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

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

Above 4,5-dihydro-1H-pyrazoles are powerful antagonists of the receptor Cannabis-1 (CB1), which can be used for the treatment of psychiatric and neurological disorders.

The cannabinoids are found in the Indian hemp plant Cannabis Sativa L. and for centuries was used as medicines (Mechoulam, R.; Feigenbaum, J.J. Prog. Med. Chem. 1987, 24, 159). However, only in the last ten years research in the field of cannabinoids has revealed important information about the receptors cannabinoids and their (endogenous) agonists and antagonists. The discovery and subsequent cloning of two different subtypes of receptors cannabinoids (CB1and ST2) stimulated the search for new antagonists of cannabinoid receptors (Munro, S.; Thomas, K.L.; Abu-Shaar, M. Nature 1993, 365, 61. Matsuda, L.A.; Bonner, T.I. Cannabinold Receptors, Pertwee, R.G. Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies are interested in the development of cannabinoid drugs for the treatment of diseases associated with disorders of the cannabinoid system. The prevalence CB1receptors in the brain, combined with a strong peripheral localization of SAINT 2-receptor makes CB1the receptor is very interesting molecular target in the search for drugs to treat diseases of the Central nervous system relevant to the field of psychiatric and neurological disorders (Consroe, P. Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS Investigatlona1 Drugs 1999, 1, 587. Greenberg, D.A.Drug News Perspect. 1999, 12, 458). To date, there are three different type of receptor antagonists CB1. Sanofi opened their diarylpyrazole representatives as selective antagonists of CB1-receptor. A representative example is the SR-141716A, which is currently in phase II clinical development as a treatment for psychotic disorders (Dutta, A.K.; Sard, H.; Ryan, W.; Razdan, R.K.; Compton, D.R.; Martin, B.R.Med. Chem. Res. 1994, 5, 54. Lan, R.; Liu, Q.; Fan, P.; Lin, S.; Fernando, S.R.; McCallion, D.; Pertwee, R.; Makriyannis, A. J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E.M.; Moerschbaecher, J.M.; Barker, L.A. CNS Drug Rev. 1999, 5, 43). Aminoalkylindole been disclosed as antagonists at the CBi receptor. A representative example is logoprado (AM-630), which was released on the pharmaceutical market in 1995. AM-630 is an antagonist CB1-receptor, but sometimes behaves as a weak partial agonist (Hosohata, K.; Quock, R.; Hosohata, Y.;

Burkey, T.N.; Makriyannis, A.; Consroe, P.; Roeske, W.R.; Yamamura, H.I.Lite Sc. 1997, 61, PL115). Recently researchers from Eli Lilly company (Eli Lilly) described aryl-aroyl-substituted benzofuran as selek is active antagonists CB 1receptor (e.g., LY-320135) (Felder, S.; Joyce, K.E.; Briley, E.J.; Glass, M.; Mackie, K.R.; Fahey, K.J.; Cullinan, G.J.; Hunden, D.C.; Johnson, D.W.; Chaney, M.O.; Koppel, G.A.; Brownstein, M. J. Pharmacol. Exp. Ther. 1998, 264, 291). Recently as ligands of cannabinoid receptors have been described 3-alkyl-5,5’-diphenylimidazole who had discovered the ability to be antagonists of cannabinoids (Napoopoo, M.; Govaerts, S.J.; Hermans, E.; Poupaert, J. H.; Lambert, D.M. Biorg. Med. Chem. Lett. 1999, 9, 2233). Interestingly, many antagonists CB1-receptor was reported to behave as inverse agonists in vitro (Landsman, R.S.; Burkey, T.N.; Consroe, P.; Roeske, W.R.; Yamamura, H.I. Eur. J. Pharmacol. 1997, 334, R1). Recent reviews provide an excellent introduction to the current state of research in the field of cannabinoids (Mechoulam, R.; Hanus, L.; Fride, E. Prog. Med. Chem. 1998, 35, 199. Lambert, D.M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, R.; Fride, E.; Di Marzo, V. Eur. J. Pharmacol. 1998, 359, 1}.

Unexpectedly, it was found that new derivatives of 4,5-dihydro-1H-pyrazole, corresponding to the formula (I), their prodrugs, their tautomers and their salts

where:

- R and R1may be the same or different and denote phenyl, thienyl or pyridyl, and these groups may be substituted by 1, 2 or 3 substituents Y, which can be the same or different, from the group comprising C1-3is alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, triptoreline, triptoreline, nitro, amine is, mono - or dialkyl (C1-2) amino, mono - or dialkyl (C1-2) amido, (C1-2) alkylsulfonyl, dimethylsulfide, C1-3-alkoxycarbonyl, carboxyl, trifloromethyl, cyano, carbarnoyl, sulfamoyl and acetyl, or R and/or R1denote naphthyl;

- R2denotes hydrogen, hydroxy, C1-3-alkoxy, atomic charges or propionyloxy;

