11β-hydroxysteroid dihydrogenase inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described compounds of formula

as well as their pharmaceutically acceptable salts where the substitutes are those as described in the patent claim. The compounds of formula (I) are 11β-hydroxysteroid dehydrogenase (11β-HSD) enzyme inhibitors.

EFFECT: making the compounds effective for treating and preventing the diseases, such as insulin-independent diabetes and metabolic syndrome, particularly obesity, eating disorders or dislipidemia.

15 cl, 1 tbl, 28 ex

 

The present invention relates to inhibitors of 11β-hydroxysteroid dehydrogenase. Inhibitors include, for example, adamantane-2-ylamide amino-1-arylpyrazole-3-carboxylic acids and their derivatives and are useful for the treatment of diseases such as diabetes type II and metabolic syndrome.

The present invention relates to the compound of formula (I):

where:

R1represents hydrogen or lower alkyl;

R2represents a lower alkyl, -(CH2)n-cycloalkyl, -(CH2)n-heteroseksualci, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)nHE, -(CH2)nCH(CH3HE or -(CH2)nOch3;

or

R1and R2together with the N atom to which they are attached, form a 5-7-membered monocyclic ring which contains the N atom to which R1and R2attached, and optionally another heteroatom selected from O and S, where a 5-7 membered monocyclic ring is unsubstituted or mono - or bisamidines substituents independently selected from hydroxy, lower alkyl and -(CH2)nIT;

R3represents one or more substituents independently selected from H, halogen, lower alkyl and lower alkoxy;

R4is own the th hydrogen, -OH, -NHC(=O)CH3or-NHS(=O)(=O)CH3;

n denotes 1, 2, 3 or 4;

and its pharmaceutically acceptable salts.

Diabetes is a serious disease that affects a growing number of people around the world. A recent report by the International Diabetes Federation suggests that in 2025 will have a total of 380 million people worldwide suffering from diabetes. The occurrence of diabetes in many countries is exacerbated by the parallel rising obesity trends. The serious consequences of diabetes include increased risk of stroke, heart disease, kidney damage, blindness and amputation. Cardiovascular diseases cause the death of more than 70% of patients with diabetes mellitus type 2 (T2DM) [article .Pourcet and other Expert Opin. Emerging Drugs, 2006, 11, SS-401].

Diabetes is characterized by decreased secretion of insulin and/or weakened the ability of peripheral tissues to respond to insulin, which leads to increased levels of glucose in plasma. There are two forms of diabetes: insulin-dependent and insulin-independent, with most patients suffering from insulin-independent form of the disease known as type 2 diabetes or insulin-dependent diabetes mellitus (NIDDM). Because of the serious consequences, there is a continuous need for monitoring diabetes.

Metabolic syndrome is a condition where patients arise Bo is her two of the following symptoms: obesity, hypertriglyceridemia, low levels of HDL-cholesterol, high blood pressure and elevated levels of glucose [article R.H.Eckel, Proc. Nutr. Soc., 2007, 66, cc.82-95; J.-P.Despres and I.Lemieux, Nature, 2006, 444, cc.881-887; E.Ratto and others, J.Am.Soc. Nephrol., 2006, 17, cc.S120-S122; A.M.McNeill, etc.. Diabetes Care, 2005, 28, cc.385-390]. This syndrome is often a precursor to type 2 diabetes and is highly prevalent in the United States, accounting for 24% [article E.S.Ford and others, JAMA, 2002, 257, s]. Therapeutic agent, which facilitates the metabolic syndrome, could be useful for potential decrease or stop the development of type 2 diabetes.

A number of tests used to evaluate patients with diabetes. The levels of fasting blood glucose tests and glucose tolerance are used for measuring the amount of glucose in the blood and the body's ability to respond to glucose. However, the level of variability of glucose levels in the blood is relatively high, especially in patients with diabetes, and therefore also use alternative tests. One of the most common is the test HbA1cthat defines the levels of glycosylated hemoglobin in red blood cells [article D.R.McCane and others, BMJ, 1994, 308, cc.1323-1328; R.J.McCarter, etc.. Diabetes Care, 2006, 29, cc.352-355]. Red blood cells have a typical lifetime of 120 days in the body, and they contain hemoglobin, which gradually becomes gli is etilirovannym, with the level of glycosylation correlated with average levels of glucose in the blood. As a result, the levels of HbA1cindicate the average blood glucose over the previous 3-4 months, and they do not change during the day. The level of HbA1cin normal blood is about 5%, and the level in poorly controlled patients with diabetes is 8% or more. The current recommendation of the American Diabetes Association is to maintain the level of HbA1cbelow 7%. This level corresponds to the average level of glucose in plasma is approximately 170 mg/DL [article D.E.Goldstein etc., Diabetes Care, 2004, 27, cc.1761-1773].

Treatment of NIDDM usually begins with weight reduction, a healthy diet and exercise programs. These factors are particularly important in relation to increased risk of cardiovascular disease associated with diabetes, but they are usually ineffective in controlling the disease. There are a number of available drugs, including insulin, Metformin, sulfonylureas, acarbose preparations, thiazolidinediones, analogues of GLP-1 and inhibitors of DPP IV. However, some of these treatments have negative side, and there is a current need for new drugs for the treatment of diabetes.

For example, Metformin is an effective agent that reduces the levels of glucose in plasma shock and increases sensitivity is lnost to insulin peripheral tissues. Metformin has a number of actions in vivo, including increased synthesis of glycogen, a polymer of the form in which is stored glucose [article R.A.De Fronzo, Drugs, 1999, 58, Suppl. 1, p.29]. Metformin also has a positive effect on the lipid profile, with favorable results on the health of the cardiovascular system. Metformin therapy leads to lower levels of LDL cholesterol and triglycerides [article S..Inzucchi, JAMA, 2002, 287, s]. Over time, however, Metformin has lost its effectiveness [article R..Turner and others, JAMA, 1999, 281, s], and, therefore, there is still a need for new methods of treatment of diabetes.

Preparations of thiazolidinediones are activators-activated nuclear receptor peroxisomes-proliferator receptor-gamma (PPARγ). They are effective for reducing the levels of glucose in the blood, and their effectiveness due to the initially low resistance to insulin in skeletal muscle [article .Tadayyon and S.A.Smith, Expert Opin. Investig. Drugs, 2003, 72, s]. Three thiazolidinedione approved for use in the USA for the treatment of diabetes, but one was subsequently withdrawn because of hepatotoxicity in the tissues. Two currently in drug, pioglitazone and rosiglitazone, are effective to reduce blood sugar levels and levels b1Cin patients with diabetes [article G.Boden and .Zhang, Expert Opin. Investig. Drugs, 2006, 15, cc.243-250; .Pourcet and others, Expert Opin. Emerging Drugs, 200, 11, cc.379-401]. However, the required period of 3-4 months to observe the total efficiency [G.Boden and .Zhang, Op. Cit.], and one of the drawbacks associated with the use of preparations of thiazolidinediones, is weight gain.

Sulfonylureas bind to the sulfonylurea receptor in pancreatic beta cells to stimulate insulin secretion and, therefore, reduce the levels of glucose in the blood. Weight gain is also associated with the use of sulfonylureas [article S..Inzucchi, JAMA, 2002, 287, s], and as well as Metformin, have reduced efficacy over time [article R..Turner and others, JAMA, 1999, 281, s]. Another problem often encountered in patients being treated with sulfonylureas, is hypoglycemia [article .Salas J.J. and Sago Adv., Drug React. Tox. Rev, 2002, 21, cc.205-217].

Acarbose is an inhibitor of the enzyme alpha-glucosidase, which breaks the disaccharides and complex hydrocarbons in the gut. It has a lower efficiency compared with Metformin or the sulfonylureas, and it causes discomfort in the intestines and diarrhea, which often leads to termination of its application [article S..Inzucchi, JAMA, 2002, 287, s].

Although drugs have been approved for the treatment of diabetes, using a number of different mechanisms, and many other drugs undergoing clinical trials remains a need for new compounds for the treatment of diabetes. poslednie the results of the United Kingdom Prospective Study shows over time, a deterioration of the function of beta-cells in patients with diabetes, regardless of what was treated patients diet, sulfonylureas, Metformin or insulin [article R.R.Holman, Metabolism, 2006, 55, cc.S2-S5].

One possible target for the treatment of diabetes, which has recently attracted much attention, is 11β-hydroxysteroid dehydrogenase type I(11β-HSD1) [see, for example, article .Wang, Curr. Opin. Invest. Drugs, 2006, 7, cc.319-323]. 11β-HSD1 is an enzyme that catalyzes the restoration of cortisone to cortisol (or dehydrocorticosterone to corticosterone in rodents). Cortisol is a corticosteroid hormone produced in the adrenal glands, and it has been shown that it increases the levels of production of glucose, mainly by increasing gluconeogenesis [article S.Khani and J.A.Tayek, Clinical. Sci., 2001, 101, cc.739-747]. A second enzyme, 11β-hydroxysteroid dehydrogenase type II (11β-HSD2), which is responsible for the oxidation of cortisol to cortisone. Enzymes have low homology and are expressed in various tissues. 11β-HSD1 is mainly expressed in several tissues, including liver, adipose tissue and brain, whereas 11β-HSD2 is mainly expressed in mineralocorticoid-binding tissues, such as kidney and colon. 11β-HSD2 prevents the binding of cortisol to mineralcorticoid receptor, and is arsenia of this enzyme, as it was found to be associated with the syndrome of apparent mineralocorticoid excess (AME).

There is evidence for transgenic mice, as well as small clinical trials in humans, which confirms therapeutic effect of inhibiting 11β-HSD1 for the treatment of diabetes mellitus type 2.

Experiments with transgenic mice suggest that modulating the activity of 11β-HSD1 could have a beneficial therapeutic action in diabetes and metabolic syndrome. For example, when a gene 11β-HSD1 block in mice, fasting does not lead to the normal increase levels G6 and RISK, and animals are not susceptible to hyperglycemia associated with stress or obesity. Moreover, animals with blocked genome, which have a tendency to obesity, high-fat diet have significantly lower levels of fasting glucose compared to controls equal weight (article Y.Kotolevtsev and others, Proc. Natl. Acad. Sci. USA, 1997, 94, s). Mice with blocked 11β-HSD1 has been shown to have an improved lipid profile, insulin sensitivity and glucose tolerance (article N..Morton and others, J.Biol. Chem., 2001, 276, s). The effect of overexpression of the gene 11β-HSD1 mice was also investigated. These transgenic mice show increased activity of 11β-HSD1 in adipose tissue, and they also have a visceral adiposity, which caused the metabolic syndrome. Levels of corticosterone increased in adipose tissue, but not in serum, and in mice increased levels of obesity, especially on a high-fat diet. Mice on low-fat diets were hyperglycemic and hyperinsulinemic and showed intolerance to glucose and insulin resistance (article H.Masuzaki and others, Science, 2001, 294, s).

