Prodrug of adenosine a2b receptor antagonists

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula in which R1 and R2 independently denote C1-6alkyl; R4 denotes phenyl, substituted with trifluoromethyl if necessary; X denotes hydrogen or methyl; and Y denotes -C(O)R, where R denotes C1-6alkyl; or Y denotes -P(O)(OR5)2, where R5 denotes hydrogen or C1-6alkyl; or pharmaceutically acceptable salts thereof. Said compounds are prodrugs of adenosine A2B receptor. The invention also relates to a pharmaceutical composition which is an adenosine A2B receptor antagonist based on the compound of formula I.

EFFECT: formula I compounds and the pharmaceutical composition can be used in treating different diseases in mammals, such as gastrointestinal disorders, immunological disorders, allergic disorders, neurological disorders, cardiovascular disorders and diseases associated with cell hyperproliferation.

13 cl, 1 tbl, 15 ex

 

The scope of the invention

The present invention relates to prodrugs of antagonists And2Bthe adenosine receptor and their use in the treatment in mammals of different painful conditions such as gastrointestinal disorders, immunological disorders, allergic disorders, neurological disorders and cardiovascular disease associated with hyperproliferating cells, and apoptosis, and the like, the Invention also relates to methods of producing such compounds and for containing pharmaceutical compositions.

The level of technology

Adenosine is a natural nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors, known as A1, A2AAnd2Band A3all of which modulate important physiological processes. For example, the receptors of adenosine A2Amodulate the expansion of coronary vessels, receptors And2Bparticipate in the activation of mast cells, asthma, vasodilation, regulation of cell growth, the functioning of the intestine and modulation of neurosecretion (Cm. Adenosine A2BReceptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Si 19:148-153), and the receptors of adenosine A3modulate the processes of cell proliferation.

Adenosine receptors And2Bare widespread and R is guiraut many biological activities. For example, adenosine binds to receptors And2Bon endothelial cells, thus stimulating angiogenesis. Adenosine also regulates the growth of populations of smooth muscle cells in blood vessels. Adenosine stimulates receptors And2Bon the fat cells, thus modulating allergic reactions Type 1. Adenosine stimulates secretory activity of the stomach by binding to And2Bin the intestine.

Although many of these biological actions of adenosine required to maintain normal tissue homeostasis, under certain physiological changes, it is desirable to modulate its effects. For example, the binding of receptors And2Bstimulates angiogenesis, promotora growth of endothelial cells. This activity is necessary for healing wounds, but hyperproliferative endothelial cells promotiom diabetic retinopathy. In addition, an unwanted increase of the blood vessels occurs in cancer processes. Accordingly, inhibition of the binding of adenosine to receptors And2Bin endothelia reduces or prevents hypervascularization, thus preventing retinopathy and inhibiting tumor formation.

Receptors And2Bfound in the colon in basolateral areas of intestinal epithelial cells, and under the appropriate esteem ligand they increased secretion of chlorides, thus causing you to have diarrhea, which is a common and potentially fatal complication of infectious diseases such as cholera and typhus. Antagonists And2Bcan therefore be used to block the secretion of chlorides in the gut, and thus they can be used in the treatment of inflammatory disorders of the gastrointestinal tract, including diarrhea.

Insensitivity to insulin increases diabetes and obesity. Insulin sensitivity decreases with the interaction with adenosine receptors And2B. Thus, blocking adenosine receptors And2Bpeople suffering from diabetes or obesity, may benefit patients with these disorders.

Other adverse biological effects of adenosine receptor And2Bis the hyperstimulation of cerebral IL-6, cytokine-related dementia and Alzheimer's. Inhibition of binding with adenosine receptors And2Bso it can soften those neurological disorders that are a consequence of the actions of IL-6.

Allergic disorders Type 1, such as chronic obstructive pulmonary disease (COPD), asthma, hay fever and allergic eczema, stimulated by binding to fat cells And2B-receptors. Accordingly, blocking these receptors adenosine provides Ter the non-therapeutic effect with respect to such violations.

There are some compounds currently used in the treatment of asthma. For example, theophylline is an effective anti-asthmatic agent, even though it is a weak antagonist of the adenosine receptor. However, its effectiveness requires a high plasma levels. Additionally, theophylline has a real side effects, most of which are the result of its action on the Central nervous system that does not provide any favorable effects against asthma and in fact he nonspecific blocking all subtypes of adenosine receptor.

Additionally, treatment with adenosine, such as inhalation of adenosine (or monophosphate adenosine), causes bronchospasm in asthmatics, but not in the normal population. This process, as is known, includes the activation of mast cells, in which it releases mediators of mast cells, including histamine, PGD2-β-hexosaminidase and tryptase. This reaction is blocked by specific blockers of histamine H1and chromulina sodium. Accordingly, there is an internal difference in the way that adenosine interacts with fat cells asthmatics, and thus antagonists And2Bespecially suitable for modulation of the functions of fat cells or activation of cells of the human lung.

In U.S. patent 6825349 open new Academy of Sciences of the agonists And 2Breceptor adenosine, which are potent and selective a2Bthe adenosine receptor. Defined category of preferred compounds disclosed in this patent application, in which position 7 xantinove part is unsubstituted. It is known that such compounds are relatively insoluble in aqueous media and are difficult to compile using conventional pharmaceutical excipients, and therefore potentially difficult to compile in a way that would ensure reproducible plasma levels of the evaluated compounds in mammals, in particular humans. The inventors have discovered compounds that are more soluble in aqueous media and/or conventional pharmaceutical excipients, and suddenly active as prodrugs of the compounds described in the '349.

The INVENTION

In U.S. patent 6825349 open new antagonists And2Bthe adenosine receptor. One variant of the invention according to the '349 represented by the following formula:

in which

R1and R2independently represent lower alkyl;

R3denotes hydrogen or, if necessary, substituted alkyl; and

R4indicates if necessary substituted phenyl

and pharmaceutically acceptable salts of this compound.

One preferred compounds within Formula A comprises compounds, in which position 7 xantinove part is unsubstituted; that is, where R3denotes hydrogen. Especially preferred are compounds in which R1and R2are different and denote lower alkyl, and R4denotes 3-triptoreline. However, it was found that the preferred compounds are relatively insoluble in aqueous media and are difficult to compile using conventional pharmaceutical excipients, and therefore potentially difficult to compile in a way that would ensure reproducible plasma levels of the evaluated compounds in mammals, in particular humans. It has been unexpectedly discovered that a small subpopulation of compounds of the Formula behaves as A prodrug preferred compounds. These compounds are selected from compounds of the Formula A in which R3denotes a substituted methyl; in particular compounds in which the substitution on the stands provides ester or a phosphate derivative. Such compounds are more soluble in aqueous media and/or conventional pharmaceutical excipients, than the compounds of Formula A, and provide a higher plasma is s levels of the active group (compounds of Formula A, in which R3is hydrogen)than by direct injection of the active group.

Accordingly, in a first aspect the present invention relates to prodrugs of Formula I, having the formula:

in which

R1and R2independently represent lower alkyl;

R4indicates if necessary substituted phenyl;

X denotes hydrogen or methyl; and

Y represents-C(O)R, where R independently represents, if necessary, substituted lower alkyl, and, if necessary, substituted aryl, or, if necessary, substituted heteroaryl; or

Y represents-P(O)(OR5)2where R5denotes hydrogen or lower alkyl, and, if necessary, substituted phenyl or heteroaryl; and their pharmaceutically acceptable salts.

One preferred group of compounds of Formula I are represented by the compounds in which R1and R2are ethyl or n-propylene, especially compounds in which R1is n-propylene, and R2- ethyl. Preferably, R4denotes 3-(trifluoromethyl)phenyl, and X is hydrogen.

One preferred subgroup includes the compounds of Formula I in which Y represents-C(O)R, especially compounds in which R is stands, ethyl, n-propylene, isopropyl, n-bootrom, isobutyl, tert.-BU the sludge or n-Pentium, more specifically where R is methyl, n-propyl or tert.-butyl. Another preferred subgroup includes the compounds of Formula I in which Y represents-P(O)(OR5)2especially where R3denotes hydrogen.

In a second aspect the present invention relates to a method of using compounds of Formula I for the treatment of a disease in a mammal, in respect of which can be improved by treatment with the antagonist And2Bthe adenosine receptor, in particular, atherosclerosis, angiogenesis, diabetic retinopathy, cancer, chronic obstructive pulmonary disease or asthma, or inflammatory disorders of the gastrointestinal tract, such as diarrhea, or neurological disorders, such as senile dementia, Alzheimer's or Parkinson's disease.

The third aspect of this invention relates to methods of preparing compounds of Formula I.

A fourth aspect of this invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compounds of Formula I and at least one pharmaceutically acceptable excipient.

Presently preferred are the following compounds:

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

[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(triptime the l)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl 2,2-dimethylpropanoate;

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

[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methyldihydromorphine.

