Pyrazolopyridine derivatives as kinase 1β-adrenergic receptor inhibitors

FIELD: chemistry.

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

EFFECT: more effective use of the compounds.

11 cl, 2 tbl

 

The sympathetic nervous system, which is a critical regulator of cardiac function, involved in the situation of occurrence of heart failure in response to stress or damage. In response to stress catecholamines (i.e. sympathetic neurotransmitter norepinephrine, and the adrenal hormone epinephrine) contact adrenergic receptors (AR) of the myocardium. These receptors, which include β1 and β2 AR, modulate cardiac function by binding to G proteins and their activation and, thus, belong to a large superfamily binding protein G receptors (GPCR). Agonist binding to the βAR, causes a conformational change in the receptor. This conformational change allows βAR to interact with the associated with membrane G-protein. As a result of interaction occurs separation of heterotrimeric G-protein into two components, namely Gα subunit and Gβγ. One of these two subunits can modulate cytosolic effector proteins, which, in turn, can regulate the production of intracellular molecules messengers. If activated by the catecholamine myocardial βAR-specific G-protein, Gs, stimulates adenylyl-cyclase to produce cAMP inside the cell, which increases chronotropy and inotropy heart (Petrofski and Koch, J. Mol. Cell. Cardiol. 2003, 35, 1167-1174).

Homologous desens the activities are geared to mobilizing βAR occurs with family serine/threonine kinases, known as kinase-binding G-protein receptor (GRK). Currently identified seven members of the GRK family. Two (GRK1 or rhodopsin kinase and GRK7) localized predominantly in the retina, while the remaining five (GRK2-7) unpredictable expressed in various tissues, including the heart. GRK have tredomen with the Central catalytic domain flanked by amino-terminal (NT) and carboxy-terminal (CT) domains, which contain specific regulatory sites (Laccarino and Koch, Assay and Drug Develop. Technol. 2003, 1(2), 347-355). The interaction between Gβγ subunit and ARTICLE cytosolic GRK has the result of moving GRK to the membrane, where it can fosforilirovanii the activated receptor. The binding of Gβγ is approximately the area length of 100 amino acids, which is part of plastikowego homology (PH) domain, found in ARTICLE GRK2. Desensitization despite the continuous presence of agonist called homologous desensitization and requires not only GRK, but also additional protein β-arrestin. β-Arrestin sterically hinder Gs-linking with a related catecholamine βAR (Petrofski and Koch, J. Mol. Cell. Cardiol. 2003, 35, 1167-1174).

Desensitization may be an adaptive response to GPCR stimulation, but can also lead to pathological loss of signaling by the receptor. It is important, is that in heart failure in humans, chronic activation of the sympathetic nervous system has harmful effects and may precipitate cardiac pathology. Constant stimulation of adrenergic receptors by catecholamines leads to selective down-regulation of β1AR (Bristow et al., New Engl. J. Med. 1982, 307 (4), 205-211). At the final stage of heart failure in humans mRNA and protein GRK2 and their activity increased approximately threefold, and this causes dysfunctional βAR signaling and loss of inotropic reserve of the patient's heart (Ungerer et al., Circulation 1993, 87, 454-463). Moreover, myocardial ischemia and hypertension, two important causes of heart failure, also correlated with elevated levels of GRK2 (Petrofski and Koch, J. Mol. Cell. Cardiol. 2003, 35, 1167-1174).

Rockman et al. (Nature 2002, 415, 206-212) showed that GRK2 plays an important role in the pathophysiology of heart failure. Targeted inhibition of GRK2, therefore, is a therapeutic approach to the treatment of heart failure.

In addition to chronic heart failure, GRK2 inhibitors may be useful in the treatment of hypertension, because increased GRK2 levels have been demonstrated in peripheral blood lymphocytes in the subgroup of patients hypertensive patients with impaired mediated β2AR by vasodilatation. Because regulation of β1AR in lymphocytes similar to that observed in cells of vascular smooth muscle in hypertensive patients, confirmed that the up-regulation of GRK2 observed in these cells, underlies the weakening mediated β2AR vasodilatative surveyed hypertensives (Gros R, et al., J. Clin. Invest. 1997, 99, 2087-2093).

Inhibitors of GRK2 can be also applicable in the treatment of myocardial ischemia, as elevated levels of GRK2 could be demonstrated in the cardiac muscle of rats deprived of oxygen for extended periods of time, and the specified up-regulation coincides with decreasing responsiveness to β-adrenergic receptor-stimulated cyclase activity (Ungerer et al., Circ. Res. 1996, 79, 455-460).

Information about the fact that elevated levels of GRK2 could be detected in the locus coerulus rats after treatment of chronic diseases morphine, confirm that inhibitors of GRK2 can be used to prevent dependence on the opiate. Increased activity of GRK2 can compensate hyperstimulation opioid receptors of the Central nervous system, and to contribute to the problem of opiate tolerance (Terwilliger et al., J. Neurochem 1994, 63, 1983-1986).

WO 2003054228 (Axxima Pharmaceuticals AG) discloses that GRK2 (along with other protein kinases, metalloprotease and phosphatase) is a potential target for medical intervention against infections of hepatitis C virus (HCV).

The term "kinase 2 binds G-protein receptor (GRK2)and kinase 1 β-adrenergic receptor (βARK-1)" are used as synonyms.

WO 2004/076450 describes substituted 6-heterocyclyl or phenyl derivatives pyrazolidine, CA is accepting as inhibitors of p38 kinase.

WO 03/068773 describes applicable for a variety of indications as inhibitors of GSK-3 derivatives pyrazolidine, where the position of the 6 optionally substituted C3-C8)cycloalkyl, heterocyclyl, heteroaryl or aryl.

WO 03/045949 describes as inhibitors of GSK-3 derivatives pyrazolidine, where the 6 position is unsubstituted.

WO 95/34563 and EP 1149583 describe in General the derivatives of pyrazolidine applicable as CRF antagonists, where the position 6 is substituted by (C1-C4) alkyl, fluorine, chlorine, bromine, iodine, -CH2OH, -CH2OCH3, -O(C1-C3)alkyl, -S(C1-C3)alkyl or-SO2(C1-C3)alkyl.

This invention relates to compounds of formula (I)

where

R1represents H or (C1-C6)alkyl, where (C1-C6)altergroup is unsubstituted or substituted by one or more groups, halogen or NH2; and

R2represents phenyl, (C3-C10)cycloalkyl or (C4-C10)heterocyclyl, which are unsubstituted or substituted by 1, 2 or 3 residues independently selected from such as:

1. (C1-C6)alkyl,

2. (C2-C6)alkenyl,

3. (C2-C6)quinil,

4. (C1-C6)alkylene-COOH,

5. (C1-C6)alkylen-C(O)O-(C 1-C6)alkyl,

6. (C1-C6)alkylen-C(O)NH2,

7. (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl,

8. (C1-C6)alkylen-O-(C1-C6)alkyl,

9. (C1-C6)alkylene-OH,

10. (C1-C6)alkylene-NH2,

11. (C1-C6)alkylene-NH-(C1-C6)alkyl,

12. (C1-C6)alkylene-N[(C1-C6)alkyl]2,

13. CN,

14. COOH,

15. C(O)O-(C1-C6)alkyl,

16. C(O)NH2,

17. C(O)NH-(C1-C6)alkyl,

18. C(O)N[(C1-C6)alkyl]2,

19. C(O)-(C1-C6)alkyl,

20. halogen,

21. NH2,

22. NH(C1-C6)alkyl,

23. N[(C1-C6)alkyl]2,

24. NH-C(O)-(C1-C6)alkyl,

25. OH,

26. O-(C1-C6)alkyl,

27. O-(C2-C6)alkenyl,

28. O-(C2-C6)quinil,

29. O-(C1-C6)alkylen-C(O)OH,

30. O-(C1-C6)alkylen-C(O)O-(C1-C6)alkyl,

31. O-(C1-C6)alkylen-C(O)NH2,

32. O-(C1-C6)alkylen-C(O)NH-(C1-C6)alkyl,

33. O-(C1-C6)alkylene-OH,

34. O-(C1-C6)alkylen-O-(C1-C6)alkyl,

35. O-(C1-C6)alkylene-NH2,

36. O-(C1-C6)alkylene-NH-(C1-C6)alkyl,

37. O-C(O)-(C1-C6)alkyl,

38. S-(C1-C6)alkyl,

39. S(O)2-(Csub> 1-C4)alkyl,

40. (C6-C10)aryl,

41. (C4-C10)heterocyclyl,

42. (C1-C6)alkylene-(C6-C10)aryl,

43. (C1-C6)alkylene-(C4-C10)heterocyclyl,

44. (C1-C6)alkylen-O-(C6-C10)aryl,

45. (C1-C6)alkylen-O-(C4-C10)heterocyclyl,

46. O-(C6-C10)aryl,

47. O-(C4-C10)heterocyclyl,

48. O-(C1-C6)alkylene-(C6-C10)aryl,

49. O-(C1-C6)alkylene-(C4-C10)heterocyclyl,

where the group (C6-C10)aryl and (C4-C10)heterocyclyl in the residuals 40.-49. are unsubstituted or substituted by 1, 2 or 3 residues independently selected from OH, halogen, NH2, O-(C1-C6)alkyl, (C1-C6)alkyl, S(O)2-(C1-C4)alkyl or (C3-C10)cycloalkyl;

and/or vicinal substituted by a residue of the formula-O-(CH2)n-O-, where n is 1, 2 or 3 and where one or more hydrogen atoms may be substituted by halogen atoms; and

R3is H; (C1-C6)alkyl or O-(C1-C6)alkyl, where (C1-C6)altergroup is unsubstituted or substituted by OH, halogen, NH2, NH(C1-C6)alkyl or-N[(C1-C6)alkyl]2; or

(C3-C10)cycloalkyl, DG is (C 3-C10)cycloalkyl is unsubstituted or substituted by one or more fluorine atoms;

or their physiologically acceptable salts.

Terms (C1-C4)alkyl, (C1-C6)alkyl or (C1-C6)alkylen should be understood as a hydrocarbon residue, which may be linear, i.e. straight-chain or branched and has 1, 2, 3, or 4, or 1, 2, 3, 4, 5 or 6 carbon atoms, respectively. This also applies if altergroup is present as a Deputy to another group, for example in alkoxygroup (O-alkyl), tighrope (S-alkyl) or-O(CH2)n-O-, alkoxycarbonyl or arylalkyl. Examples of altergroup are methyl, ethyl, propyl, butyl, pentyl or hexyl, n-isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert-pentyl. Accelgroup, unless otherwise specified, may contain one or more halogen atoms as substituents, such as altergroup can be fluorinated, for example perfluorinated. Examples of halogenated altergroup are CF3and CH2CF3, OCF3S-CF3, -O-(CF2)2-O-.

Alkenylamine are, for example, vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-METI the-2-butenyl, 5-hexenyl or 1,3-pentadienyl.

Akinyemi are, for example, ethinyl, 1-PROPYNYL, 2-PROPYNYL (=propargyl) or 2-butynyl.