Action on non-selective inhibitor of 11β-hydroxysteroid dehydrogenase karbenoksolon has been studied in several small trials in humans. In one test it was found that carbenoxolone leads to a decrease in insulin sensitivity of the whole body, and this decline is associated with decreased production of glucose in the liver (article .R.Walker and others, J.Clin. Endocrinol. Metab., 1995, 80, s). In another test, the decrease in the production of glucose and glycogenosis in response to the introduction of glucagon observed in diabetes, but not in healthy subjects (article R..Andrews and others, J.Clin. Enocrinol. Metab., 2003, 88, s.285). Finally, it was found that carbenoxolone improves cognitive function in healthy older people and in patients with type 2 diabetes (article ..Sandeep and others, Proc. Natl. Acad. Sci USA, 2004, 707, s).

Identified a number of nonspecific inhibitors of 11β-HSD1 and 11β-HSD2, including glycyrrhetic acid, abietic acid and carbenoxolone. Also, found a number of selective inhibitors of 11β-HSD1, including chenodesoxycholic the second acid, flavanone and 2'-hydroxyflavanone (article S.Diederich and others, Eur. J. Endocrinol., 2000, 142, s and R.A.S.Schweizer and others, Mol. Cell. Endocrinol., 2003, 212, p.41).

Therefore, there is a need for inhibitors of 11β-HSD1, which is effective for the treatment of diseases, such as diabetes type II and metabolic syndrome. In addition, there is a need for inhibitors of 11β-HSD1, with an IC50 value of less than 1 micron.

In another embodiment, the present invention describes a pharmaceutical composition comprising a therapeutically effective amount of a compound according to formula (I) or its pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

In another embodiment, the present invention describes a method of treating diabetes, comprising the stage of introducing a therapeutically effective amount of a compound according to formula (I) or its pharmaceutically acceptable salt to a patient in need of it.

The present invention relates to inhibitors of 11β-HSD1. In a preferred embodiment, the present invention relates to pharmaceutical compositions containing the compounds of formula (I)and their pharmaceutically acceptable salts which are useful as inhibitors of 11β-HSD1.

It should be understood that the terminology used here is given in order to describe a particular is of embodiments and is not intended to be limiting. Further, although any methods, devices and materials similar or equivalent to the one described here, can be used in the implementation or testing of the invention, the following describes the preferred methods, devices, and materials.

Preferably in the compound of formula (I) R4 and Deputy

are in TRANS-position relative to each other in the ring adamantyl.

In a preferred embodiment, the compound according to the invention can be represented by formula (Ia):

where R1, R2, R3and R4are as defined above. As used here, the term "alkyl" denotes, for example, branched or unbranched, cyclic (cycloalkyl") or acyclic, saturated or unsaturated (for example, alkenyl or quinil) hydrocarbon radical, which may be substituted or unsubstituted. For cyclic alkyl the alkyl group preferably contains from C3to C12more preferably from C4to C10more preferably from C4to C7. For acyclic alkyl the alkyl group preferably contains from C1to C10more preferably from C1to C6more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-BU the sludge, isobutyl or tert-butyl) or pentyl (including n-pentyl and isopentyl), more preferably methyl. Therefore, it is clear that the term "alkyl", as used here, includes alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or unbranched), replaced alkenyl (branched or unbranched), quinil (branched or unbranched), substituted quinil (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkenyl and substituted cycloalkenyl. A preferred example of cycloalkyl includes cycloalkenyl.

In the preferred embodiment, "cycloalkyl" group optionally can be substituted one, two, three or four substituents, where each Deputy independently represents, for example, hydroxy, alkyl, alkoxy, halogen or amino, unless otherwise noted. Examples cycloalkyl groups include, but are not limited to, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclopentyl, optionally substituted cyclohexyl, optionally substituted cyclohexenyl, optionally substituted cycloheptyl and the like or those who con the specific described here. Preferred cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Other preferred cycloalkyl are cyclopropyl, cyclobutyl and cyclohexyl.

The term "heteroseksualci" denotes a cyclic alkyl ring, where one, two or three carbon atoms in ring substituted by a heteroatom such as N, O or S. Examples geterotsiklicheskikh groups include, but are not limited to, morpholinyl, thiomorpholine, piperazinil, piperidinyl, pyrrolidinyl, azepane, tetrahydrofuranyl and the like.

Heterocytolysine groups can be unsubstituted or substituted one, two or three substituents, independently selected from methyl, hydroxyl and hydroxymethyl. Preferred heteroseksualnymi groups are morpholinyl, piperidinyl, pyrrolidinyl, azepane and tetrahydrofuranyl, optionally substituted one, two or three substituents, independently selected from methyl, hydroxyl and hydroxymethyl. Other preferred heteroseksualnymi are morpholinyl, dimethylmorpholine, methylpiperidine, hydroxypiperidine, hydroxyethylpiperazine, pyrrolidinyl, methylpyrrolidinyl, dimethylpyrimidinol, hydroxyethylpyrrolidine, azepane and tetrahydrofuranyl.

As used here, the term "lower alkyl" refers to, e.g. the, branched or unbranched, cyclic or acyclic, saturated or unsaturated (for example, alkenyl or quinil) a hydrocarbon radical, where the specified cyclic lower alkyl group is a C3C4C5With6or C7and where specified acyclic lower alkyl group is a C1With2With3or4and preferably selected from methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tert-butyl). Therefore, it is clear that the term "lower alkyl", as used here, includes, for example, lower alkyl (branched or unbranched), lower alkenyl (branched or unbranched), lower quinil (branched or unbranched), cyclonically, cyclomethicone and cyclomethicone. Lower alkyl optionally may be substituted by hydroxy. Particularly preferred examples of lower alkyl are methyl, isopropyl, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

As used here, the term "aryl" denotes, for example, substituted or unsubstituted carbocyclic aromatic group. Examples of aryl groups are phenyl, naphthyl and the like. The preferred aryl group is phenyl.

The term "heteroaryl", alone or in whom is inali with other groups, denotes monocyclic or bicyclic radicals containing from 5 to 12 atoms in the ring containing at least one aromatic ring with one, two or three heteroatoms in the ring selected from N, O and S with the remaining atoms in the ring atoms are C. One or two carbon atoms in the ring heteroaryl groups can be substituted carbonyl group. The above heteroaryl group may be independently substituted one, two or three substituents, preferably one or two substituents, such as, for example, halogen, hydroxy, C1-6alkyl, halogen, C1-6alkyl, C1-6alkoxy, C1-6alkylsulfonyl, C1-6alkylsulfonyl,1-6alkylthio, amino, amino (C1-6alkyl, mono - or disubstituted amino-C1-6alkyl, nitro, cyano, acyl, carbarnoyl, mono - or disubstituted amino, aminocarbonyl, mono - or disubstituted aminocarbonyl, aminocarbonyl C1-6alkoxy, mono - or disubstituted aminocarbonyl-C1-6alkoxy, hydroxy - C1-6alkyl, carboxyl,1-6alkoxycarbonyl, aryl (C1-6alkoxy, heteroaryl C1-6alkoxy, heterocyclyl C1-6alkoxy, C1-6alkoxycarbonyl1-6alkoxy, carbarnoyl C1-6alkoxy and carboxyl C1-6alkoxy, preferably halogen, hydroxy, C1-6alkyl, halogen, C1-6alkyl, C1-6 alkoxy, C1-6alkylsulfonyl, C1-6alkylsulfonyl, C1-6alkylthio, amino, mono-C1-6alkyl substituted amino, di-C1-6alkyl substituted amino, amino, C1-6alkyl, mono-C1-6alkyl substituted amino-C1-6alkyl, CI-C1-6alkyl substituted amino-C1-6alkyl, nitro, carbarnoyl, mono - or disubstituted aminocarbonyl, hydroxy-C1-6alkyl, carboxyl, C1-6alkoxycarbonyl and cyano. Examples of heteroaryl are thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidin, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidine, tetrahydrofuranyl, pyranyl, pyranyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepin, piperazinil, morpholinyl, thenafter, benzofuranyl, isobenzofuranyl, indolyl, oxyindole, isoindolyl, indazoles, indolinyl, 7-isoindolyl, benzopyranyl, coumarinyl, isocoumarins, chinoline, ethenolysis, naphthyridine, cinnoline, hintline, iridoviridae, benzoxazines, honokalani, bromanil, bromanil, isopropanol, phthalazine and carbolines. The preferred heteroaryl is pyridyl.

Alkyl and aryl groups can be substituted or unsubstituted. When they replaced, they usually contain, for example, from 1 to 3 substituents, preferred is part 1 Deputy. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g. substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups, such as halogenated (e.g., trifluoromethyl); oxygen-containing groups, such as alcohols (for example, hydroxyl, hydroxyalkyl, aryl(hydroxyl)alkyl), ethers (for example, alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (for example, carboxaldehyde), ketones (for example, alkylsulphonyl, alkylcarboxylic, arylcarbamoyl, arylalkylamines, arylcarboxylic)acids (e.g., carboxy, carboxylic), acid derivatives, such as esters (for example, alkoxycarbonyl, alkoxycarbonylmethyl, alkylcarboxylic, alkylcarboxylic), amides (for example, aminocarbonyl, mono - or dialkylaminoalkyl, aminocarbonyl, mono - or dialkylaminoalkyl, allumination), carbamates (e.g., alkoxycarbonyl, aryloxypropanolamine, aminocarbonyl, mono - or dialkylaminoalkyl, allmenareliars) and urea (for example, mono - or dialkylaminomethyl or arylenecarborane); nitrogen-containing groups, such as amines (for example, amino, mono - or dialkylamino, aminoalkyl, mono- or dialkylaminoalkyl), azides, NITRILES (for example, cyano, qi is nalkyl), nitro; sulfur-containing groups, such as thiols, thioethers, sulfoxidov and sulfones (for example, alkylthio, alkylsulfonyl, alkylsulfonyl, alkylthiomethyl, alkylsulfonates, alkylsulfonates, aaltio, arylsulfonyl, arylsulfonyl, alltoall, arylsulfonyl, arylsulfonyl); and heterocyclic groups containing one or more, preferably one heteroatom (for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidin, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidine, tetrahydrofuranyl, pyranyl, pyranyl, pyridyl, pyrazinyl pyridazinyl, piperidyl, hexahydroazepin, piperazinil, morpholinyl, thenafter, benzofuranyl, isobenzofuranyl, indolyl, oxyindole, isoindolyl, indazoles, indolinyl, 7-isoindolyl, benzopyranyl, coumarinyl, isocoumarins, chinoline,ethenolysis, naphthyridine, cinnoline, hintline, iridoviridae, benzoxazines, honokalani, bromanil, bromanil, isopropanol, phthalazine and carbolines).

The lower alkyl groups can be substituted or unsubstituted. When they replaced, they usually contain, for example, from 1 to 3 substituents, preferably 1 substituent.

As used here, the term "alkoxy" denotes, for example, alkyl-O-, and alcohil" oboznachaet is, for example, alkyl-CO-. Group of alkoxylates or group alkoxysilane substituent can be substituted, for example, one or more alkyl groups. The preferred alkoxysubstituted are methoxy, ethoxy, propyloxy, butylochki. Especially preferred is methoxy.

