Partial and full agonists of adenosine receptors a1

FIELD: chemistry.

SUBSTANCE: in compound of formula (I): , R1 represents C1-4-alkoxy C3-6cycloalkyl optionally substituted with atom of halogen, hydroxyl, trifluoromethyl, optionally substituted with halogen atom 5-6-member heterocyclyl, in which heteroatoms are selected from oxygen, optionally substituted with halogen atoms phenyl or optionally substituted with halogen atoms 5-6-member heteroaryl, in which heteroatoms are selected from nitrogen and/or sulfur; R2 represents hydrogen or trifluoromethyl; R3 represents hydrogen, optionally substituted with atom of halogen, C3-6cycloalkyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkyl phenyl, optionally substituted with atom of halogen, trifluoromethyl, C1-4-alkoxy heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen, oxygen or sulfur, or optionally substituted with C1-4-alkyl 5-6-member heterocyclyl, which has in ring 1-2 heteroatoms, selected from nitrogen or oxygen, R4 and R5 independently represent hydrogen; X represents covalent bond or lower alkylene; X1 represents covalent bond or lower alkylene, Y represents covalent bond or lower alkylene, optionally substituted with hydroxy or cycloalkyl; and Z represents -C=C-, -R6C=CR7- or -CHR6CHR7-, where R6 and R7 in each position represent hydrogen or lower alkyl.

EFFECT: antilipolytic effect of compounds.

30 cl, 7 dwg, 31 ex

 

The application priority is claimed in accordance with the prior patent application U.S. registration No. 60/403712, filed August 15, 2002, and provisional patent application U.S. registration No. 60/450094, filed February 25, 2003, the descriptions of which are fully incorporated herein by reference.

The technical field to which the invention relates

The present invention relates to novel compounds that are partial or full agonists of adenosine receptors (A1and to their use for the treatment of mammals from various pathological conditions, including cardiovascular disease, including arrhythmias and prevention of sudden death resulting from arrhythmia, ischemia and disorders of the Central nervous system, including pain, epilepsy and vomiting. Agonists of adenosine receptors (A1are antilipolytic agents and can be used for the treatment of metabolic disorders, including diabetes and obesity. The invention also relates to methods for their preparation and pharmaceutical compositions containing such compounds.

The level of technology

Adenosine is a existing in the nature of the nucleoside, which carries out its biological effects by interacting with a family of adenosine receptors, known as A1, A2a, A and A3, each of which modulate important physiological processes. For example, adenosine receptors (A2Amodulate coronary vasodilation, receptors of A2Binvolved in the activation of mast cells, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2BReceptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153), and adenosine receptors (A3modulate the processes of cell proliferation.

Agonists of adenosine receptors (A1modulate cardiostimulatory effects of catecholamine (mediated inhibition of adenylate cyclase) and slow heart rate (HR), as well as prolong the propagation of pulses on the AV node, which is caused mostly by activation of IKAdo. (B. Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P. 1499-1509 and J. C. Shryock and L. Belardinelli The Am. J. Cardiology, Vol. 79 (1997), p. 2-10). Stimulation of adenosine receptor A1shortens duration and reduces the amplitude of the action potential of cells of the AV node and, therefore, prolongs the refractory period of the cells of the AV node. Thus, stimulation of receptors of A1is a method for the treatment of supraventricular tachycardia, including reflexive tachycardia node, and control of ventricular rhythm during atrial fibrillation and atrial flutter.

Elevated levels neeterificirovannah freedoms who's fatty acids (nezhk) in serum is undesirable for mechanical, and electrical functions of the heart, and agonists of adenosine receptors (A1are powerful and effective inhibitors of lipolysis. This is important because the agonists of adenosine receptors (A1more profound effect in adipose tissue than in the tissues of the heart, they reduce lipolysis in concentrations that do not affect heart rate. Thus, agonists of adenosine receptors (A1can be used for the treatment of metabolic disorders, such as non-insulin-dependent diabetes mellitus and obesity, due to their antilipolytic activity. Antilipolytic effect of agonists of adenosine receptors (A1can also be used for therapy of congestive heart failure. Furthermore, agonists of adenosine receptors (A1protects against ischemia of the heart. Agonists of adenosine receptors (A1can also be used as chemotherapeutic agents in the treatment of CNS disorders, including epilepsy (anticonvulsantsa activity) and ischemia.

Accordingly, the purpose of this invention to provide compounds that are strong full agonists of adenosine receptors (A1or partial agonists of adenosine receptors (A1. Preferred compounds of the invention are selective for adenozinove the receptor A 1that minimizes undesirable side effects associated with stimulation or antagonistic effect on other adenosine receptors.

The invention

Accordingly, in the first aspect of the invention relates to compounds of the formula I:

where R1represents an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl or optionally substituted heteroaryl;

R2represents hydrogen, halogen, trifluoromethyl or cyano;

R3represents hydrogen, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl;

R4and R5independently represent hydrogen or optionally substituted acyl;

X represents a covalent bond or a lower alkylene, optionally substituted cycloalkyl;

X1is a covalent bond or alkylene;

Y is a covalent bond or a lower alkylene, optionally substituted by hydroxyl or cycloalkyl; and

Z represents-C≡C-, -R6C=CR7- or-CHR6CHR7-where R6and R7in each case represent hydrogen or lower alkyl.

The second aspect of the invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula I and at least one pharmaceutically acceptable excipient.

The third aspect of the invention relates to a method of applying the compounds of formula I in the treatment of a disease or condition in a mammal that can be effectively cured partially or fully selective agonist adenosine receptor A1. Such diseases and conditions include at least one of the following: supraventricular tachycardia, including atrial fibrillation and atrial flutter, ischemia, including one that caused the stable and unstable angina, congestive heart failure, myocardial infarction, Central nervous system disorders, including epilepsy and stroke, metabolic disorders such as obesity and diabetes, or a complication of diabetes or congestive heart failure, especially hyperlipidemia, which is facilitated by the antilipolytic action of agonists A1on adipocytes; and treatment of nausea (vomiting).

A fourth aspect of the present invention relates to methods of preparing compounds of formula I.

Of the compounds of formula I, one preferred class includes those compounds in which Z represents-C≡C, especially those compounds in which X, X1and Y are covalent bonds. A preferred group within this class includes those compounds in which R1represents an optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl and R2, R4and R5represent hydrogen.

A preferred subgroup includes those compounds of formula I in which R3represents hydrogen or optionally substituted aryl, especially optionally substituted phenyl. Especially preferred compounds within this subgroup are those compounds in which R1is cycloalkyl, especially cyclopentyl or hydroxycyclopent, or optionally substituted heterocyclyl, especially tetrahydrofuran-3-yl, and R3represents hydrogen. Other preferred compounds within this subgroup includes those compounds of formula I in which R3represents optionally substituted phenyl. Especially preferred are those compounds in which R1is cycloalkyl, especially cyclopentyl, or optionally substituted heterocyclyl, especially tetrahydrofuran-3-yl, and R3is a 2-forfinal or 2-triptoreline.

Another preferred podgroup is and includes those compounds of formula I, in which R3represents optionally substituted aryl. Especially preferred compounds within this subgroup are those compounds in which R1is cycloalkyl, especially cyclopentyl, or optionally substituted heterocyclyl, especially tetrahydrofuran-3-yl. Preferred R3groups include optionally substituted thienyl, especially 5-chlortan-2-yl.

Of the compounds of formula I to another preferred class includes those compounds in which Z represents-R6C=CR7-especially those compounds in which R6and R7represent hydrogen and X, X1and Y are covalent bonds. A preferred group within this class includes those compounds in which R1represents an optionally substituted cycloalkyl and R2, R4and R5represent hydrogen. A preferred subgroup includes those compounds of formula I in which R3represents optionally substituted aryl or optionally substituted heteroaryl. Especially preferred are those compounds in which R3includes optionally substituted phenyl, especially phenyl or 2-were, or optionally substituted thienyl, especially 5-chlortan-2-yl.

Definitions and General parameters

rementeria in the present description, the following words and phrases commonly used to refer to the following, except when the context in which they are used indicates otherwise.

The term "alkyl" refers to onorevole branched or unbranched saturated hydrocarbon chain containing from 1 to 20 carbon atoms. This term is illustrated by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term "substituted alkyl" refers to:

1) an alkyl group as defined above having 1, 2, 3, 4 or 5 substituents, for example 1 to 3 substituents selected from the group consisting of alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and-SO2-heteroaryl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, g is lagena, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl, and n is 0, 1 or 2; or

2) an alkyl group as defined above that is interrupted by 1-10 atoms independently selected from oxygen, sulfur and NRa-, where Raselected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, quinil, aryl, heteroaryl and heterocyclyl. All substituents may be optionally additionally substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano or-S(O)nR, where R is an alkyl, aryl, or heteroaryl, and n is 0, 1 or 2; or

3) alkyl group, as defined above, which contains 1, 2, 3, 4, or 5 substituents as defined above and is also interrupted by 1-10 atoms, as defined above.

The term "lower alkyl" refers to onorevole branched or unbranched saturated hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms. This term is illustrated by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl and the like.

The term "substituted lower alkyl" refers to lower alkyl as defined above containing from 1 to 5 substituents, for example 1, 2 or 3 substituent as defined for substituted alkyl, or the group of lower alkyl, as defined above, which PR is Rana 1, 2, 3, 4 or 5 atoms as defined for substituted alkyl, or the group of lower alkyl, as defined above, which contains 1, 2, 3, 4, or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4 or 5 atoms, as defined above.

The term "alkylene" refers to a double radical of a branched or unbranched saturated hydrocarbon chain, for example, containing from 1 to 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This term is illustrated by such groups as methylene(-CH2-), ethylene(-CH2CH2-), isomers of propylene (e.g.,- CH2CH2CH2- , and-CH(CH3)CH2-) and the like.

The term "lower alkylene" refers to a double radical of a branched or unbranched saturated hydrocarbon chain, for example, containing 1, 2, 3, 4, 5 or 6 carbon atoms.

The term "substituted alkylene" refers to:

(1) alkalinous group as defined above having 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, orelox is, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and-SO2-heteroaryl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl, and n is 0, 1 or 2; or

(2) alkalinous group as defined above that is interrupted by 1-20 atoms independently chosen from oxygen, sulfur and NRa-, where Raselected from hydrogen, optionally substituted alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, or groups selected from carbonyl, carboxyester, carboxamide and sulfonyl; or

(3) alkalinous group, as defined above, which contains 1, 2, 3, 4, or 5 substituents as defined above and is also interrupted by 1-20 atoms as defined above. Examples of the substituted alkylenes are chlormethine (-CH(Cl)-), aminoethyl (-CH(NH2)CH2-), methylaminoethanol (-CH(NHMe)CH2-)isomers of 2-carboxypropyl (-CH2CH(CO2H)CH2-), ethoxyethyl (-CH2CH2O-CH CH2-), ethylmethylamine (-CH2CH2N(CH3)CH2CH2-), 1 ethoxy-2-(2-ethoxyethoxy)ethane (-CH2CH2O-CH2CH2-OCH2CH2-OCH2CH2-) and the like.

The term "aralkyl" refers to an aryl group covalently associated with alkalinous group, where the aryl and alkylene defined here. "Optionally substituted aralkyl" refers to optionally substituted aryl group covalently linked with optionally substituted alkalinous group. Examples of such Uralkalij groups are benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.

The term "alkoxy" refers to the group R-O-, where R represents optionally substituted alkyl or optionally substituted cycloalkyl, or R is a group-Y-Z, in which Y represents an optionally substituted alkylene and Z represents optionally substituted of alkenyl, optionally substituted quinil; or optionally substituted cycloalkenyl, where the alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl are defined here. Preferred alkoxy groups are alkyl-O-, which include, as an example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentox, n-hexose, 1,2-Dimethylbutane and the like.

The term "ALK is ltio" refers to the group R-S-, where R is what is defined for alkoxy.

The term "alkenyl" refers to monoracial branched or unbranched unsaturated hydrocarbon group containing from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms and even more preferably from 2 to 6 carbon atoms and having 1 to 6, preferably 1, double bonds (vinyl). Preferred alkeneamine groups include ethynyl or vinyl (-CH=CH2), 1-propylene or allyl (-CH2CH=CH2), isopropylene (-C(CH3)=CH2), bicyclo[2.2.1]hepten and the like. In the case when alkenyl attached to the nitrogen, the double bond may not be in a position alpha with respect to nitrogen.

The term "lower alkenyl" refers to alkenyl, as defined above containing from 2 to 6 carbon atoms.

The term "substituted alkenyl" refers to alkenylphenol group, as defined above, containing 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, amino is arbolino, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and-SO2-heteroaryl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "quinil" refers to monoracial unsaturated hydrocarbon containing from 2 to 20 carbon atoms, preferably from 2 to 10 carbon atoms and even more preferably from 2 to 6 carbon atoms and having at least 1 and preferably 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkyline group include ethinyl (-C≡CH), propargyl (or PROPYNYL, -C≡CCH3), and the like. In the case when quinil attached to the nitrogen triple bond may not be in a position alpha with respect to nitrogen.

The term "substituted quinil" refers to alkenylphenol group, as defined above, containing 1, 2, 3, 4 or 5 substituents, and preferably 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, Ala the XI, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and-SO2-heteroaryl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term "aminocarbonyl" refers to the group-C(O)NRR where each R is independently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or where both R groups are joined to form heterocyclic groups (for example, morpholino). If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2, or 3 substituents chosen from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3 , amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term "ester" or "carboxyethyl" refers to the group-C(O)OR where R is an alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, which may be optionally additionally substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano or-S(O)nRawhere Rarepresents alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term "acylamino" refers to the group-NRC(O)R where each R is independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl. All substituents may be optionally additionally substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano or-S(O)nR, where R is an alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "acyloxy" refers to the groups-O(O)C-alkyl, -O(O)C-cycloalkyl, -O(O)C-aryl, -O(O)C-heteroaryl and-O(O)C-heterocyclyl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl and n is 0, 1 or 2.

p> The term "aryl" refers to aromatic carbocyclic group containing from 6 to 20 carbon atoms having a single ring (e.g. phenyl)or multiple rings (e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl or until). Preferred arily include phenyl, naphthyl and the like.

If the definition for the aryl substituent is not limited otherwise, such aryl groups can be optionally substituted by 1, 2, 3, 4 or 5 substituents, preferably 1, 2, or 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and-SO2-heteroaryl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3the am is but substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl, and n is 0, 1 or 2.

The term "aryloxy" refers to the group aryl-O-, where the aryl group is a defined above and includes optionally substituted aryl group, as defined above. The term "aristeo" refers to the group R-S-, where R is defined for aryl.

The term "amino" refers to the group-NH2.

The term "substituted amino" refers to the group-NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl offered so that both R groups are not hydrogen, or the group-Y-Z, in which Y represents an optionally substituted alkylene and Z represents alkenyl, cycloalkenyl or quinil. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "carboxylic" refers to the groups-C(O)O-alkyl, -C(O)O-cycloalkyl, where the alkyl and cycloalkyl are as defined here and can be optional to omnitele substituted by alkyl, alkenyl, quinil, alkoxy, halogen, CF3, amino, substituted amino, cyano or-S(O)nR, where R is an alkyl, aryl or heteroaryl, and n is 0, 1 or 2.

The term "cycloalkyl" refers to cyclic alkyl groups containing from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, as an example, patterns with a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or patterns with multiple rings, such as adamantyl and bicyclo[2.2.1]heptane, or cyclic alkyl groups, which condensed aryl group, for example, indan, and the like.

The term "substituted cycloalkyl" refers to cycloalkyl groups containing 1, 2, 3, 4 or 5 substituents, and preferably 1, 2 or 3 substituent selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl heterocyclics, hydroxyamino, alkoxyamino, nitro, -SO-and the Qila, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and-SO2-heteroaryl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "halogen" or "halo" refers to fluorine, bromine, chlorine and iodine.

The term "acyl" denotes the group-C(O)R, in which R represents hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl.

The term "heteroaryl" refers to an aromatic group (i.e. unsaturated)comprising from 1 to 15 carbon atoms and from 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring.

