Derivatives of 4,5-dihydro-1h-pyrazole possessing strong cb1-antagonistic activity

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of novel derivatives of 4,5-dihydro-1H-pyrazole that are strong antagonists of cannabinoid (CB1) receptor and useful in treatment of diseases associated with disorders of cannabinoid system. Compounds have the general formula (Ia) or (Ib) wherein symbols are given in the invention claim. Also, invention relates to method for synthesis of these compounds, their using, intermediate compounds for synthesis of proposed compounds and to a pharmaceutical composition comprising at least one of these compounds as an active component.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 1 tbl, 100 ex

 

The present invention relates to new derivatives of 4,5-dihydro-1H-pyrazole, to methods of producing these compounds and to pharmaceutical compositions containing one or more of these compounds as an active component.

Above 4,5-dihydro-1H-pyrazoles are strong antagonists of cannabinoid receptor (CB1)that can be used to treat disorders involving the cannabinoid neuropterida.

Cannabinoids are present in the Indian hemp plant Cannabis sativa, and used them as medicines for centuries (Mechoulam, R., Feigenbaum, J.J. Prog. Med. Chem. 1987, 24, 159). However, only in the last ten years for studies of cannabinoids was discovered basic information on cannabinoid receptors and their endogenous) agonists and antagonists. The discovery and subsequent cloning of two different subtypes of cannabinoid receptors (CB1and ST2) stimulated the search for new antagonists of cannabinoid receptors (Munro, S et al., Nature 1993, 365, 61; Matsuda, L.A., Bonner, T.I. Receptors cannabinoid chemistry, Pertwee, R.G. Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases associated with disorders of the cannabinoid system (Consroe, P. Neurobiology of Disease 1998, 5, 534; Pop, E. Curr. Opin. In CPNS Investigational Drugs 199, 1, 587; Greenberg, D.A. Drug News Perspect. 1999, 12, 458; Pertwee, R.G., Progress in Neurobiology 2001, 63, 569). Up to the present time know several antagonists ST1the receptors. Company Sanofi described compounds from the group of diarylpyrazole as selective antagonists ST1the receptor. A typical example is SR-141716A (Dutta, A.K. et al., Med. Chem. Res. 1994, 5, 54; Lan, R. et al., J. Med. Chem. 1999, 42, 769; Nakamura-Palacios, E.M. et al., CNS Drug Rev. 1999, 5, 43). CP-272871 represents a derivative of pyrazole similar SR141716A, but less effective and less selective with respect to the subtype ST1receptor compared with SR141716A (Meschler, J.P. et al., Biochem. Pharmacol. 2000, 60, 1315). As antagonists ST1receptor were described aminoalkylindole. A typical example is logoprado (AM-630), which was described in 1995. AM-630 represents a moderately active antagonist SV1receptor, but sometimes he behaves as a weak partial agonist (Hosohata, K. et al., Life Sc. 1997, 61, PL115). Researchers from Eli Lilly described aryl-aroyl substituted benzofuran as selective antagonists ST1receptor (e.g., LY-320135) (Felder, C.C. et al., J. Pharmacol. Exp. Ther. 1998, 284, 291). As ligands of cannabinoid receptor described 3-alkyl-5,5'-diphenylimidazole, which, as shown, are cannabinoid antagonists (Kanyonyo, M. et al., Biorg. Med. Chem. Lett. 1999, 9, 2233). Company Aventis Pharma (Aventis Pharma) for patentovany analogues of diarylpyrimidine as antagonists ST 1receptors (Mignani, S. et al., Patent FR 2783246, 2000; Chem. Abstr. 2000, 132, 236982). As antagonists ST1firm Sanofi-Synthelabo were patented tricyclic pyrazoles (Barth, F. et al., Patent WO 0132663, 2001; Chem. Abstr. 2001, 134, 340504). Interesting is the fact that many antagonists ST1receptors behave as inverse agonists in vitro (Landsman, R.S. et al., Eur. J. Pharmacol. 1997, 334, R1). The state of research in the field of cannabinoids in detail in the reviews (Mechoulam, R. et al., Prog. Med. Chem. 1998, 35, 199; Lambert, D.M. Curr. Med. Chem. 1999, 6, 635; Mechoulam, R. et al., Eur. J. Pharmacol. 1998, 359, 1; Williamson, E.M., Evans, F.J. Drugs 2000, 60, 1303; Pertwee, R.G. Addiction Biology 2000, 5, 37; Robson, P. Br. J. Psychiatry 2001, 178, 107; Pertwee, R.G. Prog. Neurobiol. 2001, 63, 569; Goya, P., Jagerovic, N. Exp. Opin. Ther. Patents 2000, 10, 1529; Pertwee, R.G. Gut 2001, 48, 859).

It has been unexpectedly discovered that a potent and selective antagonism towards cannabinoid ST1receptors appears new derivatives of 4,5-dihydro-1H-pyrazole of the formula (Ia) or (Ib), their prodrugs, tautomers and salts

where

- R and R1independently represent phenyl, thienyl or pyridyl, and these groups may be substituted by 1, 2 or 3 substituents Y, which can be the same or different, selected from the group1-3the alkyl or alkoxy, hydroxyl, halogen, trifloromethyl, triptoreline, triptoreline, nitro, amino, mono - or dialkyl(C1-2)-amino, mono - or d is alkyl(C 1-2)-amido, (C1-3)-alkylsulfonyl, dimethylsulfide,1-3-alkoxycarbonyl, carboxyl, triftormetilfullerenov, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R1represent naphthyl,

- R2represents hydrogen, hydroxyl, C1-3-alkoxy, atomic charges or propionyloxy,

- R3represents a hydrogen atom or a branched or unbranched1-8is an alkyl group or a C3-7-cycloalkyl group, with the alkyl or cycloalkyl group may be substituted by a hydroxy-group,

- R4represents a hydrogen atom or a branched or unbranched1-8-alkyl, C3-8-cycloalkenyl,2-10-heteroalkyl,3-8nah heterologously or4-10nah geterotsiklicheskikh fragment, and the specified portion may contain one or more heteroatoms selected from the group (O, N, S), and these fragments can be replaced by a keto group, triptorelin group1-3is an alkyl group, hydroxyl, amino, monoalkylamines or dialkylamino group or fluorine atom, or R4represents amino, hydroxy, phenoxy or benzyloxy group, or R4represents a branched or unbranched1-8-alkoxy, C3-85-8cycloalkenyl or6-9cyclooctylamino group, and these groups may contain a sulfur atom, nitrogen or oxygen, keto group or-SO2group, With1-8-alkoxy, C3-8Alchemilla,5-8cycloalkenyl or6-9cycloalkenyl group may be substituted by a hydroxy-group, triptorelin group, amino group, monoalkylamines or dialkylamines or fluorine atom, or R4represents phenyl, benzyl, pyridyloxy, thienyl, pyridylmethylene or fenetylline group, where the aromatic ring may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning indicated above, or