As used here, the term "halogen" denotes, for example, fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine and more preferably fluorine or chlorine.

"Pharmaceutically acceptable salt" refers to conventional acid additive salts or basic additive salts which retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable organic or inorganic acids or organic or inorganic bases. Examples of the acid additive salts include salts derived from inorganic acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and salts derived from organic acids such as n-toluensulfonate acid, salicylic acid, methanesulfonate acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid and the like. Examples of the basic additive salts include salts, obtained with the hydroxides of ammonium, potassium, sodium and Quaternary ammonium compounds, such as, for example, a hydroxide of Tetramethylammonium. Chemical modification of pharmaceutical compounds (i.e. drug) in g is a well-known technique used to improve properties, including physical or chemical stability, such as hygroscopicity, flowability or the solubility of the compounds. See, for example, the book .Ansel and others, Pharmaceutical Dosage Forms and Drug Delivery Systems (6th edition, 1995) s and cc.1456-1457.

"Pharmaceutically acceptable ester" refers to the usual way esterified compound of the formula I containing a carboxyl group, esters retain the biological effectiveness and properties of the compounds of formula I and are oxidized in vivo (in the organism) to the corresponding active carboxylic acid. Examples of ester groups, which are (in this case hydrolyzed in vivo into the corresponding carboxylic acids are groups in which the hydrogen is replaced by lower alkyl, which optionally is substituted, for example a heterocycle, cycloalkyl etc. Examples of substituted lower alilovic esters are esters in which the lower alkyl substituted by pyrrolidino, piperidine, morpholine, N-methylpiperazine etc. Group that is cleaved in vivo, maybe nab the emer, ethyl morpholinoethyl and diethylaminoethyl. In the context of the present invention is NH2also denotes ester as-NH2can be derived in vivo and replaced by a hydroxy-group with formation of the corresponding carboxylic acid.

Other information in relation to the examples and the use of esters for the delivery of pharmaceutical compounds available in Design of Prodrugs, edited by Bundgaard H. (Elsevier, 1985). Cm. books .Ansel and others, Pharmaceutical Dosage Forms and Drug Delivery Systems (6th edition, 1995) cc.108-109; Krogsgaard-Larsen and others, in Textbook of Drug Design and Development (2nd edition, 1996) cc.152-191.

Preferred is a compound of formula (I), where R1represents hydrogen and R2represents a lower alkyl, -(CH2)n-cycloalkyl, -(CH2)n-heteroseksualci, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)nHE, -(CH2)nCH(CH3HE or -(CH2)nOch3.

Preferred is a compound of formula (I), where R1represents lower alkyl and R2represents a lower alkyl, -(CH2)n-cycloalkyl, -(CH2)n-heteroseksualci, -(CH2)n-aryl, -(CH2)n-heteroaryl, -(CH2)nHE, -(CH2)nCH(CH3HE or -(CH2)nOch3.

It is preferable from the Association of the formula (I), where R1represents methyl.

Also preferred is a compound of formula (I), where R1represents hydrogen.

Preferred is a compound of formula (I), where R1and R2together with the N atom to which they are attached, form an unsubstituted 5-7-membered monocyclic ring which contains the N atom to which R1and R2attached. Especially preferred is the compound of formula (I), where R1and R2together with the N atom to which they are attached, form piperidinyl, pyrrolidinyl or azepane.

Preferred is a compound of formula (I), where R1and R2together with the N atom to which they are attached, form an unsubstituted 5-7-membered monocyclic ring which contains the N atom to which R1and R2attached, and another heteroatom selected from O and S. Particularly preferred is a compound of formula (I), where R1and R2together with the N atom to which they are attached, form morpholinyl.

Preferred is a compound of formula (I), where R1and R2together with the N atom to which they are attached, form a 5-7-membered monocyclic ring which contains the N atom to which R1and R2attached, where a 5-7 membered monocyclic ring is mono - or business is emenim hydroxy, lower alkyl or -(CH2)nHE. Especially preferred is the compound of formula (I), where R1and R2together with the N atom to which they are attached, form methylpiperidine, hydroxypiperidine, hydroxyethylpiperazine, ethylpyrrolidin, dimethylpyrimidinol or hydroxyethylpyrrolidine.

Preferred is a compound of formula (I), where R1and R2together with the N atom to which they are attached, form a 5-7-membered monocyclic ring which contains the N atom to which R1and R2attached, and another heteroatom selected from O and S, where a 5-7 membered monocyclic ring is mono - or bisamidines hydroxy, lower alkyl or -(CH2)nHE. Especially preferred is the compound of formula (I), where R1and R2together with the N atom to which they are attached, form dimethylmorpholine.

Preferred is a compound of formula (I), where R2represents isopropyl, -CH2-phenyl, -CH2-pyridinyl, -CH2-cyclopropyl, cyclohexyl, cyclobutyl, -CH2CH2-phenyl, hydroxypropyl, hydroxyethyl, hydroxybutyl, -CH2-tetrahydrofuranyl or methoxypropyl.

Preferred is a compound of formula (I), where-NR1R2is pyrrolidinyl, dimethylpyrrole dinil, methylpyrrolidinyl, methylpiperidine, morpholinyl, dimethylmorpholine, azepane, hydroxyethylpiperazine, hydroxyethylpyrrolidine, hydroxypiperidine or hydroxypyrrolidine.

R3can represent from one to five substituents, preferably three, more preferably two and more preferably one.

Preferred is a compound of formula (I), where R3represents hydrogen or halogen, and particularly preferred is a compound of formula (I), where R3represents hydrogen.

Preferred is a compound of formula (I), where R4represents hydrogen, -HE or N(=O)CH3and particularly preferred is a compound of formula (I), where R4represents hydrogen.

Preferred is a compound of formula (I)selected from the following compounds:

adamantane-2-alamid 5-isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-benzylamino-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 1-phenyl-5-[(pyridine-3-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(cyclopropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-cyclohexylamino-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-cyclobutylamine-1-phenyl-1H-shall irsol-4-carboxylic acid;

adamantane-2-alamid 5-(2,5-dimethylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(2-methylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(3-methylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(benzylmethylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(methylphenethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(2,6-dimethylmorpholine-4-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 1-phenyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-azepin-1-yl-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-morpholine-4-yl-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(3-hydroxyethylpiperazine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-((S)-2-hydroxyethylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(4-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(3-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(3-hydroxypyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(2-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(2-HYDR is xicillin)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(3-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(4-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 1-phenyl-5-[(tetrahydrofuran-2-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-[(2-hydroxyethyl)methylamino]-1-phenyl-1H-pyrazole-4-carboxylic acid and

adamantane-2-alamid 5-(3-methoxypropylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid.

Preferred is a compound of formula (I)selected from the following compounds:

adamantane-2-alamid 5-isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(cyclopropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(2-methylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(3-methylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(methylphenethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(2,6-dimethylmorpholine-4-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 1-phenyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-azepin-1-yl-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-morpholine-4-yl-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 5-(4-hydroxypiperidine the n-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;

adamantane-2-alamid 1-phenyl-5-[(tetrahydrofuran-2-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid and

adamantane-2-alamid 5-(3-methoxypropylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid.

The present invention also relates to a method for obtaining compounds of formula (I)comprising the reaction of the compound in accordance with formula (II):

with the compound of the formula HNR1R2;

or the reaction of the compound in accordance with formula (III):

with the compound in accordance with formula (IV):

where R1, R2, R3and R4are as defined above.

The present invention also relates to the compound of formula (I) for use as therapeutically active substances.

The present invention also relates to the compound of formula (I) for the manufacture of medicines for the prevention or treatment of diseases caused by disorders associated with enzyme 11 beta-hydroxysteroid dehydrogenase 1.

The present invention also relates to pharmaceutical compositions containing a compound of the formula (I) and a therapeutically inert carrier.

The present invention also relates to the use of compounds of formula (I) for the manufacture of medicines Leche for the treatment or prevention of diabetes, obesity, eating disorders, or dyslipidemia.

The present invention also relates to the compound of formula (I) for use as a drug for treatment or prevention of diabetes, obesity, eating disorders, or dyslipidemia.

The present invention also relates to the use of compounds of formula (I) for the manufacture of drugs for treatment or prevention of type II diabetes.

The present invention also relates to the compound of formula (I) for use as a drug for treatment or prevention of type II diabetes.

The present invention also relates to the use of compounds of formula (I)obtained in accordance with the method in accordance with the present invention.

The present invention also relates to a method for treatment and prevention of diabetes, obesity, eating disorders, or dyslipidemia, which includes the introduction of an effective amount of the compounds of formula (I).

The present invention also relates to a method of treatment or prophylaxis of type II diabetes, which includes the introduction of an effective amount of the compounds of formula (I).

In the process of the present invention an effective amount of any one of the compounds of the present invention or a combination of any of the compounds of the present invention or its pharmaceutical is citiesi acceptable salt or a complex ester is administered by any conventional and appropriate way, known from the prior art, alone or in combination. Compounds or compositions therefore can be administered orally (e.g., buccal cavity), sublingually, parenterally (for example intramuscularly, intravenously or subcutaneously), rectally (e.g. in the form of suppositories or leaching), transdermal (e.g., skin electroporation) or by inhalation (e.g. aerosol) and in the form of solid, liquid or gaseous dosage forms, including tablets and suspensions. The introduction may be a separate unit dosage form with prolonged treatment or a single dose of ad libitum. therapeutic composition can also be present in the form of an oil emulsion or dispersion, in combination with a lipophilic salt, such as AMOVA acid or in the form of biodegradable compositions prolonged release for subcutaneous or intramuscular injection.

Useful pharmaceutical carriers for obtaining the compositions can be solids, liquids or gases; thus, the compositions can be in the form of tablets, pills, capsules, suppositories, powders, enterline covered or otherwise protected structures (such as ion-exchange resins or embedded in vesicles lipid-protein), compositions prolonged release, solutions, suspensions, Elik is IRow, aerosols and the like. The carrier may be selected from various oils, including oils, petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly when they are isotonic with blood) for injection solutions. For example, compositions for intravenous administration include sterile aqueous solutions of the active ingredient (ingredient), which is obtained by dissolving solid active ingredient (ingredient) in water to obtain an aqueous solution and obtaining a sterile solution. Suitable pharmaceutical excipients include starch, cellulose, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried cream, glycerin, propylene glycol, water, ethanol and the like. The composition can contain conventional pharmaceutical additives such as preservatives, stabilizing agents, moisturizing or emulsifying agents, salts for regulating the osmotic pressure, buffers and the like. Suitable pharmaceutical carriers and their composition described in the book Remington's Pharmaceutical Sciences from .W.Martin. Such company shall stand, in any case, contain an effective amount of the active compound together with a suitable carrier to obtain the desired dosage form for the introduction of the patient.

