Derivatives of 2-alkynyladenosine used for control inflammatory response

FIELD: organic chemistry, medicine.

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

EFFECT: valuable medicinal properties of compounds.

56 cl, 1 tbl, 21 dwg, 37 ex

 

The technical field

The present invention relates to methods and compositions for preventing tissue damage in inflammatory action.

Background of the invention

The present invention was created with funding from the U.S. government (NIH Grant ROL HL37942). The U.S. government has certain rights to this invention.

The inflammatory reaction is used to eliminate the harmful agents from the body. There is a wide range of pathogenic lesions that can trigger an inflammatory response, including infection, allergens, autoimmune incentives, the immune response to transplanted tissue, harmful chemicals and toxins, ischemia/reperfusion, hypoxia, mechanical and thermal injury. Inflammation is usually a very localized effect, serving to remove, mitigate dilution and removal of the damaging agent and the injured tissue. The reaction of the body becomes a factor of the disease in those cases when it leads to undesirable damage to the tissues of the host in the process of removing the agent-target or response to traumatic defeat.

As examples, inflammation is a component of the pathogenesis of some vascular diseases or lesions. Such examples include ischemia/reperfusion injury (N.G.Frangogiannis et al., in Mocardial Ischemia: Mechanisms, Reperfusion, Protection, M. Karmazyn, ed., Birkhuser Verlag (1996) at 236-284; H.S. Sharma et al., Med. of Inflamm., 6, 175 (1987), atherosclerosis (R. Ross, Nature, 362, 801 (1993)), inflammatory aortic aneurysm (N. Girardi et al., Ann. Thor. Surg., 64, 251 (1997); D.I. Walker et al., Brit. J. Surg., 59, 609 (1972); R.L. Pennel et al., J. Vasc. Surg., 2, 859 (1985)), and restenosis after balloonies (see R. Ross, cited above). Cells involved in the inflammatory process include white blood cells (i.e. cells of the immune system, neutrophils, eosinophils, lymphocytes, monocytes, basophils, macrophages, dendritic and mast cells), vascular endothelium, vascular smooth muscle cells, fibroblasts and myocytes.

The release of inflammatory cytokines, such as tumor necrosis factor alpha (TNFα), leukocytes is the means by which the immune system confronts pathogenic invasions, including infections. TNFα stimulates the expression and activation of adhesion factors on leukocytes and endothelial cells, primire neutrophils for enhanced anti-inflammatory response to secondary stimuli, but also enhances the adhesive oxidative activity of neutrophils. Cm. Sharma et al., cited above. In addition, macrophages/dendritic cells act as accessory cells, processarea antigen presentation to lymphocytes. Lymphocytes, in turn, are stimulated to act as a proinflammatory cytotec the ranks of the cell.

In General, cytokines stimulate neutrophils, increasing oxidative (e.g., superoxide and secondary products) and non-oxidizing (e.g., myeloperoxidase and other enzymes) inflammatory activity. Unwanted and excessive release of cytokines can cause counterproductive increased pathogenic action could result in the release of destructive tissue oxidative and non-oxidative inflammatory products (K. G. Tracey et al., J. Of Exp. Med., 167, 1211 (1988); and.et al., Rev. Infect.Dis., 9 (suppl. 5), 602 S-S 606 (1987)). For example, TNFα can induce adhesion of neutrophils to the blood vessel walls, and then their migration through the vessel to the site of damage and the release of their oxidative and non-oxidative products of inflammation.

Despite the fact that monocytes are slowly going in the inflammation, under favorable conditions, they develop into long-term, permanent helper cells and macrophages. During stimulation of the trigger inflammation monocytes/macrophages also produce and secrete a number of cytokines (including TNFα), complement, lipids, reactive oxygen species, proteases, and growth factors, rebuild tissue, and regulating the surrounding tissue function.

For example, it has been established the pathogenicity of inflammatory cytokines in arthritis (.A.Dinarello, Semin. Immunol., 4, 133 (1992)); ischemia(A.Seekamp et al., Agents-Actions-Supp., 41, 137 (1993)); septic shock (et al., Rev. Infect. Dis., 9 (suppl. 5), S602-S606 (1987)); asthma (N.M. Cembrzynska et al., Am. Rev. Respir. Dis., 147, 291 (1993)); the rejection in organ transplantation (D.K. Imagawa et al., Transplantation, 51, 57 (1991); multiple sclerosis (E.G. Hartung, Ann. Neurol., 33, 591 (1993)); AIDS (T. Matsuyama et al., AIDS, 5, 1405 (1991) and eye burns alkali (F. Miyamoto et al., Opthalmic Res., 30, 168 (1997)). In addition, the formation of superoxide in leukocytes promotes the replication of human immunodeficiency virus (HIV) (S. Legrand-Poels et al., AIDS Res. Hum. Retroviruses, 6, 1389 (1990)).

It is well known that adenosine and some of its analogues, selectivity activating the adenosine receptor subtypes, reduce the production of neutrophil inflammatory oxidative products (B.N.Cronstein et al., Ann. N.Y.Acacd Sci., 451, 291 (1985); P.A.Roberts et al., Biochem. J., 227, 669 (1985); D.J.Schrier et al., J. Immunol., 137, 3284 (1986); .N.Cronstein el al., Clinical and Immunol Immunopath., 42, 76 (1987); M.A.Iannone et al., in Topics and Perspective in Adenosine Research, E. Gerlach et al., cds., Springer-Verlag, Berlin, p. 286 (1987); S.T.McGarrity et al., J.Leukocyte Biol., 44, 411421 (1988); J.De La Harpe et al., J.Immunol, 143, 596 (1989); S..McGarrity el al., J. Immunol., 142, 1986 (1989); and .P.Nielson et al., Br.J. Pharmacol, 97, 882 (1989)). For example, it was found that adenosine inhibits the release of superoxide from neutrophils stimulated by chemoattractants, such as synthetic imitation of bacterial peptide f-met-leu-phe (fMLP), and component (C5a complement (B.N.Cronstein et al., J. Immunol., 135, 1366 (1985). Adenosine can reduce greatly increase icandy oxidative burst (hearth) PMN (neutrophil), first premirovany THF-αand then stimulated with a second stimulus, such as f-met-leu-phe (G.W. Sullivan et al., Clin. Res., 41, 172A (1993)). In addition, it was found that adenosine can reduce the level of HIV replication in T-cell lines (S. Sipka et al., Acta. Biochim. Biopys. Hung., 23, 75 (1998)). However, not confirmed by the fact that in vivo adenosine has anti-inflammatory activity (G.S. Firestein et al., Clin. Res., 41, A (1993); and B.N.Cronstein et al., Clin. Res., 244A (1993)).

It has been suggested that neutrophils is more than one subtype of adenosine receptor, which can have a reverse effect on the release of superoxide (B.N.Cronstein et al., J. Clin. Invest., 85, 1150 (1990)). The existence of receptor And2Aon neutrophils was initially established Van Calker et al. (D.Van Calker et al., Eur. J. Pharmacology, 206, 285 (1991).

Gradually developed more and more effective and/or selective compounds as agonists And2A-adenosine receptor (AR) - based assays for the binding of radio and physiological reactions. Were initially developed connections with no selectivity or have low selectivity to And2Areceptors, such as adenosine or 5'-carboxamide of adenosine, such as 5'-N-ethylcarbodiimide (NECA) (B.N.Cronstein et al., J. Immunol., 135, 1366 (1985)). Later it was found that addition of 2-alkylimidazole the residents increases the efficiency and selectivity, for example, CV1808 and CGS21680 (M.F.Jarvis et al., J. Pharmacol. Exp. Ther., 251, 888 (1989)). Derivatives of 2-alkoxy-substituted adenosine, such as WRC-0090, more effective and selective as agonists And2A-receptor in coronary artery (M Ueeda et al., J. Med. Chem., 34, 1334 (1991)). It was found that derivatives of 2-alkyldiethanolamine, for example, SHA 211 (also known as WRC-0474)are agonists And2A-receptor in coronary artery (K. Niiya et al., J. Med. Chem., 35, 4557 (1992)).

There is one description of the combination of relatively non-specific analogues of adenosine: R-phenylisopropylamine(R-PIA) and 2-chlorobenzene (CI-Ado) with a phosphodiesterase inhibitor (PDE), resulting in reduced oxidative activity of neutrophil (Maapp et al., Topics and Perspectives in Adenosine Research, E. Garlach et al., eds., Springer-Verlag, Berlin, pp. 286-298 (1987)). However, analogues of R-PIA and CI-Ado really are more effective activators of A1-adenosine receptor than And2A-adenosine receptors, and, thus, likely to cause side effects due to the activation And1receptors on the heart muscle and other tissues, causing a "heart block".

R.A.Olsson et al. (U.S. patent No. 5278150) describe selective agonists And2-adenosine receptor formula:

where the Rib is ribosyl, R1may represent H, a R2may be cycloalkyl. Stated that Yes the connections can be used to treat hypertension, atherosclerosis, as well as vasodilators.

Olsson et al. (U.S. patent No. 5140015) describe specific agonists And2-adenosine receptor formula:

where C(X)BR2can represent CH2OH, a R1may be alkyl - or alkoxyalkyl. Indicated that these compounds may be used as vasodilators or antihypertensive drugs.

Linden et al. (U.S. patent No. 5877180) is based on the discovery that certain inflammatory diseases such as arthritis and asthma, can be subjected to effective treatment by introducing compounds which are selective agonists And2A-adenosine receptor, preferably in combination with an inhibitor of phosphodiesterase type IV. A variant embodiment of the invention Linden et al. provides a method for treating inflammatory diseases by introducing an effective amount of A2A-adenosine receptor following formula:

where R and X have the values listed in the patent.

A preferred variant of the invention (Linden et al.) provides for the introduction of an inhibitor of phosphodiesterase (PDE)type IV, in combination with an agonist And2A-adenosine receptor. Inhibitor of Phosphodiesterase (PDE)type IV includes the racemic and optically active 4-(polyalkoxy is phenyl)-2-pirrolidone the following formula:

where R', R18, R19and X have the values listed in U.S. patent No. 4193926. Rolipram is an example of a suitable PDE inhibitor, type 1U represented by the above formula.

G. Cristalli (U.S. patent No. 5593975) describes derivatives of 2-arylidene, 2-cycloalkylation or 2-hydroxyethylamine in which the rest of riboside replaced carboxamido or substituted, carboxamido (R3HNC(O)-).

Derivatives of 2-alkynylamino described Miyasaka et al. (U.S. patent No. 4956345), 2-Alchemilla substituted (C3-C16)alkyl. Indicated that the compounds in accordance with U.S. patent No. 5593975 dilates blood vessels and inhibit platelet aggregation, thus, they can be used as anti-ischemic, protivoateroskleroticheskim and antihypertensive drugs.

However, there remains a need in the selective agonists And2-adenosine receptor for medical use, providing less side effects.

Brief description of the invention

The present invention includes the compounds and methods of their use for the treatment of inflammation in the tissue of the mammal. Inflammation of the tissue may be caused by pathological agents, or physical, chemical or thermal injuries, or trauma from medical procedures, such as transplantation of organs, tissues is whether cells angioplasty (RSTA), inflammation after ischemia/reperfusion or implantation. These compounds include a new class of derivatives of 2-alkenylbenzene, substituted in position Atina replaced by fragments of cycloalkyl. The rest of riboside preferably substituted in position 5'("X") N-alkyl-(or cycloalkyl)carboxyamide ("aminocarbonyl") fragment. Thus, the present invention provides a method of suppressing an inflammatory response in a mammal, such as man, and the protection of inflamed tissue by introducing an effective amount of one or more compounds in accordance with this invention.

The compounds of this invention have the following General formula (I):

where (a) each R independently represents hydrogen, C1-C6alkyl, C3-C7cycloalkyl, phenyl or phenyl(C1-C3)alkyl;

(b) X represents-CH2HE IS the CO2R2, -OC(O)R2, -CH2OC(O)R2or C(O)NRCR4;

(c) each of R2, R3and R4separately is H, C1-6alkyl, C1-6-alkyl, substituted by one to three C1-6-alkoxy, C3-7cycloalkyl, C1-6-alkylthio, halogen, hydroxy, amino, mono (C1-6-alkyl)amino, di(C1-6-alkyl)amino or6-10-aalami, where aryl can be substituted one-t is EMA halogen, C1-6-alkilani, hydroxy, amino, mono(C1-6-alkyl)amino or di(C1-6-alkyl)amino; C6-10-aryl; or (C6-10aryl substituted by one to three halogen, hydroxy, amino, mono(C1-6-alkyl) amino, di(C1-6-alkyl)amino or C1-6-alkilani;

(d) R1is (X-(Z)-)n[(C3-C10)cycloalkyl]-(Z')-, where Z and Z' independently represent (C1-C6)alkyl, optionally interrupted by one to three S or naproxenum Oh, or absent, and n is 1-3,

or their pharmaceutically acceptable salt.

This invention provides a compound of formula I, which can be used for medical treatment, preferably for the treatment or protection of tissues from inflammation, such as inflammatory response, and the use of the compounds of formula I for the manufacture of medicines for the treatment of inflammatory reaction caused by a pathological condition or symptom in a mammal, such as man, are associated with inflammation.

Despite the description of several agonists And2A-adenosine receptor as vasodilators, which can be directly used for treatment of hypertension, blood clot, atherosclerosis, etc., datasetname action of the compounds of formula (I) is not mentioned in the known sources.

This invention is also provides for the use of these compounds with phosphodiesterase inhibitor, type IV, for a synergistic reduction of the inflammatory response of immune cells.