R4represents a group NR8R9provided that R3represents a hydrogen atom or methyl group, and where R8and R9are the same or different and represent a1-4-alkyl or C2-4-triptorelin, or R8and R9together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic group having from 4 to 8 atoms in the ring, and the specified heterocyclic group may contain an oxygen atom or sulfur, or Citigroup or-SO2group, or an additional nitrogen atom, and the specified saturated or nanosys the fair heterocyclic group may be substituted With 1-4is an alkyl group, or

R3and R4together with the nitrogen atom to which they are attached, form a saturated or unsaturated monocyclic or bicyclic heterocyclic group having from 4 to 10 atoms in the cycle, and the specified heterocyclic group may contain one or more atoms from the group O, N, S), or Citigroup or-SO2group, and this group may be substituted With1-4is an alkyl, hydroxyalkyl, phenyl, thienyl, peredelnoj, amino, monoalkanolamines, dialkylaminoalkyl, monoalkylamines, dialkylamines, aminoalkyl, azetidinone, pyrrolidinyloxy, piperidinyloxy or hexahydro-1H-aspenlea group,

- R5and R6independently from each other represent a hydrogen atom or a branched or unbranched1-8is an alkyl or alkenylphenol group, and these groups may contain one or more heteroatoms from the group (O, N, S), ketogroup or-SO2group and may be substituted by hydroxyl or amino group, or R5and R6independently from each other represent a3-8-cycloalkyl group or3-8-cycloalkenyl group, which may contain in the cycle one or more heteroatoms selected from the group (O, N, S), or-SO2- the group with the specified group is s can be substituted by a hydroxy-group, the alkyl(C1-3), -SO2group, geography, amino group, monoalkylamines (C1-3or dialkylamino (C1-3), or

R5represents naftalina group or phenyl group, with the phenyl group may be substituted by 1, 2 or 3 substituents Y, where Y has the meaning specified above, provided that R6represents a hydrogen atom or a branched or unbranched alkyl group (C1-5), and the alkyl group can contain one or more heteroatoms from the group (O, N, S) or-SO2- group and can be substituted by hydroxyl, keto or amino group, or

- R5and R6together with the nitrogen atom to which they are attached, form a monocyclic, bicyclic or tricyclic alkyl or alkenylphenol group, which may contain in the cycle heteroatoms from the group (O, N, S), keto-or-SO2group, and specified monocyclic, bicyclic or tricyclic alkyl or Alchemilla group may be substituted by hydroxy group, alkyl(C1-3) group, SO2group, geography, amino group, monoalkylamines (C1-3), dialkylamino (C1-3), pyrrolidinyl group or piperidinyl group, and specified monocyclic, bicyclic or tricyclic alkyl or alkenyl the group can contain anilinophenol phenyl group, moreover, the specified annelirovaniya phenyl group may be substituted by 1 or 2 substituents Y where Y has the designation described above

- R7represents a branched or unbranched1-3alkyl.

In the compounds of formula (Ia) and (Ib) are present at least one center of chirality (position44,5-dihydro-1H-pyrazol group).

The invention relates to racemates, mixtures of diastereomers, and the individual stereoisomers of the compounds having the formula (Ia) or (Ib). Particularly interesting compounds of formula (Ia) or (Ib) have the absolute stereoconfiguration in position With44,5-dihydro-1H-pyrazol group represented by the formula (1a) and (1b*):

The invention also applies to the E isomer, Z isomer and E/Z mixtures of compounds having the formula (Ia) or (Ib).

Compounds according to the invention can be converted into a form suitable for injection, conventional methods using auxiliary substances and/or liquid or solid media.

Thanks to the powerful ST1the antagonistic activity of the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, fear, depression, attention deficit disorder, memory disorders, cognitive disorders, appetite disorders, is Irene, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette syndrome, cerebral ischemia, stroke, traumatic brain injury, stroke, spinal cord injury, neirolepticalkie disease, multiple sclerosis, viral encephalitis, disorders associated with demyelination, as well as for the treatment of pain States, including neuropathic pain, and other diseases involving cannabinoid neuropterida, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory illnesses, disorders of the gastrointestinal tract, gastric ulcers, diarrhoea and cardiovascular diseases.

The affinity of the compounds according to the invention for cannabinoid ST1the receptors was determined using membrane preparations of cells of the Chinese hamster ovary (Cho), in which cannabinoid ST1the receptor of a person firmly transfection with [3H]CP-55,940 as a radioactive ligand. After incubation of freshly prepared cell membrane preparations with [3H]-ligand, with or without added from the of dinani according to the invention the separation of bound and free ligand were carried out by filtration through filters made of fiberglass. The radioactivity on the filter was measured by liquid scintillation counter.

Antagonistic activity of the compounds according to the invention for cannabinoid ST1the receptor was determined by functional studies using Cho cells, in which cannabinoids ST1receptors are steadily ExpressionEngine. Adenylylcyclase stimulated using Forskolin, and was measured by determining the amount of the accumulated cyclic AMP. Concomitant activation of ST.1receptor agonists ST1receptor (e.g., CP-55,940 or (R)-WIN-55,212-2) may weaken due Forskolin accumulation of camp in-dependent of concentration form. This reaction, in which the mediator is ST1the receptor can be anlagenservice antagonists ST1receptor, such as compounds according to the invention.

Intermediate compounds having the formula (II) (see below), can be obtained with known methods, for example: (a) Francotte, E.; Tong, Z. Chem. Abstr. 126, 213598; (b) Rempfler, H.; Kunz, W. Chem. Abstr. 113, 40432; (c) Rempfler, H.; Kunz, W. Chem. Abstr. 107, 217473.

Intermediate compounds having the formula (III), where R2represents hydrogen (see below), can be obtained by known methods, for example, a) EP 0021506; (b) DE 2529689, c) Grosscurt, A.C. et al., J. Agric. Food Chem. 1979, 27, (2), 406.

