Pyrimidine derivatives with inhibiting action with respect to 11b-hsd1

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

 

The present invention relates to new pyrimidine derivative, useful as inhibitors of 11b-HSD1 (T2D).

The present invention relates in particular to compounds of the formula I and their pharmaceutically acceptable salts and esters:

where R1represents alkyl, cycloalkyl, cycloalkylcarbonyl, alkoxyalkyl, cycloalkylcarbonyl, heterocyclyl, geterotsiklicheskikh, aryl, arylalkyl, aryloxyalkyl, amino or aminoalkyl;

R2represents hydrogen, alkyl or aryl;

R3represents hydrogen, alkyl or aryl;

R4represents phenyl, naphthyl, thiophenyl, hinely, piperidyl, morpholyl or thiomorpholine, where phenyl, naphthyl, thiophenyl, hinely, piperidyl, morpholyl and thiomorpholine optionally substituted by one or more substituents, independently selected from alkyl, cycloalkyl, halogen, alkoxy, cyano, trifloromethyl, aryl, arylalkyl, aryloxy, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl and thiazolyl;

R5represents hydrogen, alkyl, aralkyl, cycloalkenyl or aminocarbonylmethyl

and where are excluded

N-(2,6-dimethyl-4-pyrimidinyl)benzosulfimide;

2-chloro-N-(2-methyl-4-pyrimidinyl)-p-toluensulfonate;

N-(2-(dimethylamino)-6-methyl-5-propyl-4-pyrimidinyl)benzosulfimide and 2,4,5-three the ENT-N-(2,6-dimethyl-4-pyrimidinyl)benzosulfimide.

Glucocorticoids (cortisol in humans, corticosterone in mice and rats) are an important class of adrenocorticosteroids that regulate many metabolic and homeostatic processes and form a key component of the stress response. Glucocorticoids act through intracellular glucocorticoid receptors and, in some tissues, mineralocorticoid receptors; however, both species are transcription factors to the nucleus. The effect of glucocorticoids on the tissue of the target depends not only on circulating concentrations of steroid and cellular expression of the receptor, but also on intracellular enzymes, which are mainly determined by the extent to which glucocorticoids have access to the receptors in the active form. Beta-hydroxysteroiddehydrogenase (beta-HSD) catalyzes interconversion mainly active 11-hydroxysuccinimide (cortisol in humans) in its inactive 11-cytometric (cortisone in humans).

The enzyme beta-hydroxysteroiddehydrogenase type 1 (beta-HSD1) vzaimoprevrascheny from inactive to active glucocorticoids, thereby playing a major role in the local modulation of the concentration cell agonist and thus causing activation of corticosteroid receptors in target tissues. In a recent study conducted by F.Hoffmann-La Roche, were proan the specific differences in gene expression in lean and full of people, using the technology of gene set to identify specific changes in gene expression, which may be associated with insulin resistance or altered metabolism. This study showed that mRNA for beta-HSD1 about two times stronger regulated in the adipose tissue of obese people. Moreover, overexpression of beta-SD1 in mouse adipocytes leads to visceral obesity and syndrome X-like phenotype (Masuzaki H., and others, Science, 2001, Dec 7; 294 (5549), SS. 2166-70). Together these data strongly suggest an important role HSD1 in the induction of obesity and release of glucose homeostasis and lipid parameters. Thus, selective inhibition of this enzyme could lower the levels of blood glucose in patients with type 2 diabetes, normalize elevated lipid parameters and/or lower the full weight of the patients.

The first pharmacological indicating that the inhibition beta-HSD1 a person may have favorable effects were obtained using carbenoxolone, antiulcer medication which inhibits both beta-HSD1 and its associated enzyme beta-HSD2. Treatment carbenoxolone increases insulin sensitivity, which indicates that inhibition beta-HSD1 can reduce cortisol levels in the cell and, therefore, ensat some of its harmful effects (Walker and others, J. Clin. Endocrinol. Metab., 1995; 80, s-3159).

Beta-HSD1 is expressed in many tissues, including liver, adipose tissue, smooth muscles, pancreas and brain. Its activity depends on NADP(H) and it has a relatively low affinity for its substrate (compared to beta-HSD2). Beta-HSD1 in tissue homogenates and after cleaning is bidirectional, showing reactions as betacarotene and bettereducated with increased resistance to the activity of dehydrogenase (P.M.Stewart and Z.S.Krozowski, Vitam. Horm., 1999, 57, SS-324). However, when the enzyme activity was examined in intact cells, was dominated by the activity bettereducated, which produces active glucocorticoids from inert 11-ketoform. This production glucocorticoid will increase the effective intracellular levels of glucocorticoid, thereby enhancing the activity of glucocorticoid. This is increasing the cellular concentration of cortisol, which can lead to increased production of glucose in the liver, differentiation of adipocytes and insulin resistance.

Inhibition beta-SD1 should not only reduce the typical symptoms of syndrome X/diabetes, as well as to be safe and not have severe side effects. Research nonspecific inhibitor carbenoxolone emphasize the importance of developing specific inhibitors beta-HD1. Enzyme inhibition beta-SD2 is difficult and leads to increased blood pressure. In contrast, inhibition beta-HSD1 has well tolerated, because it was found that beta-HSD1 treated mice are healthy and resistant to hyperglycemia caused by obesity or stress (Kotelevtsev Y. and others, the OEWG Natl Acad Sci U S A, 1997, Dec 23; 94 (26), SS-9). Similarly, in starvation, these mice have reduced the activation of key enzymes involved in gluconeogenesis. In addition, these mice have elevated lipid and lipoprotein profiles, suggesting that inhibition HSD1 can be highly effective and safe. Recent studies have shown that inhibitors beta-HSD1 may also be useful for reducing high blood pressure (Masuzaki H., and others, J Clin Invest., 2003, July; 112(1), SS-90; Rauz S. and others, QJM, 2003, July; 96(7), SS-90) to improve cognitive abilities (Sandeep TC. and others, the OEWG Natl Acad Sci AVE., 2004, Apr. 27; 101 (17), SS-9) or to correct violations associated with Alzheimer's disease. Along with this, inhibition beta-HSD1 can be safe and effective approach for the treatment of symptoms of diabetes, obesity and other diseases.

The compounds of formula I and their pharmaceutically acceptable salts and esters are new and have valuable pharmacological properties. In particular, they are inhibitors 11bHSD1 (T2D) and they show selectivity for the enzyme, associated with beta-SD2. Therefore, compounds that are specific inhibitors beta-HSD1 (T2D) present approach, for example, to lower glucose levels in the blood and normalize lipid parameters in patients with type 2 diabetes by modulating the local concentration of the active glucocorticoid cortisol in the target tissue (liver, adipose tissue).

Compounds of the present invention can be used for the prevention and/or treatment of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, particularly diabetes type 2.

Compounds of the present invention can also be used for the prevention and/or treatment of high eye pressure, cognitive abilities, Alzheimer's disease and/or neurodegeneration.

Objects of the present invention are the compounds of formula I and their aforementioned salts and esters as such and their use as therapeutically active substances, the method of obtaining these compounds, intermediate compounds, pharmaceutical compositions, drugs containing these compounds, their pharmaceutically acceptable salts and esters, the use of these compounds, ethers, and salts for the prophylaxis and/or treatment of diseases, especially for the treatment or prevention of diseases associated with food intake, adiposity, is dislipidemia, hypertension and/or diabetes, particularly diabetes type 2, and the application of the said compounds, salts and esters for the manufacture of drugs for treatment or prevention of metabolic diseases, obesity, dyslipidemia, hypertension and/or diabetes, particularly diabetes type 2.

Compounds of the present invention can also be combined with agonists of PPAR (alpha, gamma, Delta), DHEA (dehydroepiandrosterone), DPPIV inhibitors, insulin and/or lipase inhibitors, especially with orlistat.

In the present description, the term "alkyl", alone or in combination, denotes a linear or branched alkyl group containing from 1 to 8 carbon atoms, preferably a linear or branched alkyl group containing from 1 to 6 carbon atoms, and particularly preferably a linear or branched alkyl group containing from 1 to 4 carbon atoms. Examples of linear and branched C1-C8alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, isomers pentile, isomers of hexyl, isomers of heptyl and isomers of Attila, preferably methyl and ethyl and most preferably methyl.

The term "cycloalkyl", separately or in combination, refers to cycloalkyl ring containing from 3 to 8 carbon atoms, and preferably cycloalkyl ring containing from 3 to 6 at the MOU carbon. Examples3-C8cycloalkyl are cyclopropyl, methylcyclopropyl, dimethylcyclopropene, cyclobutyl, methylcyclobutane, cyclopentyl, methylcyclopentene, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.

The term "alkoxy", alone or in combination, signifies a group of the formula alkyl-O-, in which the term "alkyl" has the previously described meaning, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy, ethoxy and most preferably methoxy.

The term "aryl", alone or in combination, signifies a phenyl or naftalina group, preferably a phenyl group which is optionally substituted by one or more substituents, preferably 1-3, each of which is independently selected from halogen, trifloromethyl, triptoreline, amino, alkyl, alkoxy, alkylsulphonyl, cyano, carbamoyl, alkoxycarbonyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, hydroxy, nitro, alkyl-SO2-, amino-SO2-cycloalkyl and the like. Preferred is phenyl or naphthyl, especially phenyl, optionally substituted 1-3, preferably one or two, substituents, independently selected from alkyl, g is lagena, alkoxy, triptoreline, nitro and trifloromethyl. Especially preferred is phenyl.

The term "aryloxy", separately or in combination, refers to the group aryl-O-, in which the term "aryl" has the previously described meaning.

The term "aralkyl", separately or in combination, refers to arylalkyl group, in which the terms "aryl" and "alkyl" have the previously described meaning.

The term "heterocyclyl", separately or in combination, denotes a saturated, partially unsaturated or aromatic 5-to 10-membered heterocycle that contains one or more heteroatoms selected from nitrogen, oxygen and sulfur. If necessary, it can be substituted in one or more carbon atoms, for example, halogen, alkyl, alkoxy, oxo, etc. and/or on a secondary nitrogen atom (i.e.- NH-) alkyl, cycloalkyl, alcoxycarbenium, alkanoyl, phenyl or phenylalkyl, or on a tertiary nitrogen atom (i.e. =N-) oxide, with halogen, alkyl, cycloalkyl and alkoxy are preferred. Examples of such heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinil, morpholinyl, thiomorpholine, pyrazolyl, imidazolyl (for example, imidazol-4-yl and 1-benzyloxycarbonylamino-4-yl), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, hexahydropyridine, furyl, thienyl, thiazolyl, oxazolyl, indolyl (e.g., 2-indolyl), ginoli is (for example, 2-chinolin, 3-chinolin and 1 oxido-2-chinolin), ethanolic (for example, 1-ethanolic and 3-ethanolic), tetrahydropyranyl (for example, 1,2,3,4-tetrahydro-2-chinolin), 1,2,3,4-tetrahydroisoquinoline (for example, 1,2,3,4-tetrahydro-1-occaisonaly) and honokalani. Preferred examples are thiophenyl, hinely, piperidyl, morpholyl, thiomorpholine, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl and thiazolyl.

The term "amino", alone or in combination, signifies a primary, secondary or tertiary amino group attached through a nitrogen atom, where the secondary amino group is alkyl or cycloalkyl Deputy and tertiary amino group has two identical or different alkyl or cycloalkyl Deputy or two substituent at the nitrogen atom together form a loop, such as, for example, -NH2methylamino, ethylamino, dimethylamino, diethylamino, methylethylamine, pyrrolidin-1-yl or piperidino etc., preferably primary amino, dimethylamino, diethylamino and especially dimethylamino.

The term "halogen", alone or in combination, refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

The term "carbonyl", alone or in combination, refers to a group - C(O)-.

The term "hydroxy", separately or in combination, refers to a group-O-.

The term "nitro", separately or in combination, refers to a group-N 2.

The term "cyano", separately or in combination, refers to the group-CN.

The term "pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise unacceptable. Salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate acid, salicylic acid, N-acetylcysteine and the like. In addition, salts may be obtained by adding an inorganic base or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts with sodium, potassium, lithium, ammonium, calcium, magnesium and the like. Salts derived from organic bases include, but are not limited to, salts with primary, secondary and tertiary amines, substituted amines including natural substituted amines, cyclic amines and basic ion exchange resins, such as Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, primenenie resin and the like. The compound of the formula I can also be present in the form zwitterions. Particularly preferred pharmaceutically acceptable salts of the compounds of formula I are hydrochloride.

The compounds of formula I can also be solvated, for example gidratirovana. Solvation can be done through the method of obtaining, or may occur, for example, due to the hygroscopic properties of the initially anhydrous compound of formula I (hydration). The term pharmaceutically acceptable salts also include physiologically acceptable solvate.

