Antagonists of adenosine a2b receptors, pharmaceutical composition based on thereof and method for their preparing

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to antagonists of adenosine A2B receptors and their using in treatment of mammals in different pathological states, such as digestive, immunological, neurological disorders and cardiovascular diseases caused both hyper-proliferation of cells and their apoptosis and similar disorders. Also, invention relates to methods for synthesis of these compounds and pharmaceutical composition containing thereof. The aim of the present invention is use of compounds of the general formulae (I) and (II) for preparing pharmaceutical composition possessing antagonistic activity with respect to adenosine A2B receptors wherein radical values are given in the invention description.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

41 cl, 12 sch, 35 ex

 

Priority is claimed based on provisional application for patent U.S. registration No. 60/348222, filed November 9, 2001, and provisional application for patent U.S. registration No. 60/401408, filed August 5, 2002, full details of which are included in this application by reference.

The scope of the invention

This invention relates to antagonists of the receptor adenosine A2Band their use for the treatment of mammals in various pathological conditions, such as gastrointestinal disorders, immunological disorders, neurological disorders and cardiovascular diseases caused by hyperproliferative cells, and apoptosis, and the like. The invention also relates to methods of producing such compounds and for containing pharmaceutical compositions.

Background of invention

Adenosine is found in the nature of a nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors, called A1, A2A, A2Band A3, each of which modulate important physiological processes. For example, the receptors of adenosine A2Amodulate vasodilation of the coronary vessels, receptors of A2Binvolved in the activation of mast cells, asthma, VASO is ratziu, regulation of cell growth, bowel 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 the receptors of adenosine A3modulate the processes of cell proliferation.

Receptors of adenosine A2Bare ubiquitous and regulate many biological activities. For example, adenosine binds to receptors A2Bon endothelial cells, stimulates angiogenesis. Adenosine also regulates the growth of populations of smooth muscle cells in blood vessels. Adenosine stimulates receptors A2Bon the fat cells, thus modulating hypersensitivity reactions type I. Adenosine stimulates secretory activity of the stomach in conjunction with A2Bin the intestine.

Despite the fact that many of the biological effects of adenosine required to maintain normal tissue homeostasis, under some physiological changes required modulation his actions. For example, the binding of receptors A2Bstimulates angiogenesis in the growth stimulation of endothelial cells. This activity is necessary for healing wounds, but hyperproliferative endothelial cells contributes to diabetic retinopathy. Also unwanted growth of blood vessels occurs is it with neoplasia. Therefore, inhibition of binding with receptors adenosine A2Bin the endothelium will weaken or prevent hypervascularization, thus preventing retinopathy and inhibiting the formation of tumors.

Receptors A2Bfound in the colon in basolateral domains of epithelial cells of the intestine and, when they are affected by the corresponding ligand, they work by increasing the secretion of chloride, respectively, causing diarrhea, which is a common and potentially fatal complication of infectious diseases such as cholera and typhoid. Therefore, antagonists of A2Bcan be used to block the secretion of chlorides in the intestines and, thus, they are applicable in the treatment of inflammatory disorders of the gastrointestinal tract, including diarrhea.

Insensitivity to insulin exacerbates diabetes, and obesity. Insulin sensitivity decreases with the interaction with receptors adenosine A2B. Thus, blocking receptors of adenosine A2Bin patients with diabetes or obesity may help patients with these disorders.

Other adverse biological effects of adenosine, acting on receptor-a2Bis overstimulate cerebral IL-6, cytokine-related dementia and Alzheimer's. Thus the m inhibition of binding with receptors adenosine A2Bcan weaken such neurological disorders that are caused by IL-6.

Disorders associated with hypersensitivity type I, such as asthma, hay fever and atopic eczema, stimulated by the binding of A2Breceptors of fat cells. Therefore, blocking these receptors, adenosine can bring therapeutic benefits for such disorders.

There are several compounds currently used to treat asthma. For example, theophylline is an effective anti-asthmatic agent, even though it is a poor receptor antagonist of adenosine. However, required significant levels to ensure that it was effective. In addition, theophylline has significant side effects, most of which is due to its action on the Central nervous system, lack of curative effect in asthma and the fact that he nonspecific blocking all adenosine receptor subtypes.

In addition, treatment with adenosine, such as adenosine, administered by inhalation (or amp), provokes bronchoconstriction asthmatics, but not in the population of healthy people. It is known that in this process involved the activation of mast cells, as in the process are released mediators the research cells, including histamine, PGD2-β-hexosaminidase and tryptase, and because the process can block specific blocker of histamine H1and kromolin-sodium. Thus, there is a significant difference between the path of interaction of adenosine with fat cells from asthmatics and, therefore, antagonists of A2Bin particular, applicable to modulate the function of fat cells or the activation of human lung cells.

Thus, the need to obtain compounds that are effective antagonists of A2Bfully or partially selective in relation to receptor A2Bapplicable for the treatment of various pathological conditions associated with the modulation of receptor-A2Bfor example, malignant tumors, asthma and diarrhea.

SUMMARY of the INVENTION

The purpose of this invention is to provide antagonists of receptor-A2B. Thus, in the first aspect of the invention relates to compounds of formula I and formula II:

The formula IFormula II

where:

R1and R2independently selected from hydrogen, optionally substituted alkyl or the group-D-E, in which D is a covalent bond or alkylene and E oznachaet is optionally substituted by alkoxygroup, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted of alkenyl or optionally substituted quinil, provided that when D is a covalent bond, E cannot be alkoxygroup;

R3means hydrogen, optionally substituted alkyl or optionally substituted cycloalkyl;

X is optionally substituted, Allen or optionally substituted, heteroaryl;

Y is a covalent bond or alkylene, in which one carbon atom can be optionally replaced by-O-, -S - or-NH -, and optionally substituted hydroxyl group, alkoxygroup, optionally substituted amino group or -- COR, where R is a hydroxyl group, alkoxygroup or amino group;

provided that when the optional substitution group is a hydroxyl group or amino group, it can not be located adjacent to the heteroatom; and

Z signifies optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl; or

Z means a hydrogen when X is optionally substituted by heteroatom, and Y is a covalent bond;

provided that when X is optionally substituted by arilena, Z is neoba is consequently substituted monocyclic heteroaryl.

The second aspect of the present invention relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of formula I or formula II, or a mixture thereof and at least one pharmaceutically acceptable excipient.

The third aspect of the present invention relates to a method of using compounds of formula I and formula II for the treatment of a disease or condition of a mammal, which can be successfully treated with receptor antagonist A2Bincludes introduction to the needy in the mammal a therapeutically effective dose of the compounds of formula I or formula II, or a mixture thereof.

Such diseases include, but are not limited to the specified at least one of the following diseases: asthma, inflammatory disorders of the gastrointestinal tract, including diarrhea, cardiovascular diseases such as atherosclerosis, neurological disorders, such as senile dementia, Alzheimer's disease and Parkinson's disease and diseases associated with angiogenesis, such as diabetic retinopathy and malignant tumor.

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

One preferred group of compounds of formulas I and II are compounds in which R1and R2independently are water is Odom, optionally substituted lower alkyl or a group-D-E, where D is a covalent bond or alkylene, and E is optionally substituted phenyl, optionally substituted cycloalkyl, optionally substituted of alkenyl or optionally substituted quinil, particularly compounds in which R3is hydrogen.

In this group the first preferred class of compounds includes compounds in which R1and R2independently denote a lower alkyl, optionally substituted by cycloalkyl, preferably n-drank, and X is optionally substituted phenylene. In this preferred subclass of compounds are compounds in which Y is alkylene, including alkylene, in which a carbon atom is replaced by oxygen atom, preferably-O-CH2-especially where oxygen is the point of joining the phenylene. In this subclass, preferably Z represents optionally substituted oxadiazole, in particular, optionally substituted [1,2,4]oxadiazol-3-yl, especially [1,2,4]oxadiazol-3-yl, substituted by optionally substituted phenyl.

A second preferred class of compounds includes compounds in which X is optionally substituted 1,4-pyrazolines. In this preferred subclass of compounds are compounds in which Y I have ever alkylene, especially the lower alkylene, and Z denotes hydrogen, optionally substituted phenyl or optionally substituted oxadiazole. In this subclass one preferred option includes compounds in which R1represents lower alkyl, optionally substituted by cycloalkyl, and R2is hydrogen. More preferred are compounds in which Y is -(CH2)- or-CH(CH3)and Z denotes optionally substituted phenyl. Another preferred are compounds in which Y is -(CH2)- or-CH(CH3)and Z denotes optionally substituted oxadiazole, in particular 3,5-[1,2,4]oxadiazol. This subclass also preferred are such compounds in which R1and R2independently represent lower alkyl, optionally substituted by cycloalkyl, especially n-propyl. More preferred are such compounds in which Y is a covalent bond, -(CH2)- or-CH(CH3)and Z denotes hydrogen or optionally substituted phenyl, in particular, where Y is a covalent bond, and Z represents hydrogen.

At present, the preferred compounds are:

1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-propyl-8-[1-benzylphenol-4-yl]-1,3,7-Triger the purine-2,6-dione;

1-butyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-propyl-8-[1-(phenylethyl)pyrazole-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazole-4-yl)-1-propyl-1,3,7-trihydroxypurine-2,6-dione;

8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazole-4-yl)-1-butyl-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione;

1-methyl-3-sec-butyl-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione;

1-cyclopropylmethyl-3-methyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dimethyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

3-methyl-1-propyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

3-ethyl-1-propyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-ethyl-3-methyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-{1-[(2-methoxyphenyl)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]ethyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-tregetour the n-8-yl))pyrazolyl]-2-phenylacetic acid;

8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione; and

8-{4-[5-(4-forfinal)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

Definitions and General options

Used in this sense, in General, it is understood that the following words and phrases shall have the meanings specified below, except the value that is specified in the context in which they are used.

The term "alkyl" refers to monological (one free link) branched or unbranched saturated hydrocarbon chain containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Examples of the specified term are groups such 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, preferably from 1 to 3 substituents selected from the group consisting of alkenyl, quinil, alkoxygroup, cycloalkyl, cycloalkenyl, acyl, alluminare, alloctype, amino, aminocarbonyl, alkoxycarbonylmethyl, sidegroup, ceanography, halo is s, hydroxyl group, geograpy, thiocarbonyl, carboxyl group, carboxyethyl, aristocraty, heteroanalogues, heterocyclisation, thiol, allylthiourea, aryl, alloctype, heteroaryl, aminosulfonyl, aminocarbonylmethyl, heterokaryosis, heterocyclyl, heterozygosity, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If you do not particularly limited by the definition, all substituents optionally may be additionally substituted by 1, 2 or 3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

2) an alkyl group as defined above, the chain of which is interrupted by 1 to 10 atoms independently selected from oxygen, sulfur and NRa-, where Raselected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, quinil, aryl, heteroaryl and heterocyclyl. All the optional substituents can be further substituted by alkyl, alkoxygroup, halogen, CF3, amino group, substituted amino group, cyano, or-S(O)nR, where R of the mean alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

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

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

The term "substituted lower alkyl" refers to lower alkyl defined above, having from 1 to 5 substituents, preferably 1, 2 or 3 substituent as defined for substituted alkyl, or a lower alkyl group as defined above that is interrupted by 1, 2, 3, 4 or 5 atoms defined for substituted alkyl, or a lower alkyl group as defined above, which has 1, 2, 3, 4, or 5 substituents as defined above and is also interrupted by 1, 2, 3, 4 or 5 above defined atoms.

The term "alkylene" refers to biradical branched or unbranched saturated hydrocarbon chain containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This term illustrates that their groups, as a methylene (-CH2-), ethylene (-CH2CH2-), isomers of propylene (e.g.,- CH2CH2CH2- , and-CH(CH3)CH2-) and the like.

The term "lower alkylene" refers to biradical branched or unbranched saturated hydrocarbon chain, preferably containing 1, 2, 3, 4, 5 or 6 carbon atoms.

The term "substituted alkylene" refers to:

(1) the group alkylene, which is defined above, having 1, 2, 3, 4 or 5 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxygroup, cycloalkyl, cycloalkenyl, acyl, alluminare, alloctype, amino, aminocarbonyl, alkoxycarbonylmethyl, sidegroup, ceanography, halogen, hydroxyl group, geograpy, thiocarbonyl, carboxyl group, carboxyethyl, aristocraty, heteroanalogues, heterocyclisation, thiol, allylthiourea, aryl, alloctype, heteroaryl, aminosulfonyl, aminocarbonylmethyl, heterokaryosis, heterocyclyl, heterozygosity, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If you do not particularly limited by the definition, all substituents optionally may be additionally substituted by 1, 2 or 3 substituents selected from alkyl, Carbo is a strong group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2; or

(2) the group alkylene, which is 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 is a group selected from carbonyl, carboxyphenoxy group, carboxyamide and sulfonyl; or

(3) the group alkylene, which is defined above, which has 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-CH2CH2-), 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 the group of alkylene, where aryl and alkylene have the meanings defined the military in this description. "Optionally substituted aralkyl" refers to optionally substituted aryl group covalently linked with optionally substituted by a group of alkylene. Examples of such Uralkalij groups are benzyl, phenylethyl, 3-(4-methoxyphenyl)propyl, and the like.

The term "alkoxygroup" refers to the group R-O-, where R is optionally substituted alkyl or optionally substituted cycloalkyl or R is a group-Y-Z, in which Y is optionally substituted by alkylene and Z is optionally substituted by alkenyl, optionally substituted quinil or optionally substituted cycloalkenyl, where the alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl have the meanings given in the description. The preferred alkoxygroup is optionally substituted alkyl-O - and include as an example, methoxy, ethoxy-, n-propoxy, isopropoxy, h-butoxy-, tert-butoxy-, second -, butoxy, h-pentox, h-hexose-, 1,2-Dimethylbutane, cryptometer and the like.

The term "allylthiourea" refers to the group R-S-, where R is a group as defined for alkoxygroup.

The term "alkenyl" refers to monoracial branched or unbranched unsaturated hydrocarbon group preferably containing from 2 to 20 carbon atoms, more preferably from 2 to 10 atoms of carbon is and even more preferably from 2 to 6 carbon atoms and having 1 to 6, preferably 1 double bond (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 associated with nitrogen, the double bond may not be in the alpha position relative to the nitrogen.

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

The term "substituted alkenyl" refers to alkenylphenol group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2 or 3 substituent selected from the group consisting of alkyl, alkenyl, quinil, alkoxygroup, cycloalkyl, cycloalkenyl, acyl, alluminare, alloctype, amino, aminocarbonyl, alkoxycarbonylmethyl, sidegroup, ceanography, halogen, hydroxyl group, geograpy, thiocarbonyl, carboxyl group, carboxyethyl, aristocraty, heteroanalogues, heterocyclisation, thiol, allylthiourea, aryl, alloctype, heteroaryl, aminosulfonyl, aminocarbonylmethyl, heterokaryosis, heterocyclyl, heterozygosity, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteropar the La. If you do not particularly limited by the definition, all substituents optionally may be additionally substituted by 1, 2 or 3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "quinil" refers to monoracial unsaturated hydrocarbon, preferably containing from 2 to 20 carbon atoms, more 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 provisions of unsaturation of acetylene (triple bond). Preferred alkyline group include ethinyl, (-CCH), propargyl (or prop-1-in-3-yl, -CH2CCH) and the like. In the case when quinil associated with the nitrogen triple bond may not be in the alpha position relative to the nitrogen.

The term "substituted quinil" refers to alkenylphenol group, which is defined with 1, 2, 3, 4 or 5 substituents, and preferably 1, 2 or 3 substituent selected from the group consisting of alkyl, alkenyl, quinil, alkoxygroup, cycloalkyl, cycloalkenyl, acyl, alluminare, alloctype, amino, aminocarbonyl, alkoxycarbonylmethyl, azido the group, ceanography, halogen, hydroxyl group, geograpy, thiocarbonyl, carboxyl group, carboxyethyl, aristocraty, heteroanalogues, heterocyclisation, thiol, allylthiourea, aryl, alloctype, heteroaryl, aminosulfonyl, aminocarbonylmethyl, heterokaryosis, heterocyclyl, heterozygosity, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If you do not particularly limited by the definition, all substituents optionally may be additionally substituted by 1, 2 or 3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "aminocarbonyl" refers to the group-C(O)NRR where each R independently denotes hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both R groups are associated with the formation of the heterocyclic group (for example, morpholinopropan). If you do not particularly limited by the definition, all substituents optionally may be further substituted by 1-3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl the th group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "alluminare" refers to the group-NRC(O)R where each R independently denotes hydrogen, alkyl, aryl, heteroaryl or heterocyclyl. If you do not particularly limited by the definition, all substituents optionally may be further substituted by 1-3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "alloctype" 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 you do not particularly limited by the definition, all substituents optionally may be substituted by alkyl, carboxyl group, carboxylation, aminocarbonyl, a hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, cyano, or-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "aryl" refers to aromatic carbocyclic group of from 6 to 20 carbon atoms, having one cycle (e.g., phenyl) or multiple cycles (e.g., biphenyl), or mn is the number of condensed (fused) cycles (for example, naphthyl or until). Preferred arily include phenyl, naphthyl and the like.