This invention also provides a pharmaceutical composition comprising an effective amount of the compounds of formula I or its pharmaceutically acceptable salt, in combination with a pharmaceutically acceptable diluent or carrier and optionally in combination with an inhibitor of phosphodiesterase (PDE)type IV. The composition is preferably provided in the form of a standard dosage forms.

In addition, this invention provides a therapeutic method for preventing or treating a pathological condition or symptom in a mammal, such as man, when it is assumed activity And2A-adenosine receptor and desirable agonism specified activity, comprising the administration to a mammal in need of such treatment, an effective amount of the compounds of formula I or its pharmaceutically acceptable salt. It is assumed that the activation And2A-adenosine receptor inhibits inflammation, affecting neutrophils, mast cells, monocytes/macrophages, T-cells and/or eosinophils. Inhibition of these inflammatory cells leads to the protection of tissues after their defeat.

Inflammatory reaction that can be treated (including prevention) of the compound of formula I is not battelino with PDE inhibitor, type IV include inflammation caused by:

(a) autoimmune stimulation (autoimmune disease), such as lupus erythematosus, multiple sclerosis, infertility caused by endometriosis, diabetes mellitus type I, including the destruction of pancreatic islets leading to diabetes and the inflammatory consequences of diabetes, including leg ulcers, Crohn's disease, ulcerative colitis, inflammatory bowel disease, osteoporosis and rheumatoid arthritis;

(b) allergic diseases such as asthma, hay fever, rhinitis, vernal conjunctivitis and other eosinophiluria state;

(c) skin diseases such as psoriasis, contact dermatitis, eczema, infectious skin ulcers, open wounds, cellulitis;

(d) infectious diseases, including sepsis, septic shock, encephalitis, infectious arthritis, endotoxic bacterial toxic shock, gram negative shock, the reaction of ERISA-Herxheimer, shingles, toxic shock, cerebral malaria, bacterial meningitis, respiratory distress syndrome in adults (ARDS), Lyme disease, HIV infection (enhanced TNFa-HIV-replication, inhibition of TNFα-activity of nucleoside reverse transcriptase inhibitor);

(e) devastating diseases: cachexia after cancer and HIV;

(f) transplantation of an organ, tissue or cells (e.g. bone marrow, horns is s, kidneys, lungs, liver, heart, skin, pancreatic islets), including rejection in transplantation and disease graft-versus-host;

(g) side effects of drug therapy, including adverse effects from treatment with amphotericin b, from immunosuppressive therapy, such as treatment with interleukin-2, side effects from treatment ACTS, GM-CSF, cyclosporine, and adverse effects of treatment with aminoglycosides, stomatitis and mucositis induced immune suppression;

(h) cardiovascular conditions, including diseases of the circulatory induced or caused by inflammatory reaction, such as ischemia, atherosclerosis, peripheral vascular disease, restenosis after angioplasty, inflammatory aortic aneurysm, vasculitis, stroke, spinal cord injury, congestive heart failure, hemorrhagic shock, ischemic/reperfusion injury, vasospasm after subarachnoid hemorrhage, vasospasm after stroke, pleurisy, pericarditis, and cardiovascular complications of diabetes;

(i) dialysis, including pericarditis caused by peritoneal dialysis;

(j) gout and

(k) chemical or thermal injury caused by burns, acid, alkali, etc.

Particularly interesting and effective application of these compounds for the treatment of inflammatory reactions, svannah transfer body, tissues or cells, i.e. transplantation of allogeneic or xenogeneic tissue recipient is a mammal, autoimmune diseases and inflammatory conditions caused by circulatory pathologies and their treatment, including angioplasty, stent introduction, shunt or implantation. It has been unexpectedly found that the introduction of one or more compounds of the formula (I) is effective after the occurrence of inflammatory reactions, for example, after the defeat of the object pathology or injury, initiating an inflammatory response.

The invention also includes a method of measuring the response or binding of the compounds of formula I, or with the indicated sites And2A-adenosine receptor comprising said receptors, in vivo or in vitro, with the amount of compounds of formula I effective to bind these receptors. Tissue or cells, including associated ligand receptor sites can be used to measure the selectivity of test compounds for specific receptor subtypes, the number of bioactive compounds in blood or other physiological fluids, or can be used as a tool to identify potential therapeutic agents for the treatment of diseases or conditions associated with activation site of the receptor by contact those agents with specified complex and the ligand-receptor and measuring the degree of substitution of the ligand and/or binding agent, either the cellular response to the specified agent (e.g., accumulation of camp).

Detailed description of the invention

If not stated otherwise, the definitions have the following meanings. Halogen means fluorine, chlorine, bromine or iodine. Alkyl, alkoxy, aralkyl, alkylaryl, etc. denote both straight and branched alkyl groups, however, the reference to an individual radical such as "propyl"implies only the radical with a straight chain, while the isomer branched chain, such as "isopropyl", specified specifically. Aryl includes phenyl radical or an ortho-condensed bicyclic, carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic. Heteroaryl includes a radical attached via a carbon ring, monocyclic aromatic ring containing five to six ring atoms consisting of carbon and one to four heteroatoms, each selected from the group comprising seperatedly oxygen, sulfur and N(X), where X is absent or is H, O, (C1-C4)alkyl, phenyl or benzyl, as well as radical ortho-condensed bicyclic heterocycle containing from about eight to ten received from him the ring atoms, especially lansoprozole or derivative obtained in rez is ltate its condensation with propylene, trimethylenebis or tetramethylenebis dyadically.

The person skilled in the art should be understood that the compounds of formula (I) have several chiral centers and can be isolated in optically active and racemic forms. The movie riboside formula (I) is preferably derived from D-ribose, i.e. the 3', 4'-hydroxyl group are alpha-groups with respect to the sugar ring, and 2'- and 5'-groups are beta-groups (3R, 4S, 2R, 5S). If two groups on tsiklogeksilnogo group is in position 4, they are preferably TRANS-groups. Some compounds may exhibit polymorphism. It is implied that the present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric forms or a mixture of the compounds in accordance with this invention, described here with useful properties in this area is well known how to obtain optically active forms (for example, the decomposition of the racemic form by recrystallization or enzymes, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine the activity of the agonist adenosine, applying the described tests or other similar studies, is well known in the area is I.

Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values that are within established ranges for the radicals and substituents.

Specifically, (C1-C6)alkyl may represent methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl or hexyl. In this description, the term "cycloalkyl" means bicycloalkyl (norbornyl, 2.2.2-bicycloalkyl etc) and tricyclohexyl (substituted etc.), optionally containing one or two N, O or S. Cycloalkyl also implies (cycloalkyl)alkyl. Thus, (C3-C6)cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and (C3-C6)cycloalkyl(C1-C6)alkyl may be cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl; 2-cyclopropylethyl, 2-cyclobutylmethyl, 2-cyclopentylmethyl or 2-cyclohexylethyl.

(C1-C6)alkoxy may represent methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentox, 3 pentox or hexyloxy; (C2-C6)alkenyl may represent vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl; and (C2-C6)quinil may be ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl; (C1-C6)alkanoyl can represent acetyl, propanol or butanol; halogen(C1-C6)alkyl may be iodomethyl, methyl bromide, chloromethyl, vermeil, trifluoromethyl, 2-chloroethyl, 2-foretel, 2,2,2-triptorelin or pentafluoroethyl; hydroxy(C1-C6)alkyl may be hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 4-hydroxybutyl, 1-hydroxyphenyl, 5-hydroxyphenyl, 1-hydroxyhexyl or 6-hydroxyhexyl; (C1-C6)alkoxycarbonyl (CO2R2) may be methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl or hexyloxybenzoyl; (C1-C6)alkylthio can imagine methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, pentylthio or hexylthio; and (C2-C6)alkanoyloxy can imagine acetoxy, propenyloxy, butanoyloxy, isobutyryloxy, pentanoate or hexanoate; aryl may be phenyl, indenyl or naphthyl, and heteroaryl may present the identification of furyl, imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazol, pinacolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl (or its N-oxide), Tittel, pyrimidinyl (or its N-oxide), indolyl, ethanolic (or its N-oxide) or chinolin (or its N-oxide).

The specific value of R is amino, monomethylamine or cyclopropylamino.

The specific value of R1is carboxy or (C1-C4)alkoxycarbonylmethyl(C1-C4)alkyl.

The specific value of R2is H or (C1-C4)alkyl, i.e. methyl or ethyl.

The specific value of R3is H, methyl or phenyl.

The specific value of R4is H, methyl or phenyl.

A specific value for Z is-CH2- or-CH2-CH2-.

A specific value for X is CO2R2, (C2-C5)alcoholmeter or amido.

The specific value of n is 1.

Preferred compounds of formula (I) are those compounds in which each R represents H, X represents ethylaminomethyl, and R1is 4-carboxytetramethyl (DWH-146a), R1is 4-methoxycarbonylmethylene (DWH-146e) or R1is 4-ecotoxicologically (JMR-193). They are presented below (DWH-146 (acid) and the methylether (e)), and JMR-193.

DWH-146 (acid, X=N; ether, X=Me)

Synthesis of methyl 4-[3-(6-amino-9-(5-[(ethylamino)carbonyl]-3,4-dihydroxyethylene-Z-furanyl-N-2-purinol)-2-PROPYNYL]-1-cyclohexanecarboxylate (DWH-146e) carry out cross-linking modderspruit (N-ethyl-1'-deoxy-1'-(amino-2-iodine-N-purine-9-yl)-β-D-ribofuranoside) with methyl 4-(2-PROPYNYL)-1-cyclohexanecarboxylate, applying the catalyst Pd11. Synthesis derived oddenino exercise of guanosine. Guanosin initially treated with acetic anhydride, which acetaline sugar hydroxyl, and then glorious position 6 of the chloride of Tetramethylammonium and phosphorus oxychloride. Iodination position 2 is carried out in the modified reaction Sandmeyer with subsequent substitution of 6-Cl and sugar acetates ammonia. The hydroxyl 2' and 3' protect as acetonide, and hydroxyl-5' idiot to acid with potassium permanganate. Removing protection from acetonide 2' and 3', etherification Fisher 5' acid ethanol and converting the received complex ethyl ester in ethylamide ethylamine gives N-ethyl-1'-deoxy-1'-(amino-2-iodine-N-purine-9-yl)-β-D-ribofuranoside.

Acetylene (methyl 4-(2-PROPYNYL)-1-cyclohexanecarboxylate) synthesized on the basis of TRANS-1,4-cyclohexanedimethanol. First TRANS-diol monotonicity with subsequent substitution tosilata Ani is Mr. acetylene. Hydroxyl get varieties of hydroxyazetidine oxidized to acid reagent Jones, followed by methylation of (trimethylsilyl)diazomethane, receiving 4-(3-PROPYNYL)-1-cyclohexanecarboxylate.

The reaction of cross-linking is carried out in the following, the above-described conditions. To a solution of N,N-dimethylformamide (0.5 ml), acetonitrile (1 ml), triethylamine (0.25 ml) and N-ethyl-1'-deoxy-1'-(amino-2-iodine-N-purine-9-yl)-β-D-ribofuranoside (25 mg, 0.06 mol) is added bis(triphenylphosphine)palladium-dichloride (1 mg, 2 mol.%) and copper iodide (I) (0,06 mg, 5 mol.%).

To the obtained mixture is added methyl 4-(2-PROPYNYL)-1-cyclohexanecarboxylate (54 mg, 0.3 mmol) and the reaction mixture was stirred in an atmosphere of N2for 16 hours. The solvent is removed in vacuo and the resulting residue is subjected to flash chromatography in 20% methanol in chloroform (Rf=0,45)to give 19 mg (not quite white solid, TPL 125°C (decomposition)) methyl 4-[3-(6-amino-9-(5-[(ethylamino)carbonyl]-3,4-dihydroxyethylene-Z-furanyl)-N-2-purinol]-2-PROPYNYL-1-cyclohexanecarboxylate (DWH-146e).

DWH-e and JMR193 much more effective as inhibitors in inflammatory systems models than the comparative compound, CGS21680 (2-[p-(carboxyethyl)phenylethylamine]-5'-N-ethylcarbodiimide). For example, DWH-146e approximately 80 times stronger in respect of A2Areceptors and 40 reselection relative And 2Ain comparison with a3-receptors than CGS21680.

Examples of pharmaceutically acceptable salts are organic additive, acid salts formed with acids forming physiologically acceptable anion, for example tosylate, methanesulfonate, malate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-Ketoglutarate and α-glycyrrhizinate. Can also be formed of suitable inorganic salts, including hydrochloride, sulfates, nitrates, bicarbonates and carbonates.

Pharmaceutically acceptable salts may be obtained using standard methods, well known in this field, such as the interaction sufficiently basic compound such as an amine with a suitable acid to obtain a physiologically acceptable anion. Can be also obtained salts of carboxylic acids, alkali metal (e.g. sodium, potassium or lithium) or alkaline earth metal (e.g. calcium).

The compounds of formula I may be prepared as pharmaceutical compositions and administered to the host is a mammal, such as man, in various forms, taking into account the chosen route of administration, i.e. oral or parenteral, intravenous, intramuscular, local, or subcutaneous.

Thus, these compounds may be introduced systemically, e.g. by oral way is m, in combination with a pharmaceutically acceptable excipient, such as an inert diluent or assimilated edible carrier. They can be enclosed in capsules with hard or soft gelatin shells, can be compressed into tablets, or directly mixed in the food of the patient. Oral therapeutic introduction of the active compound may be mixed with one or more forming substances and used in the form of tablets for swallowing, cheek tablets, pastilles, capsules, elixirs, suspensions, syrups, wafers and the like, Such compositions and preparations should contain at least 0.1% of active compound. Of course, the percentage composition of the compositions and preparations may vary, and typically is from about 2 to 60% by weight of certain dosage forms. The number of active compound in these compositions for therapeutic applications is such that it provides an effective level of dosing.

