, such as dimethylformamide and dimethylacetamide) at 0oC to 50oC (preferably at about room temperature for from 30 minutes to 20 hours the General formula (IX), and it is conducted by reacting the compound (VIII) with an alkali metal cyanide, such as lithium cyanide, sodium cyanide and potassium cyanide, or a derivative of malonic acid having the formula: M+-CH(CO2R7a)2(where R7a has the same meaning defined above, and M represents an alkali metal atom) in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, or amides, such as dimethylformamide and dimethylacetamide) at 0oC to 50oC (preferably at about room temperature for from 30 minutes to 10 hours (preferably from 1 hour to 5 hours).

Meanwhile, this stage also conducted preferably in the presence of sodium iodide.

Stage E3 is the stage of obtaining the compound (VIa), which corresponds to the compound (VIa) in which R7is a hydrogen atom and p is 0, obtained by interaction of a compound that corresponds to the compound (IX) in which R9is cyano, with an acid (preferably a mineral acid, such as hydrochloric acid, nitric acid and sulfuric acid) in aqueous solution at 0oC to 150oC (preferably, from 30oC to what corresponds to the compound (VIa), in which R7is a hydrogen atom and p is 1, receive, if desired, by reacting compounds corresponding to the compound (IX) in which R9is a group having the formula-CH(CO2R7a)2(where R7a has the same meaning as defined above) with a base (preferably, hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide) in an inert solvent (preferably water ethers, such as water ether and aqueous tetrahydrofuran or aqueous alcohol such as aqueous methanol and aqueous ethanol) at 0oC to 50oC (preferably at about room temperature for from 30 minutes to 10 hours (preferably from 1 hour to 5 hours) for hydrolysis, and then by heating in an inert solvent (preferably, aromatic hydrocarbons such as benzene, toluene and xylene) at the 50oC to 200oC (preferably, from 100oC to 150oC) for from 30 minutes to 10 hours (preferably from 1 hour to 5 hours).

Moreover, the corresponding ester can be obtained, if desired, by reacting thus obtained, carboxylic acid derivative with dia is sustained fashion, ethers such as ether and tetrahydrofuran) at 0oC to 50oC (preferably at about room temperature for from 5 minutes to 2 hours (preferably, from 10 minutes to 1 hour), or by reacting the thus obtained carboxylic acid derivative with a C1- C6alcohol, such as methanol, ethanol and hexanol similar stage A1 of the above method A. the Corresponding acyl derivative can be obtained by reacting carboxylic acid derivative with a C1-C6alkylhalogenide similar to the method of obtaining the mixed anhydride at stage A1 of the above method A.

Method F is a method of obtaining compound (VIc), which corresponds to the compound (VIa) in which p is 1.

Stage F is the stage of obtaining compounds having the formula (X) and it is conducted by reacting the parent compound with C1-C6alkylaminocarbonyl, such as methylcarbonate, ethylchloride, isobutylparaben and Eximgarant in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform) in price -50oC to 50oC (preferably from -20oC and 0oC) for from 30 minutes to 10 hours (preferably from 1 hour to 5 hours), and then by reacting the obtained product with diazomethane in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform) at -50oC to 50oC (preferably from -20oC and 0oC) for from 30 minutes to 10 hours (preferably from 1 hour to 5 hours).

Stage F2 is the stage of obtaining the compound (VIc) and it is conducted by reacting the compound (X) with excess water or C1-C6alcohol serving as an inert solvent in the presence of a derivative of silver, such as silver carboxylate, such as acetate, silver benzoate, silver, sulfonate silver, such as silver methanesulfonate, benzoylphenyl silver and p-toluensulfonate, powder of silver and silver oxide (preferably, benzoate of silver or silver oxide) in the presence or absence of organic amines (e.g. triethylamine, pyridine) at 0oC to 50oC (preferably at about room temperature for from 30 minutes to 10 hours (PR is tsya hydrogen atom, produced by interaction of the compound (X) with water, and the connection that corresponds to the connection (VIc), in which R7is C1-C6alkyl group, is produced by the interaction of the compound (X) with C1-C6the alcohol. Thus obtained carboxylic acid can be etherification or allerban similar stage E3 above method E.

Method G is a method of obtaining compound (IVd), which corresponds to the compound (IVa) in which R4a is a hydrogen atom.

Stage GI is the stage of obtaining compounds having General formula (XII), and it is conducted by protecting the hydroxyl group of compounds having General formula (XI). The reaction of the hydroxyl protecting group change depending on the type of protective group, and it is carried out by interaction, is well known in synthetic organic chemistry.

When the protective group is a 5 - or 6-membered cyclic ether group, a hydroxyl group can be protected by reacting the corresponding compounds with simple unsaturated ether such as dihydrofuran, dihydropyran, 4-methoxythiophene and dihydrothiophene in an inert solvent (PR is telengard and chloroform) in the presence of acid (e.g., mineral acid such as hydrochloric acid, sulfuric acid and nitric acid, or organic acid such as acetic acid, triperoxonane acid, methanesulfonate acid and p - toluensulfonate acid, preferably hydrochloric acid) at 0oC to 50oC (preferably at room temperature) for from 30 minutes to 5 hours (preferably from 1 hour to 2 hours). When the protective group is a group of three-C1-C4alkylsilane group, optionally substituted benzyl group or optionally substituted benzyloxycarbonyl group, a protected hydroxyl group is carried out by reacting the corresponding compound with a halide, such as trimethylsilane, triethylsilane, tert-butyldimethylsilyloxy, tert-butyldimethylsilyloxy, benzylchloride, benzylbromide, methylbenzylamine, methoxybenzylidene, tormentilla, chlorobenzylchloride, benzyloxycarbonylamino, methylbenzyloxycarbonyl, methoxybenzeneboronic, forbindelsesfaneblad and chlorobenzylchloride, in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, halogenated Plevo the IDA,

such as dimethylsulfoxide) in the presence of a base (mainly alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, or amines, such as triethylamine, pyridine and N-methylmorpholine) at 0oC to 50oC (preferably at room temperature) for from 30 minutes to 24 hours (preferably from 1 hour to 20 hours).

Stage G2 is the stage of obtaining compounds having the General formula (XIII), and it is conducted by halogenation or sulfonation compounds (XII). This stage is similar to stage E1 of the above method E.

Stage G3 is the stage of obtaining compounds having General formula (XIV), and it is conducted by reacting the compound (XIII) with cyanides of alkali metals such as lithium cyanide, sodium cyanide and potassium cyanide, or aside alkali metals such as lithium azide, sodium azide and potassium azide, in an inert solvent (preferably, ethers such as ether and tetrahydrofuran, amides such as dimethylformamide and dimethylacetamide, or sulfoxidov, such as dimethylsulfoxide) at 0oC to 200oC (preferably, from 50oC to 150oC) for from 15 minutes to 20 hours (preferred the Ulu (XV), and it is carried out by the recovery of the compound (XIV). This stage is carried out analogously to stage D1 above method D.

Stage G5 is the stage of obtaining the compound (IVd) and it is conducted by removing hydroxyamino group of compounds (XV) and, if desirable, by protecting the amino group.

Hydroxyamino group is removed according to the method commonly used in synthetic organic chemistry.

When the protective group is a 5 - or 6-membered cyclic ether group, methoxybenzyl group or methoxybenzylideneamino group protective group is removed by reacting the corresponding compound with acid. This reaction is carried out analogously to the reaction of removing protection, in which the protective group for a group such as amino group, etc. is tert-butilkoi group on stage A1 of the above method A.

When the protective group is tizamidine silyl group, the protective group is removed by reacting the corresponding compound with the compound that gives the anion fluoride, such as tetrabutylammonium fluoride in an inert solvent (preferably, ethers, such as tetrahydrofuran job (preferably, from 10 o'clock till 18 o'clock).

When the protective group is optionally substituted benzyl group or optionally substituted benzyloxycarbonyl group, the protective group is removed, exposing the corresponding connection catalytic recovery. This reaction is carried out analogously to the reaction of removing the protection in which aminosidine group optionally protected with benzyl group on stage A1 of the above method A.

The reaction of the protection of the amino group performed similarly to stage C1 of the above method C.

Method H is a method of obtaining compounds having General formula (IVe) included in the compound (IVa).

Stage H1 is the stage of obtaining compounds having the General formula (XVII), and it is conducted by reacting compounds having the General formula (XVI) with concentrated ammonia at 0oC to 50oC (preferably at room temperature) for from 30 minutes to 20 hours (preferably from 1 hour to 10 hours).

Stage H2 is the stage of obtaining compound (IVe), and it is carried out by the recovery of the compound (XVII). This stage is conducted similarly to the phase DI above method D.

M is x2">

Stage I1 is the stage of obtaining compounds having General formula (XVIIa), and it is conducted by reacting compounds having the General formula (XVIII) with concentrated ammonia is similar stage H1 above method H.

Stage I2 is the stage of obtaining compound (IVf) and it is conducted by restoring compound (XVIIa). This stage is carried out analogously to stage D1 above method D.

Method J is the method of obtaining compounds having General formula (IVg) included in the compound (IVa).

Stage J1 is the stage of obtaining compounds having the General formula (XX), and it is conducted by reacting compounds having the General formula (XIX) with an oxidizing agent (for example, chromic acid - pyridine, dimethylsulfoxide-oxalicacid, dimethylsulfoxide-gaseous chlorine, dimethylsulfoxide-anhydride triperoxonane acid and succinimidylester chloride, preferably dimethylsulfoxide-oxalicacid) in an inert solvent (preferably, halogenated hydrocarbons such as dichloromethane and chloroform, amides such as dimethylformamide and dimethylacetamide, and sulfoxidov, such as dimethylsulfoxide) at from ABOUTo

Stage J2 is the stage of obtaining compounds having the General formula (XXI), and it is conducted by reacting compound (XX) with a compound having the formula: (R12)3P+(CH2)qOH Ya-(where q has the same meaning defined above, R12represents C6-C10aryl group, and Ya represents a halogen atom) in an inert solvent (preferably, ethers such as ether and tetrahydrofuran) in the presence of a base (preferably strongly basic amines such as 1,5 - diazabicyclo[4,3,0] non-5-ene and 1,8-diazabicyclo[5,4,0] undec-7-ene, and alkality, such as utility) at -20oC to 150oC (preferably from 0oC to 100oC) for from 1 hour to 10 days, preferably from 5 hours to 7 days).

Stage J3 is the stage of obtaining compound (IVg) and its conduct, subjecting the compound (XXI) catalytic recovery similar stage A1 of the above method A. Method It is a method of obtaining compounds having General formula (IVh) included in the compound (IVa).

Stage K1 is the stage of obtaining compounds having General formula (XIXa), and it is performed by restoring the compounds having General formula (VI). This is ia connections (settle down under), and it is carried out by oxidation of the compound (XIXa). This stage is conducted similarly to stage J1 method D.

Stage K3 is the stage of obtaining compound (IVh), and it is conducted by reacting compound (settle down under) with the reagent Grignard, such as methylmagnesium and methylmagnesium in an inert solvent (preferably, ethers such as ether and tetrahydrofuran) at -20oC to 50oC (preferably from 0oC to 30oC) for from 10 minutes to 5 hours (preferably from 15 minutes to 2 hours).

After completion of the reaction, the desired compound in each reaction is recovered from the reaction mixture by conventional means. For example, the desired compound can be obtained by collecting the precipitated crystals by filtration; or by removing insoluble substances, if necessary, if the reaction mixture contains insoluble substances, neutralizing the reaction solution, if necessary, if the reaction solution is acidic or alkaline, extracting immiscible with water, an organic solvent, such as ethyl acetate, drying of the organic layer and evaporation of the extracting solvent. If necessary, the desired compound can be Dalnie compounds (VI), (VII), (XI), (XVI) and (XVIII) are known and easily obtained by known methods (for example, Chem. Abst. 64, 3379f (1966), Chemische, Berichte, 67, 1783 (1934), Chemische, Berichte, 71, 759 (1938), J. Am. Chem. Soc., 62, 2891 (1940), J. Am. Chem. Soc., 82, 3257 (1960), J. Am. Chem. Soc., 88, 3522 (1966), Tetrahedron, 21, 2725 (1965), Tetrahedron, 48, 9753 (1992), and so on)

The original compound (III) can be easily obtained by reacting compound (VI) is similar stage B2 method B.

The compound having General formula (I) or its pharmacologically acceptable salt according to the present invention show a strong relaxing effect on collateral vessels without causing unwanted side effects such as headache, dizziness, tachycardia, or harmful effects to the digestive system, liver, bones and so on, they are not short on action. Therefore, it can be used as a therapeutic agent and a prophylactic agent (preferably, a therapeutic agent) through the toad.

B when the compound (I) of the present invention and its pharmacologically acceptable salt is used as a therapeutic agent or preventive agent for breast toad, the compound or its mixture with a pharmaceutically acceptable fill the powder, syrup or drugs for injection.

These drugs get by known methods using additives such as fillers (for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, a-starch, dextrin and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low hydroxypropylmethyl cellulose, hypromellose, carboxymethylcellulose, calcium carboxymethylcellulose and transverse cross-linked sodium carboxymethylcellulose; gum Arabic; dextran; Pullulan; derivatives of silicate, such as light silicic acid anhydride, synthetic aluminum silicate and magnesium aluminate meta - silicic acid; derivatives of phosphate such as calcium phosphate; carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate), binders (for example, the above-mentioned fillers; gelatin; polyvinylpyrrolidone; and Macrogol); loosening agents (for example, the above-mentioned fillers; chemically modified derivatives of starch-cellulose, such as sodium croscarmellose, sodium carboxymethyl starch and crosslinked as calcium stearate and magnesium stearate; colloidal silica; waxes such as beeswax and spermaceti; boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; carboxylate sodium, such as sodium benzoate; sulfates such as sodium sulfate; leucine; laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicic acids such as silicic acid anhydride and silicic acid hydrate; and starch derivatives among the above fillers), stabilizers (for example, p - hydroxybenzoate, such as methylparaben and propylparaben; alcohols, such as chlorobutanol, benzyl alcohol and finitely alcohol; benzalconi chloride; phenols such as phenol and cresol, thimerosal; acetic anhydride; and sarbianova acid); correcting substances, such as commonly used sweetening agents, podmylivaya agents and odorants), thinners and solvents for injection agents (e.g., water, ethanol and glycerol).

Although the dose varies depending on the condition and age treat the patient, it is desirable to introduce from 1 to 6 times a day, depending on the state: in the case of oral administration the lower bound is 1 mg at each meal (preferably 5 mg), and the upper Grand the leaves of 0.1 mg at each meal (preferably, 0.5 mg), and the upper limit is 100 mg (preferably 50 mg) for adults.

[Best mode for carrying out the invention]

The present invention will be described more specifically below by means of examples, reference examples, examples, research, and examples of the preparation, however, the invention is not restricted by them.

Example 1

N-[TRANS-4-nitrosomethylethylamine] -(4R) - 2-oxo-thiazolidin-4-ylcarbonyl (Compound 1-32 N)

In 7 ml of dry benzene added 0.35 g of (4R)-2-oxo-4 - thiazolidinones acid and 0.42 ml of oxalicacid and at room temperature, thereto was added a few drops of dimethylformamide and stirred at room temperature for 2 hours. The solvent drove under reduced pressure to obtain the carboxylic acid as a pale yellow oil.