Intermediate compounds having the formula (III), where R2is a Hydra is xygraph, can be obtained by the interaction of the compounds having formula (II)with hydrazine or hydrazine hydrate

This reaction is preferably conducted in an organic solvent, such as ethanol, gives compound having the formula (III), where R2represents a hydroxy-group.

A way which is suitable for the synthesis of compounds according to the invention are the following:

The way of synthesis And

Stage 1: the interaction of compounds having the formula (III),

with a compound having the formula (IV).

This reaction is preferably carried out in an organic solvent, e.g. dichloromethane, and get a compound with formula (V), where R, R1, R2, R5and R6marked as specified above for compound (Ia), and which are new.

Stage 2: interaction of compounds having the formula (V)with the compound R7-X, where X is the group that you want, for example jodido group, and R7has the meaning indicated above for (Ib), gives compound having the formula (Ib).

Preferably, this reaction is carried out in the presence of a base, such as triethylamine.

Stage 3: the interaction of compounds having the formula (Ib), with an amine having the formula HNR3R4where R3and R4have the above values, similar to the method described in Synth. Commun. 1996, 26, (23), 4299.

This reaction gives a compound having the formula (Ia).

Path synthesis A1

Stage 1: the Interaction of compounds having the formula (V),

with an amine having the formula HNR3R4where R3and R4have the above notation, in the presence of mercury salts (II), for example, HgCl2that gives compound having the formula (Ia).

This reaction is preferably carried out in an organic solvent, for example acetonitrile, similar to the method described in Synth. Commun. 1996, 26, (23), 4299.

The way of synthesis of A2

Stage 1: the Interaction of compounds having the formula (III),

with the derived isocyanate having the formula (VI), followed by treatment with the amine HNR5R6.

This reaction is preferably carried out in an organic solvent, similar dichlormethane, and this gives compound having the formula (VII). The compounds of formula (VII), where R, R1, R2, R5and R6have the values specified above for compound (Ia), are new.

Stud is I 2: interaction of the compounds of formula (VII) with a halogenation agent, for example, PCl5that gives compound of formula (VIII)

where R10represents a halogen atom such as chlorine atom. This reaction is preferably carried out in an organic solvent such as chlorobenzene.

Compounds having the formula (VIII), where R, R1, R2, R5and R6have the values specified above for compound (Ia), and where R10represents a halogen atom, are new.

Stage 3: the interaction of compounds having the formula (VIII)is preferably carried out in an inert organic solvent, such as dichloromethane, with an amine having the formula HNR3R4where R3and R4have the meanings specified above, gives compound having the formula (Ia).

Path synthesis A3

Stage 1: the interaction of compounds having the formula (III),

with a compound having the formula (IX),

gives compound having the formula (Ib), (see, for example, Chem. Ber. 1966, 99, 2885 and Chem. Ztg. 1984, 108, (12), 404).

Obtaining compounds is illustrated by the following examples.

Example 1

3-(4-Chlorophenyl)-N'-(((ethyl)propylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine

Stage A: To a stirred solution of ((ethyl)propylamino)sulfosalicylate (5,98 grams of 25.4 mmol) in dry chlormethine in nitrogen atmosphere add 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (6,52 grams, to 25.4 mmol). After stirring for 90 minutes the resulting solution was concentrated in vacuo and purified column chromatography (CH2Cl2, silica gel, Rf˜0,45). The resulting solid is recrystallized from diethyl ether, obtaining 3-(4-chlorophenyl)-N-(((ethyl)propylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (6,57 g, yield 56%). Melting point: 144-146°C.

Stage b: To a stirred suspension of 3-(4-chlorophenyl)-N-(((ethyl)propylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (2,32 g, 5 mmol) in acetonitrile (20 ml) add cold methylamine (4 ml). To the resulting solution was added a solution of HgCl2(1.5 grams) in acetonitrile (10 ml). The resulting black suspension is stirred for 4 hours. The precipitate is removed by filtration. The filtrate was concentrated in vacuo, dissolved in dichloromethane and successively washed with water to 0.5 N. NaOH solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oily substance is crystallized from diethyl ether, obtaining 3-(4-chlorophenyl)-N'-(((ethyl)propylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (1,78 g, yield 77%). The melting temperature (Tpl.): 129-131°C.

Similarly receive the compounds of formula (Ia), n is listed below:

2. 3-(4-chlorophenyl)-N'-(((ethyl)methylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=112-115°C.

3. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-hydroxyethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=104-106°C.

4. 3-(4-chlorophenyl)-N-(2-hydroxyethyl)-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MS (ESI+):490(MN+).

5. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-(morpholine-4-yl)ethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MS (ESI+):547(MN+).

6. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(2-(morpholine-4-yl)ethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

7. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-(dimethylamino)ethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MS (ESI+):505(MH+).

8. 3-(4-chlorophenyl)-N-(3-(dimethylamino)propyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

9. 3-(4-chlorophenyl)-N-(2-(piperidine-1-yl)ethyl)-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MS (ESI+):557(MN+).

10. 3-(4-chlorophenyl)-N-(2-(morpholine-4-yl)ethyl)-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MS (ESI+):559(MN+); Tpl.=174-176°C.

11. 3-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carbox midin. Amorphous substance.

12. 3-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

13. 3-(4-chlorophenyl)-N-(3-(dimethylamino)propyl)-N'-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MS (ESI+):519(MN+).

14. 3-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine hemifumarate. Tpl.=182-185°C.

15. 3-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

16. 3-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((pyrrolidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

17. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(1-methylpiperidin-4-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

18. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(2-hydroxyethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=123-126°C.

19. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance. Rf˜0,4 (diethyl ether).

20. 3-(4-chlorophenyl)-N'-(((ethyl)propylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=129-131°C.

21. 3-(4-chlorophenyl)-N-methyl-N'-((pyrrolidin-1-yl)sulfonyl)-4-phenyl-4,5-Digi the ro-1H-pyrazole-1-carboxamidine. Amorphous substance. Rf˜0,3 (MTBE).

22. 3-(4-chlorophenyl)-N-methyl-N'-(((methyl)propylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=132-134°C.

23. 3-(4-chlorophenyl)-N,N-dimethyl-N'-((pyrrolidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance. Rf˜0,25 (MTBE).

24. 3-(4-chlorophenyl)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=175-177°C.