- AA denotes one of the groups (i), (ii), (iii), (iv) or (v):

where:

- R4and R5independently of one another denote hydrogen or C1-8branched or unbranched alkyl or C1-8cycloalkyl or R4represents acetamido, or dimethylamino, or 2,2,2-triptorelin, or phenyl, or pyridyl, provided that R5denotes hydrogen;

- R6denotes hydrogen or C1-3unbranched alkyl;

- b denotes sulfonyl or carbonyl;

- R3denotes benzyl, phenyl, thienyl or pyridyl which may be substituted by 1, 2 or 3 substituents Y, which can be the same or different, or R3represents C1-8branched or unbranched alkyl or C3-8cycloalkyl, or R3denotes naphthyl,

are potent and selective antagonists of cannabis-CB1-receptor.

Due to the availability of powerful CB1antagonistic activity of the compounds with the according to the present invention is suitable for treatment of psychiatric disorders, such as psychosis, anxiety, depression, attention deficit disorder, memory disorders and appetite disorders, obesity, neurological diseases such as dementia, dystonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, disease, Tourette's, cerebral ischemia, as well as in the treatment of pain syndromes and other diseases of the Central nervous system, involving cannabinoid neurotransmission, and for the treatment of gastrointestinal disorders and cardiovascular diseases.

The affinity of the compounds according to the present invention for cannabinoid CB1receptors determined using membrane preparations from cells of the Chinese hamster ovary (Cho-cells)that stably transfirieran human cannabis-ST1receptor in combination with [3H]CP-55940 as a radioactive ligand. After incubation of freshly prepared drug cell membranes containing [3H]-ligand, with or without added compounds according to the present invention, carry out the separation of bound and free ligand by filtration through glass-fiber filters. The radioactivity on the filter is measured by liquid scintillation counter.

Antagonistic activity of the compounds according to the present invention in respect of cannabinoid CB1determined by the t to the functional tests using Cho cells, which stably expressed human cannabinoid-CB1-receptors. Adenylylcyclase stimulate the use of Forskolin and measure in determining the amount of the accumulated cyclic AMP. Concomitant activation of CB1receptor agonists CB1receptor (for example, CF-S or (R)-WIN-55212-2) can reduce Forskolin-induced accumulation of camp-dependent concentration. The response mediated CB1receptor, can be antianaerobic antagonists CB1-receptor, such as compounds according to the present invention.

In the compounds of formula (I) has at least one chiral center (C4-the position of the 4,5-dihydro-1H-pyrazol group).

The present invention relates to racemates, mixtures of diastereomers, and the individual stereoisomers of the compounds having formula (I).

The present invention also applies to E-isomer, Z-isomer, and a mixture of E/Z-isomers of the compounds having formula (I)in which AA is set to (i) or (ii)above.

Compounds according to the present invention can be converted into a form suitable for insertion in the usual ways (e.g., mixing) with the use of additional substances and/or liquid or solid media.

Compounds according to the present invention in the region have the formula (III) (vide Infra), where R2denotes hydrogen, can be obtained in accordance with methods known, for example, from: (a) EP 0021506; (b) DE 2529689.

Below is a diagram of a suitable synthesis for the preparation of compounds according to the present invention:

The method of synthesis And (for compounds having formula (I)in which AA is set to (i) or (ii)above).

Stage 1 of the method And

The reaction of the compound having the formula (II)

with hydrazine or hydrazine hydrate. This reaction gives a compound having the formula (III),

where R2denotes a hydroxy-group. The above reaction is preferably carried out in polar solvent such as, for example, ethanol. Compounds having the formula (III)in which R2denotes a hydroxy-group, a R and R1have the values specified above for the compounds (I)are new.

Stage 2 methods And

The reaction of the compound having the formula (III)with a compound having the formula (IVa), or a compound having the formula (IVb),

where R7denotes a lower alkyl group, such as, for example, 2-methyl-2-thiopseudourea, or an acceptable salt in the presence of a base. This reaction gives the derivative of 4,5-dihydro-1H-pyrazole-1-carboxamidine having the formula (V)

where AA is the value of (i) or (ii)above. Compounds having the formula (V), where AA is the value of (i) or (ii)above, and in which R, R1and R2have the values specified above for the compounds (I)are new.

In the alternative case, the compound having the formula (III)is subjected to reaction with so-called guanidium agent. Examples of such guanylurea agents are 1H-pyrazole-1-carboxamidine and its salts (for example, cleaners containing hydrochloride salt) and 3,5-dimethyl-1H-pyrazole-1-carboxamidine and its salts (such as nitrate salt) and other Specified reaction gives carboxamidine derivative having the formula (V).