Meanwhile, 0.51 g of the hydrochloride of TRANS-4-nitroxide of enciclopediamedicaju suspended in 10 ml of dry dichloromethane and thereto with stirring dropwise added to 0.95 ml of triethylamine and 5 ml of a solution of carboxylic acid in dry dichloromethane under cooling on ice and stirred at the same temperature for 1 hour. The solvent is kept at reduced pressure. The remainder is astorias for separation and purification, and was led from the ether with the receipt of 0.30 g of the desired compound in the form of a colorless crystalline product.

So pl.: 117-119oC (decomposition)

An NMR spectrum (CDCl3+d6-DMSO) ppm: 0,90-of 1.15 (4H, m), 1,40-1,60 (1H, m), 1.60-to 1,95 (5H, m), 3,14 (2H, m), 3,60-of 3.78 (2H, m), 4,20-to 4.38 (3H, m), 7,10 (1H, usher.), to 7.67(1H, user.)

Example 2

N-[CIS-4-nitrosomethylethylamine] -(4R)-2 - oxothiazolidine-4-ylcarbonyl (Compound 1-32 N)

In 8 ml of dry tetrahydrofuran added 0.40 g of (4R)-2-oxo-4 - thiazolidinones acid and 0.73 g of the hydrochloride CIS-4 - nitrosomethylethylamine, and with stirring was added to 1.14 ml of triethylamine and 0.70 ml diphenylphosphonate while cooling on ice, and the resulting mixture was stirred at room temperature for 4 hours. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 2/1). Thus obtained yellow oil was treated with ether to obtain 0,69 g of pale yellow crystalline product. Pale yellow crystalline product was dissolved in acetone, were added ethyl acetate, acetone drove away under reduced pressure, and the residue was left to stand at room the KTA.

So pl.: 94-96oC (decomposition)

An NMR spectrum (CDCl3+d6-DMSO) ppm: 1,30-of 1.65 (8H, m), 1,65 of-1.83 (1H, m), 1,87-2,05 (1H, m), 3,13-to 3.35 (2H, m), 3,60 is 3.76 (2H, m), 4,23-to 4.33 (1H, m), to 4.38 (2H, J=7 Hz), 7,05-7,20 (1H, usher.), of 7.69 (1H, s).

Example 3

N-[TRANS-4-(2-nitroxyethyl) cyclohexylmethyl]- (4R)-2-oxo-thiazolidin-4-ylcarbonyl (Compound N 1-169)

In 20 ml of anhydrous tetrahydrofuran suspended 191 mg of (4R)-2-oxo - 4-thiazolidinones acid and 294 mg of the hydrochloride of TRANS-4- (nitroxyethyl)cyclohexylethylamine and with stirring, thereto was added 0.54 ml of triethylamine and 0.28 ml diphenylphosphonate while cooling on ice, the resulting mixture was stirred at room temperature for 4 hours. The solvent is kept under reduced pressure, and the residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ ethyl acetate = 1/3) and recrystallized from dichloromethane - Diisopropylamine to obtain 200 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 78-80oC

An NMR spectrum (CDCl3) ppm: 0,82-1,08 (4H, m), 1,25-1,90 (8H, m), 3,05 is 3.23 (2H, m), 3,66 (1H, DD, J=4,6 Hz, J=11.2 Hz), a-3.84 (1H, DD, J=8.6 Hz, J= 11.2 Hz), 4,32-and 4.40 (1H,m), 4,51 (2H, t, J=6.6 Hz), 6,50-6,70 (2H, m)

Example 4

N-[TRANS-4-(3-nitrosopropane) cyclohexylmethyl 908 mg of (4R)-2-oxo-4-thiazolidinones acid and 1.30 grams of the hydrochloride of TRANS-4-(3-nitrosopropane) cyclohexylethylamine, received 898 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 110-112oC

An NMR spectrum (CDCl3) ppm: 0,80-1,08 (4H, m), 1,10-1,90 (10H, m), 3,05-of 3.25 (2H, m), 3,63 (1H, DD, J=4.5 Hz, J=11 Hz), 3,81 (1H, DD, J=8.6 Hz, J=11 Hz), 4,30-and 4.40 (1H,m), 4,43 (2H, t, J=7,6 Hz), 6,45-6,70 (2H, m)

Example 5

N-[TRANS-4-(1-nitroxyethyl) cyclohexylmethyl] - (4R)-2-oxothiazolidine-4-ylcarbonyl (Compound N 1-1201)

Using the method similar to example 3, using 311 mg of (4R)-2-oxo-4-thiazolidinones acid and 421 mg of the hydrochloride of TRANS-4-(3-nitrosopropane) cyclohexylethylamine, got 305 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 85-87oC (decomposition)

An NMR spectrum (CDCl3) ppm: 0,85-1,25 (5H, m) of 1.32 (3H, d, J=5,9 Hz), 1,40-to 1.67 (2H, m), 1.70 to of 1.97 (4H, m), 3,10-of 3.28 (2H, m), 3,62 (1H, DD, J=4 Hz, J=11 Hz), 3,82 (1H, DD, J=8.6 Hz, J=11 Hz), 4,32-and 4.40 (1H,m), 4,86-5,00 (1H, m) of 6.26 (1H, s), 6.48 in (1H, user.)

Example 6

N-[TRANS-1-(4-microclimatological) ethyl] - (4R)-2-oxothiazolidine-4-ylcarbonyl (Compound N 1-1192)

Using the method similar to example 3, using 300 mg of (4R)-2-oxo-4-thiazolidinones acid and 400 mg of hydrochloride of TRANS-1-(4-microclimatological)-ethylamine was obtained the desired compound, two isomers (based on therefore, its in the form of a colorless crystalline product.

Isomer A

Thin layer chromatography: Rf = 0,27 (solvent for pickup: cyclohexane/ethyl acetate = 1/2)

So pl.: 147-150oC (decomposition)

An NMR spectrum (CDCl3) ppm: 0,92-1,20 (4H, m) of 1.13 (3H, d, J=6.6 Hz), 1.30 and of 1.95 (6H, m), 3,63 (1H, DD, J=4,6 Hz, J=11 Hz), 3,80 (1H, DD, J=8.6 Hz, J= 11 Hz), with 3.89 (1H, DD, J=6,6 Hz, J=16 Hz), 4,27 (2H, d, J=6.6 Hz), 4,30 was 4.42 (1H, m), 6,23 (1H, d, J=8.6 Hz), is 6.54 (1H, s)

Isomer B

Thin layer chromatography: Rf = 0,14 (solvent for pickup: cyclohexane/ethyl acetate = 1/2)

So pl.: 131-133oC (decomposition)

An NMR spectrum (CDCl3) ppm: 0,92-1,20 (4H, m) to 1.14 (3H, d, J=6.6 Hz), 1.25 and a 1.96 (6H, m), 3,60 (1H, DD, J=4 Hz, J=11 Hz), a-3.84 (1H, DD, J=8.6 Hz, J=11 Hz), a 3.87-4,00 (1H, m) to 4.33 (2H, d, J=6.6 Hz), 4,30-and 4.40 (1H, m), the 6.06 (1H, s), 6,24 (1H, d, J=8.6 Hz)

Example 7

N-[TRANS-4-(1-methyl-2-nitroxyethyl) cyclohexylmethyl] -(4R)-2-oxothiazolidine-4-ylcarbonyl (Compound N 1-1210)

Using the method similar to example 3, using 76,9 mg of (4R)-2-oxo-4-thiazolidinones acid and 110 mg of the hydrochloride of TRANS-4-(1-methyl-2-nitroxyethyl)- cyclohexylethylamine, received 91 mg of the desired compound as a colourless oil.

An NMR spectrum (d6-DMSO) ppm: 0,78-of 1.45 (6H, m) to 0.89 (3H, d, J=6.9 Hz), to 2.94 (2H, t, J=6.2 Hz), 3.25 to 3.40 in (1H, m), the 3.65 (1H, DD, J=8.5 Hz, J=11 Hz), 4,22-and 4.40 (2H,m), 4,45-of 4.57 (1H, m), 8,00 (1H, t, J=5.6 Hz), of 8.25 (1H, s)< / BR>
Example 8

N-[TRANS-2-(4-n is similar to example 3, when using 152 mg of (4R)-2 - oxo-4-thiazolidinones acid and 205 mg of the hydrochloride of TRANS-2- (4-microclimatological)-ethylamine, got 221 mg of the desired compound in the form of a colorless crystalline product. So pl.: 82-84oC

An NMR spectrum (CDCl3) ppm: 0,85-of 1.55 (5H, m), 1,62 - 1,90 (5H, m), 3,20-of 3.43 (2H, m) to 3.64 (1H, d,d, J=4,6 Hz, J=11 Hz), with 3.79 (1H, DD, J=8.6 Hz, J= 11 Hz), 4,27 (2H, d, J=6.4 Hz), 4,30-and 4.40 (1H, m), of 6.71 (1H, t, J=5.3 Hz), 7,05 (1H, s)

Example 9

N-[TRANS-2-[4-(3-nitrosopropane) cyclohexyl] ethyl]-(4R)-2-oxothiazolidine-4-ylcarbonyl (Compound No. 1 - 207)

Using the method similar to example 3, when used to 98.6 mg of (4R)-2-oxo-4-thiazolidinones acid and 149 mg of the hydrochloride of TRANS-2-[4-(3-nitrosopropane) cyclohexyl]- ethylamine, received 83 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 101-103oC (decomposition)

An NMR spectrum (d6-DMCO) ppm: 0.75 to 0,98(4H, m), 1,10 - to 1.38 (6H, m), 1,60-1,80 (6H, m), 3,05-3,17 (2H, m), 3,20 - to 3.38 (1H,m), 3,64 (1P, DD, J=8,3 Hz, 7=11 Hz), with 3.79 (1H, DD, J=8.6 Hz, J=11 Hz), 4,17-to 4.28 (1H,m), of 4.49 (2H, t,J=6.6 Hz), 4,30-and 4.40 (1H, m), to 7.99 (1H, t, J=5.4 Hz), of 8.25 (1H, s)

Example 10

N-(3-Microclimatological)-(4R)-2 - oxothiazolidine-4-ylcarbonyl (Compound N 1-669)

Using the method similar to example 3, using of 1.05 g of (4R)-2 - oxo-4-thiazolidine the RA, namely, 301 mg of isomer A and 231 mg of isomer B in the form of a colorless crystalline product, respectively.

Isomer A

Thin layer chromatography: Rf = 0.52 in (the solvent for the pickup: ethyl acetate)

So pl.: 173-177oC (decomposition)

An NMR spectrum (CDCl3+d6-DMSO) ppm: 0,90-1,50 (4H, m), 1,72 is 2.10 (5H, m), 3,60-are 3.90 (3H, m), 4,22-and 4.40 (3H, m), 6,97 (1H, d, J=7.9 Hz), to 7.59 (1H, s)

Isomer B

Thin layer chromatography: Rf = 0,43 (solvent for pickup: ethyl acetate)

So pl.: 141-143oC (decomposition)

An NMR spectrum (CDCl3+d6-DMSO) ppm: 0.88 to of 1.52 (4H, m), 1.70 to to 2.25 (5H, m), 3,60-are 3.90 (3H, m), 4,22 is 4.35 (3H, m), 6,92 (1H, d, J=7,6 Hz) to 7.50 (1H, s)

Example 11

N-(4-Microclimatological)-(4R)-2-oxothiazolidine-4 - ylcarbonyl (Compound N 1-1)

Using the method similar to example 3, using 486 mg of (4R)-2-oxo-4-thiazolidinones acid and 837 mg of the hydrochloride of 4 - nitrosomethylethylamine received 602 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 124-126oC (decomposition)

An NMR spectrum (CDCl3+d6-DMSO) ppm: 1,15 is 2.00 (9H, m), 3,60-of 3.77 (2H, m), 3,98 is 4.13 (1H, m), 4,25 is 4.35 (1H, m), 4,37 (2H, d, J=6,7 Hz) 6,86 (1H, d, J=6.9 Hz), 7,73 (1H, s)

Example 12

N-(TRANS-2-microclimatological)-(4R)-2 - oxothiazolidine-4-ylcarbonyl Borovoy acid and 541 mg of hydrochloride of TRANS-2 - nitrosomethylethylamine, received 319 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 108-111oC (decomposition)

An NMR spectrum (CDCl3) ppm: 1.00 m and 1.35 (4H, m), 1,40 - 1,90 (6H, m), 3,22-3,50 (2H, m), 6,63 (1H, DD, J=5.3 Hz, J=a 10.6 Hz), 3,81 (1H, DD, J=8.6 Hz, J= a 10.6 Hz), 4,32-4,60 (3H, m), of 6.68 (1H, usher.), 6,76 (1H, s)

Example 13

N-(CIS-2-nitrosomethylethylamine)-(4R)-2 - oxothiazolidine-4-ylcarbonyl (Compound N 1-633)

Using the method similar to example 3, using 480 mg of (4R)-2 - oxo-4-thiazolidinones acid and 570 mg of the hydrochloride of the CIS-2 - nitrosomethylethylamine, received 61 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 74-77oC (decomposition)

An NMR spectrum (CDCl3) ppm: 0,80 is 1.70 (8H, m), 1,88 e 2.06 (1H, m), 2.06 to 2,22 (1H, m), 3,13-3,50 (2H, m), 3,60-3,70 (1H, m), 3.75 to 3,90 (1H, m), 4,30-to 4.62 (3H, m), of 6.75 (1H, s), at 6.84 (1H, s)

Example 14

N-(3-Nitrosomethylethylamine)-(4R)-2 - oxo-thiazolidin-4-ylcarbonyl (Compound N 1-681)

Using the method similar to example 3, using 490 mg of (4R)-2 - oxo-4-thiazolidinones acid and 890 mg of the hydrochloride of 3-nitrosomethylethylamine received 850 mg of the desired compound as a yellow oil.

An NMR spectrum (CDCl3+d6-DMSO) ppm: 0,60-1,10 (2H, m), 1.20 of ethylcyclopentane)-(4R)-2 - oxothiazolidine-4-ylcarbonyl (Compound N 1-525)

Using the method similar to example 3, using 294 mg of (4R)-2 - oxo-4-thiazolidinones acid and 471 mg of the hydrochloride of 2-nitrosomethylethylamine obtained in reference example 79, received the desired connection, two isomers, namely, 153 mg of isomer A and 88 mg of isomer B in the form of a colorless crystalline product, respectively.

Isomer A

Thin layer chromatography: Rf = 0,57 (solvent for pickup: ethyl acetate)

So pl.: 109-111oC

An NMR spectrum (CDCl3+d6-DMSO) ppm: 1,40-2,10 (6H, m), 2,40 - of 2.58 (1H, m), of 3.69 (2H, d, J=7,3 Hz), 4,23-4,60 (4H, m),? 7.04 baby mortality (1H, d, J=7.9 Hz), 7,82 (1H, s).