25. 3-(4-chlorophenyl)-N'-((hexahydro-1H-azepin-1-yl)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

26. 3-(4-chlorophenyl)-N'-((dipropylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=141-142°C.

27. 3-(4-chlorophenyl)-N'-(((isopropyl)methylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=134-136°C.

28. 3-(4-chlorophenyl)-N-methyl-N'-((octahydrate-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=165-168°C.

29. 3-(4-chlorophenyl)-N-ethyl-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

30. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=166-168°C.

Example 31

3-(4-Chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-propyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine

Stage A: To p is remesiana solution chlorosulfonylisocyanate (1.73 ml, 20 mmol) in dry dichloromethane (20 ml) very slowly add a solution of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (5,13 grams, 20 mmol) in dry dichloromethane (125 ml) at -5°C. After stirring for 30 minutes the reaction mixture is allowed to warm to room temperature and continue stirring for another 2 hours. After cooling to 0°add liquid dimethylamine (5 ml) and the resulting solution is stirred for an additional hour at 0°and for 2 hours at room temperature. The solution is washed with water, filtered through Hyflo and concentrated in vacuo. Flash chromatography (MTBE, Rf˜0,3) gives 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide and 4.75 g, 58%). Tpl.=210-212°C.

Stage b: a Mixture of 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1,47 g, 3.62 mmol) and pentachloride phosphorus (0,80 grams of 3.84 mmol) in chlorobenzene (20 ml) is refluxed for 1 hour. After complete concentration in vacuum is obtained 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxymethylated suspended in dry dichloromethane and conduct the reaction with cold ad-Propylamine (1.0 ml) at 0°C. After stirring for 1 hour the mixture was dissolved in ethyl acetate, washed with water and will contentresult in vacuum. The residue is purified column chromatography (dichloromethane/acetone = 19/1 (about./about., Rf˜0,35), getting oily substance (0,82 g). Crystallization from diethyl ether, followed by recrystallization from ethanol gives 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-propyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (0,38 g, yield 23%). Tpl.=127-129°C.

In a similar way, prepare the following compounds having the formula (Ia):

32. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(2-foradil)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=128-131°C.

33. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-N-(2,2,2-triptorelin)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=158-159°C.

34. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=170-172°C.

Example 35

Methyl ester of 3-(4-chlorophenyl)-N-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid

Stage A: To a stirred solution of (piperidine-1-yl)sulfosalicylate (54,77 g, 266 mmol) in dry dichloromethane (900 ml) under nitrogen atmosphere add 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (68.3 g, 266 mmol). After stirring for 16 hours add an additional amount of dichloromethane. The resulting solution washed twice is an ode, dried over Na2SO4and concentrated in vacuo. After adding MTBE residue crystallized. Crystalline material is collected and washed with MTBE, getting 3-(4-chlorophenyl)-4-phenyl-N-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (77.6 per gram, yield 63%).

Stage b: To a stirred solution of 3-(4-chlorophenyl)-4-phenyl-N-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-thiocarboxamide (30 grams, 64,9 mmol) in acetone (1 l) was added triethylamine (18,0 ml, 130 mmol). To the resulting yellow solution add methyliodide (9,12 g, 64 mmol) and the resulting solution was stirred for 16 hours at room temperature. The resulting precipitate removed by filtration. The filtrate is washed with water, concentrated in vacuo, receiving a yellow solid substance. By recrystallization from MTBE receive the methyl ester of 3-(4-chlorophenyl)-N-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid (27,9 g, yield 90%). Tpl.=192-194°C.

Similarly receive the compounds of formula (Ib)below:

36. Methyl ester of 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=159-160°C.

37. Methyl ester of 3-(4-chlorophenyl)-N-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=141-143°C.

38. Metrov the th ether 3-(4-chlorophenyl)-4-phenyl-N-((1,2,3,4-tetrahydroisoquinoline-2-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=143-145°C.

39. Methyl ester of 3-(4-chlorophenyl)-N-(((ethyl)phenylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=143-146°C.

40. Methyl ester of 3-(4-chlorophenyl)-N-((diethylamino)sulfonyl)-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Amorphous substance.

41. Methyl ester of 3-(4-chlorophenyl)-N-((diethylamino)sulfonyl)-4-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Amorphous substance.

42. Methyl ester of 3-(4-chlorophenyl)-N-(piperidine-1-yl)sulfonyl)-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Amorphous substance.

43. Methyl ester of 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Amorphous substance.

44. Methyl ester of 3-(4-chlorophenyl)-N-(((ethyl)methylamino)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=133-136°C.

45. Methyl ester of 3-(4-chlorophenyl)-N-(piperidine-1-yl)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=182-185°C.

46. Methyl ester of 3-(4-chlorophenyl)-N-(morpholine-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=202-204°C.

47. Methyl ester of 3-(4-chlorophenyl)-4-(2-forfinal)-N-(morpholine-4-yl)sulfonyl)-4,5-dihydro-1H-feast of the evils-1-iminodicarboxylic acid. Tpl.=205-207°C.

48. Methyl ester of 3-(4-chlorophenyl)-4-(2-forfinal)-N-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=196-198°C.

49. Methyl ester of 3-(4-chlorophenyl)-4-(2-forfinal)-N-((dimethylamino)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=181-183°C.

50. Methyl ester of 3-(4-chlorophenyl)-4-(2,6-differenl)-N-(morpholine-4-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=231-233°C.

51. Methyl ester of 3-(4-chlorophenyl)-4-(2,6-differenl)-N-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=221-225°C.

52. Methyl ester of 3-(4-chlorophenyl)-4-(2,6-differenl)-N-((dimethylamino)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=181-185°C.

53. Methyl ester of 3-(4-chlorophenyl)-N-((1,1-diocletianopolis-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=216-217°C.

54. Methyl ester 3-(5-chlortan-2-yl)-N-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Amorphous substance.

Example 55

3-(4-chlorophenyl)-N-methyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine

To the cooled mixture (<0° (C) methyl ester of 3-(4-chlorophenyl)-N-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-they are thiocarbonic acid (10.0 grams, 21 mmol) in methanol (75 ml) is added a cold methylamine (15 ml). The obtained mixture is allowed to warm to room temperature and stirred for 3 hours at 50°C. After cooling to room temperature the mixture was concentrated in vacuo, dissolved in dichloromethane, washed twice with water, dried over Na2SO4, filtered and concentrated in vacuo. Subsequent flash chromatography (EtOAc/MeOH/NH4OH (25% aq.)=95/5/0,5 (about./vol.), followed by recrystallization from diisopropyl ether gives 3-(4-chlorophenyl)-N-methyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine (7,87 g, yield 81%) as a white solid. Tpl.=175-177°C.