The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, moistening agents, emulsifying agents, sweetening agents, coloring agents, flavouring agents, salts for regulating the osmotic pressure, buffers, agents for covering or antioxidants. They can also contain other therapeutically active substances, including additional active ingredients other than the compounds of formula I.

"Therapeutically effective amount" or "dose" of compounds in accordance with this invention can vary widely and can be determined by a method known from the prior art. This dosage should be adjusted to the individual requirements in each particular case, including the specific input connection (connection), route of administration, treatable condition, and treated the patient. Usually for oral or parenteral administration to adult humans weighing approximately 70 kg is suitable daily dosage from about 0.01 mg/kg to about 50 mg/kg, although the upper limit may be exceeded when necessary the STI. The dosage is preferably from about 0.3 mg/kg to about 10 mg/kg per day. The preferred dosage may be from about 0,70 mg/kg to about 3.5 mg/kg per day. The daily dosage may be administered in a single dose or multiple doses, or for parenteral administration, it may be administered by continuous infusion.

Compounds of the present invention can be obtained by any conventional method. Suitable methods of obtaining these compounds are given in the examples. Usually the compounds of formula I can be obtained in accordance with the following schemes. Sources of starting materials for these reactions are also described.

Scheme 1

As shown in chart 1, 1-aryl-5-(substituted amino)pyrazole-4-carboxamide derivative of formula 1 can be obtained from ethyl(ethoxymethylene)cyanoacetate formula 2 (which is available from Aldrich) by the following sequence of reactions:

the reaction arylhydrazines with getting aminopyrazole formula 3;

the reaction of Sandmeyer aminopyrazoles derived with getting chloropyrazole formula 4;

the hydrolysis of the ethyl ester of chloropyrazole formula 4 with obtaining a carboxylic acid of formula 5;

the condensation of the carboxylic acid of formula 5 with the derived aminoadamantana formula 6 to obtain 1-aryl-5-chloropyrazole-4-carboxamide form is s 7; and

the substitution of chlorine in the 1-aryl-5-chloropyrazole-4-carboxamide formula 7 with obtaining substituted 5-aminopyrazole formula 1.

The first reaction in the sequence can usually be carried out by treatment of ethyl(ethoxymethylene)cyanoacetate formula 2 with hydrazine of the formula ArNHNH2in an inert solvent, such as ethanol, at the boiling temperature of the solvent. Suitable for the reaction conditions can be found in the prior art, for example in articles A.Costanzo and others, J.Heterocycl. Chem., 1994, 31, cc.1369-1376; Marr and others, J.Heterocycl. Chem., 2001, 38, cc.1045-1050; A.Costanzo and others, J.Heterocycl. Chem., 1992, 29, cc. 1499-1505; N..Peet and others, J.Med. Chem., 1992, 35, cc.3263-3269 and patent J.R.Beck US 4,631,343.

The reaction of Sandmeyer intermediate compounds of formula 3 include diazotization of the amino group in the presence of glorieuses agent such as chloride copper(I) or copper chloride(II) or nitrosylchloride. The reaction is usually carried out by treating compound of formula 3 alkyllithium, such as tert-butylnitrite or isoamylase, in an inert solvent, such as acetonitrile or a halogenated hydrocarbon (e.g. carbon tetrachloride)at a temperature of from about 50°to about 65°, in the presence of a chlorine source, such as a chloride of copper(1). Alternatively, the reaction may be carried out by treating compound of formula 3 with sodium nitrite in the presence of an aqueous solution of hydrochloric acid and chlorin the existing agent, such as chloride, copper(II), initially at a temperature preferably below 10°C and most preferably at a temperature of about 0°C and then at a temperature of about 40°C. Suitable for the reaction conditions can be found in the prior art, for example, in the patent of J.-J.Liu and other, US 2006079511; article S.Yamamoto and others, J.Heterocycl. Chem., 1991, 28, cc.1545-1547; and in the patent I.Aoki and other, ER 220695. As a final example, the transformation of aminopyrazole formula 3 in chloropyrazole formula 4 can be carried out by treatment of a solution of the compound of formula 3 in an inert solvent such as a chlorinated hydrocarbon (e.g. chloroform) with hydrogen chloride and then with liquid nitrosylchloride at a temperature below about 10°C and then at a temperature of about room temperature. Suitable for the reaction conditions can be found in the prior art, for example in articles J.R.Beck and others, J.Heterocycl. Chem., 1988, 25, cc.955-958 or J.R.Beck and others, J.Heterocycl. Chem., 1987, 24, cc.267-270.

Cleavage of compounds of formula 4 to the corresponding carboxylic acid of formula 5 was carried out under the reaction conditions which are known in the field of organic synthesis, many of which are described in "Protective Groups in Organic Synthesis" [.W.Greene and P.G.M.Wuts, 2-e edition, John Wiley & Sons, N.Y. 1991]. For example, the reaction can usually be carried out by treating compound of formula 4 with one equivalent of alkali metal hydroxide, such as hydro is led potassium, sodium hydroxide or lithium hydroxide, preferably lithium hydroxide, in a suitable solvent such as a mixture of tetrahydrofuran, methanol and water. The reaction may be carried out at a temperature from about 0°C. to about room temperature, preferably at a temperature of about room temperature. In another example, the ester may be treated with a strong inorganic acid, for example halogen acid, such as hydrogen chloride or hydrogen bromide, in aqueous solution, preferably at the boiling temperature of the solvent.

Carboxylic acid of formula 5 can be converted usually in amide of formula 7 by treatment of carboxylic acid patterns 5 hydrochloride adamantane derivative of formula 6 in the presence of a suitable base, such as diisopropylethylamine, condensing agent, such as hexaphosphate O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, and in the optional additional presence of a substance that increases the reaction rate, such as 1-hydroxybenzotriazole or 1-hydroxy-7-asobancaria, in an inert solvent such as a chlorinated hydrocarbon (e.g. dichloromethane) or N,N-dimethylformamide or N-methylpyrrolidinone, at a temperature of from about 0°C. to about room temperature, preferably at a temperature of about room temperature. Numerous other condenser the matter of agents known to the specialist in the art of organic synthesis, and description of many of them published [article by S.-Y.Han, and Y.-A.Kim, Tetrahedron, 2004, 60, cc.2447-2467]. Alternatively, the reaction can be carried out by conversion of the carboxylic acid of formula 5 in an activated ester derivative, such as N-hydroxysuccinimidyl ether and subsequent reaction with adamantane derivative of formula 6 or the corresponding acid salt additive. This reaction sequence can be carried out by reaction of the carboxylic acid of formula 5 with N-hydroxysuccinimide in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, in an inert solvent, such as tetrahydrofuran, at a temperature from about 0°C. to a temperature of about room temperature. The N-hydroxysuccinimidyl ether is then treated adamantane derivative of formula 6 or a corresponding acid salt additive, in the presence of a base such as an organic base (e.g. triethylamine or diisopropylethylamine and the like) in a suitable inert solvent such as N,N-dimethylformamide, at a temperature of about room, getting a 1-aryl-5-chloropyrazole-4-carboxamide of the formula 7.

1-Aryl-5-chloropyrazole-4-carboxamide formula 7 can then be converted into a compound of the invention of formula 1 by heating it with an amine of the formula HR1R2in an inert solvent, such as N-metier is olidine, at a temperature of about 250°C., under microwave izlucheniem.

Scheme 2

Alternative obtaining the intermediate of formula 4 is shown in scheme 2, based on pyrazole-4-carboxylate ester of formula 8, processing gloriouse agent. The reaction is usually carried out by treating compound of formula 8 N-chlorosuccinimide in the absence of a solvent at a temperature of about 120°C. the Exact conditions of this reaction can be found in the prior art, for example in the article .Morimoto and others, J.Heterocycl. Chem., 1997, 34, cc.537-540. The technique is useful for producing compounds of formula 8 below.

Scheme 3

The second alternative method of preparing compounds of formula 4 is shown in scheme 3. In accordance with this method, the reaction of commercially available diethylethoxymethylenemalonate formula 9 with arylhydrazines formula ArNHNH2can be carried out in various conditions. For example, the compound of formula 9 may be subjected to reaction with arylhydrazines or acid additive salt arylhydrazines in an inert solvent, such as alcohol (e.g. ethanol). In the case of using an acid additive salt arylhydrazines reaction is carried out in the additional presence of a base such as tertiary alkylamine (for example, triethylamine or visapro ylethylamine). The reaction is usually carried out at a temperature from about -20°to about 80°C. examples of the conditions for this reaction can be found in the prior art, for example in the patent R.Gehring and other, US 4,804,398; article W.Holzer and .Schmid, J.Heterocycl. Chem.. 1995, 32, cc.1341-1349. The intermediate compound of formula 10 is then heated to a temperature of about 170°C and distillation of the liberated ethanol. This process leads to the production of 5-hydroxypyrazol formula 11. Conditions for this reaction can be found in the prior art, for example in the patent R.Gehring and other, US 4,804,398. Alternatively, the intermediate compound of formula 10 may be heated at boiling in ethanol in the presence of a base such as potassium carbonate, to obtain 5-hydroxypyrazol formula 11. Conditions for this reaction can be found in the prior art, for example in the article W.Holzer and .Schmid, J.Heterocycl. Chem., 1995, 32, cc.1341-1349. 5-Hydroxypyrazol formula 11 can then be turned into chloropyrazole formula 4 by reaction of chlorination. The reaction typically can be performed by heating 5-hydroxypyrazol formula 11 with gloriouse agent such as phosphorus oxychloride, in the absence of additional solvents, at a temperature of about 100°C. the Exact conditions for such a reaction can be found in the prior art, for example in articles W.Holzer and .Hahn, J.Heterocycl. Chem., 2003, 40, cc.303-308; H.A.DeWald and others, J.Med. Chem., 1981, 24, cc.982-987.

Scheme 4

Alternative obtain the intermediate compounds of formula 5 is shown in scheme 4, in which signon formula 16 is subjected to reaction [3+2] dipolar cyclopamine with diethylazodicarboxylate with subsequent selective decarboxylation of the intermediate connection diapir formula 17. This reaction sequence starts with the aniline of formula 12, where Ar represents an aromatic group, many examples of which are commercially available. Aniline of formula 12 in turn derived N-arigliano formula 13 by heating with Chloroacetic acid in water at boiling (for more details see D.L.Hammick and D.J.Voaden, J.Chem. Soc., 1961, SS-3308). The derived N-arigliano formula 13 then nitrogenous obtaining N-nitrosoproline formula 14 by treatment with sodium nitrite in aqueous hydrochloric acid at a temperature of about 0°C (for more details see article D.L.Hammick and D.J.Voaden, J.Chem. Soc., 1961, cc.3303-3308 or F. Dumitrascu, etc., ARKIVOC, 2002, cc.80-86). The compound of formula 14 is then treated with acetic acid and pyridine to obtain Sidney formula 15. Signon then glorious obtaining chloridea formula 16. The chlorination reaction can be carried out by processing sydnone formula 15 with chlorine in a mixture of sodium acetate and acetic acid at a temperature of about room (see F.Dumitrascu and others, ARKIVOC, 2002, cc.80-86); processing signon the formula 15 dichloride of yogashala in a mixture of triethylamine and dichloromethane (see article S.Ito and .Turnbull, Synth. Commit., 1996, 26, cc.1441-1446); or processing sydnone formula 15 N-chlorosuccinimide in an inert solvent, such as dimethylformamide, at a temperature of about room (see .Turnbull etc., J. Heterocycl. Chem., 1994, 31, cc.1631-1636). Chlorides formula 16 can then be treated with an excess of diethylazodicarboxylate in ethylene glycol at 120°C To produce the product [3+2] dipolar cyclopamine 17. The compound of formula 17 can then be treated with 20% aqueous solution of hydrochloric acid at boiling for the implementation of hydrolysis up in primary forms, which is subjected to selective decarboxylation by heating to a temperature of about 250°C. (bath temperature) with a monocarboxylic acid of formula 5. The specific conditions of the reactions, which chloridea formula 16 yield of monocarboxylic acid of formula 5 can be found in the prior art, for example in the article .Dickopp, Chem. Ber., 1974, 707, cc.3036-3042.