Alternatively, the compound having the formula (III)is subjected to reaction with so-called protected guanidium agent. Examples of such protected guanylurea agents are N-(benzyloxycarbonyl)-1H-pyrazole-1-carboxamide, N-(Gert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and N,N’-bis-(mper-butoxycarbonyl)-1H-pyrazole-1-carboxamidine and other Specified reaction network after removal of protection: a compound having the formula (V).

Stage 3 method And

The compound having the formula (V)is subjected to reaction with an optionally substituted compound of formula R3-SO2X or R3-COX, where R3has the above meaning and X denotes a halogen atom. The reaction preferably is carried out in the presence of a base, such as triethylamine, in an aprotic solvent such as acetonitrile. This reaction gives the compound (I), in which b denotes sulfonyloxy group or carbonyl group, respectively.

The method of synthesis A1 (for compounds having formula (I)in which AA is set to (i) or (ii)above).

Stage 1 of the method A1

The reaction of the compound having the formula (III)

with thioisocyanate derivative having the formula (VI)

The above reaction is preferably carried out in an inert organic solvent such as, for example, acetonitrile.

This reaction gives thiocarboxamide derivative having the formula (VII). Compounds having the formula (VII)in which R, R1, R2, R3and b have the meanings described above for compound (I)are new.

Stage 2 method A1

The reaction of the compound having the formula (VII)with an amine in

the presence of mercury salts (II), such as, for example, HgCl2that gives compound having the formula (I)in which AA is set to (i) or (ii)above.

This reaction is preferably carried out in a polar organic solvent, such as, for example, acetonitrile.

The method of synthesis A2 (for compounds having formula (I)in which AA has a signature is a group of (i) or (ii), above).

Stage 1 of the method A2

The reaction of the compound having the formula (III),

with the derived complex ester carbamate having formula (VIII)

where R7denotes a lower alkyl group, e.g. methyl.

The above reaction is preferably carried out in an inert organic solvent such as, for example, 1,4-dioxane.

This reaction gives the derivative of 4,5-dihydropyrazol-1-carboxamide having the formula (IX). Compounds having the formula (IX)in which R, R1, R2, R3and b have the values specified above for the compounds (I)are new.

Stage 2 method A2

The reaction of the compound having the formula (IX)with a halogenation agent such as, for example, PCl5gives a halogenated derivative of 4,5-dihydropyrazol-1 carboxymethyl having the formula (X)

where R8represents a halogen atom, such as chlorine. The above reaction is preferably carried out in an inert organic solvent such as, for example, chlorobenzene.

Compounds having the formula (X)in which R, R1, R2, R3and Bb have the values specified above for compound (I)in which R8denotes a halogen atom, are new is I.

Stage 3 method A2

The reaction of the compound having the formula (X)with an amine gives compound having the formula (I), where AA is the value of (i) or (ii)above.

The reaction is preferably carried out in an inert organic solvent such as, for example, dichloromethane.

The method of synthesis A3 (for compounds having formula (I)in which AA is set to (i) or (ii)above).

Stage 1 of the method A3

The reaction of the compound having the formula (III)

with the derived complex ester dayimmediate having the formula (XI)

where R9represents C1-3is an alkyl group.

The above reaction is preferably carried out in a polar organic solvent, such as, for example, acetonitrile.

This reaction gives the derivative complex carboxamidates ether having the formula (XII)

where R9represents C1-3is an alkyl group. Compounds having the formula (XII)in which R, R1R2, R3and b have the values specified above for compound (I)in which R9represents C1-3is an alkyl group, are new.

Stage 2 method A3

The reaction of the compound having the formula (XII)with an amine gives compound having the formula (I)in which AA is set to (i) or (ii), is shown above.

The above reaction is preferably carried out in a polar organic solvent, such as, for example, methanol.

The method of synthesis for compounds having formula (I)in which AA is set to (iii) or (iv)above).

Stage 1 of the method

The reaction of the compound having the formula (III)

with a compound having the formula (XIII), or a compound having the formula (XIV), respectively

where Bb, R3and R4have the above meanings and Z represents a so-called a group to delete.

This reaction provides compounds having the formula (I)in which AA is set to (iii) or (iv), respectively.

The method of synthesis for compounds having formula (I)in which AA is set to (v)above).

Stage 1 of the method

The reaction of the compound having the formula (III),

with aziridine derivative having the formula (XV), or with a compound having the formula (XVI), respectively,

where R6has the values indicated above, Z denotes the so-called deleted the group and Prot denotes the so-called protective group such as tert-butoxycarbonyl, benzyloxycarbonyl etc.

These reactions give compounds having the formula (XVII),

where AA is set to (v)above. Compounds having the formula (XVII)in which R, R1and R2have the meanings described above for compound (I), and in which AA above has a value (v) and in which Prot is a so-called protective group, are new.

Subsequent removal of the so-called protective group is carried out in accordance with known methods (see, for example: T.W. Greene, P.G.M. Wuts, "Protective Groups in Organic Synthesis", third edition, John Wiley & Sons, Inc., New York, 1999), leads to the formation of compounds (V)in which AA is set to (v)above. Compounds having the formula (V)in which R, R1and R2described above for compound (I) in which AA is set to (v)above, are new.