Similarly receive the following compounds of formula (Ia), including compounds of table 1:

56. 3-(4-chlorophenyl)-N-cyclopropyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=142-144°C.

57. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=180-182°C.

58. 3-(5-chlortan-2-yl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=122-123°C.

59. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-isopropyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=169-170°C.

60. 3-(4-chlorophenyl)-N'-((dimethylene is about)sulfonyl)-N-(1-methylpiperidin-4-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=144-146°C.

61. 3-(4-chlorophenyl)-N-cyclopropyl-N'-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=150-151°C.

62. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-ethyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=116-119°C.

63. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N,N-dimethyl-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=135-137°C.

64. N'-((diethylamino)sulfonyl)-N,N-dimethyl-3-(4-forfinal)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=159-160°C.

65. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-isopropyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=81-85°C.

66. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-ethyl,N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

67. 3-(4-chlorophenyl)-N-ethyl,N-methyl-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=178°C.

68. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-ethyl-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=162 to 165°C.

69. 3-(4-chlorophenyl)-N-methyl-N'-((1,2,3,4-tetrahydroisoquinoline-2-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous substance.

70. 3-(4-chlorophenyl)-N'-(((ethyl)phenylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=145-147°C.

71. N'-((diethylamino)with Lionel)-3-(4-chlorophenyl)-N-methyl-4-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=109-111°C.

72. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=157-159°C.

73. 3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=85-89°C.

74. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=178-182°C.

75. 3-(4-chlorophenyl)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=168-170°C.

76. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=65-68°C.

77. 3-(4-chlorophenyl)-N'-(((ethyl)methylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=125-128°C.

78. 3-(4-chlorophenyl)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=174-177°C.

79. 3-(4-chlorophenyl)-4-(2,6-differenl)-N-methyl-N'-(morpholine-4-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=223-235°C.

80. 3-(4-chlorophenyl)-4-(2,6-differenl)-N'-((dimethylamino)sulfonyl)-N-methyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=214-216°C.

81. 3-(4-chlorophenyl)-4-(2,6-differenl)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine pl.=260-263°C.

82. 3-(4-chlorophenyl)-4-(3-forfinal)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=170°C.

83. 3-(4-chlorophenyl)-4-(2-forfinal)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=223-225°C.

84. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-(2-forfinal)-N-methyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=173-175°C.

85. 3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-(3-forfinal)-N-methyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=110°C.

86. 3-(4-chlorophenyl)-4-(2-forfinal)-N-methyl-N'-(morpholine-4-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=165-168°C.

87. 3-(4-chlorophenyl)-N'-((1,1-diocletianopolis-4-yl)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=268-271°C.

88. 3-(4-chlorophenyl)-N'-((4-hydroxypiperidine-1-yl)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. Tpl.=80°C.

Table 1
Example: R11R12Tpl.(°)Salt form
89: 4-methyl-1,4-diazepan-1-ylDimethylamino197-2000.5 fumarate
90: 1,4-diazepan-1-yl Piperidine-1-ylAmorphous substance
91: 1,4-diazepan-1-ylDimethylaminoAmorphous substance
92: 4-methyl-1,4-diazepan-1-ylPiperidine-1-yl159-164
93: 4-methylpiperazin-1-ylDimethylamino191-193

Example 94

Methyl ester of 3-(4-chlorophenyl)-N-((4-methylpiperazin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid

Part a: a Mixture of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3,21 g, 11.3 mmol), dimethyl ether [(4-methylpiperazin-1-yl)sulfonyl]diotomaceous acid (is 3.08 grams of 12.0 mmol) and pyridine (25 ml) is heated under stirring at 100°C for 24 hours in nitrogen atmosphere. After cooling to room temperature the mixture was concentrated in vacuo, water is added and the resulting mixture extracted with dichloromethane. The dichloromethane extract washed twice with water, dried over Na2SO4, filtered and concentrated in vacuo. Subsequent purification with flash chromatography gives the methyl ester of 3-(4-chlorophenyl)-N-((4-methylpiperazin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid (4,24 g, yield 76%) as a solid amorphous material. (Rf˜ 0,1, EtOAc/methanol = 95/5 (about./vol.)).

Similarly receive the following compounds having the formula (Ib):

95. Methyl ester of 3-(4-chlorophenyl)-N-(((2-(dimethylamino)ethyl)ethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=158°C.

96. Methyl ester of N-((diethylamino)sulfonyl)-3-(4-forfinal)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Amorphous substance. Rf˜0,4 (MTBE).

97. Methyl ester of 3-(4-chlorophenyl)-N-(([1,4']bipiperidine-1'-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Tpl.=245°C.

98. Methyl ester of 3-(4-chlorophenyl)-N-(((1-methylpiperidin-4-yl)methylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Oily substance. Rf˜0,15 (methanol/dichloromethane = 5/95 (about./vol.)).

99. Methyl ester of 3-(4-chlorophenyl)-N-((4-methyl-1,4-diazepan-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid. Amorphous substance. Rf˜0,10 (methanol/dichloromethane = 5/95 (about./vol.)).

Example 100

(-)-(4S)-3-(4-chlorophenyl)-N-methyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine

(-)-(4S)-3-(4-Chlorophenyl)-N-methyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine (3.8 g, 8.3 mol) ([α25D]=-139°,=0,006, Meon) are obtained in the form of a solid amorphous substances, the separation of chiral chromatography of racemic 3-(4-chlorophenyl)-N-methyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine (7,87 grams, of 17.1 mmol)using chiral stationary phase Chiralpak AD. The mobile phase consists of a mixture of methanol/diethylamine=999/1 (about./vol.).

In a similar manner from the corresponding racemates receive these optically pure compounds:

101. (-)-(4S)-3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (Chiral stationary phase: Chiralcel OD). The mobile phase consists of a mixture of hexane/2-propanol =80/20 (vol./about.) ([α25D]=is 147°, C=0.01, Meon). Amorphous substance.

102. (-)-(4S)-3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (Chiral stationary phase: Chiralpak AD). The mobile phase consists of a mixture of methanol/diethylamine =999/1 (about./about.) ([α25D]=-171°, C=0,005, Meon). Amorphous substance.