The term "Allen" refers to biradical aryl group as defined above. The term is illustrated by such groups as 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, 1,4'-biphenylene and the like.

If you do not particularly limited definition of the substituent of the aryl or arylene, such aryl or allenbyi group optionally can be substituted by 1-5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxygroup, cycloalkyl, cycloalkenyl, acyl, alluminare, alloctype, amino, aminocarbonyl, alkoxycarbonylmethyl, sidegroup, ceanography, halogen, hydroxyl group, geograpy, thiocarbonyl, carboxyl group, carboxyethyl, aristocraty, heteroanalogues, heterocyclisation, thiol, allylthiourea, aryl, alloctype, heteroaryl, aminosulfonyl, aminocarbonylmethyl, heterokaryosis, heterocyclyl, heterozygosity, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If you do not particularly limited by the definition, all substituents optionally may be further substituted by 1-3 substituents you the security of alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "alloctype" refers to the group aryl-O-, where the aryl group has the meaning given above, and includes optionally substituted aryl group, which is also defined above. The term "aristocrata" refers to the group R-S-, where R has the meaning defined for aryl.

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

The term "substituted amino group" refers to the group-NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyethyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl, provided that both groups R are not hydrogen, or the group-Y-Z, in which Y is optionally substituted by alkylene, and Z is alkenyl, cycloalkenyl or quinil. If you do not particularly limited by the definition, all substituents optionally may be further substituted by 1-3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is Osnach the em 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 have the meanings defined herein, and optionally may be additionally substituted by alkyl, alkenyl, quinil, alkoxygroup, halogen, CF3, amino group, substituted amino group, cyano, or-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "cycloalkyl" refers to carbocyclic groups of 3-20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, as an example, adnakolava patterns, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or patterns from a variety of rings, such as adamantyl, bicyclo[2.2.1]heptane,

1,3 .3m-trimethylbicyclo[2.2.1]hept-2-yl,

(2,3,3-trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic group, which condensed aryl group, for example, indan, and the like.

The term "substituted cycloalkyl" refers to cycloalkyl groups having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2 or 3 substituent selected from the group consisting of alkyl, alkenyl, quinil, alkoxygroup, cycloalkyl, cycloalkenyl, acyl, alluminare, alloctype, amino, Aminata is bonila, alkoxycarbonylmethyl, sidegroup, ceanography, halogen, hydroxyl group, geograpy, thiocarbonyl, carboxyl group, carboxyethyl, aristocraty, heteroanalogues, heterocyclisation, thiol, allylthiourea, aryl, alloctype, heteroaryl, aminosulfonyl, aminocarbonylmethyl, heterokaryosis, heterocyclyl, heterozygosity, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If you do not particularly limited by the definition, all substituents optionally may be additionally substituted by 1, 2 or 3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is 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" means a group-C(O)R, in which R is hydrogen, optionally substituted alkyl, optionally substituted by cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted by heteroaryl.

The term "heteroaryl" refers to an aromatic cyclic GRU is PE (for example, fully unsaturated)containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 carbon atoms and 1, 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulphur, at least one cycle. Such heteroaryl groups can have a single cycle (e.g., pyridyl or furyl) or multiple condensed cycles (for example, indolizinyl, benzothiazolyl or benzothiazyl). Examples of heteroaryl include, but are not limited, [1,2,4]oxadiazole, [1,3,4]oxadiazole, [1,2,4]thiadiazole, [1,3,4]thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazin, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, hemolysin, isoquinoline, quinoline, phthalazine, naftemporiki, cinoxacin, hinzelin, cinnolin, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazol, fenesin, isoxazol, phenoxazin, phenothiazines, imidazolidin, imidazolyl and the like, as well as N-alkoxy-nitrogen containing heteroaryl compounds.

The term "heteroaryl" refers to biradical heteroaryl group as defined above. The term is illustrated by such groups as 2.5-imidazole, 3,5-[1,2,4]oxadiazole, 2,4-oxazole, 1,4-pyrazole and the like. For example, 1,4-pyrazolin represents:

where A denotes the point of binding.

If not particularly limited to the determination of the Deputy heteroaryl or Goethe is Marilena, such heteroaryl or heteroarenes group optionally can be substituted by 1-5 substituents, preferably 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxygroup, cycloalkyl, cycloalkenyl, acyl, alluminare, alloctype, amino, aminocarbonyl, alkoxycarbonylmethyl, sidegroup, ceanography, halogen, hydroxyl group, geograpy, thiocarbonyl, carboxyl group, carboxyethyl, aristocraty, heteroanalogues, heterocyclisation, thiol, allylthiourea, aryl, alloctype, heteroaryl, aminosulfonyl, aminocarbonylmethyl, heterokaryosis, heterocyclyl, heterozygosity, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. Unless specifically limited by the definition, all substituents optionally may be further substituted by 1-3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

The term "heteroalkyl" refers to a heteroaryl group covalently associated with the group is Oh alkylene, where heteroaryl and alkylene have the meaning given in the description. "Optionally substituted heteroaryl" refers to optionally substituted heteroaryl group, covalently linked with optionally substituted by a group of alkylene. Examples of such heteroaryl groups are 3-pyridylmethyl, quinoline-8-retil, 4-methoxythiazole-2-ylpropyl and the like.

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

The term "heterocyclyl" refers to monological (one free link) saturated or partially unsaturated group having a single cycle or multiple condensed cycles containing from 1 to 40 carbon atoms and from 1 to 10 heteroatoms, preferably 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur, phosphorus and/or oxygen in the loop. Heterocyclic groups can have a single cycle or multiple condensed cycles and include tetrahydrofuranyl, morpholino, piperidinyl, piperazine derivatives, dihydropyridines and the like.

Unless specifically limited by the definition of the substituent of the heterocyclic group, such heterocyclic groups optionally can be substituted by 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxygroup, cycloalkyl, cycloalkenyl, acyl, alluminare, aciloc is gruppy, amino group, aminocarbonyl, alkoxycarbonylmethyl, sidegroup, ceanography, halogen, hydroxyl group, geograpy, thiocarbonyl, carboxyl group, carboxyethyl, aristocraty, heteroanalogues, heterocyclisation, thiol, allylthiourea, aryl, alloctype, heteroaryl, aminosulfonyl, aminocarbonylmethyl, heterokaryosis, heterocyclyl, heterozygosity, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. Unless specifically limited by the definition, all substituents optionally may be further substituted by 1-3 substituents selected from alkyl, carboxyl group, carboxyethyl, aminocarbonyl, hydroxyl group, alkoxygroup, halogen, CF3, amino group, substituted amino group, ceanography and-S(O)nR, where R is alkyl, aryl or heteroaryl and n is 0, 1 or 2.

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

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

The term "heteroaryl" refers to the group-S-heteroaryl, where the heteroaryl group has the meaning defined above including optionally substituted heteroaryl group, which is also defined above.

The term "sulfoxide" refers to the group-S()R, in which R denotes alkyl, aryl or heteroaryl. "Substituted sulfoxide" refers to the group-S(O)R, in which R is substituted alkyl, substituted aryl or substituted heteroaryl that are defined in this specification.

The term "sulfon" refers to the group-S(O)2R, in which R denotes alkyl, aryl or heteroaryl. "Substituted sulfon" refers to the group-S(O)2R, in which R is substituted alkyl, substituted aryl or substituted heteroaryl that are defined in this specification.

The term "ketogroup" refers to the group-C(O)-. The term "thiocarbonyl" refers to the group-C(S)-. The term "carboxyl group" refers to the group-C(O)-OH.

"Optional" or "optionally" means that the described event or circumstance can take place or not take place, and that the description includes instances when the specified event or circumstance occurs and instances where it does not.

It is implied that the term "compound of formula I and formula II includes compounds according to the invention that is claimed, and pharmaceutically acceptable salts, pharmaceutically acceptable esters, prodrugs, hydrates and polymorphs of such compounds. In addition, the compounds according to the invention can have one or more asymmetric centers and can be obtained in the form of a racemic mixture or in the form of the CTD is lnyh enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of formula I depends on the number of asymmetric centers (there are 2npossible stereoisomers, where n denotes the number of asymmetric centers). Individual stereoisomers can be obtained by separation of the racemic or prizemistoj mixture of the intermediate product at any suitable stage of the synthesis or separation of the compounds of formula I by conventional means. Individual stereoisomers (including enantiomers and diastereoisomers), as well as racemic and nerezisca mixture of stereoisomers are included in the scope of the present invention, it is understood that they are all represented by the structures shown in this description, unless otherwise stated.

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

"Stereoisomers are isomers that differ only in how the atoms are arranged in space.

"Enantiomers" are a pair of stereoisomers that are nesovmestimymi when applying mirror images of each other. A mixture of 1:1 pair of enantiomers is a "racemic" mixture. The term±used in a suitable case to denote a racemic mixture.

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

The absolute stereochemistry is determined according to the R-S Kanna-Ingold-Prelog. When the compound is a pure enantiomer the stereochemistry of each chiral carbon atom can be characterized as either R or S. the Split connection, the absolute configuration is not known, indicate the (+) or (-)depending on the direction (right or levogyrate), in which they rotate the plane of polarized light with a wavelength of line D of sodium.

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

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

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

(ii) suppression for the of Alemania, that is, delay the development of clinical symptoms; and/or

(iii) the weakening of the disease, i.e. ensuring the regression of clinical symptoms.

In many cases, the compounds according to this invention can form a salt with the acid and/or base due to 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 otherwise undesirable. Pharmaceutically acceptable basic additive salts can be obtained from inorganic and organic bases. Salts derived from inorganic bases include, but are only as 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 cyclooctylamine, trisam is on 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, in which at least two of the substituents on Amina different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclyl and the like. Also included amines in which two or three deputies, together with the amino nitrogen form a heterocyclic or heteroaryl group.

Specific examples of suitable amines include, but are only as 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 acid salt additive can be obtained from inorganic and organically the acids. Salts derived from inorganic acids include salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include the salts of 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 acid, econsultancy acid, para-toluensulfonate acid, salicylic acid and the like.

Used in this sense, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, agents for isotonicity and slow absorption and the like. The use of such media and agents for pharmaceutically active substances is well known in this field. Except when any conventional medium or agent is not compatible with the active ingredient, it is assumed their use in therapeutic compositions. The composition may include additional active ingredients.

Nomenclature

Name and numbering with the of dinani according to the invention is illustrated on a typical compound of the formula I, in which R1is n-propylene, R2is n-propylene, R3is hydrogen, X is phenylene, Y is-O-(CH2and Z represents 5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-yl,

called:

8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

Parameters of reactions synthesis

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

The term "q.s." means adding a quantity sufficient to achieve the specified function, for example, to bring the solution to the desired volume (i.e. 100%).

The synthesis of compounds of formula I

The compounds of formula I, where R1and R2represent the same group, R3means hydrogen and Y includes an oxygen atom, sulfur or nitrogen, can be obtained as shown in reaction scheme I.

p> The REACTION SCHEME 1

Formula I, where R3means hydrogen

where Bz denotes benzyl, Boc means tert-butyloxycarbonyl and L is-O-, -S - or-NH-.

You should note that when R3is hydrogen, formula I and II are one and the same connection as a consequence of tautomerism.

Step 1 - Obtaining the compounds of formula (2)

The compound of formula (1), which is secured in position N-7, commercially available or can be obtained by methods well known in the art (see, for example, Synthetic Communications, 20 (16), 2459-2467 (1990)). The compound of formula (1) is subjected to interaction with at least two equivalents of the compounds of formula R1LG, where LG is the deleted group, preferably chlorine, bromine or iodine, in the presence of a strong base such as sodium hydride. The reaction is carried out in a polar solvent, for example DMF, at temperatures near room temperature, with subsequent interaction at a temperature of about 30-100°C, for example, about 70°C for about 6-24 hours. When the reaction is largely completed, the product formula (2) is recovered by conventional means, for example, removal of solvent under reduced pressure followed by chromatography of the residue on silica gel.

It should be noted that casanatense only gives the compounds of formula (2), in which R1and R2represent the same group. Method of producing compounds of the formula (2), in which R1and R2different, as shown below in reaction scheme III.

Another synthesis necessary for obtaining compounds of formula (2), in which R1and/or R2are aryl or heteroaryl groups, and the synthesis is shown in reaction scheme III.

Stage 2 - Obtaining the compounds of formula (3)

Then the compound of the formula (2) halogenous in position 8, when receiving the connection formulas (3)through interaction with a halogenation agent, such as N-chlorosuccinimide, receiving 8-chlorine substituted compound of formula (3). In General, the compound of the formula (2) is dissolved in an inert solvent, for example tetrahydrofuran, and add N-bromosuccinimide (or N-chlorosuccinimide). The reaction is carried out at a temperature of about 0-30°C, e.g. at about room temperature, for example, for 1-10 hours, for example, about 4 hours. When the reaction is largely completed, the product of formula (3) was isolated in the usual way and recrystallized.

Stage 3 - Obtaining the compounds of formula (4)

Then the compound of formula (3) is converted into a compound of the formula (4) as a result of interaction with an appropriately substituted derivatives Bronevoy acid in the presence of a complex of palladium(0). For example, when the and X is optionally substituted phenyl, the compound of the formula (3) is subjected to interaction with the optional substituted phenylboronic acid. The reaction is carried out in an inert solvent, for example, a mixture of toluene/ethanol, in the presence of an aqueous solution of sodium carbonate and tetrakis(triphenylphosphine)palladium(0) approximately at the temperature of education phlegmy (boiling under reflux)for about 24 hours. When the reaction is largely completed, the product of formula (4) is recovered by conventional means, for example, removal of solvent under reduced pressure followed by chromatography of the residue on silica gel.

Stage 4 - Obtaining the compounds of formula (5)

a) Then the protective benzyl group of compounds of formula (4) replaced Boc, receiving the compound of formula (5). In General, the compound of formula (4) is dissolved in an inert solvent, for example methanol, and add the hydrogenation catalyst. The reaction mixture is stirred in hydrogen atmosphere at a temperature of about 0-30°C, e.g. at about room temperature, approximately 8-24 hours, for example, about 18 hours. When the reaction is largely completed, the catalyst was removed by filtration and the product emit the usual way.

b) Then the product is dissolved in an inert solvent, for example methanol, to which was added an excess of di-tert-BUTYLCARBAMATE and spatial zatrudnienie, for example ethyldiethanolamine. The mixture is refluxed for about 8-24 hours, for example, about 18 hours. When the reaction is largely completed, the catalyst was removed by filtration, and the compound of formula (5) is recovered by conventional means, for example, removal of solvent under reduced pressure followed by chromatography of the residue on silica gel.

Stage 5 - Obtaining the compounds of formula I, where R3is hydrogen

Then the compound of formula (5) is converted into a compound of formula I as a result of interaction with the compound of the formula Z-Y-LG, where Z and Y have the meanings defined above, and LG is the deleted group, preferably halogen, more preferably chlorine at the same time to remove the Boc protective group). The reaction is carried out in the presence of a strong base such as sodium hydride, in an inert polar solvent, preferably DMF, at a temperature of about 0-30°C, preferably at about room temperature for about 8-24 hours, preferably about 16 hours. Protective Boc-group is removed in the sequence of reactions. When the reaction is largely completed, the product of formula I, where R3means hydrogen, there are the usual ways, for example by chromatography on silica gel.

Stage 5 - Obtaining the compounds of formula I where R 3is a group other than hydrogen

The compound of the formula I, in which R3is hydrogen, can be converted into a compound of formula I, in which R3is not hydrogen, as a result of interaction with the compound of the formula R3-LG, where LG denotes the deleted group, preferably iodine or bromine. The reaction is carried out in the presence of a mild base, for example potassium carbonate, in an inert polar solvent, preferably DMF, at a temperature of about 30-100°C, preferably about 70°C for about 8-24 hours, preferably about 16 hours. When the reaction is largely completed, the product of formula I, where R3is a group other than hydrogen, there are the usual ways, for example by chromatography on silica gel.