Stage 2 of the method

The compound having the formula (V)in which AA is set to (v)above, is subjected to reaction with an optionally substituted compound of formula R3-SO2X or R3-MOR, where R3has the above meaning and X denotes a halogen. The above reaction is preferably carried out in the presence of a base, such as triethylamine, in an aprotic solvent such as acetonitrile. This reaction gives the compound (I), in which b denotes sulfonyloxy group or carbonyl group, respectively.

Alternatively, the above connection is a group of having the formula (V)can be subjected to reaction with the compound of the formula R3-COOH via the formation of the active complex ether or in the presence of the so-called binding reagent.

The following examples illustrate the obtaining of such compounds.

Example I

3-(4-Chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1H-pyrazole

2-(4-Chlorobenzoyl)-2-phenyloxirane (112 grams; 0.43 mol) is dissolved in ethanol (650 ml) at 35°C. To the resulting mixed solution was added N2H4·H2O (42 ml), and formed 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1H-pyrazole slowly precipitates. After settling in for 16 hours, the crystalline material is collected by filtration and successively washed with ethanol, water and ethanol, and then dried to obtain 3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1H-pyrazole (92 grams; yield 78%). Melting point: 195-196°C.

Example II

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

Part a: Stir a mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (5.13 grams; 20.0 mmol), hydroiodide 2-methyl-2-thiopseudourea (5,00 grams; 23,0 mmol) and pyridine (10 ml) is heated at 110°C for 1 hour. After maturation for one night at room temperature, add diethyl ether and precipitated sludge FDS is given by filtration. The precipitate is washed three times with portions of diethyl ether to obtain a solid substance (9 grams). Melting point: ~230°C. the Specified solid material was dissolved in methanol (20 ml). To the resulting solution was added successively with 2 n sodium hydroxide solution (12 ml) and water (200 ml). The resulting precipitate is collected by filtration, washed twice with diethyl ether and then diisopropyl ether. The obtained solid material is dried in vacuum to obtain 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (5.1 grams; yield 88%). Melting point: 187-189° C.

Part b: To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.50 grams; by 1.68 mmol) and 4-perpenicularity (0.34 gram; a 1.75 mmol) in acetonitrile (10 ml) is added N,N-dimethyl-4-aminopyridine (0.020 grams; 0,175 mmol) and triethylamine (1 ml). The resulting solution was stirred at room temperature for 30 minutes. After adding 2 n sodium hydroxide solution and extraction with ethyl acetate (400 ml), an ethyl acetate layer was concentrated in vacuo. The resulting crude residue is then purified flash chromatography (petroleum ether/diethyl ether = 1/1 (volume/volume) and then ethyl acetate). Subsequent concentration in vacuo gives a solid 3-(4-chlorophenyl)-4,5-dihydro-N-((4-forfinal)sulfonyl)-4-phenyl-1H-pyrazole-1-carboxy-midin 0.55 gram; yield 72%). Melting point: 214-215°C.

In a similar way we obtain compounds having the formula (I)listed below:

4,5-Dihydro-N-((4-forfinal)sulfonyl)-3-(4-methoxyphenyl)-4-(4-methoxyphenyl)-1H-pyrazole-1-carboxamidine. Melting point: 155-156°C;

4,5-Dihydro-3-(4-methoxyphenyl)-4-(4-methoxyphenyl)-N-((4-methoxyphenyl)sulfonyl)-1H-pyrazole-1-carboxamidine. Melting point: 148-150°C;

3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-N-((2,4,6-trimetilfenil)sulfonyl)-1H-pyrazole-1-carboxamidine. Melting point: 221-222°C;

3-(4-Chlorophenyl)-4,5-dihydro-N-((4-forfinal)sulfonyl)-4-hydroxy-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 227-228°C.

Example III

3-(4-Chlorophenyl)-4,5-dihydro-N-(1-naphtol)-4-phenyl-1H-pyrazole-1-carboxamidine

To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.75 grams; 2.5 mmol) and 1-nafolklore (0.4 ml; 2,70 mmol) in acetonitrile (15 ml) was added triethylamine (1 ml). The resulting mixture was stirred at room temperature for 1 hour. After adding 2 n sodium hydroxide solution and extraction with ethyl acetate, an ethyl acetate layer was concentrated in vacuo. The resulting crude residue is then purified flash chromatography (petroleum ether/diethyl ether = 3/1 (volume/volume) and then ethyl acetate). Subsequent concentration in vacuo gives 3-(4-chlorophenyl)-4,5-dihydro-N-(1-naphtol)4-phenyl-1H-pyrazole-1-carboxamidine (0.94 gram; yield 83%). Melting point: 206-207°C.