If the definition for the heteroaryl substituent is not limited otherwise, such heteroaryl groups can be optionally substituted by 1 to 5 substituents, preferably 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, alloc and, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyethyl (alkyl ether), arieti, heteroaryl, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, aralkyl, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and-SO2-heteroaryl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl and n is 0, 1 or 2. Such heteroaryl groups can contain one ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazole or benzothiazyl). Examples of nitrogen-containing heterocycles and heteroaryl include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, hemolysin, isoquinoline, quinoline, phthalazine, naftemporiki, cinoxacin, hinzelin, cinnolin, pteridine, carbazole, ka is Bolin, phenanthridine, acridine, phenanthroline, isothiazol, fenesin, isoxazol, phenoxazin, phenothiazines, imidazolidin, imidazolyl and the like, as well as N-alkoxy-nitrogen containing heteroaryl compounds.

The term "heteroaromatic" refers to a group heteroaryl-O-.

The term "heterocyclyl" refers to onorevole saturated or partially unsaturated group containing one ring or multiple condensed rings, having from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, preferably from 1 to 4 heteroatoms selected from nitrogen, sulfur, phosphorus and/or oxygen within the ring.

If a definition is not otherwise limited for the heterocyclic substituent, such heterocyclic groups can be optionally substituted by from 1 to 5 and preferably 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl, heterocyclic hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, SO2-aryl and-SO 2-heteroaryl. If the definition is not limited otherwise, all substituents may be optionally additionally substituted 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano and-S(O)nR, where R is an alkyl, aryl or heteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocycles include tetrahydrofuranyl, morpholino, piperidinyl and the like.

The term "thiol" refers to the group-SH.

The term "substituted, alkylthio" refers to the group-S-substituted alkyl.

The term "heteroaryl" refers to the group-S-heteroaryl, where the heteroaryl group is a defined above including optionally substituted heteroaryl group, as defined above.

The term "sulfoxide" refers to the group-S(O)R, in which R represents alkyl, aryl or heteroaryl. "Substituted sulfoxide" refers to the group-S(O)R, in which R is a substituted alkyl, substituted aryl or substituted heteroaryl, as defined here.

The term "sulfon" refers to the group-S(O)2R, in which R represents alkyl, aryl or heteroaryl. "Substituted sulfon" refers to the group-S(O)2R is where R is a substituted alkyl, substituted aryl or substituted heteroaryl, as defined here.

The term "keto" refers to the group-C(O)-.

The term "thiocarbonyl" refers to the group-C(S).

The term "carboxy" refers to the group-C(O)-OH.

"Optional" or "optionally" means that the described in the subsequent event or condition may or may not take place and that the description includes instances when the specified event or condition occurs and instances in which they are not.

The term "compound of formula I" is intended to encompass the compounds of the invention as disclosed, and their polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable esters and prodrugs of such compounds. In addition, the compounds of the invention can possess one or more asymmetric centers and may be obtained as racemic mixtures or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of formula I depends on the number of asymmetric centers (there are 2nstereoisomers, where n is the number of asymmetric centers). The individual stereoisomers may be obtained by separation of the racemic or prizemistoj mixture of the intermediate product at some suitable stage of the synthesis or separation from the unity of formula I by conventional means. Individual stereoisomers (including individual enantiomers and diastereoisomers), as well as racemic and nerezisca mixture of stereoisomers are included in the scope of the present invention, and the premise that they all describe the structures of this description, unless specifically stated otherwise.

"Isomers are different compounds that have the same molecular formula.

"Stereoisomers are isomers that differ only in the arrangement of atoms in space.

"Enantiomers" are a pair of stereoisomers that are not imposed mirror images of each other. A mixture of 1:1 pair of enantiomers represents a "racemic" mixture. The term "(±)" is used to denote a racemic mixture, where this is appropriate.

"Diastereoisomer" are stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

The absolute stereochemistry is described by the R-S system Cahn-Ingold-Prelog. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be described or R, or S. the Split connection, the absolute configuration of which is unknown, indicate the (+) or (-) depending on the direction (right or levogyrate),in which they rotate plane polarized light at a wavelength of, the respective band D of sodium.

The term "therapeutically effective amount" refers to that amount of the compounds of formula I, which is sufficient for effective treatment, as defined below, when administered to a mammal in need of such treatment. Therapeutically effective amount should vary depending on the subject and the disease condition to be treated, the weight and age of the subject, the severity of the disease condition, the route of administration and the like, which can be easily determined by a person skilled in the technical field.

The term "treating" or "treatment" means any treatment of a disease in a mammal, including:

(i) preventing the disease, i.e. blocking the development of clinical symptoms;

(ii) inhibition of the disease, i.e. stopping the development of clinical symptoms; and/or

(iii) facilitation of the disease, i.e. the stimulation of the regression of clinical symptoms.

In many cases, the compounds of this invention are capable of forming acid and/or basic salts in the presence of amino and/or carboxyl groups or similar groups. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds of formula I and which are not biologically or other education is ω undesirable. Pharmaceutically acceptable salt additive bases can be derived from inorganic and organic bases. Salts derived from inorganic bases include, only as an example, salts of sodium, potassium, lithium, ammonium, calcium and magnesium. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines followed, diallylamine, triallylamine, substituted alkylamines followed, di(substituted alkyl)amines, three(substituted alkyl)amines, alkenylamine, dialkanolamine, trialkylamine, substituted alkanolamine, di(substituted alkenyl)amines, three(replaced alkenyl)amines, cyclooctylamine, di(cycloalkyl)amines, three(cycloalkyl)amines, substituted cycloalkene, disubstituted cycloalkenyl, tizamidine cyclooctylamine, cyclooctylamine, di(cycloalkenyl)amines three(cycloalkenyl)amines, substituted cycloalkenyl, disubstituted cycloalkenyl, tizamidine cyclooctylamine, arylamine, diarylamino, triarylamine, heteroaromatic, digitalairlines, triethanolamine, heterocyclic amines, diheterocyclanes amines, trilateration amines, mixed di - and triamine, where at least two of the substituents on Amina different and selected from the group consisting of alkyl, substituted alkyl, alkenyl, replaced alkene is a, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclyl and the like. Also included amines, where two or three deputies, together with aminoazoles, form a heterocyclic or heteroaryl group.

Specific examples of suitable amines include, only as an example, Isopropylamine, trimethylamine, diethylamine, three(isopropyl)amine, three(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, geranamine, choline, betaine, Ethylenediamine, glucosamine, N-alkylguanine, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

Pharmaceutically acceptable additive salts of the acids may be derived from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almond acid, methanesulfonic the lot, econsultation, p-toluene-acid, salicylic acid and the like.

Used here, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, enrobing agents, antibacterial and antifungal agents, isotonic and delaying the absorption of the agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Covers the use in therapeutic compositions of any conventional medium or agent, except incompatible with the active ingredient. The composition may also include additional active ingredients.

Used here, the term "agonist" refers to the ability of the compound to interact with a receptor and cause maximum physiological effect (i.e., activate or stimulate the receptor). This effect is known as internal efficiency. Specialists in the art there are many known full agonists adenosine receptor (A1for example N6-cyclopentylamine (CPA or CCPA). Some agonists of the adenosine A1it is designated as "partial agonists", because they interact with the receptors of A1adenosine, but induce a response that is less than the maximum when compared with that which they agonist, as a CPA.

Internal efficiency is its differential effect on the selected fabric. Thus, the connection can be a full agonist in this tissue, but partial in others. Compounds identified in this invention possess a therapeutically acceptable affinity to receptor-A1adenosine, but have internal efficiency, ranging from full agonists, partial agonists. That is, some compounds may have no action in respect of this effector system in this cell type, but can be full agonists in cells of a different type and/or other effector systems. Partial agonist intended for the selected target, probably causes less side effects compared to full agonist, as it seems, should cause less desensitization of receptor-A1(R. B. Clark, B. J. Knoll, R. Barber TiPS, Vol. 20 (1999) p. 279-286) and less side effects. Chronic introduction of a full agonist (R-N6-phenylisopropylamine, R-PIA) for 7 days resulted in data demonstrate that differently modulated receptor A1in relation dromotropic response in Guinea pigs (note: there was a decrease in the number of receptors D. M. Dennis, J. C. Shryock, L. Belardinelli JPET, Vol. 272 (1995) p. 1024-1035). It was shown that the inhibitory effect of the agonist A1on products : the Yu of camp by adenylate cyclase in adipocytes leads to data demonstrate that differently modulated after chronic application of agonist (A 1(W. J. Parsons and G. L. J. Biol. Chem. Vol. 262 (1987) p. 841-847).

Nomenclature

Names and numbering of the compounds according to the invention are illustrated with typical compounds of the formula I, in which R1is cyclopentyl, R2represents hydrogen, R3is a 2-forfinal, R4and R5both represent hydrogen, X, X1and Y represents a covalent bond and Z represents-C≡C-:

called: (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-[2-(2-forfinal)ethinyl]oxolan-3,4-diol, or an alternate may be named: (4S,2R,3R,5R)-2-[6-(cyclopentylamine)-9H-purine-9-yl]-5-[2-(2-forfinal)ethinyl]tetrahydrofuran-3,4-diol.

The parameters of the synthesis reaction

The terms "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions described directly in connection with this reaction [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine and the like]. Unless otherwise noted, solvents used in reactions of this invention are inert organic solvents.

The term "q.s." means adding the number, dostatochno is to attain the preset functions for example, to bring the solution up to the desired volume (i.e. 100%).

The synthesis of compounds of formula I

The compounds of formula I, where R3represents hydrogen, X1and Y represents a covalent bond and Z represents-C≡C-get on the basis of the compounds of formula (1), as shown in reaction scheme I.

Stage 1 - Getting formula (2)

The parent compound of formula (1) are commercially available (for example, the compound of formula (1)in which R2represents hydrogen, can be bought from Aldrich, Milwaukee) or get them using methods well-known to specialists in this field of technology. The compound of the formula (2) is usually derived from the compounds of formula (1) by interacting with 2,2-dimethoxypropane in an inert solvent, preferably in N,N-dimethylformamide, in the presence of catalytic amounts of an acid catalyst, preferably p-toluenesulfonic acid, at a temperature of about 40-90°C, preferably at about 70°C, for about 24 to 72 hours, preferably for about 48 hours. After almost a full completion of the reaction product of the formula (2) is recovered by conventional means, for example by removing the solvent under reduced pressure and purification of the residue by chromatography.

Stage 2 - Received the e formula (3)

6-Chloro radical in the compound of the formula (2) replace by reacting with the compound of the formula R1XNH2where X has the values specified above, in the presence of a base, such as triethylamine. The reaction is carried out in an inert Protestantism solvent, for example ethanol, at a temperature which is approximately equal to the boiling temperature under reflux, for about 14-48 hours, preferably about 16 hours. After almost a full completion of the reaction product of the formula (3) is recovered by conventional means, for example by removing the solvent under reduced pressure followed by crystallization of the residue from a suitable solvent.

It should be noted that stage 1 and 2 can be performed in reverse order.

Stage 3 - Getting formula (4)

Hydroxymethylene compound of the formula (3) are oxidized to the aldehyde of formula (4) using modifications of oxidation by Moffat. Typically, the compound of formula (3) add a mixture of 1,3-dicyclohexylcarbodiimide DCC, dimethyl sulfoxide and pyridine. The initial reaction is carried out at a temperature of from about -5° up to about 10°C, preferably about 0°C and then at room temperature for about onset 6 to 48 hours, preferably about 18 hours. After virtually complete reaction of the aldehyde of formula (4) is recovered by conventional means, for example by using the distribution is of product between ethyl acetate and water and removal of the solvent under reduced pressure. The product is used in the next stage without additional purification.

Stage 4 - Getting formula (5).

4'-Aldehyde group is then converted into etinilnoy group by interacting with bromomethylphosphonate in the presence of a strong base, preferably tert-butoxide potassium. The reaction is carried out in an inert solvent, preferably tetrahydrofuran, at a temperature of about -80°C, allowing the reaction mixture to gradually warm to room temperature for about 1-3 days period. After almost a full completion of the reaction product of the formula (5) is recovered by conventional means, for example by removing the solvent under reduced pressure with subsequent distribution between solvent such as ethyl acetate, and water, removing the solvent under reduced pressure. The residue can then be further purified by chromatography on silica gel with obtaining 5'-etinilnoy the compounds of formula (5).

Stage 5 - Obtaining the compounds of formula I

Protected acetonide compound of the formula (5) is then converted into the compound of the formula I in which Y is a covalent bond, Z represents-C≡C and R3represents hydrogen, by treatment with an acid such as organic acid, for example acetic acid. The reaction is carried out in a mixture of Ki is lots and water, at about 50-100°C, preferably about 80-90°C, for about 10-48 hours, preferably about 16 hours. After almost a full completion of the reaction product of formula I produce by conventional means, for example by removing the solvent under reduced pressure, followed by chromatography of the residue on silica gel.

Alternative obtaining the compounds of formula I

The compounds of formula I in which R3represents hydrogen, X1and Y represents a covalent bond and Z represents-C≡C-may be an alternative produced from the compounds of formula (1), as shown in reaction scheme IA. This method of synthesis is preferred when R' part of a Deputy, for example hydroxyl Deputy.

Stage 1 is carried out, as shown in reaction scheme I.

Stage 2 - Getting formula (4a)

Hydroxymethylene compound of the formula (2) are oxidized to the aldehyde of the formula (4a) using modifications of oxidation by Moffat. Typically, the compound of the formula (2) add a mixture of DCC, dimethyl sulfoxide and pyridine. The initial reaction is carried out at a temperature of from about -5° up to about 10°C, preferably about 0°C and then at room temperature for about onset 6 to 48 hours, preferably about 18 hours. After almost full completion of reaction the AI aldehyde of the formula (4a) is recovered by conventional means, for example, by the product distribution between ethyl acetate and water and removal of the solvent under reduced pressure. The product is used in the next stage without additional purification.

Stage 3 - Getting formula (5a)

5'-Aldehyde group is converted into etinilnoy group by interacting with bromomethylphosphonate in the presence of a strong base, preferably tert-butoxide potassium. The reaction is carried out in an inert solvent, preferably tetrahydrofuran, at a temperature of about -80°C, allowing the reaction mixture to gradually warm to room temperature for about 1-3 days period. After almost a full completion of the reaction product of the formula (5a) was isolated in the usual way.

Stage 4 - Getting formula (5)

6-Chloro part in the compound of formula (5a) substituted by reacting with the compound of the formula R1XNH2where X has the values specified above, in the presence of a base, such as triethylamine. The reaction is carried out in an inert Protestantism solvent, for example ethanol, at a temperature which is approximately equal to the boiling temperature under reflux, for about 14-48 hours, preferably about 16 hours. After almost a full completion of the reaction product of the formula (5) was isolated in the usual way.

Stage 5 - Receipt fo the mules I

The compound of the formula (5) is then converted into a compound of formula I, as shown in reaction scheme I above.

Obtaining the compounds of formula I in which R3is not hydrogen

Obtaining the compounds of formula I in which R3is not hydrogen, X1is a covalent bond, and Y have the values specified above, and Z represents-C≡C is presented in reaction scheme II.

Stage 1 - Getting formula (6)

4'-Etinilnoy compound of the formula (5) is converted into the compound of the formula (6) by reacting with the compound of the formula R3Y-LG, in which LG represents a removable group, preferably halogen, such as iodine or bromine. The reaction is carried out in the presence of catalytic amounts of dichlorobis(triphenylphosphine)palladium (II) iodide, copper (II) plus tertiary amine, such as triethylamine, in an inert solvent, for example tetrahydrofuran, at a temperature equal to room temperature for about 15 minutes. After almost a full completion of the reaction product of formula I produce by conventional means, for example by removing the solvent under reduced pressure, followed by preparative chromatography on silica gel with obtaining 5'-mestnogo etinilnoy the compounds of formula I.

Stage 2 - Getting formula I/p>

The compound of formula (6) is then subjected to unprotect the same way as shown above in reaction scheme 1, by treatment with acid, preferably an organic acid, for example acetic acid, to obtain the compounds of formula I.

Alternative obtaining the compounds of formula I in which R3is not hydrogen

Alternatively, the compound of formula I, in which R3is not hydrogen, X1is a covalent bond, and Y have the values specified above, and Z represents-C≡C-, can be obtained directly from the compounds of formula I in which R3represents hydrogen as shown in reaction scheme IIA.

Stage 1

4'-Etinilnoy compound of the formula I is converted into the compound of the formula I, in which R3is not hydrogen, by reacting with the compound of the formula R3Y-LG, in which LG represents a removable group, preferably halogen, such as iodine or bromine. The reaction is carried out in the presence of catalytic amounts of dichlorobis(triphenylphosphine)palladium (II) and copper iodide (I) plus tertiary amine, such as triethylamine, in an inert solvent, for example tetrahydrofuran, at a temperature equal to room temperature for about 15 minutes. After almost complete Rea is the product of the formula I, in which R3is not hydrogen, there are the usual ways, for example by removing the solvent under reduced pressure, followed by preparative chromatography on silica gel to obtain 4'-substituted etinilnoy the compounds of formula I.