Definitions and General options

In the present description, the following words and phrases generally have the meanings set forth below, except when the context in which they are used indicates otherwise.

The term "alkyl" refers to monoracial branched or unbranched saturated hydrocarbon chain having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. This term is illustrated by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-hexyl tert.-butyl, n-decyl, tetradecyl, etc.

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, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, phosphate, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl is about, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If the definition is not limited to other values, all substituents may if necessary be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2; or

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

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

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

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

The term "alkylene" refers to the divalent radical is branched or unbranched saturated hydrocarbon chain having 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 is illustrated by such groups as methylene (-CH2-), ethylene (-CH2CH2-), isomers of propylene (e.g.,- CH2CH2CH2- , and-CH(CH3)CH2and so on

The term "lower alkylene" refers to the divalent radical is branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5 or 6 carbon atoms.

The term "lower alkylene" refers to a twin-shaft the resultant radical branched or unbranched saturated hydrocarbon chain, preferably having from 1, 2, 3, 4, 5 or 6 carbon atoms.

The term "substituted alkylene" refers to:

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

2) alkalinous group, as defined above that is interrupted by 1-20 atoms independently chosen from oxygen, sulfur and NRand-, where Randselected from hydrogen, if necessary, substituted alkyl, cycloalkyl, cyclo is kanila, aryl, heteroaryl and heterocyclyl, or groups selected from carbonyl, carboxyester, carboxyamide and sulfonyl; or

3) alkalinous group, as defined above, having 1, 2, 3, 4 or 5 substituents 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-ethoxy-ethoxy)ethane (-CH2CH2O-CH2CH2-OCH2CH2-OCH2CH2and so on

The term "aralkyl" refers to an aryl group linked covalent bond with alkalinous group, where the aryl and alkylene such as defined here. "If necessary substituted aralkyl" refers to, if necessary, substituted aryl group, linked covalent bond with, if necessary, replaced alkalinous group. Such kalkilya groups are illustrated by benzyl, ventilation, 3-(4-methoxyphenyl)propylene, etc.

The term "alkoxy" refers to the group R-O-, where R denotes if necessary substituted alkyl or, if necessary, substituted cycloalkyl, or R denotes GRU is PU-Y-Z, in which Y is an if necessary substituted by alkylene, and Z denotes, if necessary, replaced alkenyl, if necessary substituted quinil; or if necessary replaced cycloalkenyl, where the alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl such as defined here. The preferred alkoxygroup are, if necessary, replaced by the group alkyl-O - and include, for example, methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, tert.-butoxy, Deut.-butoxy, n-pentox, n-hexose, 1,2-Dimethylbutane, triptoreline etc.

The term "alkylthio" refers to the group R-S-, where R has the meaning given to alkoxy.

The term "alkenyl" refers to monoracial branched or unbranched unsaturated hydrocarbon group preferably having 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 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]heptan etc. When alkenyl attached to the nitrogen, the double bond may not be in the position alpha with respect to nitrogen.

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

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

The term "quinil" refers to an unsaturated hydrocarbon manordeilo, preferably having from 2 to 20 carbon atoms, more preferably from 2 to 10 carbon atoms and more is preferably from 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkyline group include ethinyl, (-C≡CH), propargyl (or prop-1-in-3-yl, -CH2OCH), etc. When quinil attached to the nitrogen triple bond may not be in the position alpha with respect to nitrogen.

The term "substituted quinil" refers to alkynylaryl groups, 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, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If the definition is not limited to other values, all substituents may if necessary be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

The term "aminocarbonyl" otnositsa the group-C(O)NRR, where each R independently represents hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or where both groups R are connected, forming a heterocyclic group (for example, morpholino). If the definition is not limited to other values, all substituents may if necessary be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

The term "acylamino" refers to the group-NRC(O)R where each R independently represents hydrogen, alkyl, aryl, heteroaryl or heterocyclyl. If the definition is not limited to other values, all substituents may if necessary be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

The term "acyloxy" refers to the groups-O(O)C-alkyl, -O(O)C-cycloalkyl, -O(O)C-aryl, -O(O)C-heteroaryl, and-O(O)C-heterocyclyl. If the definition is not limited to other values, all substituents may if necessary be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, Carbo is valkila, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

The term "aryl" refers to aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g. phenyl) or multiple rings (e.g., biphenyls), or multiple condensed (fused) rings (e.g., naphthyl or until). Preferred arily include phenyl, naphthyl, etc.

The term "Allen" refers to diradical aryl group as defined above. This term is illustrated by such groups as 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, 1,4'-biphenylene etc.

If the definition is not limited to other values for aryl or ellenboro substituent, such aryl or Allen can if necessary be replaced by 1 to 5 substituents, preferably from 1 to 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, Alcock is amino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If the definition is not limited to other values, all substituents may if necessary be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

The term "aryloxy" refers to the group aryl-O-, where the aryl group is above a certain value, and includes, if necessary, substituted aryl groups as also defined above. The term "aristeo" refers to the group R-S-, where R has the meaning as defined for aryl.

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

The term "substituted amino" refers to the group-NRR where each R is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyethyl (for example, benzyloxycarbonyl), aryl, heteroaryl and heterocyclyl, provided that both groups of R does not represent hydrogen, or the group-Y-Z, in which Y is an if necessary substituted by alkylene, and Z denotes alkenyl, cycloalkenyl or quinil. If the definition is not limited to other values, all substituents may if necessary be optional samewe is s 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

The term "carboxylic" refers to the groups-C(O)O-alkyl, -C(O)O-cycloalkyl, where the alkyl and cycloalkyl such as defined here, and may be, if necessary, optionally substituted alkyl, alkenyl, quinil, alkoxy, halogen, CF3, amino, substituted amino, cyano or-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

The term "cycloalkyl" refers to carbocyclic groups consisting of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, for example, a ring structure with a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like, or a ring structure with multiple rings, such as substituted, 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, etc.

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

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

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

The term "heteroaryl" refers to an aromatic cyclic group is e (that is, fully unsaturated), having 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 sulfur in the composition at least one ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl, benzothiazolyl or benzothiazyl). Examples of heteroaryl include, but are not limited to, [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, fentazin, imidazolidin, imidazolin, etc. and N-alkoxy-nitrogen-containing heteroaryl compounds.

The term "heteroaryl" refers to diradical heteroaryl group, as defined above. This term is illustrated by such groups as 2.5-imidazole, 3,5-[1,2,4]oxadiazole, 2,4-oxazole, 1,4-pyrazole, etc. for Example, 1,4-pyrazolin represents:

where A denotes the attachment point.

If the definition is not limited to other values for heteroaryl or heteroarenes Deputy, such Goethe is aeril or heteroaryl can be, if necessary substituted by 1-5 substituents, preferably 1-3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaromatic, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If the definition is not limited to other values, all substituents may if necessary be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

The term "heteroalkyl" refers to a heteroaryl group, connected by a covalent bond with alkalinous group where heteroaryl and alkylene such as defined here. "If necessary substituted heteroalkyl" refers to, if necessary, substituted heteroaryl group, connected by a covalent bond with, if necessary, replaced by Ala is lenovos group. Such heteroalkyl groups are illustrated 3-pyridylmethyl, quinoline-8-ilation, 4-methoxythiazole-2-ylpropyl etc.

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

The term "heterocyclyl" refers to monologically saturated or partially unsaturated group having a single ring or multiple condensed rings, having 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 composition of the rings. Heterocyclic groups can have a single ring or multiple condensed rings and include tetrahydrofuranyl morpholino, piperidinyl, piperazine derivatives, dihydropyridine etc.

If the definition is not limited to other values for the heterocyclic substituent, such heterocyclic groups can be, if necessary substituted by 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, quinil, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonyl, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyamide, aaltio, heteroaromatic, heterocyclic, thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonyl, heteroaryl and, heterocyclyl, heterocyclic, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl and-SO2-heteroaryl. If the definition is not limited to other values, all substituents may if necessary be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyamide, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(O)nR, where R denotes alkyl, aryl or heteroaryl and n=0, 1, or 2.

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

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

The term "heteroaryl" refers to the group-S-heteroaryl in which heteroaryl is the same as defined above, including, if necessary, substituted heteroaryl groups as also defined above.

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

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

The term "keto" refers to the group-C(O)-. The term "thiocarbonyl" refers to the group-C(S)-. The term "carboxy" refers to the group-C(O)-HE.

"If necessary" means that the described event or circumstance may or may not take place, and that the description includes options where specified event or circumstance occurs and ways in which he(it) has no place.

The term "compound of Formula I comprises compounds according to the invention, as they are disclosed, and pharmaceutically acceptable salts, pharmaceutically acceptable esters, prodrugs, hydrates and polymorphs of such compounds. Additionally, the compounds according to the invention can have one or more centers of asymmetry, and can be obtained as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers in any given compound of Formula I depends on the number of centers of asymmetry (can be 2npossible stereoisomers, where n denotes the number of centers of asymmetry). The individual stereoisomers may be obtained by separation of the racemic or prizemistoj mixture of the intermediate at some appropriate stage of the synthesis or separation of the compounds of Formula I by conventional means. Individual stereoisomers (including individual enantion the market and diastereoisomer), as well as racemic and nerezisca mixture of stereoisomers are within the scope of the present invention, and all of them are be represented by the structures shown in the present description, unless otherwise specified.