"Pharmaceutically acceptable esters" refers to that of the compounds of General formula (I) can be obtained derivative functional groups with obtaining derivatives, which are able to turn back into the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ether derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl the haunted esters. In addition, any physiologically acceptable equivalents of the compounds of General formula (I), similar metabolically labile esters, which are capable of being converted into the parent compound of General formula (I) in vivo, are also included in the scope of the present invention.

The compounds of formula I can contain one or more asymmetric centers and may exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric of racemates or mixtures diastereoisomeric racemate.

Preferred are the compounds of formula I and their pharmaceutically acceptable salts, especially the compounds of formula I.

Preferred are the compounds of formula I, where

R1represents alkyl, cycloalkyl, alkoxyalkyl, cycloalkylcarbonyl, heterocyclyl, geterotsiklicheskikh, aryl, arylalkyl, aryloxyalkyl, amino or aminoalkyl;

R2represents hydrogen or alkyl;

R3represents hydrogen or alkyl;

R4represents phenyl, naphthyl, thiophenyl, hinely, piperidyl, morpholyl or thiomorpholine, where phenyl, naphthyl, thiophenyl, hinely, piperidyl, morpholyl and thiomorpholine optionally substituted by one or more substituents, independently selected from alkyl, the cycle is of alkyl, halogen, alkoxy, cyano, trifloromethyl, aryl, arylalkyl, aryloxy, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl and thiazolyl;

R5represents hydrogen or alkyl;

and their pharmaceutically acceptable salts and esters

and where are excluded

N-(2,6-dimethyl-4-pyrimidinyl)benzosulfimide;

2-chloro-N-(2-methyl-4-pyrimidinyl)-p-toluensulfonate;

N-(2-(dimethylamino)-6-methyl-5-propyl-4-pyrimidinyl)benzosulfimide and

2,4,5-trichloro-N-(2,6-dimethyl-4-pyrimidinyl)benzosulfimide.

Other preferred are the compounds of formula I, where R1represents alkyl, cycloalkyl, alkoxyalkyl, cycloalkylcarbonyl, heterocyclyl, geterotsiklicheskikh or aryl.

Especially preferred are the compounds of formula I, where R1represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropylmethoxy, 2-methylthiazolyl, morpholinylmethyl or phenyl.

Also preferred are the compounds of formula I, where R2represents hydrogen.

Another preferred embodiment of the present invention are the compounds of formula I, where R2represents methyl.

Preferred are the compounds of formula I, where R3represents hydrogen.

Another preferred is the embodiment of the present invention are the compounds of formula I, where R5represents hydrogen.

Other preferred are the compounds of formula I, where R5represents methyl.

Also preferred are the compounds of formula I, where R4represents phenyl, naphthyl, thiophenyl, chinolin or piperidyl, where phenyl, naphthyl, thiophenyl, chinosol and piperidyl optionally substituted by one or more, preferably 1-3 substituents, independently selected from alkyl, halogen, alkoxy, trifloromethyl, aryl, oxazolyl and pyridinyl.

Other preferred are the compounds of formula I, where R4represents phenyl substituted by one or more, preferably 1-3 substituents, independently selected from alkyl, cycloalkyl, halogen, alkoxy, trifloromethyl, phenyl and oxazolyl.

Preferred are the compounds of formula I, where R4represents phenyl, naphthyl, chinolin or piperidyl.

Also preferred are the compounds of formula I, where R4is thiophenyl, morpholyl or thiomorpholine where thiophenyl, morpholyl and thiomorpholine optionally substituted by one or more, preferably 1 to 3 substituents, independently selected from alkyl, cycloalkyl, halogen, alkoxy, cyano, trifloromethyl, aryl, arylalkyl, aryloxy, oxazolyl, pyridinyl, pyrimidinyl, Piras is Lila, imidazolyl and thiazolyl.

Examples of preferred compounds of formula (I) are:

1) 3-chloro-2-methyl-N-(2-methylpyrimidin-4-yl)benzosulfimide;

2) 3-chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide;

3) N-(2-cyclopropylamino-4-yl)-2,5-diftorbenzofenonom;

4) (2-cyclopropylamino-4-yl)amide, naphthalen-2-sulfonic acid;

5) (2-cyclopropylamino-4-yl)amide-biphenyl-4-sulfonic acid;

6) (2-cyclopropylamino-4-yl)amide, the quinoline-8-sulfonic acid;

7) N-(2-cyclopropylamino-4-yl)benzosulfimide;

8) N-(2-cyclopropylamino-4-yl)-5-fluoro-2-methylbenzenesulfonamide;

9) N-(2-cyclopropylamino-4-yl)-3-methoxybenzenesulfonamide;

10) N-(2-cyclopropylamino-4-yl)-2-methoxy-5-methylbenzenesulfonamide;

11) 3-chloro-N-(2-cyclopropylamino-4-yl)-4-methoxybenzenesulfonamide;

12) 5-chloro-N-(2-cyclopropylamino-4-yl)-2-methoxybenzenesulfonamide;

13) 5-fluoro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide;

14) of 3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

15) N-(2-isopropylpyrimidine-4-yl)-4-(1,3-oxazol-5-yl)benzosulfimide;

16) of 2,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-6-methylbenzenesulfonamide;

17) of 2,3-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

18) (2-isopropylpyrimidine-4-yl)amide 4,5-dichlorothiophene-2-sulfonic acid;

19) (2-isoprop pyrimidin-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid;

20) 3-chloro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide;

21) N-(2-isopropylpyrimidine-4-yl)-3-triftoratsetilatsetonom;

22) N-(2-isopropylpyrimidine-4-yl)-2-triftoratsetilatsetonom;

23) (2-isopropylpyrimidine-4-yl)amide 5-chlorothiophene-2-sulfonic acid;

24) N-(2-isopropylpyrimidine-4-yl)-4-triftoratsetilatsetonom;

25) (2-isopropylpyrimidine-4-yl)amide piperidine-1-sulfonic acid;

26) (2-isopropylpyrimidine-4-yl)amide, naphthalen-2-sulfonic acid;

27) (2-isopropylpyrimidine-4-yl)amide-biphenyl-4-sulfonic acid;

28) 2.5-debtor-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

29) N-(2-isopropylpyrimidine-4-yl)-3,4-dimethoxybenzenesulfonamide;

30) N-(2-tert-butylpyridinium-4-yl)-3,4-dichlorobenzenesulfonate;

31) N-(2-tert-butylpyridinium-4-yl)-5-fluoro-2-methylbenzenesulfonamide;

32) (2-tert-butylpyridinium-4-yl)amide, naphthalen-2-sulfonic acid;

33) N-(2-tert-butylpyridinium-4-yl)-2,5-diftorbenzofenonom;

34) N-(2-tert-butylpyridinium-4-yl)-4-(1,3-oxazol-5-yl)benzosulfimide;

35) 3-chloro-N-(2-ethylpyrimidine-4-yl)-2-methylbenzenesulfonamide;

36) of 2,4-dichloro-N-(2-ethylpyrimidine-4-yl)-6-methylbenzenesulfonamide;

37) 4-chloro-N-(2-ethylpyrimidine-4-yl)-2,5-dimethylbenzenesulfonamide;

38) 3-chloro-N-(2-cyclobutylmethyl-4-yl)-2-methylbenzenesulfonamide;

39) (2-cyclobutylmethyl-4-yl)amide, Naftalan--sulfonic acid;

40) (2-cyclobutylmethyl-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid;

41) of 2,4-dichloro-N-(2-cyclobutylmethyl-4-yl)-6-methylbenzenesulfonamide;

42) of 3,4-dichloro-N-(2-ethoxymethyleneamino-4-yl)benzosulfimide;

43) 3-chloro-N-(2-cyclopropanecarbonitrile-4-yl)-

2-methylbenzenesulfonamide;

44) 3-chloro-2-methyl-N-(2-morpholine-4-iletilerimde-4-yl)benzosulfimide;

45) (2,6-dimethylpyrimidin-4-yl)amide, naphthalen-2-sulfonic acid;

46) 3-chloro-N-(2-cyclopropylamino-4-yl)-2-N-dimethylbenzenesulfonamide;

47) of 3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-N-methylbenzenesulfonamide;

48) 3-chloro-2-methyl-N-(2-phenylpyrimidine-4-yl)benzosulfimide and

49) 3-chloro-2-methyl-N-[2-(2-methylthiazole-4-yl)pyrimidine-4-yl]benzosulfimide.

Other examples of preferred compounds are:

50) 3-chloro-N-(2-ethoxymethyleneamino-4-yl)-2-methylbenzenesulfonamide;

51) (2,5,6-trimethylpyridine-4-yl)amide, naphthalen-2-sulfonic acid;

52) 4,5-dichloro-2-fluoro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

53) 2,4-debtor-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

54) of 2-chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

55) 4-chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

56) 3-chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

57) of 2,4-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

58) of 2,4-dichloro-N - (2-isopropylpyrimidine-4-yl)-5-methylbenzenesulfonamide;

59) 2,5-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

60) (2-isopropylpyrimidine-4-yl)amide 3-bromo-5-chlorothiophene-2-sulfonic acid;

61) of 2,4-dichloro-N-(2-cyclopropylamino-4-yl)-6-methylbenzenesulfonamide;

62) 4-chloro-N-(2-cyclopropylamino-4-yl)-2,5-dimethylbenzenesulfonamide;

63) N-(2-cyclopropylamino-4-yl)-2,4-dimethoxybenzenesulfonamide;

64) 3-chloro-N-(2-cyclopentenopyridine-4-yl)-2-methylbenzenesulfonamide;

65) (2-cyclopropylamino-4-yl)amide 5-phenylthiophene-2-sulfonic acid;

66) 3-chloro-N-(2-cyclopropylmethoxy-4-yl)-2-methylbenzenesulfonamide;

67) 2-[(3,4-dichlorobenzenesulfonyl)-(2-isopropylpyrimidine-4-yl)

amino]-N,N-dimethylacetamide;

68) N-benzyl-3-chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide;

69) 3-chloro-N-cyclopropylmethyl-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide and

70) 3-chloro-2-methyl-N-(6-phenylpyrimidine-4-yl)benzosulfimide.

Examples of especially preferred compounds of formula (I) are:

3-chloro-2-methyl-N-(2-methylpyrimidin-4-yl)benzosulfimide;

3-chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide;

N-(2-cyclopropylamino-4-yl)-2,5-diftorbenzofenonom;

(2-cyclopropylamino-4-yl)amide, naphthalen-2-sulfonic acid;

(2-cyclopropylamino-4-yl)amide-biphenyl-4-sulfonic acid;

5-fluoro-N-(2-isopropyl shall eremein-4-yl)-2-methylbenzenesulfonamide;

3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

N-(2-isopropylpyrimidine-4-yl)-4-(1,3-oxazol-5-yl)benzosulfimide;

2,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-6-methylbenzenesulfonamide;

2,3-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

(2-isopropylpyrimidine-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid;

3-chloro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide;

N-(2-isopropylpyrimidine-4-yl)-3-triftoratsetilatsetonom;

N-(2-isopropylpyrimidine-4-yl)-2-triftoratsetilatsetonom;

(2-isopropylpyrimidine-4-yl)amide 5-chlorothiophene-2-sulfonic acid;

N-(2-isopropylpyrimidine-4-yl)-4-triftoratsetilatsetonom;

(2-isopropylpyrimidine-4-yl)amide, naphthalen-2-sulfonic acid;

(2-isopropylpyrimidine-4-yl)amide-biphenyl-4-sulfonic acid;

2.5-debtor-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;

N-(2-isopropylpyrimidine-4-yl)-3,4-dimethoxybenzenesulfonamide;

N-(2-tert-butylpyridinium-4-yl)-4-oxazol-5-albenzaalbenza;

3-chloro-N-(2-ethylpyrimidine-4-yl)-2-methylbenzenesulfonamide;

2,4-dichloro-N-(2-ethylpyrimidine-4-yl)-6-methylbenzenesulfonamide;

3-chloro-N-(2-cyclobutylmethyl-4-yl)-2-methylbenzenesulfonamide;

(2-cyclobutylmethyl-4-yl)amide, naphthalen-2-sulfonic acid;

(2-cyclobutylmethyl-4-yl)amide 5-pyridin-2-althofen-2-sulfonic sour is s;

2,4-dichloro-N-(2-cyclobutylmethyl-4-yl)-6-methylbenzenesulfonamide;

3-chloro-N-(2-cyclopropylamino-4-yl)-2-N-dimethylbenzenesulfonamide and

3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-N-methylbenzenesulfonamide.

Methods for obtaining compounds of formula I are the object of the invention.