In a similar way we obtain a compound having the formula (I)below:

3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-N-(2-pyridyl)-1H-pyrazole-1-carboxamidine. Melting point: 118°C (decomposition).

Example IV

N1N1-Dimethyl-N2-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine

Part a: Stir a mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (to 12.0 grams; 46.8 mmol), dimethyl ether [(4-chlorophenyl)sulfonyl]diotomaceous acid (CAS: 13068-12-7) (9,20 grams; and 31.1 mmol) and triethylamine (15 ml) in acetonitrile (200 ml) heated at boiling temperature under reflux for 20 hours. Contribute an additional portion of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (to 12.0 grams; 46.8 mmol) and the resulting mixture is heated at boiling temperature under reflux for 16 hours. After concentration in vacuum, add dichloromethane and the resulting solution washed twice with water and dried over anhydrous Na2SO4. After filtration and evaporation in vacuo the resulting residue is then purified flash chromatography (diethyl ether/petroleum ether = 1/1 (volume/volume)) to obtain methyl ester of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidates acid (12.5 grams; you are the od 80% of dimethyl ether [(4-chlorophenyl)sulfonyl]diotomaceous acid) as amorphous solids.

Part b: To a stirred mixture of methyl ester of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidates acid 4.20 grams; 8,30 mmol) in methanol (75 ml) is added dimethylamine (10 ml) and dichloromethane (75 ml) and the resulting solution was stirred at room temperature for 6 hours. Evaporation in vacuum and subsequent purification with flash chromatography (diethyl ether/petroleum ether = 1/1 (volume/volume) and then diethyl ether) to give a solid, which was then purified by repeated crystallization from diisopropyl ether to obtain N1N1-dimethyl-N2-((4-chlorophenyl) sulfonyl)-3(4-chlorophenyl) -4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (2,63 grams; yield 63%). Melting point: 182°C.

In a similar way we obtain compounds having the formula (I)listed below:

N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-(3-pyridyl)-1H-pyrazole-1-carboxamidine. Melting point: 101-105°C;

N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-(4-pyridyl)-1H-pyrazole-1-carboxamidine. Melting point: 112-115°C;

N1Nl-Dimethyl-N2-((4-chlorophenyl)sulfonyl)-3(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: amorphous substance;

N-Ethyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-hydroxy-4-phenyl-lH-piraso the-1-carboxamidine. Melting point: 183-185°C.

Example V

N-Methyl-N’-(3-(trifluoromethyl)benzoyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine

Part a: To 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (5.13 grams; 20.0 mmol) in acetonitrile (80 ml) at 0°C add 3-(trifluoromethyl)benzoylisothiocyanate (4,62 grams; 20.0 mmol) and the resulting mixture is stirred for 1 hour. Formed yellow precipitate is collected by filtration and washed with a small portion of acetonitrile and water, respectively, and then dried in vacuum to obtain 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-N-((3-trifluoromethyl)benzoyl)-1H-pyrazole-1-thiocarboxamide (compared to 8.26 grams; yield 85%). Melting point: 180-182°C.

Part b: To a stirred suspension of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-N-((3-trifluoromethyl)benzoyl)-1H-pyrazole-1-thiocarboxamide (4,88 grams; 10.0 mmol) in acetonitrile (50 ml) is added a cold methylamine (5 ml) to give a green solution. After adding a solution of HgCl2(3.0 grams; 11 mmol) in 25 ml of acetonitrile, the mixture is stirred for three hours. The precipitate is removed by filtration through hyflo and the filtrate is collected and concentrated in vacuo. After adding ethyl acetate and 0.5 N. NaOH an ethyl acetate layer is collected, washed with saturated aqueous NaCl and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Chromatography (dichlormethane = 9/1 (volume/volume)) gives N-methyl-N’-(3-(trifluoromethyl)benzoyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (0.99 grams; yield 20%) as a foam. Melting point: amorphous substance. Rf(silica gel: dichloromethane/acetone=9/1 (volume/volume)) = 0,3.

Example VI

N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-Piramal-1-carboxamidine

Part a: To a solution of methyl ester of N-((4-chlorophenyl)sulfonyl)carbamino acid (CAS: 34543-04-9) (2.99 grams; to 12.0 mmol) and pyridine (4 ml) in 1,4-dioxane (20 ml) is added 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (3.39 grams; 13,2 mmol) and the resulting mixture is stirred for 4 hours at 100°C. After concentration in vacuo the residue is dissolved in dichloromethane,

sequentially washed with water, 1 N. Hcl and water, dried over anhydrous Na2S4, filtered and concentrated in vacuo to a volume of 20 ml. Add methyl tert-butyl ether (60 ml) and the resulting solution was concentrated to a volume of 20 ml. of the Resulting crystals are collected by filtration and re-crystallized from methyl tert-butyl ether with 3(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamide (4.75 grams; yield 76%). Melting point: 211-214°C.