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

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

"Enantiomers" are a pair of stereoisomers that are non-overlapping mirror mirroring each other. A mixture of 1:1 pair of enantiomers represents a "racemic" mixture. The term "(±)" is used to denote a racemic mixture where it is needed.

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

The absolute stereochemistry determined by the R-S Cahn-Ingold-Prelog. When the compound is a pure enantiomer the stereochemistry at each chiral carbon may be specified as R or S. the Split connection, the absolute configuration of which is unknown, are determined by (+) or (-) depending on the direction (right or levogyrate), in which they reject the plane of polarized light at a wavelength of D-if the AI sodium.

The term "therapeutically effective amount" refers to that amount of the compounds of Formula I that is sufficient to effect the treatment, as defined below, when administered to a mammal. A therapeutically effective amount varies depending on the patient and treatable condition, body weight and age of the patient, severity of the disease condition, the route of administration, etc. that can be easily determined by the expert.

The term "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) inhibiting the disease, i.e. stopping the development of clinical symptoms; and/or

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

In many cases, the compounds according to the present invention can form a salt with the acid and/or base due to the presence of amino and/or carboxyl groups, or such 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 salts of the connection base can be derived from inorganic and organizations of the practical reason. Salts derived from inorganic bases include, only as an example, salts of sodium, potassium, lithium, ammonium, calcium and magnesium. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines followed, diallylamine, triallylamine, substituted alkylamines followed, di(substituted alkyl)amines, three(substituted alkyl)amines, alkenylamine, dialkanolamine, trialkylamine, substituted alkanolamine, di(substituted alkenyl)amines, three(replaced alkenyl)amines, cyclooctylamine, di(cycloalkyl)amines, three(cycloalkyl)amines, substituted cycloalkene, the disubstituted cycloalkenyl, Transnistria cyclooctylamine, cyclooctylamine, di(cycloalkenyl)amines three(cycloalkenyl)amines, substituted cycloalkenyl, the disubstituted cycloalkenyl, Transnistria cyclooctylamine, arylamine, diarylamino, triarylamine, heteroaromatic, digitalairlines, triethanolamine, heterocyclic amines, diheterocyclanes amines, trilateration amines, mixed di - and tri-amines where at least two of the substituents on Amina are different and selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, hetero is the Tcl etc. Also in the scope of the invention include amines, where two or three deputies, together with the amino nitrogen, form a heterocyclic group or heteroaryl.

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

Pharmaceutically acceptable salt accession acid can be derived from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, almond acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, etc.

In the framework of the invention the pharmaceutical is Ki acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and inhibits the absorption of funds, etc. the Use of this medium and means for pharmaceutically active substances is well known in the prior art. Except when any standard environment or tools are incompatible with the active ingredient, its use in therapeutic compositions is possible. Supplementary active ingredients can also be included in the composition.

In the framework of the invention, the term "prodrug" denotes a compound that is metabolized in vivo into the compound, which is active as an antagonist of A2Bthe adenosine receptor.

Nomenclature

The name and numbering of the compounds according to the invention are exemplified by the compounds of Formula I in which R1denotes n-propyl, R2denotes ethyl, R4denotes 3-tryptophanyl, X denotes hydrogen, and Y represents-C(O)CH2CH2CH3;

which is called

[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methylbutanoate.

The parameters of the synthesis reaction

The terms "solvent", "inert organic solvent" or "inert solvent" mean a solvent inert under the conditions of the reaction, described as applied to them [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), simple, diethyl ether, methanol, pyridine and the like]. Unless otherwise stated, solvents used in the reactions according to the present invention are inert organic solvents. The term "q.s." means adding a quantity sufficient to achieve the claimed function, for example, to bring the solution up to the desired volume (i.e. 100%).

The synthesis of compounds of Formula I

Method of producing compounds of the Formula I in which Y denotes an if necessary substituted lower alkyl, and, if necessary, substituted aryl, or, if necessary, substituted heteroaryl shown in Reaction Scheme I.

A REACTION SCHEME I

where R1, R2, R4X and Y have the meanings given above.

In General, the compound of formula (1) is introduced into the reaction in a polar solvent, for example N,N-dimethylformamide, with a compound of formula YOCHXCl. The reaction is carried out at a temperature of from about 30 to 80°C., preferably about 60°C, in the presence of a base, preferably an inorganic base, e.g. potassium carbonate, for about 8-24 hours. When the reaction is basically C is completed, the product of Formula I produce by conventional means, for example, preparative chromatography.

The original compound of formula (1) can be obtained by methods disclosed in U.S. patent 6825349, or disclosed in Application for U.S. patent No. 10/719102, publication number 20040176399, the entire contents of which are hereby incorporated by reference.

When Y represents-C(O)R, where R is a heterocycle, the compound of the formula (2) (RC(O)OCHXCl) is commercially available or can be obtained as shown below, using, for example, pyridine.

In General, the carboxylic acid of the formula (a) is introduced into the reaction in an inert solvent, for example dichloromethane, with CHLOROTHALONIL derivative of the formula (b) in the presence of Quaternary salts, for example tetrabutylammonium sulfate. The reaction is carried out at a temperature of approximately 0°C, in the presence of a base, preferably an inorganic base, for example sodium bicarbonate, followed by reaction at room temperature for about 2-10 hours. When the reaction is substantially completed, the product, the chloromethylpyridine-3-carboxylate, isolated by conventional means.

Urethane derivatives can be obtained as shown in reaction scheme II.

A REACTION SCHEME II

where R1, R2and R4have the meanings set is installed above and RandRbNH denotes Amin.

In General, the amine of formula RandRbNH is introduced into the reaction in a polar solvent, for example N,N-dimethylformamide, chloromethylphosphonate at a temperature of approximately 0°C, in the presence of a base, preferably an inorganic base, for example potassium carbonate, in a period of approximately 1 hour. Then add a solution of the compound of formula (1) in a polar solvent at 0°C and carry out the reaction in the mixture for 24 hours, allowing the temperature to rise to room temperature. When the reaction is substantially completed, the product of Formula I produce by conventional means, for example, preparative chromatography.

To obtain the ether derivative compounds of formula (1), the compound of formula (1) is introduced into the reaction in the usual manner with a suitable CHLOROTHALONIL ether.

The method of obtaining the compounds of Formula I in which Y represents-P(O)(OH)2shown in reaction scheme III.

A REACTION SCHEME III

Stage 1

In General, the compound of the formula (2) is injected into the reaction with the compound of the formula (1) in a polar solvent, for example N,N-dimethylformamide, at a temperature of about 30-90°C, in the presence of a base, preferably an inorganic base, for example potassium carbonate, for about 4-24 hours. When the reaction in the OS is the RAM is completed, the product of formula (3) is recovered by conventional means and purified, for example, preparative chromatography.

Stage 2

In the product of formula (3) remove the protective group in the usual way using a strong acid, for example triperoxonane acid, or, alternatively, a weak acid, such as formic acid, in an inert solvent, for example dichloromethane. The reaction is carried out at about room temperature for about 4-24 hours. When the reaction is substantially completed, the product of Formula I in which Y represents-P(O)(OH)2allocate conventional means and purified, for example, preparative chromatography.

The source material of the Formula (2)

The compound of the formula (2), di-tert.-butylchloroformate, derived from bis(tert.-butoxy)phosphino-1-ol as shown below.

Stage 1

In General, the compound of formula (a), bis(tert.-butoxy)phosphino-1-ol, is introduced into reaction with an oxidant such as potassium permanganate, in the presence of a weak base, such as potassium bicarbonate, in aqueous solvent. The reaction is carried out initially at a temperature of approximately 0°C, and then at about room temperature for about 1 hour. When the reaction is substantially completed, the product of formula (b), di-tert.-butylhydrazine, there are the usual medium is you for example, acidification and filtration of the formed phosphate.

Stage 2

Originally salt Tetramethylammonium (b) obtained by reaction of di-tert.-butylhydrazine hydroxide of Tetramethylammonium in an inert solvent, for example acetone, at a temperature of approximately 0°C. Tetramethylammonium salt of di-tert.-butylhydrazine produce by conventional means, for example by removal of solvent.

Then Tetramethylammonium salt of di-tert.-butylhydrazine enter into reaction with a derivative dehalogenation, such as dibromomethane or chloroiodomethane, in an inert solvent, for example 1,2-dimethoxyethane. The reaction is carried out at a temperature of about 60-90°C. When the reaction is substantially completed, the product formula (2) is recovered by conventional means.