103. (-)-(4S)-3-(4-chlorophenyl)-N-methyl-N'-(morpholine-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine.([α25D]=-144°, C=0.01, Meon). (Chiral stationary phase: Chiralpak AD). The mobile phase consists of ethanol. Amorphous substance.

1. Compounds of General formula (Ia) or (Ib)

where R represents a phenyl or thienyl, substituted with halogen;

R1represents phenyl which may be substituted by 1-2 substituents selected from the ha is Ohana and trifloromethyl, or R1represents pyridyl;

R2represents hydrogen or hydroxyl;

R3represents a hydrogen atom or a branched or non-branched C1-8is an alkyl group or a C3-7-cycloalkyl group, with the alkyl group may be substituted by a hydroxy-group;

R4represents a hydrogen atom or a branched or non-branched C1-8is an alkyl group which may be substituted triptorelin group, amino, monoalkylamines or dialkylamines or fluorine atom, or

R4is a branched or non-branched C1-8-alkoxy, or pyridyloxy group, substituted C1-3alkyl group, heteroseksualci-alkyl group, where heteroseksualci is morpholino or piperidino, or

R3and R4together with the nitrogen atom to which they are attached, form a saturated, monocyclic heterocyclic group having from 6 to 7 atoms in the cycle, which contains 2 nitrogen atom, and the group may be substituted With1-4is an alkyl group;

R5and R6independently from each other represent a hydrogen atom or a branched or non-branched C1-8is an alkyl group, or R5is a FeNi is inuu group, or R5and R6together with the nitrogen atom to which they are attached, form a monocyclic heterocyclic group having 5 to 8 atoms in the cycle, and which may optionally contain in the cycle the oxygen atom or SO2group, and this group may be substituted by alkyl(C1-3) group or piperidino group, or R5and R6together with the nitrogen atom to which they are attached represent a 6-membered heterocyclic group, anilinophenol with a phenyl group;

R7represents a C1-3alkyl, and their stereoisomers, and salts.

2. The compound according to claim 1, which is a

3-(4-chlorophenyl)-N'-(((ethyl)propylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-(((ethyl)methylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-hydroxyethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(2-hydroxyethyl)-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-(morpholine-4-yl)ethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(2-(morpholine-4-yl)ethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-(2-(dimethylamino)ethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(3-(dimethylamino)propyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(2-(piperidine-1-yl)ethyl)-N-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(2-(morpholine-4-yl)ethyl)-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(3-(dimethylamino)propyl)-N'-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

hemifumarate 3-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(2-(dimethylamino)ethyl)-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)-N'-((pyrrolidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-(((diethylamino)sulfonyl)-N-(1-methylpiperidin-4-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-x is arvanil)-N'-(((dimethylamino)sulfonyl)-N-(2-hydroxyethyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-(((ethyl)propylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-methyl-N'-((pyrrolidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-methyl-N'-(((methyl)propylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N,N-dimethyl-N'-((pyrrolidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((hexahydro-1H-azepin-1-yl)sulfonyl)-4-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dipropylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-(((isopropyl)methylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-methyl-N'-((octahydrate-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-ethyl-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)Sul who were radioactive)-N-propyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(2-foradil)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-phenyl-N-(2,2,2-triptorelin)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

methyl ester of 3-(4-chlorophenyl)-N-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-4-phenyl-N-((1,2,3,4-tetrahydroisoquinoline-2-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-(((ethyl)phenylenesulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-((diethylamino)sulfonyl)-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-((diethylamino)sulfonyl)-4-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-(piperidine-1-yl)sulfonyl)-4-(3-trifluoromethyl)phenyl-45-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-((dimethylamino)sulfonyl)-4-(3-trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-(((ethyl)methylamino)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-(piperidine-1-yl)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-(morpholine-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-4-(2-forfinal)-N-(morpholine-4-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-4-(2-forfinal)-N-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-4-(2-forfinal)-N-((dimethylamino)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-4-(2,6-differenl)-N-(morpholine-4-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-4-(2,6-differenl)-N-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-4-(2,6-differenl)-N-((dimethylamino)sulfonyl)-4,5-dihydro-1H-pyrazole-1-iminodiethanol sour is you,

methyl ester of 3-(4-chlorophenyl)-N-(1,1-diocletianopolis-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester 3-(5-chloranil)-N-((diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

3-(4-chlorophenyl)-N-methyl-4-phenyl-N′-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-cyclopropyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(5-chlortan-2-yl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-isopropyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-(1-methylpiperidin-4-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-cyclopropyl)-N'-(diethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-(diethylamino)sulfonyl)-N-ethyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N,N-dimethyl-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

N'-(diethylamino)sulfonyl)-N,N-dimethyl-3-(4-forfinal)-4-phenyl-4,5-dihyd is about-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl-N'-(diethylamino)sulfonyl)-N-isopropyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-ethyl,N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-ethyl,N-methyl-N'-(piperidine-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-ethyl-4-hydroxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-methyl-N'-((1,2,3,4-tetrahydroisoquinoline-2-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-(((ethyl)phenylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

N'-((diethylamino)sulfonyl)-3-(4-chlorophenyl)-N-methyl-4-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(pyridin-4-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole--carboxamide,

3-(4-chlorophenyl)-N'-(((ethyl)methylamino)sulfonyl)-N-methyl-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-4-(2,6-differenl)-N-methyl-N'-(morpholine-4-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-4-(2,6-differenl)-N'-((dimethylamino)sulfonyl)-N-methyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-4-(2,6-differenl)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-4-(3-forfinal)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-4-(2-forfinal)-N-methyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-(2-forfinal)-N-methyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-4-(3-forfinal)-N-methyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-4-(2-forfinal)-N-methyl-N'-(morpholine-4-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((1,1-diocletianopolis-4-yl)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

3-(4-chlorophenyl)-N'-((4-hydroxypiperidine-1-yl)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-piraso the-1-carboxamidine,

methyl ester of 3-(4-chlorophenyl)-N-((4-methylpiperazin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-(((2-dimethylamino)ethyl)ethylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of N-((diethylamino)sulfonyl)-3-(4-forfinal)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-(([1,4']bipiperidine-1'-yl) sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-(((1-methylpiperidin-4-yl)methylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

methyl ester of 3-(4-chlorophenyl)-N-((4-methyl-1,4-diazepan-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-iminodicarboxylic acid,

(-)-(4S)-3-(4-chlorophenyl)-N-methyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine,

(-)-(4S)-3-(4-chlorophenyl)-N'-((diethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

(-)-(4S)-3-(4-chlorophenyl)-N'-((dimethylamino)sulfonyl)-N-methyl-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine,

(-)-(4S)-3-(4-chlorophenyl)-N-methyl-N'-(morpholine-4-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine

or compounds of General formula

moreover, when R11is a 4-methyl-1,diazepan-1-yl, R12represents a dimethylamino;

when R11represents 1,diazepan-1-yl, R12represents piperidine-1-yl;

when R11represents 1,diazepan-1-yl, R12represents a dimethylamino;

when R11is a 4-methyl-1,diazepan-1-yl, R12represents piperidine-1-yl;

when R11is a 4-methylpiperazin-1-yl, R12represents a dimethylamino;

and their stereoisomers and salts.