Tablets, lozenges, pills, capsules and the like may also contain the following ingredients: a binder such as tragakant, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrity agent such as corn starch, potato starch, alginic acid and the like; a lubricating agent, such as stearate is Agnes, and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring substance, such as peppermint, oil of Grushenka or cherry flavoring. If the dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as vegetable oil or polyethylene glycol. Various other materials may be present in the form of shells or any other way to modify the physical appearance of solid dosage forms. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, etc. Syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparaben as preservatives, a dye and flavoring such as cherry or orange flavouring substance. Of course, any material used in obtaining any dosage form should be pharmaceutically acceptable and substantially non-toxic in the quantities used. In addition, the active compound may be enclosed in drugs and devices with slow release.

The active compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions active with the unity or its salts can be obtained in water, optionally mixed with a nontoxic surfactant substance. Dispersion can also be obtained in glycerol, liquid polyethylene glycols, triacetin, their mixtures, as well as in oils. Under normal conditions of storage and use, these preparations contain a preservative, to prevent growth of microorganisms.

Pharmaceutical dosage forms intended for injection or infusion (infusion)may include sterile aqueous solutions, dispersions or sterile powders comprising the active ingredient intended for unplanned preparation of sterile solutions or dispersions for injection or infusion, optionally encapsulated in liposomes. In all cases, the final dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or excipient can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol, liquid polyethylene glycol and the like), vegetable oils, non-toxic glycerin esters, and their suitable mixtures. The desired fluidity can be maintained, for example, by the formation of liposomes, by the use of the required particle size when using dispersions or by the use of surfactants. Dei is a journey of microorganisms can be prevented by various antibacterial and antifungal agents, for example parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like In many cases, preferably the inclusion isotonic agents such as sugars, buffers or sodium chloride. Prolonged absorption of the compositions for injection can be achieved using the compositions of agents delaying the absorption such as aluminum monostearate and gelatin.

Sterile injectable solutions, get, introducing the active compound in the required amount in the appropriate solvent with various of the above ingredients, followed, in accordance with the requirements, sterilization by filtration. When using sterile powders for obtaining sterile injectable solutions, the preferred methods are vacuum drying and drying by freezing, providing powder of the active ingredient plus any additional desired ingredient present in the solutions previously subjected to sterilization by filtration.

The local introduction of these compounds may be applied in pure form, i.e. when they are in the form of liquids. However, it is often desirable to apply them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be solid or liquid form.

Applicable solid socialinclusion finely ground solids, such as talc, clay, microcrystalline cellulose, silicon dioxide, aluminum oxide, etc. Applicable liquid carriers include water, alcohols or glycols or a mixture of water-alcohol/glycol, in which these compounds can be effectively dissolved or dispersed, optionally with non-toxic surfactants. To optimize the properties for a specific purpose, can be added adjuvants such as fragrances and additional antimicrobial agents. The liquid compositions can be applied using absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using a spray injection or aerosol type.

Thickeners such as synthetic polymers, fatty acids, salts and esters of fatty acids, fatty alcohols, modified cellulose or modified mineral materials can also be employed with liquid carriers to obtain the applied pastes, gels, ointments, Soaps, etc. imposed directly on the patient's skin.

Examples of dermatological compositions which can be used to deliver compounds of formula I in the skin, described Jacquet et al. (U.S. patent No. 4608392), Geria (U.S. patent No. 4992478), Smith et al. (U.S. patent No. 4559157) and Wortzman(U.S. patent No. 4820508).

Effective doses of the compounds of formula I can be determined by comparing their effectiveness in vitro and in vivo in animal models. Methods of extrapolation of effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. patent No. 4938949. Effective dose of PDE inhibitors, type IV, known in this area. For example, see U.S. patent No. 5877180, Col.

In General, the concentration of the compounds (compounds) of the formula (I) in a liquid composition, such as a lotion, is about 0.1-25 wt.%, preferably about 0.5-10% wt. Concentration in semi-solid or solid composition such as a gel or powder, is approximately 0.1-5% wt., preferably about 0.5 to 2.5 wt.%.

The number of connections or an active salt or derivative necessary for treatment varies not only from the particular salt selected but also on the method of administration, the nature of being treated condition, age and condition of the patient, and ultimately determined by the treating physician or Clinician.

However, in General, a suitable dose is in the range from about 0.5 to 100 μg/kg, for example from about 10 to 75 mg/kg of body weight per day may 3 to about 50 micrograms per kilogram of body weight of the recipient per day, preferably in the range from 6 to 90 g/is g/day, most preferably in the range from 15 to 60 mg/kg/day.

This connection is preferably in the form of dosage forms, for example, containing 5 to 1000 mg, expediently from 10 to 750 mg, most preferably from 50 to 500 μg of the active ingredient in dosage form.

Ideally, the active ingredient must be introduced in such a way as to achieve maximum plasma concentrations of the active compounds comprising from about 0.1 to 10 nm, preferably from about 0.2 to 10 nm, most preferably from about 0.5 to 5 nm. This can be achieved, for example, as a result of intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or oral administration in the form of a bolus containing about 1-100 μg of active ingredient. The desired level in the blood can be maintained by continuous infusion, which provides about 0.01 to 5.0 mg/kg/hour, either periodic infusions containing about 0.4-15 mg/kg of active ingredient (ingredient).

The desired dose may be entered as a single dose or in divided doses, administered through the respective periods of time, such as two, three, four or more divided doses per day. In turn divided dose may b the th also separated, for example, on a discrete number of injections (doses), such as repeated inhalation through insufflator or instillation of a few drops in the eye. For example, it is desirable to enter the details of the composition intravenously over a long period of time after the defeat that caused the inflammation.

The ability of compounds in accordance with the present invention to act as an agonist (or antagonist)2A-adenosine receptor may be determined using pharmacological models which are well known in this field, or use the following tests.

Further, the present invention is described with reference to the following detailed examples, which are given to illustrate the invention and not to limit. In NMR spectra further Hz - Hertz, s - singlet, d - doublet, t - triplet, m = multiplet, ush - broadened.

Example 1

TRANS-(1-[4-[Hydroxymethyl)cyclohexyl]methyl)-4-methyl-bansilalpet (5.2)

Sodium hydride (1,69 g, 70 mmol) are added to a solution of 10 g (70 mmol) [4-(hydroxymethyl)cyclohexyl]methane-1-ol (5.1) in 700 ml of tetrahydrofuran, stirred for 1 hour, then add p-toluensulfonate (13.3 g, 70 mmol) and the reaction mixture is subjected to boiling under reflux for 5 hours. Then the reaction mixture was cooled to 0°C and slowly quenched with water until disappearance reacts onopening hydride. After blanking the hydride reaction mixture is diluted with simple ether (700 ml) and extracted 2 times with 10% aqueous potassium carbonate (700 ml). The organic portion is dried using sodium sulfate, and the solvent is removed under reduced pressure. The product was then purified by chromatography on a column of silica gel, elwira a mixture of acetone-dichloromethane (5:95) to obtain compound 5.2 (35%).

1H NMR (300 MHz, CDCl3) δ 7.75 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 3.79 (d, J=6.35 Hz, 2H), 3.39 (d, J=6.35 Hz, 2H), 2.42 (s, 3H), 1.75 (m, 4H), 1.59 (m, 1H), 1.37 (m, 1H), 0.9 (m, 4H).13With NMR (300 MHz, CDCl3) δ 145.3, 133.4, 130.3, 130.3, 128.3, 128.3, 75.8, 68.5, 40.6, 37.8, 28.9, 28.9, 28.9, 28.9, 22.1.

Example 2

(4-Prop-2-vinylcyclohexane)methane-1-ol (5.3)

Complex litigation-Ethylenediamine (90%) (6.4 g, 70 mmol) is added slowly to a solution of 5.2 (3 g, 10 mmol) in 40 ml of dimethyl sulfoxide. The reaction mixture allow to mix for 5 days and then slowly quenched at 0°With water. The mixture is diluted with simple ether (300 ml) and extracted 3 times with saturated aqueous ammonium chloride (200 ml). Organic matter is dried with sodium sulfate. The solvent is removed under reduced pressure and the product purified by chromatography on a column of silica gel, elwira a mixture of ethyl acetate-hexane (20:80) to give the compound 5.3 (85%).

1H NMR (300 MHz, CDCl3) δ 3.41 (d, J=6.5 Hz, 2H), 2.07 (DD, J=2.5, 6.5 Hz, 2H), 1.96-1.75 (m, 5H), 1.41 (m, 2H, of 0.95 (m, 4).13C NMR (300 MHz, CDCl3) δ 83.8, 69.6, 68.9, 40.7, 37.7, 32.3, 32.3, 29.6, 29.6, 26.5.

Example 3

4-Prop-2-vinylcyclohexane acid (5.4)

A solution of chromium trioxide (1.1 g, 11 mmol) in 1.5 M sulfuric acid (40 ml, 27 mmol) support at a temperature of 0°C for more than 2 hours, during which the add connection 5.3 (0,46 g, 3 mmol) in 80 ml of acetone. Then the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture was diluted with simple ether (200 ml) and extracted 2 times with water. Organic matter is dried with sodium sulfate. The solvent is removed under reduced pressure and the product purified by chromatography on a column of silica gel, elwira a mixture of acetone-dichloromethane (70:30) to obtain the compound 5.4 (75%).

1H NMR (300 MHz, CDCl3) δ 2.24 (dt, J=3.66, 12.1 Hz, 1H), 2.10 (DD, J=2.7, 6.5 Hz, 2H), 2.04-1.89 (m, 5H), 1.76 (d, J=2.3 Hz, 1H), 1.43 (DQC, J=3.28, 13.1 Hz, 2H), 1.03 (DQC, J=3.28, 13.1 Hz, 2H).13With NMR (300 MHz, CDCl3) δ 183.2, 83.3, 69.9, 43.4, 36.7, 31.8, 28.9, 26.3.

Example 4

Methyl 4-prop-2-vinylcyclohexane (5.5)

A solution of (trimethylsilyl)diazomethane (2.0 M) in hexano (1 ml, 2 mmol) are added to a solution of compound 5.4 (0.34 g, 2 mmol) in 15 ml of a mixture methanol:dichloromethane (3:7). The solvents are removed under reduced pressure, obtaining a 100% conversion of starting material into product.

1H NMR (300 MHz, CDCl3) δ 2.24 (is t, J=3.66, 12.1 Hz, 1H), 2.10 (DDD, J=2.7, 6.5 Hz, 2H), 2.06 (DD, J=1.54, 6.54 Hz, 1H), 2.00-1.89 (m, 3H), 1.76 (d, J=2.3 Hz, 1H). 1.43 (DQC, J=3.28, 13.1 Hz, 2H), 1.03 (DQC, J=3.28, 13.1 Hz, 2H).13With NMR (300 MHz, CDCl3) δ 176.8, 83.3, 69.8, 51.9, 43.4, 36.7, 31.9, 29.2, 26.3.

Example 5

[(2R,3R,4R,5R)-3,4-Deacetylase-5-(2-amino-6-oxogedunin-9-yl)oxolan-2-yl]acetate (6.2)

A suspension of 113 g (0.4 mol) of dry guanosine (6.1), acetic anhydride (240 ml, 2.5 mol), dry pyridine (120 ml) and dry DMF (320 ml) was heated for 3.75 hours at 75°s, not allowing the temperature to exceed 80°C. a Clear solution is then transferred into a 3 l Erlenmeyer flask, which was filled with 2-propanol. After cooling the solution to room temperature to initiate crystallization and give her the opportunity to proceed at 4°With during the night. The white solid precipitate was filtered, washed with 2-propanol and recrystallized from him, receiving the connection 6.2 (96%).

1H NMR (300 MHz, CDCl3) δ 8.20 (s, 1H, H-8), 6.17 (d, J=5.41 Hz, 1H, H-1') 5.75 (t, J=5.39 Hz, 1H, H-2'), 5.56 (t, J=5.0, H-3'), 4.41 (m, 3H, H-4', 5'), 2.14 (s, 3H, AC), 2.11 (s, 3H, AC), 2.10 (s, 3H, AC).13With NMR (300 MHz, CD3OD) δ 171.0, 170.3, 170.2, 157.7, 154.8, 152.4, 136.7, 117.7, 85.5, 80.4, 73.0, 71.3, 64.0, 31.3, 21.2, 21.0.

Example 6

[(2R,3R,4R,5R)-3,4-Deacetylase-5-(2-amino-6-globulin-9-yl)oxolan-2-yl]acetate (6.3)

In a 1000 ml flask 80 g (of € 0.195 mol) of [(2R,3R,4R,5R)-3,4-deacetylase-5-(2-amino-6-oxogedunin-9-yl)oxolan-2-yl]methyl acetate (6,2), tetramethyl Manihari (44 g, 0.4 mol), anhydrous acetonitrile (400 ml) and N,N-dimethylaniline (25 ml). The flask was placed in an ice salt bath and cooled to 2°C. To this solution is added dropwise POCl3(107 ml, 1.15 mol) with speed, maintaining temperature below 5°With (45 minutes). Then remove the flask from the ice bath, equipped with a condenser, placed in an oil bath and enable the mixture to boil under reflux for 10 minutes, the color of the solution changed to red-brown. Then the solvent is removed under reduced pressure, obtaining an oily residue, which is transferred into a beaker containing 1000 g of ice and 400 ml of CHCl3and let the mixture mixed for 1.5 hours, to decompose the remaining POCl3. Then the organic phase is removed, the aqueous phase is extracted with 3×50 ml CHCl3and combined with the organic phase. The combined organic substances are then subjected to back extraction with 50 ml of water, followed by stirring with 200 ml saturated NaHCO3. After that, the organic phase is extracted with NaHCO3, until the aqueous extract will not be neutral (2). The organic phase is finally extracted with a saturated saline solution and then dried over MgSO4for 16 hours. To the solution was added 800 ml of 2-propanol, and the solution was concentrated under reduced pressure. To oily is mu solid substance add 200 ml of 2-propanol and the solution placed in the refrigerator overnight. The crystalline product is filtered, washed and allow to dry over night, receiving the connection 6.3 (77%).