Obtaining compounds of formula I of the present invention may be sequential or convergent synthesis methods. The synthesis according to the invention is shown in the following diagrams. The skills required for the reaction and purification of the final products, well-known specialist in this field of technology. Deputies and instructions used in the following description of the processes have the meanings specified above, unless specifically stated otherwise.

Typically, the compounds of type I easily get sulfonylamine appropriately substituted 4-aminopyrimidines And sulphonylchloride under various conditions known to a person skilled in the art. Examples of such conditions are as shown in the diagram below, for example, pyridine at elevated temperatures or THF at boiling in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride, triethylamine or the like.

The compound I with R5=N, obtained in this way is optional then bytesneeded nitrogen atom, sulfonamidnuyu group by treatment with a base, such as sodium hydride, cesium carbonate, potassium carbonate or the like, in a solvent such as DMF or THF, followed by alkylation of the resulting anion with alkylhalogenide, such as methyliodide, ethylbromide, benzylbromide or the like, for introducing the desired substituent R5.

Appropriately substituted 4-aminopyrimidine And are either commercially available, known from the prior art or can be obtained analogously to known sources from known starting materials. In the conventional method of synthesis used amidine or salt of amidine as starting materials, which - after the release of the free amidine processing base, such as triethylamine, ethoxide sodium, potassium carbonate or the like, if the starting materials used salts of amidine - treated with Acrylonitrile, such as 2-chloroacrylonitrile or 3-ethoxyacrylate in conditions that have already been described earlier (for example, J. Heterocyclic Chem., 1977, 14, SC-1414). Other alternative approaches to obtain the appropriately substituted 4-aminopyrimidines also available from the prior art.

In the presence of the appropriately substituted side chain in position 2 4-aminopyrimidine intermediate compounds And, for example, in the presence of the leaving group, that is Oh how the halogen in the side chain, possible additional, but optional modification. For example, the leaving group may be replaced by suitable processing of the source material (a) alcohols and the basis for obtaining aryl or alkyl esters or (b) amines to obtain aminoalkyl derivatives, as shown in the diagram below. When the leaving group is attached directly to the pyrimidine nucleus in position 2, it is possible a similar reaction with alcohols to obtain O-substituted 2-hydroxy-4-aminopyrimidine (scheme B).

The transformation of compounds of formula I in a pharmaceutically acceptable salt can be carried out by treatment of such compounds, inorganic acid, for example halogen acid, such as, for example, hydrochloric acid or Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate acid. The corresponding salts of carboxylic acids can also be obtained from compounds of formula I by treatment with physiologically acceptable bases.

The conversion of compounds of formula I in a pharmaceutically acceptable esters Il the amides can be carried out, for example, treatment with a suitable amine groups or hydroxyl groups present in the molecules of carboxylic acid, such as acetic acid condensing agent such as hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium (THIEF) or N,N-dicyclohexylcarbodiimide (DCCI) to obtain the ester of carboxylic acid or carboxylic acid amide.

The preferred method of obtaining the compounds of formula I, as defined above, involves the reaction of compounds of the formula:

in the presence of compounds of the formula:

where R1-R5are as defined above. Especially preferred is the above method, for example, pyridine or THF, especially in the presence of a base, such as, for example, potassium carbonate, sodium carbonate, sodium hydride or triethylamine. Very preferred is the above reaction in the presence of pyridine at a temperature from 50°C to 70°C. Even more preferred is the above method in the presence of THF under boiling under reflux.

Preferred intermediate compounds are:

2-cyclopropylamino-4-ylamine;

2-isopropylpyrimidine-4-ylamine;

2-tert-butylpyridinium-4-ylamine;

2-ethylpyrimidine-4-ylamine;

2-cyclobutylmethyl-elamin;

2-ethoxymethyleneamino-4-ylamine;

2-cyclopropanecarbonitrile-4-ylamine;

2-morpholine-4-iletilerimde-4-ylamine;

2-phenylpyrimidine-4-ylamine and

2-(2-methylthiazole-4-yl)pyrimidine-4-ylamine.

The above-described compounds of formula I for use as therapeutically active substances is another object of the present invention.

It is also an object of the present invention are compounds as described above for the manufacture of medicines for the prevention and treatment of diseases caused by disorders associated with enzyme beta-hydroxysteroiddehydrogenase 1 (11bHSD1).

Similarly, the object of the present invention are pharmaceutical compositions containing a compound of formula I as described above and a therapeutically inert carrier.

Another preferred embodiment of the present invention is the use of compounds of formula I as described above, for the manufacture of medicines for the treatment and prevention of diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension.

Especially preferred is the use of the compounds of formula I as described above, for the manufacture of drugs for treatment and prophylaxis of diabetes type II.

Another object of the present invention relates to the compounds is of formula I, as described above, obtained in accordance with any one of the methods described above.

It is also an object of the invention is a method for the treatment and prevention of diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension, which includes the introduction of an effective amount of the compounds of formula I as described above.

Especially preferred is a method of treatment and prophylaxis of diabetes type II, which includes the introduction of an effective amount of the compounds of formula I as described above.

Analysis techniques

Transient expression and partial purification

cDNA encoding a protein beta-HSD1 person, cloned in the expression vector pcDNA3 (Stratagene). This design (for more details see Alex Odermatt, etc. J. Biol Chem., 1999, T, VIP, SS-28770) was used for transient protein expression in cells NC (the number ATSS: CRL-1573, described Graham, F.L., Smiley, J., Russell, W.C., Nairn, R. (1977)), using lipofectamine. 48 h after transfection, the cells were twice washed in ice PBS (phosphate buffered saline). To 1 volume of cell suspension in PBS was added 2 volumes of chilled ice buffer for lysis (50 mm Tris; pH 7.5; 1 mm EDTA; 100 mm NaCl). Cells were subjected to lysis using the Potter homogenization (20 strokes). The resulting homogenizate were treated with ultrasound using ultrasonic shunt (10% yield; 2×30 sec) and was purified nor cocorote by centrifugation (10 min ×9000 g; 4°C). The microsomal fraction was collected using a high-speed centrifugation (60 min ×110'000 g). The resulting residue re-suspended in buffer to store (20 mm Tris; pH 7.5; 1 mm EDTA; 10% glycerol) and repeated centrifugation. The resulting residue containing the microsomal fraction was again placed in the buffer for storage and aliquots were kept frozen in liquid nitrogen until use.

Generation of stable cell lines expressing beta-HSD1

The same design used for transient expression beta-HSD1 person, also used to establish stability of cell lines expressing the protein. Briefly, (NEC) cells were transfusional using design beta-HSD1 using the reagent lipofectamine (Gibco BRL) according to the manufacturer's instructions. Two days after transfection initiated selection of geneticin (0.8 mg/ml), and provided several stable clones. One of the clones was then used for pharmacological characteristics.

Microsomal analysis

Microsome assay, isolated from cells NECK, transitional expressing beta-HSD1 person (details see above)were incubated in the buffer for analysis (100 mm NaCl; 1 mm EDTA; 1 mm EGTA; 1 mm MgCl; 250 mm sucrose; 20 mm Tris, pH 7,4; cortisone 50-200 nm and NADPH (1 mm) together with the test substances in various concentrations. After 60 min after inquire the project at 37°C. the assay was stopped by heating to 80°C (5 min) and addition of an inhibitor of carbenoxolone (1 μm). The amount of cortisol obtained in this analysis were determined using commercially available ELISA kit is based Cortisol-detection (manufactured Assay Design, Inc.). Inhibitors characterized by their values IC50, i.e. the concentration at which the production of cortisol was decreased by 50%.

In this test, the preferred compounds as described above have the values IC50below 1000 nm; more preferred compounds have values IC50below 100 nm. The most preferred compounds have values IC50below 10 nm.

Cell analysis

To measure the impact of inhibitors in intact cells NECK, stably expressing beta-HSD1 person (see above) were cultured in 96-well-plates in DMEM. To the cells was added first, inhibitors, and after 60 min cortisone. After 60 min after the start of incubation at 37°C in atmosphere containing 5% CO2part of the medium was removed and measured the conversion of cortisone to cortisol by using a commercially available ELISA kit (manufactured Assay Design, Inc.).

The following table shows the results obtained in microsomal analysis using the presented compounds according to the invention as the test compounds.

Connection11-HSD1 person IC 50(nm)
Example 520
Example 26167

Compounds as described above have the values IC50below 100 microns; more preferred compounds have values IC50below 20 μm, especially below 5 microns. The most preferred compounds have values IC50below 0.5 μm. The results obtained using the above test.

The compounds of formula I and their pharmaceutically acceptable salts and esters can be used as drugs (e.g., in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered orally, for example, orally (for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasal (e.g., in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the introduction can also be carried out parenterally, for example intramuscularly or intravenously (for example, in the form of solutions for injection).

The compounds of formula I and their pharmaceutically acceptable salts and esters can be mixed with pharmaceutically inert, inorganic or organic adjuvants to obtain tablets, coated tablets, pills and the solid gelatin capsules. For example, can be used lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. as such adjuvants for tablets, coated tablets, dragées and hard gelatin capsules.

Suitable adjuvants for hard gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, liquid polyols etc

Suitable adjuvants for obtaining solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils etc.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid and liquid polyols etc

Moreover, the pharmaceutical preparations can contain preservatives, soljubilizatory, substances that increase the viscosity stabilizers, moistening agents, emulsifiers, sweeteners, colorants, odorants, salts for regulating the osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

In accordance with the invention the compounds of formula I and their pharmaceutically acceptable salts can be used for preventive care is IKI and treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly diseases associated with food intake and obesity. The dosage may vary within wide limits and, of course, will depend on the specific requirements in each case. Usually in the case of oral administration suitable daily dosage ranges from about 0.1 mg to 20 mg per 1 kg body weight, preferably from about 0.5 mg to 4 mg per 1 kg of body weight (for example, about 300 mg for humans), divided preferably 1 to 3 separate doses, which may contain, for example, the same number. However, it is clear that the above upper limit may be exceeded if necessary.

The present invention is further illustrated by examples which are not limiting in nature.

Example 1. 3-Chloro-2-methyl-N-(2-methylpyrimidin-4-yl)benzosulfimide

2-Methylpyrimidin-4-ylamine (91 mg, Gabriel, Chem. Ber., 1904, 37, s) and 3-chloro-2-methylbenzenesulfonamide (179 mg) was dissolved in pyridine (5 ml) and the resulting mixture was stirred at 50-60°C for 48 hours. The mixture then was evaporated in vacuum and the residue was dissolved in ethyl acetate. The solution is twice washed with 1 m solution of CuSO4, dried Na2SO4, was filtered and was evaporated. The residue was purified accelerated chromatography (CH2CL2/Meon/NH390:10:0.5) is obtaining telemag the product 3-chloro-2-methyl-N-(2-methylpyrimidin-4-yl)benzosulfimide in the form of a yellow powder (22 mg). MS (ESI-): 297,1 ([M-H]-).

Example 2. 3-Chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide

Stage A. 2-Cyclopropylamino-4-ylamine

Cyclopropanecarbonitrile hydrochloride (3.0 g) was added to a solution of sodium methoxide (5.4 M, 4.61 in ml) and the mixture was stirred for 1 hour. The suspension was filtered to remove precipitated NaCl and the filtrate was evaporated in vacuum to obtain a light brown residue (2.86 g). 3-Ethoxyacrylate (2.55 ml) was added and the mixture was heated at 135°C for 3 hours and then stirred at RT for 12 hours. The reaction mixture was directly subjected to rapid chromatography (silica gel, ethyl acetate and the desired product 2-cyclopropylamino-4-ylamine was isolated as a light brown foam (1,53 g).1H NMR (δ, CDCl3): of 8.09 (d, 1H), 6,18 (d, 1H), and 4.68 (br s, 2H), 2,04-to 1.98 (m, 1H), 1,08 of-1.04 (m, 2H), 0,97 to 0.92 (m, 2H). MS (ESI): 136,2 (MH+).

An alternative method of implementation stage And

Cyclopropanecarbonitrile hydrochloride (to 7.61 g) was dissolved in ethanol (125 ml) was added triethylamine (19,35 ml) and 2-chloroacrylonitrile (5,52 ml). The obtained orange-yellow solution was boiled under reflux for 30 minutes. The mixture was cooled and left in the refrigerator over night. Solids were removed by filtration and the filtrate was concentrated in vacuum. The residue was purified accelerated chromatography (ethyl acetate/methanol 91) to obtain 2-cyclopropylamino-4-ylamine of 4.2 g) as a pale brown solid, which was still contaminated with undesirable component, but it is further used without additional purification.1H NMR (δ, DMSO-d6only the signal of the product): 7,88 (d, 1H), only 6.64 (br s, 2H), 6,16 (d, 1H), 1,89-to 1.82 (m, 1H), 0,87 is 0.81 (m, 4H).