Isomer B

Thin layer chromatography: Rf = 0,49 (solvent for pickup: ethyl acetate)

So pl.: 103-105oC

An NMR spectrum (CDCl3+D6-DMSO) ppm: 1,40-2,10 (6H, m), 2.40 a-to 2.57 (1H, m), 3,70 (2H, d, J=6.6 Hz), 4,20 is 4.35 (2H, m), 4,25-4,58 (2H, m), 7,05 (1H, d, J=7.9 Hz), to 7.67 (1H, s)

Example 16

N-(2-Nitrosomethylamino)-(4R)-2 - oxothiazolidine-4-ylcarbonyl (Compound N 1-525)

Using the method similar to example 3, using 444 mg of (4R)-2-oxo-4-thiazolidinones acid and 532 mg of the hydrochloride of 2-nitrosomethylethylamine obtained in reference example 81, received the desired connection, two isomers, namely, 148 mg of the isomer is cologna chromatography: Rf = 0,27 (solvent for pickup: cyclohexane/ethyl acetate =1/2)

So pl.: 96-98oC

An NMR spectrum (CDCl3+d6-DMSO) ppm: 1,20 was 2.25 (7H, m), to 3.58 is 3.76 (2H, m), 3.95 to to 4.17 (1H, m), 4,23-of 4.35 (1H, m), 4,42 (1H, DD, J=7,3 Hz, J=a 10.6 Hz), 4,55 (1H, DD, J=5,9 Hz, J=a 10.6 Hz), 7,22 (1H, d, J=7,4 Hz), 7,54 (1H, s)

Isomer B

Thin layer chromatography: Rf = 0,18 (solvent for pickup: cyclohexane/ethyl acetate = 1/2)

So pl.: 118-120oC

An NMR spectrum (CDCl3+d6-DMSO) ppm: 1,36 was 2.25 (7H, m), 3,68 (2H, d, J=6.2 Hz), 3,97-to 4.15 (1H, m), 4,23-of 4.35 (1H, m), 4,42 (1H, DD, J=7,2 Hz, J=10.5 Hz), of 4.44 (1H, DD, J=5,9 Hz, J=10.5 Hz), 7.23 percent (1H,d, J=7.5 Hz), 7,53 (1H, s)

Example 17

N-[4-(4-Nitroxymethyl) yclohexanol] -(4R)- 2-oxothiazolidine-4-ylcarbonyl (Compound N 1-1224)

Using the method similar to example 3, using 32.4 mg (4R)-2-oxo-4-thiazolidinones acid and 49 mg of the hydrochloride of 4-(2-nitroxyethyl)cyclohexylethylamine, received 44 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 90-93oC (decomposition)

An NMR spectrum (CDCl3) ppm: 0,80-of 1.05 (4H, m), 1,05 - 2,05 (1 H, m), 3,06-3,30 (2H, m), 3,62 (1H, DD, J=4.5 Hz, J=11.3 Hz), 3,82 (1H, DD, J=8.6 Hz, J= 11.3 Hz), 4,30-and 4.40 (1H, m), of 4.45 (2H, t, J=6.6 Hz), 6,33-6,60 (2H, m) 6,86 (1H, d, J=6.9 Hz), 7,73 (1H, s)

Example 18

The hydrochloride of N-(5-nitroxymethyl-2-piperidinylmethyl) -(4R)-2-oxothiazolidine-4-ylcarboxamine (Compound N 1-1040)

In 40 ml of dry tetrag the dihydrochloride of 5-nitroxymethyl-2-piperidinylidene, and thereto under stirring were added to 0.94 ml of triethylamine and 0,188 ml diethylthiophosphate under ice cooling, and the mixture was stirred at room temperature for 5 hours. To the reaction mixture were added 0,463 ml of di-tert-BUTYLCARBAMATE and a catalytic amount of 4-dimethylaminopyridine, the resulting mixture was stirred at room temperature for 1 hour. Then thereto was added 2.0 ml of di-tert-BUTYLCARBAMATE and the mixture was stirred at 30oC for 1.5 hours. The insoluble residue was filtered, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 2/3-1/6), and the fraction with Rf 0.14 when thin-layer chromatography (solvent for pickup: cyclohexane/ethyl acetate = 1/2) was collected by separation. Thus obtained foam was dissolved in 5.0 ml of a mixture of 4 G. hydrochloric acid-dioxane, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 20 ml of ether, the crystals were collected by filtration to obtain 40 mg of the desired compound as a pale yellow crystalline product.

So pl.: 95-99oC (decomposition)

An NMR spectrum (CDCl3) ppm: 1,20-1,50 (Ilony example 1

TRANS-4-N - butoxycarbonylmethylene acid

In 50 ml of water was dissolved 5.0 g of TRANS-4-aminomethylenemalonate acid, and thereto was added 6.6 ml of triethylamine. Then to the mixture was added 11.2 ml of a solution of di-tert-BUTYLCARBAMATE in dioxane (20 ml), the mixture was stirred at room temperature for 3 hours. Dioxane drove under reduced pressure and the solution was added citric acid to a final aqueous solution to bring the pH to 4.0. The mixture was extracted with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent drove to obtain a colorless crystalline substance. To the crystalline substance was added isopropyl ether, crystalline substance was collected by filtration and dried to obtain 7.0 g of the desired compound in the form of a colorless crystalline product.

So pl.: 126-128oC

An NMR spectrum (CDCl3) ppm: 0,85-1,05 (2H, m), 1,30 - 1,60 (9H, m), 1,75-of 1.92 (2H, m), 1,95-2,12 (2H, m), 2,18 to 2.35 (1H, m), 2,85 was 3.05 (2H, m), 4,60 (1H, user.)

Reference example 2

TRANS-4-N-tert-butoxycarbonylamino - 1-hydroxymethylcellulose

In anhydrous tetrahydrofuran (60 ml) was dissolved 5.0 g of referene under stirring and cooling on ice, the mixture was allowed to mix at room temperature for 2 hours. To the reaction mixture was added excess desativado sodium sulfate, the insoluble part was filtered, and the filtrate was subjected to distillation under reduced pressure. The residue was dissolved in dichloromethane and dried over anhydrous magnesium sulfate, and the solvent drove away. Thus obtained residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane - ethyl acetate (2:1) to obtain 1.4 g of the desired compound in the form of a colorless crystalline product.

So pl.: 88-89oC

An NMR spectrum (CDCl3) ppm: 0,85-1,05 (4H, m), 1,25-1,52 (11H, m), 1,75-1,90 (4H, m), 2,98 (2H, t, J=6.4 Hz), of 3.45 (2H, d, J=6.2 Hz), br4.61 (1H, user.)

Reference example 3

TRANS-4-N-tert-butoxycarbonylamino-1-nitroxymethyl-cyclohexane

To 24 ml of anhydrous acetonitrile under stirring and cooling on ice was added to 1.3 g tetrafluoroborate nitronium and 1.19 g of 2,4,6-collidine, the mixture was stirred at the same temperature for 0.5 hours. To the reaction mixture was added 1.2 g of the compound in reference example 2, and the resulting mixture was stirred at room temperature for 70 minutes. The solvent drove penny by removal of the solvent under reduced pressure was purified by chromatography on a column of silica gel, using as an eluting solvent cyclohexane-ethyl acetate (9: 1) obtaining of 1.09 g of the desired compound as a pale yellow crystalline product.

So pl.: 65-67oC

An NMR spectrum (CDCl3) ppm: 0,85-of 1.13 (4H, m), 1,44 (10H, s), 1.60-to 1,95 (5H, m), 2,98 (2H, t, J=6.4 Hz), 4,27 (2H, d, J=6.4 Hz), 4,59 (1H, user.)

Reference example 4

Hydrochloride, TRANS-4-nitrosomethylethylamine

1.1 g of the compound in reference example 3 was dissolved in 15 ml of a mixture of 4 G. hydrochloric acid/dioxane and stirred at room temperature for 1 hour. The precipitated crystalline substance was collected by filtration and was intensively washed with dioxane and ether. Then the crystalline product was washed with ethanol and ether, and dried to obtain 0.25 g of the desired compound as a colourless crystalline substance, and the solvent drove away. Thus obtained residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (2:1) to obtain 1.4 g of the desired compound in the form of a colorless crystalline product.

So pl.: 166-168oC (decomposition)

An NMR spectrum (d6-DMSO) ppm: 0,85-1,10 (4H, m), 1,45 - 1,90 (6H, m), 2,62 (2H, d, J=6.8 Hz), 4,37 (2H, the ol was dissolved 3.0 g of CIS-1,4-cyclohexanedicarboxylic acid and added 33,0 ml trimethylsilyldiazomethane (2 M solution in hexane). The mixture was stirred at room temperature overnight. The solvent is kept at reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was intensively washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is kept at reduced pressure obtaining of 3.46 g of the desired compound as a yellow oil.

An NMR spectrum (CDCl3) ppm: 1.60-to to 1.98 (8H, m), 2.40 a is 2.55 (2H, m), 3,68 (6H, m)

Reference example 6

Monomethyl CIS-1,4-cyclohexanedicarboxylate

In 35 ml of methanol was dissolved of 3.46 g of dimethyl CIS-1,4 - cyclohexanedicarboxylate and to it was added a 17.3 ml of 1 N. aqueous sodium hydroxide solution, and the resulting mixture was stirred at room temperature for 1.5 hours. The solvent is kept under reduced pressure and the resulting aqueous solution was washed with ethyl acetate. Diluted hydrochloric acid was bringing the pH of the mixture to 1 while cooling on ice and the mixture was extracted with ethyl acetate. The extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent drove under reduced pressure to obtain a colorless crystalline substance. To crystallinum of 1.76 g of the desired compound as a pale yellow crystalline product.

So pl.: 91-93oC

An NMR spectrum (CDCl3+d6-DMSO) ppm: 1,60-2,00 (8H, m), 2,42-2,52 (2H, m) to 3.67 (3H, s)

Reference example 7

CIS-4-carbamoyltransferase acid

In 55 ml of concentrated aqueous ammonia was dissolved 5.29 g monomethyl CIS-1,4-cyclohexanecarboxylate, and the mixture was left at room temperature for 6 days. Concentrated hydrochloric acid was bringing the pH of the mixture to 1 while cooling on ice, the precipitated crystalline substance was collected by filtration and washed with water to form a brown crystalline product. The crystalline product was recrystallized from ethyl acetate to obtain 2,96 g of the desired compound as pale yellow columnar crystalline product.

So pl.: 209-211oC

An NMR spectrum (d6-DMSO) ppm: of 1.30 and 1.80 (6H, m), 1,80 is 1.96 (2H, m), 2.05 is-2,22 (1H, m), 2,30-to 2.40 (1H, m), to 6.67 (1H, s), 7,17 (1H, s), 12,09 (1H, s)

Reference example 8

CIS-4-tert-butoxycarbonylamino-1 - hydroxymethylcellulose

In 35 ml of tetrahydrofuran suspended 3,40 g of CIS-4-carbamoyltransferase acid and thereto was added with stirring to 50.0 ml of 1 M lydialydia while cooling with ice. The mixture was stirred at room temperature for 0.5 hours and livadnogo sodium sulfate under stirring and cooling on ice to decompose the excess lydialydia. The insoluble portion was separated by filtration on Celite (Celite) and the solvent is kept at reduced pressure. The residue was dissolved in dichloromethane and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure to obtain a colorless oil. The oil was dissolved in 30 ml of methanol, was added 3.0 ml of di-tert - BUTYLCARBAMATE and the mixture was stirred at room temperature for 0.5 hours. The solvent is kept under reduced pressure and the resulting residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 2/1) to obtain a colorless crystalline product. To the crystalline product was added isopropyl ether and the crystalline substance was collected by filtration to obtain 1,69 g of the desired compound in the form of a colorless crystalline product.

So pl.: 93-95oC

An NMR spectrum (CDCl3) ppm: 1,28-1,75 (20H, m), of 3.07 (2H, t, J=6.6 Hz), 3,53 (2H, d, J=4.6 Hz), 4,56 (1H, user.)

Reference example 9

CIS-N-tert-butoxycarbonyl-4 - microclimatological-methylamine

Using methods similar to reference example 3, using 1.60 g of CIS-N-tert - butoxycarbonylamino-1-hydroxymethylcellulose product.

So pl.: 64-66oC

An NMR spectrum (CDCl3) ppm: 1,25-1,75 (18H, m), 1,88-2,02 (1H, m), is 3.08 (2H, t, J=6.6 Hz), 4,36 (2H, d, J=7,3 Hz), of 4.54 (1H, user.)

Reference example 10

Hydrochloride CIS-4-nitrosomethylethylamine

Using methods similar to reference example 4, using 1.40 g of CIS-N-tert-butoxycarbonyl - 4-nitroxymethyl-cyclohexylethylamine and 14.0 g of 4 n/ a mixture of hydrochloric acid-dioxane, got 0,94 g of the desired compound as a pale yellow crystalline product.

So pl.: 181-182oC (decomposition)

An NMR spectrum (CDCl3) ppm: 1,25-1,75 (18H, m), 1,88 - 2,02 (1H, m), is 3.08 (2H, t, J=6.6 Hz), 4,36 (2H, d, J=7,3 Hz), of 4.54 (1H, user.)

Reference example 11

TRANS-N-tert-butoxycarbonyl-4-(2 - diazoacetic)-cyclohexylethylamine

In 60 ml of dry tetrahydrofuran was dissolved 3.00 g of TRANS-4-N-tert - butoxycarbonyloxyimino acid, and thereto were added to 1.28 ml of N-methylmorpholine and 1, 51 ml of isobutylphthalate at 20oC, the resulting mixture was stirred at 20oC for 2 hours. Osadovskaya salt of hydrochloric acid and N-methylmorpholine was separated by filtration, and the filtrate was added to 200 ml of diazomethane in ether, obtained from 7.0 g of N-nitrosomethyl-urea at 20oC. the Reaction mixture was stirred at-2 is whether under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluting solvent: dichloromethane/ethyl acetate = 8.1) to obtain a pale yellow crystalline substance. The crystalline substance was recrystallized from isopropyl ether to obtain 948 mg of the desired compound as a pale yellow crystalline product.

So pl.: 106-107oC

An NMR spectrum (CDCl3) ppm: 0,85-of 1.07 (2H, m), 1,30 -1,55 (12H, m), 1,78 is 1.96 (4H, m), 2.05 is-is 2.37 (1H, m), 2,98 (2H, t, J=7.4 Hz), 4,59 (1H, usher.), of 5.26 (1H, s)

Reference example 12

Methyl TRANS-4-N-tert-butoxycarbonylmethylene

In 30 ml of methanol was dissolved 923 mg of TRANS-N-tertbutoxycarbonyl-4-(2-diazoacetic)cyclohexylethylamine, and thereto was added dropwise 5.0 ml of a solution of 128 mg of silver acetate in triethylamine at room temperature, the resulting mixture was stirred at room temperature for 1 hour and 25 minutes. To the reaction mixture were added 10 ml of a saturated solution of sodium chloride, the resulting mixture was stirred at room temperature for 5 minutes and filtered using Celite. The filtrate is kept under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was intensively washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by chromatogr crystalline substances. The crystalline substance was recrystallized from isopropyl ether to obtain 796 mg of the desired compound in the form of colorless needle-like crystalline product.

So pl.: 53-55oC

An NMR spectrum (CDCl3) ppm: 0,85-1,12 (4H, m), 1,25 - 1,58 (1H, m) of 1.44 (9H, s), 1,63-of 1.88 (5H, m), 2,20 (2H, d, J=6,7 Hz), 2,96 (2H, t, J=6.4 Hz), 3,66 (3H, s) and 4.65 (1H, user.)

Reference example 13

TRANS-N-tert-butoxycarbonyl-4-(2-hydroxyethyl)-cyclohexylethylamine

In 10 ml of ethanol and 7.0 ml of tetrahydrofuran was dissolved 796 mg of methyl TRANS-4-N-tert - butoxycarbonylmethylene, were added under stirring 1.55 g of anhydrous calcium chloride while cooling on ice. The resulting mixture was stirred under cooling on ice for 1 hour, thereto was added 530 mg of sodium borohydride, the mixture was stirred at the same temperature for 30 minutes, at room temperature for 1 hour and 25 minutes, and then at 40-45oC for 4 hours. To the reaction mixture was added 5.0 ml of acetone and the resulting mixture was stirred for 1 hour and filtered using Celite. The filtrate is kept under reduced pressure, and the residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 3/1) to receive what lay 619 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 78-80oC

An NMR spectrum (CDCl3) ppm: 0,83-of 1.05 (4H, m), 1,25-of 1.55 (4H, m) of 1.44 (9H, s), 1,65-of 1.88 (4H, m), 2,59 (1H, s), 2,95 (2H, t, J=6.3 Hz), 3,66 (2H, t, J=6,7 Hz), 4,84 (1H, user.)