(C3-C10)cycloalkylcarbonyl are cyclic altergroup containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in the ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl, which can also be substituted and/or unsaturated. Unsaturated cyclic accelgroup and unsaturated cycloalkyl groups, such as, for example, tetrahydronaphthyl, cyclopentenyl or cyclohexenyl can be connected through any carbon atom. Used herein, the term alkyl also includes cycloalkyl-substituted accelgroup, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl-, 1-cyclopropylethyl-, 1-cyclobutylmethyl-, 1-cyclopentylmethyl-, 2-cyclopropylethyl-, 2-cyclobutylmethyl-, 2-cyclopentylmethyl-, 3-cyclopropylmethyl-, 3-cyclobutylmethyl -, etc. in the specified group a subgroup of cycloalkyl and acyclic sub-group can be unsaturated and/or substituted. Of course, cyclic altergroup must contain at least three carbon atoms, and unsaturated altergroup must contain at least two carbon atoms. Thus, the group, such as (C1-C4)-alkyl, should be regarded as containing, among others, formulated the initial acyclic (C 1-C4)-alkyl, (C3-C4-cycloalkyl, cyclopropyl-methyl.

(C6-C10)allgraph means an aromatic ring or ring system that contains two aromatic rings are condensed, or otherwise associated, for example phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha - or beta-tetralone, indanyl or indan-1-he-yl group. Phenyl is the preferred (C6-C10)arrgroups.

(C4-C10)heterocyclyl means 4-10-membered mono - or bicyclic ring system which contains, besides carbon one or more heteroatoms, such as, for example, 1, 2, 3 or 4 nitrogen atom, 1 or 2 oxygen atoms, 1 or 2 sulfur atom, or a combination of various heteroatoms. For example, C6-heterocyclyl may contain 5 carbon atoms and 1 nitrogen atom, as in the case of pyridyl or piperidinyl. Heterocyclyl-residues can be attached at any position, such as position 1, position 2, position 3, position 4, position 5, position 6, position 7 or position 8. Heterocyclyl contains (1) aromatic (C5-C10)heterocyclyl group [(C5-C10)heteroaryl], or (2) saturated (C4-C10)heterocyclyl, or (3) mixed aromatic/saturated condensed (C8-C10)heterocyclyl is.

(C5-C10)heteroaryl preferred as a (C4-C10)heterocyclyl.

Suitable (C4-C10)heterocyclyl includes acridines, azetidin, benzimidazolyl, benzofuran, benzomorphans, benzothiazyl, benzothiophene, benzoxazole, benzthiazole, benzotriazolyl, asterisell, benzisoxazole, benzisothiazole, carbazolyl, 4aH-carbazolyl, carbolines, furanyl, hintline, chinoline, 4H-hemolysins, honokalani, hinokitiol, bromanil, bromanil, cinnoline, decahydroquinoline, 2H,6H-1,5,2-detainer, dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furutani, homomorpholine, homopiperazine, imidazolidinyl, imidazolyl, imidazolyl, 1H-indazole, indoline, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isopropanol, isoindolyl, isoindolines, isoindolyl, ethenolysis (benzimidazolyl), isothiazolin, isoxazolyl, morpholinyl, naphthyridine, octahydronaphthalene, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridines, phenanthrolines, phenazines, phenothiazines, phenoxathiin, phenoxazines, phthalazine, piperazinil, piperidinyl, prolinol, pteridinyl, purinol, pyranyl, pyrazinyl, pyrazolidine, pyrazoline, pyrazolyl, pyridazinyl, pyridinyl, paradoxicaly, pericom gasoli, peridotite, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinoline, tetrahydroquinoline, 6H-1,2,5-thiadiazine, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xantinol. Pyridyl includes 2-, 3 - and 4-pyridyl. Thienyl includes 2 - and 3-thienyl. Furyl includes 2 - and 3-furyl. Also included are the corresponding N-oxides of these compounds, for example 1-hydroxy-2-, 3 - or 4-pyridyl.

Substitution in residue (C4-C10)heterocyclyl can be free of the carbon atoms or nitrogen atoms.

Preferred examples of (C4-C10)heterocyclyl residues are 2 - or 3-thienyl, 2 or 3-furyl, 1-, 2 - or 3-pyrrolyl, 1-, 2-, 4 - or 5-imidazolyl, 1-, 3-, 4 - or 5-pyrazolyl, 1,2,3-triazole-1-, -4-or-5-yl, 1,2,4-triazole-1-, -3 or-5-yl, 1 - or 5-tetrazolyl, 2-, 4 - or 5-oxazolyl, 3-, 4 - or 5-isoxazolyl, 1,2,3-oxadiazol-4 or-5-yl, 1,2,4-oxadiazol-3 or-5-yl, 1,3,4-oxadiazol-2-yl or-5-yl, 2-, 4 - or 5-thiazolyl, 3-, 4 - or 5-isothiazole, 1,3,4-thiadiazole-2 or-5-yl, 1,2,4-thiadiazole-3-or-5-yl, 1,2,3-thiadiazole-4-or-5-yl, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, 3 - or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6 - or 7-indolyl, 1-, 2-, 4 - or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6 - or 7-indazole, 2-, 3-, 4-, 5-, 6-, 7- or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7 - or 8-ethanolic, 2-, 4-, 5-, 6-, 7 - or 8-hintline, 3-, 4-, 5, 6-, 7 - or 8-indolinyl, 2-, 3-, 5-, 6-, 7 - or 8-honokalani, 1-, 4-, 5-, 6-, 7 - or 8-phthalazine. Also included are the corresponding N-oxides, for example 1-hydroxy-2-, -3 or-4-pyridyl. Especially preferred (C4-C10)heterocyclyl-residues are 2 - or 3-furyl, 2 - or 3-pyrrolyl, 3-, 4 - or 5-pyrazolyl and 2-, 3 - or 4-pyridyl.

In monosubstituted phenylpropan Deputy may be in position 2, position 3 or position 4, the preferred position 3 and position 4. If panelgroup shall be two Deputy, they may be in positions 2,3, the provisions of 2.4, the provisions of 2.5, the provisions of 2.6, the provisions of 3.4 or the provisions of 3.5. In phenylpropan carrying three Deputy, deputies may be in positions 2,3,4, clauses 2,3,5, the provisions 2,3,6, the provisions of 2,4,5, regulations or 2,4,6 positions 3,4,5.

The allegations related to phenylpropan, respectively applied to the divalent groups formed from panelgroup, i.e. phenylene, which may be unsubstituted or substituted, 1,2-phenylene, 1,3-phenylene or 1,4-phenylene. These assertions are also respectively applied to the sub-group of the aryl in arylalkylamine. Examples of arylalkylamine, which can also be unsubstituted or substituted in the subgroup aryl, as well as in the subgroup of alkylen, are benzyl, 1-phenylethylene, 2-phenylethylene, 3-phenylpropyl, 4-phenylbutyl, 1-IU the Il-3-phenyl-propylene.

“Halogen” means fluorine, chlorine, bromine or iodine.

Picture of replacement of pyrazolidine numbered according to the IUPAC rules:

The preferred embodiment of the present invention is a compound of formula (I), where:

R1and R3have the above meanings; and

R2represents phenyl or (C4-C10)heterocyclyl, which are unsubstituted or substituted as defined above.

Additional preferred embodiment of the present invention is a compound of formula (I), where:

R1represents H;

R2represents phenyl or (C4-C10)heterocyclyl, which are unsubstituted or substituted as defined above; and

R3is H; (C1-C6)alkyl, which is unsubstituted or substituted by OH, halogen, NH2, NH(C1-C6)alkyl or-N[(C1-C6)alkyl]2; or (C3-C10)cycloalkyl, which is unsubstituted or substituted by one or more fluorine atoms;

or its physiologically acceptable salt.

Additional preferred embodiment of the present invention is a compound of formula (I), where:

R1represents H;

R2represents phenyl or (C4-C10)Goethe is accelgroup, which are unsubstituted or substituted as defined above; and

R3represents H;

or its physiologically acceptable salt.

Additional preferred embodiment of the present invention is a compound of formula (I), where:

R1represents H;

R2represents phenyl or (C5-C10)heteroaryl, which are unsubstituted or substituted as defined above; and

R3represents H;

or its physiologically acceptable salt.

Additional preferred embodiment of the present invention is a compound of formula (I), where:

R1is N;

R2is (C5-C10)heteroaryl, which is unsubstituted or substituted as defined above; and

R3is N;

or its physiologically acceptable salt.

Preferred (C5-C10)heteroarylboronic as group R2are benzofuranyl, indolyl, furanyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidyl, chinoline, thienyl, tetrazolyl, triazolyl, morpholine, pyrrolidine, piperazinil and piperidinyl. Particularly preferred benzofuranyl, indolyl, furanyl, pyridyl, pyrrolyl and pyrazolyl.

More preferably, when R2presents (C5-C10)heteroa the sludge of the formula (II):

where:

X represents N-R4or O,

R4is H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)quinil, (C1-C4)alkylen-phenyl or C(O)-(C1-C4)alkyl;

R5is

1. H,

2. (C1-C4)alkyl,

3. (C1-C4)alkenyl,

4. (C2-C4)quinil,

5. (C1-C4)alkylen-phenyl,

6. C(O)-(C1-C4)alkyl,

7. COOH,

8. C(O)O-(C1-C4)alkyl,

9. C(O)NH2,

10. halogen,

11. OH,

12. O-(C1-C4)alkyl,

13. O-(C1-C4)alkylene-OH,

14. O-(C1-C4)alkylene-NH2,

15. O-(C1-C4)alkylen-O-(C1-C4)alkyl,

16. O-(C1-C4)alkylen-phenyl,

17. O-(C1-C4)alkylene-(C5-C6)heterocyclyl,

18. O-(C1-C4)alkylen-C(O)OH,

19. O-(C1-C4)alkylen-C(O)O-(C1-C6)alkyl, or

20. O-(C1-C4)alkylen-C(O)NH2;

m denotes 1 or 2;

or burningup;

or pyridium;

or terralingua, which is unsubstituted or substituted (C1-C6)alkyl;

or personalcopy, which is unsubstituted or substituted by phenyl.

Additional preferred embodiment of this invention is the connection fo the formula (I), where:

R1is H; and

R2is (C5-C10)heteroaryl formula (II)

where

X represents N-R4,

R4represents N, CH3CH(CH3)2, benzyl, C(=O)CH3CH2CH=CH2or CH2C≡CH,

R5represents N, CH3, OCH3, COOH, C(O)OCH3C(O)NH2, O-benzyl, F, Cl, Br, OH, O(CH2)2OH, O(CH2)2OCH3, O(CH2)2NH2, OCH2C(O)OH, OCH2C(O)NH2, OCH2C(O)O-(tert-butyl),

m denotes 1 or 2;

or R2is pyridium;

or R2is burningup;

or R2is terralingua formula (VII)

where R8represents H or (C1-C6)alkyl;

or R2is personalcopy formula (VIII)

where R9represents phenyl, and

R3is N;

or its physiologically acceptable salt.

Optically active carbon atoms present in the compound of formula (I)may independently from each other to have the R configuration or S configuration. The compounds of formula (I) can be represented in the form of pure enantiomers or pure diastereomers or as mixtures of enantiomers and/who do diastereomers, for example in the form of racemates. This invention relates to the pure enantiomers and mixtures of enantiomers, as well as to pure diastereomers and mixtures of diastereomers. The invention contains a mixture of two or more than two stereoisomers of the formula I and includes all ratios of the stereoisomers in the mixtures. When the compounds of formula (I) can be represented as E isomers or Z isomers (or CIS isomers or TRANS isomers), the invention relates both to the pure E isomers and the pure Z isomers, and mixtures of E/Z in all relationships. The invention also includes all tautomeric forms of the compounds of formula (I).