Suitability, testing and introduction

General fitness

The compounds of Formula I effective in vivo for the treatment of conditions that respond to the introduction of the antagonists A2Bthe adenosine receptor. Such conditions include, but are not limited to, at least one condition from among diarrhea, atherosclerosis, restenosis, diabetic retinopathy, cancer, senile dementia, Alzheimer's disease, Parkinson's disease, traumatic brain damage and allergic reactions Type 1, including chronic obstructive disease of the Le is the fir (COPD), asthma, allergic eczema and hay fever.

The pharmaceutical composition

The compounds of Formula I is usually administered in the form of pharmaceutical compositions. The invention therefore relates to pharmaceutical compositions that contain, as the active ingredient one or more compounds of the Formula I, or 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, penetration enhancers, soljubilizatory and adjuvants. The compounds of Formula I can be administered individually or in combination with other therapeutic agents. Such compositions produced by the method known in the field of pharmacy (see, for example, Remington''s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17thEd. (1985) and "Modern Pharmaceutics", Marcel Dekker, Inc. 3rdEd (G.S. Banker & CT. Rhodes, Eds.).

Introduction

The compounds of Formula I can be administered in a single dose or multiple doses by any of the accepted methods of introducing tools that have similar applicability, for example, as described in the patents and patent applications incorporated by reference, including rectal, buccal, intranasal and transcutaneous route, intra-arterial injection, intravenously, intraperitone the social, parenterally, intramuscularly, subcutaneously, orally, tapicerki, by inhalation or by using impregnated or coated device such as a stent, for example, or injected into the artery cylindrical polymer.

One method of administration is parenteral, especially by injection. Shape, in which new compositions according to the present 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 similar pharmaceutical carriers. Aqueous solutions in saline is also traditionally used for injection, but less preferred in the context of the present invention. Can also be used ethanol, glycerin, propylene glycol, liquid polyethylene glycol and the like (and suitable mixtures of these substances), cyclodextrin derivatives and vegetable oils. Internal fluidity can be maintained, for example, by use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by using surfactants. Prevention of the action of microorganisms can be carried out with various antibacterial and antifungal agents, for example, the p parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like

Sterile injectable solutions, get, including the compound of Formula I in the required amount in the appropriate solvent with various other ingredients such as those listed above, if necessary, with subsequent sterilizing filtration. In General, dispersion receive, including the various sterilized active ingredients into a sterile vehicle, which contains the basic dispersion medium and other necessary ingredients from above. In the case of sterile powders for obtaining sterile injectable solutions, the preferred methods of obtaining methods are vacuum drying and drying by sublimation, which lead to the powder of the active ingredient plus any additional desired ingredient from a previously sterile filtered solution.

Oral administration is another route of administration of compounds of Formula I. Introduction can be carried out using capsules or tablets, coated intersolubility coating, etc. In obtaining pharmaceutical compositions that include at least one compound of Formula I, the active ingredient is usually diluted by excipients and/or included in such media, which may be in the form of a capsule, sachet, paper or the other of the container. When excipient serves as a diluent, it may be solid, semi-solid or liquid material (as described above), which acts as a carrier, or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, candies, Sasha, those capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (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, gum Arabic, calcium phosphate, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The compositions may additionally include lubricants, such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspendresume agents; preservatives, such as methyl - and propylhydroxybenzoate; sweetening means; and aromatic funds.

The composition of the invention can be designed to provide a fast, slow or delayed release of the active ingredient after administration to the patient, with the COI is whether the procedures known in this field. System drug delivery controlled release for oral administration include solutions the osmotic pump system of dissolution containing polymer coated tanks or formulations of the drug-polymer matrix.

Examples of controlled release systems are shown in U.S. Patents 3845770; 4326525; 4902514 and 5616345. In another composition for use in the methods according to the present invention using the device for percutaneous delivery ("patches"). Such transdermal patches may be used to provide continuous or intermittent infusion of the compounds according to the present invention in controlled amounts. Construction and use of transdermal patches for the delivery of pharmaceutical agents known in the prior art. See, for example, the U.S. patents 5023252, 4992445 and 5001139. Such patches can be created for continuous, pulsating delivery or on demand delivery of pharmaceutical products.

The compositions are preferably in dosage forms. The term "dosage form" refers to physically discrete units suitable as single doses to humans and other mammals, each form contains a predetermined amount of the active substance, designed the e thus, to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient (for example, tablet, capsule, ampoule). The compounds of Formula I are effective in a wide range of doses and are usually put in pharmaceutically effective amounts. Preferably, for oral administration, each dosage form contains from 10 mg to 2 g of compound of Formula I, more preferably from 10 to 700 mg, and for parenteral administration, preferably from 10 to 700 mg of the compounds of Formula I, more preferably about 50-200 mg Will be clear, however, that the amount of injected compounds of Formula I will be determined by the physician in light of the attendant circumstances, including the condition to be treated, the chosen route of administration, the actual input connection and its relative activity, the age, body weight and individual response of the patient, severity of the patient's symptoms, etc.

For solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient, getting a preliminary composition comprising a homogeneous mixture of compounds according to the present invention. Under the instruction of these prior compositions as homogeneous is meant that the active ingredient is dispersed evenly throughout the composition so that h the Oba composition could be readily subdivided into equally effective dosage forms, such as tablets, pills and capsules.

Tablets or pills according to the present invention may have a coating or may be otherwise designed to provide a dosage form having an advantage in terms of duration of action, or to provide protection against the acidic environment of the stomach. For example, the tablet or pill can include the internal dose component and the external dose component, the latter is in the form of a protective coating. These two components can be separated intersolubility layer, which serves for resistance to degradation in the stomach and pass an internal component in the intact condition in the duodenum or to delay the release. For such intersolubility layers or coatings can be used a variety of materials, including a large 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 as described above. Preferably, the composition is administered oral or nasal respiratory route for me is private or systemic action. The compositions are preferably in pharmaceutically acceptable solvents can be sprayed by means of inert gases. Sprayable solutions can be inhaled directly from the spraying device or spray device can be attached to the face mask or to the intermediate mechanism for creating positive pressure. Compositions in the form of a solution, suspension or powder may be administered, preferably orally or through the nose, using devices that provide the composition in a suitable manner.

The following examples are included to demonstrate preferred embodiments of the invention. The specialist will be clear that the techniques disclosed in the examples that follow represent techniques discovered by the authors as a well-functioning in practice of the invention, and thus, it can be assumed that they constitute preferred modes for its practice. However, in light of the present disclosure specialist will be understood that in the disclosed private options for implementation may be introduced various changes to the collection, however, like or similar result without deviation from the spirit and scope of the invention.

EXAMPLE 1

Obtaining the compounds of Formula I

Obtaining the compounds of formula I, where R1denotes n-propyl, R 2denotes ethyl, R4denotes 3-triptoreline, X is hydrogen and Y denotes n-butanol

To a solution of 3-ethyl-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione (250 mg, of 0.56 mmol) in N,N-dimethylformamide (10 ml) was added potassium carbonate (230 mg, 1,68 mmol), then chloromethylated (230 mg, 1,68 mmol)and the mixture was stirred at 60°C for 16 hours. The solid was filtered and the solvent removed from the filtrate under reduced pressure. The residue was subjected to chromatography on silica gel, elwira 30% ethyl acetate/hexane, receiving [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methylbutanoate (150 mg).1H NMR (CDCl3): δ 7,98 (s, 1H), of 7.97 (s, 1H), 7,65 was 7.45 (m, 4H), 6.35mm (s, 2H), 5,44 (s, 2H), 4,19 (kV., J=8 Hz, 2H), 3,98 (sq, J=2 Hz, 2H), 2,33 (t, J=8 Hz, 2H), 1,75-to 1.60 (m, 4H), of 1.36 (t, J=8 Hz, 3H), of 0.96 (t, J=8 Hz, 3H), of 0.92 (t, J=8 Hz, 3H).

B.Obtain other compounds of Formula I

Similarly, following the procedure of 1A above, but replacing chlorociboria chloromethyl-2,2-dimethylpropanoate received [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl 2,2-dimethylpropanoate.1H NMR (CDCl3): δ 7,98 (s, 1H), of 7.97 (s, 1H), 7,65 was 7.45 (m, 4H), 6,33 (s, 2H), 5,43 (s, 2H), 4,19 (sq, J=8 Hz, 2H), 3,98 (sq, J=2 Hz, 2H), 1,75-of 1.64 (m, 2H), of 1.37 (t, J=8 Hz, 3H), of 1.16 (s, 9H), is 0.96 (t, J= Hz, 3H).

Similarly, following the procedure of 1A above, but replacing chlorociboria chloromethylation received [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]acetate.1H NMR (CDCl3): δ 7,98 (s, 1H), of 7.97 (s, 1H), 7,65 was 7.45 (m, 4H), 6.35mm (s, 2H), 5,44 (s, 2H), 4,19 (sq, J=8 Hz, 2H), 3,98 (sq, J=2 Hz, 2H), 2,33 (t, J=8 Hz, 2H), 1,75-to 1.60 (m, 4H), of 1.36 (t, J=8 Hz, 3H), of 0.96 (t, J=8 Hz, 3H), of 0.92 (t, J=8 Hz, 3H).