For ways to get the stage And see: Singh, and since Joey was gone, J. Heterocyclic Chem., 1977, 14 (8), SS-1414.

Stage B. 3-Chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide

This product was obtained analogously to example 1 from 2-cyclopropylamino-4-ylamine (0.126 g) and 3-chloro-2-methylbenzenesulfonamide (0.2 g) as a pale yellow solid (0,067 g). MS (ESI-): 322,2 ([M-H]-).

Example 3. N-(2-Cyclopropylamino-4-yl)-2,5-diftorbenzofenonom

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0,150 g) and 2,5-differentialthreshold (0,236 g) as a pale yellow foam (0.1 g). MS (ESI): 312,1 (MN+).

Example 4. (2-Cyclopropylamino-4-yl)amide, naphthalen-2-sulfonic acid

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0.1 g) and naphthalen-2-sulphonylchloride (0,044 g) as a pale yellow foam (0.1 g). MS (ESI-): 324,1 ([M-H]-).

Example 5. (2-Cyclopropylamino-4-yl)amide-biphenyl-4-sulfonic acid

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0.1 g) and biphenyl-sulphonylchloride (0.18 g) as a pale yellow foam (to 0.032 g). MS (ESI-): 350,2 ([M-H]-).

Example 6. (2-Cyclopropylamino-4-yl)amide, the quinoline-8-sulfonic acid

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0.1 g) and quinoline-8-sulphonylchloride (0.16 g) as a pale yellow foam (8 mg). MS (ESI): 325,1 ([M-H]-).

Example 7. N-(2-Cyclopropylamino-4-yl)benzosulfimide

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0.1 g) and benzosulfimide (0.125 g) as a pale yellow foam (36 mg). MS (ESI-): 274,0 ([M-H]-).

Example 8. N-(2-Cyclopropylamino-4-yl)-5-fluoro-2-methylbenzenesulfonamide

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0.1 g) and benzosulfimide (0,178 g) as a pale yellow foam (76 mg). MS (ESI): 306,2 ([M-H]-).

Example 9. N-(2-Cyclopropylamino-4-yl)-3-methoxybenzenesulfonamide

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0,13 g) and 3-methoxybenzenesulfonamide (0.2 g) as a white foam (108 mg). MS (ESI-): 304,1 ([M-H]-).

Example 10. N-(2-Cyclopropylamino-4-yl)-2-methoxy-5-methylbenzenesulfonamide

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0.15 g) and 2-methoxy-5-methylbenzenesulfonamide (0.3 g) in the form of light is lo brown solid (63 mg). MS (ESI-): 318,0 ([M-H]-).

Example 11. 3-Chloro-N-(2-cyclopropylamino-4-yl)-4-methoxybenzenesulfonamide

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0.15 g) and 3-chloro-4-methoxybenzenesulfonamide (0.32 g) as a pale brown solid (40 mg). MS (ESI): 340,1 (MN+).

Example 12. 5-Chloro-N-(2-cyclopropylamino-4-yl)-2-methoxybenzenesulfonamide

This product was obtained analogously to example 2, stage a and B, from 2-cyclopropylamino-4-ylamine (0.15 g) and 5-chloro-2-methoxybenzenesulfonamide (0.32 g) as a pale brown solid (15 mg). MS (ESI-): 338,1 ([M-H]-).

Example 13. 5-fluoro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide

Stage A. 2-Isopropylpyrimidine-4-ylamine

This compound was obtained analogously to example 2, stage And, of cyclopropanecarbonitrile hydrochloride (3 g) and 3-ethoxyacrylate (2.5 ml) to give 2-isopropylpyrimidine-4-ylamine (1,36 g) as a pale yellow foam. MS (ESI): 138,1 (MN+).

Stage B. 5-fluoro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide

This product was obtained analogously to example 1 from 2-isopropylpyrimidine-4-ylamine (0,13 g) and 5-fluoro-2-methylbenzenesulfonamide (0.32 g) as a pale yellow foam (72 mg). MS (ESI-): 308,1 ([M-H]-).

Example 14. 3,4-Dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide/p>

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0,23 g) and 3,4-dichlorobenzenesulfonate (0,41 g) as a pale yellow solid (295 mg). MS (ESI-): 343,9 ([M-H]-).

Example 15. N-(2-Isopropylpyrimidine-4-yl)-4-(1,3-oxazol-5-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0,174 g) and 4-(1,3-oxazol-5-yl)benzosulfimide (0.31 g) as a pale yellow foam (295 mg). MS (ESI-): 343,0 ([M-H]-).

Example 16. 2,4-Dichloro-N-(2-isopropylpyrimidine-4-yl)-6-methylbenzenesulfonamide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.15 g) and 2,4-dichloro-6-methylbenzenesulfonamide (0,284 g) as a pale yellow powder (87 mg). MS (ESI-): 358,0 ([M-H]-).

Example 17. 2,3-Dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.15 g) and 2,3-dichlorobenzenesulfonyl (0,268 g) as a pale yellow powder (110 mg). MS (ESI-): 343,9 ([M-H]-).

Example 18. (2-Isopropylpyrimidine-4-yl)amide 4,5-dichlorothiophene-2-sulfonic acid

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.15 g) and 4,5-dichlorothiophene-2-sulphonylchloride (0,275 g) as a pale yellow foam (28 mg). MS (ESI-): 350,0 ([M-H]-).

Example 19. (2-Isopropyl shall eremein-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.2 g) and 5-pyridin-2-althofen-2-sulphonylchloride (0,379 g) as a pale yellow foam (24 mg). MS (ESI-): 359,0 ([M-H]-).

Example 20. 3-Chloro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0,13 g) and 3-chloro-2-methylbenzenesulfonamide (0.2 g) as a pale yellow foam (72 mg). MS (ESI-): 324,1 ([M-H]-).

Example 21. N-(2-Isopropylpyrimidine-4-yl)-3-triftoratsetilatsetonom

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.2 g) and 3-triftormetilfullerenov (0,357 g) as a pale yellow foam (62 mg). MS (ESI-): 344,0 ([M-H]-).

Example 22. N-(2-Isopropylpyrimidine-4-yl)-2-triftoratsetilatsetonom

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.2 g) and 2-triftormetilfullerenov (0,357 g) as a pale yellow powder (60 mg). MS (ESI-): 344,1 ([M-H]-).

Example 23. (2-Isopropylpyrimidine-4-yl)amide 5-chlorothiophene-2-sulfonic acid

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.2 g) and 5-chlorothiophene-2-sulphonylchloride (0,316 g) as a pale yellow powder (49 mg). MS (ESI-): 316,0 ([M-H]-).

Example 24. N-(2-Isopropylpyrimidine-4-yl)-4-t is attorneyassigned

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.2 g) and 4-triftormetilfullerenov (0,357 g) as a light brown foam (211 mg). MS (ESI-): 344,1 ([M-H]-).

Example 25. (2-Isopropylpyrimidine-4-yl)amide piperidine-1-su Lanovoy acid

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0.2 g) and piperidine-1-sulphonylchloride (0,295 g) except that the condensation reaction was carried out at an elevated temperature of 105°C. the Desired product was obtained as a pale yellow foam (139 mg). MS (ESI-): 283,1 ([M-H]-).

Example 26. (2-Isopropylpyrimidine-4-yl)amide, naphthalen-2-sulfonic acid

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0,13 g) and naphthalen-2-sulphonylchloride (0,344 g) with the following modification: the pyridine was replaced with THF (5 ml) and potassium carbonate (0,144 g) was used as the base in this reaction, which was carried out at the boil under reflux for 24 hours. After cooling, the mixture was filtered, evaporated in vacuum and the product was isolated by rapid chromatography. The desired product was obtained as a yellow foam (53 mg). MS (ESI-): 326,2 ([M-H]-).

Example 27. (2-Isopropylpyrimidine-4-yl)amide-biphenyl-4-sulfonic acid

This product was obtained analogously to example 13 from 2-isopropylpyrimidine the-4-ylamine (0,13 g) and biphenyl-4-sulphonylchloride (0,383 g) with the following modification: pyridine substituted dioxane (5 ml) and potassium carbonate (0,144 g) was used as the base in this reaction, which was carried out at 90°C for 12 hours. After cooling, the mixture was filtered, evaporated in vacuum and the product was isolated by rapid chromatography. The desired product was obtained as a yellow foam (31 mg). MS (ESI-): 352,2 ([M-H]-).

Example 28. 2.5-Debtor-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0,13 g) and 2,5-differentialthreshold (0,322 g) with the following modification: the pyridine was replaced with THF (5 ml) and potassium carbonate (0,144 g) was used as the base in this reaction, which was carried out at the boil under reflux for 12 hours. After cooling, the mixture was filtered, evaporated in vacuum and the product was isolated by rapid chromatography. The desired product was obtained as a yellow foam (78 mg). MS (ESI-): 312,0 ([M-H]-).

Example 29. N-(2-Isopropylpyrimidine-4-yl)-3,4-dimethoxybenzenesulfonamide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (0,13 g) and 3,3-dimethoxybenzenesulfonamide (0,359 g) with the following modification: the pyridine was replaced with THF (5 ml) and potassium carbonate (0,144 g) was used as the base in this reaction, which was carried out at the boil under reflux for 12 hours. After cooling, the mixture was filtered, evaporated in vacuum and the product was isolated hasten the authorized chromatography. The desired product was obtained as a yellow foam (21 mg). MS (ESI-): 336,1 ([M-H]-).

Example 30. N-(2-tert-Butylpyridinium-4-yl)-3,4-dichlorobenzenesulfonate

Stage A. 2-tert-Butylpyridinium-4-ylamine

This product was obtained analogously to example 13, step A, from tert-BUTYLCARBAMATE hydrochloride (3.0 g) and 3-ethoxyacrylate (2.2 ml) as a yellow foam (2.28 g). MS (EI): 151,0 (M+), 136,0 ([M-CH3]+).

Stage B. N-(2-tert-Butylpyridinium-4-yl)-3,4-dichlorobenzenesulfonate

This product was obtained analogously to example 13, step B, from 2-tert-butylpyridinium-4-ylamine (0.15 g) and 3,3-dichlorobenzenesulfonate (0,244 g) as a white foam (0,134 g). MS (ESI-): 357,9 ([M-H]-).

Example 31. N-(2-tert-Butylpyridinium-4-yl)-5-fluoro-2-methylbenzenesulfonamide

This product was obtained analogously to example 30 from 2-tert-butylpyridinium-4-ylamine (0.15 g) and 5-fluoro-2-methylbenzenesulfonamide (0.21 g) as a light brown foam (118 mg). MS (ESI-): 322,2 ([M-H]-).

Example 32. (2-tert-Butylpyridinium-4-yl)amide, naphthalen-2-sulfonic acid

This product was obtained analogously to example 30 from 2-tert-butylpyridinium-4-ylamine (0.15 g) and naphthalen-2-sulphonylchloride (0,23 g) as a pale yellow foam (141 mg). MS (ESI-): 340,1 ([M-H]-).

Example 33. N-(2-tert-Butylpyridinium-4-yl)-2,5-diftorbenzofenonom

This product was obtained analogously to example 30 from 2-t is et-butylpyridinium-4-ylamine (0.15 g) and 2,5-differentialthreshold (0.21 g) as a light brown foam (156 mg). MS (ESI-): 326,2 ([M-H]-).

Example 34. N-(2-tert-Butylpyridinium-4-yl)-4-(1,3-oxazol-5-yl)benzosulfimide

This product was obtained analogously to example 30 from 2-tert-butylpyridinium-4-ylamine (0.2 g) and 4-(1,3-oxazol-5-yl)benzosulfimide (0,322 g) as a white foam (104 mg). MS (ESI-): 357,2 ([M-H]-).

Example 35. 3-Chloro-N-(2-ethylpyrimidine-4-yl)-2-methylbenzenesulfonamide

Stage A. 2-Ethylpyrimidine-4-ylamine

This intermediate compound was obtained respectively in example 2, step A, an alternative way of obtaining from hydrochloride of propionamide (1.45 g, obtained from propionitrile similar to the procedure described in articles Synth. Commun., 1982, 12 (13), SS. 989-993, and Tetrahedron Lett., 1990, 31 (14), SS-1972) and 2-chloroacrylonitrile (1,17 ml). 2-Ethylpyrimidine-4-ylamine was obtained as a pale brown solid (0,89 g).1H NMR (δ, DMSO-d6): of 7.96 (d, 1H), of 6.68 (br s, 2H), 6,21 (s, 1H), to 2.55 (q, 2H), of 1.18 (t, 3H).