Part b: a Mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamide (3,67 grams; of 7.75 mmol) and pentachloride phosphorus (1.69 grams; 8,14 mmol) in chlorobenzene (40 ml) is heated at the boiling point under reflux for 1 hour. obrazovavshijsya after careful concentration in vacuum N-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxymethylated suspended in dichloromethane and conduct the reaction with cold methylamine (1.5 ml). After stirring at room temperature for 1 hour the mixture was concentrated in vacuo. The residue is crystallized from diethyl ether to obtain N-methyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine (2,29 grams; yield 61%). Melting point: 96-98°C (Razlog.).

In a similar way we obtain compounds having the formula (I)listed below:

N-Methyl-N’-((3-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 156 to 160°C;

N-Methyl-N’-((4-chlorophenyl)sulfonyl)-3-(5-chloro-2-thienyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: amorphous substance;

N-Propyl-N’-((4-forfinal)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Heat of fusion: 129-138°C;

N-(2-Propyl)-N’-((4-forfinal)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 110-112°C;

N-Methyl-N’-((2-propyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: amorphous substance;

N-(2-Propyl)-N’-((4-chlorophenyl)sulfonyl)-3-(4-pyridyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: amorphous substance;

N1-Ethyl-N1N-methyl-N2((4-chlorophenyl)sulfonyl)-3(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 184°C;

N1-Ethyl-N 1N-methyl-N2((4-forfinal)sulfonyl)-3(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 173-176°C;

N1N1-Dimethyl-N2((4(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 195-196°C;

N1N1-Dimethyl-N2((3-were)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 195-198°C;

N1N1-Dimethyl-N2((3-methoxyphenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 204-206°C;

N-Ethyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: amorphous substance;

N-Dimethylamino-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 155-159°C;

N-Methyl-N’-((4-(trifluoromethyl)phenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: amorphous substance;

N1N1-Dimethyl-N2((2-were)sulfonyl)-3(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 148-151°C;

N-Methyl-N’-((2,4-differenl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 85° C;

N-Acetamido-N1-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-f the Nile-1H-pyrazole-1-carboxamidine. Melting point: amorphous substance;

N-(2,2,2-Triptorelin)-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: amorphous substance;

N-(2-Pyridyl)-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 142-146°C;

N-(4-Pyridyl)-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-lH-pyrazole-1-carboxamidine. Melting point: 204-206°C;

N-Phenyl-N’-((4-chlorophenyl)sulfonyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamidine. Melting point: 158-160°C;

Example VII

3(4-Chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)butanoyl]-4,5-dihydro-4-phenyl-1H-pyrazole

To a stirred mixture of 3-((4-chlorophenyl)sulfonyl) butyric acid (1.85 grams; 7,00 mmol), diisopropylethylamine (3 ml) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.50 grams; 15.7 mmol) is added 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (3,00 grams; 11.7 mmol) and the resulting mixture is stirred for 16 hours at room temperature. After concentration in vacuo the resulting residue is purified flash chromatography (petroleum ether/diethyl ether = 1/2 (volume/volume) and then diethyl ether) to give 3-(4-chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)butanoyl]-4,5-dihydro-4-phenyl-1H-pyrazole (3,69 grams; yield 63%) as diastereomeric mixture. Melting point: amorphoides.

In a similar way we obtain compounds having the formula (I)listed below:

3-(4-Chlorophenyl)-1-[3-(phenylsulfonyl)propanol]-4,5-dihydro-4-phenyl-1H-pyrazole. Melting point: 122-123°C;

3-(4-Chlorophenyl)-1-[3-((4-chlorophenyl)sulfonyl)propanoic]-4,5-dihydro-4-phenyl-1H-pyrazole. Melting point: 178-181°C;

Example VIII

3(4-Chlorophenyl)-4,5-dihydro-4-phenyl-1-[2-((3-(trifluoromethyl)phenyl)sulfonyl)ethyl]-1H-pyrazole

To a stirred mixture of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.7 grams; 6,60 mmol) and collidine (2 ml) in acetonitrile (25 ml) is added slowly a solution of 2-((3-(trifluoromethyl)phenyl)sulfonyl)ethylchloride (1.5 grams; of 5.50 mmol) in acetonitrile (20 ml) and the resulting solution is heated at boiling temperature under reflux for 16 hours. After concentration in vacuo the residue is dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. Received an ethyl acetate layer is successively washed with 1 N. a solution of hydrochloric acid and aqueous sodium hydrogen carbonate solution.

Subsequent purification with flash chromatography (petroleum ether/diethyl ether = 1/2 (volume/volume)) gives an oil which is crystallized from diisopropyl ether to form a 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1-[2-((3-(trifluoromethyl)phenyl)sulfonyl)ethyl]-1H-pyrazole (0.52 grams; yield 19%). Melting point: 118-119°C.