1H NMR (300 MHz, CD3OD) δ 8.31 (s, 1H, H-8), 7.00 (s, 2H, NH2) 6.06 (d, J=5.8 Hz, 1H, H-1'), 5.83 (t, J=6.16 Hz, 1H, H-2'), 5.67 (m, 1H, H-3'), 4.29 (m, 3H, H-4', 5'), 2.07 (s, 3H, AC), 1.99 (s, 3H, AC), 1.98 (s, 3H, AC).13With NMR (300 MHz, CD3OD) δ 171.0, 170.4, 170.2, 160.8, 154.6, 150.8, 142.2, 124.5, 85.8, 80,6. 72.8, 71.2, 63.9, 21.4, 21.3, 21.1.

Example 7

[(2R,3R,4R,5R)-3,4-Deacetylase-5-(6-chloro-2-iturin-9-yl)oxolan-2-yl]acetate (6.4)

Soliditet (5 ml, 37 mmol) are added to a solution 5,12 g (12 mmol) of [(2R,3R,4R,5R)-3,4-deacetylase-5-(2-amino-6-globulin-9-yl)oxolan-2-yl]methyl acetate (6.3), I2(3.04 from g, 12 mmol), CH2I2(10 ml, 124 mmol) and Cul (2.4 g, 12.6 mmol) in THF (60 ml). The mixture is heated at the boil under reflux for 45 minutes and then allowing to cool to room temperature. To this solution add 100 ml of saturated Na2S2O3eliminating reddish color caused by the presence of iodine. The aqueous solution is extracted with 3 chloroform, which merge together, dried over MgSO4and concentrate under reduced pressure. The product is then purified on a column of silica gel, using CHCl3-Meon (98:2) to give [(2R,3R,4R,5R)-3,4-deacetylase-5-(6-chloro-2-iturin-9-yl)oxolan-2-yl]methyl acetate (6.4) (80% crystallized from EtOH).

1H NMR(300 MHz, CDCl3) δ 8.20 (s, 1H, H-8), 6.17 (d, J=5.41 Hz, 1H, H-1'), 5.75 (t, J=5.39 Hz, 1H, H-2'), 5.56 (t, J=5.40 Hz, 1H, H-3'), 4.38 (m, 3H, H-4', 5'), 2.14 (s, 1H, AU), 2.11 (s, 1 H, AC), 2.10 (s, 1H, AU).

Example 8

(4S,2R,3R,5R)-2-(6-Amino-2-iturin-9-yl)-5-(hydroxymethyl)oxolan-3,4-diol (6.5)

Into the flask containing 6.0 g (11.1 mmol) of [(2R,3R,4R,5R)-3,4-deacetylase-5-(6-chloro-2-iturin-9-yl)oxolan-2-yl]methyl acetate (6.4), add 100 ml of liquid NH3at -78°and the solution is allowed the opportunity to mix for 6 hours. After this solution allow to warm to room temperature overnight with simultaneous evaporation of NH3getting a brown oil. The product is crystallized from hot isopropanol, receiving the connection 6.5 (80%), TPL 143-145°C, r.f.=0.6 20% Meon/CHCl3.

1H NMR (300 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.68(c, 2H), 5.75(d, J=6.16, 1H), 5.42 (d, J=5.40 Hz, 1H), 5.16 (d, J=4.62 Hz, 1H), 4.99 (t, J=5.39 Hz, 1H), 4.67 (d, J=4.81 Hz, 1H), 4.06 (d, J=3.37 Hz, 1H), 3.89 (m, 1H), 3.54 (m,, 2H).

Example 9

[(1R,2R,4R,5R)-4-(6-Amino-2-iturin-9-yl)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]Oct-2-yl]methane-1-ol (6.6)

To a solution of 2.0 g (5.08 mmol) of (4S,2R,3R,5R)-2-(6-amino-2-iturin-9-yl)-5-(hydroxymethyl)oxolan-3,4-diol (6.6) in 100 ml of acetone added 9.6 g of p-toluensulfonate acid and 5 ml of dimethoxypropane. The reaction mixture was stirred at room temperature for 1 hour, during which add 15 g of NaHCO3and then stirred for further in accordance with the s 3 hours. The residue is filtered and washed 2X EtOAc. Then the filtrate is concentrated under reduced pressure. The residue is subjected to chromatography on a column of silica gel with Meon-CHCl3(1:99)to give compound 6.6 (72%) in the form of solids, TPL 185-187°C.

1H NMR (300 MHz, DMSO-d6) δ 8.22 (s, 1H, H-8), 7.69 (s, 2H, NH2), 6.00 (d, J=2.70 Hz, 1H, H-1'), 5.21 (m, 1H, H-2'), 5.07 (Ushs, 1H, OH), 4.88 (m, 1H, H-3'), 4.13 (m, 1H, H-4'), 3.47 (m, 2H, H-5'), 1.49 and 1.28 (s, 3H, C(CH3)2).

Example 10

(2S,1R,4R,5R)-4-{6-Amino-2-iturin-9-yl)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxylic acid (6.7)

To a stirred solution of 1.6 g (3.7 mmol) [(1R,2R,4R,5R)-4-(6-amino-2-iturin-9-yl)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]oxy-2-yl]methane-1-ol (6.6) in 200 ml of H2O type of 0.60 g of KOH and, dropwise, a solution of 1.70 g (10,8 mmol) KMnO4in 50 ml of N2O. the Mixture is placed in a dark place at room temperature to 225 hours. Then the reaction mixture was cooled to 5-10°and discolor the solution of 4 ml of 30% H2O2in 16 ml of water while maintaining the temperature below 10°using an ice-salt bath. The mixture is filtered through celite, and the filtrate concentrated under reduced pressure to approximately 10 ml and then acidified to pH 4 2 N. HCl. The precipitate is filtered off and washed with simple ether, receiving after drying, the connection 6.7 (70%) as a white solid, TPL 187-190°C.1H I Is R (300 MHz, DMSO-d6) δ 8.11 (s, 1H, H-8), 7.62 (s, 2H, NH2), 7.46 (s, 1H, COOH), 6.22 (s, 1H, H-1'), 5.42 (d, J=5.71 Hz, 1H, H-2'), 5.34 (d, J=6.16 Hz, 1H, H-3'), 4.63 (s, 1H, H-4'), 1.46 and 1.30 (s, 3H, C(CH3)2).

Example 11

(2S,3S,4R,5R)-5-(6-Amino-2-iturin-9-yl)-3,4-dihydroquinoxaline-2-carboxylic acid (6.8)

The solution 1,72 g (of 3.85 mmol) (2S,1R,4R,5R)-4-(6-amino-2-iturin-9-yl)-7,7-dimethyl-3,6,8-dioxabicyclo[3.3.0]octane-2-carboxylic acid (6.7) in 80 ml of 50% HCOOH stirred at 80°C for 1.5 hours. The reaction mixture is evaporated under reduced pressure, dissolved in H2O and the solution again evaporated. This process is repeated until then, while the remainder will not lose the smell of formic acid. As a result of recrystallization from water gain of 1.33 g (85%) of compound 6.8 in the form of a white solid, TPL 221-223°C, decomp.

1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H, H-8), 7.68 (s, 2H, NH2), 5.90 (d, J=6.55 Hz, 1H, H-1'), 4.42 (m, 1H, 4-2'), 4.35 (d, J=2.31 Hz, 1H, 11-4'), 4.22 (m, 1H, H-3').

Example 12

[2S,3S,4R,5R)-5-(5-Amino-2-iturin-9-yl)-3,4-dihydroquinoxaline-2-yl]-N-ethylcarbodiimide (6.9)

To a chilled (5° (C) and stirred solution of 1.29 g (3,17 mmol) (2S,3S,4R,5R)-5-(6-amino-2-iturin-9-yl)-3,4-dihydroquinoxaline-2-carboxylic acid (6.8) in 150 ml of absolute ethanol are added dropwise to 1.15 ml ice SOCl2. The mixture is stirred at room temperature overnight, and then its pH was adjusted to 8 with saturated water is passed NaHCO 3. The mixture is filtered, then the filtrate concentrated under reduced pressure, obtaining white solid, which is dried and re-dissolved in 20 ml of dry ethylamine at -20°C for 3 hours and then at room temperature overnight. The reaction mixture was diluted with absolute ethanol, the precipitated product is filtered and washed with dry simple ether, receiving 530 mg (72%) 6.9 in the form of pure solids, TPL 232-234°C.

1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H, H-8), 8.12 (t, 1H, NH), 7.73 (s, 2H, NH2), 5.85 (d, J=6.93 Hz, 1H, H-1'), 4.54 (m, 1H, H-2'), 4.25 (d, J=1.92 Hz, 1H, H-4'), 4.13 (m, 1H, H-3'), 3.28 (m, 2H, CH2CH3), 1.00 (t, J=7.2 Hz, 3H, CH2CH3).

Example 13

Methyl 4-(3-{9-[(4S,5S,2R,3R)-5-(N-ethylcarbazole)-3,4-dihydroquinoxaline-2-yl]-6-aminopurin-2-yl}prop-2-inyl)cyclohexanecarboxylate (DWH-146e)

To a degassed solution of 25 mg (0,063 mmol) of [(2S,3S,4R,5R)-5-(6-amino-2-iodopsin-9-yl)-3,4-dihydroquinoxaline-2-yl]-N-ethylcarbodiimide (6.9)and 16.9 mg (0,094 mmol) of (5.5) and 0.75 Cul 5 ml (each) of triethylamine (TEA) and acetonitrile is added 15 mg of Pd(PPh3)4. The solution is stirred for 24 hours at 70°C, then filtered through celite and subjected to chromatography on silica gel with Meon-CHCl3(5:95)to give compound DWH-146e (24%).

Example 14

(4-Prop-2-vinylcyclohexane)acetate (5.6)

Acetic anhydride (0,92 ml, 8.25 mmol) and the feast of the Dean (0.2 ml, 2.5 mmol) are added to a solution of compound 5.3 (250 mg, of 1.65 mmol) in 25 ml of a simple ester. The reaction mixture is allowed the opportunity to mix at room temperature for 24 hours. To the reaction mixture, water is added, and the organic phase is then extracted with 10% NaHCO3. The organic layer is dried with MgSO4and evaporated. The residue is subjected to chromatography on silica gel with EtOAc-hexane (5:95)to give compound 5.6 (47%).

Example 15

[4-(3-{9-(4S,5S,2R,3R)-5-(N-Ethylcarbazole)-3,4-dihydroquinoxaline-2-yl]-6-aminopurin-2-yl}prop-2-inyl)cyclohexyl]acetate (JMR 193)

To a degassed solution of 125 mg (0.29 mmol) of [(2S,3S,4R,5R)-5-(6-amino-2-iturin-9-yl)-3,4-dihydroquinoxaline-2-yl]-N-ethylcarbodiimide (6.9), 150 mg (0.77 mmol) of the compound (5.6) and 1.0 mg Cul 1.3 ml of TEA and 4 ml of TMP add 25 mg of Pd(PPh3)4. The solution is stirred for 72 hours at 60°C, after which it was filtered through celite and subjected to chromatography on silica gel with Meon-CHCl3(5:95)to give compound JMR193 (10%).

Example 16

[(2S,3S,4R,5R)-5-(6-Amino-2-{3-[4-(hydroxymethyl)cyclohexyl]prop-2-inyl}purine-9-yl)-3,4-dihydroquinoxaline-2-yl]-N-ethylcarbodiimide

A. (4-Prop-2-vinylcyclohexane)methane-1-ol

Complex litigation-Ethylenediamine (90%) (6.4 g, 70 mmol) is added slowly to a solution of TRANS-[4-(hydroxymethyl) cyclohexyl]methyl 4-methylbenzenesulfonate (3 g, 10 mmol) in 40 ml of dimethyl sulfoxide. The reactions which authorized the mixture allow to mix for 5 days, and then it slowly quenched at 0°With water. This mixture is diluted with simple ether (300 ml) and washed 3 times with saturated aqueous ammonium chloride (200 ml). Organic matter is dried with sodium sulfate. The solvent is removed under reduced pressure. The product was then purified by chromatography on a column of silica gel, elwira a mixture of ethyl acetate-hexane (20:80) and receiving the product (85%).

1H NMR (300 MHz, CDCl3) d 3.41 [d, J=6.5 Hz, 2H), 2.07 (DD, J=2.5, 6.5 Hz, 2H), 1.96-1.75 (m, 5H), 1.41 (m, 2H), 0,95 (m, 4).13With NMR (300 MHz, CDCl3d 83.8, 69.6, 68.9, 40.7, 37.7, 32.3, 32.3, 29.6, 29.6, 26.5.

B. [(2S,3S,4R,5R)-5-(6-Amino-2-{3-[4-(hydroxymethyl)cyclohexyl]prop-1-inyl}purine-9-yl)-3,4-dihydroquinoxaline-2-yl]-N-ethylcarbodiimide (JMR2037)

Pd(PPh3)4, 10 mg, add to a degassed solution of 28 mg (0,065 mmol) of [(2S,3S,4R,5R)-5-(6-amino-2-iodopsin-9-yl)-3,4-dihydroquinoxaline-2-yl]-N-ethylcarbodiimide, 30 mg (0.20 mmol ) (4-prop-2-vinylcyclohexane)methane-1-ol, 1.0 mg Cul 1 ml of triethylamine (TEA), 1 ml DMF and 1 ml of acetonitrile. The solution is stirred for 60 hours at room temperature, after which it was filtered through celite and subjected to chromatography on silica gel with Meon-CHCl3(7:93)to give 5 mg (17%) connection JMR2037. Specified in the title compound was subjected to the tests described here on the binding, in which it was found that it is associated with recombinant And2Areceptormediated, while Ki is 694±69 nm.