Stage B. 3-Chloro-N-(2-ethylpyrimidine-4-yl)-2-methylbenzenesulfonamide

This compound was obtained respectively in example 2, step B, 2-ethylpyrimidine-4-ylamine (0.25 g) and 3-chloro-2-methylbenzenesulfonamide (0.55 g) as a colorless solid (86 mg). MS (ESI-): 310,0 ([M-H]-).

Example 36. 2,4-Dichloro-N-(2-ethylpyrimidine-4-yl)-6-methylbenzenesulfonamide

This product was obtained analogously to example 35 from 2-ethylpyrimidine-4-ylamine (0,19 g) and 2,4-dichloro-6-METI is benzosulfimide (0,48 g) as light brown solid (78 mg). MS (ESI): 346,0 (MN+).

Example 37. 4-Chloro-N-(2-ethylpyrimidine-4-yl)-2,5-dimethylbenzenesulfonamide

This product was obtained analogously to example 35 from 2-ethylpyrimidine-4-ylamine (0,19 g) and 4-chloro-2,5-dimethylbenzenesulfonamide (0,423 g) as light brown solid (59 mg). MS (ESI): to 326.1 (MN+).

Example 38. 3-Chloro-N-(2-cyclobutylmethyl-4-yl)-2-methylbenzenesulfonamide

Stage A. 2-Cyclobutylmethyl-4-ylamine

This intermediate compound was obtained respectively in example 2, step A, the method of the hydrochloride of cyclobutanecarboxylic (0.3 g, obtained from cyclobutanecarbonitrile similar to the procedure described in articles Synth. Commun., 1982, 12 (13), SS-993, and Tetrahedron Lett., 1990, 31 (14), SS-1972) and 3-ethoxyacrylate (0.3 g). 2-Cyclobutylmethyl-4-ylamine was obtained as a pale brown solid (0.26 g).1H NMR (δ, DMSO-d6): 7,98 (d, 1H), 6,66 (br s, 2H), 6,21 (s, 1H), 3,35-3-37 (m, 1H), 2.33-of 2.23 (m, 2H), 2,19-2,12 (m, 2H). 1,99-of 1.88 (m, 1H), 1,82-of 1.74 (m, 1H).

Stage B. 3-Chloro-N-(2-cyclobutylmethyl-4-yl)-2-methylbenzenesulfonamide

This compound was obtained respectively in example 2, step B, 2-cyclobutylmethyl-4-ylamine (0.15 g) and 3-chloro-2-methylbenzenesulfonamide (0.27 g) as a pale brown solid (47 mg). MS (ESI): 338,1 (MN+).

Example 39. (2-Cyclobutylmethyl-4-yl)amide, naphthalen-2-sulfonic acid

This product has received counterparts is but example 38 2-cyclobutylmethyl-4-ylamine (0,19 g) and naphthalen-2-sulphonylchloride (0.27 g) as an orange solid (53 mg). MS (ESI-): 338,3 ([M-H]-).

Example 40. (2-Cyclobutylmethyl-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid

This product was obtained analogously to example 38 2-cyclobutylmethyl-4-ylamine (0.25 g) and 5-pyridin-2-althofen-2-sulphonylchloride (0,47 g) as light brown solid (36 mg). MS (ESI): 373,1 (MN+).

Example 41. 2,4-Dichloro-N-(2-cyclobutylmethyl-4-yl)-6-methylbenzenesulfonamide

This product was obtained analogously to example 38 2-cyclobutylmethyl-4-ylamine (0,144 g) and 2,4-dichloro-6-methylbenzenesulfonamide (0.3 g) as a pale brown solid (36 mg). MS (ESI): 372,1 (MN+).

Example 42. 3,4-Dichloro-N-(2-ethoxymethyleneamino-4-yl)benzosulfimide

Stage A. 2-Ethoxymethyleneamino-4-ylamine

2-Ethoxymethyleneamino-4-ylamine (which was described earlier in the BE 641253, 1964, Ciba Ltd.) was obtained analogously to example 2, step A, an alternative method known hydrochloride 2-methoxyacetanilide (0.3 g, obtained from 2-methoxyacetanilide similar to the procedure described in articles Synth. Commun., 1982, 12 (13), SS-993, and Tetrahedron Lett., 1990, 31 (14), SS-1972), and 2-chloroacrylonitrile (0.2 ml). 2-Ethoxymethyleneamino-4-ylamine was obtained as a whitish solid (0.11 g).1H NMR (δ, CDCl3): by 8.22 (d, 1H), 6,32 (d, 1H), 4.98 (br s, 2H), 4,49 (s, 2H), 3,50 (s, 3H). MS (ESI): 140,3 (MH+).

Stage B. 3,4-Dichloro-N-(2-ethoxymethyleneamino-4-yl)be solarpanel

This compound was obtained analogously to example 2, step B, 2-ethoxymethyleneamino-4-ylamine (50 mg) and 3,4-dichlorobenzenesulfonate (111 mg) as a pale yellow solid (10 mg). MS (ESI): 348,3 (MN+).

Example 43. 3-Chloro-N-(2-cyclopropanecarbonitrile-4-yl)-

2-methylbenzenesulfonamide

Stage A. 2-Cyclopropanecarbonitrile-4-ylamine

Hydroxymethylpropane (0.17 g) was dissolved in THF (2 ml) was added a dispersion of sodium hydride at 0°C (55% in oil, 0.1 g). The mixture was stirred for 30 minutes and then was added dropwise a solution of 2-chloromethylpyridine-4-ylamine (0.2 g, EP 61318 A2, 1982; EP 60094 A2, 1982) in THF (7 ml). The resulting mixture was boiled under reflux for 2 hours, cooled and added to water. The mixture was extracted with ethyl acetate and the organic layers were combined, dried Na2SO4, was filtered and was evaporated. The residue was purified accelerated chromatography (ethyl acetate/methanol 9:1) to obtain 2-cyclopropanecarbonitrile-4-ylamine in the form of a colorless solid (54 mg).1H NMR (δ, l3): by 8.22 (d, 1H), 6,32 (d, 1H), to 4.98 (br s, 2H), 4,58 (s, 2H), 3.46 in (d, 2H), 1,21-1,12 (m, 1H), 0,59-of 0.53 (m, 2H), 0,27-0,24 (m, 2H). MS (ESI): 180,3 (MH+).

Stage B. 3-Chloro-N-(2-cyclopropanecarbonitrile-4-yl)-2-methylbenzenesulfonamide

This compound was obtained analogously to example 2, step B, 2-cyclopropylmethoxy pyrimidin-4-ylamine (54 mg) and 2-chloro-3-methylbenzenesulfonamide (81 mg) as a pale yellow solid (13 mg). MS (ESI): 368,0 (MN+).

Example 44. 3-Chloro-2-methyl-N-(2-morpholine-4-iletilerimde-4-yl)benzosulfimide

Stage A. 2-Morpholine-4-iletilerimde-4-ylamine

Using the technique described in the article in J. Chem. Soc. Perkin. Trans. I, 1996, s, 2-chloromethylpyridine-4-ylamine (0.35 g, EP 61318 A2, 1982; EP 60094 A2, 1982) was dissolved in ethanol (10 ml) was added triethylamine (0.51 ml) and morpholine (0,21 ml). The mixture was boiled under reflux for 48 hours and then cooled and evaporated in vacuum. The residue was dissolved in ethyl acetate and washed with 3N NaOH, saturated NaCl. The aqueous layer was then extracted 5 times with ethyl acetate and the combined organic layers were dried Na2SO4, was filtered and was evaporated. Express chromatography (ethyl acetate/methanol 8:2) yielded the desired product 2-morpholine-4-iletilerimde-4-ylamine in the form of a light brown solid (0,23 g).1H NMR (δ, DMSO-d6): to 7.99 (d, 1H), 6,79 (br s, 2H), 6,28 (d, 1H), 3,56-of 3.53 (m, 4H, to 3.36 (s, 2H), 2,46 is 2.43 (m, 4H). MS (ESI): 194,9 (MH+).

Stage B. 3-Chloro-2-methyl-N-(2-morpholine-4-iletilerimde-4-yl)benzosulfimide

This compound was obtained analogously to example 2, step B, 2-morpholine-4-iletilerimde-4-ylamine (230 mg) and 2-chloro-3-methylbenzenesulfonamide (319 mg) as a pale yellow solid (65 mg). MS (ESI): 383,1 (MN+).

Example 45. (2,6-Dimethylpyrimidin-4-yl)amide, naphthalen-2-sulfo the OIC acid

This product was obtained analogously to example 1 from 2,6-dimethylpyrimidin-4-ylamine (0.1 g, commercially available) and naphthalen-2-sulphonylchloride (0,185 g) as a white foam (119 mg). MS (ESI-): 312,0

([M-H]-).

Example 46. 3-Chloro-N-(2-cyclopropylamino-4-yl)-2-N-dimethylbenzenesulfonamide

3-Chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide (80 mg, example 2) was dissolved in DMF (2 ml) in an argon atmosphere at RT was added cesium carbonate (121 mg). After 20 minutes, was added dropwise methyliodide (46 mg, 0,02 ml) and the resulting mixture was stirred for 2 hours. The reaction mixture was poured into a mixture of ice/water, saturated NaCl, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium chloride, dried Na2SO4, was filtered and was evaporated. The residue was purified accelerated chromatography (gradient ethyl acetate in heptane) to give after drying in a vacuum - 3-chloro-N-(2-cyclopropylamino-4-yl)-2-N-dimethylbenzenesulfonamide as the main product (50 mg, colorless oil). MS (ESI): 338,1 (MN+).

As a by-product of this reaction was also provided 3-chloro-N-[2-cyclopropyl-3-methyl-3H-pyrimidine-(4E)-ilidene]-2-methylbenzenesulfonamide in the form of a white foam (11 mg). MS (ESI): 338,0 (MN+).

Example 47. 3,4-Dichloro-N-(2-isopropylpyrimidine-4-yl)-N-methylbenzenesulfonamide

This product recip is whether analogously to example 46 from 3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide (76 mg, example 14) by treatment with cesium carbonate (107 mg) and methyliodide (40 mg) in DMF (2 ml). 3,4-Dichloro-N-(2-isopropylpyrimidine-4-yl)-N-methylbenzenesulfonamide was obtained as a colourless oil (55 mg). MS (ESI): 360,1 (MN+).

Example 48. 3-Chloro-2-methyl-N-(2-phenylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 1 from 2-phenylpyrimidine-4-ylamine (134 mg, obtained as described in example 2, step A, in accordance with the methodology described in the article by Singh and since Joey was gone, J. Heterocyclic Chem., 1977, 14 (8), SS-1414) and 2-chloro-3-methylbenzenesulfonamide (194 mg) as a colourless solid (60 mg). MS (ESI): 360,3 (MN+).

Example 49. 3-Chloro-2-methyl-N-[2-(2-methylthiazole-4-yl)pyrimidine-4-yl]benzosulfimide

Stage A. 2-(2-Methylthiazole-4-yl)pyrimidine-4-ylamine

This product was received as described in example 2, step A, of the hydrochloride of 2-utiltity-4-carboxamidine (3 g) processing ethoxide sodium (3,13 ml of a 5.4 M solution) and 3-ethoxyacrylate (1.73 ml) to give 2-(2-utiltity-4-yl)pyrimidine-4-ylamine (2,56 g) as a brown solid. MS (ESI): 193.3 M. (MN+).

Stage B. 3-Chloro-2-methyl-N-[2-(2-methylthiazole-4-yl)pyrimidine-4-yl]benzosulfimide

This product was obtained analogously to example 1 from 2-(2-methylthiazole-4-yl)pyrimidine-4-ylamine (179 mg) and 2-chloro-3-methylbenzenesulfonamide (200 mg) as a pale yellow foam (54 mg). MS (ESI-): 379,0 ([M-H]-).

Example 50. 3-Chloro-N-(2-ethoxymethyleneamino-4-yl)-2-methylbenzenesulfonamide

This product was obtained analogously to example 42, step B, 2-ethoxymethyleneamino-4-ylamine (obtained in example 42, step a, 50 mg) and 3-chloro-2-methylbenzenesulfonamide (97 mg) as a pale yellow solid (11 mg). MS (ESI): 328,1 (MN+).

Example 51. (2,5,6-Trimethylpyridine-4-yl)amide, naphthalen-2-sulfonic acid

Stage A. 2,5,6-Trimethylpyridine-4-ylamine

4-Chloro-2,5,6-trimethylpyridine (143 g, CAS 34916-70-6, see Curd, R., J. Chem. Soc., 1946, 362, s) was treated with 100% NH3(900 g) at 100-150°C for 6 hours. The reaction mixture was cooled and evaporated. The residue was dissolved in water (200 ml) and was extracted with l3. The organic layer was separated and the aqueous layer was saturated

Na2CO3. The aqueous solution was extracted four times l3and the combined organic extracts were evaporated to obtain 30 g of residue. This residue was dissolved in ethyl acetate and precipitated with petroleum ether. The solid was filtered and dried to obtain 17 g of 2,5,6-trimethylpyridine-4-ylamine. tPL187°C.

