Method for treating inflammation or inflammation-induced disease in dogs

FIELD: veterinary science.

SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.

EFFECT: higher efficiency of therapy.

4 cl,262 ex, 12 tbl

 

The scope of the invention

This invention relates to the field of methods of treatment of inflammation associated with inflammatory diseases (disorders), such as arthritis in animals.

Prior art

There are few drugs that can be successfully used in veterinary medicine to treat inflammation [Compendium of Veterinary Products (K. Bennet 2d ed., 1993)]. Cm. also The Merck Veterinary Manual, 1504-1509 (7 th ed., 1991).

Prostaglandins play a major role in the inflammatory process, and inhibition of production of prostaglandins, especially the production of PGG2, PGH2and PGE2a common goal of creating anti-inflammatory drugs. However, conventional non-steroidal anti-inflammatory drugs (SPULS, NSAIDs), which are active in the reduction caused by prostaglandin pain and swelling associated with inflammation, is also active in the impact on other regulated by prostaglandins processes not associated with the inflammatory process. Thus, the use of high doses of the most common SPULS can produce serious side effects, including life-threatening ulcers, which limits their therapeutic potential [.MacAllister et al., JAVMA, 202, 71 (1993)]. Alternative NCPLS is the use of corticosteroids, which are even more potent FOB is cnie effects, especially when they are used with long-term therapy [R. McDonald and V. Langston, Use of Corticosteroids and Non-steroidal Anti-inflammatory Agents, in Textbook of Veterinary Internal Medicine, 284 (Ettinger and Feldman 4 th ed., 1995)].

Carprofen described for the treatment of osteoarthritis in dogs [P. Vasseur et al., JAVMA, 206, 807 (1995)]. Piroxicam is used in the treatment of carcinoma in dogs [D. Knapp et al., J. of Vet. Int. Med., 8, 273 (1994)].

It was found that earlier SPULS prevent the production of prostaglandins by inhibiting enzymes in the arachidonic acid/prostaglandin pathways in human rights, including the enzyme cyclooxygenase (SOH) [S. Rubin and M. Papich, Nonsteroidal Anti-inflammatory Drugs, in Current Veterinary Therapy, X, 47-54 (1989)]. The recent discovery of the inducible enzyme associated with inflammation (called cyclooxygenase II (SOH II)" or "prostaglandin G/H synthase DACA"), provides a viable target of inhibition which more effectively reduces inflammation and produces fewer side effects and less drastic side effects.

Pyrazoles have been described for use in the treatment of inflammation. In Pat. U.S. No. 5134142 Matsuo et al. describes 1,5-diaryl-pyrazoles and in particular 1-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-3-trifluoromethyl-pyrazole, as having anti-inflammatory activity.

In Pat. U.S. No. 3940418 R. Hamilton describes tricyclic 4,5-dihydrobenzo[g]indazols as anti-inflammatory drugs. In addition, R. Hamilton [J. Heterocyclic Chem., 13 545 (1976)] describes tricyclic 4,5-dihydrobenzo[g]indazols as anti-inflammatory drugs. In Pat. U.S. No. 5134155 describes the condensed tricyclic pyrazoles having a saturated ring, connecting with the bridge connection, the pyrazole and phenyl radical, as HMG-CoA reductase inhibitors. In the publication EP 477 049, published on 25 March 1992, describes [4,5-dihydro-1-phenyl-1H-benzo[g]indazol-3-yl]amides as having protivopsychoticheskogo activity. In the publication EP 347 773, published December 27, 1989, describes [4,5-dihydro-1-phenyl-1H-benzo[g]indazol-3-yl]propanamide as Immunostimulants. M. Hashem et al. [J. Med. Chem., 19, 229 (1976)] describes the condensed tricyclic pyrazoles having a saturated ring, connecting with the bridge connection, the pyrazole and phenyl radical, as antibiotics.

The literature describes certain substituted personalresponsibility as synthetic intermediates. In particular, 4-[5-(4-chlorophenyl)-3-phenyl-1H-pyrazole-1-yl]benzosulfimide obtained from compounds of pyrazoline as intermediate for compounds having hypoglycemic activity [R.Soliman et al., J. Pharm. Sci., 76, 626 (1987)]. 4-[5-[2-(4-Bromophenyl)-2H-1,2,3-triazole-4-yl]-3-methyl-1H-pyrazole-1-yl]benzosulfimide obtained from compounds of pyrazoline, and it is described as potentially having hypoglycemic activity [N. Mokhtar, Pak. J. Sci. Ind. Res., 31, 762 (1988)]. Similarly receive 4-[4-bromo-5-[2-(4-chlorophenyl)-2H-1,2,3-triazole-4-yl]-3-ethyl-1H-pyrazole-1-yl]benzosulfimide [N. Mokhtar, Pak. J. Sci. Ind. Res., 34, 9 (1991)].