General method 4: getting 2-AAs (2-alkenylbenzene)

In a flame-dried 25 ml round bottom flask under nitrogen atmosphere download 2 NECA (40 mg) and dissolved in 2 ml of DMF. Then add the appropriate alkyne (approximately 0.1 ml), followed by adding 4 ml of acetonitrile and 0.1 ml of tea. All three solvent Tegaserod nitrogen for at least 24 hours. To this solution was added 5 mol.% Pd(PPh3)4and 6 mol.% iodide of copper. Yellowish solution was stirred at room temperature for 24 hours or until completion of the reaction according to HPLC. If the reaction is not complete, add an additional catalyst, Cul, tea. After completion of the reaction under vacuum to remove solvents and red-black residue is transferred into a small amount of DMF. This solution is added to the preparative silicagel plate for TLC (Analtech 1000 microns, 20 cm ×20 cm) and elute first 120 ml of a mixture of 40% hexane/CH2Cl2and then 40 ml of the Meon. Collect UV-active band (usually yellow) in the middle part of the plate, slowly washed 4×25 ml of 20% MeOH/CH2Cl2and concentrate. Then the product is distilled HPLC with reversed phase.

Example 17

4-{3-[6-Amino-9-(5-ethylcarboxyl-3,4-dihydroxyacetophenone-2-yl)-N-purine-2-yl]prop-inyl}cyclohexanecarbonyl acid (ATL146a)

Interaction ATL146e with five equivalents of LiOH in a mixture of THF/water for 6 hours gives ATL146a (7 mg, 72%) as a white solid, which crystallized from a mixture of Meon/water (0.1% of TFU) after purification HPLC with reversed phase.

1H NMR (DMSO-d6) δ to 8.70 (s, 1H), to 8.41 (s, 1H), 7.62mm (s, 2H), of 5.89 (d, J=7,25 Hz, 1H), 4.53-in (m, 1H), 4,27 (s, 1H), 4,08 (d, J=3.6 Hz, 1H), 2,29 (d, J=6,4 Hz, 2H), 2,15 of 1.99 (m, 1H), 1,92 to 1.76 (m, 4H), 1,52-to 1.38 (m, 1H), 1,38-1,19 (m, 2H), of 1.02 (t, J=6.3 Hz, 3H).

13With NMR (DMSO-d6) 176,7, 169,2, 155,6, 148,9, 145,2, 141,6, 119,0, 87,7, 85,0, 84,6, 81,6, 73,1, 71,9, 43,2, 35,9, 33,3, 31,2, 28,3, 25,6, 15,0. MS high. authorised. (bombard. fast, atoms) m/z 474,2196 [(M+N)+calculated for C22H29N6O6474,2182].

Example 18

Ethylamide 5-{6-amino-2-[3-(4-hydroxymethylcellulose)prop-1-l]purine-9-yl}-3,4-dihydroxyacetophenone-2-carboxylic acid (JR2037)

Interaction (4-prop-2-vinylcyclohexane)methane-1-ol (5.3) (30 mg, 0.2 mmol) with 2-oNECA (28 mg, 0.07 mmol) under the General conditions described above gives JR2037 (7 mg, 24%) as a white solid.

1H NMR (CD3OD) δ by 8.22 (s, 1H), of 5.92 (d, J=7.7 Hz, 1H), 4,70-of 4.66 (DD, J=7,7 Hz, 4.8 Hz, 1H), and 4.40 (d, J=1.2 Hz, 1H), 4,25-to 4.23 (DD, J=4,8 Hz, 1.2 Hz, 1H), 3,51-3,37 (m, 2H), and 3.31 (d, J=6 Hz, 2H), 2,30 (d, J=6,8 Hz, 2H), 1,94-1,89 (m, 2H), 1,83-of 1.78 (m, 2H), 1,64-of 1.42 (m, 2H), 1,12 (t, J=7,3 Hz, 3H), 1,09-of 0.91 (m, 4H).

13With NMR (CD3OD) δ 170,3, 155,4, 148,5, 146,0, 141,6, 118,8, 88,7, 85,5, 84,, 80,6, 73,1, 71,3, 66,8, 39,6, 36,9, 33,3, 31,5, 28,6, 25,6, 13,5. MS high. authorised. (bombard. fast, atoms) m/z 459,2373 [(M+H)+calc. for C22H31N6O5459,2356].

Example 19

Methyl ester of 4-{3-[6-amino-9-(3,4-dihydroxy-5-hydroxymethylfurfural-2-yl)-N-purine-2-yl]prop-2-inyl}cyclohexanecarboxylic acid (JR2145)

JR2145 synthesized in accordance with the General Protocol 4 using alkyne (5.5) and 10 mg (of 0.025 mmol) of 2-oddenino. The product is isolated in the form of an off-white solid: yield of 5.5 mg (48%).

1H NMR (CD3OD) δ 8,35 (s, 1H), by 5.87 (d, J=6,5 Hz, 1H), 4,70-of 4.66 (DD, J=6,4 Hz, 5.6 Hz, 1H), 4.26 deaths (DD, J=5.0 Hz, 2.3 Hz, 1H), 3,85 (DD, J=a 12.7 Hz, 2.3 Hz, 1H), 3,70 (DD, J=12.3 Hz, 2.7 Hz, 1H)and 3.59 (s, 3H), 2,31 (d, J=6,6 Hz, 2H), 1,95 (m, 4H), 1,61-1,20 (m, 6N). APCI m/z (relates. intensive.) 446,3 (MN+, 100) 314,5 (30). MS high. authorised. (bombard. fast. atoms) m/z 446,2040 [(M+N)+calc. for C21H29N5O6446,2040].

Example 20

4-{3-{6-Amino-9-(3,4-dihydroxy-5-hydroxymethylfurfural-2-yl)-N-purine-2-yl]prop-2-inyl}cyclohexylmethyl ether acetic acid (JR2147)

Specified in the title compound, JR2147, synthesized in accordance with the General Protocol 4 using alkyne (5.3) and 10 mg (of 0.025 mmol) of 2-oddenino. The product is isolated in the form of an off-white solid: yield of 4.8 mg (48%).

1H NMR (CD3OD) δ of 8.25 (s, 1H), of 5.75 (d, J=6,5 Hz, 1H), 4,70-of 4.66 (DD, J=8,1 Hz, 4.6 Hz, 1H), and 4.40 (d, J=1.2 Hz, 1H), 4,25-to 4.23 (DD, J=4,6 Hz, 1.2 Hz, 1H), 3,83 (d, J=6,5, 2H), 3,53-of 3.31 (m, 2H), to 2.29 (d, J=6,5 Hz, 2H), of 1.97 (s, 3H), 1,93-1,89 (m, 2H), 1,79 is 1.75 (m, 2H), 1,64-of 1.42 (m, 2H), 1,12 (t, J=7,3 Hz, 3H), 1,09-of 0.91 (m, 4H). APCI m/z (relates. intensive.) 460,3 (MN+, 100), 328,5 (35). MS high. authorised. (bombard. fast. atoms) m/z 460,2193 [(M+N)+calc. for C22H30N5O6460,2196].

Example 21

2-Aminoethylamide ether 4-{3-[6-amino-9-(5-ethylcarboxyl-3,4-dihydroxyacetophenone-2-yl)-N-purine-2-yl]prop-2-inyl}cyclohexanecarboxylic acid (JR3033)

Specified in the title compound, JR3033, synthesize, interacting clean triperoxonane acid for 2 h with the product of the interaction of 2-oNECA and JR3115 in accordance with the General method 4. The product is isolated in the form of a salt with TFU: yield 9 mg (98%). APCI m/z (relates. intensive.) 516,4 (MN+, 100), 343,3(10).

Example 22

Ethylamide 5-{6-amino-2-[3-(4-ethylcarboxyl)prop-1-inyl]purine-9-yl}-3,4-dihydroxyacetophenone-2-carboxylic acid (JR3037)

In a sealed tube containing 5 ml of fresh ethylamine, add 10 mg (0.02 mmol) ATL146e. The flask was sealed and the contents stirred at 60°With over 80 hours After expiration of this time the reaction is about 50% according to HPLC. The vessel is cooled to 0&x000B0; With open and ethylamine are removed in vacuum, receiving 4.5 mg (73%) JR3037 in the form of a white solid substance and produce, regenerating 4.0 mg source material after purification of the residue HPLC with reversed phase.

Spectra1H NMR (CD3CD d4) δ,13With NMR (CD3CD d4) δ consistent with the above structure. APCI m/z (relates. intensive.) 500,8 (MN+, 100), 327,4 (3).

Example 23

Ethylamide 5-{6-amino-2-[3-(4-carbamoylmethyl)prop-1-inyl]purine-9-yl}-3,4-dihydroxyacetophenone-2-carboxylic acid (JR3055)

In a sealed tube containing 10 ml of a saturated solution of MeOH/NH3add 5 mg (0.01 mmol) ATL146e. The flask is closed and the contents stirred at 25°C for 48 hours, the Vessel is cooled to 0°With open and ammonia are removed, barbotine N2within 1 hour. Then in vacuum to remove residual solvent, getting a 4.0 mg (83%) JR3055 in the form of a white solid after purification of the residue HPLC with reversed phase.

1H NMR (CD3OD-d6) δ to 8.41 (s, 1H), 5,98 (d, J=7.2 Hz, 1H)and 4.65 (DD, J=7,3 Hz, 4.8 Hz, 1H), to 4.41 (d, J =2.0 Hz, 1H), 4,28 (DD, J=4,6 Hz, 2.0 Hz, 1H), 3,35 (m, 2H), 2,37 (d, J=6,4 Hz, 2H), 2,10 (m, 1H), 1,90 (m, N), 1,53 (m, N), of 1.23 (m, N), of 1.12 (t, J=7,3 Hz, 3H).13With NMR (CD3OD-d4) δ complies with the above structure. APCI m/z (attributes, intensive.) 472,3 (MN+, 100), 299,4 (10).

Example 24

These are the amide 5-{6-amino-2-[3-(4-methylcarbamoylmethyl)prop-1-inyl]purine-9-yl}-3,4-dihydroxyacetophenone-2-carboxylic acid (JB3065)

In a sealed tube containing 10 ml of 2.0 M of methylamine in methanol, add to 16.5 mg (0.03 mmol) ATL146e. The flask is closed and the contents stirred at 70°C for 120 hours, the Vessel is cooled to 0°With open and the solvent is removed in vacuum, obtaining 8.0 mg (48%) JR3065 in the form of a white solid after purification of the residue HPLC with reversed phase. APCI m/z (relates. intensive.) 486,3 (MN+, 100), 313,4 (35).

Example 25

1-(4-Prop-2-vinylcyclohexane)alanon (JR3115)

In a 50 ml flame-dried round bottom flask under nitrogen atmosphere add 840 mg (4,43 mmol) Cul and 2 ml of anhydrous THF and the solution cooled to -40°With bath acetonitrile/dry ice. To this solution parts within 30 minutes added 6.8 ml (9.50 mmol) of 1.4 M MeLi in ether) and the contents stirred for a total time equal to 2 hours. In a separate flask, prepare the acid chloride of 4-prop-2-vinylcyclohexane acid (88), stirring 88 in 5 ml of SOCl2at 50°C for 3 hours and then viparita thionyl chloride under reduced pressure, obtaining a yellow oily substance. This residue is transferred in 2 ml of THF and added dropwise to a solution of metallobeta at -60°C. the Flask was washed with an additional 2 ml of THF and this solution was also added dropwise. The reaction mixture is stirred for 40 m the chickpeas and then quenched with methanol, leading to the formation of bubbles, and the reaction mixture changes color from orange to yellow. The reaction mixture is stirred for an additional 30 minutes at room temperature, then add 5 ml of EtOAc and 3 ml of a saturated solution of NH4Cl. After two minutes of mixing, add 20 ml of water and 20 ml of EtOAc and light green organic layer is separated from the blue of the water layer. The aqueous layer was extracted with additional 3×15 ml of EtOAC, dried and concentrated to obtain residue, which was subjected to chromatography using a mixture of EtOAc/hexane. APCI m/z (relates. intensive.) 165,1 (MN+,100).

Example 26

Ethylamide 5-(6-amino-2-{3-[4-(1-hydroxyethyl)cyclohexyl]prop-1-inyl}purine-9-yl)-3,4-dihydroxyacetophenone-2-carboxylic acid

Specified in the title compound, JR3121, synthesize, interacting NaBH4in THF with the product of the interaction of 2-NECA and JR3115 in accordance with the General method 4. The product is isolated in the form of an off-white solid. Yield 7 mg (52%). APCI m/z (relates. intensive.) 473,4 (MN+, 100).

Example 27

Isopropyl 4-prop-2-vinylcyclohexane

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (103 mg, 0.54 mmol) and dimethylaminopyridine (12 mg, 0,098 mmol) are added to a solution of 4-prop-2-initimage inkarbaeva acid (78 mg, 0.47 mmol) in anhydrous methylene chloride (8.0 ml). After stirring at room temperature for 1.5 h add isopropyl alcohol (2.0 ml, 26 mmol) and the mixture is stirred for 19 h at room temperature. Add water (25 ml) and the mixture is extracted with methylene chloride (3×15 ml). The combined extracts washed with water (25 ml) and saturated salt solution (20 ml), dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product is purified column chromatography, elute with a mixture of hexane/ether (95:5). Yield 76 mg, 78%.