Obtaining the compounds of formula I in which Z represents-CH=CH-

Obtaining the compounds of formula I, in which X1is a covalent bond and Z represents-CH=CH-, shown in reaction scheme III.

Stage 1 - Getting formula (7)

4'-Aldehyde group is converted into atenilol group using the Wittig reaction, by reacting the compounds of formula (4), the receipt of which is shown above, with R3Y-CH2P(Ph)3Br (where Ph represents phenyl) in the presence of a base, for example aqueous sodium hydroxide. The reaction is carried out in an inert solvent, for example dichloromethane, at a temperature equal to room temperature over a period of about 1-10 hours. After almost a full completion of the reaction product of the formula (7) is recovered by conventional means, for example by removing the solvent under reduced pressure with subsequent distribution between solvent such as ethyl acetate, and water, removing the solvent under reduced pressure. The balance can be additional is but purified by chromatography on silica gel to obtain 4'-atenilol the compounds of formula (7).

Stage 2 - Obtaining the compounds of formula I in which Z represents-CH=CH-

The compound of formula (7) is then subjected to unprotect the same way as shown above in reaction scheme 1, by treatment with an acid, for example an organic acid such as acetic acid, to obtain the compounds of formula I.

A. Obtaining the compounds of formula I in which Z represents-CH2CH2-

Obtaining the compounds of formula I, in which X1is a covalent bond and Z represents-CH2CH2-shown in the reaction scheme IV.

The compound of formula I in which Z represents-CH2CH2-receive from the compounds of formula I in which Z represents-CH=CH- (or, alternatively, may be applied compound of formula I in which Z represents-C≡C-). Typically, the compound of formula I in which Z represents-CH=CH-, dissolved in an inert solvent and mixed with a catalyst such as palladium hydroxide, and reagent transfer in catalytic hydrogenation, such as cyclohexen. The reaction is carried out in an inert solvent, for example ethanol, at room temperature, for about 10-48 hours. After almost a full completion of the reaction product of formula I produce usually the diversified ways, for example, removal of solvent under reduced pressure followed by chromatography, to obtain the compounds of formula I in which Z represents-CH2CH2-.

B. Receipt of the formula I, where R2represents hydrogen and X1represents CH2.

The compounds of formula I, where R3represents hydrogen, Y represents a covalent bond, X1represents CH2and Z represents-C≡C-, can be obtained from the compounds of formula (4), as shown in reaction scheme V.

Stage 1 - Getting formula (8)

Hexamethyldisilazane N-sodium enter into interaction with benzyloxyacetophenone chloride (formula 4a) at a temperature of about -80°C for about 1 hour. The compound of the formula (4)obtained as shown in reaction scheme 1, or ways, well known to experts in the art, is dissolved in an inert solvent, for example tetrahydrofuran, and added dropwise to the reaction mixture, the temperature allowed to rise to room temperature and stirred for 4-24 hours, preferably 8 hours. After almost a full completion of the reaction the product is isolated and purified by conventional means, for example by crystallization of the residue.

Stage 2a - Floor is a group of formula (9)

The compound of formula (9) are obtained in the usual way from the compounds of formula (8) by hydrogenation in the presence of a catalyst such as Pd/C. After almost full completion of the reaction product of the formula (9) is recovered by conventional means and used without further purification.

Stage 2b - Getting formula (10)

The compound of formula (9) is subjected to removal of protection by hydrogenation in the presence of a catalyst such as palladium hydroxide, and reagent transfer in catalytic hydrogenation, such as cyclohexen. The reaction is carried out in an inert solvent, for example ethanol, at room temperature, for about 2-7 days period, preferably 5 days, with about 75-100°C, preferably about 80°C. After almost full completion of the reaction product of the formula (10) was isolated by conventional means, for example by removing the solvent by filtration, followed by purification by chromatography on silica gel, to obtain the compounds of formula (10).

Stage 3 - Getting formula (11)

Hydroxymethylene compound of formula (10) are oxidized to the aldehyde of the formula (11) using modifications of oxidation by Moffat. Typically, the compound of formula (10) is injected into the interaction of with a mixture of dicyclohexylcarbodiimide, dimethyl sulfoxide and pyridine. The initial reaction is carried out at a temperature of about -5°-10°C, preference is sustained fashion about 0° C and then at room temperature for about onset 6 to 48 hours, preferably about 18 hours. After virtually complete reaction of the aldehyde of the formula (11) was isolated in the usual way. The product, for example, is used in the next stage without additional purification.

Stage 4 - Getting formula (12)

4'-Aldehyde group is converted into etinilnoy group by interacting with bromomethylphosphonate in the presence of a strong base such as tert-butoxide potassium. The reaction is carried out in an inert solvent, for example tetrahydrofuran, at a temperature of about -80°C, allowing the reaction mixture to gradually warm to room temperature and stirring for about 1-3 days. After almost a full completion of the reaction product of the formula (12) is isolated and purified by conventional means, for example by chromatography on silica gel, to obtain the 5'-Ainring the compounds of formula (12).

Stage 5 - Getting formula I

Protected acetonide compound of the formula (12) is then converted into the compound of the formula I in which Y is a covalent bond, Z represents-C≡C and R3represents hydrogen, by treatment with an acid, for example acetic acid. The reaction is carried out in a mixture of acid and water at about 50 to 100°C, preferably about 80-90°C, for about 10-48 hours, etc is doctitle about 16 hours. After almost a full completion of the reaction product of formula I is isolated and purified by conventional means, for example chromatography of the residue on silica gel.

Obtaining compounds of formula I, where X1represents (CH2)2

The compounds of formula (1), where X1represents (CH2)2receive, as shown in the reaction scheme V, but with substitution of the compounds of formula (4a) of the compound of formula (4b).

The synthesis of compounds (4a) and (4b)

Chlorine(phenylmethoxy)ethane and triphenylphosphine enter into interaction in an inert solvent, for example benzene, and support under conditions of boiling under reflux overnight. After almost a full completion of the reaction product of the formula (4a) was isolated in the usual way.

Similarly, replacement of chlorine(phenylmethoxy)methane chlorine(phenylmethoxy)ethane get the compound of formula (4b).

The compounds of formula I, where X1represents (CH2)2and R3represents hydrogen, is converted into the compounds of formula I, where X1represents (CH2)2and R3is other than hydrogen, as shown in reaction scheme II above.

Application, research and introduction

Common applications

The compounds of formula I effective p and the treatment of conditions with a known response to the introduction of partial or full agonist adenosine receptor (A1. Such conditions include, but are not limited to, acute and chronic disorders of heart rhythm, especially those diseases that have a high rate of heart contractions, in which the speed is determined by the violations of sinoatrial, atrial tissue and tissue of the AV node. Such disorders include, but are not limited to, atrial fibrillation, supraventricular tachycardia and atrial flutter, congestive heart failure, and sudden death resulting from arrhythmia, non-insulin-dependent diabetes mellitus, hyperglycemia, epilepsy (anticonvulsantsa activity) and heart and neurotoxity.

Agonists A1because of their inhibitory effect on the formation of cyclic AMP, have antilipolytic action in adipocytes, which leads to a reduced release neeterificirovannah fatty acids (nezhk) (E. A. van Schaick et al J. Pharmacokinetics and Biopharmaceutics, Vol. 25 (1997) p. 673-694 and P. Strong Clinical Science Vol. 84 (1993) p. 663-669). Non-insulin dependent diabetes mellitus (NIDDM) is characterized by insulin resistance, which leads to hyperglycemia. Factors contributing to the observed hyperglycemia, are the absence of normal seizure of glucose and activation glikogensintetazy (GS) skeletal is ysz. It was shown that elevated levels of nezhk inhibits stimulated insulin seizure of glucose and glycogen synthesis (D. Thiebaud et al Metab. Clin. Exp. Vol. 31 (1982) p. 1128-1136, and G. Boden et al J. Clin. Invest. Vol. 93 (1994) p. 2438-2446). In 1963 P. J. Randle suggested a hypothesis about the cycle of glucose and fatty acids (P. J. Randle et al. Lancet (1963) p. 785-789). In accordance with the limitation of supply peripheral tissues fatty acids contributes to the utilization of carbohydrates (P. Strong et al. Clinical Science Vol. 84 (1993) p. 663-669).

Were the advantages of agonist A1disorders of the Central nervous system (L. J. S. Knutsen and T. F. Murray. In Purinergic Approaches in Experimental Therapeutics, Eds. K. A. Jacobson and M. F. Jarvis (1997) Wiley-Liss, N. Y., P.423-470). In short, based on experimental models of epilepsy have shown that mixed agonist-A2A:A1, matrifocal, is a strong anticonvulsant against attacks caused by the inverse benzodiazepine agonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM, H. Klitgaard. Eur. J. Pharmacol. (1993) Vol. 224, p. 221-228). In other studies, which are applied in CGS 21680, agonist A2A, it was concluded that anticonvulsantsa activity was caused by the activation of receptor-A1(G. Zhang et al. Eur. J. Pharmacol. Vol. 255 (1994) p. 239-243). In addition, selective adenosine agonists A1as has been shown to have anticonvulsants activity on the model of DMCM (L. J. S. Knutsen In an Adenosine Adenne Nucleotides: From Molecular Biology to Integrative discrimination; eds. L. Belardinelli and A. Pelleg, Kluwer: Boston, 1995, pp. 479-487). The second area where adenosine agonist A1has the advantage, are animal models of forebrain ischemia, as shown by Knutsen et al. (J. Med. Chem. Vol. 42 (1999) p. 3463-3477). I believe that the advantage of nerozumite partly due to the inhibition of the release of excitatory amino acids (ibid.).

Study

The research activity is carried out, as described in the patent and literature references cited above, and the examples described below and by using the methods that are obvious to a person skilled in this technical field.

The pharmaceutical composition

The compounds of formula I is usually administered in the form of pharmaceutical compositions. The present invention therefore offers the pharmaceutical compositions which contain as active ingredient one or more compounds of the formula I, or their pharmaceutically acceptable salts, or esters, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, amplifiers suction, soljubilizatory and adjuvants. The compounds of formula I can be entered separately or in combination with other therapeutic agents. Such compositions have the way well known in the pharmaceutical field (see, for example, Remington''s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17thEd. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3rdEd. (G.S. Banker & C.T. Rhodes, Eds.).

Introduction

The compounds of formula I can enter as a single or separate doses by any acceptable route of administration of agents having similar properties, for example as described in those patents and patent applications, which are included as references, including rectal, cheek, intranasal and transcutaneous path, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, local injection, in the form of inhalant or through an impregnated or coated device such as, for example, a stent or injected into the artery cylindrical polymer.

One of the ways of administration is parenterally, by injection. Shape, in which new compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions with hemp oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, maniowy, dextrose, or a sterile aqueous solution, and similar pharmaceutical carriers. Aqueous solutions in saline solution also typically used on the I injection but are less preferred in the context of the present invention. Can also be applied to ethanol, glycerin, propylene glycol, liquid polyethylene glycol and the like (suitable mixture), cyclodextrin derivatives and vegetable oils. Proper fluidity can be maintained, for example, by applying a coating such as lecithin, by the maintenance of desired particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are enabling the compounds of formula I in the required amount of the appropriate solvent with various other ingredients as required, as listed above, followed by sterilization by filtration. Typically, the dispersion is obtained by integrating various sterilized active ingredients into a sterile vehicle, which contains basal dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for obtaining sterile injectable solutions, the preferred methods of obtaining are ways of drying the vacuum and liofilizirovanny, which give a powder of the active ingredient plus any additional desired ingredient from their pre-sterilized by filtration of the solution.

Another way of introducing the compounds of the formula I is oral administration. The introduction can be performed by means of capsules or tablets, coated for intestinal absorption, or the like. Upon receipt of pharmaceutical compositions that include at least one compound of formula I, the active ingredient is usually diluted with filler and/or included in such media, which may be in the form of a capsule, sachet, paper bag or other container. When the excipient serves as a diluent, it may be solid, semi-solid or liquid substance (as above), which acts as a solvent, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, those capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or liquid medium), ointments containing for example up to 10% by weight of active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mA the bat, starches, Arabic gum, calcium phosphate, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; moisturizing agents; emulsifying and suspendresume agents; preserving agents such as methyl -, propargyloxy-benzoate; sweeteners and flavouring agents.

Compositions of the invention can be designed to provide rapid, continuous or delayed release of the active ingredient after administration to the patient using procedures known in the art. Delivery system with controlled release of drugs for oral administration include solutions of osmotic pumps and system decomposition containing polymer coated tanks or formulations of the drug - polymer matrix. Examples of systems with controlled release is presented in U.S. patent Nos. 3845770; 4326525; 4902514 and 5616345. In another composition for use in the methods of the present invention is used in devices for percutaneous delivery ("patches"). Such transdermal patches may be used to provide continuous or intermittent injection of the compounds of the present invention to the controlled quantities. Design and application of transcutaneous patches for delivery of pharmaceutical agents is well known in the art. See, for example, U.S. patent Nos. 5023252, 4992445 and 5001139. Such patches can be designed for continuous, pulsating delivery or delivery on demand of pharmaceutical agents.

The compositions are in unit dosage forms. The term "unit dosage forms" refers to physically discrete units suitable as single doses to humans and other mammals, each unit contains a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds of formula I effective in a wide range of doses, and they are usually administered in pharmaceutically effective amounts. For example, for oral administration, each unit dosage form contains from 10 mg to 2 g of compound of formula I, more preferably from 10 to 700 mg, and for parenteral administration, preferably from 10 to 700 mg of the compounds of formula I, more preferably about 50-200 mg. Should be understood, however, that the actual amount of injected compounds of formula I should be determined by a physician taking into account soposto the existing circumstances, including a subject to treatment of a condition selected route of administration, the input current connection and its relative activity, the age, weight and response of the particular patient, the severity of symptoms in a patient and the like.

For solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient with the formation of a solid pre-composition containing a homogeneous mixture of the compounds of the present invention. The homogeneity of the preliminary data of the compositions indicates that the active ingredient dispersed randomly in the composition so that the composition can be easily divided into equally effective unit dosage forms such as tablets, pills and capsules.

The tablets or pills of the present invention can be coated or otherwise prepared to receive a unit dosage form that provides the advantage of prolonged action, or to protect against acidic conditions in the stomach. For example, the tablet or pill can enable the internal dose and external dose, the latter is in the form of the shell with respect to the first. Two components can be separated by a layer for absorption in the intestine, which prevents the destruction in the stomach and provides responsive is the internal component of the intact 12-duodenum, or delayed release. For such enteric layers or coatings can be applied to many substances, and these substances include a number of polymeric acids and mixtures of polymeric acids with such materials, such as shellac, cetyl alcohol and cellulose acetate.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents or their mixtures and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Compositions administered via the oral or nasal respiratory route for local or systemic action. Compositions in pharmaceutically acceptable solvents can be sprayed with the use of inert gases. Sprayed solutions can be ingalirovat right out of the spraying device or spray device can be connected with veil facial masks or intermediate mechanism for breathing at high pressure. Compositions in the form of a solution, suspension or powder can be entered, for example, oral or intranasal from devices that deliver the composition in a suitable manner.

The following examples are included to demonstrate preferred implementations of the invention. Specialists in the art should be understood that disclosed in PR the measures, methods, which correspond to the representative methods are disclosed by the inventor, as working effectively in the practical implementation of the invention, can thus be regarded as established preferred ways of its practical implementation. However, in light of the present disclosure specialists in the art it should be clear that disclosed in a specific implementation, you can make a lot of changes and still get the same or similar result without going beyond the spirit and scope of the invention.

Example 1

Obtaining the compounds of formula (3)

A.Obtaining the compounds of formula (3), where R1is cyclopentyl, R2represents hydrogen and X represents a covalent bond

To a solution of (2S,1R,4R,5R)-2-hydroxymethyl-5-(6-globulin-9-yl)tetrahydrofuran-3,4-diol acetonide, a compound of the formula (2), in which R2represents hydrogen (to 4.98 g, 15 mmol)in ethanol (80 ml) was added cyclopentylamine (0.6 ml, 30 mmol) and triethylamine (6,27 ml, 45 mmol) and the mixture is boiled under reflux for 16 hours. The solvent was then removed under reduced pressure and the residue was distributed between ethyl acetate and 10%citric acid solution in water and then water. The ethyl acetate was removed from the organic what about the layer with obtaining {(1R,2R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol, the compound of the formula (3).