The diastereomers, E/Z isomers, can be separated into the individual isomers, for example, chromatography. The racemates can be separated into two enantiomers by conventional methods, such as chromatography on chiral phases or by decomposition into constituent parts, for example by crystallization of the diastereomeric salts obtained with optically active acids or bases. Stereochemical homogeneous compounds of formula (I) can be also obtained using stereochemical homogeneous starting materials or by using stereoselective reactions.

Physiologically acceptable salts of the compounds of formula (I) are non-toxic salts which are physiologically acceptable, in particular headlight is asepticheski used salt. Such salts of compounds of formula (I)containing acidic groups such as carboxyl group COOH, are, for example, alkali metal salts or salts of alkaline earth metals such as sodium, potassium salts, magnesium salts and calcium salts, and also salts with physiologically acceptable ions, Quaternary ammonium bases, such as Tetramethylammonium or tetraethylammonium, and additive, acid salts with ammonia and physiologically acceptable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or Tris-(2-hydroxyethyl)amine. The group's main character, is contained in the compounds of the formula I, for example amino groups or amidinopropane form an acid additive salt, for example, with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic acids and sulfonic acids, such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate acid. The invention also includes the acid additive salts with the joining of the formula (I), which contain, for example, two main groups, with one or two equivalents of acid.

Salts of compounds of formula (I) can be obtained by conventional methods known to experts in this field, for example by combining the compounds of formula (I) with inorganic or organic acid or base in a solvent or diluent or of another salt by casinoonline or anyoneeven. This invention also includes all salts of the compounds of formula (I), which because of low physiological tolerance are not directly applicable in pharmaceutical preparations, but are suitable, for example, as intermediates for further chemical modifications of the compounds of formula (I) or as starting materials for producing the physiologically acceptable salts.

The anions of these acids that may be present in the acid additive salts of compounds of formula I, are also examples of anions that may be present in compounds of formula (I), if they contain one or more positively charged groups, such trialkylamine-substituents, i.e. groups of the formula (alkyl)3N connected through a positively charged nitrogen atom, R represents, or quaternionic the nitrogen atom of the ring in the heterocyclic group. As the rule is, the compound of formula (I) contains one or more physiologically acceptable anions or anionic equivalents as counterions, if it contains one or more positively charged groups such as trialkylamine. The compounds of formula (I), which simultaneously contain a basic group or a positively charged group and an acid group, such as amidinopropane and carboxypropyl, can also be represented as zwitterion (betaines), which are also included in this invention.

This invention also includes all of the solvate of the compounds of formula (I), for example hydrates or adducts with alcohols. The invention also includes derivatives and modifications of the compounds of the formula I, for example, prodrugs, protected forms and other physiologically acceptable derivatives, including esters and amides of the acid groups, as well as active metabolites of compounds of formula I.

The compounds of formula (I), which due to their chemical structures are in enantiomeric forms, can be separated into pure enantiomers by salt with enantiomerically pure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiomerically pure compounds such as amino acids, separation of the thus obtained diastereomers the removal of the chiral auxiliary groups.

The compounds of formula (I) can be isolated, or in a free form, or, in the case of acidic or basic groups, converted into a physiologically acceptable salt. Obtaining physiologically acceptable salts of the compounds of formula (I)capable of salt formation, including their stereoisomeric forms, conduct a manner that is itself known. With bases, such as hydroxides, carbonates, bicarbonates, alkoxides, and also ammonia or organic bases, for example trimethyl - or triethylamine, ethanolamine or triethanolamine or, alternatively, amino acids, for example lysine, ornithine or arginine, carboxylic acids form stable alkali metal salts, alkaline earth metal or optionally substituted ammonium salts. If the compounds of formula (I) contain basic groups, stable acid salt additive can also be obtained with the use of strong acids. For this purpose, suitable inorganic and organic acids, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, methansulfonate, benzolsulfonat, p-toluensulfonate, 4-bromobenzophenone, cyclohexanesulfonyl, triftormetilfullerenov, acetic, oxalic, tartaric, succinic or triperoxonane acid.

The invention therefore also relates to compounds of formula (I), and/is whether their physiologically acceptable salts, and/or their prodrugs for use as pharmaceuticals (or medicaments), to the use of compounds of formula (I), and/or their physiologically acceptable salts and/or their prodrugs for the production of pharmaceutical preparations for the treatment and prevention of chronic heart failure, hypertension, myocardial ischemia and viral infections hepatitis C (HCV) and to avoid dependence on the opiate.

This invention also relates to pharmaceutical preparations (or pharmaceutical compositions)which contain an effective amount of at least one of the compounds of formula (I), and/or its physiologically acceptable salts and/or prodrugs and pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable substances carrier (or carriers) and/or additives (or fillers).

The pharmaceutical preparations can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard or soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. The introduction, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable solutions or solutions for llivan what I microcapsules, implants or rods, or subcutaneously, or topically, e.g. in the form of ointments, solutions or tinctures, or otherwise, for example in the form of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention is get known in themselves ways and familiar to specialists in this field, using pharmaceutically acceptable inert inorganic and/or organic matter-carriers and/or additives in addition to the compound (compounds) of the formula (I), and/or its (their) physiologically acceptable salts and/or its (their) prodrugs. For more pills, tablets, coated tablets and hard gelatin capsules can be applied, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and other Substances-carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. with Suitable substances-carriers to obtain solutions, such as solutions for injection, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oil and other Suitable substances-carriers for microcapsules, implants or rods are, for example, copolymers of glycolic sour the s and lactic acid. The pharmaceutical preparations generally contain from about 0.5 to about 90% by weight of compounds of formula (I), and/or their physiologically acceptable salts and/or their prodrugs. The amount of active ingredient of formula (I), and/or its physiologically acceptable salts and/or its prodrugs in the pharmaceutical preparations normally is from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.

In addition to the active ingredients of formula (I), and/or their physiologically acceptable salts and/or prodrugs and to the substances-the media, the pharmaceutical preparations can contain one or more additives such as, for example, fillers, agents, causing disintegration, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, soljubilizatory, agents for achieving depot effect, salts for modifying the osmotic pressure, agents for covering or antioxidants. They can also contain two or more compounds of the formula (I), and/or their physiologically acceptable salts and/or their prodrugs. When the pharmaceutical preparation contains two or more compounds of the formula (I), the choice of individual compounds can be designed to achieve specific common pharmaco is oricheskogo profile of a pharmaceutical product. For example, a very potent compound with a shorter duration of action may be combined with long-acting combination of lower efficiency. The flexibility allowed in the choice of substituents in the compounds of formula (I), allows a significant regulation of biological and physico-chemical properties of compounds and, therefore, enables the selection of these desirable compounds. Moreover, in addition to at least one compound of formula (I), and/or its physiologically acceptable salts and/or its prodrugs in the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.

As GRK2 inhibitors compounds of formula (I)and their physiologically acceptable salts and their prodrugs, as a rule, applicable to the treatment and prevention of conditions resulting from the activity of GRK2 or βARK-1, or conditions for which the activity of GRK2 or βARK-1 is undesirable, or States, which can have a beneficial effect by inhibiting GRK2 or βARK-1 or decrease its activity, or States for the prevention, relief or treatment for which the attending physician is desirable inhibition of GRK2 or βARK-1 or a decrease of its activity.

When using compounds of formulas is (I) the dose can vary within wide limits and, as is customary and is known to the attending physician, must be brought into compliance with individual conditions in each individual case. It depends on the specific compound, the nature and severity of the disease requiring treatment, the method and schedule for the implementation and on what, acute or chronic, condition and cure or prevention is conducted. The appropriate dosage can be established using clinical approaches well known in medicine. As a rule, the daily dose to achieve the desired outcomes in an adult weighing about 75 kg, equal to from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 50 mg/kg, in particular from about 0.1 to about 10 mg/kg (in each case in mg per kg of body weight). The daily dose may be divided, especially in the case of the introduction of relatively large amounts, in several parts, for example, for 2, 3 or 4 one-time introductions. As usual, depending on individual behaviour, it may be necessary to deviate upward or downward from the nominal daily dose.

In addition, the compounds of formula (I) can be used as intermediates synthesis for the preparation of other compounds, in particular other pharmaceutically active ingredients that can be obtained from compounds of the formula I, for example, the introduction of the batch is Italy or modification of functional groups.

The compounds of formula (I), as a rule, can be obtained according to the following scheme:

On the first path R2the aldehyde (II), 3-aminopyrazole (III) and R3-containing methylpiruvate (IV) is mixed in dichloroethane (DCE) in the presence of acid, preferably acetic acid, and the mixture is heated up to 50-120°C, preferably 60-100°C, and then the reaction mixture is oxidized, preferably opening for access of air, whereby to receive an aromatic system (VI) 1H-pyrazolo[3,4-b]pyridine.

Alternative way R2the aldehyde (II), 3-aminopyrazole (III) and R3-containing methyl-pyruvic acid (V) are mixed in ethanol and heated to 50-120°C, preferably 60-100°C. Subsequent oxidation, preferably by exposure to air, gives the acid derivative (VII) 1H-pyrazolo[3,4-b]pyridine.

Cleavage of ester can be carried out by standard methods, for example impact ester (VI) basis. Details of the methods of obtaining given in various standard references such as J. March, Advanced organic Chemistry, 4th ed., John Wiley & Sons, 1992.

The corresponding amides of formula (I), where R1represents hydrogen, can be obtained by the reaction of ester (VI) with a suitable reagent, such as, for example, ammonia in methanol, or by activating derived carbon is acid (VII) Boc 2O and processing the obtained tert-butyl ether complex NH4HCO3. When tert-butyl ester is formed when N1 or N2 of pyrazolidine, it can be removed by TFA treatment. The compounds of formula (I), where R1represents optionally substituted C1-C6)altergroup can be obtained by linking the corresponding (C1-C6)alkyl-NH2derivative (VIII) (VII) in the presence of a standard coupling agent, such as, for example, DIC, dicyclohexylcarbodiimide, EDC, HOBT, etc.

Protective groups which can be present in the products obtained in the reaction mix, then remove the standard procedures. For example, protective tert-butylrubber, in particular tert-butoxycarbonyl, which represents a protected form of amidinopropane may be deprived of protection, i.e. transformed into amidinopropane, processing triperoxonane acid. As previously explained, after the reaction of a combination of functional groups can also be formed from the respective groups predecessors. In addition, the transformation into a physiologically acceptable salt or prodrug of the compounds of formula (I) can then be carried out by known processes.

Typically, the reaction mixture containing the target compound of formula (I) or an intermediate connection, processed and, if lateline, the product is then purified by traditional processes, well known to specialists in this field. For example, the synthesized compound can be purified using well known methods such as crystallization, chromatography or liquid chromatography high-resolution reversed-phase (RP-HPLC), or other methods of separation based on, for example, size, charge or hydrophobicity of the compounds. In a similar manner well known techniques, such as analysis of amino acid sequences, NMR, IR and mass spectrometry (MS)can be used to characterize the compounds according to the invention.

It is clear that modifications that do not significantly affect the activity of different variants of the embodiment of the present invention, included in the open here the invention. Accordingly, the following examples are intended to illustrate but not to limit the present invention.