1H NMR (CDCI3) δ 0,96-1,12, 1,19-1,25, 1,33-1,52, 1,86-2,00 (4 x m, 10H, 9 x cyclohexyl, acetylene), 1,20 (d, 6N, -och(CH3)2), is 2.09 (DD, 2H, -C6H10CH2CLOS), 2,16 (TT, 1H, 1 x cyclohexyl), equal to 4.97 (m, 1H, -och(CH3)2).

Example 28

Isopropyl ester of 4-{3-[6-amino-9-(5-ethylcarboxyl-3,4-dihydroxyacetophenone-2-yl)-N-purine-2-yl]prop-2-inyl}cyclohexanecarboxylic acid

1H NMR (CD3OD) δ 1,13-1,26, 1,36-1,50, 1,54-3,67, 1,94-2,03 (4 x m, N, cyclohexyl, 2 x-CH3, -NHCH2CH3), a 2.36 (d, 2H, -C6H10CH2SS-), of 3.45 (m, 2H, -NHCH2CH3), the 4.29 (DD, 1H, 3'-H), of 4.45 (d, 1H, 4'-H), 4.72 in (DD, 1H, 2'-H), 5,97 (d, 1H, 1'-H), of 8.28 (s, 1H, 8-H). APCI m/z (relates. intensive.) 515,6 (MH+, 100).

Example 29

tert-Butyl 4-prop-2-vinylcyclohexane the t

Specified in the title compound, AWW, synthesized as described for OVA using tert-butyl alcohol instead of isopropyl alcohol. Yield 56 mg, 56%.

1H NMR (CDCl3) δ 0,97-1,12, 1,18-1,23, 1,32-1,52, 1,85-2,00 (4 x m, 10H, 9 x cyclohexyl, acetylene), USD 1.43 (s, N, 3 x-PRAS3), 2,05-of 2.16 (m, 3H, -C6H10CH2CLO, 1 x cyclohexyl).

Example 30

tert-Butyl ether 4-{3-[6-amino-9-(5-ethylcarboxyl-C,4-dihydroxyacetophenone-2-yl)-N-purine-2-yl]prop-2-inyl}cyclohexanecarboxylic acid

Specified in the title compound, ATL211 receive in the form of a product of the interaction of 2-oNECA and JR3115 in accordance with the General method 4. The output of 27.5 mg, 63%.

1H NMR (CD3OD) δ 1,08-1,23, 1,33-1,49, 1,54-1,67, 1,92-2,03 (4 x m, 10H, cyclohexyl), of 1.17 (t, 3H, -NHCH2CH3), was 1.43 (s, N, 3 x-CH3), is 2.41 (d, 2H, -C6H10CH2SS-), 3,40 (m, 2H, -NHCH2CH3), 4,32 (DD, 1H, 3'-H), to 4.46 (d, 1H, 4'-H), 4,70 (DD, 1H, 2'-H), 6,03 (d, 1H, 1'-H), 8,46 (s, 1H, 8-H). APCI m/z (relates. intensive.) 529,6 (MH+,100).

Example 31

Studies on the binding of radioligand

Linking And2A-receptors is determined by radioligand125I-ZM241385. Figure 2 shows the competition of selective agonists for binding to recombinant And2A-adenosine receptor of human rights. Connection DWH-146e in the above the first degree of selectivity against recombinant A 2A-subtype human (hA2A). The selectivity for And3receptor (not shown) is less impressive, but nevertheless above approximately 50 times. Connection DWH146e approximately 5 and 50 times more effective than WRC0470 and CGS21680, respectively (Figure 1). Unexpected and interesting discovery is that the ester DWH-146e around 50 times more effective than acid DWH-146a (Figure 1).

Example 31A

Action DWH-146e and JMR193 on the oxidative activity of neutrophils

A. The Materials.

f-met-leu-phe (fMLP), luminal, superoxide dismutase, cytochrome C, fibrinogen, the adenosine deaminase and tripney get blue from Sigma Chemical. Hipac-ficoll buy from ICN (Aurora, OH), and Cardinal Scientific (Santa Fe, NM) and Accurate Chemicals, and Scientific (Westerbury, NY). Endotoxin (LPS; E. coli K235) obtained from List Biologicals (Campbell, CA). Balanced salt Hanks solution (HBSS) and samples with a lysate of amoebocytes acquire the Bio-Wittaker (Walkersville, MD). Serum albumin human (HSA) obtained from the Cutter Biological (Elkhart, IN). Recombinant factor tumor necrosis alpha man is Dianippon Pharmaceutical Co. Ltd. (Osaka, Japan). ZM241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a] [1,3,5]triazine-5-yl-amino]ethyl)phenol) was presented to Simon Poucher, Zeneca Pharmaceuticals, Cheshire, UK. Prepare the uterine solutions (1 mm and 10 mm in DMSO) and stored them at -20°C.

C. Obtaining human neutrophils.

Purified neutrophils (p is blithedale 98% neutrophils and > 95% viable, as determined by exclusion using Trypanosoma blue, containing <1 platelet 5 neutrophils and <50 PG/ml of endotoxin (sample lysate of amoebocytes), obtained from normal heparinized (10 units/ml) venous blood in the one-step procedure division hipac-ficoll (A. Ferrante et al., J. Immunol. Meth., 36, 109 (1980) ).

C. the Release of inflammation reactive oxygen premirovany and stimulated human neutrophils.

Chemiluminescence

Reinforced lyuminola chemiluminescence, a measure of oxidative activity of neutrophils, depends on the generation of superoxide and mobilization of myeloperoxidase, an enzyme lysosomal granules. Light radiates unstable high-energy oxygen produced by activated neutrophils. Purified neutrophils (5-10×105/ml) incubated in a balanced salt Hanks solution containing 0.1% serum albumin (1 ml) with DWH-146a, DWH-146e, CGS 21680 or JMR193 or without them, with rolipram or without him, and tumor necrosis factor-alpha (1 u/ml) or without it, for 30 minutes at 37°to shake an ice bath. Then determine reinforced lyuminola (1×10-4M), stimulated with f-met-leu-phe (1 MSM) chemiluminescence on the photometer Chronolog® (Crono-log Corp., Havertown, PA) at 37°for 2-minut. The chemiluminescence is defined as the relative maximum of the emitted light (=the height of the curve) compared with that in samples with tumor necrosis factor alpha and without DWH, JMR or rolipram.

D. Results

As shown in figure 2, as JMR193 and DWH-146e reduce oxidative activity of human neutrophils stimulated with f-met-leu-phe and premirovannogo by tumor necrosis factor alpha, in the measurement of enhanced lyuminola chemiluminescence more effective than the agonist And2A-adenosine receptor CGS21680. The horizontal axis shows the concentration of CGS21680, DWH-146a, DWH-146e or JMR193 (log nM). The vertical axis shows the resulting peak activity of human neutrophils as the relative amount of stimulated release of reactive oxygen species as measured by enhanced lyuminola chemiluminescence, in comparison to the control samples that were not premirovany by tumor necrosis factor alpha. Mean values SEM (n=4-5 separate experiments).

Data below the horizontal axis in figure 2 show the magnitude of the EU50to reduce the activity of human neutrophils (based on the data of Figure 2). Mean values SEM (n=4-5 separate experiments). *p<0.05, the reduction IC50compared with CGS21680.

JMR193 and DWH-146e reduce oxidative emission stimulated neutrophil-EC50less than 1 nm (0.8 and 0.3 nm, meet the but). Agonists And2A-adenosine receptor of the free acid DWH-146a and CGS21680, in contrast, is not so effectively inhibit the oxidative burst (53 and 9 nm, respectively; Figure 2). Inhibition of DWH-146e oxidative release of stimulated neutrophils was suppressed selective antagonist of the A2A-AR ZM241385.

As shown in Figure 3, JMR193 (1 nm) with rolipram (100 nm) synergistically reduces stimulated the release of reactive oxygen. Neutrophils will primesouth by tumor necrosis factor-alpha (1 u/ml) and stimulated with f-met-leu-phe (1 mm). The vertical axis shows percentage inhibition of oxidative activity, as measured by enhanced lyuminola by chemiluminescence. Mean values SEM (n=4) separate experiments. *p<0.05 synergies between JMR193 and rolipram instead of additive activity.

As shown in figure 4, the selective antagonist And2A-adenosine receptor ZM241385 (100 nm) (ZM) counteracts oxidative activity of human neutrophils, inhibiting JMR193 (10 nm), as follows from the results reinforced lyuminola chemiluminescence. Average SEM of 4 separate experiments. *p=0,0004 ZM241385 counteracts inhibiting JMR193 oxidative activity.

E. [camp]ihuman neutrophils and adhesion of neutrophils to the biological surface.

24-well plate for culturing tissue procurement is to see the human fibrinogen (5 mg/ml of 1.5% sodium bicarbonate; 0.5 ml/well; Sigma Chemical) overnight at 37°With 5% CO2.

Neutrophils (3-4×106/0.5 ml/sample) was incubated in the wells of the tablet coating for 45 minutes in 0.5 ml HBSS containing 0.1% HSA and ADA (1 u/ml) in the presence and absence of recombinant human TNFα(10 IU/ml), DWH-146e (3 to 300 nm), rolipram (300 nm) and/or ZM241385 (100 nm). After incubation the wells, add 0.5 ml of HCl (0,2 N.) and incubated for 45 minutes, extragere camp. Then the samples are centrifuged at microfuge for 2 minutes to remove cell debris. Polumillimetrovy samples frozen for analysis at camp (C. Brooker et al., Science, 194, 270 (1976)). Walls washed twice with normal saline, and the remaining monolayer hydrolyzing 0.2 ml of 0.2 N. NaOH containing SDS for 2 hours at room temperature. Then the protein samples frozen (-70° (C) for further analysis of the protein to determine the comparative adhesion of PMN (K.R. Stowell et al., Anal. Biochem., 85, 572 (1978)).

Results

DWH-146e (30-300 nm) separately and synergistically with rolipram (300 nm) increases the content of camp in human neutrophils and together with rolipram synergistically reduces the adhesion of neutrophils to covered fibrinogen surface (Figure 5). Action DWH-146e (300 nm) + rolipram (300 nm) on the production of camp by neutrophils and adhesion prevents selective antagonist And2A-adenosine receptor, ZM241385 (Z; 100 nm). The average SEM of 5 separate experiments. *p<0,05 increased [camp] in neutrophils compared with the absence of DWH-146e; **p<0.05 decrease in the adhesion of neutrophils compared to the absence of DWH-146e.

F. Oxidizing adhesion of human neutrophils.

Ways

Using modified methods from section E, neutrophils (2×106/ml), the resulting separation of hipak-ficoll incubated for 15 minutes at 37°in 0.45 ml of balanced salt Hanks solution containing 0.1% human serum albumin and adenozindezaminazy (1 u/ml), rolipram (300 nm) and DWH-146e (3 to 300 nm). After incubation add cytochrome C (120 μm) and catalase (0,062 mg/ml) in the presence and in the absence of recombinant tumor necrosis factor alpha (1 u/ml)and 200 μl aliquots of cell suspension immediately transferred into a pair of cells 96-well mattress for tissue culture coated overnight with human fibrinogen. Determine the optical density of the samples at 500 nm against the corresponding samples of superoxide dismutase (200 u/ml).

G. The Results.

As shown in Fig.6, the inhibition of stimulated tumor necrosis factor alpha release of superoxide adhesive neutrophils human fibrinogen coated surfaces provide rolipram (300 nm) and DWH-146e. DWH-146e srigaitalian release of adhesion of neutrophils, as well as the synergies reduces oxidative emission in the presence of rolipram, which in itself has no effect on the oxidative activity of neutrophils. The horizontal axis shows the concentration of DWH-146e in nm, and the vertical axis is the amount of superoxide released by neutrophils determined by measuring the reduction of cytochrome C. There is a marked synergism with DWH-146e and inhibitor of PDE type IV, rolipram, in reducing oxidative activity of adhesion of human neutrophils stimulated by tumor necrosis factor alpha. Mean values SEM repeats 4-5 separate experiments. *p<0.05 decrease in the release of superoxide compared with when no DWH-146e; **p<0.05 decrease in the release of superoxide compared with the presence of rolipram and lack of DWH-146e.

Example 32

Treatment of ischemic/reperfusion kidney injury using DWH-146e

To determine, does the activation And2A-adenosine receptor induced DWH-146e, creatinine plasma after 24 and 48 hours after the ischemic/reperfusion damage in rats, the kidney of rats subjected to 45 min ischemia and 24 - or 48-hour reperfusion. DWH-146e (0,004 mg/kg/min) or filler begin to continuously enter via mini-pump for 5 hours prior to ischemia/reperfusion. As shown in Fig.7, DWH-146e significantly reduces creatinine in plasma 7/7 rats (P&t; 0.05) and at 6/6 rats receiving DWH-146e (P<0,001), after 24 and 48 hours, respectively.

To determine whether the action DWH-146e on the reduction of creatinine in the plasma of rats subjected to ischemia/reperfusion-mediated And2Areceptor, kidneys of rats subjected to 45 min of ischemia, and then a 48-hour reperfusion. DWH-146e (0,004 mg/kg/min) begin to continuously enter via mini-pump for 5 hours before ischemia. As shown in Fig, the improvement in renal function was completely eliminated antagonist And2AZM241385 (of 0.003 µg/kg/min - equimolar speed of delivery compared with DWH-146e) (*P<0.001 in the case of filler instead of DWH; **p<0,05 DWH against DWH/ZM. N=5 for filler, DW; N=6 for DWH/ZM. ANOVA followed by Bonferroni correction).

DWH-146e at concentrations that do not have hemodynamic action, prevents swelling of the kidney, necrosis and concentration of erythrocytes in internal brain substance.