Scheme 5

As shown in scheme 5, the compound according to the invention, in which R2represents hydrogen, can be obtained in four stages from 1-aryl-5-aminopyrazole-4-carboxylate ester of formula 3 by transformation of aminosalicylates in the carbamate, which can then be alkylated to obtain the intermediate compounds of formula 19. Removing the protective gr is PP with carbamate and ethyl ether then leads to the production of intermediate compounds 21, which may be condensed with adamantanamine formula 6 to obtain the product of formula 1.

The transformation of the amine of formula 3 in the carbamate of formula 18 can be any conventional methods, some of which are well-known specialist in the field of organic synthesis. For example, the amine can be processed by chloroformiate lower alkyl (such as ethyl chloroformate) in the presence of a base such as sodium hydride, in an inert solvent, such as dimethylformamide or tetrahydrofuran. Alternatively, the amine of formula 3 can be treated with excess phenylcarbamate in the presence of a base such as sodium hydride, in an inert solvent, such as dimethylformamide, to obtain the bis(phenoxycarbonyl)derivatives as described in patent L.R.Hatton etc., GB 2,101,999. The reaction can also be carried out using pyridine as base and chloroform as solvent. In this case, the reaction is preferably carried out at a low temperature, such as about 0°C. Conditions for this transformation can be found in the prior art, for example in the patent L.R.Hatton and other, US 4,629,495. This bis(phenoxycarbonyl)amino derivatives can then be processed treat-butanol at boiling point to obtain the intermediate compounds of formula 18 where R' is a tert-butyl. The conditions for this pre the treatment can be found in the prior art, for example in the patent L.R.Hatton and other, US 4,629,495.

Alkylation of the carbamate of formula 18 alkylating agent of formula R1X can be performed using various techniques which are known. Leaving group X can be a halogen (e.g. bromine or iodine), or it can be a sulphonate ester (for example, mesilate, toilet or nosrat) and so the Reaction is usually carried out by treatment of the carbamate base, such as sodium hydride, in an inert solvent, such as tetrahydrofuran, at a temperature from about room temperature to the boiling point of the solvent, depending on the reaction of alkylating agent.

Urethane protective group is then removed from the carbamate of formula 19 with obtaining an amine of the formula 20, using conditions well known from technician level to bring about this transformation, which can be specific to the nature of R'group. Numerous examples of suitable conditions are given in the book "Protective Groups in Organic Synthesis" [.W.Greene and P.G.M.Wuts, 2-e edition, John Wiley & Sons, N.Y. 1991]. For example, for the compounds of formula 19 in which R'represents the tert-butyl protective group can be removed by treating compound of formula 20 acid, such as triperoxonane acid, in an inert solvent such as a halogenated hydrocarbon (e.g. dichloromethane), when t is mperature around the room. For compounds of formula 19 in which R' represents methyl or ethyl, the protective group can be removed by heating the compounds of formula 19 with potassium hydroxide in ethylene glycol at a temperature of about 100°C. the Conditions for this reaction can be found in the prior art, for example in the patent .Matsushita and other, ER 885890.

Ethyl ester of the compound of formula 20 can then be removed hydrolytically under conditions well known in the field of organic synthesis. For example, the compound of formula 20 can be treated with one equivalent of alkali metal hydroxide, such as potassium hydroxide, sodium hydroxide or lithium hydroxide, preferably lithium hydroxide, in a suitable solvent such as a mixture of tetrahydrofuran, methanol and water. The reaction may be carried out at a temperature from about 0°C. to a temperature of about room temperature, preferably at a temperature of about room temperature.

Alternatively, carbamate and ester can be removed in one stage of the compounds of formula 19 by exposure to the compounds of formula 19 acidic conditions, for example by heating in dilute aqueous hydrochloric acid at the boiling point.

The connection according to the invention of formula 1 can then be obtained by the reaction of carboxylic acid structure 21 or a suitable derivative, such as an activated ester, with the production of the output adamantane of formula 6 or a corresponding acid salt additive (for example, hydrochloride) in the presence of, if necessary, by condensing agent, many examples of which are well known in the field of peptide chemistry. The reaction is usually carried out by treatment of carboxylic acid patterns 21 hydrochloride adamantane derivative of formula 6 in the presence of a suitable base, such as diisopropylethylamine, condensing agent, such as hexaphosphate O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, and in the optional additional presence of a substance that increases the reaction rate, such as 1-hydroxybenzotriazole or 1-hydroxy-7-asobancaria, in an inert solvent such as a chlorinated hydrocarbon (e.g. dichloromethane) or N.N-dimethylformamide or N-methylpyrrolidinone, at a temperature from about 0°C. to a temperature of about room preferably at a temperature of about room temperature. Alternatively, the reaction can be carried out by conversion of the carboxylic acid of formula 21 in activated ether derivative, such as N-hydroxysuccinimidyl ether, and then reaction with adamantane derivative of formula 6 or a corresponding acid salt additive. This reaction sequence can be carried out by reaction of the carboxylic acid of formula 21 with N-hydroxysuccinimide in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide is d, in an inert solvent, such as tetrahydrofuran, at a temperature from about 0°C. to a temperature of about room temperature. The N-hydroxysuccinimidyl ether is then treated adamantane derivative of formula 6 or a corresponding acid salt additive, in the presence of a base such as an organic base (e.g. triethylamine or diisopropylethylamine or similar), in a suitable inert solvent such as N,N-dimethylformamide, at a temperature of about room temperature.

To obtain hydrazines are known various methods, and they have recently been described in the review "The Chemistry of The Hydrazo, Azo, and Azoxy Groups. Part 1" [J.Timberlake and J.Stowell; S.Patai Ed.; John Wiley & Sons, Ltd. London, 1975, cc.69-107]. Examples of methods useful for obtaining arylhydrazines include diazotization of aniline and subsequent restoration of diazonium salts (.Barraja and others, Bioorg. Med. Chem., 2006. 14, cc.8712-with 8,728; R.V.Bonnert and others, WO 2005019171; J.-Y.Winum and others, J.Med. Chem., 2005, 48, cc.2121-2125; .Y.S. Lam and others, J.Med. Chem., 2003, 46, cc.4405-4418); substitution of the leaving group of the electron-deficient aryl ring (.R.Barbachyn and others, J.Med. Chem., 2003, 46, cc.284-302; .Pal and others, J.Mad. Chem., 2003, 46, cc.3975-3984; N.Pommery and others, J.Med. Chem., 2004, 47, cc. 6195-6206); amination of aniline with O-mesitylsulfonylhydroxylamine (D.W.Brown and others, Tetrahedron, 1993, 49, cc.8919-8932). The most commonly used method is the diazotization of aniline and subsequent restoration of diazonium salts. In addition, b is more hundreds substituted or unsubstituted arylhydrazines are commercially available from Available Chemicals Directory.

Hydrochloride 2-adamantanamina available from Aldrich. 2-Amino-5-hydroxyadamantane (formula 22) can be obtained by hydrogenation of the imine derived from 5-hydroxy-2-adamantanone and 1-S-α-methylbenzylamine in accordance with the methodology described in article L.Jaraskova, etc., Tetrahedron Lett., 2006, 47, cc.8063-8067.

Scheme 6

As shown in scheme 6, 2-amino-5-acetamidomalonate (formula 25) can be obtained on the basis of 2-amino-5-hydroxyadamantane (22). Cbz-protective compound of formula 23 get usually from 2-amino-5-hydroxyadamantane treatment benzylchloride in the presence of a base, such as triethylamine, in an inert solvent, such as dichloromethane, at a temperature of about room temperature. The alcohol of formula 23 is then treated inorganic acid, such as sulfuric acid in acetonitrile, at room temperature in a reaction known as the Ritter reaction. Conditions for this reaction can be found in the documents L.Jaroskova and others, WO 2006024627; .Gopalan and others, WO 2006090244; and article R. .Hill, J.Am. Chem. Soc., 1965, 87, cc.5646-5651. Carbobenzoxy group is then removed from the compound of formula 24 by hydrogenation with a noble metal catalyst to obtain an amine of formula 25. For example, the compound of formula 24 can be gidrirovanie at 50 psi in the presence of catalytic amount of 5% palladium-on-coal in an alcohol solvent (such the AK ethanol) at room temperature.

Scheme 7

As shown in figure 7, the alcohol of formula 23 may be of Ritter reaction with chloroacetonitrile, in the presence of sulfuric acid at a temperature of about room temperature to obtain chloroacetyl derivative of formula 26. This compound is then subjected to reaction with thiourea in the presence of acetic acid in ethanol at a temperature from about 50°C to about 120°C to obtain an amine of formula 27. Conditions for the reaction of Ritter and removing the protective groups from chloracetamide can be found in the prior art, for example in the documents I.R.Gladwell, WO 2007010356; .Gopalan and others, WO 2006090244; and A.Jirgensons, etc., Synthesis, 2000, cc.1709-1712. Amine of formula 27 can then be processed by methanesulfonamido in the presence of a base such as triethylamine or diisopropylethylamine, in an inert solvent, such as dichloromethane, at a temperature of about room, getting sulfonamida formula 28. Carbobenzoxy group is then removed from the compounds of formula 28 by hydrogenation with a noble metal catalyst to obtain an amine of formula 29. For example, the compound of formula 28 can gidrirovaniya at 50 psi in the presence of catalytic amount of 5% palladium-on-coal in an alcohol solvent (such as ethanol) at room temperature.

Scheme 8

As shown in scheme 8, 1 kilpert the-4-carboxylate ester of formula 11 can be usually obtained by the reaction of (etoxycarbonyl)of malondialdehyde with arylhydrazines. Synthesis of (etoxycarbonyl)malondialdehyde described in two stages of ethylpropyl article S.H.Bertz and others, J.Org. Chem., 1982, 47, cc.2216-2217. The compound of formula 11 is typically receive treatment (etoxycarbonyl)of malondialdehyde by arylhydrazines in an inert solvent such as a lower alcohol (e.g. ethanol) at room temperature. Conditions suitable for this reaction can be found in the prior art, for example in staste W.Holzer and G.Seringer, J.Heterocycl. Chem., 1993, 30, cc.865-872.