Reference example 14

TRANS-N-tert-butoxycarbonyl-4-(2-nitroxyethyl)-cyclohexylethylamine

Using methods similar to reference example 3, using the 574 mg of TRANS-N-tert - butoxycarbonyl-4-(2-hydroxyethyl)cyclohexylethylamine and 418 mg of Porterfield nitronium received 437 mg of the desired compound in the form of colorless needle-like crystalline product.

So pl.: 60-61oC

An NMR spectrum (CDCl3) ppm: 0,82-of 1.05 (4H, m), 1,25-1,50 (2H, m) of 1.44 (9H, s) of 1.62 (2H, q, J=6,6 Hz, J=13,2 Hz), 1.70 to a 1.88 (2H, m), 2,90-of 3.00 (2H, m), of 4.49 (2H, t, J=7,6 Hz), 4,65-is 4.85 (1H, user.)

Reference example 15

Hydrochloride, TRANS-4-(2-nitroxyethyl) cyclohexylethylamine

Using methods similar to reference example 4, using 437 mg of TRANS-N-tert-butoxycarbonyl-4-(2 - nitroxy)-ethylcyclohexylamine and 2.0 ml of a mixture of 4 G. hydrochloric acid-dioxane, got 298 mg of the desired compound as a pale yellow crystalline product.

So pl.: 175-176oC (decomposition)

An NMR spectrum (CDCl3+d6-DMSO) ppm: 0,85-1,12 (4H, m), 1,20-2,02 (8H, m), 2,65-is 2.88 (2H, m), of 4.49 (2H, t, J=7,6 Hz), 8,20 at 8.60 (3H, user.)

Ssylochku dichloromethane was dissolved 10.0 g of TRANS-4-N-tert - butoxycarbonylamino-1-hydroxymethyl-cyclohexane, and thereto were added to 14.3 ml of triethylamine and 14.3 g of anhydride methanesulfonic acid under stirring and cooling on ice, the resulting mixture was stirred at the same temperature for 50 minutes. The solvent is kept under reduced pressure and the residue was dissolved in ethyl acetate. The resulting solution was intensively washed with an aqueous solution of citric acid, an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent drove under reduced pressure to obtain a colorless crystalline substance. To the crystalline substance was added isopropyl ether and collected crystalline substance by filtration to obtain 13,24 g of the desired compound in the form of a colorless crystalline product.

So pl.: 105-107oC

An NMR spectrum (CDCl3) ppm: 0,83-of 1.13 (4H, m), 1.30 and of 1.53 (1H, m) of 1.44 (9H, s), 1.60-to of 1.94 (5H, m), 2,88-3,10 (2H, m) of 3.00 (3H, s), a 4.03 (2H, d, J= 6.6 Hz), 4,59 (1H, user.)

Reference example 17

TRANS-N-tert-butoxycarbonyl-4-iodometrically

In 130 ml of anhydrous acetone was dissolved 13,24 g of TRANS-N-tert-butoxycarbonyl-4 - methanesulfonylaminoethyl, were added 12,32 g of sodium iodide, and the resulting mixture was heated under reflux for 3 hours and 45 minutes. The solvent is kept at porom sodium thiosulfate and aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 4/1) to obtain pale yellow crystalline substance. The crystalline substance was recrystallized from hexane to obtain 13,67 g of the desired compound in the form of a colorless crystalline product.

So pl.: 81-83oC

An NMR spectrum (CDCl3) ppm: 0,83-1,10 (4H, m), 1,25 - of 1.52 (2H, m) of 1.44 (9H, s), 1,67-2,02 (4H, m), 2,98 (2H, t, J=6.4 Hz), 3,10 (2H, d, J=6.4 Hz), 4,58 (1H, user.)

Reference example 18

Diethyl TRANS-4-N-tert-butoxycarbonylmethylene

In 10 ml of anhydrous dimethylformamide was dissolved 0,856 ml of diethylmalonate, were added to 123.5 mg of sodium hydride with stirring on ice, the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added 1.0 g of TRANS-N-tert-butoxycarbonyl-4-iodometrically, the mixture was heated under stirring at an internal temperature of 70oC for 1 hour and 30 minutes. The mixture is then left to settle, to it was added an excess of an aqueous solution of ammonium chloride and the solvent is kept under reduced pressure what does over anhydrous magnesium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 4/1) to obtain 946 mg of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,78-1,08 (4H, m), 1,10-to 1.60 (8H, m) of 1.44 (9H, s), 1,65-1,90 (6H, m), 2,95 (2H, t, J=6.3 Hz), 3,44 (1H, t, J=7.8 Hz), 4,10-of 4.35 (4H, m), 4,59 (1H, user.)

Reference example 19

TRANS-3-(4-N-tert - butoxycarbonylmethylene) propionic acid

In 110 ml of methanol was dissolved 11,64 g of diethyl TRANS-4-N - tert-butoxycarbonylmethylene, were added 80,0 ml of 10% aqueous sodium hydroxide solution under stirring at room temperature, the mixture was stirred at the same temperature for 2 hours and 10 minutes. Methanol drove away under reduced pressure, was added with stirring an aqueous solution of citric acid while cooling on ice to bring the pH of the mixture to 4 and extracted with ethyl acetate. The extracts were intensively washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The obtained crystals suspended in 180 ml of xylene and heated under reflux for 1,TBA isopropyl ether to obtain crystalline product, the crystalline product was collected by filtration to obtain to 6.88 g of the desired compound in the form of a colorless crystalline product.

So pl.: 90-92oC

An NMR spectrum (CDCl3) ppm: 0,82-of 1.05 (4H, m), 1,13-a 2.00 (8H, m) of 1.44 (9H, s), a 2.36 (2H, t, J=7,6 Hz), 2,96 (2H, t, J=6.3 Hz), 4,60 (1H, user.)

Reference example 20

TRANS-3-(4-N-tert-butoxycarbonylmethylene) propanol

In 10 ml of dry tetrahydrofuran was dissolved 1.0 g of TRANS-3- (4-N-tert-butoxycarbonylmethylene) propionic acid, thereto was added under stirring of 0.54 ml of triethylamine and 0.15 ml of isobutylphthalate while cooling on ice, the mixture was stirred at the same temperature for 30 minutes. The insoluble portion was separated by filtration using Celite, and the filtrate was added with stirring dropwise to 5 ml of an aqueous solution of 0.40 g of sodium borohydride while cooling on ice, the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added 10 ml of acetone, and the resulting mixture was stirred at room temperature for 10 minutes. The solvent is kept at reduced pressure. To the residue were added water and ethyl acetate, separated ethyl acetate layer was washed with an aqueous solution of sodium chloride and dry what about the crystalline product. The crystalline product was recrystallized from a mixture solution of hexane and a small amount of isopropyl ether to obtain 763 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 76-80oC

An NMR spectrum (CDCl3) ppm: 0,80-of 1.05 (4H, m), 1,05-1,90 (10H, m) of 1.44 (9H, s), 2,96 (2H, t, J=6.3 Hz), 3,63 (2H, t, J=6.5 Hz), 4,59 (1H, user.)

Reference example 21

TRANS-N-tert-butoxycarbonyl-4-(3 - nitroxymethyl)-cyclohexylethylamine

Using methods similar to reference example 3, using 4.0 g of TRANS-3-(4-N - tert-butoxycarbonylmethylene)propanol are 2.87 g Porterfield nitronium, got 2.20 g of the desired compound in the form of colorless needle-like crystalline product.

So pl.: 94-95oC

An NMR spectrum (CDCl3) ppm: 0,78-1,02 (4H, m), 1,07 - of 1.55 (4H, m) of 1.44 (9H, s), 1,65-of 1.88 (6H, m), of 2.97 (2H, t, J=6.4 Hz), 4,43 (2H, d, J=6.8 Hz), 4,58 (1H, user.)

Reference example 22

Hydrochloride, TRANS-4-(3-nitrosopropane) cyclohexylethylamine

Using methods similar to reference example 4, using 2,19 g of TRANS-N-tert-butoxycarbonyl-4-(3 - nitrosopropane) cyclohexylethylamine and 20.0 ml of a mixture of 4 G. hydrochloric acid-dioxane, received of 1.57 g of the desired compound as a colourless crystalline 1,35-1,87 (7H, m), 2,62 (2H, d, J=6.5 Hz), 4,50 (2H, t, J=6.6 Hz), the 7.85-to 8.20 (3H, user.)

Reference example 23

TRANS-4-benzoyloxymethyl-1 - hydroxymethylcellulose

In 10 ml of tetrahydrofuran suspended 1.51 g of sodium hydride (content 55%) and was added dropwise with stirring a solution of 5.0 g of TRANS-1,4 - dihydroxybenzylamine dissolved in 20 ml of tetrahydrofuran while cooling on ice, the reaction mixture was stirred at room temperature for 50 minutes. To the reaction mixture under stirring and cooling on ice was added 3,79 ml benzylbromide, and the mixture was stirred while cooling on ice for 1 hour and then at room temperature. The insoluble portion was separated by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was intensively washed with an aqueous solution of sodium chloride, 10% aqueous solution of hydrochloric acid, an aqueous solution of sodium chloride and aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 20/1-5/1) to give 1.75 g of the desired compound in the form of best, ,46 (2H, t, J=5.3 Hz), 4,50 (2H, s), 7,20-7,40 (5H,

Reference example 24

TRANS-4 - benzyloxyacetaldehyde

A solution of 60 ml of anhydrous dichloromethane and of 1.33 ml of dimethyl sulfoxide was cooled in a bath of dry ice and acetone, and thereto was added dropwise 1,30 ml oxalicacid, the mixture was stirred at the same temperature for 10 minutes. Thereto was added dropwise a solution of 1.75 g of TRANS - 4-benzoyloxymethyl-1-hydroxymethylcytosine dissolved in 10 ml anhydrous dichloromethane, the mixture was stirred at the same temperature for 3 hours and 45 minutes. To the reaction mixture was added 5.2 ml of triethylamine at the same temperature, a bath of dry ice and acetone was removed, the temperature of the mixture was gradually returned to the 0oC adding thereto an excess of an aqueous solution of ammonium chloride. To the reaction mixture were added 200 ml of ethyl acetate, the mixture was intensively washed with an aqueous solution of sodium chloride, 10% aqueous solution of hydrochloric acid, aqueous sodium bicarbonate solution and an aqueous solution of sodium chloride. The mixture was dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (elution solvent: cyclohex(CDCl3) ppm: 0,95-to 1.14 (2H, m), 1,20-of 1.39 (2H, m), 1,50-1,70 (1H, m), 1,90-of 2.08 (4H, m), 2,10-of 2.25 (1H, m), 3,30 (2H, d, J=5,9 Hz), 4,50 (2H, s), 7,20 - 7,40 (5H, m), 9,62 (1H, d, J=1.3 Hz)

Reference example 25

TRANS-4-benzoyloxymethyl-1-(1 - hydroxyethyl) cyclohexane

In 50 ml of tetrahydrofuran was dissolved 1.27 g of TRANS-4-benzyloxyacetaldehyde and added dropwise to 6.7 ml Metalmania bromide (0.9 M solution in tetrahydrofuran), while cooling the mixture in a bath of dry ice and acetone, the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added to 11.0 ml of 10% aqueous solution of acetic acid, and then thereto was added 200 ml of ethyl-acetate. The solution was intensively washed with an aqueous solution of sodium chloride, 10% aqueous solution of hydrochloric acid, an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and dried over without water magnesium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ ethyl acetate = 5/1-4/1) to obtain 807 mg of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,90-of 1.15 (4H, m) of 1.20 (3H, d, J=5,9 Hz), 1,20-2,05 (7H, m), 3,32 (2H, d, J=6.6 Hz), 3,52 - 3,68 (1H, m), of 4.54 (2H, s), 7,25 EN

In 50 ml of dry dimethyl sulfoxide was dissolved 2.0 g of TRANS-4-benzoyloxymethyl-1-(1 - hydroxyethyl)cyclohexane and added 2,24 ml of triethylamine and a 1.88-tert-butyldimethylsilyloxy under stirring at room temperature, the mixture was stirred at room temperature for 2 hours and 50 minutes. To the reaction mixture were added 200 ml of ethyl acetate. The solution was intensively washed with an aqueous solution of citric acid, an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride. The mixture was dried over anhydrous magnesium sulfate and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 50/1) to give 2.76 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,02 (3H,s) of 0.03 (3H, s), 0,80-1,30 (4H, m) to 0.88 (9H, s) a 1.08 (3H, d, J=6.6 Hz), 1,45 - 1,90 (6H, m), with 3.27 (2H, d, J=6.6 Hz), 3.45 points-of 3.60 (1H, m), 4,50 (2H, s), 7,20-7,40 (5H, m)

Reference example 27

TRANS-4-hydroxymethyl-1-(1 - butyldimethylsilyloxy)-cyclohexane

In 50 ml of dry ethanol was dissolved 2.7 g of TRANS-4 - benzoyloxymethyl-1-(1-tert-butyldimethylsilyloxy)- cyclohexane, were added 2.0 g of 10% palladium on coal, poluchennom to the reaction mixture were added 2.0 g of 10% palladium on charcoal, and the resulting mixture was heated under reflux for 4 hours and 15 minutes with stirring in a stream of hydrogen. After the reaction palladium on coal was separated by filtration, and the solvent is kept at reduced pressure to obtain 1.85 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,03 (3H, s), and 0.04 (3H, s), 0.70 to of 1.95 (11H, m) to 0.88 (9H, s) 1,09 (1,5 H, d, J=6 Hz), 1,13 (1,5 H, l, J=6 Hz), of 3.45 (2H, d, J=6 Hz), 3,50-3,62 (1H, m)

Reference example 28

TRANS-4-(1-tert - butyldimethylsilyloxy)cyclohexanedimethanol

In 50 ml of dry dichloromethane was dissolved 1.85 g of TRANS-4-hydroxymethyl-1-(1 - tert-butyldimethylsilyloxy) cyclohexane 1.89 ml of triethylamine, and with stirring was added 1.77 g of the anhydride methanesulfonic acid while cooling on ice, the mixture was stirred at the same temperature for 35 minutes. To the reaction mixture were added 200 ml of ethyl acetate, the mixture was intensively washed with an aqueous solution of sodium chloride, an aqueous solution of citric acid, an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride. The mixture was dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. OS is = 5/1) to obtain a 2.01 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,02 (3H, s) of 0.03 (3H, s) to 0.88 (9H, s), 0,94-of 1.30 (5H, m) a 1.08 (3H, d, J=6.6 Hz), 1,50 - of 1.95 (5H, m) to 2.99 (3H, s), 3,50-3,62 (1H, m), a 4.03 (2H, d, J=6,6 Hz)

Reference example 29

TRANS-4-azidomethyl-1-(1-tert - butyldimethylsilyloxy)-cyclohexane

In 50 ml of dry dimethylformamide suspended 2.0 g of TRANS-4-(1-tert - butyldimethylsilyloxy) cyclohexylsulfamate and 1.85 g of sodium azide, the resulting mixture was stirred at 110oC for 45 minutes. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed three times with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure to obtain 1.7 g of the desired compound as a pale yellow oil. This oil is used for the subsequent reaction without purification.