Similarly, following the procedure of 1A above, but replacing chlorociboria chlorine(2S)-1-[benzyloxycarbonyl]pyrrolidin-2-carboxylate, was obtained [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl (2S)-1-[benzyloxycarbonyl]pyrrolidin-2-carboxylate. NMR of this compound was satisfactory.

C.Obtain other compounds of Formula I

Similarly, following the procedure of 1A above, but replacing chlorociboria other compounds of formula YOCHXCl, in which X and Y have the meanings given above were obtained the following compounds of Formula I:

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

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

[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]-3-(triptime the l)benzoate;

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

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

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

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

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

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

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

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

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

2-({[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl}oxycarbonyl)acetic acid;

3-({[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl}oxycarbonyl)propanoic acid;

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

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

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

[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl-3-[(oxiranylmethyl)methoxy]butanoate;

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

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

[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl-4-morpholine-4-eventout; and

[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methylpyridin-3-carboxylate.

EXAMPLE 2

Obtaining a urethane derivative compounds of Formula (1)

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

Chloromethylphosphonate (0,319 mmol) and 1-methylpiperazine (0,319 mmol) were mixed in N,N-dimethylformamide (2 ml) at 0°C in the presence of potassium carbonate (1,325 mmol). After 1 hour was added before artelino cooled solution of 3-ethyl-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione (0,265 mmol) in N,N-dimethylformamide (1 ml), and the mixture was stirred for 24 hours, allowing the temperature to rise to room temperature. The solvent was removed under reduced pressure, and the residue was subjected to preparative thin-layer chromatography, elwira 5% methanol/methylene chloride, receiving 150 mg of [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl-4-methylpiperazine. Similarly, there were obtained the following compounds:

N-[2-(dimethylamino)ethyl]{[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methoxy}carboxamide;

N-[2-(dimethylamino)ethyl]{[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methoxy}-N-methylcarbamate; and

N-[((2S)-1-ethyl(2-piperidyl))methyl]{[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methoxy}carboxamide.

EXAMPLE 3

Receiving phosphate derivative compounds of Formula (1)

Obtain [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methyldihydromorphine

Stage 1 -Obtaining di-tert.-butylchloroformate (Formula (2))

a)Obtaining di-tert.-butylhydrazine

To a stirred solution of bis(tert.-butoxy)f is Spino-1-ol (0,78 g, 4 mmol) and potassium bicarbonate (0.6 g, 2.4 mmol) in water (4 ml) at 0°C was added (in portions) potassium permanganate (0,44 g, 2.8 mmol). The mixture was allowed to warm to room temperature and was stirred for 1 hour. Added decolorizing activated carbon (60 mg)and the mixture was stirred at 60°C for 15 minutes, and then filtered. The thus obtained solid substance was washed with water (30 ml)and the combined filtrate was treated with an additional 100 mg of decolorizing activated carbon at 60°C for 20 minutes. The mixture was filtered, and the filtrate was cooled to 0°C and carefully acidified with concentrated hydrochloric acid (2 ml) under stirring. The precipitate was filtered, washed with cold water, receiving di-tert.-butylhydrazine in the form of a solid white color.

Getting Tetramethylammonium salts of di-tert.-butylhydrazine

A solution of di-tert.-butylhydrazine obtained in stage a), was dissolved in acetone (10 ml) and cooled to 0°C. To this solution was added a 10%aqueous solution of hydroxide of Tetramethylammonium (2.4 ml, 2.6 mmol), and the homogeneous solution was evaporated under reduced pressure, obtaining a solid, which was recrystallized from heated under reflux 1,2-dimethoxyethane, receiving di-tert.-butylhydrazine of Tetramethylammonium in the form of a solid white color is the same.

Di-tert.-butylhydrazine of Tetramethylammonium obtained at stage b, was dissolved in heated under reflux 1,2-dimethoxyethane (15 ml), and added chloroiodomethane (3.2 g, to 18.1 mmol), and the mixture was heated under reflux for 90 minutes. The solvent was removed under reduced pressure, and the residue, di-tert-butylchloroformate, used without further purification.

Stage 2

A solution of 3-ethyl-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione (of 0.47 g, 1 mmol) was dissolved in 20 ml of N,N-dimethylformamide, was added potassium carbonate (0,42 g, 4 mmol), then di-tert-butylchloroformate (0.34 g, of 1.32 mmol)and the mixture was stirred at 60°C over night. The reaction mixture was cooled and filtered precipitate was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified preparative thin-layer chromatography, elwira 4% methanol/methylene chloride, getting tert-butyl[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methyl methylethylacetate (0.26 g) in the form of a colorless oil.

Stage 3

A solution of tert-butyl[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methyl methylethylacetate (80 mg, 0.12 mmol) was dissolved in methylene chloride (6 ml) was added triperoxonane acid (0.7 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the solid white residue was ground into powder with simple ether and was taken by filtration, receiving [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methyldihydromorphine (41 mg).

NMR1H-NMR (DMSO-d6) δ to 8.70 (s, 1H), 8,15 (s, 1H), 7,74 (s, 1H), 7,69-7,71 (m, 1H), 7,60-7,63 (m, 2H), 6,12 (d, 2H, J=5.4 Hz), 5,54 (s, 2H), 4,06 (square, 2H, J=13,8 Hz), of 3.84 (t, 2H, J=7.4 Hz), 1,52-of 1.62 (m, 2H), 1,25 (t, 3H, J=7,0 Hz)of 0.87 (t, 3H, J=7.4 Hz); MSm/z579,02 (M++Na).

EXAMPLE 4

Obtaining the compounds of Formula (1)

Obtaining the compounds of Formula I in which R1denotes n-propyl, R2denotes ethyl, R4denotes 3-triptoreline, X is hydrogen and Y denotes n-butanol

A.Getting chloromethylpyridine-3-carboxylate

A mixture of nicotinic acid (200 mg, 1.6 mmol), sodium bicarbonate (540 mg, 6.4 mmol) and tetrabutylammonium sulfate (54 mg, 0.16 mmol) was dissolved in a mixture of 4 ml of dichloromethane and 4 ml of water and cooled to 0°C. To this stirred mixture was added chlormethiazole (165 μl, 1.6 mmol) in 1 ml dichloromethane, and the mixture was allowed to warm to room temperature, stirring overnight. The organic layer was separated, washed with brine, drying is whether over sodium sulfate and concentrated under reduced pressure to a yellow oil, which was dissolved in dichloromethane and filtered through a cartridge with silica gel. Removal of solvent under reduced pressure was obtained chloromethylpyridine-3-carboxylate (70 mg).

B. Obtaining[3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methylpyridin-3-carboxylate

A solution of 3-ethyl-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-2,6-dione (200 mg, 0.43 mmol) was dissolved in 2 ml N,N-dimethylformamide, was added potassium carbonate (120 mg, 0.86 mmol), then the chloromethylpyridine-3-carboxylate (220 mg, 1.3 mmol). The mixture was stirred at 60°C overnight, the solid material was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by thin-layer chromatography, elwira 5% methanol/dichloromethane, receiving [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl pyridine-3-carboxylate (66 mg).

NMR of the product was satisfactory.

EXAMPLE 5

Received gelatin capsules containing the following ingredients:

Number
Ingredient(mg/capsule)
Activelyengaged 30,0
Starch305,0
Magnesium stearate5,0

The above ingredients were mixed and filled into hard gelatin capsules.

EXAMPLE 6

The formula tablets were obtained using the ingredients listed below:

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

The components were mixed and extruded, getting pills.

EXAMPLE 7

Got a dry powder composition for inhalation containing the following components:

Ingredientwt.%
The active ingredient5
Lactose95

The active ingredient was mixed with the lactose and the mixture is added to the device for inhalation of a dry powder.

EXAMPLE 8

Tablets, each containing 30 mg of active ingredient, was 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
The sodium carboxymethyl starch4.5 mg
Magnesium stearate0.5 mg
Talc1.0 mg
The total number of120 mg

The active ingredient, starch and cellulose was passed through a sieve with a pore size No. 20 mesh U.S. and carefully move is stirred. The solution of polyvinylpyrrolidone were mixed with the obtained powder, and the resulting mixture was passed through a sieve with a pore size No. 16 mesh U.S. thus Obtained granules were dried at a temperature of from 50°C to 60°C and passed through a sieve with a pore size No. 16 mesh U.S. Sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a sieve with a pore size No. 30 mesh U.S, was added to the granules which, after mixing, extruded on a machine for tabletting, getting a tablet weight of 120 mg each.

EXAMPLE 9

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

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

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

EXAMPLE 10

Suspensions, each of the I of which contains 50 mg of active ingredient in a dose of 5.0 ml, received 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 benzoate10.0 mg
Flavoring and coloringq.v.
Purified water to5.0 ml

The active ingredient, sucrose and xanthan resin were mixed, passed through a sieve with a pore size No. 10 mesh U.S., and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, flavoring and dye was diluted part of water was added under stirring. Then added water in an amount sufficient to obtain the required volume.