Abbreviations:

ACNacetonitrile
anh.anhydrous
cpd.connection
DIADaminobutiramida-azodicarboxylate
DIC diisopropylcarbodiimide
DMSOthe sulfoxide
Et2Oethyl simple ether
MeOHmethanol
DMFdimethylformamide
DCMdichloromethane
DCE1,2-dichloroethane
EQ.equivalent(s)
HPLCliquid chromatography high-resolution
K.T.room temperature
THFtetrahydrofuran
TFAtriperoxonane acid
TLCthin-layer chromatography
hhour(s)
Rtretention time

Synthesis of intermediate compounds:

4-Hydroxy-1-methyl-1H-indole-3-carbaldehyde (I-1)

Stage 1:

Synthesis of 4-hydroxy-1-methyl-N-methyl-indole-3-carbaldehyde

To a solution of 4-benzyloxy-1H-indole-3-carbaldehyde (0.5 g, 2.0 mmol) in anhydrous DMF (8.0 ml) add methyliodide (0,148 ml of 2.40 mmol) and potassium carbonate (0,552 g, 4.0 mmol) with vigorous stirring. This solution is stored and then mixed for 36 h at K.T. the Solvent is evaporated, getting a white solid. The solid is dissolved in ethyl acetate (100 ml), filtered and the solvent is evaporated by receiving light grey solid. The solid is triturated with Et2O to remove residual DMF, and filtered, obtaining a product in the form of flocculent light gray solids 0.40 g (yield: 75%);1H NMR (DMSO d6) 3,85 (s, 3H), to 5.35 (s, 2H), 6,9 (DD, 1H), 7,20 (m, 2H), 7,40 (m, 3H), 7,55 (m, 2H), 8,1 (m, 1H), 10,3 (s, 1H); MS m/e 265 (M+).

Stage 2:

The compound obtained in stage 1 (0.5 g, 1.9 mmol), dissolved in DCM (10 ml) and to the solution was added 48% HBr (3.0 ml). This solution was left to mix overnight at K.T. the Solvent is evaporated, receiving a dark purple solid. The crude product is triturated twice with ethyl acetate (with the subsequent removal of ethyl acetate under reduced pressure). The crude product is purified column chromatography. Conditions: 0.75 g of the crude compound on 25 g of silica for flash chromatography; hexane/those who acetate (50/50). The appropriate fractions are collected and evaporated, receiving the product as a pale green solid 0,275 g (yield: 82%);1H NMR (DMSO-d6) 3,85 (s, 3H), 6,60 (d, 1H), 7,00 (d, 1H), 7,20 (m, 1H), 8,35 (s, 1H), and 9.6 (s, 1H), 10,6 (s, 1H); MS m/e 175 (M+).

5-Hydroxy-1-methyl-1H-indole-3-carbaldehyde (I-2)

To a solution of 5-methoxy-1-methyl-1H-indole-3-carbaldehyde (4.5 g, to 23.8 mmol, 150 ml DCM) is added a solution of BBr3(2 M in DCM, 60 ml, 5 EQ.) at -10°C with stirring for 5 minutes the Cooling bath removed and the reaction mixture is slowly heated to K.T. Reaction monitor TLC (2% MeOH in DCM) and LCMS (after 3.5 h the source material is). The reaction mixture was then cooled to -10°C and slowly add 16 ml of MeOH. the pH of the mixture was adjusted to 8 by adding a feast upon. NaHCO3and/or 4 N. NaOH. Organic solvents are removed under reduced pressure and the remaining aqueous mixture is extracted with ethyl acetate (30 ml × 5). The organic layers are combined, washed with saturated salt solution (10 ml × 1), dried over Mg2SO4, filtered and dried under reduced pressure, obtaining mentioned in the title compound as 4,06 g purple powder (yield: 97%), which is used without further purification. LCMS (2-85% ACN/H2O for 7 min): 176,1 (40%). Rf0,11 (2% MeOH in DCM).

4-[2-(2-pyridyloxy)ethyl]-1-methyl-1H-indole-3-carbaldehyde (I-3)

A solution of 88 mg (0.5 mmol), I-1, 262 mg (1 mmol) PPh3and 123 mg (1 mmol) in dry 2-pyridyl-1-ethanol, 4 ml of dry THF and a solution of 202 mg (1 mmol) of DIAD in 1 ml of dry THF is cooled to -10°C and quickly mix. The temperature was raised to K.T. and stirring is continued for 2 hours. The reaction mixture control LCMS, evaporated and purified HPLC (RP YMC-Pack ODS-AM, AM12S05-2520WT, S-5 μm, 12 nm, gradient C/water (+0.1% of TFA), 10-100% for 20 min, 10 ml/min, UV detection 280 nm). Relevant fractions lyophilized during the night. LCMS (2-85% ACN/H2O): shows the MH+ ion of m/z=281 (100%). Yield: 90 mg (64%).

5-(N-piperidinyloxy)-1-methyl-1H-indole-3-carbaldehyde (I-4)

Specified in the header of the connection will receive is equivalent to issuing the I-3 on the basis of 88 mg (0.5 mmol) of I-2 and 129 mg (1 mmol) 2-(N-piperidino)ethanol. LCMS shows the MH+ ion of m/z=287 (100%). The HPLC purification gives the yield 65 mg (yield: 45%) after HPLC/lyophilization.

tert-Butyl ester 3-(3-formyl-1-methyl-1H-indol-5-intoximeter)piperidine-1-carboxylic acid (I-5)

To a solution of aldehyde I-2 (400 mg, 2.3 mmol) in DMF (10 ml) is added tert-butyl ester 3-methyl bromide-piperidine-1-carboxylic acid (760 mg, 2.7 mmol) and triamide N'-tert-butyl-N,N,N',N',N",N"-HEXAMETHYL-phosphoramide (1,16 ml, 4.6 mmol). After heating at 100°C for 6 h, evaporation and purification by chromatography on silica gel (ethyl the Etat:hexane 6:4) to obtain 350 mg (yield: 21%) indicated in the title compounds as solids after evaporation to dryness. LC/MS (M+H)+ 373.

2-(3-Formyl-1-methyl-1H-indol-5-yloxy)ndimethylacetamide (I-6)

5-Hydroxy-1-methyl-1H-indole-3-carbaldehyde (I-2) (0.5 g, of 2.86 mmol), 2-bromoacetamide (of 0.43 g, 3.1 mmol) and triamide N'-tert-butyl-N,N,N',N',N",N"-HEXAMETHYL-phosphoramide (2,18 ml, 8.6 mmol) dissolved in betwedn. DMF (3 ml) in a sealed tube. The resulting solution was then sealed and heated at 120°C (track by LCMS). The reaction is terminated after 3.5 hours the Mixture is cooled to room temperature, add 20 ml of water and 6 N. HCl to pH 2-3. The mixture was then extracted with ethyl acetate (20 ml × 6). The organic layers are combined, washed with saturated salt solution (10 ml × 2), dried over Mg2SO4, filtered and dried under reduced pressure, obtaining mentioned in the title compound as 0.5 g of orange powder (crude yield: 76%, used without further purification). LCMS (2-85% ACN/H2O for 7 min): M+233,1 (100%); purity 95% (at 220 nm).

The synthesis of compounds according to the invention:

4-{-4-[2-(2-pyridyloxy)ethyl]-1-methyl-1H-indolyl}-7-Aza-indazol-6-carboxamide (example 1)

Stage 1: Synthesis of 4-{-4-[2-(2-pyridyloxy)ethyl]-1-methyl-1H-indolyl}-6-methoxycarbonyl-7-Aza-indazole:

A solution of 86 mg of the aldehyde I-3 (0.2 mmol), 18 mg of methylpiruvate (0.2 mmol) and 20 mg of 3-aminopyrazole (0.2 mmol) in DCE (2 ml, 1% acetic acid) n is grebaut in a sealed tube at 90°C for 12 hours and cooled to K.T. The reaction mixture is evaporated under reduced pressure and the residue is separated by prep-HPLC (RP YMC-Pack ODS-AM, AM12S05-2520WT, S-5 μm, 12 nm, gradient ACN/water (+0.1% of TFA), 10-100% for 20 min, 10 ml/min, UV detection 280 nm). Crude yield 32 mg (39%).

Stage 2:

The crude product from step 1 was dissolved in 2 ml of 7 N. NH3/MeOH, sealed and heated at 80°C for 6 h and the solvent is removed under reduced pressure. The residue is purified by prep-HPLC (RP YMC-Pack ODS-AM, AM12S05-2520WT, S-5 μm, 12 nm, gradient ACN/water(+0.1% of TFA), 10-100% for 20 min, 10 ml/min, UV detection 280 nm) and after lyophilization receive 1 mg of pure product (1% of total output).

1H NMR (600 MHz, DMSO-d6, SM_6425) δ ppm: 13,63 (users, 1H), to 8.41 (d,J=5,0, 1H), 8,23 (s, 1H), of 8.09 (s, 1H), 7,97 (users, 1H), to 7.84 (s, 1H), 7,65 (users, 1H), 7,52 (m, 1H), 7.23 percent (m, 1H), 7,19 (DD,J=8,1, 7,1 Hz, 1H), 7,14 (l,J=8,1 Hz, 1H), 6.87 in (userd, 1H), of 6.71 (d,J=7,1 Hz, 1H), 4,37 (t, 2H), of 3.84 (s, 3H), of 3.13 (t, 2H).

LCMS (2-85% ACN/H2O): shows the MH+ ion of m/z=413 (100%), Rt=3,27.

5-[(N-piperidinyloxy)-1-methyl-1H-indol-3-yl]-7-Aza-indazol-6-carboxamide (example 2)

Stage 1:

Synthesis of 5-(N-piperidinyloxy)-1-methyl-1H-indol-3-yl}-6-methoxycarbonyl-7-Aza-indazole

Receiving, by analogy with stage 1 of example 1 from 65 mg of I-4. Prep-HPLC purification gives 17 mg (yield: 18%)is used in the next stage.

Stage 2:

Receiving the s by analogy with stage 2 of example 1 from 17 mg of the above compound. Prep-HPLC purification gives 7 mg of a solid (yield: 7%)

1H NMR (600 MHz, DMSO-d6, SM_6425) δ ppm: 13,77 (users, 1H), and 8.50 (s, 1H), compared to 8.26 (s, 1H), 8,11 (s, 1H), 8,00 (users, 1H), 7,71 (users, 1H), 7,56 (l,J=9,0 Hz, 1H), 7,49 (l,J=2.4 Hz, 1H), 7,07 (DD,J=to 9.0, 2.4 Hz, 1H), 4,36 (t, 2H), 3,90 (s, 3H), 3,40-to 3.58 (m, 6H), 1,58 is 1.75 (m, 6H). (LCMS main peak: 287 mmu). Rt=3,31.

Amide 4-(1-methyl-5-(piperidine-3-ylethoxy)-1H-indol-3-yl)-1H-pyrazolo(3,4-b)pyridine-6-carboxylic acid (example 3)

Stage 1:

Synthesis of ester methyl 4-(5-(tert-butoxycarbonyl-piperidine-3-ylethoxy)-1-methyl-1H-indol-3-yl)-1H-pyrazolo(3,4-b)pyridine-6-carboxylic acid

To a solution of I-5 (350 mg, 946 mmol) in DCE (4 ml) add a solution of 1H-pyrazole-3-ylamine (83 mg, 1 mmol) in DCE (4 ml), a solution of methylpiruvate (102 mg, 1 mmol) in DCM (4 ml) and acetic acid (500 μl). The solution was stirred at 80°C for 8 h, evaporated and purified prep-HPLC (water with 0.1% TFA, using a gradient from 25% to 85% ACN over 9 minutes). Evaporation to dryness gives 108 mg (yield: 22%) compounds as solids. LC/MS (M+H)+ 520.