An NMR spectrum (CDCl3) ppm: 0,02 (3H, s) of 0.03 (3H, s) to 0.88 (9H, s), 0.90 or of 1.28 (5H, m) a 1.08 (3H, d, J=6.6 Hz), 1,40 - of 1.94 (5H, m), of 3.12 (2H, d, J=6.6 Hz), 3,48-3,62 (1H, m)

Reference example 30

TRANS-N-tert-butoxycarbonyl-4-(1-tert - butyldimethylsilyloxy)cyclohexylethylamine

In 50 ml of dry ethanol was dissolved 1.7 g of TRANS-4-azidomethyl-1-(1-tert - butyldimethylsilyloxy) cyclohexane, to 2.57 ml of di-tert - BUTYLCARBAMATE and a catalytic amount of 4 - dimethylaminopyridine,of 1 hour. After the reaction palladium on coal was separated by filtration, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 50/1-10/1) to obtain 1.13 g of the desired compound in the form of a colorless crystalline product.

So pl.: 67-70oC

An NMR spectrum (CDCl3) ppm: 0,02 (3H, s) of 0.03 (3H, s), 0,80-of 1.92 (10H, m) to 0.88 (9H, s) of 1.07 (3H, d, J=5,9 Hz), the 1.44 (9H, s), 2,95 (2H, t, J=6 Hz), 3.45 points-of 3.60 (1H, m), of 3.56 (1H, user.)

Reference example 31

TRANS-H-tert-butoxycarbonyl-4-(1 - hydroxyethylcellulose

In 20 ml of dry tetrahydrofuran was dissolved 1.3 g of TRANS-N-tert-butoxycarbonyl-4-(1-tert - butyldimethylsilyloxy)cyclohexylethylamine and dropwise with stirring was added a 5.25 ml of tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) under cooling on ice, the mixture was stirred at room temperature for 55 minutes. Then dropwise added 5 ml of tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) and the mixture was stirred at room temperature overnight and then at 50oC for 9 hours. To the reaction mixture were added 200 ml of ethyl acetate and the mixture is intensively washed with water rest the ohms of sodium chloride. The mixture was dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 2/1) to obtain 701 mg of the desired compound in the form of a colorless crystalline product. Next, 38 mg of the desired product was obtained from the mother liquor.

So pl.: 75-76oC

An NMR spectrum (CDCl3) ppm: 0,80-1,97 (11H, m), 1,16 (1H, d, J=6.6 Hz), the 1.44 (9H, s), of 2.97 (2H, t, J=6.6 Hz), 3,48-3,62 (2H, m), of 4.57 (1H, user.)

Reference example 32

TRANS-N-tert-butoxycarbonyl-4-(1 - nitroxyethyl)-cyclohexylethylamine

Using methods similar to reference example 3, using 739 mg of TRANS-N-tert - butoxycarbonyl-4-(1-hydroxyethyl)cyclohexylethylamine and 561 mg Porterfield nitronium received 533 mg of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,84-1,97 (10H, m) is 1.31 (3H, d, J=5,9 Hz), the 1.44 (9H, s), of 2.97 (2H, t, J=6 Hz), 4,56 (1H, usher.), 4,85-to 4.98 (1H, m)

Reference example 33

Hydrochloride, TRANS-4-(1-nitroxyethyl) cyclohexylethylamine

Using methods similar to reference example 4, using 533 mg of TRANS-N-tert-butoxycarbonyl-4-1 - nitroxyethyl) cyclohexylethylamine and 10.0 ml of a mixture of 4 G. hydrochloric cysts.sq.: 160-163oC (decomposition)

An NMR spectrum (d6-DMSO) ppm: 0,80-1,20 (4H, m) of 1.28 (3H, d, J=6.6 Hz), 1,42-1,90 (6H, m), 2.63 in (2H, d, J=7,3 Hz), 4.92 in-5,08 (1H, m), 7,80-to 8.20 (3H, user.)

Reference example 34

TRANS-4-benzoyloxymethyl-1-(1 - methanesulfonylaminoethyl)-cyclohexane

In 50 ml of anhydrous dichloromethane was dissolved 1.50 g of TRANS-4-benzoyloxymethyl-1-(1 - hydroxyethyl) cyclohexane and its 1.68 ml of triethylamine, and thereto was added with stirring 1,58 g methanesulfonic acid while cooling on ice, the mixture was stirred at room temperature for 1 hour and 25 minutes. The solvent is kept under reduced pressure and to the residue was added 150 ml of ethyl acetate. The mixture was intensively washed with an aqueous solution of sodium chloride, 10% aqueous solution of hydrochloric acid, an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel using dichloromethane as eluent to obtain 1,71 g of the desired compound as a pale yellow oil.

An NMR spectrum (CDCl3) ppm: 0,85-1,20 (4H, m) of 1.39 (3H, d, J=5,9 Hz), 1,45-of 1.95 (6H, m), 2,99 (3H, s), or 3.28 (2H, d, J=6.6 Hz), of 4.49 (2H, s), 4,55-and 4.68 (1H, m), 7,20-7,40 (5 is Informatica suspended 1.70 g of TRANS-4-benzoyloxymethyl-1-(1-methanesulfonylaminoethyl)- cyclohexane and 1.69 g of sodium azide, and the mixture was stirred at 110oC for 30 minutes. To the reaction mixture were added 200 ml of ethyl acetate and the mixture was washed three times with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent drove under reduced pressure to obtain 1.48 g of the desired compound as a pale yellow oil. This connection is used for the subsequent reaction without purification.

An NMR spectrum (CDCl3) ppm: 0,85-of 1.16 (4H, m), 1,20 is 1.96 (6H, m) of 1.24 (3H, d, J=6.6 Hz), 3,20-to 3.33 (3H, m), of 4.49 (2H, s), 7,20-7,40 (5H, m)

Reference example 36

TRANS-4-(1-N-tert - butoxycarbonylamino)-1-hydroxymethylcellulose

In 50 ml of dry ethanol was dissolved 1.48 g of TRANS-4-benzoyloxymethyl-1-(1 - azidoethyl)cyclohexane, 1,20 ml of di-tert-BUTYLCARBAMATE and a catalytic amount of 4-dimethylaminopyridine, and thereto was added 1.0 g of 10% palladium on charcoal, the mixture was stirred in hydrogen atmosphere at a pressure of 1 ATM at room temperature for 1 hour, at 50oC for 40 min and then was heated under reflux for 1 hour. Then thereto was added 1.0 g of 10% palladium on coal and the resulting mixture was heated under reflux in an atmosphere of hydrogen at 1 ATM for 1 hour and 20 minutes. Then they added 2.0 g of 10% p. the hours. In addition, there was added 5 drops of 10% aqueous hydrochloric acid solution and the mixture was heated in an atmosphere of hydrogen at 1 ATM under reflux for 4 hours and 45 minutes. After completion of the reaction, palladium on coal was separated by filtration, and the solvent is kept at reduced pressure. The residue was dissolved in a mixture solution of 10 ml of methanol and 10 ml of dichloromethane, to which was added to 0.72 ml triethylamine, 1,20 ml of di-tert-BUTYLCARBAMATE and a catalytic amount of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 150 ml of ethyl acetate and the mixture was intensively washed with an aqueous solution of citric acid, an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (5:2-2:1) to give 617 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 93,5-95oC

An NMR spectrum (CDCl3) ppm: 0,83-1,92 (11H, m) a 1.08 (3H, d, J=6.6 Hz), the 1.44 (9H, s), 3,40-3,62 (3H, m), 4,28 is 4.45 (1H,rimasta ways similar reference example 3, using 860 mg of TRANS-4-(1-tert - butoxycarbonylamino)-1-hydroxymethylcytosine and 555 mg Porterfield nitronium received 587 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 45-47oC

An NMR spectrum (CDCl3) ppm: 0,92-of 1.92 (10H, m) a 1.08 (3H, d, J=7,3 ), THE 1.44 (9H, s), 3,40-of 3.60 (1H, m), 4,25-and 4.40 (1H, m), 4.26 deaths (2H, d, J=6,6 Hz)

Reference example 38

Hydrochloride of 1-(TRANS-4 - microclimatological) ethylamine

Using methods similar to reference example 4, using 660 mg of N-tert-butoxycarbonyl-1- (TRANS-4-microclimatological) ethylamine and 10 ml of a mixture of 4 G. hydrochloric acid-dioxane, got 502 mg of the desired compound as a pale yellow crystalline product.

So pl.: 168-169oC (decomposition)

An NMR spectrum (d6-DMSO) ppm: 0,90-1,10 (4H, m) of 1.13 (3H, d, J=6.6 Hz), 1,35-of 1.88 (6H, m), 2,92-3,10 (1H, m), 4,37 (2H, d, J=6.6 Hz), 7,75-8,00 (3H, user.)

Reference example 39

TRANS-4-N-tert - butoxycarbonylmethylene

In 50 ml of dry dimethylformamide suspended 5,86 g of TRANS-N-tert-butoxycarbonyl-4 - methanesulfonylaminoethyl, 3.28 g of sodium iodide and 1.07 g of sodium cyanide, and the mixture was heated under stirring at 110oC the paths were intensively washed with an aqueous solution of sodium chloride, aqueous citric acid solution, aqueous solution of sodium chloride, an aqueous solution of sodium thiosulfate, an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure, and the residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (10:1-5:1) to obtain a 3.87 g of the desired compound in the form of a colorless crystalline product.

So pl.: 78-79oC

An NMR spectrum (CDCl3) ppm: 0,85 of 1.28 (4H, m), 1.30 and a 2.00 (6H, m) to 1.48 (9H, s), 2,30 (2H, d, J=6.6 Hz), to 3.02 (2H, t, J=6.3 Hz), to 4.52 - 4,70 (1H, m)

Reference example 40

TRANS-4-N-tert-butoxycarbonylmethylene acetic acid

In a mixture solution of 20 ml conc. hydrochloric acid and 10 ml conc. sulfuric acid suspended 1,02 g of TRANS-4-N-tert - butoxycarbonylmethylene, the obtained mixture was heated under reflux for 1 hour and 25 minutes. The reaction mixture was poured into 150 ml of ice water and neutralized with excess sodium bicarbonate. Then thereto was added 200 ml of dioxane and 5.0 ml of di-tert-BUTYLCARBAMATE, and the mixture was mixed to the volume of about 100 ml under reduced pressure and extracted three times with 300 ml of ethyl acetate. The extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure obtaining of 0.98 g of the desired compound in the form of a colorless crystalline product.

So pl.: 123-124oC

An NMR spectrum (CDCl3) ppm: 0,85-1,10 (4H, m), 1.30 and 1,90 (6H, m) of 1.44 (9H, s), of 2.23 (2H, d, J=7,0 Hz), of 2.97 (2H, t, J=6.3 Hz), 4,50-of 4.66 (1H, m)

Reference example 41

Methyl 2-(TRANS-4-N-tert - butoxycarbonylmethylene) propionate

In 20 ml of dry tetrahydrofuran was dissolved 0,49 ml diisobutylamine and to it was added dropwise 2,19 ml of utility (1.6 M solution in tetrahydrofuran) under cooling in a bath of dry ice and acetone. Bath with dry ice and acetone was removed, and the mixture was stirred until then, until the temperature becomes 0oC. To the reaction mixture again was added dropwise a solution obtained by dissolving 500 mg of methyl TRANS-4-tert - butoxycarbonyl-aminomethylenemalonate in 5 ml of dry tetrahydrofuran while cooling in a bath of dry ice and acetone. The resulting mixture was stirred for 1 hour and 30 minutes, and then thereto was added 0,26 ml iodomethyl, then the mixture was stirred at the same temperature for 2 hours and 15 minutes. The temperature, R the IDA ammonium. The reaction mixture was extracted with 150 ml of ethyl acetate, the extracts were intensively washed with an aqueous solution of sodium chloride, an aqueous solution of citric acid, an aqueous solution of sodium chloride, an aqueous solution of sodium thiosulfate, an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure, and the residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (10:1-6:1) to give 250 mg of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,80-1,10 (4H, m), is 1.11 (3H, d, J=6.9 Hz), 1,25-of 1.85 (6H, m) of 1.44 (9H, s), 2,16-of 2.34 (1H, m), 2,96 (2H, t, J=6.3 Hz), 3,66 (3H, s), of 4.57 (1H, user.)

Reference example 42

TRANS-4-N-tert - butoxycarbonylamino-1-(2-hydroxy-1-methylethyl) cyclohexane

In 5 ml of dry tetrahydrofuran was dissolved 95 mg of methyl 2-(TRANS-4 - N-tert-butoxycarbonylmethylene)-propionate, thereto was added dropwise 0,32 ml of socialogical (1.0 M solution in tetrahydrofuran) under cooling in a bath of dry ice and acetone, the resulting mixture was stirred for 30 minutes. To the reaction mixture but was washed with an aqueous solution of sodium chloride, aqueous citric acid solution, aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is kept under reduced pressure, and the residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (4:1) to give 80 mg of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,80-to 1.83 (12H, m) to 0.89 (3H, d, J=7,l Hz) of 1.44 (9H, s), 2,95 (2H, t, J=6.4 Hz), 3,47 (1H, DD, J=7,6 Hz, J=10.5 Hz), 3,61 (1H, DD, J=5,9 Hz, J=10.5 Hz), 4,47 with 4.65 (1H, m)

Reference example 43

TRANS-4-N-tert - butoxycarbonylamino-1-(1-methyl-2-nitroxyethyl) cyclohexane

Using methods similar to reference example 3, using 210 mg of TRANS-4-N-tert-butoxycarbonylamino-methyl-1-(2-hydroxy-1 - methylethyl)cyclohexane and 151 mg of Porterfield nitronium received 150 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 55-57oC

An NMR spectrum (CDCl3) ppm: 0,84-1,86 (11H, m) to 0.96 (3H, d, J=6.9 Hz), the 1.44 (9H, s), 2,96 (2H, t, J=6.3 Hz), 4,27 (1H, DD, J=7,2 Hz, J=10.4 Hz), of 4.44 (1H, DD, J=5.8 Hz, J=10.4 Hz), 4,50 with 4.64 (1H, m)

Reference example 44

Hydrochloride, TRANS-4-(1-methyl-2 - nitroxyethyl) cycle is oxcarbazepine-methyl-1-(1-methyl-1-nitroxyethyl)cyclohexane, and 10.0 ml of a mixture of 4 N. hydrochloric acid-dioxane, received 111 mg of the desired compound as a pale yellow crystalline product.

So pl.: 114-116oC (decomposition)

An NMR spectrum (CDCl3) ppm: 0,80-1,85 (11H, m) of 0.90 (3H, d, J=6.8 Hz), 2.57 m)-2,70 (2H, m), 4,36 (1H, DD, J=6,9 Hz, J=10.3 Hz), to 4.52 (1H, DD, J=5.8 Hz, J=10.5 Hz), 7,60-of 7.90 (3H, user.)