Protection against kidney damage, provided DWH-e (0,01 µg/kg/min subcutaneously within 48 hours), correlates with a dramatic inhibition of adhesion of neutrophils to vascular endothelium. I believe that inhibition under the action of DWH-146e interaction between neutrophils and the vascular endothelium is responsible, at least partially, for the protection of the kidney from damage.

In order to determine, does the activation of A2AAR the number of neutrophils in the inner brain is the first substance rats subjected to ischemia/reperfusion using Neuroludica®, kidney consider when 100-fold increase and make the extraction of the entire kidney. Count the number of polymorphonuclear leukocytes, considering the sections of the kidney at 250-fold increase. Renal sections impose optical frames, examined under a microscope and count all of polymorphonuclear leukocytes (PMN) within each frame. This system ensures that each PMN will only be counted once. As shown in Fig.9, the density of neutrophils is 15,65/mm2when using filler and 3,02/mm2when treatment with the use of DWH-146e.

Example 33

Action DWH-146e on reperfusion lung injury

A. Ways.

Used standalone, perfusion whole blood, ventilated rabbit lung model. Rabbits-donors are removing lung after pulmonary arterial injection PGEi1and washing Euro-Collins preservative, then light save for 18 hours at 4°C. Group I of the lung (n=9) control group. Group II lung (n=9) reperfusion whole blood, which is first passed through a filter that removes leukocytes. In group III (n=9) to reperfused blood type DWH-146e (25 µg/kg) immediately after reperfusion and administered during reperfusion period (1 mcg/kg/min). All light machining is shown reperfusion for 30 minutes and record the pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), air compliance (CPL) and arterial oxygenation. Write down the activity of myeloperoxidase (MPO), to determine the amount of sequestration of neutrophils, as well as measure the wet/dry weight ratio for determination of pulmonary edema.

Century Results.

Arterial oxygenation in groups II and III significantly above oxygenation in group I after 30 minutes of reperfusion (514,27±35,80 and 461,12±43,77 against 91,41±20,58 mmHg, p<0,001. As shown in Figure 10, the group of light III shows the growing consumption of pO2during reperfusion. The absence of leukocytes in the lung group II improves arterial oxygenation in the early reperfusion. *p=0.004 (group II vs. groups I and III); **p<0,001 (groups II and III vs. group I).

As shown in figure 11, the average PVR in group II significantly lower compared to control lungs (*p<0,001). PVR group III lung is significantly lower than even the lungs, reperfusion blood without cells (**p<0,001 vs. groups I and II). Pulmonary vascular resistance significantly lower in group III (22,783±357 Dean·s·cm-5compared with both groups II and I (31,057±1743 and 36,911±2173 Dean·s·cm-5, p<0,001). Air compliance better in groups II and III compared to group I (1,68±0.08 and 1,68±0,05 against 1,36±of 0.13, p=0.03). Permeability m is crossdev in group III is reduced to 106,82± 17,09 compared to 165,70±21,83 ng blue dye Evans/GM tissue in group I (p=0.05). As shown in Fig, myeloperoxidase activity in group III significantly lower than in group I (*p=0.03). MPO = myeloperoxidase. The myeloperoxidase activity in group III is 39,88±4,87 compared to 88,70±18,69 ΔOD/GM/min in group I (p=0.03), and myeloperoxidase activity in group II is 56,06±7,46.

C. Conclusions.

DWH-146e reduces the sequestration of neutrophils in the lungs and dramatically improves the function of the lung transplant. Neutrophils are important components of the inflammatory cascade reperfusion damage, and their source can be as circulating blood, and himself pulmonary implant. Selective activation And2Aadenosine terminates macropropositions inflammatory response and reduces reperfusion lung injury after transplantation.

Results light microscopy show that the control light in the group I have a heavy infiltration by leukocytes and edema in the alveolar spaces after 18 hours of ischemic storage and 30 minutes of reperfusion. In group II (light subjected to reperfusion devoid of leukocytes in blood) and in group III (light receiving DWH-146e during reperfusion) such infiltration was much weaker.

Example 34

Action DWH-146e on education neointima polietileno damage

Activation of leukocytes in the release of inflammatory cytokines occurs after subcutaneous coronary intervention and may play a role in restenosis. In mice the formation of healthy neointima in the presence of an intact endothelial lining occurs after ligation of the common carotid artery. Using this model, mice C57/BL6 randomisiert during ligation of the carotid artery for a 7-day infusion via osmotic pump DWH-146e (n=7) or filler (n=8).

On the 14th day after ligation of the carotid artery histomorphometry shows a significant decrease in the area neointima (0,005±0,004 mm2against 0,021±0,014 mm2, p=0.02)and the ratio of the area neointima to medium in size (0,13±0,07 against 0,64±0,44, p=0.01) in treated animals compared with control. The average size in both groups was almost identical (0,035±0,007 mm2against being 0.036±0,009 mm2p=0,81). Such limitation of growth neointima lasted 28 days. Fig summarizes the effect of DWH-146e on growth inhibition neointima on mice LCCA. These experiments show that the model of ligation of the carotid artery of a mouse prolonged stimulation And2A(7 days) with the use of DWH-146e leads to a significant reduction education neointima at least 21 days, possibly through its action is and the activation and function of leukocytes.

Example 35

Inhibition of endotoxin-stimulated release of TNFα human monocytes

A. The Materials.

Hipac-ficoll buy from ICN (Aurora, OH), Cardinal Scientific (Santa Fe, NM), Accurate Chemicals and Scientific (Westbury, NY). Endotoxin (LPS; E. coli 0111B4) obtained from List Biologicals (Campbell, CA). Balanced salt Hanks solution (HBSS) and set for samples with lysate of amoebocytes buy from BioWittaker (Walkersville, MD). Serum albumin human (HSA) obtained from the Cutter Biological (Elkhart, IN). ZM241385 (4-(2-[7-amino-2-(2-furyl) [1,2,4]triazole[2,3-a][1,3,5]triazine-5-ylamino]ethyl]phenol) was presented to Simon Poucher, Zeneca Pharmaceuticals, Cheshire, UK. Prepare the uterine solutions (1 mm and 10 mm in DMSO) and stored them at -20°C.

C. Production of TNFα purified adhesive by human monocytes.

Ways

Rich monocyte monolayer (>65% monocytes) get incubare 1 ml mononuclear fraction of cells (5×105/ml), the resulting separation of hipak-ficoll (A. Ferrante et al., J. Immunol. Meth., 36, 109 (1980)) in the wells of a 24-hole tablet for the cultivation of tissues (1 h; 37°C; 5% CO2). Unattached leukocytes are removed by washing and the culture medium (1 ml balanced salt Hanks solution containing 0.1% serum albumin human, adenoidectomies [5 u/ml] and 1% V / V heat inactivated autologous serum)is added to wells containing designee mononuclear cells. As indicated above, add the following connections: (1) endotoxin (100 ng/ml) and selective antagonist And2AAR ZM241385 (100 nm), and (2) selective agonists And2A-adenosine receptor JMR193 (1-1000 nm), DWH-146e (1-1000 nm) and CGS21680 (10-1000 nm). Then the samples are incubated for 4 hours (37°C; 5% CO2) and the supernatant layers together. Suspended cells are removed by centrifugation, and free from cell samples frozen (-70°). TNFα they are free from cell supernatant fluids (n=6), using the ELISA kit (Coulter/Immunotech, Miami, FL).

C. The Results.

As shown in Figure 10, 14, agonists A2A-receptor adenosine reduces the production of TNFα endotoxin-stimulated adhesion of monocytes. Selective antagonist of A2AAR ZM241385 (100 nm) opposes the action JMR193 on the production of TNFα (Fig).

Thus, DWH-146e and JMR193 reduce LPS endotoxin-stimulated production of TNFα human monocytes as a result of mechanism-specific binding of the agonist with a2A-adenosine receptor.

Example 36

Activity DWH-146e in a model of peritonitis in mice

Preliminary studies of experimental peritonitis include the injection zymosan (Zym) as a strong incentive inflammation (Y. Zhang et al., Eur. J. Pharmacol., 313, 237 (1996)). As shown in Fig, after the injection, zymosan average concentrate the radio leukocytes, defined by hemocytometer neubauer is 7,325±to 1.893/mm3. Intraperitoneal injection of DWH-146e dose, part 2.5 mg/kg, one hour before zymosan inhibits the development of peritonitis, the average atom concentration of leukocytes ±SEM is 2,012±374/mm36 hours later (p<0,05). Thus, these studies indicate that a2AAR is a tool for mediating PMN infiltration into the peritoneum after the introduction of zymosan.

Example 37

Cardiotoxic, mediated anti-inflammatory effect JMR193

Compounds in accordance with the present invention are exploring inducyruya myocardial "stunning", heart failure, post-re, time periods, cessation of coronary blood flow by re-occlusion of a blood supply in the coronary artery.

A. the Effect of four cycles of occlusion-reperfusion.

The left anterior descending (LAD) coronary artery in a group of dogs isolated and enclosed in a loop obturator. Blood flow in LAD-artery of dogs subjected to occlusion of 4 times within 5 minutes. After each occlusion of the blood flow to resume in ten minutes. One group of six dogs after each period of occlusion pour in a solution containing the compound acetate (JMR193)obtained in example 15 (JMR193) (0,01 µg/kg/min). The second group of six dogs after the Ute solution containing filler (medium). After the last cycle of occlusion-reperfusion injury in cardiac function of animal control within 3 hours. The results are presented on Fig and 18. Fig shows systolic left ventricular (LV) reaction thickening in 6 control dogs. Heart thickening is reduced by approximately 50% after 3 hours after the last occlusion. Fig shows LV reaction thickening in 6 dogs received an intravenous infusion of the test compound, JMR193 (0,01 µg/kg/min), since the baseline period and throughout the experiment. Cardiac function in the infusion JMR193 almost normalized after 90 minutes after reperfusion.

C. Action ten cycles of occlusion-reperfusion.

Two additional groups of dogs subjected to ten (instead of 4) cycles of occlusion-reperfusion, with each occlusion lasts 5 minutes, interrupted by 5 minutes of reperfusion. In this example, two animals pour in a solution containing the compound acetate (JMR193)obtained in example 15 (a 0.01 mcg/kg/min)after each period of occlusion. The other three animals pour in a solution containing the filler (the media). After the last cycle of occlusion-reperfusion injury in cardiac function of animal control within 3 hours.

The results are presented on Fig and 20. On Fig shows systolic left ventricular response to thickening of the 3 control dogs. This is a more severe cardiac lesions than in example 23A, but the result LV-thickening is completely absent soon after reperfusion and remained unchanged in 3 hours. Fig shows LV thickening in 2 of the dogs received an intravenous infusion of the test compound, JMR193 (0,01 µg/kg/min), since the baseline period and throughout the experiment. Compared with the control group, the dogs treated with the infusion JMR193 demonstrate a significant and noticeable improvement of cardiac function immediately after reperfusion, which lasted 3 hours.

C. Effect of acetate compounds JMR193 on the absorption of neutrophils during occlusion-reperfusion.

Some animals injected neutrophils labeled with radioactive isotopes. Neutrophils isolated from the blood of dogs, incubated with a compound containing99mTc, and re-injected dogs. Neutrophils labeled with99mTc, is injected as a marker to determine the degree of inflammation in reperfusion zone after four cycles of ischemia-reperfusion. Inflammation caused by cycles of occlusion-reperfusion, is the cause adhesion of radioactive neutrophils, the number of which counted using a gamma camera. JMR193 inhibits adhesion of neutrophils. The results are presented on Fig, where the localization of neutrophils labeled with99mTc in dogs receiving only filler (solid is olasky), higher than in dogs treated with JMR193 (hatched bars). Thus, reducing the amount of radiolabelled neutrophils in the Central ischemic zone, caused by the infusion JMR193 illustrates the decrease (*) in cardiac inflammation.

The studies described in the examples 23A and 23C show that cardiac inflammation plays an important negative role in causing myocardial lesion. In addition, the introduction of agonist And2A-adenosine receptor, such as, for example, JMR193 or prevents light damage (Fig and 18), or substantially alleviates myocardial dysfunction that accompanies a heavy defeat (Fig and 20).

All publications, patents and patent documents are hereby incorporated by reference as if they were separately listed as references. The invention is described with reference to various specific and preferred options and ways of its implementation. It is understood that many possible variations and modifications, if they do not violate the nature and scope of this invention.

1. The compound of formula (I)

where (a) each R independently represents hydrogen, C1-C6alkyl, C3-C7cycloalkyl, phenyl or phenyl (C1 -C3)alkyl;

(b) X and X' each independently represents-CH2OH, -CO2R2, -OC(O)R2, -CH2OS(O)R2or C(O)NR3R4;

(c) each of R2, R3and R4independently represents H, C1-6-alkyl; or C1-6-alkyl, substituted by one to three groups C1-6-alkoxy, C1-6-alkylthio, halogen, hydroxy, amino, mono(C1-6-alkyl)amino, di(C1-6-alkyl)amino;

(d) Z and Z' independently represent a (C1-C6)alkyl, optionally interrupted by one to three S atoms or naproxenum Oh, or absent, a n is 1-3;

or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which X' represents-CH2HE or-C(O)NR3R4.