Stage 2:

The product obtained in stage 1 (200 mg, 385 μmol) is treated with 20 ml of 7 n ammonia in methanol at 70°C for 3 h and evaporated to dryness. The solid is treated with 50% TFA in DCM (6 ml) for 2 h and evaporated to dryness. Cleaning prep-HPLC (water with 0.1% TFA with a gradient from 5 to 45% ACN in accordance with the ie 9 minutes) give 40 mg (yield: 48%) of product as a solid.

1H NMR 600 MHz (DMSO-d6) δ (ppm): 3,90 (1H, m), 3,86 (3H, s), 6,92 (1H, d), 7,41 (1H, s), 7,46 (1H, d), of 7.69 (1H, s), to 7.99 (1H, m)to 8.12 (1H, s)8,23 (1H, s), 8,51 (1H, s)13,82 (1H, s); NOE confirms defined structure. LC/MS (M+H)+ 405. Rt=3,38.

Amide 4-(1-methyl-1H-indol-3-yl)-1H-indazol-6-carboxylic acid (example 4)

Stage 1: Synthesis of ester methyl 4-(1-methyl-1H-indol-3-yl)-1H-indazol-6-carboxylic acid

A solution of 1-methyl-1H-indole-3-carbaldehyde (4 mmol, 0,636 g), methylpiruvate (4 mmol, 0,361 ml) and 3-aminopyrazole (4 mmol, 0,388 g) in DCE (12 ml, 1% acetic acid) is heated in a sealed tube at 100°C for 17.5 hours. After that, the mixture is cooled to K.T. and evaporated under reduced pressure.

Then 10 ml of Et2O add to the residue, the precipitate is filtered off, washed with Et2O (10 ml × 2) and dried. A new precipitate from the mother liquor (reduced to 20 ml), filtered and washed again. After 2 additional cycles obtain 0.8 g of the crude product. The remaining solution condense again, add 10 ml of MeOH and a new precipitate is filtered and washed twice with 1 ml Et2O. After two repetitions obtain 1.3 g of the crude product (LCMS: >90% purity @ 220 nm) and used without further purification in the next stage. 70 mg of the indicated crude product is optionally purified MS-det is ciruelas HPLC, getting 21 mg of pure indicated in the title compound as a red powder. (LCMS main peak: 307 mmu).

Stage 2:

of 0.67 g of the above crude product is dissolved in 7 BC, NH3/MeOH (25 ml), sealed and heated at 70-80°C for 18 hours the Solvent is removed under reduced pressure. The residue is purified by chromatography on silica gel (ethyl acetate/hexane), to obtain 0.2 g of the crude product and re-clean MS-HPLC run. In the end obtain 7 mg of pure compound (total yield: 10%).

1H NMR (600 MHz, DMSO-d6) δ (ppm): 13,80 (user., 1H), 8,56 (s, 1H), 8,29 (s, 1H), they were 8.22 (s, 1H), 8,13 (s, 1H), 8,00 (l,J=8,1 Hz, 1H), 7,73 (s, 1H), 7.62mm (l,J=8,1 Hz, 1H), 7,34 (DD,J=8,1, 8,1 Hz, 1H), 7,29 (DD,J=8,1, 8,1 Hz, 1H), 3,94 (s, 3H), NOE study (DMSO-d6) confirms defined structure. (LCMS main peak: 292,2 mmu). Rt=4,10.

Amide 4-(5-bromo-1H-indol-3-yl)-1H-pyrazolo(3,4-b)pyridine-6-carboxylic acid (example 5)

To a solution of 5-bromo-1-H-indole-3-carbaldehyde (1220 mg, 5.4 mmol) in dry ethanol (18 ml) add a solution of pyruvic acid (475 mg, 5.4 mmol) in dry ethanol (18 ml). The mixture is heated at 80°C for 1 h and add a solution of 1H-pyrazole-3-ylamine (448 mg, 5.4 mmol) in dry ethanol (18 ml). The reaction mixture is heated at 80°C for 24 h, exposed to air at K.T. within 24 h and evaporated to dryness, receiving not the shelled solid. The solid is dissolved in a mixture of pyridine/ethyl acetate 1:1 (60 ml) and treated with ammonium bicarbonate (948 mg, 12 mmol) and di-tert-butyl-dicarbonate (2,19 g, 12 mmol) for 16 h at K.T. Mixture is then evaporated to dryness, re-dissolved in ethyl acetate (100 ml) and washed with water/saturated salt solution (3×), dried (Na2SO4), filtered and evaporated to dryness. The solid is treated with TFA (50% in DCM) for 2 h at K.T., carefully neutralized aqueous Na2CO3, extracted with ethyl acetate, dried (Na2SO4), filtered, evaporated and purified by chromatography on silica gel (ethyl acetate:hexane 8:2 gradient to pure ethyl acetate). The product is then purified by chromatography prep-HPLC water with 0.1% TFA with a gradient from 15% to 85% ACN for 9 minutes. Get to 3.3 mg (<1% yield) of product as a solid.

1H NMR (600 MHz, DMSO-d6) δ (ppm): 7,37 (d, 1H), 7,51 (d, 1H), 7,63 (s, 1H), 8,01 (s, 1H), of 8.09 (s, 1H), 8,29 (s, 1H), 8,48 (s, 1H), 12,12 (s, 1H), 13,80 (s, 1H).

NOE confirms defined structure. LC/MS (M+H)+ 356. Rt=4,11.

Amide 4-(4-methyl-1H-indol-3-yl)-1H-pyrazolo(3,4-b)pyridine-6-carboxylic acid (example 6)

Specified in the header of the connection will receive is similar to obtaining a sample of 5 based on 4-methyl-1-H-indole-3-carbaldehyde (477 mg, 3 mmol)to give 11 mg (yield: 1%) of solid product.

1 H NMR 600 MHz (DMSO-d6) δ ppm: 2,20 (s, 3H), 6.87 in (d, 1H), to 7.09 (DD, 1H), 7,33 (d, 1H), 7,71 (s, 1H), 7,72 (s, 1H), 7,78 (s, 1H), 8,01 (s, 1H), 8,12 (s, 1H), 11,72 (s, 1H), 13,79 (s, 1H); NOE confirms defined structure. LC/MS (M+H)+ 292. Rt=3,86.

Amide 4-(4,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrazolo(3,4-b)pyridine-6-carboxylic acid (example 7)

Specified in the header of the connection will receive is similar to obtaining a sample of 5 based on 4,6-dimethoxy-1-methyl-1H-indole-3-carbaldehyde (657 mg, 3 mmol)to give 11 mg (yield: 1%) of solid product.

LC/MS (M+H)+ 352.1H NMR 600 MHz (DMSO-d6) δ (ppm): 3,71 (s, 3H), 3,79 (s, 3H), 3,82 (s, 3H), 6,32 (s, 1H), of 6.68 (s, 1H), to 7.59 (s, 1H), 7,74 (s, 1H), of 7.90 (s, 1H), 8,11 (s, 1H), 8,23 (s, 1H), 13,66 (s, 1H); NOE confirms defined structure.

Amide 4-(5-carbamoylmethyl-1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (example 8)

Stage 1:

Synthesis of ester methyl 4-(5-carbamoylmethyl-1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid

A mixture of 2-(3-Formyl-1-methyl-1H-indol-5-yloxy)ndimethylacetamide (I-6, untreated, ~3 mmol, 0.7 g), methylpiruvate (3 mmol, 0.3 ml), 3-aminopyrazole (3 mmol, 0.29 grams) and Na2SO4(betwedn. 0.5 g) in DCE (10 ml) is heated with vigorous stirring in a sealed tube at 100°C for 17 hours. After that, the mixture is cooled to K.T. and evaporated when s is low pressure.

Then 12 ml of H2O, 12 ml of DMF and 15 ml of MeOH added to the residue. The mixture is subjected to ultrasonic treatment for 5 minutes and stirred for an additional 10 minutes. The precipitate is filtered off, washed with H2O (2 ml × 5) and dried (0.3 g). And a liquid layer, and the residue analyzed by LCMS and the precipitate contains essentially expected is specified in the header connection (M+: 380,2 (100%); LCMS: purity 90% @ 220 nm). The crude product is used without further purification in the next stage.

Stage 2:

Synthesis of amide 4-(5-carbamoylmethyl-1-methyl-1H-indol-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid

The above crude product (0.3 g) dissolved in 7 BC, NH3/MeOH (60 ml), sealed and heated at 80°C during the night. The solvent is removed under reduced pressure. The residue is dissolved in DMSO (5 ml), filtered and purified MS-triggered HPLC and receive 0.1 g of pure compound (total yield: 10%). LCMS (2-85% ACN/H2O): 365,2 (100%); purity 100% at 220 nm. Rt=3,38.

1H NMR (600 MHz, DMSO-d6) δ (ppm): 13,81 (s, 1H), charged 8.52 (s, 1H), of 8.27 (s, 1H), 8,15 (s, 1H), 8,01 (s, 1H), 7,74 (s, 1H), 7.62mm (s, 1H), EUR 7.57 (d,J=9,0 Hz, 1H), 7,50 (d,J=2.3 Hz, 1H), 7,39 (s, 1H), 7,07 (DD,J=2,3, 9.0 Hz, 1H), 4,47 (s, 2H), 3,93 (s, 3H). NOE study (DMSO-d6) confirms defined structure.

Examples in the following table 1 can be obtained similarly to the above procedures, the m Peaks of the MS is given as the main parent peaks. A slightly modified procedure used for example 55, which is obtained analogously to example 5, getting the corresponding carboxylic acid and then treated with aminoethanol under standard conditions amide combinations using DIC as a binder reagent.

System LC/MS was used to obtain data K.T. and the main peak MS, was a Waters 2790-ZQ, column YMC ProC18 S-5 120A 2 × 50 mm, the method was 0.1% TFA in water with a gradient of ACN 2-85% within 6.85 minutes. MS ionization method was the method of ESI.

Materials and methods

The analysis reveals phosphorylation of Biot is melirovannyh dimers bovine tubulin (250 nm; TEBU-BIO, # T333)deposited on a 384-well tablets 100 nm GRK2, which was pre-incubated with the compound is an inhibitor for 30 minutes at room temperature in buffer for analysis (20 mm Tris-HCl pH to 7.4, 2 mm EDTA)containing 2,25% DMSO. The phosphorylation reaction was started by addition of tubulin, MgCl2(10 mm), ATP (3 μm), [γ-33P]-ATP (0,4 MX/40 ál) to the pre-incubated complex GRK2/connection. Then the mixture for analysis were incubated for 30 min at room temperature before the kinase reaction was stopped by the addition of 0.8% BSA, and 0.8% Triton X-100, 80 mm EDTA and 400 μm ATP, followed by incubation for 2-24 h at +4°C. Due to the high energy γ-particles free33P-ATP is removed stage washing (3 × 100 μl of 1 × PBS pH 8.0) using a device for washing Tecan Power washer 384 to restore the original activity. Limit33P determined by scintillation counting (60 μl scintillator, Ultimagold MV, 30 sec edit), using a Microbeta counter-counter (delay time 30 min).