B.Obtaining compounds of formula (3) with varying X, R1and R2

Similarly, following the way of 1A above, but replacing cyclopentylamine other amines of formula R1XNH2it was obtained the following compound of formula (3):

{(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-[6-(oxolan-3-ylamino)purine-9-yl]bicyclo[3.3.0]Oct-2-yl}methane-1-ol.

C.Obtaining compounds of formula (3) with varying X, R1and R2

Similarly, following the way of 1A above, but replacing cyclopentylamine other amines of formula R1XNH2receive the following compounds of formula (3):

{(1R,2R,4R,5R)-4-[6-(cyclopentylmethyl)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[2-trifluoromethyl-6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-cyclobutylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-cyclohexylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-l-ol;

{(1R,2R,4R,5R)-4-[2-fluoro-6-cyclohexylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-cyclohexylethylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(3-forcecapitalize)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(4-triftormetilfullerenov)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(3-methoxycarbonylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(phenylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(benzylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(4-forgenerating)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(pyridine-3-ylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(thiazol-2-ylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(tetrahydropyran-3-ylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol;

{(1R,2R,4R,5R)-4-[6-(tetrahydropyran-3-ylmethylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol and

{(1R,2R,4R,5R)-4-[6-(5-torcetrapib-3-ylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol.

D.Obtaining compounds of formula (3) with varying X, R1and R2

Similarly, following the way of 1A above, but replacing cyclopentylamine other amines of formula R1XNH2get other compounds of formula (3).

Example 2

Obtaining the compounds of formula (4)

A.u> Obtaining the compounds of formula (4), where R1is cyclopentyl, R2represents hydrogen and X represents a covalent bond

A mixture of {(1R,2R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol (0,94 g, 25 mmol), dimethyl sulfoxide (7 ml), dicyclohexylcarbodiimide (1.55 g) and pyridine (0.2 ml) was stirred at 0°within a few minutes and then added triperoxonane acid (0.1 ml). The mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture is then distributed between ethyl acetate and water and washed with water. The solvent was removed from the organic layer under reduced pressure to obtain the product, (2S,1R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carbaldehyde, the compound of formula (4).

B.Obtaining compounds of formula (4) with varying R1

Similarly, following the way of 2A above, but replacing {(1R,2R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol {(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-[6-(oxolan-3-ylamino)purine-9-yl]bicyclo[3.3.0]Oct-2-yl}methane-1-I, was obtained the following compound of formula (4): (2S,1R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-[6-(oxolan-3-ylamino)purine-9-yl]bicyclo[3.3.0]octane-2-carboxy edege.

C.Obtaining compounds of formula (4) with varying X, R1and R2

Similarly, following the way of 2A above, but replacing {(1R,2R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol with other compounds of formula (3), gain the following compounds of formula (4):

{(1R,2R,4R,5R)-4-[6-(cyclopentylmethyl)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[2-trifluoromethyl-6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-cyclobutylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-cyclohexylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[2-fluoro-6-cyclohexylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-cyclohexylethylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(3-forcecapitalize)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(4-triftormetilfullerenov)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(3-methoxycarbonylamino)purine-9-yl] -7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(Fenelon the but)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(benzylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(4-forgenerating)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(pyridine-3-ylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(thiazol-2-ylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(tetrahydropyran-3-ylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde;

{(1R,2R,4R,5R)-4-[6-(tetrahydropyran-3-ylmethylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde and

{(1R,2R,4R,5R)-4-[6-(5-torcetrapib-3-ylamino)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde.

D.Obtaining compounds of formula (4) with varying X, R1and R2

Similarly, following the way of 2A above, but replacing {(1R,2R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol with other compounds of formula (3)obtain other compounds of formula (4).

Example 3

Obtaining the compounds of formula (5)

A.Obtaining the compounds of formula (5), where R1is cyclopentyl, and R2represents hydrogen

To a suspension of tert-buto is sid potassium (0.84 g, 7.5 mmol) in tetrahydrofuran (5 ml) at -78°With added bromomethylphenyl (1.64 g, 3.75 mmol) in small portions and the mixture was stirred for 2 hours. To this mixture was added a solution of (2S,1R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde (0,932 g, 2.5 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred for 2 hours at -78°C. the Reaction mixture was then allowed to warm to room temperature and was stirred for 6 days, after which extinguished aqueous solution of ammonium chloride and distributed between water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed from the filtrate under reduced pressure to obtain [9-((1R,2S,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-9-yl]cyclopentylamine, the compound of formula (5).

B.Obtaining compounds of formula (5) with varying R1

Similarly, following the way of 3A above, but replacing (2S,1R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxaldehyde {(1R,2S,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-[6-(oxolan-3-ylamino)purine-9-yl]bicyclo[3.3.0]octane-2-carboxaldehyde was obtained following the compound of the formula (5): (1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-9-yl]oxolan-3-ylamine.

C.Obtaining the compounds is of the formula (4) with varying X, R1and R2

Similarly, following the way of 3A above, but replacing {(1R,2R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol with other compounds of formula (3), gain the following compounds of formula (4):

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]cyclopentylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-2-trifluoromethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]cyclopentylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]cyclobutylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]cyclohexylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]-2-fluoro-6-cyclohexylamino;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]cyclohexylethylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]-3-perticipantilor;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]-4-triftormetilfullerenov;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]-3-methoxycarbonylamino;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]-phenylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]benzylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-DIMET the l-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl](4-forfinally);

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]-pyridine-3-ylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-Ilorin-9-yl]-thiazole-2-ylamine;

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl](tetrahydropyran-3-ylamine);

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]-tetrahydropyran-3-ylmethylamino and

{(1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-9-yl]-5-torcetrapib-3-ylamine.

D.Obtaining compounds of formula (5) with varying X, R1and R2

Similarly, following the way of 3A above, but replacing {(1R,2R,4R,5R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}methane-1-ol with other compounds of formula (4)obtain other compounds of formula (5).

Example 4

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1is cyclopentyl, R2R3R4and R5represent hydrogen, X, X1and Y represents a covalent bond and Z represents-C≡C

[9-((1R,2R,4R,5R)-4-Ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine (0.28 g) was dissolved in 20 ml of a mixture of acetic acid:water (80:20) and stirred the night at 75° C. the Solvent was removed under reduced pressure and the residue was purified preparative TLC with elution with a mixture of methanol:methylene chloride (1:8), with (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-itinerarary-3,4-diol, a compound of formula I.

B.Obtaining the compounds of formula I, where R1represents a tetrahydrofuran-3-yl, R2R3R4and R5represent hydrogen, X, X1and Y represents a covalent bond and Z represents-C≡C

Similarly, following the way of 4A above, but replacing [9-((1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine (1R,2R, 4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)-purine-9-yl]oxolan-3-Ilumina receive the following compounds of formula I:

(4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylmethyl)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[2-trifluoromethyl-6-(cyclopentylamine)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclobutylamine)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclohexylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[2-fluoro-6-(cyclohexylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclohexylethylamine)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(3-forticlient is amino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(4-triftormetilfullerenov)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(3-methoxycarbonylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(phenylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(benzylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(4-forgenerating)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(pyridine-3-ylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(thiazol-2-ylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(tetrahydropyran-3-ylamino)purine-9-yl]-5-itinerarary-3,4-diol;

(4S,2R,3R,5R)-2-[6-(tetrahydropyran-3-ylmethylamino)purine-9-yl]-5-itinerarary-3,4-diol and

(4S,2R,3R,5R)-2-[6-(5-torcetrapib-3-ylamino)purine-9-yl]-5-itinerarary-3,4-diol.

C. Obtaining the compounds of formula I with varying X, R1and R2

Similarly, following the way of 4A above, but replacing [9-((1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine other compounds of formula (5)obtain other compounds of formula I.

Example 5

Obtaining the compounds of formula 6

A. Obtaining the compounds of formula (6), where R1is cyclopentyl, R2represents hydrogen, R3is a 2-triptoreline, Y is a covalent bond, and Z before the hat is-C≡ C

To a solution of [9-((1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine (40 mg, 0.12 mmol), the compound of formula (5), in tetrahydrofuran (4 ml) under nitrogen atmosphere was added in catalytic amounts (3 mg) dichlorobis(triphenylphosphine)palladium (II) iodide copper (II) and then 1-iodine-2-triptoreline (0.25 ml, 0.3 mmol). Then was added triethylamine (0.4 ml) and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure and the residue was purified preparative TLC with elution with a mixture of methanol:methylene chloride (6.5:1) to obtain [9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-(trifluoromethyl)- phenyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine, the compound of formula (6).

B. Obtaining the compounds of formula (6), where R1is cyclopentyl or tetrahydrofuran-3-yl, R2R4and R5represent hydrogen, X, X1and Y represents a covalent bond and Z represents-C≡C - with varying R3

Similarly, following the way of 5A above, but replacing [9-((1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine suitable compounds of the formula (5)are the following compounds of formula (6):

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-(reformer)phenyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]oxolan-3-ylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]oxolan-3-ylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-chlorophenyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]oxolan-3-ylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[Tien-2-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]oxolan-3-ylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-chlorophenyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine and

{9-[(1R,2R,4R,5R)-7,7-dimethyl-4-(2-(2-thienyl)ethinyl)-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl]purine-6-yl}cyclopentylamine.

C. Obtaining the compounds of formula (6) with varying R1R2R3R4R5X, X1and Y, where Z represents a-C≡C

Similarly, following the way of 5A above, but optionally replacing [9-((1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine other compounds of formula (5), and optionally replacing 1-iodine-2-cryptomaterial other compounds of formula R3Y-LG, where LG represents a removable group, will receive the following compounds of formula I:

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-were]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[unilateral]-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[5-chlortan-2-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[4-methylisoxazol-3-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[3,5-dimethylisoxazol-4-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[cyclopentyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forcelogix]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[piperidine-2-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[4-methylpiperazin-1-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[pyridin-2-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[6-herperidin-2-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[thiazol-2-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[pyrimidine-2-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-2-trifluoromethyl-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]cyclopentylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]cyclobutylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]cyclohexylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl](2-forcelogix)amine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]cyclohexylethylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]-3-perticipantilor;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]-4-triftormetilfullerenov;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]-3-methoxycarbonylamino;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]phenylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl](4-forfinal)amine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]benzylamine;

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]pyridine-3-ylamine;

[9-((1R,2R,4R,5R)-7,7-dim the Tyl-4-{2-[2-forfinal]ethinyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl-purine-6-yl]thiazol-2-ylamine and

[9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[Tien-2-yl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl](5-pterocaulon-3-ylamine).

D. Obtaining the compounds of formula I with varying X, R1and R2

Similarly, following the way of 5A above, but optionally replacing [9-((1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine other compounds of formula (5), and optionally replacing 1-iodine-2-cryptomaterial other compounds of formula R3Y-LG, where LG represents the group that you want receive other compounds of formula I.

Example 6

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1is cyclopentyl, R2R4and R5represent hydrogen, R3is a 2-triptoreline, X, X1and Y represents a covalent bond and Z represents-C≡C

a) To a solution of (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-itinerarary-3,4-diol (40 mg, 0.12 mmol) in tetrahydrofuran (4 ml) under nitrogen atmosphere was added a catalytic amount (3 mg), (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-itinerarary-3,4-diol (II) and copper iodide(I) and then 1-iodine-2-triptoreline (0,042 ml). Then was added triethylamine (0.4 ml) and the mixture per massively for 15 minutes at room temperature. The solvent was removed under reduced pressure and the residue was purified preparative TLC, using for elution of methanol:methylene chloride (about 6.5:1), with (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5- {2-[2-(trifluoromethyl)phenyl]ethinyl}-oxolan-3,4-diol, a compound of formula I.

b) Alternatively, the acetonide protective group was removed from [9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-(trifluoromethyl)-phenyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine, the compound of formula (6), in the same way as in example 4, to obtain the (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine 9-yl]-5-{2-[2-(trifluoromethyl)phenyl]ethinyl}oxolan-3,4-diol, a compound of formula I.

B.Obtaining the compounds of formula I, where R1is cyclopentyl or tetrahydrofuran-3-yl, R2R4and R5represent hydrogen, X, X1and Y represents a covalent bond and Z represents-C≡C-, with varying R3

Similarly, following the method 6A(a)described above, but optionally replacing (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-itinerarary-3,4-diol with other compounds of formula I in which R3represents hydrogen, and optionally replacing 1-iodine-2-cryptomaterial other compounds of formula R3Y-LG, where LG represents a group to delete, or:

following the method 6A(b), isonomy above, but replacing [9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-(trifluoromethyl)-phenyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine other compounds of formula (6);

were obtained the following compounds of formula I:

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-{2-[2-(trifluoromethyl)phenyl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-{2-[2-chlorophenyl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-{2-[Tien-2-yl]ethinyl}oxolan-3,4-diol and

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[Tien-2-yl]ethinyl}oxolan-3,4-diol.

C. Obtaining the compounds of formula I with varying R1R2R3R4R5X, X1and Y, and where Z represents a-C≡C

Similarly, following the method 6A(a)described above, but optionally replacing (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-itinerarary-3,4-diol with other compounds of formula I in which R3represents hydrogen, and optionally replacing 1-iodine-2-cryptomaterial other compounds of formula R3Y-LG, where LG represents a group to delete, or:

following the method 6A(b)above, but substituting [9-((1R,2R,4R,5R)-7,7-dimethy the-4-{2-[2-(trifluoromethyl)-phenyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine other compounds of formula (6); get the following compounds of formula I:

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[phenyl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[2-chlorophenyl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[2-were]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{5-chlortan-2-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[4-methylisoxazol-3-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[2,5-dimethylisoxazol-4-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[cyclopentyl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[2-forcelogix]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[piperidine-2-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[4-methylpiperazin-1-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[pyridin-2-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[6-herperidin-2-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[thiazol-2-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]-5-{2-[pyrimidine-2-yl]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-cyclopentylmethyl)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

4S,2R,3R,5R)-2-[6-(cyclopentylmethyl)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclobutylamine)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclohexylamino)purine-9-yl]-5-{2-[2-forfinal]ethyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(2-forcecoercion)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclohexylethylamine)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(3-forcecapitalize)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(4-triftormetilfullerenov)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(3-methoxycarbonylamino)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(phenylamino)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(4-forgenerating)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(benzylamino)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(pyridine-3-ylamino)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(thiazol-2-ylamino)purine-9-yl]-5-{2-[2-forfinal]-ethinyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(oxolan-3-ylmethylamino)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol and

(4S,2R,3R,5R)-2-[6-(5-pterocaulon-3-ylamino)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol.

D. Obtaining the compounds of formula I with varying R1R2R3R4R5X, X1 and Y, and where Z represents a-C≡C

Similarly, following the way of 6A above, but replacing [9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-(trifluoromethyl)phenyl]ethinyl}-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine other compounds of formula (6), obtain other compounds of formula I.

Example 7

Obtaining the compounds of formula (7)

A. Obtaining the compounds of formula (7), where R1represents a tetrahydrofuran-3-yl, R2represents hydrogen, R3is a 4-forfinal, X and Y are covalent bonds, and Z represents-CH=CH-

To a solution of (2S,1R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-[6-(oxolan-3-ylamino)purine-9-yl]bicyclo[3.3.0]octane-2-carbaldehyde, the compound of formula (4) (200 mg)in methylene chloride (5 ml) was added (4-forfinal)triphenylphosphine bromide (459 mg, 1 mmol), followed by adding dropwise an aqueous solution of 50% sodium hydroxide. After complete addition, the mixture was stirred for 2 hours, then washed with water. The organic layer was separated, dried and the solvent was removed under reduced pressure. The residue was purified preparative thin-layer chromatography, elwira with ethyl acetate, to obtain the pure (9-{4-[2-(4-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)oxolan-3-Il is in, the compound of formula (7).