Phytotoxicity derivatives of pyrazole described [M. Sasso et al., Il. Farmaco-Ed. Sci., 40, 272 (1985)], in particular, for 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3,4-dicarboxylic acid.

Use sterilisation esters for antidiabetic drugs described [N. Mokhtar, Pharmazie, 33, 649-651 (1978)]. Use stillerstrong acids for antidiabetic drugs described [R.Soliman et al., Pharmazie, 33, 184-5 (1978)]. Describes the use of 4-[3,4,5-triple-substituted pyrazole-1-yl]benzosulfimide as intermediates for antidiabetic agents based on sulfonylurea, and in particular, 1-[4-(aminosulfonyl)phenyl]-3-methyl-5-phenyl-1H-pyrazole-4-dicarboxylic acid [R. Soliman et al., J. Pharm. Sci., 72, 1004 (1983)]. Received a number of 4-[3-substituted methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide as intermediates for antidiabetic agents, and more specifically 4-[3-methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide [Feid-Allah., H., Pharmazie, 36, 754 (1981)]. In addition, 1-(4-[aminosulfonyl]phenyl-5-phenylpyrazol-3-carboxylic acid was obtained from the above 4-[3-methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide connection [R.Soliman et al., J. Pharm. Sci., 70, 602 (1981)].

However pyrazolyl benzosulfimide compounds have not been previously described as veterinary products.

WO 95/15316 describes IP the use pyrazolyl benzene-sulfonamides for the treatment of inflammation or inflammatory diseases. WO 95/15318 describes the use parasailing compounds for treatment of inflammation and inflammatory diseases. EP-A 0554829 describes the use of 1,5-diarylpyrazole compounds for treatment of inflammation and inflammatory diseases.

Description of the INVENTION

The class of compounds used in the treatment of veterinary diseases associated with inflammation, is determined by the formula I:

where R1selected from aryl and heteroaryl, where R1substituted in position capable of substitution by one or more radicals selected from sulfamyl, halogen, alkyl, alkoxy, hydroxyl, halogenoalkane and

where R2selected from hydrido, halogen, alkyl, halogenoalkane, cyano, nitro, formyl, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyethyl, alkoxycarbonylmethyl, amidino, cyanoaniline, cyanoalanine, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N-arylenecarborane, N,N-dialkylaminoalkyl, N-alkyl-N-arylenecarborane, cycloalkylcarbonyl, heterocyclization, carboxymethylaminomethyl, alcoxycarboxylates, alkylcarboxylic, alkylcarboxylic, hydroxyalkyl, halogenoalkane, carboxylphenyl, alkoxycarbonylmethyl, aminomar is organogenesis, alkylaminocarbonyl, N-alkylamino, N,N-dialkylamino, N-arylamino, N-aralkylamines, N-alkyl-N-aralkylamines, N-alkyl-N-arylamino, aminoalkyl, N-acylaminoalkyl, N,N-dialkylaminoalkyl, N-alluminare, N-aralkylamines, N-alkyl-N-aralkylamines, N-alkyl-N-alluminare, aryloxy, Alcoxy, aaltio, Uralkali, alkylthio, alkylsulfonyl, alkylsulfonyl, N-alkylaminocarbonyl, N-arylaminomethylene, arylsulfonyl, N,N-dialkylaminoalkyl, N-alkyl-N-arylaminomethylene, heterocycle,

where R3selected from hydrido, alkyl, halogen, halogenoalkane, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyethyl, alkoxycarbonylmethyl, amidino, cyanoaniline, aminocarbonyl, alkoxy, N-alkylamino, N,N-dialkylamino, aminocarbonyl, N-alkylaminocarbonyl, N-arylenecarborane, N,N-dialkylaminoalkyl, N-alkyl-N-arylenecarborane, alkylcarboxylic, alkylcarboxylic, hydroxyalkyl, alkylthio, alkylsulfonyl, alkylsulfonyl, N-alkylaminocarbonyl, N-arylaminomethylene, arylsulfonyl, N,N-dialkylaminoalkyl, N-alkyl-N-arylaminomethylene, cycloalkyl, heterocycle, heterocyclyl and aralkyl;

where R4selected from aralkyl, aryl, cycloalkyl, cycloalkenyl and heterocycle; where R4optional replaced in position, which is obnam to the substitution, one or more radicals selected from halogen, alkylthio, alkylsulfonyl, alkyl, alkenyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N-arylenecarborane, N,N-dialkylaminoalkyl, N-alkyl-N-arylenecarborane, halogenoalkane, hydroxyl, alkoxy, hydroxyalkyl, halogenoalkane, sulfamyl, N-alkylaminocarbonyl, amino, N-alkylamino, N,N-dialkylamino, heterocycle, cycloalkyl, nitro, acylamino,

or where R3and R4together form

where m is from 1 to 3 inclusive;