Similar is cnym way to get the connection having the formula (I)listed below:

3-(4-Chlorophenyl)-1-[2-(benzylmethyl)ethyl]-4,5-dihydro-4-phenyl-1H-pyrazole. Melting point: 161°C;

3-(4-Chlorophenyl)-1-[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-phenyl-1H-pyrazole. Melting point: amorphous substance;

3-(4-Chlorophenyl)-1-[2-((4-chlorophenyl)sulfonyl)ethyl]-4,5-dihydro-4-hydroxy-4-phenyl-1H-pyrazole. Melting point: 127-128°C.

Example IX

N-[2-(3-(4-Chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-yl)ethyl]-3-(trifluoromethyl)Bearshare

Part a: Mix a solution of 3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (5,00 grams; of 19.5 mmol) and N-(tert-butoxycarbonyl)aziridine (2.00 grams; 14.0 mmol) in toluene (100 ml) is heated at boiling temperature under reflux for 16 hours. After concentration in vacuo the residue is purified flash chromatography (petroleum ether/diethyl ether = 3/1 (volume/volume) and then petroleum ether/diethyl ether = 1/1 (volume/volume)). After concentration in vacuum, the oily residue is crystallized from diisopropyl ether to obtain 1-[2-((tert-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.91 grams; yield 34%). Re-crystallization of the mother liquor gives an additional amount of crystalline 1-[2-((tert-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.19 g).

Part b: RA is Toro 1-[2-((tert-butoxycarbonyl)amino)ethyl]-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.91 grams; 4.8 mmol) in dichloromethane (50 ml) is added triperoxonane acid (5 ml) and the resulting solution was stirred at room temperature for 5 hours. After concentration in vacuo the resulting residue is dissolved in ethyl acetate and washed with 2 N. a solution of sodium hydroxide. Received an ethyl acetate layer is dried over magnesium sulfate, filtered and concentrated in vacuo to obtain 1-(2-amino-ethyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (1.44 grams; quantitative yield) as oil.

Part C: To a solution of 1-(2-amino-ethyl)-3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole (0.56 grams; of 1.87 mmol) and diisopropylethylamine in acetonitrile (20 ml) is added 3-(trifluoromethyl)phenylsulfonyl (0.35 ml; to 2.18 mmol) and the resulting solution was stirred at room temperature for 20 minutes. After concentration in vacuo the resulting residue is dissolved in ethyl acetate and washed with 2 N. a solution of sodium hydroxide. Received an ethyl acetate layer was concentrated in vacuo. The oil obtained is crystallized from a small amount of diisopropyl ether to obtain in crystalline form of N-[2-(3-(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-yl)ethyl]-3-(trifluoromethyl)benzosulfimide (0.44 grams; yield 46%). Melting point: 94-96°C.

1. Derivatives of 4,5-dihydro-1H-pyrazole of the formula (I)

DG the R stands for phenyl, thienyl or pyridyl, and these groups may be substituted C1-3alkoxygroup or halogen;

R1denotes phenyl which may be substituted C1-3alkoxy or peredelnoj group;

R2denotes hydrogen or hydroxy;

AA denotes one of the groups (i), (ii), (iii), (iv) or (v):

where R4and R5independently of one another denote hydrogen or C1-8branched or unbranched alkyl or R4represents acetamido, or dimethylamino, or 2,2,2-triptorelin, or phenyl, or pyridyl, provided that R5denotes hydrogen;

R6denotes hydrogen or C1-3unbranched alkyl;

b denotes sulfonyl or carbonyl;

R3denotes benzyl, phenyl or pyridyl which may be substituted by 1, 2 or 3 substituents Y, which can be the same or different and selected from the group comprising C1-3alkyl or C1-3alkoxy, halogen, trifluoromethyl, or R3denotes naphthyl,

and its racemates, mixtures of diastereomers and the individual stereoisomers as well as E-isomers and Z-isomers and mixture of E/Z compounds of formula (1), where AA has the values of (i) or (ii), and salts thereof.

2. The compound of formula (I) according to claim 1, characterized in that R denotes 4-chloraniline gr the PPU, R1denotes phenyl, R2denotes hydrogen, AA denotes the group (i)in which R4denotes hydrogen and R5denotes methyl, V denotes sulfonyl and R3represents 4-chlorophenyl, and its salts.

3. Pharmaceutical composition for the treatment of diseases mediated ST1receptor selected from such as psychiatric illness, such as psychosis, anxiety, depression, attention deficit disorder, memory disorders and appetite disorders, obesity, neurological diseases such as Parkinson's disease, dementia, dystonia, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, disease, Tourette's, ischemia, pain syndromes and other disorders of the Central nervous system, involving cannabinoid neurotransmission, disease of the gastrointestinal tract and cardiovascular disease, comprising a pharmacologically active amount of at least one compound according to one of claims 1 and 2 in as an active ingredient and a pharmaceutically acceptable carrier and/or at least one pharmaceutically acceptable auxiliary substance.