B.Obtaining the compounds of formula (7), where R1is cyclopentyl or tetrahydrofuran-3-yl, R2R4and R5represent hydrogen, X, X1and Y represents a covalent bond and Z represents-CH=CH-, with varying R3

Similarly, following the method 7A described above, but optionally replacing (2S,1R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-[6-(oxolan-3-ylamino)purine-9-yl]bicyclo[3.3.0]octane-2-carbaldehyde other compounds of formula (4), and optionally replacing (4-forfinal)triphenylphosphine bromide other compounds of formula R3YCH2P(PH)3Br, received the following compounds of formula (7):

(9-{4-[2-(5-chlortan-2-yl)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-14-[2-(3,5-dimethylisoxazol-4-yl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(4-methylisoxazol-3-yl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(2-were]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine and

(9-{4-[2-(phenyl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine.

C. Obtaining the compounds of formula (7) with varying R1R2, R, 3R4R5X, X1- , Y -, and Z represents-CH=CH-

Similarly, following the method 7A described above, but optionally replacing (2S,1R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-[6-(oxolan-3-ylamino)purine-9-yl]bicyclo[3.3.0]octane-2-carbaldehyde other compounds of formula (4), and optionally replacing (4-forfinal)triphenylphosphine bromide other compounds of formula R3YCH2P(PH)3Br, you get the following compounds of formula I:

(9-{4-[2-(2-were]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(2-forfinal]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(phenyl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(cyclopentyl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(2-forcelogix]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-4-[2-(piperidine-2-yl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(4-methylpiperazin-1-yl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(pyridin-2-yl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(6-perperi the Jn-2-yl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(thiazol-2-yl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(pyrimidine-2-yl]vinyl(1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine;

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylmethyl;

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-2-trifluoromethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylmethyl;

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclobutylmethyl;

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclohexylamine;

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)(2-forcecoercion);

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclohexylethylamine;

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)(3-perticipantilor);

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)(4-triftormetilfullerenov);

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)(3-methoxycarbonylamino);

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)phenylamine;

(9-{4-[2-(-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)(4-forfinally);

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)benzylamine;

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)pyridine-3-ylamine);

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)thiazol-2-ylamine and

(9-{4-[2-(2-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)(5-pterocaulon-3-ylamine).

D. Obtaining the compounds of formula (7) with varying R1R2R3R4R5X, X1- , Y -, and Z represents-CH=CH-

Similarly, following the method 7A described above, but optionally replacing (2S,1R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-[6-(oxolan-3-ylamino)purine-9-yl]bicyclo[3.3.0]octane-2-carbaldehyde other compounds of formula (4), and optionally replacing (4-forfinal)triphenylphosphine bromide other compounds of formula R3YCH2P(PH)3Br, obtain other compounds of formula I.

Example 8

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1represents a tetrahydrofuran-3-yl, R2represents hydrogen, R3is a 4-forfinal, X and Y are covalent bonds, and Z represents-CH=CH-

the Acetonide protective group is then removed from (9-{4-[(1E)-2-(4-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)oxolan-3-ylamine, the compound of formula (7), in the same way as shown in example 4, to obtain 5-[2-(4-forfinal)vinyl]-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol, a compound of formula I.

B. Obtaining the compounds of formula I, where R1is cyclopentyl or tetrahydrofuran-3-yl, R2R4and R5represent hydrogen, X, X1and Y represents a covalent bond and Z represents-CH=CH-, with varying R3

Similarly, following the way of 8A above, but replacing (9-{4-[(1E)-2-(4-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)oxolan-3-ylamine other compounds of formula (7), were obtained the following compounds of formula I:

5-[(1E)-2-(methoxycarbonylmethyl](4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol;

5-[(1E)-2-(2-were)vinyl](4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol;

5-[2-(5-chlortan-2-yl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol;

5-[2-(3,5-dimethylisoxazol-4-yl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol;

5-[2-(4-methylisoxazol-3-yl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol;

5-[2-(2-were)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol and

5-[2-(phenyl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol.

C. the Floor is the group of the compounds of formula I with varying R 1R2R3R4R5X, X1- , Y -, and Z represents-CH=CH-

Similarly, following the way of 8A above, but replacing (9-{4-[(1E)-2-(4-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)oxolan-3-ylamine other compounds of formula (7), given the following compounds of formula I:

5-[2-(2-were)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(phenyl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(cyclopentyl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forcelogix)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-piperidine-2-yl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(4-methylpiperazin-1-yl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-pyridin-2-yl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(6-herperidin-2-yl)vinyl](4S,2R,3R,5R)-2-[6-cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-thiazol-2-yl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(pyrimidine-2-yl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-cyclopentyl is ethylamino)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-cyclobutylamine)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(cyclohexylamino)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(2-forcecoercion)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(2-forceclassselection)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(3-forcecapitalize)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(4-triftormetilfullerenov)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(3-methoxycarbonylamino)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(phenylamino)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(benzylamino)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(pyridine-3-ylamino)purine-9-yl]oxolan-3,4-diol,

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(thiazol-2-ylamino)purine-9-yl]oxolan-3,4-diol and

5-[2-(2-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(5-pterocaulon-3-ylamino) purine-9-yl]oxolan-3,4-diol.

D. Obtaining the compounds of formula I with varying R1R2R3R4R5X, X1- , Y -, and Z represents-CH=CH-

Similarly, following the way of 8A above, but replacing (9-{4-[(1E)-2-(4-forfinal)vinyl](1R,2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-yl} - purine-6-yl)oxolan-3-ylamine other compounds of formula (7), get other compounds of formula I.

Example 9

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1represents a tetrahydrofuran-3-yl, R2represents hydrogen, R3is a 4-forfinal, X and Y are covalent bonds, and Z represents-CH2CH2-

To a solution of 5-[2-(4-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol (40 mg) in ethanol (5 ml) and cyclohexene (2 ml) was added palladium hydroxide (50 mg) and the mixture was stirred for 24 hours. The catalyst was filtered and the solvent was removed under reduced pressure. The residue was purified preparative thin-layer chromatography to obtain pure (4S,2R,3R,5R)-5-[2-(4-forfinal)ethyl]-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol, a compound of formula I.

B. Obtaining the compounds of formula I, where R1is cyclopentyl or tetrahydrofuran-3-yl, R2R4and R5represent hydrogen, X, X1and Y represents a covalent bond and Z represents-CH2CH2-with varying R3

Similarly, following the way of 9A above, but replacing 5-[2-(4-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-and the]oxolan-3,4-diol with other compounds of formula I, in which Z represents-CH=CH-, were obtained the following compounds of formula I:

(4S,2R,3R,5R)-5-[2-(methoxycarbonyl)ethyl]-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol;

(4S,2R,3R,5R)-5-[2-(2-were)ethyl]2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol;

(4S,2R,3R,5R)-5-[2-phenylethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol;

(4S,2R,3R,5R)-5-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol and

(4S,2R,3R,5R)-5-[2-(5-chlortan-2-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol.

C. Obtaining the compounds of formula I with varying R1R2R3R4and R5X, X1, Y and Z are-CH2CH2-

Similarly, following the way of 9A above, but replacing 5-[2-(4-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol with other compounds of formula I in which Z represents-CH=CH-, get the following compounds of formula I:

(4S,2R,3R,5R)-5-[2-(4-methylisoxazol-3-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol;

(4S,2R,3R,5R)-5-[2-(2-were)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol;

(4S,2R,3R,5R)-5-[2-(2-were)ethyl]-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol;

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(phenyl)ethyl]-2-[6-(cyclopentylamine)purine-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(cyclopentyl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forcelogix)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-piperidine-2-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(4-methylpiperazin-1-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-pyridin-2-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(6-herperidin-2-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-thiazol-2-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-pyrimidine-2-yl)ethyl]-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(cyclopentylmethyl)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(cyclobutylmethyl)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(cyclohexylamino)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(2-forcecoercion)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(2-forceclassselection)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(3-forcecapitalize)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(4-triftormetilfullerenov)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(3-otoxic is chlopheniramine)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(phenylamino)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(benzylamino)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(pyridine-3-ylamino)purine-9-yl]oxolan-3,4-diol,

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(thiazol-2-ylamino)purine-9-yl]oxolan-3,4-diol and

(4S,2R,3R,5R)-5-[2-(2-forfinal)ethyl]-2-[6-(5-pterocaulon-3-ylamino)purine-9-yl]oxolan-3,4-diol.

D. Obtaining the compounds of formula I with varying R1R2R3R4and R5X, X1, Y and Z are-CH2CH2-

Similarly, following the way of 9A above, but replacing 5-[2-(4-forfinal)vinyl](4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]oxolan-3,4-diol with other compounds of formula I in which Z represents-CH=CH-, get other compounds of formula I.

Example 10

Obtaining the compounds of formula (8), where R1is cyclopentyl and R2represents hydrogen

To a stirred solution of chloride benzyloxyacetophenone (7,71 g is 18.40 mmol) in tetrahydrofuran (40 ml) was added dropwise N-sodium-hexamethyldisilazane (1M in THF, 17,50 ml) and the mixture was stirred at -78°C for 1 hour. Then {(2S,1R,4R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo the[3.3.0]Oct-2-yl}Formaldehyd, the compound of the formula (4) (of 3.73 g, 10 mmol), was dissolved in tetrahydrofuran (10 ml) and was slowly added. The mixture is slowly brought to room temperature and was stirred over night, extinguished H2O (60 ml) and was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with water (2 × 50 ml), dried over Na2SO4and evaporated under reduced pressure. Column chromatography gave (9-{4-[2-(phenylmethoxy)vinyl](2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine, the compound of formula (8).

Example 11

Obtaining the compounds of formula (9), where R1is cyclopentyl and R2represents hydrogen.

A mixture of 9-{4-[(1E)-2-(phenylmethoxy)vinyl(2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine, the compound of formula (8), (1.90 g, 3,98 mmol), and catalytic amount of Pd/C in methanol (30 ml) was stirred in hydrogen atmosphere (67 psi) overnight. Pd/C was filtered through celite and washed with methanol. The filtrate was concentrated and the residue (9-{4-[(1E)-2-(phenylmethoxy)vinyl](2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine, the compound of formula (9), was used without further purification.

Example 12

Obtaining the compounds of formula (10), where R1is a qi is lipantil and R 2represents hydrogen.

A mixture of 9-{4-[(1E)-2-(phenylmethoxy)vinyl](2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl} - purine-6-yl)cyclopentylamine, the compound of formula (9), and Pd(OH)2in cyclohexane (45 ml) and ethanol (30 ml) was stirred at 80°C for 5 days. The mixture was filtered through celite and washed with ethanol. The filtrate was concentrated under reduced pressure and the residue was purified column chromatography to obtain 2-{(1R, 2R,4R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}Ethan-1-ol, the compound of formula (10).

Example 13

Obtaining the compounds of formula (11), where R1is cyclopentyl and R2represents hydrogen.

To a cooled on ice to a solution of 2-{(1R,2R,4R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}Ethan-1-ol, the compound of formula (10) (0,90 g, 2,31 mmol), dicyclohexylcarbodiimide (1,43 g, 6,93 mmol) and pyridine (0,19 ml, 2,31 mmol) in dimethyl sulfoxide (16 ml) was slowly added triperoxonane acid (0,09 ml, 1.15 mmol). The resulting mixture was stirred in an atmosphere of N2at room temperature over night. N,N'-dicyclohexylmethane then was filtered and washed with ethyl acetate (60 ml). The filtrate was washed with water (3 x 40 ml), dried over Na 2SO4and concentrated under reduced pressure. The residue, 2-{(1R,2R,4R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}Ethan-1-he, the compound of formula (11), was used without further purification.

Example 14

Obtaining the compounds of formula (12), where R1is cyclopentyl and R2represents hydrogen.

To a stirred solution of tert-butoxide potassium (0,78 g, 6,93 mmol) in tetrahydrofuran (45 ml) was added in small portions at -78°C bromide (methyl bromide)triphenylphosphine (1.51 g, with 3.27 mmol). The resulting mixture was stirred at -78°C for 2 hours. Was slowly added 2-{(1R,2R,4R)-4-[6-(cyclopentylamine)purine-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl}Ethan-1-he, the compound of formula (11), (0,89 g, 2,31 mmol)dissolved in THF (15 ml) and the mixture was stirred in an atmosphere of N2at -78°C for 3 hours, slowly brought to room temperature and was stirred for 4 days. The reaction mixture was extinguished saturated aqueous NH4Cl (15 ml) and was diluted with H2O (60 ml) and then was extracted with EtOAc (3 x 50 ml). The combined organic layers were washed H2O (2 x 50 ml), dried over Na2SO4and evaporated under reduced pressure to obtain {9-[4-((2E)-3-bromoprop-2-enyl)(2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-and the]purine-6-yl}cyclopentylamine, the compound of the formula (12), which was isolated by column chromatography.

To a stirred solution of {9-[4-((2E)-3-bromoprop-2-enyl) (2R,4R,5R)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl]purine-6-yl}cyclopentylamine (0.40 g, 0.86 mmol) in tetrahydrofuran (25 ml) was added in small portions at -78°C potassium tert-piperonyl (0,78 g, 6,93 mmol). The resulting mixture was stirred at -78°C for 30 minutes, then slowly brought to room temperature and was stirred overnight. The reaction mixture was extinguished saturated aqueous ammonium chloride (5 ml) and was diluted with H2O (30 ml), then was extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with water (2 x 30 ml), dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure to obtain [9-((2R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-prop-2-invisible[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine, the compound of formula (13), which was isolated by column chromatography.

Example 15

Obtaining the compounds of formula I

Obtaining the compounds of formula I, where R1is cyclopentyl, R2and R3represent hydrogen, X and Y represent a covalent bond, X1represents-CH2- and Z represents-C≡C

[9-((2R,4R,5R)-7,7-dimethyl-3,6,8-trioxa-4-ol is n-2-invisible[3.3.0]Oct-2-yl)purine-6-yl]cyclopentylamine, the compound of formula (13), was stirred in an aqueous solution of 80% acetic acid (20 ml) at 80°C in a sealed tube for 2 days. The solvent was removed under reduced pressure and the residue was purified preparative thin-layer chromatography to obtain (4S,2R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-prop-2-inlocale-3,4-diol, a compound of formula I.

Example 16

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1is cyclopentyl, R2represents hydrogen, R3is a 2-forfinal, X and Y represent a covalent bond, X1represents-CH2- and Z represents-C≡C

To a stirred solution of (4S,2R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-prop-2-inlocale-3,4-diol (0,017 g, 0.05 mmol) and 1-fluoro-2-yogashala (of 0.02 ml, 0.13 mmol) in THF (3,50 ml) in an atmosphere of N2added a catalytic amount of dichlorobis(triphenylphosphine)palladium (II) and copper iodide (I). Then add Et3N (0,20 ml). The resulting mixture was stirred in an atmosphere of N2at 75°C for 2 days. The solvent was removed under reduced pressure and the residue was purified preparative thin-layer chromatography to obtain (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-[3-(2-forfinal)prop-2-inyl]oxal is n-3,4-diol, the compound of formula I.

B. Obtaining the compounds of formula I, where R1is cyclopentyl, R2R4and R5represent hydrogen, X and X1represent a covalent bond, Y represents CH2and Z represents-C≡C-, with varying R3

Similarly, following the procedures of examples 10-16 above receive the following compounds of formula I, in which X1represents-CH2- and Z represents-C≡C-:

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol and

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[2-(trifluoromethyl)phenyl]prop-2-inyl}oxolan-3,4-diol.

C. Obtaining the compounds of formula I with varying R1R2R3R4and R5X, X1and Y represents CH2and Z represents-C≡C

Similarly, following the procedures of examples 10-16 above receive the following compounds of formula I, in which X1represents-CH2- and Z represents-C≡C-:

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[4-methylisoxazol-3-yl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[2-were]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-{3-[forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[phenyl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[cyclopentyl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[2-forcelogix]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[piperidine-2-yl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[4-methylpiperazin-1-yl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[pyridin-2-yl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[6-herperidin-2-yl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[thiazol-2-yl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{3-[pyrimidine-2-yl]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclopentylmethyl)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclobutylmethyl)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(cyclohexylamino)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(2-forcecoercion)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(2-forceclassselection)purine-9-yl]-5-{3-[2-forfinal]prop-2-ine the}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(3-forcecapitalize)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(4-triftormetilfullerenov)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(phenylamino)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(benzylamino)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(pyridine-3-ylamino)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol;

(4S,2R,3R,5R)-2-[6-(thiazol-2-ylamino)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol and

(4S,2R,3R,5R)-2-[6-(5-pterocaulon-3-ylamino)purine-9-yl]-5-{3-[2-forfinal]prop-2-inyl}oxolan-3,4-diol.