Scheme 9

As shown in scheme 9, 1-arylpyrazole-4-carboxylate ester of formula 11 can be usually obtained in two steps from commercially available 1,3-dimethyluracil-5-carboxaldehyde (formula 30). Thus, the aldehyde was treated with arylhydrazines formula ArNHNH2in water in the presence of acetic acid at a temperature of about 100°C To produce hydrazone of formula 31. It was then heated in the presence of sodium methoxide in methanol at boiling point with getting 1-arylpyrazole-4-carboxylate ester of formula 11. Conditions suitable for this reaction can be found in the prior art, for example in the article .Hirota and others, J.Chem. Soc. Perkin Trans. I, 1983, cc.1293-1297.

Scheme 10

As shown in scheme 10, 1-arylpyrazole-4-carboxylate ester of formula 11 can be isolated as a minor product of the reaction [3+2] dipolar qi is adorablee Sidney formula 15 (received as described above) with the lowest alkylphosphonates (for example, methylpropionate). The reaction is usually carried out by the processing sydnone formula 15 methylpropionate in an inert solvent, such as 1,2-dichlorobenzene, isobutyl alcohol, n-xylene or dimethylformamide, at boiling point. Conditions suitable for this reaction can be found in the prior art, for example in the article that is-.Chang and others, Heterocycles, 2006, 68, cc.1007-1015.

The present invention is hereinafter described by means of examples, which are intended for illustration only and do not limit the scope of the invention.

Examples

Reagents available from Aldrich, Sigma, Bachem Biosciences, Advanced ChemTech, Lancaster and Argonaut Argogel, and used without additional purification. Unless otherwise stated, all reagents were obtained from commercial sources. Spectra LC/MS (liquid chromatography/mass spectrometry (MS) were recorded using the following system. To measure the mass spectrum of the system has the configuration Micromass Platform II: API ionization in the positive electrospray (mass range: 150-1200 of atomic mass units). Simultaneous chromatographic separation was performed using the following HPLC system: column, ES Industries Chromegabond WR-18 3u 120Å (3,2×30 mm) Cartridge; mobile phase A: water (0.02% TFUC) and phase B: acetonitrile (0.02% TFUC); gradient from 10% B to 90% B over 3 min; trim 1 minute; flow rate 2 ml/min

p> Compounds were purified by various methods of chromatography, including short column chromatography on silica gel and elwira mixtures of solvent ethylacetate and hexane or other suitable solvents. Some compounds were purified HPLC reverse phase using methods well known to the person skilled in the technical field.

Intermediate compound 1: Ethyl ester of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid

To a suspension of copper chloride (I) (5,1 g, 51,5 mmole, 1.2 equivalents) in acetonitrile (100 ml) at 0°C was added dropwise tert-butylnitrite (7,6 ml, and 63.9 mmole, 1.5 equivalent). The reaction mixture was stirred at 0°C for 10 minutes. Was added dropwise a solution of ethyl ester of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (available from Aldrich; 10.0 g, 43,2 mmole, 1 equivalent) in acetonitrile (30 ml) at 0°C for 15 minutes. The reaction mixture was stirred at room temperature for 1 hour, then at 65°C for 1 hour. After complete disappearance of starting material (according to TLC), the reaction mixture was poured into 6N hydrochloric acid solution (200 ml) and was extracted with dichloromethane (3×300 ml). The combined organic layers were dried with magnesium sulfate and purified column chromatography (elwira heptane, then 20% ethyl acetate in heptane) to give the floor is gross ester 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (7,3 g, 66%), for which the analysis of NMR and HPLC showed a purity of 78%. This material was used directly in the next stage without additional purification.

Intermediate compound 2: 5-Chloro-1-phenyl-1H-pyrazole-4-carboxylic acid

To a solution of ethyl ester of 5-chloro-1-phenyl - 1H-pyrazole-4-carboxylic acid (intermediate compound 1; and 7.3 g of 29.1 mmole) in tetrahydrofuran (70 ml) was added a solution of lithium hydroxide in water (7,3 g, 305 mmol) in water (70 ml). To the reaction mixture was added dropwise methanol (~10 ml) until then, until there is only one layer. The reaction mixture was stirred at 70°C for 1 hour (over the course of the reaction was observed according to TLC). The reaction mixture was acidified to pH 3 1N hydrochloric acid and washed with dichloromethane (3×200 ml). The organic layer was dried with magnesium sulfate and evaporated to obtain 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (5.8 g, 91%), for which HPLC analysis showed a purity of 85%. This material was used directly in the next stage without additional purification.

Intermediate compound 3: Adamantane-2-alamid 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid

To a solution of 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 2; 5.8 g, 26,1 mmole) in tetrahydrofuran (70 ml) was added hydrochl the reed 2-adamantanone (available from Aldrich; 6.0 g, 32.0 mmole, 1.2 equivalent) and diisopropylethylamine (5.7 ml, 32.7 mmole, 1.2 equivalent). Portions were added hydrochloride 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC; 7.5 g, 39.1 mmole, 1.5 equivalent) with stirring. After adding the EDC reaction mixture was stirred at 70°C for ~2 hours (over the course of the reaction was observed according to TLC and LCMS). The reaction mixture was dissolved in dichloromethane (300 ml), washed with 1N hydrochloric acid (2×200 ml) and a saturated solution of sodium chloride (200 ml), then dried with magnesium sulfate, was filtered, evaporated and purified column chromatography (elwira 20% ethyl acetate in heptane) to obtain adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (4,2 g, 11.8 mmole, 45%), for which HPLC analysis showed a purity of 90%. This material was used directly in the next stage without additional purification.

Method And

To a solution of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3; 1 equivalent) in N-methylpyrrolidinone (10 volumes) was added amine (R1R2NH; 20 equivalents). The reaction mixture was heated under microwave radiation (250°C, 150W) for 20 minutes. Took several approaches (usually 2-3 led to complete disappearance of starting material, the course of reactions was observed by p. the data LCMS). Compounds were purified by chromatography, was suirable the following sequence of solvents: heptane; 10% ethyl acetate in heptane; 20% ethyl acetate in heptane and 50% ethyl acetate in heptane.

Example 1: Adamantane-2-alamid 5-isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and Isopropylamine. Mass spectrum (ES) MH+=379.

Example 2: Adamantane-2-alamid 5-benzylamino-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-benzylamino-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and benzylamine. Mass spectrum (ES) MH+=427.

Example 3: Adamantane-2-alamid 1-phenyl-5-[(pyridine-3-ylmethyl)amino-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid phenyl-5-[(pyridine-3-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 3-(aminomethyl)pyridine. Mass spectrum (ES) MH+=428.

Example 4: Adamantane-2-alamid 5-(cyclopropylamino)-1-Fenin-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(cyclopropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and cyclopropanemethylamine. Mass spectrum (ES) MH+=391.

Example 5: Adamantane-2-alamid 5-cyclohexylamino-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-cyclohexylamino-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and cyclohexylamine. Mass spectrum (ES) MH+=419.

Example 6: Adamantane-2-alamid 5-cyclobutylamine-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-cyclobutylamine-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and cyclobutylamine. Mass spectrum (ES) MH+=391.

Example 7: Adamantane-2-alamid 5-(2,5-dimethylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(2,5-dimethylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (temporarily the second connection 3) and 2,5-dimethylpyrimidine. Mass spectrum (ES) MH+=419.

Example 8: Adamantane-2-alamid 5-(2-methylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(2-methylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 2-methylpyrrolidine. Mass spectrum (ES) MH+=405.

Example 9: Adamantane-2-alamid 5-(3-methylpiperidin-1-yl)-1-phenyl - 1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(3-methylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 3-methylpiperidine. Mass spectrum (ES) MH+=419.

Example 10: Adamantane-2-alamid 5-(benzylmethylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(benzylmethylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and N-methylbenzylamine. Mass spectrum (ES) MH+=441.

Example 11: Adamantane-2-alamid 5-(methylphenethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(methylphenethylamino)-1-phenyl-1H-pyrazole-4-carb is new acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and N-methylphenethylamine. Mass spectrum (ES) MH+=455.

Example 12: Adamantane-2-alamid 5-(2,6-dimethylmorpholine-4-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(2,6-dimethylmorpholine-4-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and 2,6-dimethylmorpholine. Mass spectrum (ES) MH+=435.

Example 13: Adamantane-2-alamid 1-phenyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid phenyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and pyrrolidine. Mass spectrum (ES) MH+=391.

Example 14: Adamantane-2-alamid 5-azepin-1-yl-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-azepin-1-yl-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and hexamethylenimine. Mass spectrum (ES) MH+=419.

Example 15: Adamantane-2-alamid 5-morpholine-4-yl-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-morpholine-4-yl-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamant is n-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and the research. Mass spectrum (ES) MH+=407.

Example 16: Adamantane-2-alamid 5-(3-hydroxyethylpiperazine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(3-hydroxyethylpiperazine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 3-piperidinemethanol. Mass spectrum (ES) MH+=435.

Example 17: Adamantane-2-alamid 5-((S)-2-hydroxyethylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-((S)-2-hydroxyethylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and L-prolinol. Mass spectrum (ES) MH+=421.

Example 18: Adamantane-2-alamid 5-(4-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(4-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 4-hydroxypiperidine. Mass spectrum (ES) MH+=421.

Example 19: Adamantane-2-alamid 5-(3-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-alamid 5-(3-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 3-hydroxypiperidine. Mass spectrum (ES) MH+=421.

Example 20: Adamantane-2-alamid 5-(3-hydroxypyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(3-hydroxypyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and DL-3-pyrrolidinone. Mass spectrum (ES) MH+=407.

Example 21: Adamantane-2-alamid 5-(2-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(2-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 1-amino-2-propanol. Mass spectrum (ES) MH+=395.

Example 22: Adamantane-2-alamid 5-(2-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(2-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and ethanolamine. Mass spectrum (ES) MH+=381.

Example 23: Adamantane-2-alamid 5-(3-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(3-hydroxypropylamino)-1-phenyl-1H-p is razol-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 3-amino-1-propanol. Mass spectrum (ES) MH+=395.

Example 24: Adamantane-2-alamid 5-(4-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-(4-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 4-amino-1-butanol. Mass spectrum (ES) MH+=409.

Example 25: Adamantane-2-alamid 1-phenyl-5-[(tetrahydrofuran-2-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid phenyl-5-[(tetrahydrofuran-2-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate compound 3) and tetrahydrofurfurylamine. Mass spectrum (ES) MH+=421.

Example 26: Adamantane-2-alamid 5-[(2-hydroxyethyl)methylamino]-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-alamid 5-[(2-hydroxyethyl)methylamino]-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 2-(methylamino)ethanol. Mass spectrum (ES) MH+=396.