Table 2
ExampleIC50 (βARK-1), [µm]
30,7
40,27
8162,1
641,3

1. Derivatives pyrazolopyrimidine formula (I)

where R1represents H or (C1-C6)alkyl, where (C1-C6)altergroup is unsubstituted or substituted by a group of IT; and
R2represents phenyl or a mono - or bicyclic 5-to 10-membered heteroaryl group which contains an oxygen atom or 1-2 nitrogen atom, which is unsubstituted or substituted 1, 2 or 3 residues independently selected from such as:
(1) (C1-C6)alkyl,
(2) (C2-C6)alkenyl,
(3) (C2-C6)quinil,
(4) (C1-C6)alkylene-COOH,
(5) (C1-C6)alkylen-C(O)O-(C1-C6)alkyl,
(6) (C1-C6)alkylen-C(O)NH2,
(7) (C1-C6)alkylen-C(O)NH-(C1-C6)alkyl,
(8) (C1-C6)alkylen-O-(C1-C6)alkyl,
(9) (C1-C6)alkylen-HE,
(10) (C1-C6)alkylene-NH2,
(11) (C1-C6)alkylene-NH-(C1-C6)alkyl,
(12) (C1-C6)alkylene-N[(C1-C6)alkyl]2,
(13) COOH,
(14) C(O)O-(C1-C6)alkyl,
(15) C(O)NH2,
(16) C(O)NH-(C1-C6)alkyl,
(17) C(O)N[(C1 -C6)alkyl]2,
(18) C(O)-(C1-C6)alkyl,
(19) halogen,
(20) NH2,
(21) NN(C1-C6)alkyl,
(22) N[(C1-C6)alkyl]2,
(23) NH-C(O)-(C1-C6)alkyl,
(24) HE,
(25) O-(C1-C6)alkyl,
(26) O-(C1-C6)alkylen-C(O)HE,
(27) O-(C1-C6)alkylen-C(O)O-(C1-C6)alkyl,
(28) O-(C1-C6)alkylen-C(O)NH2,
(29) O-(C1-C6)alkylen-C(O)NH-(C1-C6)alkyl,
(30) O-(C1-C6)alkylen-HE,
(31) O-(C1-C6)alkylen-O-(C1-C6)alkyl,
(32) O-(C1-C6)alkylene-NH2,
(33) O-(C1-C6)alkylene-NH-(C1-C6)alkyl,
(34) O-C(O)-(C1-C6)alkyl,
(35) phenyl,
(36) (C1-C6)alkylen-phenyl,
(37) (C1-C6)alkylen-O-phenyl,
(38) O-phenyl,
(39) O-(C1-C6)alkylether,
(40) O-(C1-C6)alkalinetrio,
where heterocyclyl in the group (40) is selected from pyridyl, piperidinyl, pyrrolidinyl and morpholinyl, and where R2represents phenyl may be substituted vicinal balance-O(CH2)n-O-, where n is 1 or 2;
R3represents H;
or their physiologically acceptable salts.

2. The compound according to claim 1, where the specified heterogroup R2is benzofuranyl, indolyl, furanyl, pyrrolyl, piraso the mud.

3. The compound according to claim 1, where the specified heterogroup R2represents a group of formula (II),

where X is N-R4or,
R4is H, (C1-C4)alkyl, (C1-C4)alkenyl, (C1-C4)quinil, (C1-C4)alkylen-phenyl or C(O)-(C1-C4)alkyl;
R5is
(1) H,
(2) (C1-C4)alkyl,
(3) (C1-C4)alkylen-phenyl,
(4) C(O)-(C1-C4)alkyl,
(5) COOH,
(6) C(O)O-(C1-C4)alkyl,
(7) C(O)NH2,
(8) halogen,
(9) HE,
(10) O-(C1-C4)alkyl,
(11) O-(C1-C4)alkylen-HE,
(12) O-(C1-C4)alkylene-NH2,
(13) O-(C1-C4)alkylen-O-(C1-C4)alkyl,
(14) O-(C1-C4)alkylen-phenyl,
(15) O-(C1-C4)alkalinetrio,
(16) O-(C1-C4)alkylen-C(O)HE,
(17) O-(C1-C4)alkylen-C(O)O-(C1-C6)alkyl, or
(18) O-(C1-C4)alkylen-C(O)NH2;
where heterocyclyl in the group (15) selected from pyridyl, piperidinyl, pyrrolidinyl and morpholinyl; and m is 1 or 2;
or R2is burningup;
or terralingua, which is unsubstituted or substituted (C1-C6)alkyl;
or personalcopy, which is unsubstituted or substituted what anilam.

4. The compound according to claim 1, where
R2is heteroaryl formula (II),

where X is an N-R4,
R4represents N, CH3CH(CH3)2, benzyl, C(=O)CH3CH2CH=CH2or CH2With≡CH,
R5represents N, CH3The co3, COOH, C(O)och3C(O)NH2, O-benzyl, F, Cl, Br, HE, O(CH2)2HE, O(CH2)2Och3, O(CH2)2NH2The co2(O)HE, OCH2C(O)NH2The co2C(O)O-(tert-butyl),
,,,,
,or;
m denotes 1 or 2;
or R2is burningup;
or R2is terralingua formula (VII)

where R8represents H or (C1-C6)alkyl;
or R2is personalcopy formula (VIII)

where R9represents phenyl.

5. The method of obtaining the compounds of formula (I) according to claim 1, where R1means hydrogen, according to which:
in the first stage, R2the aldehyde (II), 3-aminopyrazole (III) and R3-substituted methylpyrrole the (IV)

mixed in dichloroethane in the presence of acid and the mixture is heated up to 50-120°C. and then oxidized, preferably by subjecting the effects of air, which results in aromatic systems (VI) 1H-pyrazolo [3,4-b] pyridine

and in the second stage ester (VI) is subjected to interaction with an appropriate reagent, such as, for example, ammonia in methanol, to obtain the compounds of formula (I), where R1represents hydrogen.

6. The method of obtaining the compounds of formula (I) according to claim 1, where R1means hydrogen, according to which:
in the first stage, R2the aldehyde (II)defined in claim 5, 3-aminopyrazole (III)defined in claim 5, and R2-containing methyl-pyruvic acid (V)

mixed in ethanol and heated to 50-120°C, then oxidized to obtain an acid derivative (VII) 1H-pyrazolo[3,4-b]pyridine

and in the second phase derivative (VII) carboxylic acids activate Vos2O and treated with NH4HCO3obtaining the compounds of formula (I), where R1represents hydrogen.

7. The method of obtaining the compounds of formula (I) according to claim 1, where R1means optionally substituted C1-C6)accelgroup, in accordance with which the derivative (VII) carbó the OIC acid

subjected to interaction with binding reagent and R1-NH2derivative (VIII) with a compound of formula (I), where R1represents an optionally substituted C1-C6)altergroup.

8. The method according to claim 7, where the derivative (VII) carboxylic acid get subjecting ester (VI)

the impact base.

9. Applying at least one of the compounds of formula (I) and/or its physiologically acceptable salts according to one of claims 1 to 4 to obtain drugs, which represent the kinase inhibitor 1β-adrenergic receptor.

10. Applying at least one of the compounds of formula (I) and/or its physiologically acceptable salts according to one of claims 1 to 4 to obtain drugs for the treatment and prevention of chronic heart failure, hypertension, myocardial ischemia and to prevent dependence on the opiate.

11. Drug representing kinase inhibitor 1β-adrenergic receptor containing an effective amount of at least one compound according to any one of claims 1 to 4 and/or its pharmacologically acceptable salt, physiologically tolerated excipients and carriers and, where appropriate, additional additives and/or other active ingredients.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel pyrazole derivatives of formula (I) or pharmaceutically acceptable salts thereof, having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths accompanied by high level of Trk, to a method of producing said derivatives, use thereof to prepare a medicinal agent, pharmaceutical compositions based on said derivatives, a method of inhibiting Trk activity and a method of obtaining antiproliferative action. where A denotes a single bond or C1-2alkylene; where the said C1-2alkylene can be optionally substituted with one R22; ring C is a phenyl or a 5-6-member heterocyclic ring with 1-2 heteroatoms selected from N or S. Values of R1-R7, R22 and n are given in the formula of invention.

EFFECT: obtaining pharmaceutically acceptable salts having tyrosine kinase Trk inhibiting properties and used for treating or preventing malignant growths.

20 cl, 5 dwg, 193 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the following compounds: N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trofluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazole-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4-(,2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazole-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trifluoro-1-methyl-ethoxy)-benzamide, 3-chloro-N-[2-[(N,N-dimethylglicyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide, 3-chloro-N-(2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-[(3-hydroxy)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide, as well as to their pharmaceutically acceptable salts.

EFFECT: obtained compounds and salts can be used for treatment cell proliferative diseases and disorders by modulating activity of mitotic kinesin CENP-E.

26 cl, 102 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel acetylenyl-pyrazole-pyrimidine derivatives of general formula (I), having mGluR2 (metabotropic glutamate receptor) antogonist properties). In compounds of general formula (I): either E and J denote N, G denotes C and L denotes N, M denotes CH, or M denotes N, L denotes CH; or L and G denote N, E denotes C, and J and M denote CH; or J, G and L denote N, E denotes C, and M denotes CH; or E and L denote N, J and M denote CH, and G denotes C; R1 denotes H, halogen, CF3, CHF2 or C1-6alkyl; R2 denotes H, halogen, C1-6-alkyl, C1-6-alkoxy, CF3 or CHF2, wherein R1=R2≠H; R3 denotes H; -C(CH3)2OH; linear C1-4-alkyl or C3-4-cycloalkyl, which are possibly substituted with one or more substitutes selected from a group comprising 1-3 F and 1-2 OH; A is selected from a group comprising phenyl or a 5- or 6-member heteroaryl having in the ring 1-2 heteroatoms selected from nitrogen, sulphur or nitrogen and sulphur in the 5-member ring, and 1-2 nitrogen atoms i the 6-member ring, and possibly substituted with 1-3 Ra; Ra denotes halogen; hydroxy; cyano; CF3; NReRf; C1-C6-alkyl, possibly substituted amino or hydroxy; ; C1-6-alkoxy; C3-4-cycloalkyl; CO-NRbRc, SO2-NRbRc; or SO2-Rd-; Rb and RC can be identical or different and are selected from a group comprising H; normal or branched C1-6-alkyl, possibly substituted with one or more substitutes selected from a group comprising F, cyano, hydroxy, C1-6-alkoxy, -NH-C(O)-O-C1-6-alkyl, amino, (C1-6-alkyl)amino, di(C1-6-alkyl)amino, heterocycloalkyl having 6 ring atoms, from which 1-2 heteroatoms are selected from nitrogen or nitrogen and oxygen, or a 6-member heteroaryl with one nitrogen heteroatom in the ring; or a 6-membeer heteroaryl with one nitrogen heteroatom in the ring; or Rb and Rc, together with the nitrogen atom with which they are bonded, can form a heterocyclic ring having 6 members in the ring, from which 1-2 atoms are selected from nitrogen and/or oxygen, and which can be substituted with C1-6-alkyl; Rd denotes OH or C1-6-alkyl; Re and Rf denote H, C1-6-alkyl, possibly substituted hydroxy, -C(O)- C1-6-alkyl; S(O)2-C1-6-alkyl.

EFFECT: compounds can be used in preparing medicinal agents for treating central nervous system (CNS) disorders, such as Huntington's chorea, amyotrophic lateral sclerosis, dementia caused by AIDS, parkinsonism etc.