D. Obtaining the compounds of formula I with varying R1R2R3R4and R5X, X1and Y represents CH2and Z represents-C≡C

Similarly, following the procedures of examples 10-16 above, obtain other compounds of formula I, in which X1represents-CH2- and Z represents-C≡C.

Example 17

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1is a 2-hydroxycyclopent, R2represents hydrogen, R3represents hydrogen, X, X1and Y represents a covalent bond and Z submitted the a-C≡ C

1) To a suspension of tert-butoxide potassium (0.84 g, 7.5 mmol) in tetrahydrofuran (5 ml) was added in small portions at -78°C bromomethylphenyl (1.64 g, 3.75 mmol) and the mixture was stirred for 2 hours. To this mixture was added a solution of (2S,1R,4R,5R)-4-[6-globulin-9-yl]-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carbaldehyde (1 mmol) in tetrahydrofuran (20 ml) and the mixture was stirred for 2 hours at -78°C. the Reaction mixture was then allowed to warm to room temperature and was stirred for 24 hours, then extinguished aqueous solution of ammonium chloride and distributed between water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and the solvent removed from the filtrate under reduced pressure to obtain (1R,5R,6R,8R)-6-(6-globulin-9-yl)-8-ethinyl-3,3-dimethyl-2,4,7-dioxabicyclo[3.3.0]octane.

2) To a solution of (1R,5R,6R,8R)-6-(6-globulin-9-yl)-8-ethinyl-3,3-dimethyl-2,4,7-dioxabicyclo[3.3.0]octane (50 mg) and TRANS-2-aminocyclopentane (0.04 g) in ethanol was added triethylamine (0,12 ml) and the mixture was stirred at 60°C for 32 hours. The solvent was then removed under reduced pressure and the residue was dissolved in ethyl acetate, washed with diluted nitric acid, then with saturated salt solution, dried over sodium sulfate, filtered and the solvent removed from the filtrate p. and reduced pressure to obtain 2-[9-((1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl)purine-6-yl]cyclopentane-1-ol.

3) In a sealed tube, 2-[9-((1R,2R,4R,5R)-4-ethinyl-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]-Oct-2-yl)purine-6-yl]cyclopentane-1-ol were stirred in 10 ml of a mixture of 80% acetic acid/water over night. The solvent was then removed under reduced pressure and the residue was purified preparative thin-layer chromatography, elwira a mixture of 10% methanol/methylene chloride to obtain (4S,2R,3R,5R)-5-ethinyl-2-{6- [(2-hydroxycyclopent)amino]purine-9-yl}oxolan-3,4-diol.

All the compounds of formula I were characterized by NMR spectra and mass spectra. For example:

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-itinerarary-3,4-diol:

1H-NMR (CDCl3): 1,54-to 1.79 (m, 6H), 2.06 to a 2.13 (m, 2H), 3,47 (s, 1H), 4,45-4,58 (m, 2H), 4,71 (s, 1H), 4,94 (s, 1H), 6,01 (d, 1H, J=5,09 Hz), 6,38 (s, 1H, NH), 8,03 (s, 1H), compared to 8.26 (s, 1H). MH+317.

(4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-[2-(2-forfinal)ethinyl]oxolan-3,4-diol:

1H-NMR (CDCl3) 1,51-to 1.77 (m, 6H), 2,08 with 2.14 (m, 2H), 4,03 (s, 1H, OH), 4,56 (s, 1H, OH), br4.61 (d, 1H, J=4,30 Hz), 4,78-to 4.81 (m, 1H), total of 5.21 (s, 1H), 5,94 (d, 1H, J=6,65 Hz), 6,07 (d, 1H, J=5,48 Hz), 6,56 (s, 1H, NH), 7,01-7,07 (m, 2H), 7,26-7,35 (m, 2H), 8,11 (s, 1H), 8,28 (s, 1H). MH+412.

Example 18

Get hard gelatin capsules containing the following ingredients:

Number
Ingredient(mg/capsule)
The active ingredient30,0
Starch305,0
Magnesium stearate5,0

The above ingredients are mixed and used to fill hard gelatin capsules.

Example 19

The formula tablets get using the following ingredients:

Number
Ingredient(mg/tablet)
The active ingredient25,0
Cellulose, microcrystalline200,0
Colloidal silicon dioxide10,0
Stearic acid5,0

The components are mixed and pressed to form tablets.

Example 20

Get the dry powder composition for inhalation containing the following components:

IngredientWeight %
The active ingredient5
Lactose95

The active ingredient is mixed with the lactose and the mixture is bring in a device for inhalation of a dry powder.

Example 21

Tablets, each containing 30 mg of active ingredient, was prepared as follows:

 NumberIngredient(mg/tablet)The active ingredient30.0 mgStarch45.0 mgMicrocrystalline cellulose35,0 mgPolyvinylpyrrolidone (as 10% solution in sterile water)4.0 mgCarboximetilkrahmal sodium4.5 mgMagnesium stearate0.5 mgTalc1.0 mgOnly120 mg

The active ingredient, starch and cellulose are passed through sieve No. 20 mesh U.S. and mix thoroughly. With the obtained powders are mixed solution of the polyvinylpyrrolidone, and then pass through a sieve of 16 mesh US. Thus obtained granules are dried at a temperature of from 50°C to 60°and pass through a sieve of 16 mesh US. Then to the pellet add carboximetilkrahmal sodium, magnesium stearate and talc, previously passed through sieve No. 30 mesh U.S., and after adding granules pressed on for tabletting machine to obtain tablets with a weight of each 120 mg

Example 22

Suppositories, each containing 25 mg of active ingredient, was prepared as follows:

IngredientNumber
The active ingredient25 mg
Glycerides of saturated fatty acids to2000 mg

The active ingredient is passed through sieve No. 60 mesh U.S. and suspended in the glycerides of saturated fatty acids, previously melted using the minimum required heating. The mixture was then poured into a suppository form with a nominal capacity of 2.0 g and allow it to cool.

Example 23

Suspensions, each containing 50 mg of active ingredient 5.0 ml, was prepared as follows:

IngredientNumber
The active ingredient50.0 mg
Xanthan gum4.0 mg
Carboxymethylcellulose sodium (11%)
Microcrystalline cellulose (89%)50.0 mg
Sucrose1,75 g
Sodium benzoate10.0 mg
Perfume and dyeq.v.
Purified water to5.0 ml

The active ingredient, sucrose and xanthan gum are blended, passed through sieve No. 10 IU the USA, then mixed with a previously prepared solution of microcrystalline cellulose and carboxymethylcellulose sodium in the water. Sodium benzoate, fragrance and dye diluted with some water and add with stirring. Add the required amount of water to obtain the desired volume.

Example 24

Composition for subcutaneous administration may be obtained in the following way:

IngredientNumber
The active ingredient5.0 mg
Corn oil1.0 ml

Example 25

The preparation for injection get with the following structure:

IngredientsNumber
The active ingredient2.0 mg/ml
Mannitol, USP50 mg/ml
Gluconic acid, USPq.s. (pH 5-6)
Water (distilled, sterile)q.s. to 1.0 ml
Gaseous nitrogen, NFq.s.

Example 26

Preparation for local application receives the following structure:

grams
Ingredients
The active ingredient0,2-10
Span 602,0
Twin 602,0
Mineral oil5,0
Vaseline0,10
Methylparaben0,15
Propylparaben0,05
BHA (bottled hydroxyanisol)0,01
Waterq.s. 100

All of the above ingredients, except water, are combined and heated to 60°under stirring. Then add the required amount of water at 60°With thorough stirring to emulsify the ingredients, and then add water until q.s. 100 g

Example 27

Composition for continuous release

WeightPreferred
IngredientRange (%)Range (%)The most preferred
The active ingredient50-9570-9075
Microcrystalline cellulose (filler)1-355-1510,6
Copoly the EP methacrylic acid 1-355-12,510,0
Sodium hydroxide0,1-1,00,2-0,60,4
The hypromellose0,5-5,01-32,0
Magnesium stearate0,5-5,01-32,0

The compositions of the present invention with a constant release was prepared as follows: compound, pH-dependent binder and any optional fillers, thoroughly mix (dry mixing). Mixed dry mixture then granularit in the presence of an aqueous solution of a strong base, which is sprayed on the mixed powder. The granulate is dried, sieved, mixed with an optional lubricating agents (such as talc or magnesium stearate and pressed into tablets. Preferred aqueous solutions of strong bases are solutions of hydroxides of alkali metals such as sodium hydroxide or potassium, such as sodium hydroxide, in water (optionally containing up to 25% mix with water, solvents such as lower alcohols).

The resulting tablets may be optionally coated with film forming agent for identification, flavor and ease of swallowing. Forming a film agent should usually be in the range of between 2% and 4% of the mass of the table is TCI. Suitable film forming agents are well known in the art and include hydroxypropyl, methylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butylmethacrylate the copolymer is Eudragit® E Röhm. Pharma), and the like. Data film forming agents may optionally contain dyes, plasticizers and other ingredients.

Compressed tablets have a hardness sufficient to resist compression 8 Kp. Tablet size should depend primarily on the number of connections per tablet. Tablets typically comprise from 300 to 1100 mg free base compounds. For example, tablets typically include the free base compound in a quantity ranging from 400-600 mg, 650-850 mg and 900-1100 mg

To influence the rate of dissolution control the time during which the powder containing the compound is mixed with moisture. For example, the total time of mixing the powder, i.e. the time during which the powder exhibit with sodium hydroxide solution typically ranges from 1 to 10 minutes and preferably from 2 to 5 minutes. After granulation, the particles removed from the pellet and placed on the platform for drying liquid for drying at about 60°C.

Example 28

Substance

Agonists A1adenosine is 8-cyclopentyl-1,3-dipropylamine (CPX) and 8-cyclopentyl-1,3-dimethylxanthine (CPT), agonists A1adenosine N6-cyclopentylamine (CPA), 2-chloro - N6-cyclopentylamine (CCPA) and N6-cyclohexylbenzene (CHA), inhibitor adelaideans Erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an inhibitor adenosines yotubeguis and Forskolin were obtained from Research Biochemicals (Natick, MA). {[(5-{6-[(3R)oxolan-3-yl]amino} - purine-9-yl)(3S,2R,4R)-3,4-dihydroquinoxaline-2-yl]-methoxy}-N-methylcarbamate, molecular weight 394,38, is a derivative of selective full agonist of the receptor of A1adenosine CVT-510. Adenosine was obtained from Sigma Chemical (St. Louis, MO). Radioligand 8-cyclopentyl-1,3-dipropyl-[2,3-3H(N)]xanthine ([3H]CPX) was obtained from New England Nuclear (Boston, MA.). Concentrated source solutions (10-100 mm) CVT-2759, CPX, CPT, CPA, CCPA, CHA and Forskolin was dissolved in dimethyl sulfoxide, was stored in aliquot at -80°and diluted in saline solution for use in experiments. The final content of DMSO in physiological solution during the experiments did not exceed 0.1%. Adenosine and EHNA was dissolved in saline immediately before use.

The checked binding cells DDT1

Cell culture

Cells DDT (line smooth muscle cells VAS duct hamster) were grown as monolayers in Petri dishes using eagle medium, modified by Dulbecco (DMEM), containing 2.5 mg ml-1amphotericin B, 100 U ml-1penicillin G, 0.1 mg ml-1streptomycin sulfate and 5% serum fruits calves, in a humidified atmosphere of 95% air and 5% CO2. Cells were subculturally twice a week by dispersion in a balanced salt Hanks solution (HBSS) without divalent cations and containing 1 mm EDTA. The cells were then sown in the environment for growth at a density of 1.2 x 105cells on the Cup and the experiments were conducted in 4 days, approximately one day before confluently.

The membrane preparations

Cell layers were washed twice in HBSS (2 x 10 ml), scraped from the plate with a rubber truncheon in 5 ml of 50 mm Tris-HCl buffer pH of 7.4 at 4°and the suspension is homogenized for 10 sec. The homogenate was centrifuged at 27000 x g for 10 min, resuspendable in the buffer and again centrifuged as described above. The protein content was determined using the Biorad Protein Assay Kit (Richmond, CA) using bovine serum albumin as standard. This membrane suspension was stored with dimethylsulfoxide (DMSO) in He buffer (10 mm HEPES, 1 μm EDTA with a pH of 7.4) and stored in liquid nitrogen at -80°C.

Competitive binding analysis:

The compounds of formula I were analyzed in terms of their affinity to the receptor sites of adenosine A1in the cells of DDT. Briefly, 50-70 µg memb the data of protein were incubated in a mixture, containing 2U/ml adelaideans, 10 mm GTP-γS 5 mm the HE buffer containing 5 mm MgCl2in a glass tube. The original solutions of compounds of the invention serially diluted (10-10M to 10-4M) in buffer HE or applied only HE buffer (control to determine non-specific binding) was added to the incubation mixture. Finally, added tretirovanie cyclopentadienones (3H-CPA) to a final concentration of 1.5 nm. After incubation at 23°C for 90 minutes the reaction was stopped by filtration on a collector cells Brandel MR24 and washing cooled to the temperature of the ice buffer Tris-EDTA (three times the approximate volume of 10 ml/wash) through the filters Whatman GF/B (pre-soaked for 1 hour in 0.3% polyethylenimine to reduce nonspecific binding). The filters are transferred to scintillation vials and added 5 ml of Scintisafe (VWR, Brisbane, CA). The amount of radioactivity, detained on the filters was determined by liquid scintillation spectrometry. Determination of protein was carried out according to the method of Bradford (1976. Anal. Biochem. 72:248) using bovine serum albumin as the standard.

In this test it was shown that the compounds of formula I are agonists of A receptor1adenosine.

Example 29

The checked binding [35S]GTPγS

The ability of agonists to activate G-proteins were determined using radioactively labeled GTP ([35S]GTPγS). Briefly, membrane proteins (30-50 µg/test tube) were placed in glass tubes containing 50 mm Tris-HCl buffer pH 7,4,

5 mm MgCl2, 100 mm NaCl, 1 mm dithiothreitol, 0.2 units ml-1adelaideans, 0.5% BSA, 1 mm EDTA, 10 mm GDF and 0.3 nm [35S]GTPγS. In separate test tubes were added various concentrations of the compounds of the invention (putative receptor agonists A1adenosine), known full agonist receptor A1adenosine N cyclopentylamine (CPA or CCPA), or the control tube contained 10 μm GTPγS without agonist (to determine non-specific binding). Tubes for testing were incubated for 90 minutes at 37°C. agonist-Stimulated binding was assessed by determining the difference between total binding in the presence of the alleged agonists and basal binding determined in the absence of CPA. The results were expressed as percent stimulation of putative agonists relative to the full agonist CPA after subtraction of nonspecific binding.

In this test it was shown that the compounds of formula I are agonists of A receptor1adenosine.

Example 30

Isolated perfezione heart Morskie the x-pigs

Guinea pigs (Hartley) of both sexes with weighing 300-350 g anaesthetize the penthrane and slaughtered by decapitation. Open the chest, quickly remove the heart and washed with chilled on ice modified Krebs solution-Henseleit (K-H). Components of the modified solution (K-H are (in mm) 117,9 NaCl, 4,8 KCl, And 2.5 CaCl2, 1,18 MgSO4, 1,2 KH2PO4and 0.5 Na2EDTA, 0,14 ascorbic acid, 5.5 dextrose, 2,0 pyruvic acid (sodium salt) and 25 NaHCO3. Solution K-H continuously hairout 95% O2-5% CO2and the pH adjusted to a value of 7.4. For perfusion of the heart by way of Langendorf isecheno the aorta is put on a glass cannula and strengthen the ligature. Retrograde perfusion of the aorta begin immediately at constant speed DC 10 ml/min modified solution K-H, heated to 36.0±0,5°C. Side entrance cannula is used to join lines of perfusion to the pressure sensor Gould for measuring coronary perfusion pressure. Coronary perfusion pressure is continuously recorded on a strip chart recorder (Gould RS3400, Cleveland, OH) for each experiment. Coronary conductance (ml·min-1·mm Hg-1) calculated as the ratio of coronary flow (10 ml/min) perfusion pressure (mm Hg). To facilitate the flow from the left ventricle of the leaf Mitra is inogo valve is incised using a thin equipped with spring scissors. If necessary, the heart is subjected to electrical stimulation at a constant rate using external electrodes. After the excision and annexation of equipment continuously monitor interval stimulus-bundle of his (S-H) and coronary perfusion pressure, and every heart give to stabilize for 20-40 min before drug administration. Experimental interventions always precede the test measurements, and they are always accompanied them. Criteria for exclusion of hearts from the study are 1) coronary perfusion pressure of <50 mm RT. Art., 2) the lack of stability coronary perfusion pressure in a period of stabilization and 3) the impossibility of electrical stimulation of the heart at a constant rate throughout the experiment.