EXAMPLE 11

the left is for subcutaneous administration may be obtained in the following way:

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

EXAMPLE 12

Get the drug for injection having the following composition:

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

EXAMPLE 13

Get the product for topical application having the following composition:

Ingredientgrams
The active ingredient0,2-10
Span 602,0
Tween 602,0
Mineral oil5,0
Vaseline0,10
Methylparaben0,15
Propylparaben0,05
BGA (bottled hydroxyanisol)0,01
Waterq.s. 100

All the ingredients, except water, are combined and heated to 60°C under stirring. Sufficient amount of water with a temperature of 60°C is added under vigorous stirring to emulsify the ingredients, and then add q.s. water up to 100 g

EXAMPLE 14

Tests And2Bthe adenosine receptor

Methods

The binding of the labeled ligand with a2Bthe adenosine receptor.

cDNA And2Breceptor adenosine man steadily transferout cells HEK-293 (called cells HEK-A2B). A monomolecular layer of cells HEK-A2B washed with PBS once and harvested in a buffer containing 10 mm HEPES (pH 7.4), 10 mm EDTA, and protease inhibitors. These cells are homogenized in polirone within 1 minute position in the NII 4 and centrifuged at 29000 g for 15 minutes at 4°C. Precipitated cells are washed once with buffer containing 10 mm HEPES (pH of 7.4), 1 mm EDTA and protease inhibitors, and re-suspended in the same buffer, supplemented with 10%sucrose. Frozen aliquots maintained at -80°C. Begin tests on competition, 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 adelaideans. Test samples are incubated for 90 minutes, stopped by filtration using a Packard Harvester, and washed four times chilled on ice buffer TM (10 mm Tris, 1 mm MgCl2, pH 7.4). The nonspecific binding determined in the presence of 10 μm ZM214385. The affinity of compounds (i.e., the value of Ki), calculated using the software GraphPad.

The binding of the labeled ligand with other adenosine receptor

Human cDNA And1, A2AAnd3adenosine receptor stably transferout in CHO cells or cells HEK-293 (called CHO-A1, HEK-A2A, CHO-A3). Membranes obtained from these cells using the same Protocol as described above. Begin tests on competition, mixing 0.5 nm3H-CPX (CHO-A1), 2 nm3H-ZM214385 (HEK-A2A) or 0.1 nm125I-AB-MECA (CHO-A3) with different concentrations of the test compounds and the respective membranes in TE buffer (50 mm Tris and 1 mm EDTA for CHO-A1 and HEK-2A) or buffer (50 mm Tris, 1 mm EDTA and 10 mm MgCl2for CHO-A3), supplemented with 1 unit/ml adelaideans. Test samples are incubated for 90 minutes, stopped by filtration using a Packard Harvester and washed four times chilled on ice buffer TM (10 mm Tris, 1 mm MgCl2, pH 7.4). The nonspecific binding determined in the presence of 1 μm CPX (CHO-A1), 1 μm ZM214385 (HEK-A2A) and 1 μm IB-MESA (CHO-A3). The affinity of compounds (i.e., the value of Ki), calculated using the software GraphPad.

Measurement of camp

Monomolecular layer transfected cells are harvested in PBS containing 5 mm EDTA. Cells are washed once with DMEM and re-suspended in DMEM containing 1 unit/ml adelaideans, density 100000-500000 cells/ml 100 ál of cell suspension is mixed with 25 µl, containing various agonists and/or antagonists, and the reaction samples maintained at 37°C for 15 minutes. At the end of 15 minutes, add 125 ál of 0.2 N. HCl to stop the reaction. Cells are centrifuged for 10 minutes at 1000 rpm and 100 μl of supernatant are collected and acetimidoyl. The concentration of camp in the supernatant was measured using the direct cyclic amp-test from Assay Design.

A2Aand a2Badenosine receptors combine with proteins Gs and thus agonists A2Athe adenosine receptor (such as CGS21680) or a2Bthe adenosine receptor (such as NECA) increased accumulation of camp, then the AK antagonists of these receptors prevents the increase in the accumulation of camp, caused by agonists. And1and A3adenosine receptors combine with proteins Gi, and thus agonists And1the adenosine receptor (such as CPA) or a3the adenosine receptor (such as IB-MESA) inhibited the increase in the accumulation of camp induced by Forskolin. Antagonists And1and A3receptors prevents the inhibition of the accumulation of camp.

EXAMPLE 15

Comparison of the bioavailability of the prodrugs And2Bthe adenosine receptor with an antagonist And2Breceptor adenosine

The following studies were performed to compare the pharmacokinetic antagonist And2Breceptor adenosine and its prodrugs. Selected related compound was a compound of the formula A in which R1denotes n-propyl, R2denotes ethyl, R3denotes hydrogen and R4denotes 3-triptoreline; i.e.,

where Z denotes hydrogen (compound 1).

Prodrugs selected for comparison were the following:

where Z denotes-CH2-O-C(O)CH2CH2CH3(compound 2);

where Z denotes-CH2-O-C(O)CH3(compound 3);

where Z denotes-CH2-O-C(O)C(CH3)3(compound 4);

where Z denotes-CH2-O-C(O)N(CH3)CH2CH2N(CH3)2(connected to the e 5);

where Z denotes-CH2-O-P(O)(OH)2(compound 6),

where Z denotes(compound 7);

where Z denotes(compound 8),

where Z denotes(compound 9),

where Z denotes-CH2-O-C(O)NHCH2CH2N(CH3)2(compound 10);

where Z denotes-CH2-Och3(compound 11) and

where Z denotes methyl (compound 12).

Studies were performed on rats Sprague Dawley. Test compounds were administered orally by feeding groups of three rats using a single oral dose of the test compound in 2 and 30 mg/kg All oral dose were obtained in the form of a suspension in a mixture of DMSO/ethanol/PEG300/A 0.1% N-methyl-D-glucamine or in the form of a suspension in 0.5% methylcellulose in water. Blood samples were obtained sequentially from each rat at time 0, 5, 15, 30 minutes, and then at time 1, 1,5, 2, 4, 6, 8 and 24 hours after injection.

The determination of concentrations of compounds 1 and a corresponding prodrug in plasma

Concentration of the compound 1 and/or a corresponding prodrug in plasma of rats were determined by HPLC in tandem with mass spectrometry (LC/MS/MS). Briefly, 0.1 ml of plasma sample was treated with 0.5 ml of a mixture acetonitrile-methanol (9:1, vol/vol.), containing 25 ng of compound 1, having in position 3 datarecovery instead of ethyl (Internal Standard, LS.), to precipitate the protein. The mixture was filtered through a filter with 96 holes and the filtrate was collected and evaporated to dryness on the evaporator for tablets with 96 wells. The remainder resuspendable with 400 μl of 20% methanol and subjected to the analysis of LC/MS/MS. Quantitative analysis of compound 1 was carried out by mass spectrometry, using the mode Multiple Reaction Monitoring (MRM), monitoring the transitions m/z 447,1>159,1 for compounds 1 and 452,1>159,1 for I.S. Limit in this test was 0.38 ng/ml for analysis of samples of the oral dose and 10 ng/ml in the analysis of samples with intravenous dose using 0.1 ml of plasma.

Pharmacokinetic analysis

Decompartmentalise pharmacokinetic parameters were determined using a commercial program WinNonLin Professional, Version 4.1 (Pharsight, Mountain View, CA). Plasma concentration below the detection level was considered to be zero for calculation of means and pharmacokinetic parameters.

For oral administration was determined maximum concentration (Cmaxand the time to reach Cmax(Tmax), AUC(0-t)AUC(0-∞)and bioavailability (%F). Oral bioavailability was determined by the ratio adjustable dose AUC(0-∞)the appropriate oral dose and the mean AUC(0-∞)for intravenous doses of 0.1 and 0.5 mg/kg

The results are presented below in table form. The table shows financial p the tats, obtained when using the suspension of the test compound in suspension in a mixture of DMSO/ethanol/PEG300/A 0.1% N-methyl-D-glucamine in rats.

The prodrugConnection 1
ConnectionAverage adjustable dose AUCAverage Cmax(ng/ml)Average adjustable dose AUCAverage Cmax(ng/ml)
Connection 1Not applicableNot applicable7001900
Connection 2Not found<5 ng/ml137903220
Connection 3Not found<5 ng/ml99931767
Connection 4Not found<5 ng/ml576 1008
Connection 5Not found<5 ng/ml2021466
Connection 6Not found<5 ng/ml1180028700
Connection 751,030,01817408
Compound 8Not found<5 ng/ml1089241
Connection 94,576,391062160
Connection 10Not found<5 ng/ml38436,9
Connection 11533158Not found<5 ng/ml
Connection 12926279Not found<5 ng/ml

When the introduction is carried out in suspension in 0.5% methylcellulose in water to rats at a dose of 30 mg/kg compound 6 provides a regulated dose AUC connection 11800 ng/h/ml and Cmax 28700 ng/ml of Compound 2 provides a regulated dose AUC connection 1 8300 ng/h/ml and Cmax 19200 ng/ml Compound 1 itself provides a regulated dose AUC connection 1 700 ng/h/ml and Cmax 1900 ng/ml.