Stage b (2,5,6-Trimethylpyridine-4-yl)amide, naphthalen-2-sulfonic acid

This product was obtained with low yield analogously to example 1 from 2,5,6-trimethylpyridine-4-ylamine (100 mg) and naphthalen-2-sulphonylchloride (165 mg) to obtain (2,5,6-trimethyl rimidine-4-yl)amide, naphthalen-2-sulfonic acid as a light brown foam (8 mg). MS (ESI-): 326,3 ((M-N)-).

Example 52. 4,5-Dichloro-2-fluoro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 4,5-dichloro-2-forbindelsesfaneblad (384 mg) as an orange powder (107 mg). MS (ESI-): 362,0 ((M-N)-).

Example 53. 2,4-Debtor-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 2,4-differentialthreshold (300 mg) as a yellow powder (68 mg). MS (ESI-): 312,0 ((M-N)-).

Example 54. 2-Chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 2-chlorobenzenesulfonamide (308 mg) as a pale yellow foam (127 mg). MS (ESI-): 310.0 ((M-N)-).

Example 55. 4-Chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 4-chlorobenzenesulfonamide (308 mg) as a pale yellow foam (127 mg). MS (ESI-): 310,0 ((M-N)-).

Example 56. 3-Chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 3-chlorobenzenesulfonamide (308 mg) as a pale yellow foam (175 mg). MS (ESI-): 310,0 ((M-N)-

Example 57. 2,4-Dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 2,4-dichlorobenzenesulfonyl (358 mg) as an orange powder (163 mg). MS (ESI-): 344,0 ((M-N)-).

Example 58. 2,4-Dichloro-N-(2-isopropylpyrimidine-4-yl)-5-methylbenzenesulfonamide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 2,4-dichloro-5-methylbenzenesulfonamide (378 mg) as an orange powder (194 mg). MS (ESI-): 358,0 ((M-N)-).

Example 59. 2,5-Dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 2,5-dichlorobenzenesulfonate (358 mg) as an orange powder (160 mg). MS (ESI-): 344,0 ((M-N)-).

Example 60. (2-Isopropylpyrimidine-4-yl)amide 3-bromo-5-chlorothiophene-2-sulfonic acid

This product was obtained with low yield analogously to example 13 from 2-isopropylpyrimidine-4-ylamine (200 mg) and 3-bromo-5-chlorothiophene-2-sulphonylchloride (431 mg) as an orange powder (12 mg). MS (ESI-): 393,8 ((M-N)-).

Example 61. 2,4-Dichloro-N-(2-cyclopropylamino-4-yl)-6-methylbenzenesulfonamide

This product was obtained analogously to example 2 from 2-cyclopropylamino-4-ylamine (190 mg) and 2,4-dichloro-6-methylbenzenesulfonamide (438 mg) in the form of a Saint is to brown solid (75 mg). MS (ESI): 358,1 (MN+).

Example 62. 4-Chloro-N-(2-cyclopropylamino-4-yl)-2,5-dimethylbenzenesulfonamide

This product was obtained analogously to example 2 from 2-cyclopropylamino-4-ylamine (190 mg) and 4-chloro-2,5-dimethylbenzenesulfonamide (403 mg) as a pale brown solid (73 mg). MS (ESI): 338,0 (MN+).

Example 63. N-(2-Cyclopropylamino-4-yl)-2,4-dimethoxybenzenesulfonamide

This product was obtained with low yield analogously to example 2 from 2-cyclopropylamino-4-ylamine (150 mg) and 2,4-dimethoxybenzenesulfonamide (315 mg) as a colourless solid (13 mg). MS (ESI-): 334,1 ((M-N)-).

Example 64. 3-Chloro-N-(2-cyclopentenopyridine-4-yl)-2-methylbenzenesulfonamide

Stage A. 2-Cyclopentenopyridine-4-ylamine

This product was obtained analogously to example 2, step A, an alternative way of obtaining from hydrochloride of cyclopentanecarboxaldehyde (CAS 68284-02-6) (500 mg) and 2-chloroacrylonitrile (324 mg) to obtain 2-cyclopentenopyridine-4-ylamine in the form of an amorphous transparent substances (142 mg). MS (ESI): 164,6 (MN+). This product was contaminated with some by-products that cannot be identified.

Stage B. 3-Chloro-N-(2-cyclopentenopyridine-4-yl)-2-methylbenzenesulfonamide

This product was obtained analogously to example 2, step B, 2-cyclopentenopyridine-4-ylamine (158 mg) and 3-chloro-2-methylbenzoyl is vanilloid (261 mg) as a pale brown solid (75 mg). MS (ESI): 352,4 (MN+).

Example 65. (2-Cyclopropylamino-4-yl)amide 5-phenylthiophene-2-sulfonic acid

This product was obtained analogously to example 2 from 2-cyclopropylamino-4-ylamine (100 mg) and 5-phenylthiophene-2-sulphonylchloride (203 mg, CAS 97272-02-1 received in accordance with the methodology described in article Sone and others, Bull. Chem. Soc. J., 1985, 58(3), s) as a colourless solid (33 mg). MS (ESI-): 356,3 ((M-N)-).

Example 66. 3-Chloro-N-(2-cyclopropylmethoxy-4-yl)-2-methylbenzenesulfonamide

Stage A. 2-Cyclopropylmethoxy-4-ylamine

Cyclopropylmethanol (724 mg) was dissolved in DMF (4 ml) and treated with sodium hydride (401 mg, 60% in mineral oil) at 0°C for 30 minutes. Then was added dropwise a solution of 4-amino-2-chloropyrimidine (260 mg, CAS 7461-50-9 or received in accordance with the methodology described in the article in J. Am. Chem. Soc., 1930, 52, SS-1157) in DMF (4 ml). The mixture was stirred at room temperature for 1 hour and then stirred at 50°C during the night. The mixture was poured into water and the mixture was saturated with NaCl. The aqueous solution was then extracted with ethyl acetate and the organic layer was washed with a saturated solution of sodium chloride, dried Na2SO4and was evaporated to dryness. The residue was purified accelerated by chromatography on silica gel using a gradient of ethyl acetate in heptane as eluent. The desired product floor is made in the form of a light yellow oil (169 mg). MS (EI): to 166.2 (M+N+).

Stage B. 3-Chloro-N-(2-cyclopropylmethoxy-4-yl)-2-methylbenzenesulfonamide

This product was obtained with a low yield analogously to example 1 from 2-cyclopropylmethoxy-4-ylamine (220 mg) and 3-chloro-2-methylbenzenesulfonamide (161 mg) to give the desired product as a pale yellow foam (14 mg). MS (ESI-): 352,1 ((M-N)-).

Example 67. 2-[(3,4-Dichlorobenzenesulfonyl)-(2-isopropylpyrimidine-4-yl)amino]-N,N-dimethylacetamide

3,4-Dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide (80 mg, example 14) was dissolved in DMF (1 ml) and treated with cesium carbonate (113 mg). To the mixture was added 2-chloro-N,N-dimethylacetamide (37 mg) and the resulting suspension was stirred at room temperature for 48 hours and then at 80°C for 24 hours. The mixture was diluted with ethyl acetate, washed with a saturated solution of sodium chloride, dried Na2SO4and was evaporated to dryness. The residue was purified accelerated by chromatography on silica gel using DHM/Meon/NH4OH 9:1:0.1 as eluent. The desired product was obtained as a colourless faded substances (28 mg). MS (ESI): that amount to 431,3 (MN+).

Example 68. N-Benzyl-3-chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide

This product was obtained analogously to example 67 3-chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide (120 mg, example 2)using the be pillored (61 mg) as the alkylating agent. The desired product was obtained as a colourless oil (74 mg). MS (EI): 414,1 (M+N+).

Example 69. 3-Chloro-N-cyclopropylmethyl-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide

This product was obtained analogously to example 67 3-chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide (120 mg, example 2)using bromelicola (65 mg) as an alkylating agent.

The desired product was obtained as a colourless oil (89 mg). MS (EI): 377 (M+), 378,3 (M+N+).

Example 70. 3-Chloro-2-methyl-N-(6-phenylpyrimidine-4-yl)benzosulfimide

This product was obtained analogously to example 1 from 6-phenylpyrimidine-4-ylamine (97 mg, CAS 3435-29-8) and 3-chloro-2-methylbenzenesulfonamide (128 mg) to give the desired product as a pale yellow foam (67 mg). MS (ESI-): 358,0 ((M-N)-).

Example

The compound of the formula I can be used in a known manner as an active ingredient to obtain tablets of the following composition:

Pills

The active ingredient200 mg
Microcrystalline cellulose155 mg
Corn starch25 mg
Talc25 the g
The hypromellose20 mg
-----
425 mg

Example B

The compound of the formula I can be used in a known manner as an active ingredient to obtain capsules of the following composition:

On capsule

The active ingredient100.0 mg
Corn starch20.0 mg
Lactose95,0 mg
Talc4.5 mg
Magnesium stearate0.5 mg
------
220,0 mg

1. The compounds of formula I:

where R1represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropylmethoxy, 2-methylthiazolyl, morpholinylmethyl or phenyl;
R2represents hydrogen, C1-4alkyl or phenyl;
R3represents the waters of the genus, With1-4alkyl or phenyl;
R4represents phenyl, naphthyl, thiophenyl, chinolin or piperidyl, where phenyl, naphthyl, thiophenyl, chinosol and piperidyl optionally substituted from one to three substituents, independently selected from C1-4of alkyl, halogen, C1-4alkoxy, cyano, trifloromethyl, phenyl, facil-C1-4of alkyl, phenyloxy, oxazolyl and pyridinyl;
R5represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6cycloalkyl-C1-4alkyl or aminocarbonyl1-4alkyl;
and their pharmaceutically acceptable salts and esters;
and N-(2,6-dimethyl-4-pyrimidinyl)benzosulfimide;
2-chloro-N-(2-methyl-4-pyrimidinyl)-p-toluensulfonate;
N-(2-(dimethylamino)-6-methyl-5-propyl-4-pyrimidinyl)benzosulfimide and
2,4,5-trichloro-N-(2,6-dimethyl-4-pyrimidinyl)benzosulfimide and
4-chloro-N-(2,6-dimethylpyrimidin-4-yl)-benzosulfimide excluded.

2. Compounds according to claim 1, where
R1represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropylmethoxy, 2-methylthiazolyl, morpholinylmethyl or phenyl;
R2represents hydrogen or C1-4alkyl;
R3represents hydrogen, C1-4alkyl;
R5represents hydrogen or C1-4alkyl.

3. Compounds according to claim 1, where R2represents bodoro is.

4. Compounds according to claim 1, where R2represents methyl.

5. Compounds according to claim 1, where R3represents hydrogen.

6. Compounds according to claim 1, where R5represents hydrogen.

7. Compounds according to claim 1, where R5represents methyl.

8. Compounds according to claim 1, where R4represents phenyl, naphthyl, thiophenyl, chinolin or piperidyl, where phenyl, naphthyl, thiophenyl, chinosol and piperidyl optionally substituted from one to three substituents, independently selected from C1-4of alkyl, halogen, C1-4alkoxy, trifloromethyl, phenyl, oxazolyl and pyridinyl.

9. Compounds according to claim 1, where R4represents phenyl, substituted with one to three substituents, independently selected from C1-4of alkyl, halogen, C1-4alkoxy, trifloromethyl, phenyl and oxazolyl.

10. Compounds according to claim 1, where R4represents phenyl, naphthyl, chinolin or piperidyl.

11. Compounds according to claim 1, where R4is thiophenyl, optionally substituted from one to three substituents, independently selected from C1-4of alkyl, halogen, C1-4alkoxy, cyano, trifloromethyl, phenyl, phenyl-C1-4of alkyl, phenyloxy, oxazolyl and pyridinyl.