3. The compound according to claim 2, in which X' is C(O)NR3R4.

4. The compound according to claim 3 in which R3represents H, a R4is (C1-C4)alkyl.

5. The compound according to claim 1, in which each R represents H or (C1-C4)alkyl.

6. The compound according to claim 1, in which Z' is-CH2- or-CH2-CH2.

7. The connection according to claim 6, in which Z represents-CH2- or-CH2-CH2-.

8. The compound according to claim 1, in which3-C10cycloalkyl represents cyclohexyl or cyclopentyl.

9. The connection of claim 8, in which X represents a C1/sub> -C4-alkoxycarbonyl, C(O)NR3R4or acetoxymethyl.

10. The connection of claim 8, in which the X-Z is HO2C-Z.

11. The connection of claim 8, in which the X-Z and Z' has transconfiguration relatively3-C10cycloalkyl.

12. The compound according to claim 1, in which R is H, X' is ethylaminomethyl, and (X-Z)n[(C3-C10)cycloalkyl]-Z'-≡C - is 2-(4-methoxycarbonylbenzyl) ethinyl or 2-(4-carboxylatomethyl)ethinyl.

13. The compound according to claim 1, in which R is H, X' is ethylaminomethyl, a (X-Z)n[(C3-C10)cycloalkyl]-Z'-C≡C is 2-(4-ecotoxicologically) ethinyl.

14. The compound according to claim 1, which represents [4-(3-{9-(2R,3R,4S,5S)-5-(N-ethylcarbazole)-3,4-dihydroquinoxaline-2-yl]-6-aminopurin-2-yl}prop-2-inyl)cyclohexyl] acetate or its pharmaceutically acceptable salt.

15. The compound according to claim 1, which represents [(2R,3R,4S,5S)-5-(6-amino-2-{3-[4-(hydroxymethyl)cyclohexyl]-prop-1-inyl}purine-9-yl)-3,4-dihydroquinoxaline-2-yl]-N-ethylcarbodiimide or its pharmaceutically acceptable salt.

16. The compound according to claim 1, which represents methyl 4-(3-{9-[(2R,3R,4S,5S)-5-(N-ethylcarbazole)-3,4-dihydroquinoxaline-2-yl]-6-aminopurin-2-yl}prop-1-inyl)cyclo-hexanecarboxylic or its pharmaceutically acceptable salt.

17. The compound according to claim 1, represent the its a 4-(3-{9-[(2R,3R,4S,5S)-5-(N-ethylcarbazole)-3,4-dihydroquinoxaline-2-yl]-6-aminopurin-2-yl}prop-1-inyl)cyclohexane-carboxylic acid or its pharmaceutically acceptable salt.

18. The compound according to claims 1-17, as agonist activity And2A-adenosine receptor.

19. Connection p as an active agent for suppressing the inflammatory response or treatment of inflammation.

20. Connection p, in which 5'-X is CH2OH, or C(O)NR3R4.

21. Connection p, in which X' is C(O)NR3R4.

22. Connection item 21, in which R3represents H, a R4is (C1-C4)alkyl.

23. Connection p, in which each R represents H or (C1-C4)alkyl.

24. Connection p, in which Z' is-CH2- or-CH2-CH2-.

25. Connection p, in which Z represents-CH2- or-CH2-CH2-.

26. Connection p, where3-C10cycloalkyl includes cyclohexyl or cyclopentyl.

27. Connection p, in which X represents a (C1-C4-alkoxycarbonyl or acetoxymethyl.

28. Connection p, in which the X-Z is HO2C-Z-.

29. Connection p, in which the X-Z and Z' represent transconfiguration relatively3-C10cycloalkyl.

30. Connection p, in which R represents H, X represents ethylaminomethyl, and (X-Z)n[(C3-C10-cycloalkyl]-Z'-≡C - is 2-(4-methoxycarbonylbenzyl the Teal) ethinyl or 2-(4-carboxylatomethyl)ethinyl.

31. Connection p, in which R represents H, X represents ethylaminomethyl, and (X-Z)n[(C3-C10-cycloalkyl]-Z'-≡C - is 2-(4-ecotoxicologically) ethinyl.

32. Connection p representing [4-(3-{9-(2R,3R,4S,5S)-5-(N-ethylcarbazole)-3,4-dihydroquinoxaline-2-yl]-6-aminopurin-2-yl} prop-1-inyl)cyclohexyl]acetate.

33. Connection p representing [(2R, 3R, 4S,5S)-5-(6-amino-2-{3-[4-hydroxymethyl)cyclohexyl]prop-1-inyl}purine-9-yl)-3,4-dihydroquinoxaline-2-yl]-N-ethylcarbodiimide.

34. Connection p represents methyl 4-(3-{9-[(2R,3R,4S,5S)-5-(N-ethylcarbazole)-3,4-dihydroquinoxaline-2-yl]-6-aminopurin-2-yl}prop-1-inyl)cyclohexanecarboxylate.

35. Connection p, a 4-(3-{9-[(2R,3R,4S,5S)-5-(N-ethylcarbazole)-3,4-dihydroquinoxaline-2-yl]-6-aminopurin-2-yl}prop-1-inyl)cyclohexanecarbonyl acid.

36. The connection according to claim 19, in which said treatment further includes the use of an inhibitor of phosphodiesterase type IV.

37. Connection p, in which the inhibitor is rolipram.

38. The connection according to claim 19, in which the inflammatory reaction caused by ischemia.

39. The connection according to claim 19, in which the inflammatory response associated with atherosclerosis.

40. The connection according to claim 19, in which the inflammatory reaction caused by an autoimmune disease.

41. The connection according to claim 19, in which oterom inflammatory reaction caused by ischemic/reperfusion damage.

42. The connection according to claim 19, in which the inflammatory reaction occurs in the heart, kidney or lung.

43. The connection according to claim 19, in which the inflammatory reaction caused by stroke, traumatic brain or spinal cord.

44. The connection according to claim 19, in which the inflammatory reaction caused by transplantation of an organ, tissue or cell.

45. The connection according to claim 19, in which the inflammatory reaction caused by an infection.

46. The connection according to claim 19, in which the inflammatory reaction associated with skin disease.

47. The connection according to claim 19, in which the inflammatory reaction caused by angioplasty, stent introduction, shunt or implantation.

48. The connection according to claim 19, in which the inflammatory reaction caused by allergic disease.

49. The connection according to claim 19, in which the inflammatory reaction caused by the debilitating disease.

50. The connection according to claim 19, in which the inflammatory reaction caused by immunosuppressive therapy.

51. The connection according to claim 19, in which the inflammatory reaction caused by a pathological condition or symptom in a mammal, the cause of which is active And2A-adenosine receptor, and desirable agonism such activity.

52. Connection p, as an active agent of a medicinal product for the treatment of inflammation.

53. The connection at paragraph 52, in which the drug includes an inhibitor phosphodi sterzi, the type IV.

54. Connection item 53, in which the phosphodiesterase inhibitor is rolipram.

55. Connection item 53, in which the drug includes a carrier liquid.

56. Connection item 53, in which the drug is adapted for parenteral administration.



 

Same patents:

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

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

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

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

The invention relates to novel acyl derivatives of guanosine formula I, inosine formula II, xanthosine formula III, deoxyinosine formula IV, deoxyguanosine formula V, inosine - 2',3'-(acyclic)dialcohol formula VI or pharmaceutically acceptable salts

The invention relates to O6substituted derivatives of guanine, method of their production and to their use for the treatment of tumor cells

The invention relates to derivatives of adenosine General formula I, where R1is a hydrogen atom, halogen atom, lower alkyl, lower-alkyl, lower S-alkyl or phenyl, and may be in the 2 - or 5-position of the indole; n = 0, 1, and 2, R2- lower alkyl, lower alkenyl, lower quinil,3-C7-cycloalkyl or lower-alkyl, phenyl, possibly substituted by 1-4 substituents selected from a halogen atom, nitro, lower alkyl or O-alkyl groups or a group-NR6R7where R6and R7a hydrogen atom, lower alkyl; pyridyl; thienyl, naphthyl, and in the case when n = 2, R2group-NR8R9where R8and R9at the same time are lower alkyl or form together with the nitrogen atom to which they are attached, a heterocycle selected from the research, piperidine; R3and R4the same or different, is a hydrogen atom or lower alkyl, exhibiting analgesic and antihypertensive activity

The invention relates to new compounds of formula I Nu-O-Fa, where O is oxygen, Nu is a nucleoside or nucleoside analogue, including such nitrogen base, as adenine, Esenin, cytosine, uracil, thymine; Fa - acyl monounsaturated C18YPD C20-9-fatty acids, which fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or nucleoside analog, or a hydroxyl group, an acyclic chain of an analogue of the nucleoside

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: medicine, biochemistry.

SUBSTANCE: invention relates to a method for treatment of pathology or disorder taken among inflammatory diseases. Method involves using the simultaneous, separating or distributed by time at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2. Also, invention relates to the composition comprising at least a single substance inhibiting activity of NO-synthase and at least a single substance inhibiting activity of phospholipase A2 for using in the method for treatment of pathology or disorder taken among inflammatory diseases.

EFFECT: improved method for treatment.

21 cl, 4 ex

FIELD: medicine, clinical medicine, allergology.

SUBSTANCE: invention relates to treatment of allergic and/or inflammatory diseases of mucosa tissues and skin. Medicinal agent prescribed for treatment of disease is mixed with sodium chloride and water before its using and prepared solution is brought about to isotonic state by the content of sodium chloride. The prepared agent is used for rinsing pathological focus, inhalation or for curative bathes. Also, invention proposes a set designated for preparing indicated agent. Method provides enhancing effect in treatment due to elimination adverse effect of drugs in indicated diseases.

EFFECT: valuable properties of agent, improved method for treatment.

7 cl, 1 tbl, 3 dwg, 3 ex

FIELD: medicine, therapy.

SUBSTANCE: invention relates to treatment of vasculitis and erythematosus lupus. Method involves administration of 15-deoxyspergualine or its analogous by two or more courses with break for 4 days to 5 weeks. Period between successive injections of preparation within the treatment course is up to 48 h and the treatment course is at least 5-7 days. Method provides high treatment effect and reducing the total dose of 15-deoxyspergualine or its analogous.

EFFECT: enhanced effectiveness of treatment.

25 cl, 2 dwg, 3 ex

Substituted indoles // 2255087

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to new substituted indoles of the formula (I): and/or stereoisometic form of compound of the formula (I) and/or physiologically acceptable salt of compound of the formula (I) wherein R3 means residue of the formula (II): wherein D means -C(O)-; R7 means hydrogen atom (H) or -(C1-C4)-alkyl; R8 means (a) typical residue of amino acid among the group: phenylalanine or homophenylalanine wherein phenyl residue is unsubstituted or substituted with halogen atom; or (b) -(C1-C4)-alkyl wherein alkyl is a linear or branched and (b) 1) mono- or multi-substituted independently of one another with pyrrole residue wherein this residue is unsubstituted or substituted with halogen atom; (b) 2) mono- or bi-substituted independently with residue -S(O)x-R10 wherein x = 0, 1 or 2, or (b) 3) mono- or bi-substituted independently of one another -N(R10)2 wherein R10 means (a) hydrogen atom (H); (b) means -(C1-C6)-alkyl wherein alkyl is unsubstituted or substituted with halogen atom from 1 to 3 times; (c) phenyl wherein phenyl is substituted or substituted with halogen atom from 1 to 3 times; in the case (R10)2 residues R10 have values independently of one another (a), (b), (c); Z means (a) residue of heterocycles group comprising benzothiadizine, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, oxadiazolone, triazole being heterocycles are unsubstituted or substituted with -NH2=, =O, alkoxycarbonyl or aminocarbonyl from 1 to 3 times, or (b) means -C(O)-R11 wherein R11 means 1. -O-R10 or 2. -N(R10)2; R9 means (a) hydrogen atom (H); (b) means (C1-C6)-alkyl wherein alkyl is unbranched or branched and substituted with phenyl or =O independently of one another from 1 to 3 times; (c) phenyl wherein phenyl is unsubstituted or substituted with halogen atom; R1, R2 and R4 mean hydrogen atom (H); R5 means hydrogen atom (H); R6 means (a) phenyl wherein phenyl is unsubstituted or substituted with -NH2; (b) pyridine, or (c) pyrimidine being pyridine or pyrimidine is unsubstituted or substituted with groups -NH2, -NH-CH3. Compounds of the formula (I) are specific inhibitors of IkB kinase.

EFFECT: valuable biochemical properties of compounds.

3 cl, 3 tbl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

FIELD: pharmaceutical industry.

SUBSTANCE: composition contains steroid as active principle, in particular 11-β,16-α,17-α,21-tetrahydroxy-9-α-fluoro-1,4-pregnadiene-3,20-dione or pharmaceutically acceptable salt thereof and special-destination additives including microcrystalline cellulose, crospovidone, and magnesium stearate.

EFFECT: optimized bioavailability, increased storage stability, and improved organoleptic properties.

3 cl, 1 tbl

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with peroral liquid compositions which could be designed into gelatinous capsules. The suggested pharmaceutical composition includes a pharmaceutically active agent, a solubilizing agent and, not obligatory, a surface-active substance and a plastifying agent. The pharmaceutically active agent has got, at least, one acidic fragment, preferrably, that of carbonic acid being chosen out of the group of non steroid antiphlogistic preparations being acid-soluble at acid : dissolved substance ratio being from 3:1 to 10000:1. New compositions provide increased rates and degrees of absorption of pharmaceutically active agent and minimize side effects caused by such active substances.

EFFECT: higher efficiency of application.

42 cl, 39 ex

FIELD: organic chemistry, heterocyclic compounds, purines, medicine.

SUBSTANCE: invention relates to a method for treatment of arrhythmia in mammal. Method involves administration of agonist of adenosine A1-receptors in the therapeutically effective minimal dose of the formula:

wherein R1 represents optionally substituted heterocyclic group. The indicated dose of agonist is in the range from 0.0003 to 0.009 mg/kg. Method shows the enhanced effectiveness and doesn't result to undesirable adverse effects.

EFFECT: improved treatment method, valuable medicinal properties of substances.

11 cl, 1 dwg, 2 ex

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