3. The compound according to claim 1, which is (-)-(4S)-3-(4-chlorophenyl)-N-methyl-4-phenyl-N'-(piperidine-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine formula

and its salts.

4. Pharmaceutical composition having antagonistic activity against cannabinoid receptor SV containing a pharmacologically active amount of at least one compound according to claim 1 as an active ingredient.

5. A method of obtaining a pharmaceutical composition according to claim 4, characterized in that the connection lead according to claim 1 in a form suitable for injection.

6. Method of preparing compounds having the formula (Ib),

different is eat, what connection, where R, R1-2, R5-R6and R7have data in claim 1 denote the receive interaction in an organic solvent compounds having the formula (III)

with a compound having the formula (IV)

obtaining the compounds of formula (V),

which in the presence of a base interacts with the compound of the formula R7-X, where X is a leaving group as iodide.

7. Method of preparing compounds having the formula (Ib),

characterized in that the compound, where R, R1-2, R5-R6and R7have data in claim 1 denote the receive interaction in an organic solvent compounds having the formula (III)

with a compound having the formula (IX)

8. Method of preparing compounds having the formula (Ia),

characterized in that the compound, where R and R1-R6have data in claim 1 denote the receive interaction of compounds having the formula (Ib),

with an amine of the formula HNR3R4.

<> 9. Method of preparing compounds having the formula (Ia),

characterized in that the compound, where R and R1-R6have data in claim 1 denote the receive interaction of compounds having the formula (V),

with an amine of the formula HNR3R4in the presence of salts of mercury (II).

10. Method of preparing compounds having the formula (Ia),

characterized in that the compound, where R and R1-R6have data in claim 1 denote the receive interaction of compounds having the formula (III)

with the compound of the formula (VI)

with subsequent treatment in an organic solvent, an amine HNR5R6obtaining the compounds of formula (VII)

which in an organic solvent is subjected to interaction with such a halogenation agent as PCl5with obtaining the compounds of formula (VIII),

which is subjected to interaction with the amine of the formula HNR3R4.

11. Compounds of General formula (V)

where R, R1, R2, R5and R6they are the only values specified in claim 1.

12. Compounds of General formula (VII)

where R, R1, R2, R5and R6have the meanings indicated in claim 1.

13. Compounds of General formula (VIII)

where R, R1, R2, R5and R6have the meanings indicated in claim 1, and where R10represents a halogen atom.

14. The use of compounds according to claim 1 to obtain a pharmaceutical composition for treating disorders, comprising the cannabinoid neuropterida.

15. The application 14, characterized in that the disorders are psychiatric disorders such as psychosis, fear, depression, attention deficit disorder, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette syndrome, cerebral ischemia, stroke, traumatic brain injury, stroke, spinal cord injury, neirolepticalkie disease, multiple sclerosis, viral encephalitis, resstr Ista, associated with demyelination, as well as for the treatment of pain States, including neuropathic pain, and other diseases involving cannabinoid neuropterida, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory illnesses, disorders of the gastrointestinal tract, gastric ulcers, diarrhoea and cardiovascular diseases.



 

Same patents:

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

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

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

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: medicine, organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to compounds of formula I , or pharmaceutically acceptable salt or solvates thereof, wherein X and Z represent CH or N; Y represents O; R1, R2, and R3 are identical or different and represent hydrogen atom, C1-C6-alkoxy; R5 represents hydrogen atom; R5, R6, R7, and R8 are identical or different and represent hydrogen atom, halogen atom, C1-C4-alkyl, trifluoromethyl; R9 and R10 represent hydrogen atom; R11 represents optionally substituted azolyl. Also disclosed are pharmaceutical composition with inhibiting activity in relates to KDR phosphorylation and method for inhibiting of target blood-vessel angiogenesis.

EFFECT: new pharmaceuticals useful in treatment of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, arteriosclerosis, and Kaposi's sarcoma.

33 cl, 5 tbl, 75 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to piperidine- and piperazine-substituted N-hydroxyformamides of the general formula (I) or their pharmaceutically acceptable salts wherein B represents phenyl group monosubstituted at 3- or 4-position with halogen atom or trifluoromethyl group or bisubstituted at 3- and 4-position with halogen atom (that can be similar or distinct); or B represents 2-pyridyl or 2-pyridyloxy-group monosubstituted at 4-, 5- or 6-position with halogen atom, trifluoromethyl group, cyano-group or (C1-C4)-alkyl; or B represents 4-pyrimidinyl group possibly substituted with halogen atom or (C1-C4)-alkyl at 6-position; X represents carbon or nitrogen atom; R1 represents trimethyl-1-hydantoin-(C2-C4)-alkyl or trimethyl-3-hydantoin-(C2-C4)-alkyl group; or R1 represents phenyl or (C2-C4)-alkylphenyl monosubstituted at 3- or 4-position with halogen atom, trifluoromethyl group, thio-group, (C1-C3)-alkyl or (C1-C3)-alkoxy-group; or R1 represents phenyl-SO2NH-(C2-C4)-alkyl; or R1 represents 2-pyridyl or 2-pyridyl-(C2-C4)-alkyl; or R1 represents 3-pyridyl or 3-pyridyl-(C2-C4)-alkyl; or R1 represents 2-pyrimidine-SCH2CH2; or R1 represents 2- or 4-pyrimidinyl-(C2-C4)-alkyl possibly monosubstituted with one of the following substitutes: halogen atom, trifluoromethyl, (C1-C3)-alkyl, (C1-C3)-alkoxy-group, 2-pyrazinyl possibly substituted with halogen atom, or 2-pyrazinyl-(C2-C4)-alkyl possibly substituted with halogen atom. Also, invention describes a method for synthesis (variants) of compounds of the formula (I) and a pharmaceutical composition. Compounds can be used as inhibitors of metalloproteinases and useful in such morbidity states as inflammatory and allergic ones.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical compositions.