Alternatively, the benzyl protective group of the formula (4) can be replaced trimethylsilyl-ethoxymethylene protecting group (instead of the Boc-group), the subsequent removal of which can be carried out at milder reaction conditions. In General, the product from step 4a is dissolved in an inert solvent, preferably in anhydrous DMF (100 ml) and subjected to interaction with trimethylsilyl-ethoxyethanol in the presence of a base, preferably potassium carbonate. The reaction is carried out at a temperature of about 50-90°C, preferably about 70°C for example is about 1-6 days preferably about 72 hours. When the reaction is largely completed, the catalyst was removed by filtration and the product produce by conventional means, preferably flash chromatography.

Then the product is subjected to interaction with Z-Y-LG, where Z and Y have the meanings defined above, and LG denotes a group to delete, as shown in stage 5 above. Trimethylsilyl-ethoxymethyl protective group is removed from the resulting intermediate compound by treatment with an acid in proton solvent, preferably hydrochloric acid in ethanol, obtaining the compound of formula I.

Alternatively, the benzyl group of the parent substance of the formula (1) can be replaced by Boc before halogenoalkanes in stage 2. Thus, there is no need to modify the protective benzyl group on the Boc, as described above, in stage 4.

An alternative method of obtaining the compounds of formula I, where R3is hydrogen, Z is an optionally substituted 1,2,4-oxadiazoles and preferably Y is oxygen, shown in reaction scheme II.

A REACTION SCHEME II

Formula I, where R3means hydrogen,

Y represents oxygen and Z means

optionally substituted 1,2,4-oxadiazol

Step 1 - Obtaining the compounds of formula (7)

The compound of formula (6) is obtained by way of podobn the m method, shown above for compound (4). The protective group is removed by treatment with hydrogen in the presence of a catalyst, preferably Pd on coal. Thus obtained gidroksosoedinenii objective interaction with tert-butyldimethylsilyloxy in the presence of imidazole, getting tert-butyldimethylsilyloxy-derived. The specified connection is subjected to interaction with sodium hydride and the resulting anion is subjected to interaction with benzyloxyethanol, getting a connection, which is secured in position N-7 benzoyloxymethyl. Then tert-butyldimethylsilyl protective group is removed by conventional means, for example by treatment with tetrabutylammonium fluoride, and the resulting gidroksosoedinenii subjected to interaction with itacatharina or chloroacetonitrile in the presence of a strong base, for example, tert-butoxide potassium. The reaction is carried out in an inert solvent, preferably tetrahydrofuran, at about room temperature for about 6-24 hours. When the reaction is largely completed, the product of formula (7) is recovered by conventional means, for example, removal of solvent under reduced pressure followed by chromatography of the residue on silica gel.

Stage 2 - Obtaining the compounds of formula (8)

Then the compound of formula (7) is subjected to interaction with g is drochloride hydroxylamine. In General, the compound of formula (7) is dissolved in an inert solvent, for example ethanol, and adding hydroxylamine hydrochloride, together with an equivalent amount of a strong base, such as ethoxide sodium. The reaction is carried out at a temperature of about 0-30°C, e.g. at about room temperature for about 6-24 hours. When the reaction is largely completed, the product of formula (8) is recovered by conventional means, for example, removal of solvent under reduced pressure followed by chromatography of the residue on silica gel.

Stage 3 - Obtaining the compounds of formula I

Then the compound of formula (8) is subjected to cyclization to optionally substituted 1,2,4-oxadiazole formula I in result of interaction with an appropriately substituted acid chloride of the acid of the formula RC(O)Cl, in which R means an optional substitution, which leads to 5-substitution oxadiazolines cycle. In General, the compound of formula (8) is dissolved in an inert solvent, for example dioxane, and add potassium carbonate and the acid chloride of the acid. Mixture is allowed to interact for a period of approximately 10 minutes at a temperature of about 0-30°C, preferably at about room temperature. When the reaction is largely completed, the intermediate connection emit the usual way and dissolve in boiling when vysokotemperaturnoe inert solvent, for example, xylene. The mixture is subjected to interact for about 6-24 hours at a temperature of about 100-160°C, preferably at about 145°C. the Product of formula I produce by conventional means, for example, removal of solvent under reduced pressure followed by chromatography of the residue on silica gel.

Method of producing compounds of the formula I, in which R1and R2differ from each other, as shown in reaction scheme III.

A REACTION SCHEME III

where R1and R2have the meanings given above, Bz means benzyl and Hal means chlorine, bromine or iodine.

In General, the method is carried out as described in Synthetic Communications, 20 (16), 2459-2467 (1990). The reaction scheme is based on the fact that it is well known that xantina interact with alkylating agents in the following order N3 > 7 > N1. In the case of protected N7, as in the compound of formula (1), the reaction with the compound of the formula R2LG, where LG denotes the deleted group, preferably chlorine, bromine or iodine, with a small excess of R2LG in the same manner as above to obtain compounds of formula (2), gives compound of formula (9). Further interaction (9) with the compound of the formula R1LG gives compound of formula (10), in which R1and R2different.

Method of producing compounds of the formula (2), in which R2I who is hydrogen or alkyl and R 1is aryl or heteroaryl, shown in reaction scheme IV.

A REACTION SCHEME IV

The compounds of formula (2), in which R1is aryl or heteroaryl, can be obtained as described inSynthesis, 1995, s-858. In General, the compound of formula (11)obtained by methods well known in the field, is subjected to the interaction with an appropriately substituted isocyanate of formula R1NCO, receiving the compound of formula (12), which is subjected to cyclization in basic conditions, for example by treatment with ethoxide sodium, receiving the compound of the formula (2), in which R1is aryl or heteroaryl and R2is hydrogen. This method can also be used to produce compounds in which R1is alkyl, etc.

The compound of the formula (2), in which R2means hydrogen, can then optionally be subjected to interaction with alkylhalogenide formula R2hal in the same manner as shown in reaction scheme I, receiving the compound of the formula (2), in which R1is aryl or heteroaryl and R2is alkyl.

The compounds of formula (2), in which R1and R2both represent aryl or heteroaryl receive as shown in Chem. Ber., GE; 111; 1978; 982-995.

Method of producing compounds of the formula I, in which R3 is not hydrogen, is shown in reaction scheme V.

The REACTION SCHEME V

Obtaining the compounds of formula (13)

Benzyl protective group of the compounds of formula (2) is removed by hydrogenation as described in reaction scheme I, step 4. Then the resulting compound is subjected to interaction with the compound of the formula R3LG, where LG denotes the deleted group, preferably chlorine, bromine or iodine, in the presence of a base, for example potassium carbonate. The reaction is carried out in a polar solvent, for example DMF, at temperatures near room temperature, followed by reaction at a temperature of about 30-100°C, for example, about 70°C for 6-24 hours. When the reaction is largely completed, the product of formula (13) is recovered by conventional means, for example, removal of solvent under reduced pressure followed by chromatography of the residue on silica gel.

The reaction described in more detail in J. Med. Chem., 1999, 42, 2527-2534.

An alternative method of preparing compounds of formula I is shown in reaction scheme VI. The binding of 8-chlorinated derivative of formula (14) with the compound of the formula (HO)2B-X-Y-Z is a suitable method for producing compounds of formula I that do not contain heteroatoms in the chain.

The REACTION SCHEME VI

P is TORCHING the compounds of FORMULA II

Obtaining the compounds of formula II is carried out in the same way as shown above in reaction scheme I, II and III, since the compounds of formula (18), the receipt of which is shown in reaction scheme VII.

The REACTION SCHEME VII

A similar sequence of reactions claimed in U.S. patent No. 5631260, full details of which are included in this application by reference.

It should be noted that if, instead of formic acid to use RCO2H (or RCOCl), we obtain the connection formula (18), which is substituted in position 8 group R. Thus, if RCO2H is equivalent ZYXCO2H (a compound of the formula (22)), it is possible to implement an alternative synthesis of compounds of formula II, as shown in reaction scheme VIII.

The REACTION SCHEME VIII

Formula II

It should be noted that if R3is hydrogen, obtain the connection formula I or II.

The compound of formula (19) are commercially available or can be obtained by methods well known in the field. It is converted into a compound of formula II or the compound of formula I, when R3is hydrogen), as described in U.S. patent No. 5446046, full details of which are included in this application by reference.

Such a reaction can be made based on nitrosamine-derived formula (23)

The recovery of the compounds of formula (23) using a catalyst based on hydrogen oxide of platinum gives the appropriate diaminododecane (21), in which R3is hydrogen. Alternatively, the compound of formula (23) can be replaced by R3as described in the reaction scheme VII above to obtain the corresponding diaminododecane formula (21), in which R3presents another group other than hydrogen.

Alternatively, the compound of formula (23) can be transformed into a compound of formula I, in which R2is hydrogen and R1is another group other than hydrogen as shown in reaction scheme IX.

The REACTION SCHEME IX

Step 1 - Obtaining the compounds of formula (23)

Commercially available compound 6-aminouracil first similarbut, for example, when interacting with hexamethyldisilazane as a solvent in the presence of a catalyst, such as ammonium sulfate. The reaction is carried out at a temperature approximately equal to the temperature of education phlegmy for about 1-10 hours. When the reaction is largely completed, thus obtained Siciliano allocate connection in the usual way and then subjected to interaction with the compound of the formula R1Hal, where R1the meet value, defined above, preferably in the absence of solvent. The reaction is carried out at a temperature of about education phlegmy within a time period of approximately 12 hours to 7 days. When the reaction is largely completed, the product of formula (23) was isolated in the usual way.

Stage 2 - Obtaining the compounds of formula (24)

Then the compound of formula (23) is dissolved in aqueous acid solution, for example, in an aqueous solution of acetic acid, and subjected to reaction with sodium nitrite. The reaction is carried out at a temperature of about 20-50°C, preferably about 30°C, for about 30 minutes. When the reaction is largely completed, the product of formula (24) is recovered by conventional means, for example, by filtering.

Stage 3 - Obtaining the compounds of formula (25)

Then the compound of formula (24) to restore diaminopropanol. In General, the compound of formula (24) is dissolved in aqueous ammonia and then add the reducing agent, for example, hydrosulfite sodium. The reaction is carried out at a temperature of about 70°C. When the reaction is largely completed, the product of formula (25) was isolated by conventional means, for example, by filtration of the cooled reaction mixture.

Stage 4 - Obtaining the compounds of formula I

Then the compound of formula (25) is subjected to interaction with the carboxylic acid of the formula Z-Y-X-CO2 H in the presence of a carbodiimide, for example the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction is carried out at a temperature of about 20-30°C for about 12-48 hours. The product produce by conventional means, for example, by filtration, and subjected to interaction with excess hexamethyldisilazane in the presence of ammonium sulfate, for about 2 days while boiling under reflux. When the reaction is largely completed, the product of formula I produce by conventional means, for example, by filtration of the cooled reaction mixture.

A specific example of obtaining, shown in reaction scheme IX, where X is optionally substituted 1,4-pyrazolines shown in the reaction scheme X.

The REACTION SCHEME X

where SEM means 2,2-(trimethylsilyl)ethoxymethyl and halogen represents chlorine, bromine or iodine.

This reaction is described in more detail in the following examples.

Example of the synthesis of compounds of formula (22) shown in the reaction scheme XI:

The REACTION SCHEME XI

The reaction is performed, as shown in example 9. Then pyrazol product of formula (22) is subjected to interaction with the compound of the formula (21) or (25), as described above in example 9, receiving the compound of formula II and formula I, if R3is hydrogen):

Obtaining the compounds of formula I in which R1is hydrogen and R2is another group other than hydrogen, the compounds of formula (23) shown in the reaction scheme XII.

The REACTION SCHEME XII

Step 1 - Obtaining the compounds of formula (31)

The compound of formula (30) are either commercially available or obtained by methods well known in the field. It is subjected to interaction with ethylcyanoacrylate in proton solvent, for example ethanol, in the presence of a strong base, for example, ethoxide sodium. The reaction is carried out at a temperature of about education phlegmy during the period of time from about 4 to 24 hours. When the reaction is largely completed, the thus obtained compound of the formula (31) was isolated in the usual way.

Stage 2 - Obtaining the compounds of formula (23)

Then the compound of formula (31) is mixed with sodium nitrite in an aqueous solvent, for example dimethylformamide and water, and subjected to the interaction with a strong acid, for example hydrochloric acid, getting nitrosoguanidine formula (23). The reaction is carried out at a temperature of from about 50°C to 100°C for about 1 hour. When the reaction is largely completed, the product of formula (23) was isolated in the usual way.

Stage 3 - Getting with the organisations of the formula (21)

Then the compound of formula (23) to restore diaminopropanol. In General, the compound of formula (23) is dissolved in aqueous ammonia and then add the reducing agent, for example, hydrosulfite sodium. The reaction is carried out at a temperature of about 70°C. When the reaction is largely completed, the product of formula (21) is recovered by conventional means, for example, by filtration of the cooled reaction mixture.

Stage 4 - Obtaining the compounds of formula I

Then the compound of formula (21) is subjected to interaction with the carboxylic acid of the formula Z-Y-X-CO2H in the same way as described for reaction scheme IX, step 4, when receiving the connection formula I.

The compound of formula (31) can be used in an alternative synthesis, to obtain the compound of formula I, in which R1is hydrogen and R2is another group other than hydrogen, or both R1and R2are other groups other than hydrogen and are the same or different, as shown in the reaction scheme XIII.

The REACTION SCHEME XIII

Stage 1 and 2

The compound of formula (31), obtained as above, is subjected to the interaction with dimethylacetal N,N-dimethylformamide in a polar solvent, such as N,N-dimethylformamide. The reaction is carried out at about 40°C for PR is approximately 1 hour. When the reaction is largely completed, the thus obtained compound of the formula (32) is subjected to interaction with the compound of the formula R1Hal, where Hal means chlorine, bromine or iodine, in the presence of a base, e.g. potassium carbonate. The reaction is carried out at about 80°C for about 4-24 hours. When the reaction is largely completed, the product of formula (33) was isolated by conventional means, for example, by evaporation of the solvents under reduced pressure, and the residue used in the next reaction without further purification.

Stage 2

The compound of formula (33) is subjected to contact with an aqueous ammonia in a polar solvent, for example, suspended in methanol. The reaction is carried out at about room temperature for about 1-3 days. When the reaction is largely completed, the product of formula (33) was isolated by conventional means, for example, by evaporation of the solvents under reduced pressure, and rubbing the residue in water.

Then the compound of formula (34) is converted into a compound of formula I in the same way as shown above for obtaining compounds of formula (23) in the reaction scheme IX.

The PREFERRED METHODS AND FINAL STAGE

Compounds according to this invention can be obtained according to the following final stages:

1. The contacting of the compound of the formula:

in which R1, R2and X have the meanings defined in the description of the invention, L is-O-, -S - or-NH - Boc means tert-butyloxycarbonyl;

with the compound of the formula Z-Y-LG, in which Z and Y have the meanings given in the description of the invention, and LG denotes a group to delete.

2. The contacting of the compound of the formula:

Formula I, where R3is hydrogen

in which R1, R2and X, Y and Z have the meanings defined in the description of the invention,

with the compound of the formula R3-LG, where R3has the meaning given in the description of the invention, and LG denotes a group to delete.

3. The contacting of the compound of the formula:

in which R1, R2and X have the meanings defined in the description of the invention,

with the acid chloride of the acid of the formula RC(O)Cl, in which R represents optional substitution, which leads to 5-substitution oxadiazolines cycle, receiving the compound of the formula I in which Y is oxygen and Z is optionally substituted 1,2,4-oxadiazoles.

4. The contacting of the compound of the formula:

in which R1, R2and R3have the meanings defined the ri summary of the invention,

with the compound of the formula (HO)2B-X-Y-Z where X, Y and Z have the meanings given in the description of the invention.

5. The contacting of the compound of the formula:

in which R1, R2and R3have the meanings defined in the description of the invention,

with the compound of the formula ZYXCO2H (a compound of the formula (22)), in which X, Y and Z have the meanings given in the description of the invention.

Applicability, testing and introduction

General applicability

The compounds of formula I or II effective in the treatment of conditions that occur in response to the introduction of receptor antagonists of the adenosine A2B. Such conditions include, but are not limited to the specified at least one of the following conditions: diarrhea, atherosclerosis, restenosis, diabetic retinopathy, cancer, senile dementia, Alzheimer's disease, Parkinson's disease, traumatic brain damage and hypersensitivity reactions type I, including asthma, atopic eczema and hay fever.

Testing

Testing activity were performed as described in the patents and applications for patents, some of which are referenced above, and as in the following examples and methods known to experts in this field.