12. Compounds according to claim 1, selected from the following compounds:
3-chloro-2-methyl-N-(2-methylpyrimidin-4-yl)benzosulfimide;
3-chloro-N-(2-cyclopropyl is kidin-4-yl)-2-methylbenzenesulfonamide;
N-(2-cyclopropylamino-4-yl)-2,5-diftorbenzofenonom;
(2-cyclopropylamino-4-yl)aminopterin-2-sulfonic acid;
(2-cyclopropylamino-4-yl)amitriptyl-4-sulfonic acid;
(2-cyclopropylamino-4-yl)ameghinoi-8-sulfonic acid;
N-(2-cyclopropylamino-4-yl)benzosulfimide;
N-(2-cyclopropylamino-4-yl)-5-fluoro-2-methylbenzenesulfonamide;
N-(2-cyclopropylamino-4-yl)-3-methoxybenzenesulfonamide;
N-(2-cyclopropylamino-4-yl)-2-methoxy-5-methylbenzenesulfonamide;
3-chloro-N-(2-cyclopropylamino-4-yl)-4-methoxybenzenesulfonamide;
5-chloro-N-(2-cyclopropylamino-4-yl)-2-methoxybenzenesulfonamide;
5-fluoro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide;
3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
N-(2-isopropylpyrimidine-4-yl)-4-(1,3-oxazol-5-yl)benzosulfimide;
2,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-6-methylbenzenesulfonamide;
2,3-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
(2-isopropylpyrimidine-4-yl)amide 4,5-dichlorothiophene-2-sulfonic acid;
(2-isopropylpyrimidine-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid;
3-chloro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide;
N-(2-isopropylpyrimidine-4-yl)-3-triftoratsetilatsetonom;
N-(2-isopropylpyrimidine-4-yl)-2-triftoratsetilatsetonom;
(2-isopropylpyridine-4-yl)and the ID 5-chlorothiophene-2-sulfonic acid;
N-(2-isopropylpyrimidine-4-yl)-4-triftoratsetilatsetonom;
(2-isopropylpyrimidine-4-yl)amide piperidine-1-sulfonic acid;
(2-isopropylpyrimidine-4-yl)amide, naphthalen-2-sulfonic acid;
(2-isopropylpyrimidine-4-yl)amide-biphenyl-4-sulfonic acid;
2.5-debtor-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
N-(2-isopropylpyrimidine-4-yl)-3,4-dimethoxybenzenesulfonamide;
N-(2-tert-butylpyridinium-4-IO)-3,4-dichlorobenzenesulfonate;
N-(2-tert-butylpyridinium-4-yl)-5-fluoro-2-methylbenzenesulfonamide;
(2-tert-butylpyridinium-4-yl)amide, naphthalen-2-sulfonic acid;
N-(2-tert-butylpyridinium-4-yl)-2,5-diftorbenzofenonom;
N-(2-tert-butylperoxide-4-yl)-4-(1,3-oxazol-5-yl)benzosulfimide;
3-chloro-N-(2-ethylpyrimidine-4-yl)-2-methylbenzenesulfonamide;
2,4-dichloro-N-(2-ethylpyrimidine-4-yl)-6-methylbenzenesulfonamide;
4-chloro-N-(2-ethylpyrimidine-4-yl)-2,5-dimethylbenzenesulfonamide;
3-chloro-N-(2-cyclobutylmethyl-4-yl)-2-methylbenzenesulfonamide;
(2-cyclobutylmethyl-4-yl)amide, naphthalen-2-sulfonic acid;
(2-cyclobutylmethyl-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid;
2,4-dichloro-N-(2-cyclobutylmethyl-4-yl)-6-methylbenzenesulfonamide;
3,4-dichloro-N-(2-ethoxymethyleneamino-4-yl)benzosulfimide;
3-chloro-N-(2-cyclopropanecarbonitrile-4-yl)-2-methylbenzenesulfonamide;
3-chloro-2-methyl-N-(2-morpholine-4-and methylpyrimidin-4-yl)benzosulfimide;
(2,6-dimethylpyrimidin-4-yl)amide, naphthalen-2-sulfonic acid;
3-chloro-N-(2-cyclopropylamino-4-yl)-2-N-dimethylbenzenesulfonamide;
3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-N-methylbenzenesulfonamide;
3-chloro-2-methyl-N-(2-phenylpyrimidine-4-yl)benzosulfimide and
3-chloro-2-methyl-N-[2-(2-methylthiazole-4-yl)-pyrimidine-4-yl]benzosulfimide.

13. Compounds according to claim 1, selected from the following compounds:
3-chloro-N-(2-ethoxymethyleneamino-4-yl)-2-methylbenzenesulfonamide;
(2,5,6-trimethylpyridine-4-yl)amide, naphthalen-2-sulfonic acid;
4,5-dichloro-2-fluoro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
2,4-debtor-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
2-chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
4-chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
3-chloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
2,4-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
2,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-5-methylbenzenesulfonamide;
2,5-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
(2-isopropylpyrimidine-4-yl)amide 3-bromo-5-chlorothiophene-2-sulfonic acid;
2,4-dichloro-N-(2-cyclopropylamino-4-yl)-6-methylbenzenesulfonamide;
4-chloro-N-(2-cyclopropylamino-4-yl)-2,5-dimethylbenzenesulfonamide;
N-(2-cyclopropylamino-4-yl)-2,4-dimethoxybenzenesulfonamide;
3-chloro-N-(2-cyclopentenopyridine-4-yl)-2-methylbenzoyl foamed;
(2-cyclopropylamino-4-yl)amide 5-phenylthiophene-2-sulfonic acid;
3-chloro-N-(2-cyclopropylmethoxy-4-yl)-2-methylbenzenesulfonamide;
2-[(3,4-dichlorobenzenesulfonyl)-(2-isopropylpyrimidine-4-yl)amino]-N,N-dimethylacetamide;
N-benzyl-3-chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide;
3-chloro-N-cyclopropylmethyl-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide and
3-chloro-2-methyl-N-(6-phenylpyrimidine-4-yl)benzosulfimide.

14. Compounds according to claim 1, selected from the following compounds:
3-chloro-2-methyl-N-(2-methylpyrimidin-4-yl)benzosulfimide;
3-chloro-N-(2-cyclopropylamino-4-yl)-2-methylbenzenesulfonamide;
N-(2-cyclopropylamino-4-yl)-2,5-diftorbenzofenonom;
(2-cyclopropylamino-4-yl)amide, naphthalen-2-sulfonic acid;
(2-cyclopropylamino-4-yl)amide-biphenyl-4-sulfonic acid;
5-fluoro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide;
3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
N-(2-isopropylpyrimidine-4-yl)-4-(1,3-oxazol-5-yl)benzosulfimide;
2,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-6-methylbenzenesulfonamide;
2,3-dichloro-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
(2-isopropylpyrimidine-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid;
3-chloro-N-(2-isopropylpyrimidine-4-yl)-2-methylbenzenesulfonamide;
N-(2-isopropylpyrimidine-4-yl)-3-trifluoromethyl shall enthaltene;
N-(2-isopropylpyrimidine-4-yl)-2-triftoratsetilatsetonom;
(2-isopropylpyrimidine-4-yl)amide 5-chlorothiophene-2-sulfonic acid;
N-(2-isopropylpyrimidine-4-yl)-4-triftoratsetilatsetonom;
(2-isopropylpyrimidine-4-yl)amide, naphthalen-2-sulfonic acid;
(2-isopropylpyrimidine-4-yl)amide-biphenyl-4-sulfonic acid;
2.5-debtor-N-(2-isopropylpyrimidine-4-yl)benzosulfimide;
N-(2-isopropylpyrimidine-4-yl)-3,4-dimethoxybenzenesulfonamide;
N-(2-tert-butylpyridinium-4-yl)-4-oxazol-5-albenzaalbenza;
3-chloro-N-(2-ethylpyrimidine-4-yl)-2-methylbenzenesulfonamide;
2,4-dichloro-N-(2-ethylpyrimidine-4-yl)-6-methylbenzenesulfonamide;
3-chloro-N-(2-cyclobutylmethyl-4-yl)-2-methylbenzenesulfonamide;
(2-cyclobutylmethyl-4-yl)amide, naphthalen-2-sulfonic acid;
(2-cyclobutylmethyl-4-yl)amide 5-pyridin-2-althofen-2-sulfonic acid;
2,4-dichloro-N-(2-cyclobutylmethyl-4-yl)-6-methylbenzenesulfonamide;
3-chloro-N-(2-cyclopropylamino-4-yl)-2-N-dimethylbenzenesulfonamide and
3,4-dichloro-N-(2-isopropylpyrimidine-4-yl)-N-methylbenzenesulfonamide.

15. Compounds according to any one of claims 1 to 14, with inhibitory activity against the enzyme beta-hydroxysteroiddehydrogenase 1 (11bSD1)intended for the treatment and prevention of diseases related to activity of the specified enzyme, such as diabetes, obesity, Soboleva the th associated with eating, dyslipidemia and hypertension.

16. Compounds according to any one of claims 1 to 14, intended for the manufacture of drugs that are suitable for the prevention and treatment of diseases that are caused by the violation associated with the enzyme beta-hydroxysteroiddehydrogenase 1 (11bHSD1).

17. Pharmaceutical composition having inhibitory activity against the enzyme beta-hydroxysteroiddehydrogenase 1 (11bHSD1), intended for the treatment or prevention of diseases associated with the activity of the specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension, comprising the compound according to any one of claims 1 to 14, or 4-chloro-N-(2,6-dimethylpyrimidin-4-yl)-benzosulfimide and a therapeutically inert carrier.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: chemistry; medicine.

SUBSTANCE: in novel triazole derivatives of general formula I or their pharmaceutically acceptable salts R4 is hydrogen; X is selected from group, consisting of single bond, NH- and groups: , values of R1-R3 radicals are given in description, pharmaceutical composition containing them, and application of novel compounds for obtaining medication for treating hyperglycemia, insulin-resistance, type 2 diabetes, fat exchange derangements, obesity, atheroslerosis and metabolic syndrome.

EFFECT: medications possess higher efficiency.

26 cl, 8 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compounds of formula (I), their obtaining and application as elastase inhibitors, and can be applied in medicine, where Y = CH; R№ represents H or alkyl; RІ represents phenyl or 5-6-memner heteroaryl, G1 represents phenyl; R5 represents H, halogen, alkyl, CN or fluorinated alkyl; n=1-3; R4 = H; L represents bond, O, NR29 or alkyl; or R4 and L are bound together in such way that group -NR4L- represents 5-7-member asacyclic ring; G2 represents phenyl, 5-6-member heteroaryl, cycloalkyl, C4-7-heterocycle, bicycle from two condensed, bound with direct bond or separated with O atom rings, selected from phenyl, 5-6-member heteroaryl, cycloalkyl or C4-7-heterocycle; or when L does not represent bond, G2 represents H; s = 0-2; R25 represents H, alkyl or cycloalkyl; R29 represents H or alkyl.

EFFECT: obtaining novel biologically active compounds.

10 cl, 95 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to benzothiazol derivatives of general formula (I) and to their pharmaceutically acceptable acid-additive salts as adenosine receptor ligands and to based medicinal agent. In general formula (I) , R1 represents 1,4-dioxepanyl or tetrahydropyran-4-yl; R2 represents -N(R)-(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with one-two substitutes chosen from group, consisting of C1-C6alkyl or -NR2, or represents -(CH2)n-5- or 6-merous nonaromatic heterocycle containing 1-2 heteroatoms chosen of N, S or O, optionally substituted with group -(CH2)n-OH, C1-C6alkyl, C1-C6alkoxy, or represents -(CH2)n-5-or 6-merous aromatic heterocycle containing 1-2 nitrogen heteroatoms optionally substituted with the following group: C1-C6alkyl, C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), -CH2N(R)(CH2)2OCH3, -N(R)(CH2)2OCH3, - CH2-morpholinyl or -CH2-pyrrolidinyl or represents (CH2)n-C3-C6cycloalkyl optionally substituted with group hydroxy, or represents -N(R)-C3-C6cycloalkyl optionally substituted with group hydroxy or C1-C6alkyl, or represents phenyl optionally substituted with group C1-C6alkoxy, halogen, halogen-(C1-C6alkyl), C1-C6alkyl, -CH2-pyrrolidine-1-yl, CH2N(R)(CH2)2OCH3 or -CH2-N(R)C(O)-(C1-C6alkyl), or represents 1,4-dioxa-8-azaspiro[4,5]decane, or 2-oxa-5-azabicyclo[2,2,1]heptane, or 1-oxa-8-azaspiro[4,5]decane, or -N(R)-7-oxabicyclo[2,2,1]hept-2-yl, or 2-azabicyclo[2,2,2]octane; R represents hydrogen or C1-C6alkyl; n stands for 0 or 1.

EFFECT: compounds can be applied for treatment and prevention of diseases mediated by adenosine A2A and A1 receptors, eg Alzheimer's disease, some depressions, toxicomania, Parkinson's disease.