Results

According to the results shown above, you will notice that the compounds 2-6 have a perfect profile, bioavailability, providing a much higher plasma levels of the parent antagonist And2Breceptor adenosine (compound 1) after oral administration than with oral administration of the parent compound (formula 1) directly. Additionally, no trace of prodrugs is not detected in plasma. This is in sharp contrast to the compounds 7-11, which provide lower plasma levels of the parent antagonist A2Breceptor adenosine after oral administration than those obtained by oral administration of the parent compound (formula 1), and, in addition, compounds 7, 9 and 10-11 detected in the plasma nemeta is lysed. Connection 5 provides a profile of bioavailability, which is approximately the same as the parent antagonist A2Breceptor adenosine (compound 1).

1. The compound of the formula:

in which:
R1and R2independently represent C1-6alkyl;
R4denotes phenyl, if necessary substituted by trifluoromethyl;
X denotes hydrogen or methyl; and
Y represents-C(O)R, where R denotes1-6alkyl; or
Y represents-P(O)(OR5)2where R5denotes hydrogen or C1-6alkyl; or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R1and R2independently represent ethyl or n-propyl.

3. The compound according to claim 1, in which R4denotes 3-(trifluoromethyl)phenyl.

4. The compound according to claim 3 in which R1represents n-propyl and R2denotes ethyl.

5. The compound according to claim 4, in which X denotes hydrogen.

6. The compound according to claim 5, in which Y represents-C(O)R.

7. The connection according to claim 6, in which R denotes a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl.

8. The connection according to claim 7, in which R denotes methyl, namely [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]acetate.

9. The connection according to claim 7, in which R denotes h-p is sawdust, namely [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methylbutanoate.

10. The connection according to claim 7, in which R represents tert-butyl, namely [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)-1,3,7-trihydroxypurine-7-yl]methyl 2,2-dimethylpropanoate.

11. The compound according to claim 5, in which Y represents-P(O)(OR5)2.

12. Connection by claim 11, in which R5denotes hydrogen, namely [3-ethyl-2,6-dioxo-1-propyl-8-(1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-yl)(1,3,7-trihydroxypurine-7-yl)]methyldihydromorphine.

13. Pharmaceutical composition, which is the antagonist And2Bthe adenosine receptor comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns process of production of diisopropyl {[1-(hydroxymethyl)-cyclopropyl]oxy}methylphosphonate represented by the formula , which is the key intermediate compound in synthesis of antiviral nucleoside analogue. The invention also concerns new intermediate compounds of formulae and , and their production of compound (2) obtained under this invention, which is an antiviral nucleoside analogue (especially against hepatitis B virus) represented by the formula .

EFFECT: high purity grade and high output.

4 ex

FIELD: chemistry of organophosphorus compounds, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bisamidate phosphonate compounds that are inhibitors of fructose 1,6-bis-phosphatase. Invention describes a compound of the formula (IA): wherein compound of the formula (IA) is converted in vivo or in vitro to compound of the formula M-PO3H2 that is inhibitor of fructose 1,6-bis-phosphatase and wherein M represents R5-X- wherein R5 is chosen from a group consisting of compounds of the formula or wherein each G is chosen from the group consisting of atoms C, N, O, S and Se and wherein only one G can mean atom O, S or Se and at most one G represents atom N; each G' is chosen independently from the group consisting of atoms C and N and wherein two G' groups, not above, represent atom N; A is chosen from the group consisting of -H, -NR42, -CONR42, -CO2R3, halide, -S(O)R3, -SO2R3, alkyl, alkenyl, alkynyl, perhaloidalkyl, haloidalkyl, aryl, -CH2OH, -CH2NR42, -CH2CN, -CN, -C(S)NH2, -OR2, -SR2, -N3, -NHC(S)NR42, -NHAc, or absent; each B and D is chosen independently from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, aralkyl, alkoxyalkyl, -C(O)R11, -C(O)SR11, -SO2R11, -S(O)R3, -CN, -NR92, -OR3, -SR3, perhaloidalkyl, halide, -NO2, or absent and all groups except for -H, -CN, perhaloidalkyl, -NO2 and halide are substituted optionally; E is chosen from the group consisting of -H, alkyl, alkenyl, alkynyl, aryl, alicyclyl, alkoxyalkyl, -C(O)OR3, -CONR42, -CN, -NR92, -NO2, -OR3, -SR3, perhaloidalkyl, halide, or absent; all groups except for -H, -CN, perhaloidalkyl and halide are substituted optionally; J is chosen from the group consisting of -H, or absent; X represents optionally substituted binding group that binds R5 with phosphorus atom through 2-4 atoms comprising 0-1 heteroatom chosen from atoms N, O and S with exception that if X represents urea or carbamate then there are 2 heteroatoms that determine the shortest distance between R5 and phosphorus atom and wherein atom bound with phosphorus means carbon atom and wherein X is chosen from the group consisting of -alkyl(hydroxy)-, -alkynyl-, - heteroaryl-, -carbonylalkyl-, -1,1-dihaloidalkyl-, -alkoxyalkyl-, -alkyloxy-, -alkylthioalkyl-, -alkylthio-, -alkylaminocarbonyl-, -alkylcarbonylamino-, -alkoxycarbonyl-, -carbonyloxyalkyl-, -alkoxycarbonylamino- and -alkylaminocarbonylamino- and all groups are substituted optionally; under condition that X is not substituted with -COOR2, -SO3H or -PO3R22; n means a whole number from 1 to 3; R2 is taken among the group -R3 and -H; R3 is chosen from the group consisting of alkyl, aryl, alicyclyc and aralkyl; each R4 is chosen independently from the group consisting of -H and alkyl, or R4 and R4 form cycloalkyl group; each R9 is chosen independently from the group consisting of -H, alkyl, aryl, aralkyl and alicyclyl, or R9 and R9 form in common cycloalkyl group; R11 is chosen from the group consisting of alkyl, aryl, -NR22 and -OR2; each R12 and R13 is chosen independently from the group consisting of hydrogen atom (H), lower alkyl, lower aryl, lower aralkyl wherein all groups are substituted optionally, or R12 and R13 in common are bound through 2-5 atoms comprising optionally 1-2 heteroatoms chosen from the group consisting of atoms O, N and S to form cyclic group; each R14 is chosen independently from the group consisting of -OR17, -N(R17)2, -NHR17, -NR2OR19 and -SR17; R15 is chosen from the group consisting of -H, lower alkyl, lower aryl, lower aralkyl, or in common with R16 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R16 is chosen from the group consisting of -(CR12R13)n-C(O)-R14, -H, lower alkyl, lower aryl, lower aralkyl, or in common with R15 is bound through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; each R17 is chosen independently from the group consisting of lower alkyl, lower aryl and lower aralkyl and all groups are substituted optionally, or R17 and R17 at atom N are bound in common through 2-6 atoms comprising optionally 1 heteroatom chosen from the group consisting of atoms O, N and S; R18 is chosen independently among the group consisting of hydrogen atom (H), lower alkyl, aryl, aralkyl, or in common with R12 is bound through 1-4 carbon atoms forming cyclic group; each R19 is chosen independently from the group consisting of -H, lower alkyl, lower aryl, lower alicyclyl, lower aralkyl and -COR3; and under condition that when G' represents nitrogen atom (N) then the corresponding A, B, D or E are absent; at least one from A and B, or A, B, D and E is chosen from the group consisting of -H, or absent; when G represents nitrogen atom (N) then the corresponding A or B is not halide or group bound directly with G through a heteroatom; and its pharmaceutically acceptable salts. Also, invention describes a method for treatment or prophylaxis of diabetes mellitus, a method for inhibition of activity 0f fructose 1,6-bis-phosphatase, a method for decreasing blood glucose in animals, a method for treatment of diseases associated with glycogen deposition, a method for inhibition of gluconeogenesis in animal and a pharmaceutical composition based on compounds of the formula (IA).

EFFECT: valuable medicinal and biochemical properties of compounds.

69 cl, 7 tbl, 64 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 3-methyl-8-piperazino-7-(thiethanyl-3)-1-ethylxanthine hydrochloride of formula .

EFFECT: novel compound which can be used in medicine as an antiaggregation and disaggregation agent is obtained and described.

3 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing compounds of formula I, which are antagonists of adenosine receptors A2B, and useful in treating different conditions, including asthma and diarrhoea, as well as intermediate compounds for their production. In formula (I) R1 and R2 are independently optionally substituted alkyl; X is pyrazol-4-yl; Y is a covalent bond or a lower alkylene; and Z is optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl. The method involves ring closure of the compounds of formula (3): , in which R1, R2, X, Y and Z are as described above, in the presence of a base. In the method new intermediate compounds are obtained, which makes the method of producing compounds of formula I more cost effective since the primary products used are obtained using simple technology.