The pharmaceutical is a mini-composition

The compounds of formula I is usually administered in the form of pharmaceutical compositions. Therefore, the present invention offers a pharmaceutical composition, which as active constituent contain one or more compounds of the formula I or their pharmaceutically acceptable salt or ester and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, amplifiers permeability, solubilization and adjuvants. The compounds of formula I can be entered separately or in combination with other therapeutic agents. Such compositions are prepared by a method well known in the field of pharmacy (see, for example, Remington''s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3rd Ed. (G. S. Banker and C. T. Rhodes, Eds.).

Introduction

The compounds of formula I can be entered either as single or multiple doses by any acceptable route of administration funds that have a similar application, for example, as described in the patents and applications for patents, incorporated by reference, including rectal, buccal, intranasal and transdermal route, using intra-arterial injection, intravenously, intraperitoneally, parenterally, nutramigen is, subcutaneously, orally, topically, in the form of funds for inhalation or in the form of 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 parenteral administration, in particular by injection. Shape, in which new compositions according to this invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution and forms with similar pharmaceutical excipients. Aqueous solutions at physiological salt solution is also usually used for injection, but they are less preferred in the context of the present invention. You can also use ethanol, glycerin, propylene glycol, liquid polyethylene glycol and the like (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils. The proper fluidity can, for example, to support using a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions or through the use of surfactants. Protection from the action of microorganisms can be accomplished using a variety of Antibes is sterelny and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by introducing the compound of the formula I in the required amount in an appropriate solvent, if necessary, with various other ingredients enumerated above, followed by sterilization by filtration. Typically, the dispersion is prepared by introduction of various sterilized active ingredients into a sterile filler, which contains the basic 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 preparation methods are vacuum drying and freeze-drying, which give a powder of the active ingredient plus any additional desired ingredient from its previously sterile-filtered solution.

Oral administration is another route of administration of compounds of formula I. Introduction can be by using capsules or tablets with enteric-soluble coating or the like. In the preparation of pharmaceutical compositions that contain at least one compound of formula I, the active ingredient is usually diluted by excipients and/or enter into such medium that can b shall be in the form of a capsule, sachet, paper or other container. In the case when excipient serves as a diluent, it may be solid, semi-solid or liquid substance (as listed above), which acts as a filler, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, pellets, sachets, those capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% wt. active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, Arabic gum, calcium phosphate, alginates, gum tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. Drugs can additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; humidifiers; emulsifying and suspendresume agents; preservatives, such as methyl - and propylhydroxybenzoate; sweeteners and corrigentov.

Compositions according to the invention can be prepared so as to provide quick, long and slow in the release of the active ingredient after administration to the patient, using methods known in this field. Delivery system for controlled release of drugs for oral administration include solutions of osmotic pumps and dissolve system containing polymer coated tank or drugs drugs in polymer matrix. Examples of controlled release systems described in U.S. patent No. 3845770, 4326525, 4902514 and 5616345. In other preparations for use in the methods according to this invention using the device for transdermal delivery ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds according to this invention in controlled amounts. The creation and use of transdermal patches for the delivery of pharmaceutical agents is well known in this field. See, for example, U.S. patent No. 5023252, 4992445 and 5001139. Such patches can be created for continuous, pulsed delivery or delivery of pharmaceutical products "on demand".

The composition preferably is prepared in measured doses (standard) dosage forms. The term "dosage form" refers to physically discrete units suitable as single doses to humans and other mammals, each who dinica contains a predetermined amount of the active substance, designed to obtain the desired therapeutic effect, together with a suitable pharmaceutical excipient (for example, tablet, capsule, ampoule). The compounds of formula I effective in a wide range of doses and are typically administered in pharmaceutically effective amounts. Preferably for oral administration, each unit dosage 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. However, it will be clear that actually enter the amount of the compounds of formula I, will be determined by the attending physician in the light of the relevant circumstances, including the condition that should be treated, the chosen route of administration, the specific input connection and its relative activity, the age, weight and response of the individual patient, the severity of the patient's symptoms and the fact similar.

For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid pre-prepared composition comprising a homogeneous mixture of compounds according to this invention. When you indicate that the data is pre-prepared compositions are homogeneous, this means that the asset is hydrated ingredient uniformly distributed in the composition, so that the composition can be easily divided into equally effective dosage forms such as tablets, pills and capsules.

Tablets or pills according to this invention can be coated or prepared in some other way, to get the dosage form providing the advantage of prolonged action or protect against acidic conditions in the stomach. For example, the tablet or pill may contain an internal component of the dose and the external component of the dose, while the latter has the form of a shell around the first component. Two components can be separated enteric layer which serves to prevent the disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be released slowly. For such enteric layers or coatings you can use a variety of materials, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials 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, to the that described above. Preferably the composition is administered oral or nasal respiratory route for local or systemic action. The compositions are preferably in pharmaceutically acceptable solvents can be sprayed using inert gases. Sprayable solutions can be inhaled directly from the device for spraying or spraying unit can be connected to the cap, breathing mask or breathing apparatus intermittent positive pressure. Compositions in the form of a solution, suspension or powder can be entered preferably oral or nasal device that delivers the drug as appropriate.

The following examples are included to demonstrate preferred variants of the invention. Specialists in this field will understand that the techniques described in the examples that follow represent techniques discovered by the inventor, work well in practice in the case of this invention, and thus can be considered that they are the preferred methods for the practical application of the invention. However, in light of this description specialists in this field should understand that you can make many changes in the specific embodiments described and still obtain similar or gathering is the first result without departing from the essence and scope of the invention.

EXAMPLE 1

Obtaining the compounds of formula (2)

A. Obtaining the compounds of formula (2), where R1and R2both are n-propylene

To a solution of 7-benzyl-1,3,7-trihydroxypurine-2,6-dione (6.4 g; of 26.4 mmol), compounds of formula (1) in N,N-dimethylformamide (200 ml) at room temperature was added sodium hydride (2.6 g; 66 mmol). The mixture was stirred for 20 minutes, then added jumprope (6,5 ml; 66 mmol) and stirred at room temperature for 3 hours. Then the mixture was heated to 70°C and was stirred overnight. The solvent was removed under reduced pressure, dissolved in dichloromethane and passed through a layer of silica gel, washing with a mixture of 1:1 hexane/ethyl acetate. The solvent was removed under reduced pressure, obtaining the crude 7-benzyl-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (8.5 g; yield 98%)which was used in the next reaction without further purification.

B. Obtaining the compounds of formula (2), varying R1and R2

Similarly, following the method of 1(A)above, but substituting jumprope other halides, the following compounds of formula (3):

7-benzyl-1,3-dimethyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-diethyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-di(methoxyethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-di-n-util-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-Diisobutyl-1,3,7-trihydroxypurine-2,6-dione;

1,3,7-dibenzyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-di(phenylethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-dicyclopentyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-di(furan-3-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-di(4-methoxybenzyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-1,3-di(4-trifloromethyl)-1,3,7-trihydroxypurine-2,6-dione; and

7-benzyl-1,3-di(3-terbisil)-1,3,7-trihydroxypurine-2,6-dione.

EXAMPLE 2

Obtaining the compounds of formula (3)

A. Obtaining the compounds of formula (3), where R1and R2both are n-propylene

7-Benzyl-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione, a compound of the formula (2), (2.0 g; 6.1 mmol) and N-chlorosuccinimide (1.0 g; 7.4 mmol) were combined in 100 ml of tetrahydrofuran and stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with water, then with saturated salt solution and dried over magnesium sulfate. The solvent was removed in vacuum, obtaining the compound of formula (3), where R1and R2both are n-propylene, 7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione which is recrystallized from a mixture of ethyl acetate/hexane (1:50).

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

Similarly, following the way of 2A above, but replacing 7-benzyl-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (2)are the following compounds of formula (3):

7-benzyl-8-chloro-1,3-dimethyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-diethyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-di(methoxyethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-di-n-butyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-Diisobutyl-1,3,7-trihydroxypurine-2,6-dione;

8-chloro-1,3,7-dibenzyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-di(phenylethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-dicyclopentyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-di(furan-3-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-di(4-methoxybenzyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-chloro-1,3-di(4-trifloromethyl)-1,3,7-trihydroxypurine-2,6-dione; and

7-benzyl-8-chloro-1,3-di(3-terbisil)-1,3,7-trihydroxypurine-2,6-dione.

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

Similarly, following the way of 2A above, but replacing 7-benzyl-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (2)receive any compound of formula (3).

<> EXAMPLE 3

Obtaining the compounds of formula (4)

A. Obtaining the compounds of formula (4), where R1and R2both are n-propylene, X is phenyl and L is-O-

7-Benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione, a compound of the formula (3), where R1and R2both are n-propylene (5.0 g; 14 mmol), and 4-hydroxyphenylarsonic acid (2.0 g; 14 mmol) was dissolved in 100 ml of a mixture of toluene/ethanol (4:1) and stirred while boiling under reflux for 16 hours. The solvent was removed under reduced pressure and the residue was chromatographically on a column of silica gel, elwira a mixture of ethyl acetate:hexane (1:4)to give compound of formula (4), in which R1and R2both are n-propylene, X is phenyl and L is-O-, (7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione) as a pale yellow solid.

B. Obtaining the compounds of formula (4), varying R1R2X and L

Similarly, following the method 3A, described above, replacing 7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (3), gain the following compounds of formula (4):

7-benzyl-8-(4-hydroxyphenyl)-1,3-dimethyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(4-hydroxyphenyl)-1,3-diethyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(4-hydro is Setenil)-1,3-di(methoxyethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(3-methoxy-4-hydroxyphenyl)-1,3-di-n-butyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(3-gidroksipinan-2-yl)-1,3-Diisobutyl-1,3,7-trihydroxypurine-2,6-dione;

8-(2-fluoro-3-hydroxyphenyl)-1,3,7-dibenzyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(2-trifluoromethyl-4-hydroxyphenyl)-1,3-di(phenylethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(5-hydroxybenzothiazole-2-yl)-1,3-dicyclopentyl-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(4-hydroxyphenyl)-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(4-hydroxyphenyl)-1,3-di(furan-3-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(4-hydroxyphenyl)-1,3-di(4-methoxybenzyl)-1,3,7-trihydroxypurine-2,6-dione;

7-benzyl-8-(4-hydroxyphenyl)-1,3-di(4-trifloromethyl)-1,3,7-trihydroxypurine-2,6-dione; and

7-benzyl-8-(4-hydroxyphenyl)-1,3-di(3-terbisil)-1,3,7-trihydroxypurine-2,6-dione.

C. Obtaining the compounds of formula (4), varying R1R2X and L

Similarly, following the way of 3A above, but replacing 7-benzyl-8-chloro-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (3)receive any compound of formula (4).

EXAMPLE 4

Obtaining the compounds of formula (5)

A. Obtaining the compounds of formula (5), where R1and R2both are n-propylene, X is phenyl and L is-O-

The compound of the formula (4), where 1and R2both are n-propylene, X is phenyl and L is-O- (7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione) (613 mg)was dissolved in methanol (50 ml), was added a catalytic amount of palladium hydroxide and the mixture was stirred in hydrogen atmosphere at room temperature overnight. The mixture was filtered, washing the catalyst with methanol, and the solvent evaporated from the filtrate under reduced pressure, obtaining 8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine.

The obtained product was dissolved in methanol, was added di-tert-BUTYLCARBAMATE (0.7 g; 3.2 mmol) and N,N-di-isopropylaniline (1 ml) and the mixture is boiled under reflux during the night. The solvent was removed under reduced pressure and the residue was chromatographically on a column of silica gel, receiving the compound of formula (5), 7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

B. Obtaining the compounds of formula (5), varying R1R2X and L

Similarly, following the method 4A described above, replacing 7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (4)are the following compounds of formula (5):

7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dimethyl-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-diethyl-1,3,7-three is allopurin-2,6-dione;

7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(methoxyethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(3-methoxy-4-hydroxyphenyl)-1,3-di-n-butyl-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(3-gidroksipinan-2-yl)-1,3-Diisobutyl-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(2-fluoro-3-hydroxyphenyl)-1,3-dibenzyl-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(2-trifluoromethyl-4-hydroxyphenyl)-1,3-di(phenylethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(5-hydroxybenzothiazole-2-yl)-1,3-dicyclopentyl-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(furan-3-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(4-methoxybenzyl)-1,3,7-trihydroxypurine-2,6-dione;

7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(4-trifloromethyl)-1,3,7-trihydroxypurine-2,6-dione; and

7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-di(3-terbisil)-1,3,7-trihydroxypurine-2,6-dione.

C. Obtaining the compounds of formula (5), varying R1R3and X

Similarly, following the way of 4A above, but replacing 7-benzyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (3)receive any compound of formula (5).

EXAMPLE 5

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1and R2are n-propylene, X is phenyl, Y represents-O-CH2and Z means 5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-yl

A mixture of 7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione, a compound of the formula (5) (50 mg; 0,117 mmol), 3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazole (26 mg; 0,117 mmol) and sodium hydride (10 mg; 0,234 mmol) in N,N-dimethylformamide was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was purified preparative thin-layer chromatography, receiving 8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

B. Obtaining the compounds of formula I, where R1and R2are n-propylene, varying X, Y and Z

Similarly, following the way of 5A above, but optionally replacing 7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (5), and optionally replacing 3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazol other compounds of the formula Cl-Y-Z, were obtained the following compounds of formula I:

8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7 - trihydro the Rin-2,6-dione;

8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-forfinal)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-(trifluoromethyl)phenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione; and

8-{4-[5-(4-triptoreline)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

C. Obtaining the compounds of formula I, varying R1R2X, Y and Z

Similarly, following the way of 5A above, but optionally replacing 7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (5), and optionally replacing 3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazol other compounds of formula YZ, get the following compounds of formula I:

8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dimethyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-diethyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-di(methoxyethyl)-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-di-n-butyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-Diisobutyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(2-fluoro-3-Ki is roxiprin)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dibenzyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(2-trifluoromethyl-4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-di(phenylethyl)-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-trifluoromethyl-3-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dicyclopentyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-di(pyrid-4-ylmethyl)-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-hydroxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-di(furan-3-retil)-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)imidazol-2-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)oxazol-2-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)thiazol-2-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)-1,3,5-triazine-2-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)pyrimidine-2-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylpropionic]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-forfinal)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-triptoreline)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(3,4-acid)-[1,2,4]oxadiazol-3-is metoxi]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione; and

8-{5-[5-(4-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]pyridine-2-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

D. Obtaining the compounds of formula I, varying R1R2X, Y and Z

Similarly, following the way of 5A above, but optionally replacing 7-tert-butoxycarbonyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (5), and optionally replacing 3-chloromethyl-5-(4-methoxyphenyl)-[1,2,4]oxadiazol other compounds of formula YZ, you can get any compound of formula I.

EXAMPLE 6

Obtaining the compounds of formula (7)

A. Obtaining the compounds of formula (7), where R1and R2is n-propylene and X is 1,4-phenylene

a) a Solution of 7-benzyl-8-(4-benzyloxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (4,39 g, 8.17 mmol) (obtained in a manner analogous to obtain the compounds of formula (5)) in a mixture of methylene chloride-methanol (1:1)(100 ml) was stirred in hydrogen atmosphere with a catalytic amount of 10% Pd(OH)2/C at room temperature over night. The catalyst was filtered off, washed with a mixture of dichloromethane/methanol and the filtrate was evaporated under reduced pressure, obtaining a solid, which was washed with methylene chloride, obtaining the pure product 8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,-dione.

b) a Mixture of 8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (2.2 g; 6.7 mmol), tert-butyldimethylsilyloxy (2.0 g; a 13.4 mmol) and imidazole (0,91 g; a 13.4 mmol) in tetrahydrofuran (50 ml) was stirred overnight at room temperature, then boiled under reflux for 10 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane and passed through a layer of silica gel, which was then washed with ethyl acetate. The filtrate was concentrated under reduced pressure, obtaining 8-[(4-tert-butyldimethylsilyloxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

c) To a solution of 8-[(4-tert-butyldimethylsilyloxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (13,7 g; 31 mmol) in tetrahydrofuran (200 ml) was added sodium hydride (1.6 g; 40 mmol) and the mixture was stirred for 30 minutes at room temperature. Then add benzyloxyethanol (4.9 g; 31 mmol) and the mixture was stirred for 1 hour at room temperature. Then the solvent was removed under reduced pressure and the residue was dissolved in methylene chloride. The resulting solution was washed with saturated salt solution and the solvent was removed under reduced pressure. The residue was chromatographically on silica gel, elwira with ethyl acetate, receiving 7-benzoyloxymethyl-8-[(4-tert-butyldimethylsilyloxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione in the form of W is Drago substances.

d) To a solution of 7-benzoyloxymethyl-8-[(4-tert-butyldimethylsilyloxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (10.5 g; to 18.7 mmol) in tetrahydrofuran (200 ml) was added fluoride Tetra(tert-butyl)ammonium (3 g) and the mixture was stirred for 2 hours at room temperature. The product was passed through a layer of silica gel, which was rinsed with ethyl acetate. The filtrate was evaporated under reduced pressure and the residue was washed with dichloromethane, receiving 7-benzoyloxymethyl-8- (4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione as a white solid.

e) To a solution of 7-benzoyloxymethyl-8-(4-hydroxyphenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (1 g, 2.2 mmol) in tetrahydrofuran (20 ml) was added tert-piperonyl potassium (0.28 g; 2.4 mmol) and the mixture was stirred for 30 minutes at room temperature. Then add iodocyanide (0,38 g; of 2.23 mmol) and the mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and passed through a layer of silica gel, receiving 7-benzoyloxymethyl-8-(4-cinematographer)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione, a compound of the formula (7).