55 cl, 6 dwg, 321 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel derivatives of 1H-imidazo [4,5-c]quinolines of formula II or pharmaceutically acceptable salts thereof, where R3 is selected from a group comprising -Z-Y-R4, -Z-Y-X-Y-R4, -Z-R5, -Z-Het, -Z-Het'-R4, and -Z-Het'-Y-R4; Z is selected from a group which includes C1-C6alkylene; n equals 0; R1 is selected from a group comprising R4, -X-R4 and -X-Y-R4; R2 is selected from a group comprising C1-C6alkyl, C1-C6alkoxy, hydroxyC1-C6alkyl and C1-C6alkoxy-C1-C6alkyl; X is selected from a group comprising C1-C6alkylene, C6arylene, heteroarylene which is thienyl, and heterocyclylene which is piperzinyl, where the alkylene group can be optionally broken by -O- group; Y is selected from a group comprising -S(O)0-2-, -C(R6)-, -C(R6)-O-, -O-C(R6)-, -N(R8)-Q-, -C(R6)-N(R8)-, and R4 is selected from a group comprising hydrogen, C1-C6alkyl, C2alkenyl, C1-C10aryl, C6aryl-C1alkylenyl, and heteroaryl selected from pyridyl, thienyl, benzodioxanyl and others (see claim 1), where C1-C6alkyl, C2alkenyl and C6-C10aryl can be unsubstituted or substituted with one or two substitutes which are independently selected from a group comprising C1-C6alkyl, C1-C4alkoxy, CF3-O-; halogen, nitro, hydroxy, mercapto, cyano, C6-10aryl, C6aryloxy, C6aryl-C1alkyleneoxy, thienyl, morpholinyl, amino, C1alkylamino, di-C1alkylamino, heterocyclyl group and an oxo-group; R5 is selected from a group comprising and R6 is selected from a group comprising =O and =S; R7 is C2-3akylene; R8 is selected from a group comprising hydrogen and C1-C3alkyl; R10 is C4alkylene; A is selected from a group comprising -O-, -C(O)-, -S(O)0-2-, and -N(R4)-; Het is heterocyclyl selected from morpholinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl and others (see claim 1), which can be unsubstituted or substituted with one or more substitutes which are independently selected from a group comprising C1-C2alkyl, hydroxy, hydroxy-C1-C2alkyl, amino, C1-C2alkylamino, di-C1-C2alkylamino, heterocyclyl group and oxo; Het' is heterocyclylene selected from imidazolinyl and piperidinyl; Q is selected from a group comprising a covalent bond, -C(R6)-, -C(R6)-C(R6)-, -S(O)2-, -C(R6)-N(R8)-W-, -S(O)2-N(R8)- and -C(R6)-O-; V is selected from a group comprising -C(R6)-, -O-C(R6)-, -N(R8)-C(R6)-, and -S(O)2-; W is selected from a group comprising a covalent bond, , -C(O)-, and -S(O)2-; a and b are independently integers from 1 to 6, provided that a+b≤7; provided that Z can also denote a covalent bond when R3 is -Z-Het, -Z-Het'-R4, or -Z-Het'-Y-R4, or R3 is -Z-Y-R4 or -Z-Y-X-Y-R4, and Y is selected from a group comprising -S(O)0-2-, -C(R6)-, -C(R6)-O-, -C(R6)-N(R8)- and The invention also relates to a pharmaceutical composition based on the formula II compound, a method of inducing biosynthesis of cytokines, a method of treating a viral disease and an oncological disease using the compound of formula II.

EFFECT: novel derivatives of 1H-imidazo [4,5-c]quinoline, which are useful in treating viral and oncological diseases, are obtained.

37 cl, 130 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) in form of (R) or (S) isomers, separately or in a mixture, as well as their physiologically acceptable salts and hydrates, having vitronectin receptor antagonist properties. In formula (I)

G denotes Het-NH-CO-, Het-NH-CH2-, Het-; Het denotes a mono- or bicyclic system, where each ring is a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-2 nitrogen atoms as heteroatoms, where Het is unsubstituted or substituted with R9 groups; R1 denotes H, (C6-C14)-aryl, (C6-C14)aryl(C1-C4)alkyl; amino, unsubstituted, mono-or disubstituted with alkyl and/or acyl, containing 1-4 C atoms; R2 denotes H, halogen, nitro-group; alkyl containing 1-4 C atoms; amino, unsubstituted, mono- or disubstituted with alkyl and/or acyl containing 1-4 C atoms; a -(CH2)0-2-OR5 group; R3 denotes H, -CO2R5, -SO2R5 or mono- or bicyclic system, where each ring denotes a 5- or 6-member aromatic or non-aromatic ring, where at least one of the rings contains 1-4 heteroatoms selected from N, O or S, unsubstituted or substituted with R9 radicals; R4 denotes OH, (C1-C8)alkoxy-; amino, unsubstituted, mono- or disubstituted with (C1-C4)alkyl; or an aminoacid residue; R5 denotes (C1-C8)alkyl; (C6-C14)aryl; (C6-C14)aryl(C1-C4)alkyl; (C3-C12)cycloalkyl or (C3-C12)cycloalkyl(C1-C4)alkyl; bi- and tricycloalkyl(C1-C4)alkyl. Aryls, alkyls, cycloalkyls are not substituted or substituted with R9 groups; R9 denotes halogen, amino, nitro, hydroxyl, (C1-C4)alkyloxy-, carboxy, (C1-C4)alkyloxycarbonyl-, (C1-C8)alkyl, unsubstituted or substituted with halogen atoms; phenyl. The invention also relates to a methods for synthesis of formula (I) compounds, a medicinal agent and a pharmaceutical composition containing said compounds, as well as use thereof in preparing the medicinal agent.

EFFECT: improved properties of the compound.

21 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

Organic compounds // 2411239

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I, in which R1 denotes alkyl or cycloalkyl; R2 denotes phenyl-C1-C7-alkyl, di-(phenyl)- C1-C7-alkyl, naphthyl- C1-C7-alkyl, phenyl, naphthyl, pyridyl-C1-C7-alkyl, indolyl- C1-C7-alkyl, 1H-indazolyl- C1-C7-alkyl, quinolyl C1-C7-alkyl, isoquinolyl- C1-C7-alkyl, 1,2,3,4-tetrahydro-1,4-benzoxazinyl- C1-C7-alkyl, 2H-1,4-benzoxazin-3(4H)-onyl-C1-C7-alkyl, 9-xanthenyl-C1-C7-alkyl, 1-benzothiophenyl-C1-C7-alkyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 9-xanthenyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl, where each phenyl, naphthyl, pyridyl, indolyl, 1H-indazolyl, quinolyl, isoquinolyl, 1,2,3,4-tetrahydro-1,4-benzoxazonyl, 2H-1,4-benzoxazin-3(4H)-onyl, 1-benzothiophenyl, 4H-benzo[1,4]thiazin-3-only, 3,4-dihydro-1H-quinolin-2-onyl or 3H-benzoxazol-2-onyl are unsubstituted or contain one or up to 3 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy-C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkoxy-C1-C7-alkoxy- C1-C7-alkyl, C1-C7-alkanoyloxy- C1-C7-alkyl, amino- C1-C7-alkyl, C1-C7-alkoxy- C1-C7-alkylamino- C1-C7-alkyl, C1-C7-alkanoylamino- C1-C7-alkyl, C1-C7-alkylsulphonylamino- C1-C7-alkyl, carboxy- C1-C7-alkyl, C1-C7-alkoxycarbonyl- C1-C7-alkyl, halogen, hydroxy group, C1-C7-alkoxy group, C1-C7-alkoxy- C1-C7-alkoxy group, amino- C1-C7-alkoxy group, N-C1-C7-alkanoylamino-C1-C7-alkoxy group, carbamoyl- C1-C7-alkoxy group, N-C1-C7-alkylcarbamoyl-C1-C7-alkoxy group, C1-C7-alkanoyl, C1-C7-alkoxy-C1-C7-alkanoyl, C1-C7-alkoxy- C1-C7-alkanoyl, carboxyl, carbamoyl and N-C1-C7-alkoxy-C1-C7-alkylcarbamoyl; W denotes a fragment selected from residues of formulae IA, IB and IC, where () indicates the position in which the fragment W is bonded to the carbon atom in position 4 of the piperidine ring in formula I, and where X1, X2, X3, X4 and X5 are independently selected from a group containing carbon and oxygen, where X4 in formula IB and X1 in formula IC can assume one of these values or can be additionally selected from a group comprising S and O, where carbon and nitrogen ring atoms can include a number of hydrogen atoms or substitutes R3 or R4 if contained, taking into account limitations given below, required to bring the number of bonds of the carbon ring atom to 4 and 3 for the nitrogen ring atom; provided that in formula IA at least 2, preferably at least 3 of the atoms X1-X5 denote carbon and in formulae IB and IC at least one of X1-X4 denotes carbon, preferably 2 of the atoms X1-X4 denote carbon; y equals 0 or 1; z equals 0 or 1; R3, which can be bonded with any of the atoms X1, X2, X3 and X4, denotes hydrogen or a C1-C7-alkyloxy-C1-C7-alkyloxy group, phenyloxy-C1-C7-alkyl, phenyl, pyridinyl, phenyl- C1-C7-alkoxy group, phenyloxy group, phenyloxy-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, tetrahydropyranyloxy group, 2H,3H-1,4-benzodioxynyl-C1-C7-alkoxy group, phenylaminocarbonyl or phenylcarbonylamino group, where each phenyl or pyridyl is unsubstituted or contains one or up to 3 substitutes, preferably 1 or 2 substitutes independently selected from a group comprising C1-C7-alkyl, hydroxy group, C1-C7-alkoxy group, phenyl-C1-C7-alkoxy group, where phenyl is unsubstituted or substituted with a C1-C7-alkoxy group and/or halogen; carboxy- C1-C7-alkyloxy group, N-mono- or N,N-di-(C1-C7-alkyl)aminocarbonyl-C1-C7-alkyloxy group, halogen, amino group, N-mono- or N,N-di-(C1-C7-alkyl)amino group, C1-C7-alkanoylamino group, morpholino-C1-C7-alkoxy group, thiomorpholino-C1-C7-alkoxy group, pyridyl-C1-C7-alkoxy group, pyrazolyl, 4- C1-C7-alkylpiperidin-1-yl, tetrazolyl, carboxyl, N-mono- or N,N-di-(C1-C7-alkylamino)carbonyl or cyano group; or denotes 2-oxo-3-phenyltetrahydropyrazolidin-1-yl, oxetidin-3-yl-C1-C7-alkyloxy group, 3-C1-C7-alkyloxetidin-3-yl- C1-C7-alkyloxy group or 2-oxotetrahydrofuran-4-yl- C1-C7-alkyloxy group; provided that if R3 denotes hydrogen, then y and z are equal to 0; R4, if contained, denotes a hydroxy group, halogen or C1-C7-alkoxy group; T denotes carbonyl; and R11 denotes hydrogen, or pharmaceutically acceptable salts thereof. The invention also relates to use of formula I compounds, a pharmaceutical composition, as well as a method of treating diseases.

EFFECT: obtaining novel biologically active compounds having activity towards rennin.