Reference example 45

TRANS-4-tert-butyldimethylsilyloxy - 1-hydroxymethyl-cyclohexane

In 250 ml of dry dimethylformamide was dissolved 10.0 g of TRANS-1,4-dihydroxybenzylamine and 14.5 ml of triethylamine, and thereto was added dropwise with stirring a solution 10,24 g of tert-butyldimethylsilyloxy dissolved in 50 ml of dry dimethylformamide under cooling on ice, the resulting mixture was stirred under cooling on ice for 1 hour. To the reaction mixture were added 200 ml of ethyl acetate, the precipitated hydrochloride of triethylamine was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (2:1) to give 11.9 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,03 (6H, s), 0,85 was 1.04 (4H, m) to 0.89 (9H, s), 1,25-1,90 (7H, m), 3,35-to 3.50 (4H, m)

Reference example harmatan dissolved 11.9 g of TRANS-4-tert - butyldimethylsilyloxy-1-hydroxymethyl-cyclohexane, thereto was added with stirring 9,63 ml of triethylamine and 9,98 g of anhydride methanesulfonic acid while cooling on ice, the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 200 ml of ethyl acetate and the mixture was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (8:1-5:1) to give 12.2 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,03 (6H, s) of 0.82-1.14 in (4H, m) to 0.89 (9H, s), 1,35-of 1.92 (6H, m) of 3.00 (3H, s) to 3.41 (2H, d, J=6.6 Hz), Android 4.04 (1H, d, J=6,6 Hz)

Reference example 47

TRANS-4-tert - butyldimethylchlorosilane

In 100 ml of dry dimethylformamide suspended 11,0 g of TRANS-4 - methanesulfonylaminoethyl-1-tert-butyldimethylsilyloxy, by 5.87 g of sodium iodide and 1.92 g of sodium cyanide, and the mixture was stirred at 50oC for 1 hour and 45 minutes, then at 110oC for 45 minutes. The reaction mixture was poured into 100 ml of ice water and the mixture was extracted with 300 ml of ether. Exonet sodium and aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane - ethyl acetate (20: 1-5:1) to obtain the 7,41 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,03 (6H, s), 0,82 is 1.20 (4H, m) to 0.89 (9H, s), 1,34-of 1.95 (6H, m), of 2.25 (2H, d, J=6.6 Hz), to 3.41 (1H, d, J=5,9 Hz)

Reference example 48

N-tert-Butoxycarbonyl-2-(TRANS-4-tert - butyldimethylsilyloxy) ethylamine

In 20 ml of dry tetrahydrofuran was dissolved 1.0 g of TRANS-4-tert - butyldimethylchlorosilane and to it was added dropwise 3,74 ml lydialydia (1.0 M solution in tetrahydrofuran) under cooling in a bath of dry ice and acetone, the mixture was stirred 1 hour and then at 0oC for 25 minutes. Then to the mixture was added 3,74 ml of 1 N. aqueous solution of hydrochloric acid and the mixture was stirred for 20 minutes. To the reaction mixture was added to 2.06 ml of di-tert-BUTYLCARBAMATE and the mixture was stirred at room temperature for 2 hours and 15 minutes. To the reaction mixture was added 150 ml of ethyl acetate and the mixture washed with aqueous citric acid solution, aqueous solution of sodium chloride, an aqueous solution of bicarbonate and under reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluting solution of cyclohexane - ethyl acetate (40:1-20:1) obtaining of 1.05 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,03 (6H, s), 0,82-of 1.05 (4H, m) to 0.89 (9H, s), 1,10-1,90 (8H, m) of 1.44 (9H, s), 3,05-up 3.22 (2H, m), 3,39 (1H, d, J=6.3 Hz), 4,45-4,55 (1H, m)

Reference example 49

TRANS-4-(2-tert - butoxycarbonylamino)-1-hydroxymethylcellulose

In 10 ml of dry tetrahydrofuran was dissolved 1,05 g of N-tert-butoxycarbonyl - 2-(TRANS-4-tert-butyldimethylsilyloxy) ethylamine and to it was added dropwise with stirring 8,48 ml of tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) under cooling on ice, the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added 150 ml of ethyl acetate, and the mixture was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (2:1) to obtain 741 mg of the desired compound as a colourless -3,28 (2H, m), 3,40-to 3.58 (2H, m), 4,30-4,60 (1H, m)

Reference example 50

N-tert-Butoxycarbonyl-2-(TRANS-4 - microclimatological) ethylamine

Using methods similar to reference example 3, using 470 mg of TRANS-4-(2-tert - butoxycarbonylamino)-1-hydroxyethylmethylcellulose and 357 mg Porterfield nitronium received 340 mg of the desired compound as a pale yellow crystalline product.

An NMR spectrum (CDCl3) ppm: 0,85-to 1.14 (4H, m), 1,20 - 1,90 (8H, m) of 1.44 (9H, s), 3,05-3,20 (2H, m), 4.26 deaths (2H, d, J=6.5 Hz), 4,35-4,55 (1H, m)

Reference example 51

Hydrochloride of 2-(TRANS-4-microclimatological) ethylamine

Using methods similar to reference example 4, using 340 mg of N-tert-butoxycarbonyl-2- (TRANS-4-microclimatological) ethylamine and 5.0 ml of a mixture of 4 G. hydrochloric acid - dioxane, got 206 mg of the desired compound as a pale yellow crystalline product.

So pl.: 162 to 165 of theoC (decomposition)

An NMR spectrum (d6-DMSO) ppm: 0,80-1,12 (4H, m), 1,15-of 1.53 (3H, m), 1.55V and 1.80 (5H, m), 2,70-is 2.88 (2H, m), 4,36 (2H, d, J=6,l Hz), 7,70-8,10 (3H, user.)

Reference example 52

N-tert-Butoxycarbonyl-2-(TRANS-4 - methanesulfonylaminoethyl) ethylamine

In 50 ml of dry dichloromethane was dissolved 1.0 g of TRANS-4-(2-tert - butoxycarbonylmethylene acid while cooling on ice, the resulting mixture was stirred at room temperature for 40 minutes. Then drove the solvent under reduced pressure and to the residue was added 150 ml of ethyl acetate. The mixture was intensively washed with an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. To the obtained crystalline product was added isopropyl ether and the crystalline product was collected by filtration to obtain 1.13 g of the desired compound in the form of a colorless crystalline product.

So pl.: 83-84oC

An NMR spectrum (CDCl3) ppm: 0,85-to 1.14 (4H, m), 1,16-1,90 (8H, m) of 1.44 (9H, s) of 3.00 (3H, s), 3,05-3,10 (2H, m), a 4.03 (2H, d, J=6.3 Hz), 4,35 - 4,55 (1H, m)

Reference example 53

Diethyl TRANS-4-(2-N-tert - butoxycarbonylamino) cyclohexylethylamine

In 50 ml of dry dimethylformamide was dissolved 1,02 ml of diethylmalonate and thereto was added with stirring 147 mg of sodium hydride (content 55%) while cooling on ice, and the mixture was stirred for 30 minutes. To the reaction mixture was added 1.13 g of N-tert-butoxycarbonyl-2-(TRANS-4 - methanesulfonylaminoethyl)ethylamine, and the mixture was heated at premesis is assured at 110oC for 1 hour and 5 minutes. To the reaction mixture were added 200 ml of ethyl acetate and the mixture was intensively washed with an aqueous solution of sodium chloride, aqueous sodium thiosulfate solution and an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (10:1-5:1) to obtain 895 mg of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0,80-1,02 (4H, m), 1,10-1,85 (14H, m) of 1.44 (9H, s), 3,05-3,20 (2H, m), of 3.43 (1H, t, J=7,6 Hz), 4,10-to 4.28 (6H, m), 4,35 - 4,55 (1H, m)

Reference example 54

TRANS-4-(2-N-tert - butoxycarbonylamino) cyclohexylethylamine acid

In 10 ml of ethanol was dissolved 890 mg of diethyl TRANS-4-(2-N-tert - butoxycarbonylamino)cyclohexylethylamine and thereto was added with stirring 10 ml of 2.5 n sodium hydroxide while cooling on ice, the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was poured into 50 ml ice water, acidified with citric acid and was extracted with 200 ml of ethyl acetate. The extracts were washed with an aqueous solution of sodium chloride, and dried over anhydrous soulflame isopropyl ether and the crystalline product was collected by filtration to obtain 563 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 152-153oC (decomposition)

An NMR spectrum (d6-DMSO) ppm: 0,72-of 0.95 (4H, m), of 1.05 to 1.82 (10H, m) to 1.37 (9H, s), 2,82 are 2.98 (2H, m), 3,20-to 3.35 (1H, m), 6,65-to 6.80 (1H, m)

Reference example 55

3-[TRANS-4-(2-N-tert - butoxycarbonylamino)cyclohexyl] propionic acid

620 mg of TRANS-4-(2-N-tert-butoxycarbonylamino)- cyclohexylethylamine acid and 10 ml of xylene was heated under reflux for 1 hour and 40 minutes. The solvent is kept under reduced pressure and to the residue was added hexane, and the resulting crystalline product was collected by filtration to obtain 453 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 107-113oC

An NMR spectrum (CDCl3) ppm: 0,68-of 0.95 (4H, m), 1,10-of 1.80 (10H, m) to 1.37 (9H, s), 2,19 (2H, t, J=7.5 Hz), 2,85-of 3.00 (2H, m), 6,65-of 6.78 (1H, m)

Reference example 56

TRANS-4-(2-N-tert - butoxycarbonylamino)-1-(3-hydroxypropyl)cyclohexane

In 10 ml of dry tetrahydrofuran was dissolved 450 mg of 3-[TRANS-4-(2-N - tert-butoxycarbonylamino)cyclohexyl] -propionic acid and thereto was added with stirring at 0.42 ml of triethylamine and 0.22 ml of isobutylphthalate while cooling on ice, the mixture was stirred at room temperature for 3 hours. Insoluble particles of filtrowanie while cooling on ice. The mixture was stirred while cooling on ice for 20 minutes and then at room temperature for 1 hour and 40 minutes. Added an excess of an aqueous solution of ammonium chloride and the mixture was extracted with 200 ml of ethyl acetate. The extracts were intensively washed with an aqueous solution of sodium chloride, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (3:1) to give 284 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 62-64oC

An NMR spectrum (CDCl3) ppm: 0,78-of 1.05 (4H, m), of 1.05 to 1.85 (13H, m) of 1.44 (9H, s), 3,05-of 3.25 (2H, m), 3,55-3,70 (2H, m), 4,30-4,60 (1H, m)

Reference example 57

TRANS-N-tert-butoxycarbonyl-2-[4-(3 - nitroxymethyl)-cyclohexyl] ethylamine

Using methods similar to reference example 3, using 270 mg of TRANS-4-(2-N - tert-butoxycarbonylamino)-1-(3-hydroxypropyl)cyclohexane and 185 mg of Porterfield nitronium, got 195 mg of the desired compound as a pale yellow crystalline product.

So pl.: 48-49oC

JV Hydrochloride is 2-[TRANS-4-(3 - nitrosopropane) cyclohexyl]-ethylamine

Using methods similar to reference example 4, using 195 mg of TRANS-N-tert - butoxycarbonyl-2-[4-(3-nitrosopropane)cyclohexyl] - ethylamine and 10.0 ml of a mixture of 4 G. hydrochloric acid-dioxane, got 149 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 165-167oC (decomposition)

An NMR spectrum (d6-DMSO) ppm: 0,75-1,00 (4H, m), 1,05 and 1.80 (12H, m), 2,78 (2H, t, J=7,7 Hz), 4,50 (2H, t, J=6.6 Hz), 7,65 - of 7.95 (3H, user.)

Reference example 59

N-tert-Butoxycarbonyl-3 - nitrosomethylethylamine

Using methods similar to reference example 3, using 3.0 g of N-tert-butoxycarbonyl-3 - hydroxymethylcytosine and 3,48 g Porterfield nitronium, got 2.65 g of the desired compound in the form of a colorless crystalline product.

So pl.: 68-70oC

An NMR spectrum (CDCl3) ppm: 0,78 of 1.50 (4H, m) of 1.44 (9H, s), 1.70 to to 2.18 (5H, m), 3,35-to 3.58 (1H, m), the 4.29 (2H, d, J=5,9 Hz), 4,30-of 5.50 (1H, m)

Reference example 60

Hydrochloride 3-nitrosomethylethylamine

Using methods similar to reference example 4, using 2.65 g of N-tert-butoxycarbonyl-3 - nitrosomethylethylamine and to 27.0 ml of a mixture of 4 G. hydrochloric acid-dioxane, got 1,90 g of the desired compound in the form of a colorless crystalline product.), 4,35-4,50 (2H, m), 8,00-to 8.40 (3H, user.)

Reference example 61

N-tert-Butoxycarbonyl-4 - nitrosomethylethylamine

Using methods similar to reference example 3, using 3.0 g of N-tert-butoxycarbonyl-4 - hydroxymethylcytosine and 3,48 g Porterfield nitronium, got 2,34 g of the desired compound in the form of a colorless crystalline product.

So pl.: 83-84oC

An NMR spectrum (CDCl3) ppm: 1,05 is 2.10 (9H, m) of 1.45 (9H, s), 3,65-of 3.85 (1H, m), 4.26 deaths (0,3 H, d, J=6.6 Hz), 4,33 (1,7 H, d, J=6.6 Hz), 4,45-4,70 (1H, m)

Reference example 62

Hydrochloride 4-nitrosomethylethylamine

Using methods similar to reference example 4, using 2,32 g of N-tert-butoxycarbonyl-4-nitrosomethylethylamine and 23.0 ml of a mixture of 4 G. hydrochloric acid-dioxane, got to 1.34 g of the desired compound in the form of a colorless crystalline product.

So pl.: 155-157oC (decomposition)

An NMR spectrum (d6-DMSO) ppm: 1,10-2,05 (9H, m), 2,85 - 2,97 (0,14 H, m), 3,13-3,25 (0,86 H, m), 4,36 (0,28 H, d, J=6.5 Hz), of 4.44 (1,72 H, d, J=6.5 Hz), 8,00-to 8.40 (3H, user.)

Reference example 63

TRANS-2-carbamoyltransferase acid

To 40 ml of water conc. ammonia was added with stirring, 10.0 g of anhydride TRANS-1,2-cyclohexanedicarboxylic acid at room temperaure stirring until 1 conc. hydrochloric acid under ice cooling, and usageprice crystalline product was collected by filtration and washed with water. The crystalline product was recrystallized from ethanol to obtain 6,93 g of the desired compound in the form of a colorless crystalline product.

So pl.: 183-186oC

An NMR spectrum (d6-DMSO) ppm: 1,10-of 1.35 (4H, m), 1.60 - to was 2.05 (4H, m), 2,20-of 2.45 (2H, m), of 6.65 (1H, s), 7,72 (1H, s), 11,88 (1H, s)

Reference example 64

TRANS-N-tert-butoxycarbonyl-2 - hydroxymethylglycinate

In 40 ml of dry tetrahydrofuran added 4.0 g of TRANS-2-carbamoyltransferase acid dropwise and with stirring was added 54,0 ml of socialogical in tetrahydrofuran (1.0 M solution) under ice cooling, the resulting mixture was stirred at room temperature for 55 minutes and heated under reflux for 1 hour. To the reaction mixture under stirring and cooling on ice was added 13,0 g desativado sodium sulfate and the mixture was stirred for 1 hour and 15 minutes. The reaction mixture was filtered through Celite and washed with ethanol, the filtrate was concentrated to about 100 ml under reduced pressure. To the concentrate was added 6.4 ml of di-tert-BUTYLCARBAMATE when AC is th mixture was concentrated under reduced pressure and the residue was purified by chromatography on a column of silica gel, using as an eluting solvent cyclohexane-ethyl acetate (2:1) to give 1.47 g of the desired compound as a pale pink oil.

An NMR spectrum (d6- DMSO) ppm: 0,90-1,90 (10H, m) of 1.44 (9H, s), 2,90-is 3.08 (1H, m), 3,22 is 3.40 (1H, m), 3.43 points-of 3.80 (3H, m), 5,10-and 5.30 (1H, m)

Reference example 65

TRANS-N-tert-butoxycarbonyl-2 - nitrosomethylethylamine

Using methods similar to reference example 3, using 893 mg of TRANS-N-tert - butoxycarbonyl-2-hydroxymethylglycinate and 723 mg Porterfield nitronium, got 885 mg of the desired compound as a yellow oil.