B. Obtaining the compounds of formula (7), varying R1and R2

Similarly, following the way of 6A above, but replacing 7-benzyl-8-(4-benzyloxyphenyl)-1,3-dipropyl-1,3,7-tregetour the -2,6-dione other similar compounds, get other compounds of formula (7).

EXAMPLE 7

Obtaining the compounds of formula (8)

A. Obtaining the compounds of formula (8), where R1and R2is n-propylene and X is 1,4-phenylene

A solution of 7-benzoyloxymethyl-8-(4-cinematographer)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (1,15 g; 2.36 mmol) in ethanol (50 ml) was stirred with ethoxide sodium (0.25 g; 3.54 mmol) and hydroxylamine hydrochloride (0.15 g; 3.54 mmol) at room temperature over night. The solvent was removed under reduced pressure, the residue was dissolved in a mixture of dichloromethane/methanol (50:1) and the solution was passed through a layer of silica gel. The filtrate was evaporated under reduced pressure, obtaining 8-[4-(2-amino-2-(hydroxyimino)ethoxy)phenyl]-7-[(phenylmethoxy)methyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

B. Obtaining the compounds of formula (8), varying R1and R2

Similarly, following the method 7A described above, but replacing 7-benzoyloxymethyl-8-(4-cinematographer)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione other similar compounds, is given to the compounds of formula (8).

EXAMPLE 8

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1and R2are n-propylene, R3means hydrogen, X is 1,4-phenylene, Y OSN the shake-O(CH 2)and Z means 5-(2-chlorophenyl)-[1,2,4]oxadiazol-3-yl

To a solution of 7-benzoyloxymethyl-8-[4-(amino(hydroxyimino)methoxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (50 mg) in dioxane (3 ml) was added potassium carbonate (0.5 g), then 2-chlorobenzylchloride. The mixture was stirred at room temperature for 10 minutes, then the solid substance was filtered. The filtrate was evaporated under reduced pressure and the residue was dissolved in xylene. The solution was heated to 145°C overnight, then the solvent was removed under reduced pressure and the residue was chromatographically on silica gel, elwira with ethyl acetate, receiving 8-{4-[5-(2-chlorophenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3-dihydropyran-2,6-dione.

B. Obtaining the compounds of formula I, where R1and R2are n-propylene, varying X, Y and Z

Similarly, following the way of 8A above, but optionally replacing 7-benzoyloxymethyl-8-[4-(amino(hydroxyimino)methoxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione by other compounds of formula (8), and optionally substituting other compounds of formula RC(O)Cl, was obtained the following compounds of formula I:

8-(4-{[5-(3-were)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-(4-{[5-(2-forfinal)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-TRIG is Drouin-2,6-dione;

8-(4-{[5-(2-were)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-(4-{[5-(3-methoxyphenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

methyl-4-(3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydroxypurine-8-yl)phenoxy]methyl}-1,2,4-oxadiazol-5-yl)benzoate;

1,3-dipropyl-8-[4-({5-[2-(triptoreline)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)phenyl]-1,3,7-trihydroxypurine-2,6-dione;

8-(4-{[5-(2-bromophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione; and

8-(4-{[5-(2,4-acid)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

EXAMPLE 9

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1and R2are n-propylene, X is 1,4-pyrazole, R3means hydrogen, Y represents propylene and Z denotes phenyl

a)Obtaining the compounds of formula (22), in which Z signifies 1,4-pyrazole, Y means propylene and X is phenyl

a) To a solution of ethyl-4-pyrazolecarboxylate (3,57 mmol) in acetone (30 ml) was added potassium carbonate (35,7 mmol) and 1-bromo-3-phenylpropane (3,57 mmol). The suspension is boiled under reflux overnight, then the solvent was removed under reduced pressure. The residue was distributed between ethyl acetate and water, the organic layer is dried over magnesium sulfate, was filtered and the filtrate was evaporated under reduced pressure, obtaining oil, which was purified preparative TLC, receiving ethyl-1-(3-phenylpropyl)pyrazole-4-carboxylate.

b) Then the ester was dissolved in methanol (30 ml) was added potassium hydroxide (1.5 g). The mixture was boiled under reflux for 5 hours in nitrogen atmosphere, and then the solvent was removed under reduced pressure. The residue was distributed between methylene chloride and water. The aqueous layer was separated and acidified to pH 1-2 using 6 N. hydrochloric acid, then was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure, obtaining 1-(3-phenylpropyl)pyrazole-4-carboxylic acid.

c) To a solution of 1-(3-phenylpropyl)pyrazole-4-carboxylic acid (300 mg; of 1.30 mmol) in N,N-dimethylformamide (7 ml) were added hydrochloride 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (300 mg). The suspension was stirred at room temperature until, until you dissolve all the solids were then added 5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione (450 mg) and the reaction mixture was stirred at room temperature overnight. Then added 2 n sodium hydroxide (10 ml) and the suspension was heated at 120°C for 2 hours. The reaction mixture was cooled in ice water and acidified to pH 2-3. The mixture distribution is elali between water and ethyl acetate and the ethyl acetate layer and the solid is washed with water and the solvent was removed under reduced pressure. The residue is triturated in ether, obtaining the pure product 8-[1-(3-phenylpropyl)pyrazole-4-yl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

B. Obtaining the compounds of formula I, where R1and R2are n-propylene, varying X, Y and Z

Similarly, following the way of 9A above, but replacing 1-bromo-3-phenylpropane-benzylbromide, received the following connection formula I:

8-(1-benzylphenol-4-yl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

In this way received 8-{1-[(3,5-dimethylisoxazol-4-yl)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione and 8-[1-(3-cyclohexylprop)pyrazole-4-yl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

EXAMPLE 10

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1and R2are n-propylene, X is 1,4-pyrazole, R3mean 2-hydroxyethyl, Y represents methylene, and Z denotes phenyl

To a solution of 8-(1-benzylphenol-4-yl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (0.51 mmol) in N,N-dimethylformamide (2 ml) was added potassium carbonate (5.1 mmol) and 2-bromoethanol (5.1 mmol). The suspension was heated at 70°C overnight, the solvent was removed under reduced pressure and the residue was purified preparative TLC, getting pure 7-(2-hydroxyethyl)-8-(1-benzylphenol-4-yl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

<> B. Obtaining the compounds of formula I, where R1and R2are n-propylene, varying X, Y and Z

Similarly, following the way of 10A above, but replacing 2-bromoethanol other compounds of formula R3LG received the following compounds of formula I:

7-allyl-8-(1-benzylphenol-4-yl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

7-(methylethyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

7-(2-methoxyethyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

7-methyl-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione; and

7-(prop-2-enyl)-8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

EXAMPLE 11

Obtaining the compounds of formula (22)

A. Obtaining the compounds of formula HO-C(O)-XYZ in which X is phenyl, Y represents-O-CH2and Z means 5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-yl

a) a Solution of methyl-4-hydroxybenzoate (3.04 from g; 20 mmol) and 3-chloromethyl-5-(2-methoxyphenyl)-[1,2,4]oxadiazole (4,48 g; 20 mmol) in acetone (200 ml) was boiled under reflux overnight. The mixture was filtered, the solvent was removed from the filtrate and the residue was dissolved in ethyl acetate. To the obtained solution to allali methanol, to precipitate the product, methyl 4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoate.

b) a Solution of methyl-4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoate (5.0 g) and potassium hydroxide (10 g) in methanol (200 ml) was boiled under reflux for 4.5 hours. The solvent was removed under reduced pressure and the residue was distributed between methylene chloride and water. The aqueous layer was acidified using 6 N. hydrochloric acid to pH 3 and the precipitate was extracted in ethyl acetate. The solvent was removed under reduced pressure, obtaining 4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid.

B. Obtaining the compounds of formula HO-C(O)-XYZ, varying X, Y and Z

Similarly, following the method 11A described above, but replacing 3-chloromethyl-5-(2-methoxyphenyl)-[1,2,4]oxadiazol other 3-chloromethyl-5-substituted [1,2,4]oxadiazole received the following compounds of formula HO-C(O)-XYZ I:

4-{2-[5-(3-forfinal)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid;

4-{2-[(5-cyclopentyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid; and

4-{2-[(5-cyclohexyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid.

EXAMPLE 12

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1and R2are n-propylene, R3means hydrogen, X is 1,4-phenylene, Y means O(CH2)and Z oz is achet 5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-yl

A mixture of 4-{2-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid (3.0 g), 5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione (3.2 g), and hydrochloride of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (3.0 g) in N,N-dimethylformamide (50 ml) was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dried in vacuum for 1 hour. To the obtained product was added to 150 ml of 2 n sodium hydroxide and the mixture was heated at 120°C for 2 hours. The mixture was cooled to 0°C and acidified using 6 N. hydrochloric acid to pH 2-3. The mixture was distributed between water and ethyl acetate and the ethyl acetate layer was separated, together with a certain quantity of solid product. The resulting mixture was washed with water, the solvent was removed from the organic layer to a volume of about 20 ml. of the thus Obtained solid substance was filtered, washed with ethyl acetate and once with a mixture of ethyl acetate/methanol (1:1). The solid was dried in vacuum, obtaining 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione, a compound of formula I.

B. Obtaining the compounds of formula I, where R1and R2are n-propylene, varying X, Y and Z

Similarly, following the way of 12A above, but optionally replacing 4-{-[5-(2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methoxy}benzoic acid, other compounds of formula (22), and optionally replacing 5,6-diamino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula received the following compounds of formula I:

8-{4-[(3,5-dimethylisoxazol-4-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[(2-phenoxyethoxy)phenyl[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-forfinal)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(3-cyclohexyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(3-cyclopentyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[3-(3-chlorophenyl)-[1,2,4]oxadiazol-5-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[3-(4-biphenyl)-[1,2,4]oxadiazol-5-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[3-(4-isopropylphenyl)-[1,2,4]oxadiazol-5-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[3-(4-tert-butylphenyl)-[1,2,4]oxadiazol-5-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-iterator-1-yl)ethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[5-(4-chlorophenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[3-(4-were)-[1,2,4]-oxadiazol-5-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione; and

8-{4-[3,5-dimethyl[1,2,4]oxadiazol-5-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

EXAMPLE 13

Obtaining the compounds of formula I

A. Receiving from the unity of formula I, where R1and R2are n-propylene, R3means hydrogen, X is 1,4-phenylene, Y means O(CH2)and Z means 5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-yl

a) To a solution of 8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (3.8 g; the remaining 9.08 mmol) in anhydrous dimethylformamide (100 ml) was added potassium carbonate (6,27 g; to 45.4 mmol)then 2-(trimethylsilyl)ethoxymethylene (3,21 ml; 18 mol) and the mixture was stirred at 70°C for 72 hours. The solvent was removed under reduced pressure and the residue was purified flash chromatography on a column elwira a mixture of 30% EtOAc/hexane, gaining 3.7 g of 7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

b)

7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-(phenylmethoxy)phenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (1,74 g; 3,17 mmol) was dissolved in methanol (100 ml) and to the solution was added the catalyst Perlmann (1.0 g). The resulting suspension was stirred at room temperature under a positive pressure of hydrogen for 16 hours. The suspension was filtered through celite, washed several times with a mixture of 50:50 methylene chloride:methanol and the filtrate is evaporated, obtaining 7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-hydroxyphenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (1.2 g) in the form of logo solids.

c)

7-[(2-trimethylsilyl)ethoxymethyl]-8-[4-hydroxyphenyl]-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (50 mg; 0.1 mmol) was dissolved in acetone (2.5 ml)to which was added potassium carbonate (0.5 g) and then 5-chloromethyl-3-[(4-chloro)phenyl]oxadiazol (25 mg; 0.1 mmol)and the mixture was stirred at 60°C for 16 hours. The solvent was removed under reduced pressure and evaporated, and the residue was subjected to preparative thin-layer chromatography, elwira a mixture of 30% EtOAc/hexane, receiving 7-(2-trimethylsilyl)ethoxymethyl-8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione (50 mg).

d)

7-(2-trimethylsilyl)ethoxymethyl-8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione was dissolved in ethanol (2 ml), to the solution was added 1M HCl (0.5 ml). The mixture was boiled under reflux for 2 hours. The resulting white residue was collected, viparita the solvent under reduced pressure and washing the residue with ethanol (3 x 2 ml)to give pure 8-(4-{[3-(4-chlorophenyl)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

B. Obtaining the compounds of formula I, where R1and R2are n-propylene, varying X, Y and Z

Similarly, following the method 13A above, but replacing 5-x is ormetal-3-[(4-chloro)phenyl]oxadiazol similar compounds, received the following compounds of formula I:

8-(4-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-(4-{[3-(4-were)(1,2,4-oxadiazol-5-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[2-(4-iterator)ethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[2-(4-methylpyrazole)ethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-(1-{[5-(2-methoxyphenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazole-4-yl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

N-(2,6-dimetilfenil)-2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydroxypurine-8-yl))pyrazolyl]ndimethylacetamide;

8-(1-{[3-(4-were)(1,2,4-oxadiazol-5-yl)]methyl}pyrazole-4-yl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[2-(1,3-doxasozin-2-yl)ethyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydroxypurine-8-yl))pyrazolyl]-N-(2-chlorophenyl)ndimethylacetamide;

2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydroxypurine-8-yl))pyrazolyl]-N-phenylacetamide;

1,3-dipropyl-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione;

methyl-4-(3-{[4-(2,6-dioxo-1,3-dipropyl-1,3,7-trihydroxypurine-8-yl)phenoxy]methyl}-1,2,4-oxadiazol-5-yl)benzoate;

1,3-dipropyl-8-[4-({5-[2-(triptoreline)phenyl](1,2,4-oxadiazol-3-yl)}methoxy)phenyl]-1,3,7-trihydroxypurine-2,6-dione;

8-(4-{[5-(2-bromophenyl)(1,2,4-oxadiazol-3-yl)]methoxy}Hairdryer is l)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-(4-{[5-(2,4-acid)(1,2,4-oxadiazol-3-yl)]methoxy}phenyl)-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{4-[(5-methylisoxazol-3-yl)methoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(2-were)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(3-were)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-(1-{[2-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(4-were)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(2-methoxyphenyl)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(2-forfinal)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(3-methoxyphenyl)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(3-chlorophenyl)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(2-chlorophenyl)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-(1-{[4-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(4-chlorophenyl)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione;

8-{1-[(4-forfinal)methyl]pyrazole-4-yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione; and

8-{1-[(4-forfinal)methyl]pyrazole--yl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

EXAMPLE 14

Obtaining the compounds of formula (23)

A. Obtaining the compounds of formula (23), in which R1is n-bootrom

A mixture of 6-aminouracil (5 g; 10 mmol), hexamethyldisilazane (40 ml) and ammonium sulfate (260 mg; 1.97 mmol) was boiled under reflux for 4 hours. Excess HMDS was removed under reduced pressure, getting trimethylsilylpropyne derivative of 6-aminouracil.

The product was combined with 1-igbotako (10 ml) and was heated on an oil bath at 130°C for 3 days. Then the reaction mixture was cooled to 0°C was added a saturated aqueous solution of sodium bicarbonate. The resulting precipitate was filtered, washed with water, getting 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (23), which was used in the next reaction without further purification.

B. Obtain other compounds of formula (23)

Similarly, following the method 14A above, but replacing 1-idbutton other halides of the formula R1Hal received the following compounds of formula (23):

6-amino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-benzyl-1,3-dihydropyrimido the n-2,4-dione; and

6-amino-3-ethinyl-1,3-dihydropyrimidine-2,4-dione.

C. Obtain other compounds of formula (23)

Similarly, following the method 14A above, but replacing 1-idbutton other halides of the formula R1Hal, get the following compounds of formula (23):

6-amino-3-methyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(4-terbutyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(2-ethylcarboxylate)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(3-hydroxycyclopent)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione; and

6-amino-3-(piperidine-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Receipt the other compounds of formula (23)

Similarly, following the method 14A above, but replacing 1-idbutton other halides of the formula R1Hal, get other compounds of formula (23).