4. The method of obtaining pharmaceutical compositions for treating diseases mediated CB1receptor selected from such as psychiatric illness, such as psychosis, anxiety, depression, attention deficit, is osenia memory and appetite disorders, obesity, neurological diseases such as Parkinson's disease, dementia, dystonia, Alzheimer's disease, epilepsy, Huntington's disease, disease, Tourette's, ischemia, pain syndromes and other disorders of the Central nervous system, involving cannabinoid neurotransmission, disease of the gastrointestinal tract and cardiovascular disease, characterized in that the compound according to claim 1 is transferred in a form suitable for injection.

5. The method of obtaining compounds of General formula I

where R denotes phenyl, thienyl or pyridyl, and these groups may be substituted C1-3alkoxy group or halogen;

R1denotes phenyl which may be substituted C1-3alkoxy or peredelnoj group;

R2denotes hydrogen, hydroxy;

AA denotes one of the groups (i) or (ii)

where R4and R5independently of one another denote hydrogen or C1-8branched or unbranched alkyl or R4represents acetamido, or dimethylamino, or 2,2,2-triptorelin, or phenyl, or pyridyl, provided that R5denotes hydrogen;

b denotes sulfonyl or carbonyl;

R3denotes benzyl, phenyl, thienyl or pyridyl which may be substituted by 1, 2 or 3 to cover the firs Y, which may be the same or different and selected from the group comprising C1-3alkyl or C1-3alkoxy, halogen, trifluoromethyl, or R3denotes naphthyl, characterized in that the compound of formula (III)

interacts with the compound of the formula (VIII)

where R7is C1-3alkyl group, to obtain compounds of formula (IX)

which is subjected to reaction with a halogenation agent to obtain compounds of formula (X)

where R8is halogen,

which is subjected to reaction with the amine.

6. The compound of formula (III)

where r2denotes a hydroxy group;

R and R1have the meanings defined in claim 1, used in the synthesis of the compounds of formula(1).

7. The compound of formula (V)

where AA is the value of (i), (ii) or (v) according to claim 1;

R, R1and R2have the meanings defined in claim 1,

used in the synthesis of the compounds of formula (1).

8. The compound of formula (VII)

where R, R1, R2, R3and b matter, MC is connected in claim 1,

used in the synthesis of the compounds of formula (1).

9. The compound of formula (IX)

where R, R1, R2, R3and Bb have the meanings indicated in claim 1,

used in the synthesis of the compounds of formula (1).

10. The compound of formula (X)

where R, R1, R2, R3and Bb have the meanings indicated in claim 1;

R8denotes a halogen atom,

used in the synthesis of the compounds of formula (1).

11. The compound of formula (XII)

where R, R1, R2, R3and Bb have the meanings indicated in claim 1;

R9represents C1-3alkyl group,

used in the synthesis of the compounds of formula (1).

12. The compound of formula (XVII)

where R, R1and R2have the meanings indicated in claim 1;

AA has a value (v) according to claim 1;

Prot denotes the so-called protective group such as tert-butoxycarbonyl or benzyloxycarbonyl,

used in the synthesis of the compounds of formula (1).

13. The method of treatment of diseases mediated CB1receptor comprising the administration to a patient an effective amount of a compound according to claim 1.

14. The method according to item 13, wherein the disease is the tsya psychiatric illness, such as psychosis, anxiety, depression, attention deficit disorder, memory disorders and appetite disorders, obesity, neurological diseases such as Parkinson's disease, dementia, dystonia, Alzheimer's disease, epilepsy, Huntington's disease, disease, Tourette's, ischemia, pain syndromes and other disorders of the Central nervous system, involving cannabinoid neurotransmission, disease of the gastrointestinal tract and cardiovascular disease.

15. The method according to item 13, wherein the disease is a gastrointestinal disorder involving cannabinoid neurotransmission.

16. The method according to item 13, wherein the disease is a cardiovascular disease, involving cannabinoid neurotransmission.



 

Same patents:

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

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to organic chemistry and pharmacology, namely a mixture of isomers of the potassium salt of 2-[5(6)-nitro-1-(titanyl-3)benzimidazolyl-2-thio] acetic acid in a molar ratio of 1:3, manifesting cardiotonic activity

The invention relates to organic chemistry and medicine, in particular to a new connection - 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole formula I, showing inflammatory and bronchodilatory activity

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new compounds of the mixture of isomers of 2-monoethanolamine-5(6)-nitro-1-(titanyl-3)benzimidazole of the formula I

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

The invention relates to sulphonilecarbomide acids of the formula

< / BR>
and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

< / BR>
where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

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

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to organic chemistry and can find application in medicine

The invention relates to organic chemistry and can find application in medicine

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which IGN="ABSMIDDLE">

where R7denotes phenyl or pyridinyl; R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

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