An NMR spectrum (CDCl3) ppm: 0,90-1,90 (10H, m) of 1.44 (9H, s), 2,95-and 3.16 (1H, m), 3,16-3,37 (1H, m), and 4.40 (1H, DD, J=5,9 Hz, J=a 10.6 Hz), of 4.44-4,70 (2H, m)

Reference example 66

Hydrochloride of TRANS-2-nitrosomethylethylamine

Using methods similar to reference example 4, using 885 mg of TRANS-N-tert - butoxycarbonyl-2-nitrosomethylethylamine and 5.0 ml of a mixture of 4 G. hydrochloric acid-dioxane, received 600 mg of the desired compound in the form of a colorless crystalline product.

So pl.: 144-146oC (decomposition)

An NMR spectrum (CDCl3) ppm: 1,12-of 1.45 (4H, m), 1,65 is 2.10 (6H, m), 2,85 was 3.05 (1H, m), 3,13-3,30 (1H, m), a 4.53 (2H, d, J=3.3 Hz), 8,10-at 8.60 (3H, user.)

Silochrome example 63, using 20 ml of water conc. ammonia and 2.50 g of anhydride CIS-1,2 - cyclohexanedicarboxylic acids, got 2,07 g of the desired compound in the form of a colorless crystalline product.

So pl.: 156-158oC

An NMR spectrum (CDCl3) ppm: 1,30 was 2.25 (8H, m), 2,60 - of 2.75 (1H, m), 2,85-2,96 (1H, m), of 5.82-6,05 (1H, usher.), 6,10-6,28 (1H, user.)

Reference example 68

CIS-N-tert-butoxycarbonyl-2 - hydroxymethylglycinate

Using methods similar to reference example 64, using 2.0 g of CIS-2 - carbamoyltransferase acid, 29.0 ml solution lydialydia in tetrahydrofuran (1.0 M solution) and 3.2 ml of di - tert-BUTYLCARBAMATE, got 0.73 g of the desired compound as a pale pink oil.

An NMR spectrum (CDCl3) ppm: 1,20-of 1.95 (10H, m) of 1.44 (9H, s), 2,30 is 2.55 (1H, user. ), 2,90-is 3.08 (1H, m), 3,10-of 3.25 (2H, m), 3,50 - of 3.80 (2H, m), 4.80 to 5,00 (1H, user.)

Reference example 69

CIS-N-tert-butoxycarbonyl-2 - nitrosomethylethylamine

Using methods similar to reference example 3, using 2,49 g of CIS-N-tert - butoxycarbonyl-2-hydroxymethylglycinate and 2.0 g of Porterfield nitronium got to 1.79 g of the desired compound as a yellow oil.

An NMR spectrum (CDCl3) ppm: 1,20-2,20 (10H, m) of 1.44 (9H, s) 3,00-3,20 (2H, m), 4,35 with 4.65 (3H, m is s, similar to reference example 4, using 1,79 g of CIS-N-tert-butoxycarbonyl - 2-nitroxy-methylcyclohexylamine and 10.0 ml solution of 4 G. hydrochloric acid, dioxin, got to 1.15 g of the desired compound in the form of a colorless crystalline product.

So pl.: 158-160oC (decomposition)

An NMR spectrum (CDCl3) ppm: 1.30 and is 2.30 (10H, m), 2,90-3,10 (2H, m), 4,35-4,60 (2H, m), 8,00-8,50 (3H, user.)

Reference example 71

Dimethyl 1,3-cyclohexanedicarboxylate

To a solution of diazomethane-ether obtained according to the method Arndt'a (Arndt; Synth. Collect Vol. 11, 165) of 40 g of N - methylnitrosamino was added to 11.0 g of 1,3-cyclohexanedicarboxylic acid and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction the solvent drove away under reduced pressure, and the residue was dissolved in diethylacetal and washed with an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride. After drying of the residue over anhydrous magnesium sulfate, the solvent is kept at reduced pressure obtaining of 8.33 g of the desired compound as a pale yellow oil.

An NMR spectrum (CDCl3) ppm: 1,20-2,40 (9,3 H, m), 2,62-2,75 (0,7 H, m) to 3.67 (6H, m)

Reference example 72

Monomethyl 1,3-cyclohexanedicarboxylate

In 85 ml of methanol is sodium, the mixture was stirred at room temperature for 4 hours. The solvent is kept under reduced pressure and the aqueous solution washed with ethyl acetate. the pH of the solution was brought to 1 diluted hydrochloric acid while cooling and extracted with ethyl acetate. The extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is kept at reduced pressure to obtain 6.7 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 1,20-2,45 (9,3 H, m), 2,65-2,80 (0,7 H, m), 3,68 (3H, s)

Reference example 73

3-Carbamoyltransferase acid

In 70 ml of an aqueous solution of concentrated ammonia was dissolved 6.7 g monomethyl 1,3-cyclohexanedicarboxylate, the mixture was left to age at room temperature for 17 days. Concentrated hydrochloric acid while cooling brought the pH of the mixture to 1 and the mixture was extracted with ethyl acetate. The extracts were washed with an aqueous solution of sodium chloride and dried over anhydrous solution of magnesium sulfate, and the solvent is kept at reduced pressure to obtain 2.64 g of the desired compound in the form of a colorless crystalline product.

So pl.: 102-128oC

illuminometer-1-hydroxymethylcellulose

Using methods similar to reference example 8, using of 3.60 g of 3-carbamoyltransferase acid and to 53.0 g 1 M solution lydialydia in tetrahydrofuran and 4.8 ml of di - tert-BUTYLCARBAMATE, got 1.52 g of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0.50 to 1,95 (10H, m) of 1.44 (9H, s), 2,88-3,20 (2H, m), 3,40-of 3.60 (3H, m), 4,60 (1H, user.)

Reference example 75

N-tert-Butoxycarbonyl-3 - nitrosomethylethylamine

Using methods similar to reference example 3, using 1.50 g of 3-N-tert - butoxycarbonylamino-1-hydroxymethylcytosine, and 1.15 g of Porterfield nitronium was obtained 1.22 g of the desired compound as a pale yellow oil.

An NMR spectrum (CDCl3) ppm: 0,60-1,90 (10H, m) of 1.44 (9H, s), 2,90-3,13 (2H, m), 4,27 (1,5 H, d, J=5,9 Hz), 4,35 (0.5 H, d, J=6.6 Hz), 4,58 (1H, user. )

Reference example 76

Hydrochloride 3-nitrosomethylethylamine

Using methods similar to reference example 4, using 1.22 g of N-tert-butoxycarbonyl-3 - nitrosomethylethylamine and 13.0 ml of a solution of 4 G. hydrochloric acid-dioxane was obtained 0.40 g of the desired compound in the form of a colorless crystalline product.

So pl.: 109-111oC (decomposition)

An NMR spectrum (d6- is-2-hydroxymethylnicotinamide

In 60 ml of methanol was dissolved 3,18 g of 2-hydroxymethyl-cyclopentylamine and to it was added 9,72 ml of di-tert - BUTYLCARBAMATE, the resulting mixture was stirred at room temperature for 1.5 hours and then left overnight at room temperature. The solvent is kept under reduced pressure and the residue was purified by chromatography on a column of silica gel using as eluting solvent cyclohexane-ethyl acetate (4:1) to give 0.88 g of the desired compound, isomer A (compound, which has a low polarity) in the form of a colorless crystalline product, and 0.43 g of the desired compound, isomer B (compound, which has a high polarity) in the form of a colorless crystalline product.

Isomer A

Thin layer chromatography: Rf = 0,47 (solvent for pickup: cyclohexane/ethyl acetate = 2/1)

So pl.: 107-108oC

An NMR spectrum (CDCl3) ppm: 1.00 and is 1.75 (6H, m) of 1.46 (9H, s), 1,90-of 2.20 (2H, m), 3,22-of 3.48 (1H, m) and 3.59 (2H, DD, J=4.0 Hz, J=11,9 Hz), 4,05-4,20 (1H, m), 4,49 (1H, d, J=7.9 Hz)

Isomer B

Thin layer chromatography: Rf = 0,38 (solvent for pickup: cyclohexane/ethyl acetate = 2/1)

So pl.: 65-67oC

An NMR spectrum (CDCl3) ppm: 1,20-1,50 (3H, m) of 1.45 (9H, s), 1,53 is 2.10 (5H, m), 3,40-of 3.77 (3H, m), 4,55-of 4.75 (1H, user.)

Reference is locname example 3, using 1,43 g of isomer A obtained in reference example 77, and 1.76 g of Porterfield nitronium, got 0,94 g of the desired compound as a yellow oil.

An NMR spectrum (CDCl3) ppm: 1,30-2,10 (6H, m) of 1.45 (9H, s), 2,20-2,48 (1H, m), 4,00-4,20 (1H, m), 4,32 (2H, DD, J=6,6 Hz, J=a 10.6 Hz), 4,30 ñ 4.50 (1H, m), br4.61 (2H, DD, J=5,9 Hz, J=10,6 Hz)

Reference example 79

Hydrochloride of 2-nitrosomethylethylamine

Using methods similar to reference example 4, using 0,94 g of the compound obtained in reference example 78, and 9.5 ml of a solution of 4 G. hydrochloric acid - dioxane, received of 0.53 g of the desired compound in the form of a colorless crystalline product.

So pl.: 133-135oC (decomposition)

An NMR spectrum (CDCl3) ppm: 1,50-of 1.85 (5H, m), 1,90 - 2,02 (1H, m), 2,35 at 2.45 (1H, m), 3,50-3,60 (1H, m), of 4.57 (2H, d, J=7.8 Hz), 8,10-to 8.40 (1H, user.)

Reference example 80

T-tert-Butoxycarbonyl-2 - nitrosomethylethylamine

Using methods similar to reference example 3, using of 1.16 g of isomer B obtained in reference example 77, and 1.43 g of Porterfield nitronium got a 1.08 g of the desired compound as a yellow oil.

An NMR spectrum (CDCl3) ppm: of 1.30 and 1.80 (4H, m) of 1.45 (9H, s), 1,88-of 2.15 (3H, m), 3,60-of 3.80 (1H, m), to 4.38 (2H, DD, J=7,3 Hz, J=a 10.6 Hz), 4,40-4,55 (1H, m), 4,63 (2H, DD, J=5.0 Hz, J=10,6 Hz)

Ref is like example 4, using 1.08 g of the compound obtained in reference example 80, and 11.0 ml solution of 4 G. hydrochloric acid - dioxane was obtained 0.64 g of the desired compound in the form of a colorless crystalline product. So pl.: 128-132oC (decomposition)

An NMR spectrum (CDCl3) ppm: 1,35-2,05 (6H, m), 2,28-to 2.40 (1H, m), of 3.25 to 3.45 (1H, m), a 4.53 (1H, DD, J=6,9 Hz, J=10.3 Hz), 4,69 (1H, DD, J=5,9 Hz, J= 10.3 Hz), 8,15-and 8.50 (1H, user.)

Reference example 82

TRANS-4-N-tert - butoxycarbonylmethylene

To a solution of 150 ml of dry dichloromethane and of 3.64 ml of dimethyl sulfoxide was added dropwise to 3.58 ml oxalicacid when cooled in a bath of dry ice and acetone, the resulting mixture was stirred at the same temperature for 45 minutes. To the reaction mixture was added dropwise a solution of 5.0 g of TRANS-4-N-tert - butoxycarbonylamino-1-hydroxymethylcytosine dissolved in 25 ml of dry dichloromethane, and the mixture was stirred at the same temperature for 2 hours. Bath of dry ice and acetone was removed and the temperature of the reaction mixture was gradually returned to the 0oC, thereto was added 50 ml of an aqueous solution of ammonium chloride. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed with an aqueous solution of sodium chloride, 10% aqueous solution of hydrochloric acid, wodna, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel using as solvent cyclohexane-ethyl acetate (5: 1-2: 1) to obtain the 4.29 g of the desired compound in the form of a colorless crystalline product.

So pl.: 64-66oC

An NMR spectrum (CDCl3) ppm: 0,90-1,10 (2H, m), 1,16-of 1.55 (3H, m) of 1.45 (9H, s), 1,80-2,10 (4H, m), 2,10-of 2.25 (1H, m) of 3.00 (2H, t, J=6.4 Hz), 4,50-4,70 (1H, usher.), 9,62 (1H, d, J=1.2 Hz)

Reference example 83

4-(4-N-tert - Butoxycarbonylmethylene)-3-butene-1-ol

In 20 ml of dry dioxane suspended 500 mg of TRANS-4-N-tert - butoxycarbonylmethylene and 995 mg (3 - hydroxypropyl)triphenylphosphonium bromide, and thereto was added and 0.37 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene, and the mixture was heated under reflux for 2 days. Then to the reaction mixture were added 20 ml of dry acetonitrile and the mixture was heated under reflux for 3 days. Then thereto was added 995 mg (3 - hydroxypropyl)triphenylphosphonium bromide and 0.37 ml of 1,8 - diazabicyclo[5,4,0]undec-7-ene and the mixture was heated under reflux for 2 days. In addition, it was added to 995 mg (3-hydroxypropyl)triphenylphosphonium bromide and 0.37 ml of 1,8 - diazabicyclo[5,4,0]undec-7-ene and the mixture nocedal by chromatography on a column of silica gel, using as solvent cyclohexane-ethyl acetate (4:1) to give 252 mg of the desired compound as a yellow oil.

An NMR spectrum (CDCl3) ppm: 0,85-2,60 (13H, m) of 1.44 (9H, s), 2,97 (1,2 H, t, J= 6.4 Hz), 3,06 (0,8 H, t, J=6.4 Hz), 3,56-3,70 (1,2 H, m), 4,00 - 4,10 (0,8 H, m), 4,47-of 4.77 (1H, m), 5,20-of 5.50 (2H, m)

Reference example 84

4-(4-N-tert - Butoxycarbonylmethylene)butane-1-ol

To 20 ml of ethanol was added 313 mg of 4-(4-N-tert - butoxycarbonylmethylene)-3-butene-1-ol and 100 mg of 10% palladium on charcoal, and the mixture was stirred in nitrogen atmosphere at 1 ATM at 60oC for 4 hours. The insoluble part was filtered using Celite and the solvent from the filtrate drove away under reduced pressure. The residue was purified by chromatography on a column of silica gel using as solvent cyclohexane-ethyl acetate (4:1) to give 212 mg of the desired compound as a colourless oil.

An NMR spectrum (CDCl3) ppm: 0.75 to a 2.00 (17H, m) of 1.44 (9H, s), 2,96 (1,4 H, t, J= 6.4 Hz), 3,05 (0,7 H, t, J=6.4 Hz), to 3.64 (2H, t, J=6.6 Hz), 4,50-4,70 (1H, m)

Reference example 85

N-tert-Butoxycarbonyl-4-(4-nitroxymethyl) cyclohexylethylamine

Using methods similar to reference example 3, using 212 mg of 4-(4-N-tert-butoxycarbonylmethylene) butane-1 is ECTR NMR (CDCl3) ppm: 0,75-1,00 (4H, m), of 1.05 to 2.00 (12H, m) of 1.44 (9H, s), 2,96 (1,5 H, t, J=6.4 Hz), 3,06 (0.5 H, t, J=6.5 Hz), of 4.44 (2H, t, J= 6.6 Hz), 4,46 with 4.65 (1H, m)

Reference example 86

The hydrochloride of 4-(4-nitroxymethyl) cyclohexylethylamine

Using methods similar to reference example 4, using 95,9 mg of N-tert-butoxycarbonyl-4-(4 - nitroxymethyl)cyclohexylethylamine and 2.0 ml solution of 4 G. hydrochloric acid-dioxane, got 53,1 mg of the desired compound in the form of a colorless crystalline product.