Example 27: Adamantane-2-alamid 5-(3-methoxypropylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid

Adamantane-2-yl) - Rev. Mead 5-(3-methoxypropylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid was obtained by procedure a of adamantane-2-ylamide 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid (intermediate 3) and 3-methoxypropylamine. Mass spectrum (ES) MH+=409.

Example 28: the Testing of the compounds according to the invention in vitro

In vitro inhibition of 11β-HSD1 by compounds of the present invention was demonstrated using the following test.

H4IIE cells, stably transfairusa full cDNA 11 beta SD1 man, were grown and propagated in DMEM with high glucose (Invitrogen Cat# 11995-065) with 10% FCS (Invitrogen Cat# 10082-147), 100 units/ml and 100 μg/ml pen/strep (Invitrogen Cat# 15140-122) and geneticin (800 µg/ml). One day before analysis, cells were removed from flasks using a mixture of trypsin/EDTA, centrifuged and washed medium for growth (DMEM with high glucose, without phenol red; Invitrogen Cat# 21063-029 with 2% charcoal, purified FCS; Gemini Cat# 100-119). Of 500,000 cells/ml suspension in the medium for growth of 200 μl of cells were planted into each well of 96-well coated tablet (BioCoat Cat# 356461) and cultivated overnight at 37°C. the next day serially diluted compounds 11SD1 inhibitor dissolved in DMSO, was added to DMEM with BSA (2 mg/ml final). The final concentration of DMSO was 1%. The medium was removed from plates and connections in the medium was added to each well. The plates were incubated at 37°C for 1 hour for the implementation of cell capture compounds. Then to each well was added 10 μl of substrate (cortisone) (200 nm final concentration) and incubated for 2 hours at 37°C. the Tablets then PE is easily on the ice and 80 μl of medium was transferred into a 96-well plate and kept at -30°C.

Quantitative assessment of cortisol in the cellular environment was performed by competitive ELISA, using the ELISA-Light (Tropix Cat# T10206/EL100S4), the antibody of anticortisol EIA (Assay Designs, Inc. Cat# 80-1148) and conjugate cortisol enzyme (Assay Designs, Inc. Cat# 80-1147). 384-well plates (Falcon Cat# 353988) pre-covered artemisinin IgG (Sigma Cat# M-1397), suspended in 0.9% NaCl (5 mg/ml), 50 μl per well, overnight at 4°C. the Tablets were washed in PBS, 0,1% Tween-20, and then washed separately PBS. The plates were blocked by Blocking Buffer (Tropix Cat# AI075) for 2 hours at room temperature. The tablets were then washed as described above. Samples for analysis were thawed, diluted 1:8 in DMEM, 2 mg/ml BSA, 1% DMSO and 24 µl was transferred into wells pre-coated 384-well plates, as well as different numbers of standard cortisol. To each well were added 12 μl of cortisol-conjugate and 12 ál of antibody anticortisol EIA and incubated for 2 hours at room temperature on an orbital tablet shaker. The wells were then released rollover, then washed three times with 100 μl PBS, 0.05% of Tween-20 and then 2 times with 100 μl of buffer for analysis (Tropix). 60 μl of CDP-STAR (Tropix) was added to each well and incubated for 10 minutes at room temperature. The chemiluminescence was measured using counter Victor V (Perkin Elmer). Cortisol in each sample was interpolable in the standard curve obtained with known number is your cortisol. The values of the IC50was calculated by using the curve, constructed using the software XLFit4 (IDBS).

Results inhibition of in vitro 11β-HSD1 some compounds of the present invention is shown in the following table.

ConnectionNameS (µm)
Example 1Adamantane-2-alamid 5-isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid0,0013
Example 2Adamantane-2-alamid 5-benzylamino-1-phenyl-1H-pyrazole-4-carboxylic acid0,014
Example 3Adamantane-2-alamid 1-phenyl-5-[(pyridine-3-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid0,35
Example 4Adamantane-2-alamid 5-(cyclopropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid0,0019
Example 5Adamantane-2-alamid 5-cyclohexylamino-1-phenyl-1H-pyrazole-4-carboxylic acid0,0047
Example 6 Adamantane-2-alamid 5-cyclobutylamine-1-phenyl-1H-pyrazole-4-carboxylic acid0,0076
Example 7Adamantane-2-alamid 5-(2,5-dimethylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid0,004
Example 8Adamantane-2-alamid 5-(2-methylpyrrolidine-1-yl)-1-phenyl-1 H-pyrazole-4-carboxylic acid0,0013
Example 9Adamantane-2-alamid 5-(3-methylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid0,003
Example 10Adamantane-2-alamid 5-(benzylmethylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid0,0091
Example 11Adamantane-2-alamid 5-(methylphenethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid0,0037
Example 12Adamantane-2-alamid 5-(2,6-dimethylmorpholine-4-yl)-1-phenyl-1 H-pyrazole-4-carboxylic acid0,0037
Example 13Adamantane-2-alamid 1-phenyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carbon is howling acid 0,00055
Example 14Adamantane-2-alamid 5-azepin-1-yl-1-phenyl-1H-pyrazole-4-carboxylic acid0,001
Example 15Adamantane-2-alamid 5-morpholine-4-yl-1-phenyl-1H-pyrazole-4-carboxylic acid0,003
Example 16Adamantane-2-alamid 5-(3-hydroxyethylpiperazine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid0,0064
Example 17Adamantane-2-alamid 5-((S)-2-hydroxyethylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid0,042
Example 18Adamantane-2-alamid 5-(4-hydroxypiperidine-1-yl)-1-phenyl-1 H-pyrazole-4-carboxylic acid0,003
Example 19Adamantane-2-alamid 5-(3-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid0,0092
Example 20Adamantane-2-alamid 5-(3-hydroxypyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid0,013
Adamantane-2-alamid 5-(2-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid0,041
Example 22Adamantane-2-alamid 5-(2-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid0,021
Example 23Adamantane-2-alamid 5-(3-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid0,055
Example 24Adamantane-2-alamid 5-(4-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid0,0075
Example 25Adamantane-2-alamid 1-phenyl-5-[(tetrahydrofuran-2-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid0,002
Example 26Adamantane-2-alamid 5-[(2-hydroxyethyl)methylamino]-1-phenyl-1H-pyrazole-4-carboxylic acid0,014
Example 27Adamantane-2-alamid 5-(3-methoxypropylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid0.0014

It should be understood that the present invention is not limited to the network described above specific variant implementation of the invention, as options can be obtained in specific embodiments of, and they fall in the scope of the attached claims.

1. The compound of formula (I):

where R1represents hydrogen or C1-C4alkyl;
R2represents isopropyl, -CH2-phenyl, -CH2-pyridinyl, -CH2-cyclopropyl, cyclohexyl, cyclobutyl, -CH2CH2-phenyl, hydroxypropyl, hydroxyethyl, hydroxybutyl, -CH2-tetrahydrofuranyl or methoxypropyl;
or-NR1R2is pyrrolidinyl, dimethylpyrimidinol, methylpyrrolidinyl, methylpiperidine, morpholinyl, dimethylmorpholine, azepane, hydroxyethylpiperazine, hydroxyethylpyrrolidine, hydroxypiperidine or hydroxypyrrolidine;
R3represents hydrogen;
R4represents hydrogen;
and its pharmaceutically acceptable salts.

2. The compound according to claim 1, where R1represents hydrogen.

3. The compound according to claim 1, where R1represents a C1-C4alkyl.

4. The compound according to claim 1, where R1represents methyl.

5. The compound according to claim 1, selected from the following compounds:
adamantane-2-alamid 5-isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-benzylamino-1-phenyl-1H-pyrazole-4-karbonvansty;
adamantane-2-alamid 1-phenyl-5-[(pyridine-3-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(cyclopropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-cyclohexylamino-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-cyclobutylamine-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(2,5-dimethylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(2-methylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(3-methylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(benzylmethylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(methylphenethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(2,6-dimethylmorpholine-4-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 1-phenyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-azepin-1-yl-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-morpholine-4-yl-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(3-hydroxyethylpiperazine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-((S)-2-hydroxyethylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(4-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carb is new acid;
adamantane-2-alamid 5-(3-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(3-hydroxypyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(2-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(2-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(3-hydroxypropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(4-hydroxyethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 1-phenyl-5-[(tetrahydrofuran-2-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-[(2-hydroxyethyl)methylamino]-1-phenyl-1H-pyrazole-4-carboxylic acid and
adamantane-2-alamid 5-(3-methoxypropylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid.

6. The compound according to claim 1, selected from the following compounds:
adamantane-2-alamid 5-isopropylamino-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(cyclopropylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(2-methylpyrrolidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(3-methylpiperidin-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(methylphenethylamino)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(2,6-dimethylmorpholine-4-yl)-1-phenyl-1H-piraso the-4-carboxylic acid;
adamantane-2-alamid 1-phenyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-azepin-1-yl-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-morpholine-4-yl-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 5-(4-hydroxypiperidine-1-yl)-1-phenyl-1H-pyrazole-4-carboxylic acid;
adamantane-2-alamid 1-phenyl-5-[(tetrahydrofuran-2-ylmethyl)amino]-1H-pyrazole-4-carboxylic acid and
adamantane-2-alamid 5-(3-methoxypropylamine)-1-phenyl-1H-pyrazole-4-carboxylic acid.

7. The compound according to any one of claims 1 to 6, having inhibitory activity against the enzyme 11β-HSD1.

8. The compound according to any one of claims 1 to 6 for the manufacture of medicines for the prevention or treatment of diseases caused by disorders associated with enzyme beta-hydroxysteroid dehydrogenase 1.

9. Pharmaceutical composition having inhibitory activity against the enzyme 11β-HSD1 containing compound according to any one of claims 1 to 6 and a therapeutically inert carrier.

10. The use of compounds according to any one of claims 1 to 6 for the manufacture of drugs for treatment or prevention of diabetes, obesity, disorders associated with eating, or dyslipidemia.

11. The compound according to any one of claims 1 to 6 for use as a drug for treatment or prevention of diabetes, airen what I disorders associated with eating, or dyslipidemia.

12. The use of compounds according to any one of claims 1 to 6 for the manufacture of drugs for treatment or prevention of type II diabetes.

13. The compound according to any one of claims 1 to 6 for use as a drug for treatment or prevention of type II diabetes.

14. The method of treatment or prophylaxis of diabetes, obesity, disorders associated with eating, or dyslipidemia, which includes introducing the compound according to any one of claims 1 to 6 in an effective amount.