EXAMPLE 15

Obtaining the compounds of formula (24)

A. Obtaining the compounds of formula (24), in which R1is n-bootrom

A mixture of 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione (4.0 g; and 21.8 mmol) and an aqueous solution of acetic acid (120 ml) was heated at 70°C until complete dissolution and the solution was cooled to 30°C. in Small portions under stirring was added sodium nitrite (3 g), forming an orange precipitate. The reaction mixture was cooled to 0°C and the precipitate was filtered, washed with water and dried under reduced pressure, obtaining 5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione, which was used in the next reaction without further purification.

B. Obtain other compounds of formula (24)

Similarly, following the method 15A above, but replacing 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (23), were obtained the following compounds of formula (24):

5-nitroso-6-amino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amine is-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-benzyl-1,3-dihydropyrimidine-2,4-dione; and

5-nitroso-6-amino-3-ethinyl-1,3-dihydropyrimidine-2,4-dione.

C. Obtain other compounds of formula (24)

Similarly, following the method 15A above, but replacing 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione other halides of the formula (23), given the following compounds of formula (24):

5-nitroso-6-amino-3-methyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-(4-terbutyl)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-(2-ethylcarboxylate)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-(3-hydroxycyclopent)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-and the Ino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

5-nitroso-6-amino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione; and

5-nitroso-6-amino-3-(piperidine-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Obtain other compounds of formula (24)

Similarly, following the method 15A above, but replacing 6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione other halides of the formula (23), is given to the compounds of formula (24).

EXAMPLE 16

Obtaining the compounds of formula (25)

A. Obtaining the compounds of formula (25), in which R1is n-bootrom

A mixture of 5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione (2.1 g; 10 mmol) and aqueous ammonia (50 ml) was heated at 70°C until complete dissolution. Then in small portions was added hydrosulfite sodium (7 g) until the solution became clear and colorless. The reaction mixture is evaporated under reduced pressure until crystals and then was cooled to 0°C. the Precipitate was filtered, washed with cold water, getting 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (25), which was used in the next reaction without further purification.

B. Obtain other compounds of formula (25)

Similarly, following the method 16A described above, the o replacing 5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (24), were obtained the following compounds of formula (25):

5,6-diamino-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-n-propyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(2-methylpropyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-benzyl-1,3-dihydropyrimidine-2,4-dione; and

5,6-diamino-3-ethinyl-1,3-dihydropyrimidine-2,4-dione.

C. Obtain other compounds of formula (25)

Similarly, following the way of 16A above, but replacing 5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (24)are the following compounds of formula (25):

5,6-diamino-3-methyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-isopropyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(4-terbutyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(2-ethylcarboxylate)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-ethynyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-cyclopentyl-1,3-dihydropyran the Dean-2,4-dione;

5,6-diamino-3-(3-hydroxycyclopent)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-phenyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-3-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione; and

5-nitroso-6-amino-3-(piperidine-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Obtain other compounds of formula (25)

Similarly, following the way of 16A above, but replacing 5-nitroso-6-amino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (24), is given to the compounds of formula (25).

EXAMPLE 17

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1means n-butyl, R2means hydrogen, R3means hydrogen, X is 1,4-pyrazole, Y represents methylene, and Z denotes phenyl

The formula I

To a mixture of 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione (1.2 g; 6 mmol) and 1-benzylphenol-4-carboxylic acid (1.2 g; 6 mmol) in methanol (30 ml) was added the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1,16 g; 6 mmol). Has precipitated a bright yellow solid. The mixture was stirred is over night at room temperature and the solid was filtered, washed with methanol and dried under reduced pressure. The product was combined with hexamethyldisilazane (50 ml) and ammonium sulfate (18 mg) and heated at 130°C for 48 hours. Then the solvent was removed under reduced pressure and the residue triturated in a mixture of methanol:water (1:1)to give 1-butyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione, a compound of formula I.

B. Obtain other compounds of formula I

Similarly, following the method 17A described above, but replacing 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (25), were obtained the following compounds of formula I:

1-butyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-butyl-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-propyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-butyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-butyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-butyl-8-[1-(phenylethyl)pyrazole-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-(2-methylpropyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-propyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-propyl-8-[1-(phenylethyl)pyrazole-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}p is razol-4-yl)-1-propyl-1,3,7-trihydroxypurine-2,6-dione;

1-propyl-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-ethyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazole-4-yl)-1-butyl-1,3,7-trihydroxypurine-2,6-dione;

1-ethyl-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-cyclopropylmethyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-(2-methylpropyl)-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-ethinyl-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione;

1-ethinyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-benzyl-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-benzyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-(2-methylpropyl)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(2-methylpropyl)-8-(1-{[3-triptoreline]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

C. Obtain other compounds of formula I

Similarly, following the method 17A described above, but optionally replacing 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (25), and optionally replacing 1-benzylphenol-4-carboxylic acid with other compounds of formula (22), given the following compounds of formula I:

1-methyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-isopropyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-Tr is gidropony-2,6-dione;

1-n-pentyl-8-(1-{[3-chlorophenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(3-propylpentyl)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(2-phenylethyl)-8-[1-{benzyl}pyrazole-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-(2-methoxyethyl)-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(3-hydroxypropyl)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(4-terbutyl)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(2-ethylcarboxylate)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-ethynyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-cyclopentyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(3-hydroxycyclopent)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-cyclohexyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-cyclopropylmethyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-phenyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(pyrid-3-yl)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(pyrid-3-ylmethyl)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-(tetrahydrofuran-3-yl)-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione; and

1-(piperidine-4-yl)-8-(1-{[3-forfinal]IU the Il}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione.

D. Obtain other compounds of formula I

Similarly, following the method 17A described above, but optionally replacing 5,6-diamino-3-butyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (25), and optionally replacing 1-benzylphenol-4-carboxylic acid with other compounds of formula (22), is given to the compounds of formula I.

EXAMPLE 18

Obtaining the compounds of formula (31)

A. Obtaining the compounds of formula (31), in which R2is benzil

The solution ethoxide sodium was prepared from sodium (1,53 g; 67 mmol) and anhydrous ethanol (75 ml). To the resulting solution was added benzyladenine (5.0 g; 33 mmol) and ethylcyanoacrylate (3.77 g; 33 mmol). The resulting reaction mixture was stirred while boiling under reflux for 10 hours, cooled and the precipitate was filtered and washed with ethanol. The residue was dissolved in water and the pH brought to values between 5 and 6 hydrochloric acid. The solid was filtered, washed with water and dried in vacuum, obtaining 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compound of the formula (31), which was used in the next reaction without further purification.

B. Obtain other compounds of formula (31)

Similarly, following the method 18A described above, but replacing benzyladenine other what they are compounds of formula (30), received the following compounds of formula (31):

6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-n-propyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and

6-amino-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

C. Obtain other compounds of formula (31)

Similarly, following the method 18A described above, but replacing benzyladenine other compounds of formula (30), is given to the compounds of formula (31):

6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-(4-terbutyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-(2-ethylcarboxylate)-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-ethynyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-(3-hydroxycyclopent)-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-phenyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione; and

6-amino-1-(piperidine-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Obtain other compounds of formula (31)

Similarly, following the method 18A described above, but replacing benzyladenine other compounds of formula (30), is given to the compounds of formula (31).

EXAMPLE 19

Obtaining the compounds of formula (23)

A. Obtaining the compounds of formula (23), in which R2is benzil

To a solution of 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione (2.0 g; 9.2 mmol) in a mixture of 15 ml of N,N-dimethylformamide and 5 ml of water at 90°C was added sodium nitrite (1.27 g; 69 mmol). To the obtained reaction mixture was added concentrated hydrochloric acid until the colour has ceased to grow, and the mixture was heated at 70°C for 1 hour. The solvent was removed under reduced pressure, the residue was dissolved in water and added concentrated hydrochloric acid to obtain a pH of 4.0. The precipitate was filtered, washed with water and dried under reduced pressure, obtaining 6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (23).

B. Obtain other compounds of formula (23)

Similarly, following the method 19A above, but replacing 6-amino-1-benzyl-1,3-dihydr the pyrimidine-2,4-dione with other compounds of formula (31), received the following compounds of formula (23):

6-amino-5-nitroso-1-methyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-n-propyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and

6-amino-5-nitroso-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

C. Obtain other compounds of formula (23)

Similarly, following the method 19A above, but replacing 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (31), given the following compounds of formula (23):

6-amino-5-nitroso-1-methyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(4-terbutyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(2-ethylcarboxylate)-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-ethynyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(3-hydroxycyclopent)-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-cyclohexyl-1,3-Digi apyrimidine-2,4-dione;

6-amino-5-nitroso-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-phenyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-5-nitroso-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione; and

6-amino-5-nitroso-1-(piperidine-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Obtain other compounds of formula (23)

Similarly, following the method 19A above, but replacing 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (31), is given to the compounds of formula (23).

EXAMPLE 20

Obtaining the compounds of formula (21)

A. Obtaining the compounds of formula (21), in which R2is benzil

To a solution of 6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione (1,15 g; 4.7 mmol) of 12.5% aqueous ammonia (40 ml) at 70°C portions over 15 minutes was added hydrosulfite sodium (2,44 g; 14 mmol). Upon cooling the reaction mixture in a bath with ice product precipitated. It was filtered, washed with water and dried under reduced pressure, getting 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (21).

B. Obtain other compounds of formula (21)

Similarly, following the method 2A, described above, but replacing 6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (23), were obtained the following compounds of formula (21):

5,6-diamino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-n-propyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-n-butyl-1,3-dihydropyrimidine-2,4-dione; and

5,6-diamino-1-isobutyl-1,3-dihydropyrimidine-2,4-dione.

C. Obtain other compounds of formula (21)

Similarly, following the method 20A described above, but replacing 6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (23), given the following compounds of formula (21):

5,6-diamino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-isopropyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-n-pentyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-propylpentyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(2-phenylethyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(2-methoxyethyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(3-hydroxypropyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(4-terbutyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(2-ethylcarboxylate)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-ethynyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-cyclopentyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(3-hydroxycyclopent)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-cyclohexyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-phenyl-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(pyrid-3-yl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(pyrid-3-ylmethyl)-1,3-dihydropyrimidine-2,4-dione;

5,6-diamino-1-(tetrahydrofuran-3-yl)-1,3-dihydropyrimidine-2,4-dione; and

5,6-diamino-1-(piperidine-4-yl)-1,3-dihydropyrimidine-2,4-dione.

D. Obtain other compounds of formula (21)

Similarly, following the method 20A described above, but replacing 6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (23), is given to the compounds of formula (21).

EXAMPLE 21

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1means hydrogen, R2means benzyl, R3means hydrogen, X is 1,4-pyrazole, Y represents methylene, and Z denotes phenyl

The formula I

A solution of 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione (200 mg; 0.8 mmol), 1-benzylphenol-4-carboxylic acid (202 mg, 1 mmol) and hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (191 mg, 1 mmol) was dissolved in N,N-dimethylformamide and was stirred for 16 hours. Then the solvent was removed under reduced pressure and the residue was dissolved in hexamethyldisilazane (HMDS). To the resulting solution was added alpacamania and the mixture was heated at 125° C for 80 hours. Excess HMDS was removed under reduced pressure and was preparing a suspension of the residue in a mixture of 1:1 methanol and water. The solid was filtered, washed with a mixture of 1:1 methanol and water and dried under reduced pressure, obtaining 3-benzyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione, a compound of formula I.

B. Obtaining the compounds of formula I, where R1means hydrogen, R3means hydrogen, X is 1,4-pyrazole, Y represents methylene, and Z denotes phenyl, R2varies

Similarly, following the method 21A described above, but replacing 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (21), were obtained the following compounds of formula I:

3-n-propyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-isobutyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-benzyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-n-butyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(2-methylpropyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione; and

3-methyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione.

C. Obtaining the compounds of formula I, where R1means hydrogen, R2varies, R3means hydrogen, X is 1,4-pyrazole, Y represents methylene, and Z denotes phenyl

Similarly, following the method 21A, described is use, but, optionally replacing 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (21), and optionally replacing 1-benzylphenol-4-carboxylic acid with other compounds of formula (22), given the following compounds of formula I:

3-methyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-isopropyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-n-pentyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(1-propylpentyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(2-phenylethyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(2-methoxyethyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(3-hydroxypropyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(4-terbutyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(2-ethylcarboxylate)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-ethynyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-cyclopentyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(3-hydroxycyclopent)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-cyclohexyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-cyclopropylmethyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-phenyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(pyrid-3-yl)-n-propyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

(pyrid-3-ylmethyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-(tetrahydrofuran-3-yl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione; and

3-(piperidine-4-yl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione.

D. Obtaining the compounds of formula I, where R1means hydrogen, R2varies, R3means hydrogen, X is 1,4-pyrazole, Y represents methylene, and Z denotes phenyl

Similarly, following the method 21A described above, but optionally replacing 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (21), and optionally replacing 1-benzylphenol-4-carboxylic acid with other compounds of formula (22), is given to the compounds of formula I.

EXAMPLE 22

Obtaining the compounds of formula (33)

A. Obtaining the compounds of formula (33), in which R1is n-bootrom and R2is stands

A suspension of 6-amino-1-methyluracil (3.0 g) in anhydrous dimethylacetal N,N-dimethylformamide (10 ml) and N,N-dimethylacetamide (50 ml) was heated at 40°C until the disappearance of the original substance (60 min). Then was added potassium carbonate (10 g) and n-butylbromide (7,8 g) and the reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, filtered, the solvent evaporated and the product of formula (33), 6-[1-Aza-2-(dimethylamino)vinyl]-3-butyl-1-m is l-1,3-dihydropyrimidine-2,4-dione, as such, used for the next reaction.

B. Obtaining compounds of formula (33), varying R1and R2

Similarly, following the method 22A described above, but optionally replacing 6-amino-1-methyluracil other compounds of formula (31), and optionally replacing n-butylbromide other alkylhalogenide received the following compounds of formula (33):

6-[1-Aza-2-(dimethylamino)vinyl]-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1,3-dibutil-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1,3-dimethyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1,3-diethyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-methyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-methyl-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-methyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-ethyl-3-prop-2-inyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1,3-dibutil-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-methyl-3-butyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-methyl-3-sec-butyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-methyl-3-cyclopropylmethyl who -1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-ethyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

6-[1-Aza-2-(dimethylamino)vinyl]-1-ethyl-3-sec-butyl-1,3-dihydropyrimidine-2,4-dione; and

6-[1-Aza-2-(dimethylamino)vinyl]-1,3-sec-butyl-1,3-dihydropyrimidine-2,4-dione.

C. Obtaining compounds of formula (33), varying R1and R2

Similarly, following the method 22A described above, but optionally replacing 6-amino-1-methyluracil other compounds of formula (31), and optionally replacing n-butylbromide other alkylhalogenide receive other compounds of formula (33).

EXAMPLE 23

Obtaining the compounds of formula (34)

A. Obtaining the compounds of formula (34), in which R1is n-bootrom and R2is stands

6-[(1E)-1-Aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione (4.0 g)obtained in example 22A, suspended in methanol. To the resulting suspension was added an aqueous solution of ammonium hydroxide and the reaction mixture was stirred at room temperature for 48 hours. Once the original product is no longer detected, the solvents were removed under reduced pressure, the residue suspended in water and the precipitate was filtered, washed with water and dried under reduced pressure, obtaining the crude 6-amino-3-butyl-1-methyl-1,3-d is hydropyridine-2,4-dione, used in this form in the following reaction.

B. Obtaining compounds of formula (34), varying R1and R2

Similarly, following the method 23A described above, but replacing 6-[(1E)-1-Aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (33), were obtained the following compounds of formula (34):

6-amino-1,3-dipropyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1,3-dibutil-1,3-dihydropyrimidine-2,4-dione;

6-amino-1,3-dimethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1,3-diethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-methyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-methyl-3-ethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-methyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-ethyl-3-(prop-2-inyl)-1,3-dihydropyrimidine-2,4-dione;

6-amino-1,3-dibutil-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-methyl-3-sec-butyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-methyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-ethyl-3-cyclopropylmethyl-1,3-dihydropyrimidine-2,4-dione;

6-amino-1-ethyl-3-sec-butyl-1,3-dihydropyrimidine-2,4-dione; and

6-amino-1,3-sec-butyl-1,3-dihydropyrimidine-2,4-dione.