An NMR spectrum (CDCl3) ppm: 0.70 to 2,05 (16H, m), 2.70 height is 3.00 (2H, m), of 4.57 (2H, t, J=6.6 Hz), 8,15-8,50 (3H, user.)

Reference example 87

1-Benzyl-2-N-tert - butoxycarbonylamino-5-hydroxyethylpiperazine

In 100 ml of dry tetrahydrofuran was dissolved to 3.06 g of ethyl 1-benzyl-2-cyano-5 - piperidinecarboxylate and to it was added dropwise 56,2 ml of 1 M solution lydialydia in tetrahydrofuran while cooling on ice, the mixture was stirred at room temperature for 20 minutes and then was heated under reflux for 1.5 hours. The reaction mixture was added dropwise to 300 ml of ice water and the insoluble part was filtered through Celite. To the filtrate was added 3.1 ml of di-tert - BUTYLCARBAMATE and a catalytic amount of 4 - dimethylaminopyridine and the mixture peremeshivaete pH of the mixture to 7, then thereto was added 3.1 ml of di-tert-BUTYLCARBAMATE and a catalytic amount of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 2.5 hours. Moreover, to the mixture was added 3.1 ml of di-tert-BUTYLCARBAMATE and a catalytic amount of 4-dimethylaminopyridine and the mixture was stirred at room temperature for 50 minutes. Tetrahydrofuran drove under reduced pressure and the residue was extracted with ethyl acetate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 3/4-1/4) to give 1.64 g of isomer A (compound, which has a low polarity) and 0.43 g of isomer B (compound, which has a high polarity) as a yellow oil and as pale red oil, respectively.

Isomer A

Thin layer chromatography: Rf = 0,56 (solvent for pickup: dichloromethane/methanol = 9/1)

An NMR spectrum (CDCl3) ppm: the 1.44 (9H, s), 1,50-2,00 (5H, m), 2,36 is 2.75 (3H, m), 3.25 to 3.40 in (2H, m) to 3.41 (1H, d, J=13,4 Hz) and 3.59 (2H, Abq, J=13 Hz), 3,99 (1H, d, J=13,4 Hz), 4,80 (1H, usher.), 7,20-7,40 (5H, m)

Isomer B

Thin layer chromatography: Rf = 0,48 (solvent for pickup: dichloromethane/methanol = 9/1)

An NMR spectrum (CDCl3) ppm: 1,>/BR>Reference example 88

1-tert-Butoxycarbonyl-2-N-tert - butoxycarbonylamino-5-hydroxyethylpiperazine

In 20 ml of ethanol was dissolved 0.84 g of the compound (isomer B) in reference example 87 and to it was added 200 mg of 10% palladium on charcoal, the mixture was stirred in a stream of hydrogen at room temperature for 3 hours and 40 minutes. Then to the mixture was added 200 mg of 10% palladium on coal and stirred at room temperature in a stream of hydrogen for 11 hours. To the reaction mixture was added to 0.69 ml of di-tert - BUTYLCARBAMATE and the mixture was left to stand at room temperature for 8 days. The reaction mixture was filtered and the filtrate is kept under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: cyclohexane/ethyl acetate = 2/3-1/2) to give 658 mg of the desired compound as a colourless foam.

An NMR spectrum (CDCl3) ppm: USD 1.43 (9H, s) to 1.48 (9H, s), 1,55-of 1.95 (5H, m), 2,90-up 3.22 (2H, m), 3,35-the 3.65 (3H, m), 3,98 (1H, d, J=14.6 Hz), 4,13-4.26 deaths (1H, m), and 4.75 (1H, user.)

Reference example 89

1-tert-Butoxycarbonyl-2-N-tert - butoxycarbonylamino-5-nitrosomethylurea

Using methods similar to reference example 3, using 658 mg of 1-tert - butoxycarbonyl-2-N-tert-butoxycarbonylamino foam.

An NMR spectrum (CDCl3) ppm: to 1.42 (9H, m) of 1.45 (9H, m), 1,65-of 1.95 (4H, m), 2.05 is-to 2.18 (1H, m), 3,05-and 3.16 (2H, m), 3,48-3,63 (1H, m), 3,95 (1H, d, J=14,2 Hz), 4,20-and 4.40 (2H, m), of 4.54 (1H, DD, J=8.6 Hz, J=10,8 Hz), 4,78 (1H, user.)

Reference example 90

The dihydrochloride of 5-nitroxymethyl-2 - piperidinylidene

Using methods similar to reference example 4, using 523 mg of 1-tert-butoxycarbonyl-2-N-tert - butoxycarbonylamino-5-nitrosomethylurea and 20 ml of a solution of 4 G. hydrochloric acid-dioxane, got 351 mg of the desired compound as a colourless foam.

An NMR spectrum (d6-DMSO) ppm: 1,20-of 1.45 (1H, m), 1,58 - of 2.05 (4H, m), 2,20-2,40 (1H, m), 2,65-2,90 (1H, m), 2.95 and - a 3.50 (4H, m), 4,48 (2H, d, J=5.8 Hz)

Example research 1

Relaxing effect on collateral vessel with intravenous

Dog breeds Beagle (male), weighing from 9 to 13 kg, was anestesiologi when intravenous pentobarbital at a dose of 30 mg/kg and perform the experiment under artificial respiration. For measuring the pressure in the left carotid artery retrograde has introduced a polyethylene cannula (intravenous catheter Atom 2F) in one of the lateral vessels of the left thyroid artery. The blood flow in the left carotid artery from a given location of the pressure measurement was perikli 1 minute arterial clamp and measured pressure (P) and red eye reduction the sample through another plastic cannula, introduced into the femoral vein. The left carotid artery was perikli for 1 minute at 5, 15, 30, 45 and 60 minute, and each time was measured pressure (P) and a reduction in peripheral pressure (P) immediately before occlusion. Relaxing effect on collateral vessel (collateral index = CI (CI)) of the studied sample was calculated by the following formula:

CI = 100-(P,/P,)(100/(P/P).

The result of this study of the compounds of examples 1, 4, 8, and 9 showed their excellent activity, CI60(the average value of CI from 0 minutes to 60 minutes) at a dose of 0.1 mg/kg is more than 15.

Example research 2

Relaxing effect on collateral vessel with the introduction of portal vein

While samples were prepared according to the above method, the animals were laparoscopically along the middle line of the abdomen, taking part brazzeana Vienna and was cut way to introduce the sample into the portal vein. For implantation into the portal vein, brazzeana vein antiretrovirals have introduced a polyethylene cannula (intravenous catheter Atom 2F) and then through it introduced the analyzed sample. To study the initial steps of the investigated sample is first injected intravenously (femoral vein) and measured on a 60 minute EGU portal vein and measured on a 60 minute its relaxing effect on collateral vessel, these effects were compared with each other.

In the present study, the compound of example 1 showed excellent effect.

Sample preparation 1

Capsule

Connection example 1 - 20.0 mg

Lactose - 158,7

Corn starch - 70,0

Magnesium stearate - 1,3 - 250 mg

Such a powder is mixed and passed through a sieve of 60 mesh, and then the powder capsulized in a gelatin capsule No. 3 250 mg to obtain capsules.

Example preparation of 2

Tablet

Connection example 1 - 20.0 mg

Lactose - 154,0

Corn starch - 25,0

Magnesium stearate - 1.0 to 200 mg

Such a powder is mixed and with the help of teletrauma machine is prepared 200 mg tablet.

If necessary, you can cover the tablet sugar coating.

1. Derived thiazolidinone having the General formula:

< / BR>
where W represents a sulfur atom and X represents a group having the formula-N(R1)-;

R1represents a hydrogen atom;

R2and R3each represent a hydrogen atom;

R4represents a hydrogen atom;

R5our opinion is that substituted by a group having the formula-B-PBO2and, in addition, optionally substituted alkyl group having from 1 to 6 carbon atoms, where In denotes a single bond or alkilinity group having from 1 to 6 carbon atoms;

A denotes a single bond or alkilinity group having from 1 to 6 carbon atoms,

and its pharmacologically acceptable salts.

2. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where R5is cycloalkyl group having from 3 to 6 carbon atoms, or piperidinyl group, and these cycloalkyl or piperidinyl group substituted by a group having the formula-B-ONO2and, in addition, optionally substituted methyl group, where a represents methylene group, ethylene group, trimethylene group or tetramethylene group.

3. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where R5is cyclopentyloxy group or tsiklogeksilnogo group, and these groups substituted by a group having the formula-B-ONO2where In represents methylene group, ethylene group, trimethylene group or tetramethylene group.

5. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where R5represents 2 - or 3-nitrosomethylamino group, 2-, 3 - or 4 - nitrosomethylamino group, 4-(2-nitroxyethyl)tsiklogeksilnogo group, 4-(3-nitrosopropane)tsiklogeksilnogo group or 4-(4-nitroxymethyl)tsiklogeksilnogo group.

6. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where R5is 3-nitroxymethyl - cyclopentyloxy group, 2-, 3 - or 4-nitrosomethylamino group, 4-(2-nitroxyethyl)tsiklogeksilnogo group, 4-(3-nitrosopropane)tsiklogeksilnogo group or 4-(4-nitroxymethyl)tsiklogeksilnogo group.

7. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where R5represents 3 - or 4-nitrosomethylamino group, 4-(2-nitroxyethyl)tsiklogeksilnogo group, 4-(3-nitrosopropane)tsiklogeksilnogo group or 4-(4-nitroxymethyl)tsiklogeksilnogo group.

8. Propylcyclohexyl group.

9. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where a represents a single bond or alkilinity group having 1 or 2 carbon atoms.

10. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where a represents a methylene group or ethylene group.

11. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where a represents a methylene group.

12. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where W represents a sulfur atom and X represents a group having the formula-NR1-; R1represents a hydrogen atom; R2and R3each represent a hydrogen atom; R4represents a hydrogen atom; R5represents cycloalkyl group having from 3 to 6 carbon atoms or piperidinyloxy group, with the specified cycloalkyl group or piperidinyl group substituted by a group having the formula-B-PBO2and, in addition, optionally substituted methyl group, where a represents methylene group, ethylene group, trimethylene group or tetramethylene group, and a represents a single Svyatoshinsky acceptable salt p. 1 where W is a sulfur atom and X represents a group having the formula-NR1-; R1represents a hydrogen atom; R2represents a hydrogen atom; R3represents a hydrogen atom; R4represents a hydrogen atom; R5represents cyclopentyloxy group or tsiklogeksilnogo group, and these groups substituted by a group having the formula-B-PBO2where In represents methylene group, ethylene group, trimethylene group or tetramethylene group, and a represents a single bond or alkilinity group having 1 or 2 carbon atoms.

14. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where W represents a sulfur atom and X represents a group having the formula-NR1-; R1represents a hydrogen atom; R2represents a hydrogen atom; R3represents a hydrogen atom; R4represents a hydrogen atom; R5represents a 2 - or 3-nitrosomethylamino group, 2-, 3 - or 4-nitrosomethylamino group, 4-(2-nitroxyethyl)tsiklogeksilnogo group, 4-(3-nitrosopropane) tsiklogeksilnogo group, 4-(4-nitroxymethyl)-tsiklogeksilnogo g is within 1 or 2 carbon atoms.

15. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where W represents a sulfur atom and X represents a group having the formula-NR1-; R1represents a hydrogen atom; R2represents a hydrogen atom; R3represents a hydrogen atom; R4represents a hydrogen atom; R5represents a 2 - or 3-nitrosomethylamino group, 2-, 3 - or 4-nitrosomethylamino group, 4-(2-nitroxyethyl)tsiklogeksilnogo group, 4-(3-nitrosopropane) tsiklogeksilnogo group or 4-(4-nitroxymethyl)tsiklogeksilnogo group, and a represents a methylene group or ethylene group.

16. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where W represents a sulfur atom and X represents a group having the formula-NR1-; R1represents a hydrogen atom; R2represents a hydrogen atom; R3represents a hydrogen atom; R4represents a hydrogen atom; R5is a 3-nitrosomethylamino group, 2-, 3 - or 4-nitrosomethylamino group, 4-(2-nitroxyethyl)tsiklogeksilnogo group, 4-(3-nitrosopropane) tsiklogeksilnogo group or solidiron or its pharmacologically acceptable salt p. 1, where W represents a sulfur atom and X represents a group having the formula-NR1-; R1represents a hydrogen atom; R2represents a hydrogen atom; R3represents a hydrogen atom; R4represents a hydrogen atom; R5represents a 3 - or 4-nitrosomethylamino group, 4-(2-nitroxyethyl)tsiklogeksilnogo group, 4-(3-nitrosopropane) tsiklogeksilnogo group or 4-(4-nitroxymethyl) tsiklogeksilnogo group, and a represents a methylene group.

18. Derived thiazolidinone or its pharmacologically acceptable salt p. 1, where W represents a sulfur atom and X represents a group having the formula-NR1-; R1represents a hydrogen atom; R2represents a hydrogen atom; R3represents a hydrogen atom; R4represents a hydrogen atom; R5is a 4-nitrosomethylamino group, and a represents a methylene group.

19. Derived thiazolidinone under item 1, selected from the group consisting of:

N-(4-nitrosomethylethylamine)-2-oxothiazolidine-4-ylcarboxamine,

N-[2-(4-microclimatological)ethyl] -2-oxothiazolidine-4-ylcarboxamine,

N-[4-(2-n is l]-2-oxothiazolidine-4-ylcarboxamine,

N-[4-(3-nitrosopropane)cyclohexylmethyl] -2-oxothiazolidine-4-ylcarbonyl and

N-[4-(4-nitroxymethyl)cyclohexylmethyl] -2-oxothiazolidine-4-ylcarboxamine, or its pharmacologically acceptable salt.

20. Derived thiazolidinone or its pharmacologically acceptable salt according to any one of paragraphs.1-19, has a vasodilator effect on the collateral vessels.

21. The method of deriving thiazolidinone or its pharmacologically acceptable salt according to any one of paragraphs.1-19, characterized in that the compound having the following General formula, or its reactive derivative

< / BR>
where W, X, R2and R3have the same values as specified in any of paragraphs.1-19,

subjected to interaction with the compound having the General formula

< / BR>
or an acid additive salt,

where A, R4and R5have the same values as specified in any of paragraphs.1-19.

22. Pharmaceutical composition for treatment or prevention of angina containing the active compound in a mixture with a pharmaceutically acceptable carrier or diluent, where the specified active compound is derived thiazolidinone or its pharmacologically acceptable salt according to any one of paragraphs. 1-19.

 

Same patents:

The invention relates to ether compounds and their use

The invention relates to new derivatives of 2-amino-4-phenylthiazole and their salts, and method of production thereof and to pharmaceutical compositions based on them

The invention relates to new derivatives of 2-benzothiazole of the formula I, where one of the substituents R1and R2the hydroxy - group, while the other denotes hydrogen, or its pharmaceutically acceptable salt accession acid

The invention relates to a series of new derivatives of thiazolidinone and oxazolidinone containing nitroacetanilide group, and to methods of producing these compounds may find use of these compounds as vasodilators, for example, for the treatment and prevention of cardiovascular diseases

The invention relates to a new di-tert-butylaniline derivative used for the treatment of inflammatory processes, as well as caused by ischemia cell damage

The invention relates to medicine, specifically to gynecology
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