15. Method for the treatment or prevention of type II diabetes, which comprises introducing the compound according to any one of claims 1 to 6 in an effective amount.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel C-phenyl glycitol compound which serves as a preventive or therapeutic agent for sugar diabetes by inhibiting SGLT1 activity, as well as SGLT2 activity; demonstrating inhibiting effect on glucose absorption, and also acts on release of glucose with urine. The C-phenyl glycitol compound has formula (I) given below, or pharmaceutically acceptable salt or hydrate thereof, where R1 and R2 are identical or different and denote a hydrogen atom, a hydroxyl group, a C1-6 alkyl group, a C1-6 alkoxy group or a halogen atom, R3 is a hydrogen atom, a C1-6 alkyl group or a C1-6 alkoxy group, Y is a C1-6 alkylene group, -O-(CH2)n- (n is a whole number which assumes values from 1 to 4), provided that when Z denotes -NHC(= NH)NH2 or -NHCON(RB)Rc, n not equal to 1, Z is -CONHRA, -NHC(=NH)NH2 or -NHCON(RB)Rc, or The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: high efficiency of the compounds.

19 cl, 8 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: pharmaceutical compositions containing at least one compound of formula (IIIa) or (IIIb) or (IVa) or (IVb), where -X- and Y are described in the claims, or pharmaceutically acceptable salts, esters or amides thereof and a pharmaceutically acceptable carrier, which can be used in processes with modulation or E- and P-selectin expression.

EFFECT: obtaining low-molecular non-glycoside and non-peptide compounds, capable of creating antagonism to selectin-mediated processes.

11 cl, 38 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , isomer thereof of formula IA , mixture of isomers thereof IA/C , synthesis method thereof, as well as methods of producing compounds of formula IVA from compounds of formula IA, involving reduction and removal of protection from compounds of formula IA via hydrogenolysis using H2 and a catalytic amount of Pd/C, in the presence of trifluoroacetic acid to obtain a compound of formula VA; further reaction of this compound with Cbz-t-leu-OH, EDC and HOBt to obtain a compound of formula VIA; reaction of compound VIA with H2 and a catalytic amount of Pd/C in the presence of citric acid to obtain an amine and reaction of said amine and 4-amino-3-chlorobenzoic acid in the presence of CDMT and NMM to obtain a compound of formula IVA.

EFFECT: fewer synthesis steps and high output while using dynamic crystallisation.

13 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel carbamoyl benzotriazole derivatives of general formula , (values of radicals are given in the description), tautomers thereof and pharmaceutically acceptable salts and use thereof as endothelial lipase inhibitors.

EFFECT: improved properties of the derivatives.

11 cl, 148 ex

FIELD: chemistry.

SUBSTANCE: present invention is related to new quinolone derivatives of general formula (I) where R1: C3-6cycloalkyl or lower alkylene C3-6cycloalkyl, R2: -H or halogen, R3: -H, halogen, -OR0 or -O-(lower alkylene)-phenyl, R0: are the same or different from each other, and each represents -H or lower alkyl, R4: lower alkyl, halogen(lower alkyl), lower alkyleneC3-6cycloalkyl, C3-7cycloalkyl or a heterocyclic group, where cycloalkyl and the heterocyclic group specified in R4 can be respectively substituted, R5: -NO2, -CN, -L-Ra, -C(O)R0, -O-Rb, -N(R6)2, lower alkylene-N(R6)(Rc), -N(R6)C(O)-Rd, lower alkylene-N(R6)C(O)-Rd, lower alkylene-N(R0)C(O)O-(lower alkyl), -N(R0)C(O)N(R0)-Re, lower alkylene-N(R0)C(O)N(R0)-Re, -N(R0)S(O)2N(R0)C(O)-Rd, -CH=NOH, C3-6cycloalkyl, (2,4-dioxo-1,3-thiazolidin-5-yliden)methyl or (4-oxo-2-tioxo-1,3-thiazolidin-5-yliden)methyl where cycloalkyl specified in R5 can be respectively substituted, R6: H, lower alkyl, lower alkylene-CO2R0 or lower alkylene-P(O)((OPp)2, where lower alkylene specified in R6 can be substituted, L: lower alkylene or lower alkenylene which can be respectively substituted, Ra: -OR0, -O-(lower alkylene)-phenyl, -O-(lower alkylene)-CO2R0, -CO2R0, -C(O)NHOH, -C(O)N(R6)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-phenyl, -C(O)N(R0)-S(O)2-(heterocyclic group), -NH2OH, -OC(O)R0, -OC(O)-(halogen(lower alkyl)), -P(O)(ORp)2, phenyl or the heterocyclic group where phenyl or the heterocyclic group specified in Ra can be substituted, Rp: R0, lower alkylene-OC(O)-(lower alkyl), lower alkylene-OC(O)-C3-6cycloalkyl, lower alkylene-OC(O)O-(lower alkyl), Rb: H, lower alkylene-Rba or lower alkenylene-Rba where lower alkylene or lower alkenylene specified in Rb can be substituted, Rba: -OR0, -CO2R0, -C(O)N(R0)2, -C(O)N(R0)-S(O)2-(lower alkyl), -C(O)N(R0)-S(O)2-[phenyl, -C(NH2)-NOH, -C(NH2)=NO-C(O)-(lower alkylene)-C(O)R0, -CO2-(lower alkylene)-phenyl, -P(O)(ORp)2, -C(O)R0, -C(O)-phenyl, C3-6cycloalkyl, phenyl or the heterocyclic group where phenyl and the heterocyclic group specified in Rba can be substituted, Rc: H, lower alkylene-OR0, lower alkylene-CO2R0, lower alkylene-P(O)((OPp)2, phenyl where lower alkylene and phenyl are specified in Rd can be substituted, Rd: C1-7-alkyl, lower alkenyl, halogen(lower alkyl), lower alkylene-Rda, lower alkylenylene-Rda, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where lower alkylene, cycloalkyl, phenyl, naphthyl and the heterocyclic group specified in Rd can be substituted, Rda: -CN, -OR0, -O-(lower alkylene)-CO2R0, -O-naphthyl, -CO2R0, -CO2-(lower alkylene)-N(R0)2, -P(O)(ORp)2, -N(R6)2, -C(O)N(R0)-phenyl, -C(O)N(R0)-(lower alkylene which can be used by -CO2R0)-phenyl, -N(R0)C(O)-phenyl, -N(R0)C(O)-OR0, -N(R0)C(O)-O-(lower alkylene)-phenyl, -N(R0)S(O)2-phenyl, C3-6cycloalkyl, phenyl, naphthyl or the heterocyclic group, where phenyl, naphthyl and heterocyclic group specified in Ra can be substituted, Re: lower alkylene-CO2R0, phenyl, -S(O)2-phenyl or -S(O)2-(heterocyclic group), where phenyl and the heterocyclic group specified in Re can be substituted, X: CH, A: C(R7), R7: -H, or R4 and R7 together can form lower alkylene, where the substituted groups have the substituted specified in cl.1, and provided 7-(cyclohexylamino)-1-ethyl-6-fluor-4-oxo-1,4-dohydroquinoline-3-carbonitryl is excluded. Also, the invention refers to a pharmaceutical composition based on a compound of formula (I) and application of formula (I) for preparing a thrombocyte aggregation inhibitor or a P2Y12 inhibitor.

EFFECT: there are produced new quinol-4-one derivatives showing effective biological properties.

11 cl, 83 tbl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

, where X denotes a 5-member heterocylic group bonded through a carbon atom, selected from thiophenyl, furanyl, pyrazolyl and pyrrolyl, which can be substituted with 1-3 Ra groups; T denotes O, S; B is as indicated in the claim; Z1 denotes an unsubstituted cyclopropyl; Z2 denotes a hydrogen atom, C1-C8alkyl; or C1-C8alkoxycarbonyl; Z3 independently denotes a hydrogen atom. The invention also relates to a fungicidal composition containing a compound of formula (I) as an active ingredient, and a plant pathogenic fungus control method in agricultural plants.

EFFECT: obtaining compounds of formula (I), having fungicidal activity.

9 cl, 3 dwg, 255 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pharmaceutical composition having activity for stimulating formation of nerve tissue and (or) inhibiting neuron degeneration, containing a compound of formula , where each R1 is independently selected from a group consisting of H, F, CI, Br, R7 and -O-R7, where R7 denotes substituted alkyl containing 1-6 carbon atoms or an aralkyl or aryl group containing 6-14 carbon atoms; R2 is selected from O or S; R3 is selected from alkyl containing 1-6 carbon atoms or an ether containing 1-6 carbon atoms and R4 is selected from an aryl containing 6-14 carbon atoms, an aralkyl substituted with an aromatic group, substituted with a heteroatomatic group or substituted with a heteroaromatic-alkyl group, or R4 is selected from a substituted 3-quinolinylmethyl, 2-pyridyl, 2-pyridylmethyl, 2- or 4-pyrimidinyl, benzo[1,3]dioxol-5-yl or benzoxazolyl. The invention also relates to methods of stimulating formation of nerve tissue and/or inhibiting neuron degeneration, based on use of said compounds and specific compounds.

EFFECT: novel compositions and methods containing compounds which are useful for stimulating formation of nerve tissue.

23 cl, 5 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a N-(2-oxo-2-propoxyethyl)-β-phenyl-D- phenylalanyl-N-[(1-amino-6-isoquinolinyl)-methyl]-L-proline amide compound or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing said compound, as well as use of the compound to produce a medicinal agent for treating or preventing thrombin-mediated diseases. The invention also relates to a N-(carboxymethyl)-β-phenyl-D-phenylalanyl-N-[(1-amino-6-isoquinolinyl)methyl]-L-proline amide compound of pharmaceutically acceptable salt thereof.

EFFECT: obtaining novel compounds possessing useful biological properties.

5 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention describes a compound of formula (I) and pharmaceutically acceptable salt thereof, where m denotes a direct bond; n equals 0, 1, 2, 3 or 4 and n equals zero indicates a direct bond; p equals 1; s denotes a direct bond; t denotes a direct bond; R1 and R2 each independently denotes hydrogen; A denotes a radical selected from , where R4 and R5 are each independently selected from hydrogen or C1-6alkyloxy; Z denotes a radical (b-2), where R6 and R7 each independently denotes hydrogen. The invention also describes a pharmaceutical composition for treating cancer and preparation method thereof, based on compounds of formula I, use of these compounds to obtain a medicinal agent, as well as a method of producing said compounds.

EFFECT: novel compounds which can be used as p53-MDM2 interaction inhibitors are obtained and described.

10 cl, ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to hydroximoyl-tetrazole derivatives of formula (I), , where T is a tetrazole substitute, A is a phenyl or heterocycle, L1 and L2 are different linker groups, and Q is a carbocycle, use thereof as fungicide active agents, particularly in form of fungicide compositions, and methods of controlling phytopathogenic fungi, especially plants, using said compounds or compositions.

EFFECT: more effective use of the compounds.

13 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: 3-methyl-4-nitrosopyrazoles are obtained via cyclocondensation of hydrazine salts with a nitrosation product obtained from 4,4-dimethoxybutan-2-one held in aqueous hydrochloric acid first. The obtained compounds can be used as modifiers and stabilisers of rubber mixtures, particularly during vulcanisation of butadiene-nitrile rubber and as fungicides.

EFFECT: novel method of producing 3-methyl-4-nitrosopyrazoles and obtaining novel 3-methyl-4-nitrosopyrazoles.

2 cl, 4 ex

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