Fes hearts bipolar covered with Teflon electrode placed on the wall vnutriepreserdnaya partitions. Remove part of the tissue of the left and right Atria, including the sinoatrial node, how to reduce spontaneous cardiac rhythm and exposition of the atrial septum to place the electrode. Hearts subjected to electrical stimulation in a constant mode of 3.2 Hz. Stimulation provide with the help of interval generator (model 1830, WPI, Sarasota, FL) and is passed through the device for isolation of stimulus (model 1880, WPI) in the form of the header is Aulnay pulse duration of 3 MS and an intensity at least two times greater than the threshold.

S-H Interval. Lengthening the interval S-H is used as an indicator of negative dromotropic action of A1-adenosine agonists on the conduction of the AV node. Write electrogram beam GIS using a unipolar electrode placed on the right side of the interatrial septum near the AV node. The signal is continuously reflected on the display oscilloscope with a scan rate of 10 MS/see In the interval S-H use the time interval between the first artifact and the maximum deviations up signal beam GIS.

Heart to stabilize until the interval S-H and CPP does not become permanent. The test compound is injected into the perfusion system at a final concentration of 0.3, 3, 10 and in some cases 30 μm. If there is AV block second level at any concentrations up to 30 μm, the test compound is removed by washing. After washing from the first test of the second connection test the connection cannot be used at the same heart as long as the interval SH and CPP are not returned to the reference level or the interval S-H does not exceed more than 2 MS compared with controls. On the same heart may be applied up to three connections.

The compounds of formula I demonstrate the ability to delay the conduction in the AV node in this test.

The use of the 31

Antiemetic research

All experiments used adult male ferret with body weight in the range of 1-1,5 kg Vomiting caused by x-ray irradiation, morphine and cisplatin.

X-ray irradiation:

Ferrets are weighed before the experiment. On the day of the experiment each ferret gets 2 Gy (200 Rad) of x-ray irradiation to the whole body, produced over a 5 minute period. Agonists A1receptor injected subcutaneously immediately after x-ray irradiation (i.e. about 25 minutes before the onset of vomiting). In the study of the actions of the antagonist A1receptor, DPCPX, the effect of partial agonist or is simultaneous introduction of both compounds directly after x-ray irradiation, or DPCPX impose a pre-treatment for 15 minutes. In all cases for ferrets observed for 2 hours after x-ray irradiation and record the time and number of retching and vomiting and regurgitation.

Morphine:

Ferrets are weighed before the experiment. Agonist A1receptor adenosine is administered subcutaneously 15 minutes before injection subcutaneous dose of 0.5 mg kg-1morphine. (Vomiting usually begins 5 minutes after the injection of morphine.) For ferrets observed for 2 hours after a dose of morphine and record the time and if estvo of retching and vomiting and regurgitation.

Cisplatin:

Ferrets are weighed and measured to calculate the surface area of the body before the experiment. On the day of the experiment each ferret gets intraperitoneal dose of cisplatin (200 mg m-2). Agonist A1receptor adenosine injected subcutaneously immediately before the first episode of vomiting (after about 1.5 hours after administration of cisplatin). For ferrets, see for 7 hours after the first episode of vomiting and record the time and number of retching and vomiting and regurgitation.

The compounds of formula I exhibit the ability to control vomiting in this test.

Definition antilipolytic properties

Animals. Male rats Sprague-Dawley (380-420 g) were obtained from Simonsen Laboratories (Gilroy, CA). All animals were kept in humane conditions in accordance with the standards established in The Principles of Laboratory Animal Care, compiled by the National society for medical research and the Guide for the Care and Use of Laboratory Animals prepared by the Institute for resources laboratory animals, published by the National Institute of health (NIH publication 86-23, revised 1996).

The selection of adipocytes of the rat epididymis. Adipocytes were isolated from the fat pads of the epididymis of rats, as described previously (Rodbell, 1964). Briefly, rats were anestesiologi using methoxyflurane and were killed by exsanguination. Adipose tissue is epididymis was removed and placed in a modified Krebs solution (KRH), containing NaCl (100 mm), KCl (4,7 mm), CaCl2(2.5 mm), NaHCO3(3.6 mm), MgSO4(1,19 mm), KH2PO4(1,18 mm), dextrose (5 mm), pyruvic acid (5 mm), ascorbic acid (1 mm) and HEPES (5 mm), pH of 7.4. Visible blood vessels were dissected and removed, and the adipose tissue is crushed. Crushed fabric hydrolyzing 25 ml of fresh KRH solution containing collagenase type I (1 mg/ml), free fatty acid BSA [1%(wt./about.)] and nicotinic acid (2M for the inhibition of lipolysis) for 40 to 60 minutes at 37°With continuous light shaking. The cell suspension was filtered through a nylon sieve (210 m) to remove non-hydrolyzed fragments of tissue. The cell filtrate was washed three times with KRH solution containing 1% free fatty acid BSA, at 37°C. the Final suspension of adipocytes or diluted fresh KRH solution with 1% free fatty acid BSA for use in experiments with the camp, or were used to produce membranes for radioligand binding analysis.

Testing of camp in isolated rat adipocytes. Aliquots (100 μl, 45000-90000 their cells to the adipocyte suspension was placed in wells of 24-well plates for culturing containing 0.4 ml of KRH solution containing free fatty acids BSA (1%), ascorbic acid (1 mm), rolipram (10 μm), cilostamide (1 mm), adelaideans (2 U/ml) and suitable(e) agonist(s) receptor (A1adenosine. To each well was added an aliquot of 0.5 ml of KRH solution containing 60 nm isoproterenol, and incubation was performed for 4 minutes in a bath with a rotating shaker at a temperature of 37°C. the Testing was stopped by adding to each well 200 μl of 300 mm HCl for lizirovania cells. The concentration of camp in the cell lysate were determined using kits direct colorimetry camp (Assay Designs, Inc., Ann Arbor, MI).

Obtaining membranes of adipocytes and competitive binding

The testing. Freshly isolated adipocytes were added to a chilled solution containing sucrose (0,25M), EDTA (1 mm) and Tris-HCl (10 mm, pH of 7.4), and homogenized in 10 receptions with application supplied with the engine mills for cloth. The homogenate was cooled on ice and the fat layer was discarded. The homogenate was then centrifuged at 500g for 10 min at 4°C. the Supernatant under the layer of fat was removed, resuspendable in fresh buffer and homogenized a second time in six receptions with mills for cloth. Cell membranes were collected by centrifugation of the homogenate at 15000g for 15 minutes the Final precipitate membranes resuspendable in a solution containing sucrose (0,25M), phenylmethylsulfonyl (0.1 mm), leupeptin (5 μg/ml), Aprotinin (5 g/ml), adelaideans (2 U/ml) and Tris-HCl (10 mm) buffer, pH 7,4)Suspensio membranes were frozen and stored in liquid nitrogen. For testing competitive binding suspension membranes were thawed and incubated for 2 hours at room temperature in Tris-HCl (50 mm) buffer containing ADA (1 U/ml), guanosine 5-(imido)triphosphate (100 M) and [3H]CPX (1-3 nm) and successively increasing concentrations of the competing agent. At the end of the incubation, free radioligand separated from the associated with membranes radioligand by filtration through glass fiber filters GF/C (Watman, Maidstone, UK) using a fabric collector (Brandel, Inc., Gaitherburg, MD). Radioactivity was measured using liquid scintillation counter. Nonspecific binding of [3H]CPX was defined as the binding of [3H]CPX in the presence of 10 μm N6-cyclopentylamine. For each concentration of unlabeled compounds were measured in three parallel samples.

The influence of compounds of formula I on heart rate and concentration nezhk serum in awake rats

Heart rate was measured in rats with chronically installed telemetry sensors. For implantation of the sensor produced laparotomy on the middle line of the shot rats in the abdominal wall was stitched sensor for recording the ECG. Through the wall there were two electrocardiographic o passing subcutaneously (one on the left shoulder, the other on the right thigh) and fastened in place with sutures. H the frequency of heart rate in awake rats was determined using the Dataquest ART Gold System (Data Sciences International, St. Paul, MN). The electrical activity of the heart recorded during the 10-sec periods and used to calculate the heart rate in beats per minute. After recording the initial heart rate into the abdominal cavity of each rat was injected solvent (0.9% DMSO in saline, 0.5 ml)or the compound of formula I, and heart rate was monitored at intervals for a further 3 hours.

The effect of the compounds of formula I in heart rate and a decrease in the concentration nezhk serum were determined in separate groups of rats to avoid the impact of the handling of animals and collection of blood on the heart rate. Three days before the experiment in the left common carotid artery of each rat was implanted catheter (outer diameter 0.025 mm) in aseptic conditions using sterile technique. The catheter was performed subcutaneously on the dorsal surface. After recovering from the anesthesia, rats were placed in metabolic cages for ease of handling and blood sampling. Blood samples (0.2 ml) were taken before and after different time intervals after VB. injection or the compounds of formula I, or solvent (DMSO in saline). After selection of each blood sample was injected 1% sodium citrate in saline in a volume of 0.4 ml to restore blood volume and prevent when artisania in the catheter carotid artery. From each sample received the serum after centrifugation of the clotted blood. Serum samples were stored at 80°until analysis. The concentration nezhk serum was determined using a kit for enzymatic colorimetric assay (Wako Chemicals, Richmond, VA).

Antilipolytic properties of the compounds of formula I in rats with stimulated catecholamine levels nezhk investigated in rats with permanent catheters (as described above). Norepinephrine was administered either by I.V infusion into the jugular vein with a speed of 3 mcg/kg/min for 30 minutes, or by VB. injection (60 mg/kg). The compound of formula I was administered using VB. injection either before or after norepinephrine for determining whether caused by noradrenaline concentration increase nezhk can be prevented or reversed compound of formula I.

In this test the compounds of formula I showed antilipolytic properties. For example, oral administration of (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol at a dose of 1 mg/kg provided the original 40% reduction neeterificirovannah free fatty acids (nezhk), which was maintained for 1 hour, after which the level nezhk plasma was returned to normal by 2 hours. Oral administration 4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{2-[2-forfinal]ethinyl}oxolan-3,4-diol at a dose of 2.5 mg/to the provided source 60% reduction neeterificirovannah free fatty acids (nezhk), which was maintained for 90 minutes, after which the level nezhk plasma was returned to normal by 4 o'clock.

At doses of 1 mg/kg, 2.5 mg/kg and 5 mg/kg was observed effects on the heart rate.

1. The compound of formula (I)

where R1represents optionally substituted by halogen atom, hydroxy, trifluoromethyl, C1-4-alkoxy With3-6cycloalkyl, optionally substituted by halogen atom 5-6-membered heterocyclyl, in which the heteroatoms are selected from oxygen, optionally substituted by halogen atoms phenyl or optionally substituted by halogen atoms 5-6-membered heteroaryl, in which the heteroatoms are selected from nitrogen and/or sulfur;

R2represents hydrogen or trifluoromethyl;

R3represents hydrogen, optionally substituted by halogen atom3-6cycloalkyl, optionally substituted by a halogen atom, a trifluoromethyl,1-4the alkyl phenyl, optionally substituted by a halogen atom, a trifluoromethyl,1-4-the alkoxy heteroaryl, who has in the ring 1-2 of heteroatom selected from nitrogen, oxygen, or sulfur, or an optionally substituted C1-4the alkyl 5-6-membered heterocyclyl, who has in the ring 1-2 of heteroatom selected from nitrogen or oxygen;

R4and R5 independently represent hydrogen;

X represents a covalent bond or a lower alkylene;

X1is a covalent bond or a lower alkylene.

Y is a covalent bond or a lower alkylene, optionally substituted by hydroxy or cycloalkyl; and

Z represents-S≡ -,- R6C=CR7- or-CHR6CHR7-where R6and R7at each position represent hydrogen or lower alkyl, provided that R3cannot mean hydrogen,

if X is methylene, Z is a- ≡ -; each Y and X1is a covalent bond, R1-represents a C4-C7cycloalkyl, possibly substituted by halogen atom, hydroxy, C1-4alkoxy; phenyl, optionally substituted by halogen atoms; 5-6-membered heterocyclic group, in which the heteroatoms are selected from oxygen, optionally substituted by halogen atoms,

R2is hydrogen, or

if X is a covalent bond, Z means R6C=CR7-each Y and X1is a covalent bond, R1-represents a C4-C6cycloalkyl, possibly substituted by hydroxy, C1-4alkoxy, R2is hydrogen, trifluoromethyl,

2. The compound according to claim 1, where Z represents-S≡With-.

3. The connection is giving according to claim 2, where X, X1and Y are covalent bonds.

4. The compound according to claim 3, where R1represents an optionally substituted cycloalkyl, optionally substituted heterocyclyl or optionally substituted heteroaryl.

5. The compound according to claim 4, where R2, R4and R5represent hydrogen.

6. The compound according to claim 5, where R3represents hydrogen or optionally substituted aryl.

7. The connection according to claim 6, where R1represents an optionally substituted cyclopentyl or optionally substituted tetrahydrofuranyl and R3represents hydrogen, or optionally substituted phenyl.

8. The connection according to claim 7, where R3is cyclopentyl and R3represents hydrogen, namely (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-atillacolpan-3,4-diol.

9. The connection according to claim 7, where R1is a 2 hydroxycyclopent and R3represents hydrogen, namely (4S,2R,3R,5R)-5-ethinyl-2-{6-[(2-hydroxycyclopent)amino]purine-9-yl}oxolan-3,4-diol.

10. The connection according to claim 7, where R1represents a tetrahydrofuran-3-yl and R3represents hydrogen, namely (4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-itinerarary-3,4-diol.

11. The connection according to claim 7, where R1is cyclopentyl and R3is a 2-forfinal, and they are the NGOs (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-[2-(2-forfinal)ethinyl]oxolan-3,4-diol.

12. The connection according to claim 7, where R1is cyclopentyl and R3is a 2-triptoreline, namely (4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]-5-{2-[2-(trifluoromethyl)phenyl]ethinyl}oxolan-3,4-diol.

13. The connection according to claim 7, where R1represents a tetrahydrofuran-3-yl and R3is a 2-forfinal, namely (4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-{2-[2-forfinal]ethinyl} oxolan-3,4-diol.

14. The connection according to claim 7, where R1represents a tetrahydrofuran-3-yl and R3is a 2-triptoreline, namely (4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purine-9-yl]-5-{2-[2-(trifluoromethyl)phenyl]ethinyl}oxolan-3,4-diol.

15. The compound according to claim 5, where R3represents optionally substituted by a halogen atom, a trifluoromethyl,1-4alkoxy heteroaryl, which has a 1-2 ring heteroatoms selected from nitrogen, oxygen or sulfur.

16. The connection indicated in paragraph 15, where R1represents an optionally substituted cyclopentyl or optionally substituted tetrahydrofuranyl and R3represents an optionally substituted thienyl.

17. Connection P16, where R1is cyclopentyl or tetrahydrofuran-3-yl and R3represents Tien-2-yl.

18. The compound according to claim 1, where Z represents a-R6C=CR7-where R6and R7both are gorodom.

19. Connection p, where X, X1and Y are covalent bonds.

20. The connection according to claim 19, where R1represents an optionally substituted cycloalkyl.

21. Connection claim 20, where R2, R4and R5represent hydrogen.

22. Connection item 21, where R3represents optionally substituted phenyl or optionally substituted by a halogen atom, a trifluoromethyl,1-4alkoxy heteroaryl.

23. Connection p.22, where R1is cyclopentyl and R3represents a 5-chlortan-2-yl, 4-methylisoxazol-3-yl or 3,5-dimethylisoxazol-4-yl.

24. Connection p.22, where R1is cyclopentyl and R3is a 2-were, namely 5-[2-(2-were)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol.

25. Connection p.22, where R1is cyclopentyl and R3represents phenyl, namely 5-[2-(phenyl)vinyl](4S,2R,3R,5R)-2-[6-(cyclopentylamine)purine-9-yl]oxolan-3,4-diol.

26. The use of compounds of formula (I) according to claim 1 as agonists of the receptors, A1adenosine in therapeutically effective amounts for the preparation of drugs for the treatment of diseases associated with the activity of receptors And1adenosine.