C. Obtaining compounds of formula (34), varying R1and R2

Similarly, following the method 23A described above, but replacing 6-[1E)-1-Aza-2-(dimethylamino)vinyl]-3-butyl-1-methyl-1,3-dihydropyrimidine-2,4-dione with other compounds of formula (33), get other compounds of formula (34).

EXAMPLE 24

Obtaining the compounds of formula I

A. Obtaining the compounds of formula I, where R1means n-butyl, R2means methyl, X is 1,4-pyrazole, Y represents methylene, and Z means 3-forfinal

Then the compound of formula (34) is converted into a compound of formula I in the same way as shown for the conversion of compounds of formula (23) in examples 14, 15, 16 and 17. That is, conduct the reaction with sodium nitrite to 5-nitroso-6-amino derivatives, which restores up to 5,6-diamine-derivates, which, in turn, is subjected to the interaction with an appropriately substituted carboxylic acid of the formula Z-Y-X-CO2H, obtaining the compound of formula I. Thus received the following connections:

1-butyl-3-methyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-[1-phenylpyrazol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-[1,3-dimethylpyrazol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-[1-ethyl-3-methylpyrazole-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1,3-dibutil-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1,3-dibutil-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-pyrazole-4-yl-1,3,7-tregetour the -2,6-dione;

1-methyl-3-sec-butyl-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione;

1,3-dimethyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1,3-diethyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-methyl-1-propyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-ethyl-1-(prop-2-inyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-ethyl-1-propyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-sec-butyl-3-methyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-cyclopropylmethyl-3-methyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

3-ethyl-1-propyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-{1-[(2-methoxyphenyl)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

3-ethyl-1-propyl-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-cyclopropylmethyl-3-ethyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

ethyl-2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydroxypurine-8-yl))pyrazolyl]-2-phenylacetate;

1-cyclopropylmethyl-3-methyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

3-methyl-1-propyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

3-methyl-1-propyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-cyclopropylmethyl-3-methyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-Cyclops is epiletic-3-ethyl-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione;

1-sec-butyl-3-ethyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-butyl-3-methyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1-butyl-3-methyl-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-sec-butyl-3-ethyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1,3-di(sec-butyl)-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione;

1,3-di(sec-butyl)-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-di(sec-butyl)-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-sec-butyl-3-methyl-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1-sec-butyl-3-methyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-sec-butyl-3-methyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dimethyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-ethyl-3-methyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-ethyl-3-methyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-{1-[(2,5-dichlorophenyl)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-diethyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-diethyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-sec-butyl-3-ethyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]ethyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione;

2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydroxypurine-8-yl))pyrazolyl]-2-phenylacetic acid;

1,3-diethyl-8-(pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione; and

1-cyclopropylmethyl-3-ethyl-8-{1-[(3-forfinal)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione.

EXAMPLE 25

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 they fill hard gelatin capsules.

EXAMPLE 26

The composition of the tablets prepared using the ingredients below:

Number
Ingredient(mg/tablet)
The active ingredient25,0
Microcrystalline cellulose200,0
Colloidal silicon dioxide10,0
Stearic acid5,0

Compounds are mixed and pressed to form tablets.

EXAMPLE 27

Prepare medication for dry powder inhaler containing the following components:

IngredientWeight %
The active ingredient5
Lactose95

The active ingredient is mixed with the lactose and the mixture is injected into the device is a dry powder inhaler.

EXAMPLE 28

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

Number
Ingredient(mg/tablet)
The active ingredient30.0 mg
Starch45.0 mg
Microcrystalline cellulose35,0 mg
Polyvinylpyrrolidone (as 10% solution in sterile water)4.0 mg
Natrocarbonatite4.5 mg
Magnesium stearate0.5 mg
Talc1.0 mg
Total120 mg

The active ingredient, starch and cellulose is passed through 20 mesh, US standard, and thoroughly mix. With the resulting powders are mixed solution of polyvinylpyrrolidone and then pass through a sieve of 16 mesh, USA. Thus obtained granules are dried at a temperature of from 50°C to 60°C and pass through a sieve of 16 mesh, USA. Then the beads add natrocarbonatite, magnesium stearate and talc, previously passed through a sieve of 30 mesh, U.S., and after mixing is pressed in a tablet press machine, receiving tablets, each weighing 120 mg

EXAMPLE 29

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

IngredientNumber
The active ingredient25 mg
Glycerides of saturated fatty acids to2,000 mg

The active ingredient is passed through a sieve of 60 mesh, U.S., and suspended in the glycerides of saturated fatty acids, previously melted using the minimum required degree of heat. The mixture is then poured into the form of a suppository with a nominal capacity of 2.0 g and allow to cool.

EXAMPLE 30

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

IngredientNumber
The active ingredient50.0 mg
Xanthan gum4.0 mg
The sodium carboxymethyl cellulose (11%)
Microcrystalline cellulose (89%)50.0 mg
Sucrose1,75 g
Sodium benzoate100 mg
Corrigent and dyeq.v.
Purified water to50 ml

The active ingredient, sucrose and xanthan gum are blended, passed through a 10 mesh sieve, U.S., and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, corrigent and dye diluted with some water and add with stirring. Then add sufficient water to obtain the desired volume.

EXAMPLE 31

Preparation for subcutaneous injection is prepared as follows:

IngredientNumber
The active ingredient5.0 mg
Corn oil %1.0 ml

EXAMPLE 32

Prepare injection preparation having the following to the position:

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

EXAMPLE 33

Prepare medication for local application, has the following composition:

IngredientsGrams
The active ingredient2,0-10
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°C under stirring. Then add a sufficient quantity of water at 60°C with vigorous stirring to emulsify the ingredients, and then add water q.s. to 100 g

EXAMPLE 34

The composition is a delayed release

IngredientRange weight (%)The preferred range (%)The most preferred
The active ingredient50-9570-9075
Microcrystalline cellulose (filler)1-355-1510,6
Copolymer of methacrylic acid1-355-12,510,0
Sodium hydroxide0,1-1,00,2-0,60,4
The hypromellose0,5-5,01-32,0
Magnesium stearate0,5-5,01-32,0

The drugs slow release according to this invention is prepared as follows: compound and pH-dependent binder and any optional excipients are thoroughly mixed (mixing in dry form). Then mixed in the dry mixture granularit in the presence of an aqueous solution of a strong base, which inject into a Mixable powder. The granulated product is dried, sieved, mixed with an optional lubricating substances (who, akimi, 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, preferably sodium hydroxide, in water (optionally containing up to 25% miscible with water, solvents such as lower alcohols).

The resulting tablets can be coated optional film forming agent for identification purposes, taste masking, and in order to facilitate swallowing. Agent, film forming, as a rule, will be present in amounts ranging from 2% to 4% by weight of the tablet. Suitable film forming agents are well known in this field and include hypromellose, cationic methacrylate copolymers (copolymers of dimethylaminoethylmethacrylate/methylmetacrylate - Eudragit® E Röhm. Pharma), and the like. These film forming agents may not necessarily contain dyes, plasticizers and other ingredients.

Pressed tablets preferably have sufficient strength to withstand the compression of 8 kPa. The size of the tablets mainly will depend on the number of connections per tablet. Tablets will contain from 300 to 1100 mg of the compound in the form of free base. Preferably, the tablet will be with erati number of connections in the form of free base in the range of 400-600 mg, 650-850 mg and 900-1100 mg

To affect the degree of dilution control the time during which the powder containing the compound is mixed in the wet state. Preferably the total time of mixing the powder, i.e. the time during which the powder is affected by the sodium hydroxide solution will be in the range from 1 to 10 minutes and preferably from 2 to 5 minutes. After granulation, the particles removed from the pellet and placed in a fluidized bed dryer for drying at about 60°C.

EXAMPLE 35

Analyses of receptor adenosine A2B

Methods

Linking radioligand in the case of receptor adenosine A2BcDNA of the receptor adenosine A2Bman consistently has transfusional cells HEK-293 (called cells HEK-A2B). The monolayer cells HEK-A2B once were washed in PBS and collected in a buffer containing 10 mm HEPES (pH 7.4), 10 mm EDTA and protease inhibitors. These cells are homogenized in the homogenizer of the type "Polytron" for 1 minute at setting 4 and centrifuged at 29000 g for 15 minutes at 4°C. Precipitation cells were once washed with buffer containing 10 mm HEPES (pH of 7.4), 1 mm EDTA and protease inhibitors, and again suspended in the same buffer with the addition of 10% sucrose. Frozen aliquots were stored at -80°C. Analysis of competitive binding was started by mixing 10 nm3H-ZM214385(Tocris Cookson) with different concentrations of test compounds and 50 μg of membrane proteins in TE buffer (50 mm Tris and 1 mm EDTA) supplemented with 1 unit/ml adenozindezaminazy. The analyzed mixtures were incubated for 90 minutes, the analyses were stopped by filtration using a collecting device Packard and four times washed with ice-cold TM buffer (10 mm Tris, 1 mm MgCl2, pH 7,4). Nonspecific binding was determined in the presence of 10 μm ZM214385. The affinity of compounds (i.e. the values of Ki) was calculated using the computer program GraphPad.

Linking radioligand in the case of other adenosine receptor.cDNA receptors adenosine A1, A2A, A3man consistently has transfusional or in CHO cells, or in cells HEK-293 (called CHO-A1, HEK-A2A, CHO-A3). Membranes from these cells were prepared using the same Protocol as described above. Analysis of competitive binding was started by mixing 0.5 nm3H-CPX (in the case of CHO-A1), 2 nm3H-ZM214385 (HEK-A2A) or 0.1 nm125I-AB-MECA (CHO-A3) with different concentrations of the test compounds and the corresponding membranes in TE buffer (50 mm Tris and 1 mm EDTA for CHO-A1 and HEK-A2A) or in TEM buffer (50 mm Tris, 1 mm EDTA and 10 mm MgCl2for CHO-A3) supplemented with 1 unit/ml adenozindezaminazy. The analyzed mixtures were incubated for 90 minutes, the analyses were stopped by filtration using a collecting device Packard and four times washed with ice-cold TM buffer (10 mm Tris, 1 mm MgCl2, pH 7,4). Nonspecific binding was determined in presence is AI 1 μm CPX (CHO-A1), 1 μm ZM214385 (HEK-A2A) and 1 μm IB-MECA (CHO-A3). The affinity of compounds (i.e. the values of Ki) was calculated using the computer program GraphPad.

Measuring cAMP. The monolayer of transfected cells were collected in PBS containing 5 mm EDTA. Cells once were washed in DMEM and resuspendable in DMEM containing 1 unit/ml adenozindezaminazy, at a density 100000-500000 cells/ml 100 ál of cell suspension was mixed with 25 µl, containing various agonists and/or antagonists, and the reaction mixture is kept at 37°C for 15 minutes. At the end of the 15 minute period was added 125 μl of 0.2 N. HCl to stop the reaction. Cells were centrifuged for 10 minutes at 1000 R/min 100 ál nadeshiko removed and azetilirovanie. Concentration cAMP in nadeshiko was measured using the direct analysis cAMP Assay Design.

Receptors of adenosine A2Aand A2Bpaired with Gs-proteins and, accordingly, receptor agonists of the adenosine A2A(such as CGS21680) or receptor adenosine A2B(such as NECA) increase cAMP accumulation, whereas antagonists of these receptors inhibit the increase in the accumulation of cAMP induced by agonists. Receptors of adenosine A1and A3associated with Gi proteins, and accordingly receptor agonists of the adenosine A1(such as CPA) or receptor adenosine A3(such as IB-MECA) inhibited the increase in the accumulation of cAMP induced by Forskolin. Receptor antagonists A1and A3prevent the inhibition of cAMP accumulation.

Using the above test shows that the compounds according to the invention are antagonists of A2B.

Compounds according to the invention was also tested in a murine model of asthma using the methods described in U.S. patent 6387913, the relevant portion of which is included in this description by reference, and have shown that they are effective.

1. The compound of formula I or formula II

in the form of a free base, pharmaceutically acceptable salt or pharmaceutically acceptable ether complex,

where R1and R2independently selected from hydrogen, lower alkyl or the group-D-E, in which D is a covalent bond or a lower alkylene and E means the lowest cycloalkyl, phenyl or lower quinil, which may not necessarily be substituted with halogen or CF3;

R3means hydrogen or lower alkyl, optionally substituted by hydroxyl;

X is phenylene or 5-membered, heteroaryl containing two nitrogen atom as heteroatoms;

Y is a covalent bond or lower alkylene, in which one carbon atom can be optionally replaced by-O-;

Z denotes hydrogen, phenyl, neoba is consequently substituted lower alkoxygroup or lower alkyl, which may be optionally substituted with halogen; or a monocyclic 5-membered heteroaryl containing two nitrogen atom and one oxygen atom, which optionally may be substituted by phenyl or by phenyl substituted by halogen or lower alkyl;

provided that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolines associated with purine cycle carbon atom;

and provided that when X is optionally substituted by arilena, Z is optionally substituted monocyclic heteroaryl other than imidazole.

2. The compound according to claim 1,

where R3is hydrogen;

X is 5-membered heteroarenes containing two nitrogen atom as a heteroatom; and

Y is a covalent bond or lower alkylene.

3. The compound according to claim 2, where X is optionally substituted pyrazoline, Y is the lowest alkylene and Z is optionally substituted phenyl or optionally substituted oxadiazole.

4. The compound according to claim 3, where R1is lower alkyl, optionally substituted lower cycloalkyl, and R2is hydrogen.

5. The compound according to claim 4, where X is optionally substituted 1,4-pyrazolines.

6. The compound according to claim 5, where Y is -(CH2)- yl is CH(CH 3)and Z denotes optionally substituted phenyl.

7. The connection according to claim 6, where R1is n-propylene, X is 1,4-pyrazolines, Y is -(CH2)- and Z is 3-cryptomaterial, that is, 1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione.

8. The connection according to claim 6, where R1is n-propylene, X is 1,4-pyrazolines, Y is -(CH2)- and Z is phenyl, 1-propyl-8-[1-benzylphenol-4-yl]-1,3,7-trihydroxypurine-2,6-dione.

9. The connection according to claim 6, where R1is n-bootrom, X is 1,4-pyrazolines, Y is -(CH2)- and Z is 3-florfenicol, that is, 1-butyl-8-(1-{[3-forfinal]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione.

10. The connection according to claim 6, where R1is n-propylene, X is 1,4-pyrazolines, Y is-CH(CH3)- and Z is phenyl, 1-propyl-8-[1-(phenylethyl)pyrazole-4-yl]-1,3,7-trihydroxypurine-2,6-dione.

11. The compound according to claim 5, where Y is -(CH2)- or-CH(CH3)- and Z is optionally substituted by oxadiazoles.

12. Connection to item 11, where R1is n-propylene, X is 1,4-pyrazolines, Y is -(CH2)- and Z is 5-(4-chlorophenyl)-[1,2,4]oxadiazol-3-yl, that is 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazole-4-yl)-1-propyl-1,3,7-trihydroxypurine-2,6-dione.

13. Connection to item 11, where R1is n-bootrom, X is 1,4-what erusalem, Y is -(CH2)- and Z is 5-(4-chlorophenyl)-[1,2,4]oxadiazol-3-yl, that is 8-(1-{[5-(4-chlorophenyl)(1,2,4-oxadiazol-3-yl)]methyl}pyrazole-4-yl)-1-butyl-1,3,7-trihydroxypurine-2,6-dione.

14. The compound according to claim 2, where R1and R2independently are lower alkyl, optionally substituted lower cycloalkyl.

15. The connection 14, where X is optionally substituted pyrazolines.

16. The connection indicated in paragraph 15, where X is optionally substituted 1,4-pyrazolines, Y is-CH2-, -CH(CH3)- or a covalent bond and Z is hydrogen or optionally substituted phenyl.

17. Connection P16, where R1and R2are n-propylene, Y is a covalent bond and Z is hydrogen, that is, 1,3-dipropyl-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione.

18. Connection P16, where R1is second-bootrom, R2is stands, Y is a covalent bond and Z is hydrogen, 1-methyl-3-sec-butyl-8-pyrazole-4-yl-1,3,7-trihydroxypurine-2,6-dione.

19. Connection P16, where R1and R2independently are stands, n-propylene or cyclopropylmethyl, Y is methylene, and Z is 3-cryptomaterial.

20. Connection P16, where R1and R2independently are stands, n-propylene or cyclopropylmethyl, Y is methylene, and Z is 3-florfenicol.

21. The connection is .16, where R1and R2are n-propylene, Y is-CH(CH3)- and Z is 3-cryptomaterial, that is, 1,3-dipropyl-8-(1-{[3-(trifluoromethyl)phenyl]ethyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione.