EFFECT: design of a simple method of obtaining said compounds.

47 cl, 6 dwg, 30 ex

FIELD: chemistry.

SUBSTANCE: method involves alkylation of 7-potassium salt of 3-methylxanthine with 1,4-dibromobutane, with subsequent reaction of the formed 7-(4-bromobutyl)-3-methylxanthane with 1-benzhydrylpiperazine and neutralisation of the obtained base 7-/4-(4-benzhydrylpiperazinyl-1)butyl/-3-methylxanthane with organic or inorganic acid.

EFFECT: obtained compounds have better pharmacotherapeutic properties than current antihistaminic drugs.

2 cl, 1 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to substituted 8-heteroarylzantines of general formula where R represents hydrogen, (C1-C5)alkyl or halogen(C1-C8)alkyl; R1 is chosen from (C3-C6)cycloalkyl or (C3-C6)cycloalkyl(C1-C4)alkyl-; R2 is chosen from (C1-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkinyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl- or (C6-C10)aryl(C1-C8)alkyl-; X represents 3-pyridyl substituted in 6th position with Z; Z represents -NR4R5 or (C4-C10)heterocycle where heterocycle is optionally substituted with 1, 2, 3 or 4 substitutes independently chosen from (C1-C8)alkyl; each Z1 independently represents halogen or -NR7R8; R5 is chosen from -C(O)R6, -CO2R6 or -C(O)NHR7; R4 is chosen from hydrogen, (C1-C8)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C8)alkyl-, (C3-C10)heterocycle(C1-C8)alkyl-, (C6-C10)aryl, (C6-C10)aryl(C1-C8)alkyl-, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C8)alkyl-, -((CH2)2-4)Y)q-(CH2)2-4-X1, -C(O)R6, -CO2R6 or -C(O)NR7R8; or R4 and R5 together with atoms whereto attached form saturated mono-or bicyclic ring with 5, 6, 7 or 8 ring atoms and optionally containing 1 or 2 heteroatoms chosen of non-peroxide oxy (-0-) and amine -N(R9)- in the ring where the ring is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from -C(O)Ra and -C(O)NRbRc; X1 represents -OR6; and Y represents oxy (-O-); where alkyl, alkenyl, cycloalkyl, alkinyl, aryl, heterocyclic or hetero aryl groups from R1, R2, R3, R4 and R5 groups are optionally substituted by one or more substitutes independently chosen from (C1-C8)alkyl, -ORa, (C6-C10)aryl, hydroxy(C1-C8)alkyl and RbRcN(C1-C8)alkyl; where R6 represents (C1-C8)alkyl or (C4-C10)heteroaryl; where heteroaryl is optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen, -ORa and halogen(C1-C8)alkyl; where R7, R8 and R9 independently represent (C1-C8)alkyl, RaO(C1-C8)alkyl, (C6-C10)aryl or (C4-C10)heteroaryl; where heteroaryl or aryl are optionally substituted by 1, 2, 3 or 4 substitutes independently chosen from halogen and -ORa; Ra represents hydrogen or (C1-C6)alkyl; each Rb and Rc independently represents hydrogen or (C6-C10)aryl; and where n is equal to 0, 1 or 2; and q is equal to 1; or its pharmaceutically acceptable salt. In addition, the invention concerns pharmaceutical composition based on compound of formula I.

EFFECT: new substituted 8-heteroarylxantines are selective antagonists of A2B adenosine receptors.

38 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to compound of the formula (I): or (II): wherein R1 and R2 are chosen independently from hydrogen, optionally substituted alkyl or the group: -D-E wherein R represents a covalent bond or alkylene; E represents optionally substituted alkoxy-group, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted alkenyl or optionally substituted alkynyl under condition that if D represents a covalent bond then E can't represents alkoxy-group; R3 represents hydrogen atom, optionally substituted alkyl or optionally substituted cycloalkyl; X represents optionally substituted arylene or heteroarylene; Y represents a covalent bond or alkylene wherein one carbon atom can be substituted optionally for -O-, -S- or -NH-, and optionally substituted hydroxy-, alkoxy-, optionally substituted amino-group or -COR wherein R represents hydroxy-, alkoxy- or amino-group under condition that if an optional substitute represents hydroxy- or amino-group then it can't be adjacent with a heteroatom; Z represents hydrogen atom, optionally substituted monocyclic aryl or optionally substituted monocyclic heteroaryl under condition that Z represents hydrogen atom only under condition that Y represents a covalent bond, and X represents optionally substituted 1,4-pyrazolene, and under condition that if X represents optionally substituted arylene then Z represents optionally substituted monocyclic heteroaryl. Also, invention describes a method for treatment of the morbid state by inhibition of adenosine receptors describes as A2B based on compounds of the formula (I) or the formula (II). Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

32 cl, 35 ex

FIELD: organic chemistry, pharmaceutical chemistry, pharmacology, medicine.

SUBSTANCE: invention relates to novel derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d): wherein R means C2H5, R1 means , n = 1 (Ia); R means n-C3H7, R1 means Br, n = 1 (Ib); R means hydrogen atom (H), R1 means -SCH2CONHNH2, n = 0 (Ic); R means H, R1 means -SCH2CONHNH2, n = 2 (Id). Proposed compounds possess the greater hemorheological activity as compared with that of pentoxyphylline and lower toxicity. Invention provides synthesis of novel and not described previously derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d) possessing hemorheological activity.

EFFECT: improved method of synthesis, valuable medicinal property of compounds.

2 tbl, 4 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention proposes compound of the formula (1) in free form or as a salt wherein R1, R2, R3, R4 and R5 have values given in the invention claim. The claimed compounds are selective inhibitors of enzyme PDE-5 and show the high selectivity in inhibition of activity of 3',5'-cycloguanosine monophosphate phosphodiesterase being activity of PDE-5 first of all.

EFFECT: valuable biochemical properties of derivatives.

6 cl, 3 tbl, 87 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

20 cl, 5 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: compounds are suitable for use as kinase 1β-adrenergic receptor (βARK-1) inhibitors. The invention also relates to compositions containing such compounds and to use of compounds of formula to treat and prevent chronic heart failure, hypertension myocardial ischemia and hepatitis C viral infections (HCV) and for preventing opiate addiction. The invention also pertains to methods of producing formula (I) compounds.

EFFECT: more effective use of the compounds.

11 cl, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are new compounds of general formula (I): het-X-AB (I) where het is pentamerous N-heteroaryl, additionally containing one O, S or N atom as a heteroatom with heteroaryl with additional O atom being condensed with a benzene ring, or hexamerous N-heteroaryl; X means S; and where N-atom of N- heteroaryl residue and an X group are separated by one carbon atom; AB means 1,2,3-triazolo[4,5-d] pyrimidine-7-yl radical of general formula (II): where R3 is C1-8alkyl, phenyl, benzyl optionally substituted; R5-H, C1-8alkyl or phenyl.

EFFECT: production of new compounds for preparing a pharmaceutical composition either effective for treating cardiovascular, cancer, autoimmune diseases, stroke, neurodegenerative diseases, cystic fibrosis, or used in antithrombotic therapy.

9 cl, 11 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of isothiazole-3(2H)-OH-1,1-dioxides of formula (I) or pharmaceutically acceptable salts thereof, which can increase expression of LXR α and/or β, a pharmaceutical composition based on said derivatives, use thereof in preparing a medicinal agent, as well as novel intermediate compounds of formula (V) or salts thereof. In formulae (I), (V) R2 denotes phenyl, and R1 and R3 are as described in the claim.

EFFECT: improved properties of the derivatives.

7 cl, 9 dwg, 172 ex

FIELD: medicine.

SUBSTANCE: claimed is application of known anticonvulsant lamotrigine (other names of substance - lamictal, lamolep) as medication, which prevents ischemic and hypoxic disorders in acute period of craniocerebral injury. Demonstrated is prevention of secondary disorders of brain functions as a result of ischemia, hypoxia with hypercapnia, hemic hypoxia with simultaneous facilitation of recovering neuro-physical status.

EFFECT: lamotrigine increases brain stability to major factors of its secondary injury by 24,9-42,6% and improves life duration of mice in post traumatic period by 109,6%.

5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method for structural and/or functional improvement of arterioles in mammals with a pathology which is characterised by thickened walls of cerebral or renal arterioles involving introduction to said mammal of a peptide with an amino acid sequence D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID No. 5) or an inverted sequence F-A-E-K-F-K-E-A-V-K-D-Y-F-A-K-F-W-D (SEQ ID No. 444), in doses sufficient for structural and/or functional improvement of arterioles.

EFFECT: invention provides structural and/or functional improvement of arterioles and preserved functions of the essential target organs such as brain and kidneys.

20 cl, 2 ex, 29 dwg

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