27. Application connection p, where the adenosine agonist is of eceptor A 1according to claim 1 has an antilipolytic effect.

28. The use of agonist adenosine receptor (A1with antilipolytic effect on item 27 to obtain drugs for the treatment of diseases related to metabolic disorders.

29. Use p, where the metabolic disorder is the obesity.

30. Pharmaceutical composition having the properties of agonist adenosine receptors And1comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of the compounds of formula (I) by 1.

Posted priorities for claims:

15.08.2002 twelve - claims 1 to 25, characterizing the connection with the value of the X-covalent bond PP-30, characterizes the use of compounds with the value of X is a covalent bond;

25.02.2003 - claims 1, 2 characterizing the connection with the value of the X-alkylen, PP-30, characterizes the use of compounds with the value of the X-alkylen.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention pertains to the method of obtaining 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine and can be used in organic chemistry and pharmaceutical industry. The method lies in that, 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine and sodium azide interact in the presence of the above mentioned tetrametylammonium chloride boiled for 4 hours in absolute acetonitrile. The obtained compound is cleaned by elution of benzol. The residue is dissolved in chloroform and the desired product is separated during precipitation using hexane.

EFFECT: high degree of purity with high output.

1 ex

FIELD: chemistry.

SUBSTANCE: method implies that suspension 2-amino-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranozile)purine in 60% anhydrous hydrogen fluoride solution of pyridine is diazotizied with tert-butylnitrite during 1 hour at (-18) - (-22)°C. Reaction mixture is decomposed with cut ice. Reaction product is purified by, flash-chromatography on aluminum oxide. Then produced 2-fluorine-6-azido-9-(2,3,5-tri-O-acetyl-β-D-ribofuranozile)purine is hydrogenated at air pressure in 10% acetic acid solution of absolute ethyl acetate with 10% palladium on carbon solution occurrence during 18 hours. Reaction product is purified in acetonitrile solution by flash-chromatography on aluminum oxide at 50-55°C and crystallized from alcohol.

EFFECT: production of compound of high purity with high output.

2 ex

FIELD: chemistry.

SUBSTANCE: invention applied for relates to process of obtaining 2,6- dichlor-9-(2,3,5-tru-O-acetyl-β-D-ribofuranozyl) purine and may be used in organic chemistry and pharmaceutical industry. The process involves conduction of 2,6- dichlor-9-(2,3,5-tru-O-acetyl-β-D-ribofuranozyl) purine with tret-butyl nitrite in the methylene chloride medium at (-18)-(-22)°C during 2 hours in presence of pyridine hydrochloride and phosphorus oxychloride followed by decomposing the reaction mixture with chipped ice, and cleansing of the target product in methylene chloride with flash-chromatography on silica gel.

EFFECT: obtaining of substance with high grade of purity and high output by simplified technology.

1 ex

FIELD: chemistry.

SUBSTANCE: this invention covers method of production of 2-chloroadenosine and may be used in organic chemistry and pharmaceutical industry. The method includes ammonolysis of 2.6-di-chloro-9-(2,3,5-tri-O-acetyl-(β-O-ribofuranozyl)purine in absolute ethyl acetate saturated with ammonia at 0°C during 3 days with further hydrolysis of obtained 5'-0-acetyl-2-chloro-adenosine with 20% ammonia solution in methanol at 20°C during 6 hours, isolation of desired product from the reaction mixture by boiling in mixture of chloroform and methanol, their volumetric ratio 3:1, and purification by crystallization from water.

EFFECT: production of substance with high purity.

1 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I) wherein each among R represents independently hydrogen atom, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, phenyl or phenyl-(C1-C3)-alkyl; X and X' represent -CH2OH, -CO2R2, -OC(O)R2, -CH2OC(O)R2 or C(O)NR3R4 wherein R2, R3 and R4 represent independently hydrogen atom (H), (C1-C6)-alkyl substituted optionally with one-three (C1-C6)-alkoxy-groups, (C1-C6)-alkylthio-groups, halogen atoms, hydroxy-, amino-, mono-(C1-C6)-alkyl)-amino-, di-(C1-C6)-alkyl)-amino-group; Z and Z' represent independently (C1-C6)-alkyl broken optionally with one-three sulfur atoms (S) or non-peroxide oxygen atom (O), or they absent; n = 1-3; or to its pharmaceutically acceptable salt. Compounds are agonists of adenosine A2A-receptors and can be used for inhibition of inflammatory response or inflammation treatment.

EFFECT: valuable medicinal properties of compounds.

56 cl, 1 tbl, 21 dwg, 37 ex

The invention relates to nucleoside analogs of formula (1) in which R1represents H or a group protecting the hydroxyl, R2represents H, a group protecting the hydroxyl group of phosphoric acid, a protected group, phosphoric acid or a group of the formula P(R3R4in which R3and R4are the same or different and represent a hydroxyl group, a protected hydroxyl group, alkoxygroup, allylthiourea, cyanoacetylurea, amino group, substituted alkyl group; And represents alkylenes group containing from 1 to 4 carbon atoms, and a represents a substituted purine-9-ilen group or substituted 2-oxopyrimidine-1-ilen group containing at least one Deputy, selected from hydroxyl groups, protected hydroxyl groups, amino groups, protected amino groups, alkyl groups

The invention relates to medicine and provides substances that are effective against tumors and viruses, for which conventional anti-tumor agents and antiviral agents exhibit only insufficient effects, and have cancerostatic action and antiviral effects on different tumor immune

The invention relates to certain oxipurinol the nucleosides, compounds related data oxipurinol the nucleosides, acyl derivatives and compositions that contain at least one of these compounds

The invention relates to purine derivative of L-nucleoside of the formula (I), where R1, R2', R3' and R4- N; R2, R3and R5- HE; Z1- N; Z2selected from N and CH; Z3- NR-, -C(R)2, -S-, where R, same or different, selected from H, Br, NH2, alkyl and alkenyl; Z4selected from C=O, -NR-, -C(R)2- where R, same or different, selected from H and Br; Z5Is N; X is selected from H, HE, SH, -SNH2, -S(O)NH2, -S(O)2NH2Y from H and NH2; W is O, and Y represents NH2then Z3is not a-S-

FIELD: chemistry.

SUBSTANCE: novel chemical compounds of formula (I) or their pharmaceutically acceptable salts possess inhibiting activity with respect to kinase p-38 MAP and kinase FGFR, and can be used in treatment of such diseases as arthritis, obstructive lung disease, Alzheimer's disease or oncological and other diseases. In general formula (I) , R1 is hydrogen, R2 is 6-member oxygen-containing heterocyclyl, aryl, selected from unsubstituted phenyl or phenyl substituted with aliphatic acyl group which contains 1-6 carbon atoms, halogen cyano, hydroxyl, C1-6alkylsulfinyl, C1-6alkylsulfonyloxy, C1-6alkylsulfonyl, C1-6alkylsulfanyl, tret-butydimethylsilanyloxy, 6-member heterocyclyl, containing 1-2-heteroatoms, selected from nitrogen and oxygen, R3 is C1-6alkyl, Ar1 is phenyl, substituted with 1-2 substituents, selected from atoms of halogen, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, X1 is oxygen and X2 is chemical bond.

EFFECT: efficient application of invention compounds in pharmaceutical composition.

13 cl, 1 tbl, 64 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to pharmaceutical means, particularly preventer of blood vessels intima hyperplasia, containing 3(2H)-pyridazinone substance, represented by formula (I) or its pharmaceutically suitable salt.

EFFECT: obtaining highly effective preventer of blood vessels intima hyperplasia; each of radicals R1, R2, R3, X, Y, and A, having parameters, detailed in description.

5 cl, 2 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new substituted 2,3,4,5-tetrahydro-1N-pyrido[4,3-b]indoles with general formula 1.1, 1.2 or 1.3, their pharmaceutical salts and/or hydrates with antihistamine activity. In general formulae 1.1, 1.2 or 1.3 radicals assume values given below . In 1.1 compounds, R1 represents a substitute, chosen from hydrogen or unsubstituted C1-C5 alkyl; R2 represents a hydrogen atom or C1-C4 alkyl; R3i represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3; n=0 or 1-3; in 1.2 compounds R1 represents a substitute of an amino group, chosen from hydrogen or optionally substituted C1-C5 alkyl; R3 represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3, and Ar1 represents an aryl or heterocyclyl, containing at least one carboxyl and/or alkoxycarboxyl substitute or R3i represents a carboxyl and/or alkyloxycarboxyl substitute, and Ar1 represents optionally substituted aryl or heterocyclyl; in 1.3 compounds, R2 represents a hydrogen atom or C1-C4 alkyl; R3i represents one or more single or different substitutes, chosen from hydrogen, halogen, C1-C3 alkyl or CF3, and Ar2 represents optionally substituted aryl or heterocyclyl; k=0 or 1-4; m=1 or 2.

EFFECT: compounds can be used for making drug formulation for treating allergies, autoimmune diseases such as pollen allergy, urticaria, bronchial asthma etc.

17 cl, 10 dwg, 2 tbl,13 ex

FIELD: chemistry.

SUBSTANCE: new compounds with formula Ia are proposed, where: P represents pyridine or pyrimidine; R1 represents hydrogen; R2 is chosen from halogen, nitro, C0-6alkylheteroaryl, (CO)OR4, trifluoromethyl, C0-6alkylcyano, C0-6alkylNR4R5, OC1-6alkylNR4R5, C0-6alkylCONR4R5, C0-6alkyl(SO2)NR4R5 and X1R6 group, where X1 represents a direct link; R6 represents a 5- or 6-member heterocyclic group, containing one or two heteroatoms, independently chosen from N, O, and S, for which the given heterocyclic group can be unsaturated and can be substituted with by one substitute, chosen from W; m equals 0, 1, or 2; R3 is chosen from CO(OR4), C0-6alkylNR4R5, C0.6alkylCONR4R5, OC1-6alkylNR4R5 C1-6alkyl(SO2)NR4R5; n equals 1 or 2; R4 is chosen from hydrogen, C1-6alkyl; R5 is chosen from hydrogen, C1-6 alkyl, C0-6 alkyl C3-6 cycloalkyl, C0-6 alkylaryl, C0-6alkylheteroaryl and C1-6alkylNR14R15 or R4 and R5 together can form a 4-, 5-, 6- or 7-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O, where the given heterocyclic group can be substituted by group Y; and where any C1-6alkyl, indicated in defining R2-R5, can be substituted with one or more one Z group; R14 and R15 together can form a 5-member heterocyclic group, containing one or more heteroatoms, independently chosen from N and O; W and Z are independently chosen from halogen, CN, OR16, C1-6alkyl, trifluoromethyl, trifluoromethoxy, 5-member heterocyclic group, containing one heteroatom, independently chosen from N, for which the given heterocyclic group can be substituted with group Y; Y is chosen from oxo, halogen, C1-6alkyl, C0-6alkylaryl, NR16R17, phenyl, C0-6alkylaryl, where the phenyl and C0-6alkylaryl groups can be substituted with nitro, trifluoromethyl; R16 and R17 are independently chosen from hydrogen and C1-6alkyl, or where R16 and R17 together can form a 5-member heterocyclic group, containing one heteroatom, chosen from N; in form of a free base or pharmaceutical salt. Formula Ia compounds have inhibiting effect to glycogen-synthase-kinase-3 (GSK3). The invention also relates to the method of obtaining the proposed compounds and to new intermediate compounds, used in them, pharmaceutical compositions, containing the given therapeutically active compounds, and use of the given active compounds in therapy for treating conditions, related to GSK3.

EFFECT: new method of obtaining indole derivatives.

33 cl, 1 tbl, 112 ex

FIELD: medicine; pharmacology.

SUBSTANCE: admixture contains leaves of periwinkle, leaves of mint peppery, leaves of common plantain, hawthorn foetuses, rose hips, mountain ash foetuses, a grass of felon herb, sweet clover, a grass of cotton weed, camomile flowers, roots of liquorice at a proportion of components in parts accordingly 1:1:1:1:1:1:1:2:1:1:1.

EFFECT: admixture dilates an arsenal of medical products of a phytogenesis with the expressed therapeutic effect for treatment of disturbances of a cerebral circulation.

5 dwg, 3 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to medical products of antiischemic and hypolipidemic activity and can be used as new agent for correction of lipidic metabolic disorder to prevent and treat dyslipidemia, ischemic heart disease (IHD), and as rehabilitation agent at postinfarction conditions. Agent of antiischemic and hypolipidemic activity represents ecdysteroids-containing substance extracted from aerial saw-wort Serratula coronata L. (Asteraceae), containing mixed 20-hydroxyecdysone in amount not less than 75% and 25S-inocosterone in amount not less than 10%.

EFFECT: evident hypolipidemic activity and considerable reduction in common lipid, cholesterol and triglyceride content.

7 ex, 19 tbl, 24 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions concerns a composition of the prolonged release for peroral administering of a reductase inhibitor HMG-CoA. The composition which contains a solid dispersing agent including reductase inhibitor HMG-CoA, the dissolving agent and the stabilising agent is offered; the compound carrier of the prolonged release; and the accelerator of gel hydration where the compound carrier of the prolonged release is an admixture of sodium alginate and xanthic gum, and the accelerator of gel hydration is an admixture of a compound propylene glycol ether alginate and hypromellose. The method of obtaining of the specified composition, including stages is offered: the mixing of a reductase inhibitor HMG-CoA, a dissolving the agent and stabilising agent in a dissolvent with obtaining of a solid dispersing agent; homogeneous mixing of the compound carrier of the prolonged release and the accelerator of gel hydration with the solid dispersing agent with obtaining of the first admixture; additions of pharmaceutically comprehensible additives to the first admixture with obtaining of the second admixture; and dry mixing and drawing up of the second admixture in a solid composition. The composition due to the present invention can be easily and effectively received and be capable to maintain constant level of a medical product in blood by means of slow release of inhibitor HMG-CoA of a reductase with homogeneous rate within 24 hours. Accordingly the composition of the prolonged release under the present invention can be effectively used for decrease of cholesterol and triglycerides level in blood.

EFFECT: depression of cholesterol and triglycerides level in blood.

15 cl, 6 tbl, 6 ex, 6 dwg

FIELD: medicine.

SUBSTANCE: invention relates to application of L-butylftalid and containing it composition for preparation of medications for cerebral infarction prevention and treatment, particularly cerebral infarction, induced by focal cerebral ischemia. Application of L-butylftalid for preparation of medications for cerebral infarction prevention.

EFFECT: reduction of adverse reactions emergence risk and therapeutic action of medication for cerebral infarction prevention and treatment enhancement.

5 cl, 1 ex, 3 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: method of treatment or prevention of hyperlipidemia conditions and/or hypercholesterinemia implies application of composition containing cyanidin-3-O-glucoside and peonidine-3-O-glucoside. Composition contains therapeutically effective amount of black rice extract, including cyanidin-3-O-glucoside, peonidine-3-O-glucoside and one or more phytosterols and/or phytostanines. Composition contains therapeutically effective amount of black rice extract, including cyanidin-3-O-glucoside, peonidine-3-O-glucoside and one or more antioxidants. Method of treatment or prevention of hyperlipidemia conditions and/or hypercholesterinemia implies application of composition containing extract of hulled black rice external layer, thus the specified extract contains cyanidin-3-O-glucoside and peonidine-3-O-glucoside.

EFFECT: efficiency for treatment or prevention hyperlipidemia conditions and hypercholesterinemia.

29 cl, 19 dwg, 11 tbl, 11 ex

FIELD: medicine.

SUBSTANCE: invention refers to application of vasopeptidase inhibitors for treatment and/or prevention of nephropathy in diabetics or nondiabetics as well as for treatment and/or prevention of insulin resistance or metabolic disorder associated with profound glycolysis end products.

EFFECT: offered compounds have higher therapeutic efficiency in prevention and treatment of diabetic nephropathy development and higher activity in treatment and prevention of insulin resistance.

4 cl, 7 ex, 15 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns 2-(butyl-1-sulfonylamino)-N-[1(R)-(6-methoxypyridine-3-yl)propyl]benzinamide of the formula (I) , as well as its pharmaceutically acceptable salts, their obtaining and application, particularly in treatment and prevention of atrial arrhythmia types, e.g. atrial fibrillation or atrial flutter. Also, the invention describes a pharmaceutical composition including compound of the formula (I) with anti-arrhythmic effect.

EFFECT: new compound and pharmaceutical composition based there on for treatment and prevention of atrial arrhythmia.

8 cl, 1 tbl, 2 ex

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