22. Connection P16, where R1and R2are n-propylene, Y is methylene, and Z is 4-carboxyphenyl, that is, 1,3-dipropyl-8-{1-[(4-carboxyphenyl)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione.

23. Connection P16, where R1and R2are n-propylene, Y is-CH(CO2H) -, and Z is phenyl, i.e. 2-[4-(2,6-dioxo-1,3-dipropyl(1,3,7-trihydroxypurine-8-yl))pyrazolyl]-2-phenylacetic acid.

24. The compound according to claim 1,

where R3is hydrogen;

X is optionally substituted phenylene; and

Y is a covalent bond or lower alkylene, in which one carbon atom can be optionally replaced by-O-.

25. The connection point 24, where R1and R2independently denote a lower alkyl, optionally substituted lower cycloalkyl.

26. Connection A.25, where R1and R2is n-propylene and Y is-co2-.

27. Connection p, where Z is optionally substituted by oxadiazoles.

28. Connection item 27, where Z denotes 5-(2-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), that is 8-{4-[5-(2-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trigi lopurin-2,6-dione.

29. Connection item 27, where Z denotes 5-(3-methoxyphenyl)-(1,2,4-oxadiazol-3-yl), that is 8-{4-[5-(3-methoxyphenyl)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

30. Connection item 27, where Z denotes 5-(4-forfinal)(1,2,4-oxadiazol-3-yl), that is 8-{4-[5-(4-forfinal)-[1,2,4]oxadiazol-3-ylethoxy]phenyl}-1,3-dipropyl-1,3,7-trihydroxypurine-2,6-dione.

31. The use of compounds of the formula

in the form of a free base, pharmaceutically acceptable salt or pharmaceutically acceptable ether complex,

where R1and R2independently selected from hydrogen, lower alkyl or the group-D-E, in which D is a covalent bond or a lower alkylene and E means the lowest cycloalkyl, phenyl or lower quinil, which optionally may be substituted with halogen or CF3;

R3means hydrogen or lower alkyl, optionally substituted by hydroxyl;

X is phenylene or 5-membered, heteroaryl containing two nitrogen atom as heteroatoms;

Y is a covalent bond or lower alkylene, in which one carbon atom can be optionally replaced by-O-;

and Z denotes hydrogen; phenyl, optionally substituted lower alkoxygroup or lower alkyl which may be optionally substituted with halogen; Il is monocyclic 5-membered heteroaryl, containing two nitrogen atom and one oxygen atom, which optionally may be substituted by phenyl or by phenyl substituted by halogen or lower alkyl;

and provided that when X is optionally substituted by arilena, Z is optionally substituted monocyclic heteroaryl, to obtain a pharmaceutical composition having an antagonistic activity against receptor adenosine A2B.

32. Pharmaceutical composition having antagonistic activity against receptor adenosine A2Bcontaining at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to claim 1.

33. The method of obtaining the compounds of formula I or formula II

where R1and R2independently selected from hydrogen, lower alkyl or the group-D-E, in which D is a covalent bond or a lower alkylene and E means the lowest cycloalkyl, phenyl or lower quinil, which may not necessarily be substituted with halogen or CF3;

R3means hydrogen or lower alkyl, optionally substituted by hydroxyl;

X is phenylene or 5-membered, heteroaryl containing two nitrogen atom as heteroatoms;

Y is a covalent bond is whether the lower alkylene, in which one carbon atom can be optionally replaced by-O-;

and Z denotes hydrogen; phenyl, optionally substituted lower alkoxygroup or lower alkyl which may be optionally substituted with halogen; or a monocyclic 5-membered heteroaryl containing two nitrogen atom and one oxygen atom, which optionally may be substituted by phenyl or by phenyl substituted by halogen or lower alkyl;

provided that Z is hydrogen only when Y is a covalent bond and X is optionally substituted 1,4-pyrazolines associated with purine cycle carbon atom;

and provided that when X is optionally substituted by arilena, Z is optionally substituted monocyclic heteroaryl other than imidazole, comprising contacting the compounds of formula

in which R1, R2and R3have the meanings defined above, with a compound of formula Z-Y-X-CO2H, in which X, Y and Z have the meanings given above.

34. The method according to p, where R1is n-bootrom and R2and R3mean hydrogen.

35. The method according to clause 34, where X is phenyl, Y is propylene and Z is 1,4-pyrazolines

namely, obtaining 1-[(3-torfin the l)methyl]pyrazole-4-carboxylic acid.

36. The method according to p, where the reaction is carried out in the presence of hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in N,N-dimethylformamide.

37. Connection P16, where R1is n-propylene, R2is ethyl, Y is -(CH2)- and Z is 3-cryptomaterial, that is, 3-ethyl-1-propyl-8-{1-[(3-triptoreline)methyl]pyrazole-4-yl}-1,3,7-trihydroxypurine-2,6-dione.

38. The connection clause 37, where the compound is a free base.

39. The connection clause 37, where the compound is a pharmaceutically acceptable acid additive salt.

40. Connection § 39, where the pharmaceutically acceptable acid additive salt is a phosphate salt.

41. Connection § 39, where the pharmaceutically acceptable acid salt additive is toileta salt.



 

Same patents:

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention relates to novel compounds of general formula I possessing polycyclic xanthine-phosphodiesterase inhibitor properties, to a method of preparation thereof, and also to pharmaceutical composition based on these novel compounds and use of compounds for treatment of various disorders, symptoms, and maladies caused by xanthine-phosphodiesterase V, in particular erectile dysfunction. In compounds of general formula I: , R1 and R2, independently from each other, each represents branched or linear C1-C15-alkyl optionally substituted by one or several substituents selected from hydroxy, amino, alkylamino, di-C1-C4-alkylamino, and tri-C1-C4-alkylsilyloxy; benzyl optionally substituted by one or several substituents in benzene ring selected from C1-C4-alkoxy groups; R3 represents phenyl optionally substituted by one or several substituents, 6-membered nitrogen-containing heteroaryl group optionally substituted by one or several substituents, or 5-membered heterocyclic group with 1 or 2 oxygen heteroatoms, condensed with phenyl ring and optionally substituted by one or several substituents; R4 represents С315-cycloalkyl group optionally substituted by one or several substituents; С315-cycoalkenyl group optionally substituted by one or several substituents; 3-8-membered heterocyclylalkyl group or S-oxides thereof optionally substituted by one or several substituents; or indanyl group; wherein one or several substituents for all R3 and R4 groups represent, independently from each other, C1-C4-alkyl, phenyl, 6-membered nitrogen-containing heterocycle, hydroxy-C1-C4-alkyl, С14-alkylthio-C1-C4-alkyl, carboxy-C1-C4-alkyl, mono-, di-, and trihalo-C1-C4-alkyl, mono-, di-, and trihalo-C1-C4-alkoxy, C1-C4-alkoxy, hydroxy, halogen, nitro, -COOR50, -SO0-2R50, -SO2NR50R51, and -OCOR50, where R50 and R51 independently represent hydrogen atom or branched or linear optionally substituted C1-C6-alkyl.

EFFECT: expanded synthetic possibilities in heterocyclic compounds area and increased choice of erectile dysfunction treating drugs.

35 cl, 2 tbl

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to new derivatives of xanthine with integral aminirovanie alkanolamine the side chains of the formula I in the form of individual stereoisomers or as mixtures of stereoisomers, has a neuroprotective effect

The invention relates to the field of medicine and relates to a medicinal product for the treatment of shock diseases containing a compound of formula I, as well as to new compounds of General formula I

The invention relates to new derivatives of purine of formula I, II, III and IV, pharmaceutical compositions and method of treatment of a pathological state characterized by thrombotic activity

The invention relates to new biologically active compounds, methods of treating diseases with their use and pharmaceutical compositions based on these compounds

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel azaheterocycles of the general formula (I): possessing inhibitory effect on activity of tyrosine kinase and can be used in treatment of different diseases mediated by these receptors. In compound of the general formula (1) W represents azaheterocycle comprising 6-13 atoms that can be optionally annelated with at least one (C5-C7)-carbocycle and/or possibly annelated with heterocycle comprising 4-10 atoms in ring and comprising at least one heteroatom chosen from oxygen (O), sulfur (S) or nitrogen (N) atom; Ra1 represents a substitute of amino group but not hydrogen atom, such as substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-10-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; Rb represents carbamoyl group -C(O)NHRa wherein Ra represents a substitute of amino group but not hydrogen atom, such as possibly substituted alkyl, possibly substituted aryl, possibly substituted 5-10-membered heterocyclyc comprising at least one heteroatom chosen from O, S or N; Rc represents a substitute of cyclic system, such as possibly substituted (C1-C6)-alkyl, possibly substituted aryl and possibly substituted 5-6-membered heterocyclyl comprising at least one heteroatom chosen from O, S or N; or Rb and Rc form in common aminocyanomethylene group [(=C(NH2)CN], or their pharmaceutically acceptable salts. Also, invention relates to methods for synthesis of these compounds (variants), a pharmaceutical composition, combinatory and focused libraries.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved methods for synthesis and preparing.

35 cl, 16 sch, 13 tbl, 43 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to anthranilic acid amides of the formula (I): wherein R1 means hydrogen atom or (lower)-alkyl; R2 means hydrogen atom or (lower)-alkyl; R3 means perfluoro-(lower)-alkyl; X means oxygen atom or sulfur atom, or to its N-oxide or tautomer, to salts of such anthranilic acid amides, their N-oxides or their tautomers. Compounds of the formula (I) possess inhibitory activity with respect to tyrosine kinase VEGF receptors and can be used in treatment of neoplasm, retinopathy or age degeneration resulting to appearance of spots in retina in humans or mammals. Also, invention relates to using anthranilic acid amide of the formula (I) for preparing a pharmaceutical drug possessing above said activity, to a method for treatment of neoplasm disease, a pharmaceutical drug and a method for synthesis of anthranilic acid amide of the formula (I).

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical drug.

9 cl, 7 ex

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for chemotherapy of acute leucosis. Method involves isolation of blast cells and interphase cells from marrow puncture sample leukocyte fraction of blood of a patient subjected for chemotherapy. Then cells are deposited by centrifugation in medium 199 and their concentration is brought about to the level (2-3) x 106 cells/ml. Then isolated cells are incubated with each chemotherapeutic drug chosen from the following group: dexamethasone, cyclophosphanum, vincristine, teniposide, etoposide, citarabinum that are diluted preliminary with isotonic solution to the concentration 1:1000. Then cells treated with chemotherapeutic drugs are centrifuged repeatedly in medium 199 followed by carrying out the annexin test. In the schedule treatment drugs that showed the maximal percent of cells apoptosis are used. Method provides maximal decreasing adverse and toxic effects of chemotherapeutic drugs and to enhance apoptosis of tumor cells based on individual selection of chemotherapeutic drugs for a patient, to prolong remission period and to exclude using additional curative effects.

EFFECT: improved and enhanced method of chemotherapy.

2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a pharmaceutical composition comprising 4-(31-chloro-41-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline or its pharmaceutically acceptable salt (agent) and cellulose water-soluble ether, or cellulose water-soluble ester. The composition possesses the anti-proliferative effect. Cellulose ether and ester represented in the composition inhibit the precipitation rate of agent from solution in transport from stomach acid medium to upper regions of digestive tract medium with alkaline pH values that provides improved pharmacokinetic properties of the composition.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

23 cl, 4 dwg, 4 tbl, 14 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to using a combination that comprises the following components: (a) N-{5-[4-(4-methylpiperazinomethyl)benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidineamine and (b) chemotherapeutic agent chosen from zolendronic acid or letrozole wherein active components present in each case in free form or in form of pharmaceutically acceptable salt or their any hydrate. The composition is used for simultaneous, separate or successive using in aims for inhibition of progression or treatment of proliferative disease. Also, invention comprises a package containing above said components. Proposed invention group provides the synergetic therapeutic effect in treatment of diseases said above.

EFFECT: valuable medicinal properties and enhanced effectiveness of composition.

5 cl, 4 ex

FIELD: medicine.

SUBSTANCE: method involves intravenously introducing chlorine row photosensitizer at a dose of 0.8-1.0 mg/kg, 70% of the dose being drop-by-drop infused during 10 min. The remaining 30% are introduced as bolus dose 1.5 h later. Photosensitizer introduction being finished, the neoplasm is transpupillarily exposed to laser radiation at wavelength corresponding to photosensitizer light absorption maximum with some overlap of neighboring fields. Tumor periphery is irradiated with intact tissue being caught not less than 1 mm far from ophthalmoscopically visible tumor boundary at power density of 25-40 J/cm2. Then, the whole tumor surface is concentrically irradiated from periphery to the center by applying power density of 110-120 J/cm2. 2 weeks later, photosensitizer intravenous injection is repeated and transpupillary laser radiation treatment of tumor surface. 2-4 intravenous photosensitizer injection sessions and tumor surface irradiation are given to achieve its complete resorption.

EFFECT: minimized adjacent intact tissue exposure; excluded recurrence and tumor dissemination in remote postoperative period.

2 cl

FIELD: chemical-pharmaceutical industry, medicine, oncology, pharmacy.

SUBSTANCE: invention proposes a solid medicinal formulation consisting of a core comprising diindolylmethane as an active substance, a binding agent, antioxidant, a rising agent, a lubricant, a filling agent, a stabilizing agent chosen from the following group: polyvinylpyrrolidone, croscarmelose, sodium alginate, calcium glycerophosphate or their mixtures, poloxamer and an enterosoluble envelope. Invention provides preparing the effective stable agent without adverse effects.

EFFECT: improved and valuable pharmaceutical properties of formulation.

2 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition, being solid drug, comprises nucleus containing Tamoxiphene, Di-indolyl methane as active substances, binding substance, at least one antioxidant, loosener, filler, stabilizer selected from a group containing polyvinyl pyrrolidon, croscarmelose, sodium alginate, calcium glycerophosphate or their mixtures and intestine-soluble coating.

EFFECT: enhanced effectiveness of treatment; reduced risk of adverse side effects.

4 cl, 4 dwg

FIELD: medicine.

SUBSTANCE: method involves applying endolymphatic- and autohemochemotherapy. Stage I of choriocarcinoma involves administering Methotrexate 20 mg/m2 as endolymphatic therapy at 1, 4, 8, 11, 15 and 18-th day; Rubomycin 30 mg/m2 at 1, 4, 8, 11, 15 and 18-th day Vinblastin - 15 mg/m2 at 1, 8 and 16-th day as autohemochemotherapy. Stage II of the disease involves administering Methotrexate 200 mg/m2 at the first day as endolymphatic therapy; Vincristin - 1.5 mg/m2 at 5,11, and 17-th day, Rubomycin 30 mg/m2 at 5, 8, 11, 14, 17 and 20-th day in a 21 days long course with 3 weeks long pause as autohemochemotherapy. The number of courses is 1-3. Stage III of the disease involves administering Methotrexate 200 mg/m2 as endolymphatic therapy, Etoposide -100 mg/m2, Kosmogen - 0.5 mg as autohemochemotherapy at the first day; Kosmogen - 0.5 mg as autohemochemotherapy at the second day; Vincristin - 1.0 mg/m2 Cyclophosphane 600 mg/m2, in 8 days long courses with 3-4 weeks interval and the number of courses is equal to 2-3.

EFFECT: eliminated metastases in the region of sexual organs and lungs; repaired menstrual cycle.

FIELD: biology, medicine, organic chemistry.

SUBSTANCE: invention proposes compound of the general formula (I): wherein A means effector group; L means a linker link; B represents Skulachev-ion Sk or charged hydrophobic peptide. Compound can be used in preparing a pharmaceutical composition for target (directed) delivery of active substances in mitochondria carried out by electrochemical potential of hydrogen ions into mitochondria. Also, invention can be useful in treatment of diseases and states associated with disturbance of normal function of mitochondria, in particular, diseases associated with increased formation of free radicals and active forms of oxygen. The claimed invention owing to directed accumulation of biologically active substance in mitochondria provides enhancing the effectiveness of substance, to decrease total dose, probability and strength of adverse effects.

EFFECT: improved and valuable properties of method and pharmaceutical composition.

26 cl, 14 dwg, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the general formula (I): wherein Y means >C=O or -CH2; Z means >C=O or -CH2; R1 means hydrogen atom or group of the formula: -CR3R4R5; R2 is chosen independently from group comprising halogen atom, halogen-(C1-C6)-alkyl, cyano-group; m = 1-3. Also, invention relates to medicinal agents containing these compounds possessing selective inhibitory properties with respect to monoaminooxidase B activity and used in treatment and prophylaxis of Alzheimer's disease and senile feeblemindedness.

EFFECT: valuable medicinal properties of compounds.

23 cl, 1 tbl, 64 ex

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