11 cl, 338 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of pyrrolo[3,2-c]pyridine-4-one 2-indolinone of formula (I). Compound of formula (I): , where: represents single or binary bond; X and Y independently on each other are selected from C or N; X and Y represent N, then R5 and R7 are absent; R1 and R2 represent H; R3 is selected from alkyl, trifluormethyl, aryl and aralkyl, where said alkyl, aryl or aralkyl iis substituted by one or more halogens or hydroxyls; R4 is selected from alkyl, cycloalkyl, heterocycloalkyl, -[CH2CH(OH)]rCH2NR9R10 and -(CH2)nNR9R10, where said alkyl or heterocycloalkyl is probably substituted by one or more groups, selected from group, consisting of hydroxyl, amino, aminoalkyl, hydroxyalkyl and -NR9R10; X and Y represent C, then R5, R6, R7, R8 are independently on each other selected from hydrogen, halo, alkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, -OR9, -NR9R10, -NSO2R9, -NR9COR10, -NHCO2R10, where said aryl, heteroaryl, heterocycloalkyl are substituted by one or more groups, consisting of alkyl, alkoxyl and halogen; R9 and R10 independently on each other are selected from hydrogen, alkyl, cycloalkyl, where said alkyl, aryl, independently on each other are substituted by one or more groups, consisting of alkyl, aryl, hydroxyl, alkoxyl; R9 and R10 together with atom, to which they are bound, form 4-6-member rings, where 4-6-member rings can, in addition, contain one-two heteroatoms, selected from group, consisting of N and O, and each 4-6-member ring, formed in said way, is probably substituted by one or more groups, consisting of alkyl; n represents 2-6 and their pharmaceutically acceptable salts, where R1, R2, R3, R4, R5, R6, R7, R8, X, Y and -have values given in description. Also described is pharmaceutical composition, containing said compounds and possessing activity of proteinkinase inhibitor, methods of obtaining and pharmaceutical applications.

EFFECT: obtained and described are novel compounds, which can be useful as proteinkinase inhibitors.

20 cl, 131 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula pharmaceutically acceptable salts thereof, where ---- independently denotes a single or double bond; ring Q is imidazole, triazole (for example 1,2,3-triazole or 1,3,4-triazole), tetrazole or oxadiazole; B denotes C(R7)(R8) or C(R7), where if the bond between B and Y is a single bond, B denotes C(R7)(R8), and when the bond between B and Y is a double bond, B denotes C(R7); Y denotes C(R7), C(R7)(R8) or O, where if the bond between B and Y is a single bond, Y denotes C(R7)(R8) or O, and when the bond between B and Y is a double bond, B denotes C(R7); Z1 denotes -CH2-, -(CH2)2-, -CH2CH-CH3-, where Z1 is bonded on the left side to a nitrogen atom or -(CH2)3-; X denotes C(R1) or N; A denotes quinolyl, quinazolinyl or benzofuranyl, any of which is optionally substituted with 1-4 substitutes, which can be identical or different and are selected from a group comprising halogen, cyano, C1-6-alkyl, halogen-C1-6-alkyl, C(O)N(R3)(R4), 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; when R is present, each independently denotes halogen, C1-6-alkyl; each R1 denotes hydrogen or methyl; each R2 denotes cyano, C1-6-alkyl, C1-6-alkoxy, halogen-C1-6-alkyl, =O, -C(O)N(R3)(R4), -C(O)N(R3)-C1-6-alkoxy, -C(NOR5)R6, -C(O)R6, -C(O)OR7, -C(O)NHNHC(O)R6, 5-member heterocyclic ring containing 1-3 heteroatoms selected from N or O. The heterocyclic ring is optionally substituted with C1-6-alkyl; R3 and R4 independently denote hydrogen; C1-6-alkyl; C3-7-cycloalkyl; C3-7-cycloalkyl-C1-6-alkyl; or when R3 and R4 are bonded to the same nitrogen atom, they, together with the nitrogen atom, they form a 4-, 5- or 6-member ring which optionally contains one extra O atom in the ring; R5 denotes C1-4-alkyl; R6 denotes C3-7-cycloalkyl or C1-6-alkyl; R7 and R8 independently denote hydrogen or C1-6-alkyl; p equals 0, 1 or 2; r equals 0, 1, 2 or 3; s equals 0, 1, 2 or 3. The invention also relates to 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazin-3-carboxamide, 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}imidazo-[1,5-a]quinoline-3-carboxamide, dihydrochloride 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperidinyl]ethyl}[1,2,3]triazolo[1,5-a]quinoline-3-carboxamide, 7-methyl-6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4,5-dihydroimidazo[1,5-a]quinoline-3-carboxamide, to use of the compound in any of claims 1-16, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds, having 5-HT1 receptor mediated activity.

23 cl, 195 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described 3,4-substituted piperidines applicable in diagnostics and drug therapy of a warm-blooded animal, preferentially for therapy of a disease which depends on renin activity; application of a compound of such kind for preparing a pharmaceutical composition for therapy of the disease which depends on renin activity; application of the compound of such kind for therapy of the disease which depends on renin activity; the pharmaceutical compositions containing 3,4-substituted piperidine, and/or a therapeutic mode involving administration of 3,4-substituted piperidine, a method for producing 3,4-substituted piperidine. The preferential compound (which also can be presented in the form of salts) are described by formula I' wherein R1, R2, T, R3 and R4 are such as described by the patent claim.

EFFECT: production of the compounds for therapy of the disease which depends on renin activity.

28 cl, 1 tbl, 375 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: agent for treating systemic hypertension contains as an active ingredient a compound presented by formula (1): or its pharmaceutically acceptable salt.

EFFECT: preparation of the new agent for treating systemic hypertension.

12 cl, 7 ex, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , where the dotted line is either absent or denotes a double bond; R1 denotes H or C1-6-alkyl, possibly substituted with a CN group, or denotes a phenyl or sulphonyl phenyl, substituted with one or more B groups, or denotes -(CH2)m-Ra, where Ra denotes: NRiRii, C3-6-cycloalkyl, 6-member heterocycloalkyl, which denotes a univalent saturated group which contains one nitrogen heteroatom, the rest are carbon atoms, aryl, which can be substituted with one or more B groups, or denotes -(CH2)n-(CO)-Rb or -(CH2)n-(SO2)-Rb, where Rb denotes: NRiRii, 5-6-member heterocycloalkyl, which denotes a univalent saturated group containing one or more heteroatoms selected from nitrogen, oxygen, the rest are carbon atoms, aryl or 5- or 6-member heteroaryl, which denotes an aromatic ring containing two heteroatoms as ring members, the said heteroatoms selected from N or O, the rest are carbon atoms; which can possibly be substituted with one or more B groups, R2 denotes one or more H, halo, C1-6-alkyl, C1-6-alkoxy, R3 denotes H or-(CO)-Rc, where Rc denotes: C1-6-alkyl, 5-member heterocycloalkyl, which denotes a univalent saturated group containing one nitrogen heteroatom, the rest are carbon atoms possibly substituted with C1-6-alkyl, or denotes C1-6-alkyl; R4 denotes H; R5 denotes H, C1-6-alkyl, -(CH2)m-NRiRii, -(CH2)n-(CO)-Rb, where Rb denotes NRiRii or a 6-member heterocycloalkyl which denotes a univalent saturated group which contains one nitrogen heteroatom, the rest are carbon atoms, when the dotted line is absent or is absent when the dotted line denotes a double bond; R6 is absent, when the dotted line denotes a double bond; R7 denotes Cl or NReRf, where Re and Rf denotes H or C1-6-alkyl, or Re and Rf together with the nitrogen atom to which they are bonded form a 6-member heterocycloalkyl which denotes a univalent saturated group containing one or two heteroatoms selected from nitrogen, oxygen, the rest are carbon atoms; which can be substituted with C1-6-alkyl, or R6 and R7 together form a C=O group, when the dotted line is absent; B denotes halogen, C1-6-alkoxy, (CRiiiRiv)n-phenyl; Ri and Rii denote H, C1-6-alkyl -C(O)-C1-6-alkyl; Riii and Riv denote C1-6-alkyl; m equals to 1 or 2, n equals 0 or 1; as well as to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, as well as to use of compounds of formula (I), (I-a) or (1-b).

EFFECT: obtaining novel biologically active compounds having activity on V1a receptor.

12 cl, 48 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns methods of treating diseases with using VEGF antagonists. Substance of the invention involves application of a VEGF antagonist containing VEGFR1R2-FcΔ C1 (a) SEQ ID NO:4 in preparing a drug for hypertension reduction, in treating the diseases associated with administering the VEGF antagonist where the treatment is conducted by subcutaneous introduction.

EFFECT: advantage of the invention consists in reducing side effects associated with treating the diseases by administering the VEGF antagonist.

8 cl, 3 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to an agent exhibiting antihypertensive activity which represents 1-alkyl-2-alkylcarbamoylglycerins of general formula I . In formula I R means hydrocarbon radical -(CH2)nCH3 (n=10-18), R1 means methyl or ethyl. Also, the invention refers to a method for preparing the compounds of formula I. The method consists in the fact that parent 1-alkylglycerins of general formula II react with trimethylchlorosilane with using triethylamine in toluene medium at temperature -20°C to 0°C, then the reaction mass is added with appropriate alkylisocyanate and processed with ammonium bifluoride in methanol medium at room temperature.

EFFECT: preparation of the agent exhibiting antihypertensive activity.

2 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry and pharmaceutics and deals with novel anti-hypertension salt of general formula [(R1-COO-)·(H3N-R2)], where R1 is inhibitor of angiotensin-converting enzyme, selected from group, which consists of perindoprilat, ramiprilat, spiraprilat, benazeprilat, moexiprilat, trandalaprilat, fosinoprilat, enalaprilat, zofenoprilat or lisinopril, and R2 -calcium channel blocker, selected from group, consisting of amlodipine, lacidipine, felodipine, isradipine.

EFFECT: invention ensures reduction of therapeutic doses and side effects.

3 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to amide of δ-amino-γ-hydroxy-ω-arylalcane acid of formula and its pharmaceutically acceptable salts. Also described are pharmaceutical compositions, which include said compounds, and application of said compounds for preparation of medication, intended for treatment of pathological states, associated with renin activity, in particular for treatment of hypertension.

EFFECT: obtaining pharmaceutically acceptable salts, which possess rennin-inhibiting ability.

21 cl, 161 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to therapy and pharmacology, particularly to pharmacogenetic analysis, and concerns detecting genetic polymorphisms being efficacy markers of aliskiren as an antihypertensive agent. Aliskiren is used for preparing a drug for treating hypertension, for reducing mean derived systolic pressure and for reducing diastolic pressure. And aliskiren therapy is applied in a group of patients specified by genetic polymorphisms in biomarker genes where the aliskiren efficacy is indicated by genetic polymorphisms - SNP_4769 as specified in SEQ ID NO:1 in an angiotesin-converting enzyme (ACE) gene, SNP1445 as specified in SEQ ID NO:2 in an angiotensin II receptor type 2 (AGTR2) gene, and SNP_4795 as specified in SEQ ID NO:3 in an AGTR2 gene .

EFFECT: invention provides a method for determining sensitivity of a hypertensive individual to the aliskiren therapy, and application of a gene product of a gene specified in a group including the angiotesin-converting enzyme (ACE) gene and angiotensin II receptor type 2 (AGTR2) gene as a drug target.

6 cl, 1 dwg, 7 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology, endocrinology, and can be used for normalising the blood microvesicle level in impaired glucose tolerance. That is ensured by graduated physical activity, and administration of metformin 500 mg twice a day. The therapeutic course is at least 5 weeks.

EFFECT: offered combination of therapeutic modalities enables normalising the blood microvesicle level in a relatively short time that promotes prevention of thrombotic complications in the case patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gerontology, endocrinology, and can be used for pathologically raised biological age reduction in the patients with abdominal obesity. That is ensured by prescription of efficient graduated static and dynamic physical activity, daily swimming in a pool for not less than 30 minutes a day, and also administration of metformin in dosage 850 mg twice a day. The therapeutic course is 7 weeks.

EFFECT: offered combination of the modalities enables to adjust the biological and chronological ages that improves quality of life in the case patients.

2 ex, 1 dwg

FIELD: medicine, pharmaceutics.

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

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

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