8 cl, 3 dwg, 61 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: invention refers to new benzofuran and benzothiophen derivatives of general formula I, , wherein X is chosen from O and S; R1 is chosen from H, (C1-C6)alkyl, C(O)(C1-C6) alkyl and benzoyl; R2 is chosen from phenyl optionally substituted with 1 or 2 substitutes, each independently chosen from CN, NO2, (C1-C6)alkyl, (C1-C6)alkoxy, halogen, halogen(C1-C6)alkyl, pyridyl or benzo[1,3]dioxolyl optionally substituted with (C1-C6)alkyl. There are disclosed pharmaceutical composition based on compounds I and method of treatment.

EFFECT: compounds can be used to treat or prevent diseases associated with malignant cell proliferation.

26 cl, 7 tbl, 365 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I), their R and S isomers; or a mixture of R and S isomers; or pharmaceutically acceptable salts. Disclosed compounds can be used as a medicinal agent with agonist properties towards PPAR. In formula (I) and L represents (II) or (III); R1, R2, R3, Ya, R4a, R", Yb, R4b are hydrogen; R and R' are independently hydrogen, C1-C4alkoxy; n equals 0, 1 or 2; m equals 0, 1 or 2; X1 is a -Z-(CH2)P-Q-W group; X2 is -CH2-, -C(CH3)2-, -O- or -S-.

EFFECT: invention relates to a pharmaceutical composition, which contains the disclosed compound, to use of the pharmaceutical composition as a medicinal agent, to use of the disclosed compound in making the pharmaceutical composition.

13 cl, 35 ex

FIELD: chemistry.

SUBSTANCE: invention relates to inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), their enatiomers, racemates and pharmaceutically acceptable salts, as well as a pharmaceutical composition based on said inhibitors and method of treating, preventing or suppressing inflammation and other conditions which are mediated by activity of leukotriene A4-hydrolase. In general formula (II) , X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is O; Z is chosen from a group which consists of O and a bond; W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to the nitrogen atom which is bonded to the said W; R4 is chosen from a group which consists of H, OCH3 and Cl; R6 is H or F; and R2' and R3' are each independently chosen from a group which consists of: A) H, C1-7alkyl, C3-7cycloalkyl, C3-7cycloalkyl-C1-7alkyl, where each of substitutes (A) is independently substituted with 0 or 1 RQ, where each of said RQ is a carbon atom substitute, which is at least one carbon atom, separate from nitrogen atom; B) HetRa substitute; C) -C1-7alkyl-C(O)Rx; H) -C0-4alkyl-Ar5, where Ar5 is a 5-member heteroaryl, which has one heteroatom, chosen from a group >NRY, and 0 or 1 additional heteroatom -N=, and optionally contains two carbonyl groups, and optionally benzo-condensed; I) -C0-4alkyl-Ar5' , where Ar5' is a 5-member heteroaryl, which contains 3 or 4 nitrogen atoms; M) SO2C1-4alkyl; alternatively, R2' and R3', taken together with a nitrogen atom with which they are bonded, form a heterocyclic ring which contains at least one heteroatom, which is the said bonded nitrogen atom, where the said heterocyclic ring is chosen from a group which consists of i) 4-7-member heterocyclic ring HetRb, where the said 4-7-member heterocyclic ring HetRb has one heteroatom, which is the said bonded nitrogen atom, and is substituted with 0, 1 or 2 identical or different substitutes, where the said substitutes are chosen from a group which consists of -RY, -CN, -C(O)RY, -C0-4alkyl-CO2RY, -C0-4alkyl-C(O)CO2RY, -C0-4alkyl-ORY, -C0-4alkyl-C(O)NRYRZ-, -C0-4alkyl-NRYC(O)RZ-, -C(O)NRZORY, -C0-4alkyl-NRYCO2RY, -C0-4alkyl-NRYC(O)NRYRY, -C0-4alkyl-NRYC(S)NRYRZ, -NRYC(O)CO2RY, -C0-4alkyl-NRWSO2RY, 1,3-dihydrobenzoimidazol-2-on-1-yl, 1-RY-1H-tetrazol-5-yl, RY-triazolyl, 2-RY-2H-tetrazol- 5-yl, -C0-4alkyl-C(O)N(RY)(SO2RY), -C0-4alkyl-N(RY)(SO2)NRYRY, -C0-4alkyl-N(RY)(SO2)NRYCO2RY, halogen, , ,; ii) 5-7-member heterocyclic ring HetRC which has one additional heteroatom separated from the said bonded nitrogen atom by at least one carbon atom, where the said additional heteroatom is chosen from a group which consists of O, S(=O)2 and >NRM, where the said 5-7-member heterocyclic ring HetRC has 0 or 1 carbonyl group and is substituted with 0, 1 or 2 substitutes at identical or different substituted carbon atoms, where the said substitutes are chosen from a group which consists of -C(O)RY and RZ; iii) one of 1H-tetrazol-1-yl, where 1H-tetrazol-1-yl is substituted at the carbon atom by 0 or 1 substitute such as -C0-4alkyl-RZ, -C0-4alkyl-CO2RY; and iv) one of benzimidazol-1-yl, 2,8-diazospiro[4.5]decan-1-on-8-yl, 4-{[(2-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 4-{[(2-aminocyclobutanecarbonyl)amino]methyl}piperidin-1-yl, 9-yl-tert-butyl ether 3,9-diazaspiro[5.5]undecane-3-carboxylic acid, 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl, and where substitute HetRa is a 6-member heterocyclic ring, with a carbon atom at the bonding site and contains a >NRM group as a heteroatom, where the said heteroatom is separated from the said carbon atom at the bonding site with at least 1 additional carbon atom; Rk is chosen from a group which consists of H and -C1-4alkyl; RL is chosen from a group which consists of -CO2RS; RS is hydrogen; RM is chosen from a group which consists of RZ, -C(O)RY; RN is chosen from a group which consists of OCH3, CI, F, Br, I, OH, NH2, CN, CF3, CH3 and NO2; RQ is chosen from a group which consists of -CN, -C0-4alkyl-ORY, -C0-4alkyl-CO2RY, -C0-4alkyl-NRYRY, -C0-4alkyl-NRYCORY, -C0-4alkyl-NRYCONRYRZ, -C0-4alkyl-NRYSO2RY; RW is chosen from a group which consists of RY; RX is chosen from a group which consists of -ORY, -NRYRZ, -C1-4alkyl and -C1-4alkyl-RAr; RY is chosen from a group which consists of H, C1-4alkyl, -C0-4alkyl-RAr and -C0-4alkyl-RAr', each of which is substituted with 1 or 2 RN substitutes; RZ is chosen from a group which consists of RY, -C1-2alkyl-CO2RY ; RAr is a radical with a carbon atom at the bonding position, where the said radical is chosen from a group which consists of phenyl, pyridyl and pyrazinyl, where each carbon atom with permissible valence in each of the said groups is independently substituted with at least 0, 1 or 2 RN or 0 or 1 RL; RAr' is a 5-6-member ring which has 1 or 2 heteroatoms, chosen from a group which consists of O, S, N and >NRY, and has 0 or 2 unsaturated bonds and 0 or 1 carbonyl group, where each member with permissible valence in each of the said rings is independently substituted with 0 or 1 or 2 RK; Description is given of inhibitors of leukotriene A4-hydrolase (LTA4H) of formula (II), a composition which contains these inhibitions, and their use for inhibiting activity of the LTA4H enzyme, as well as for treating, preventing or suppressing inflammation and/or conditions which are associated with such inflammation. In the said formula (I): X is chosen from a group which consists of NR5, O and S, where R5 is one of H and CH3; Y is chosen from a group which consists of CH2 and O, W is chosen from a group which consists of CH2 and CHR1-CH2, where R1 is H or OH, and where the carbon group bonded to R1 in the said CHR1-CH2 is not directly bonded to a nitrogen atom; R4 is chosen from a group which consist of H, OCH3, CI, F, Br, OH, NH2, CN, CF3 and CH3; R6 is H or F; and R2 and R3 are each independently chosen from different groups.

EFFECT: new compounds have useful biological activity.

43 cl, 8 tbl, 12 dwg, 484 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (ZP) , in which U is a CH group, V is an oxygen atom, W is a hydroxyl-substituted heterocycloalkylene group which contains 5 to 7 atoms in the ring, including an N atom as a heteroatom, X is an oxygen atom, Y is , Z is C1-C6-alkylene group. Invention also relates to use of invented compounds to produce compounds of formula (I) , in which A is a nitrogen atom or CH group.

EFFECT: wider field of use of compounds.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted 2-[2-(3-oxomorpholin-4-yl)ethylthio]benzimidazoles of general formula: , where R1, R2, R3, R4, R5 are identical or different: H, lower alkyls or alkoxy groups.

EFFECT: obtaining new compounds with anxiolytic properties, which allows for their potential use in medicine for treating neuropsychic disorders.

2 cl, 4 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns compounds of the formula and other compounds listed in cl. 1 of invention claim, and pharmaceutical composition based on them, as well as method of mGluR5 receptor activity inhibition involving claimed compounds.

EFFECT: application in treatment and prevention of diseases mediated by mGluR5 receptor activity.

4 cl, 18 dwg, 1009 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns indazol derivatives of general formulae (I) or (II) , where radicals and groups are defined as shown in cl. 1 of invention claim, and their pharmaceutically acceptable salts. Also invention claims medicine, method of medicine obtainment and application of claimed compounds in treatment and/or prevention of fatty acid metabolism derangement and glucose assimilation disorders.

EFFECT: inhibition of hormone-sensitive lipases.

13 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds with general formula I, in which R1 represents hydrogen or a group, which forms a biologically labile ester, R2 represents hydrogen, C1-C4-alkyl or C1-C4-hydroxyalkyl, and R3 represents C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkyl; C1-C4-hydroxyalkyl, which is optionally substituted with a second hydroxy group and all hydroxy groups of which are optionally esterified with C2-C4-alkanoyl or amino-acid residue; (C0-C4-alkyl)2amino-C1-C6-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; phenyl-C1-C4-alkyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen; naphthyl-C1-C4-alkyl; C3-C6-oxoalkyl; phenylcarbonylmethyl, the phenyl group of which is optionally substituted 1-2 times with C1-C4-alkyl, C1-C4-alkoxy group and/or halogen, or 2-oxoazepanyl, or R2 and R3 together represent C4-C7-alkylene, methylene groups of which are optionally substituted 1-2 times with carbonyl, nitrogen, oxygen and/or sulphur and/or optionally substituted once with a hydroxy group, which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; C1-C4-alkyl; C1-C4-hydroxyalkyl, the hydroxy group of which is optionally esterified with C2-C4-alkanoyl or amino-acid residue; phenyl or benzyl, and R4 represents hydrogen or a group, which forms a biologically labile ester, where R1 and R4 groups are independently chosen from C1-C4-alkyl; C1-C4-alkoxy-C1-C4-alkoxy-C1-C4-alkyl; C3-C7-cycloalkyl; C3-C7-cycloalkyl-C1-C4-alkyl; N,N-di-(C0-C4-alkyl)amino-C1-C6-alkyl; phenyl or phenyl-C1-C4-alkyl, optionally substituted 1 or 2 times in the phenyl ring with halogen, C1-C4-alkyl or C1-C4-alkoxy group or C1-C4-alkylene chain, bonded with two neighbouring carbon atoms; dioxolanylmethyl, optionally substituted in the dioxolane ring with C1-C4-alkyl; C1-C6-alkanoyloxy-C1-C4-alkyl, optionally substituted in the oxy-C1-C4-alkyl group with C1-C4-alkyl; 1-[[(C1-C4-alkyl)carbonyl]oxy]C1-C4-alkyl esters; 1-[[(C4-C7 cycloalkyloxy)carbonyl]oxy]C1-C4-alkyl esters, 2-oxo-1,3-dioxolan-4-yl-C1-C4-alkyl esters, which optionally contain a double bond in the dioxolane ring; 2-oxo-1,3-dioxolan-4-ylmethyl; and to physiologically compatible salts of acids with formula I and/or to physiologically compatible acid-additive salts of formula I compounds. The invention also relates to a pharmaceutical composition, to use of formula I compounds in paragraph 1, to a method of obtaining formula I compounds, as well as to compounds with general formula II.

EFFECT: obtaining new biologically active compounds, with inhibitory activity towards neutral endopeptidase, endothelin converting enzyme and soluble human endopeptidase.

20 cl, 80 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: described are derivatives of 1,3,4-oxadiazol-2-on of formula (I) , where ARYL represents phenyl; Z represents -O(CH2)n- and n represents independent integer number from 1 to 5; X represents S; R1 represents C1-6alkyl; R2 represents phenyl, substituted with C1-6perfluoralkyl; or its pharmaceutically acceptable salt; based on it pharmaceutical composition; and method of disease treatment, where disease can be modulated by activity of PPAR-delta binding.

EFFECT: obtaining compounds which possess agonistic or antagonistic activity.

7 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

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