12 cl, 1 tbl, 10 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compounds of the general formula (1): wherein X is chosen from sulfur atom and methylene group; X1 is chosen from sulfur atom and methylene group; X2 is chosen from oxygen (O), sulfur (S) atoms and methylene group; X3 means -NR5 or carbonyl group; R1 means hydrogen atom or nitrile group; R and R3 are chosen independently from hydrogen atom (H) and (C1-C6)-alkyl; R4 means R4A when X3 means -NR5 and R4B when X3 means carbonyl group; R4A is chosen from -R6R7NC(=O), -R6R7NC(=S), -R8(CH2)qC(=O), -R8(CH2)qC(=S), -R8(CH2)qSO2 and -R8(CH2)qOC(=O); R4B means -R6R7N; R5 means hydrogen atom (H); R6 and R7 are chosen independently from -R8(CH2)q, or they form in common -(CH2)2-Z1-(CH2)2- or -CHR9-X2-CH2-CHR10-; R8 is chosen from hydrogen atom (H), (C1-C4)-alkyl, cycloalkyl group condensed with benzene ring, acyl, dialkylcarbamoyl, dialkylamino-group, N-alkylpiperidyl, optionally substituted aryl, optionally substituted α-alkylbenzyl, optionally substituted aroyl, optionally substituted arylsulfonyl and optionally substituted heteroaryl representing monocyclic 5- and 6-membered ring aromatic group with one or two heteroatoms chosen from nitrogen, oxygen and sulfur atoms, and derivatives of abovementioned rings condensed with benzene; R9 and R10 are chosen independently from hydrogen atom (H), hydroxymethyl and cyanomethyl groups; Z1 is chosen from -(CH2)r-, -O-, and -N((CH2)q)R8)-; Z2 means optionally the substituted ortho-phenylene group; m = 1-3; n = 0-4; p = 2-5; q = 0-3, and r = 1 or 3. Proposed compounds are inhibitors of dipeptidyl-peptidase IV and can be used in preparing pharmaceutical compositions designated for treatment of different diseases, among them, diabetes mellitus of type 2.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

22 cl, 8 tbl, 453 ex

FIELD: organic chemistry, heterocyclic compounds.

SUBSTANCE: invention describes anthrapyridone compounds of the general formula: wherein R means (C1-C4)-alkyl; Y means amino-group; X means -NH-A-NH- wherein A represents (C1-C6)-polymethylene, xylylene, dicyclohexylmethylene possibly substituted with methyl in cyclohexyl moiety, or their salts, and an aqueous composition of purple ink based on thereof. Purple ink comprising indicated anthrapyridone compounds possesses chromatic tones and brightness suitable for jet printing and give images possessing the excellent stability with respect to light, gas and water.

EFFECT: improved and valuable properties of compound and composition.

13 cl, 6 tbl, 5 ex

FIELD: organic chemical, pharmaceuticals.

SUBSTANCE: invention relates to new compounds having JAK3 kinase inhibitor activity, methods for production thereof, intermediates, and pharmaceutical composition containing the same. In particular disclosed are aromatic 6,7-disubstituted 3-quinolinecarboxamide derivatives of formula I and pharmaceutically acceptable salts thereof useful in production of drugs for treatment of diseases mediated with JAK3. In formula n = 0 or 1; X represents NR3 or O; Ar is selected from phenyl, tetrahydronaphthenyl, indolyl, pyrasolyl, dihydroindenyl, 1-oxo-2,3-dihydroindenyl or indasolyl, wherein each residue may be substituted with one or more groups selected from halogen, hydroxy, cyano, C1-C8-alkoxy, CO2R8, CONR9R10 C1-C8-alkyl-O-C1-C8-alkyl, etc., wherein R-groups are independently hydrogen atom or C1-C8-alkyl; meanings of other substitutes are as define in description.

EFFECT: new compounds having value biological properties.

17 cl, 222 ex

FIELD: pharmacy.

SUBSTANCE: invention relates to the improved formulation of aripiprazole showing the reduced hygroscopicity. These formulations are not converted to hydrate and not loss the initial solubility being even the medicinal preparation comprising anhydrous apipiprazole crystals are stored for a long time. Also, invention describes method for preparing these formulation and pharmaceutical composition based on thereof.

EFFECT: improved and valuable pharmaceutical properties of agent.

22 cl, 32 dwg, 7 tbl, 28 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted glutarimides of the general formula (I): wherein X means group of the formula -(CH2)n-(CR8R9)p-Z-(CR8R)m wherein Z means sulfur (S) or oxygen (O) atom, SO- or SO2-group, residue -NR8 (optionally as N-oxide) or the group -CR8R9; m and p mean 0 or 1; n means 0, 1, 2 or 3, and m, n and p can't mean 0 simultaneously; R1 and R2 mean carboxyl, ester or acyl group and others; R3 means hydrogen atom, hydroxyl group and others; R4 means hydrogen atom, (C1-C3)-alkyl group, fluorine atom, trifluoromethyl group; R8 and R9 means hydrogen atom, benzyl, alkyl and others, and to their physiologically acceptable salts also. Compounds of the formula (I) possess immunomodulating effect and can be used in treatment of angiopathy and/or oncohematological diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the general formula (I): wherein X1, X2, X3, X4 and X5 mean -CH2 or one of them represents -NH and another X1-X5 represent -CH2; k = 0, 1 or 2; when t = 2, then radicals R1 are similar or different; R1 represents direct or branched (C1-C8)-alkyl or (C1-C8)-alkoxy-group; A means phenyl or pyridinyl; R2 means hydrogen atom (H), hydroxyl, halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; n = 0, 1-4; radicals R2 are similar or different, when n > 1; p = 0 or 1-5; Y means -OC(O); Z means -CH, or to their pharmaceutically acceptable salts. Compounds of the formula (I) possess agonistic activity with respect to muscarinic receptors and can be used in medicine as medicinal preparations for treatment of neurodegenerative diseases or diseases associated with increased intraocular pressure.

EFFECT: valuable medicinal properties of derivatives.

6 cl, 1 tbl, 2 dwg, 16 ex

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

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

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