where a is selected from phenyl and a five - or six-membered rings of heteroaryl;

where R5is alkyl;

where R6represents one or more radicals selected from halogen, alkylthio, alkylsulfonyl, alkylsulfonyl, cyano, carboxyl, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N-arylenecarborane, alkyl, alkenyl, N,N-dialkylaminoalkyl, N-alkyl-N-arylenecarborane, halogenoalkane, hydrido, hydroxyl, alkoxy, hydroxyalkyl, halogenoalkane, sulfamyl, N-alkylaminocarbonyl, amino, N-alkylamino, N,N-dialkylamino, heterocycle, cycloalkyl, nitro, acylamino; and

where R7selected from hydrido, alkyl, aryl and aralkyl; or their pharmaceutically reception who will be Sol.

The compounds of formula I can be used, but not limited to, for treating inflammation in an animal or for treatment of other inflammation diseases (disorders), as an analgesic in the treatment of pain or as an antipyretic for the treatment of fevers. For example, the compounds of formula I can be used to treat inflammation of the musculoskeletal system, including chronic inflammation of the hard and soft tissue, joint disease and traumatic injury. The compounds of formula I may be useful to treat arthritis, including but not limited to rheumatoid arthritis, gouty arthritis and osteoarthritis, myositis and tendonitis. Such compounds of formula I may be useful in the treatment of colic in horses, mastitis, peritonitis and related skin conditions such as burns and dermatitis. The compounds of formula I can be used to treat gastrointestinal conditions such as gastritis and ulcerative colitis, viral and bacterial infections LC (GI) tract, and to prevent malignant neoplasms, including colorectal malignancy.

The compounds of formula I can be used in the treatment of inflammation in such diseases as vascular diseases, gingivitis, hypersensitivity, conjunctivitis and other Vespa is placed eyes, swelling occurring after injury or surgery, myocardial ischemia, and the like Compounds are useful as anti-inflammatory agents, such as for the treatment of arthritis, with the additional benefit is the manifestation of a significantly less harmful side effects.

These compounds are used in the treatment of the herd (companion animals, exotic animals, and of animals, including mammals, etc. preferred animals are horses, dogs and cats.

The invention preferably includes compounds which selectively inhibit cyclooxygenase II compared with cyclooxygenase I. Preferred compounds have the IC50cyclooxygenase II less than about 0.2 μm, and also have a selectivity factor (selectivity values ratio) inhibition of cyclooxygenase II in comparison with the inhibition of cyclo-oxygenase I, at least 50 and more preferably at least 100. Even more preferred compounds have the IC50Cox I is greater than approximately 1 μm, and more preferably more than 10 μm. Such preferred selectivity may indicate an ability to reduce the scope of the (distribution of) the side effects caused by conventional SPULS.

A preferred class of compounds consists of the compounds of formula I, where R1selected from aryl selected from phenyl, naphthyl and biphenyl, and five or six member ring heteroaryl, where R1substituted in position capable of substitution by one or more radicals selected from sulfamyl, halogen, lower alkyl, lower alkoxy, hydroxyl, lower halogenoalkane and

where R2selected from hydrido, halogen, lower alkyl, lower halogenoalkane, cyano, nitro, formyl, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, lower alkoxycarbonyl, amidino, cyanoaniline, lower zainoulline, lower alkoxycarbonylmethyl, aminocarbonyl, lower alkoxy, lower aryloxy, lower Alcoxy, lower aminocarbonyl, lower N-alkylaminocarbonyl, N-arylenecarborane, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylenecarborane, lower cycloalkylcarbonyl, lower heterocyclizations, lower carboxymethylaminomethyl, lower alcoxycarboxylates, lower halogenoalkane, lower carboxyglutamate, lower alkoxycarbonylmethyl, lower aminocarbonylmethyl, lower alkylaminocarbonyl, lower alkylsulphonyl, lower alkylcarboxylic, lower alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-and is alkylamino, the lower N-alkyl-N-aralkylamines, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-acylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-alluminare, lower N-aralkylamines, lower N-alkyl-N-aralkylamines, lower N-alkyl-N-alluminare, aaltio, lower Uralkali, lower hydroxyalkyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyl, lower N-alkylaminocarbonyl, N-arylaminomethylene, arylsulfonyl, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylaminomethylene, heterocycle,

where R3selected from hydrido, lower alkyl, halogen, lower halogenoalkane, cyano, nitro, formyl, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, lower alkoxycarbonyl, amidino, cyanoaniline, aminocarbonyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower aminocarbonyl, lower N-alkylaminocarbonyl, lower N-arylenecarborane, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylenecarborane, lower alkylsulphonyl, lower alkylcarboxylic, lower hydroxyalkyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyl, lower N-alkylaminocarbonyl, N-arylaminomethylene, arylsulfonyl, lower N,N-dialkylaminoalkyl, NISS the th N-alkyl-N-arylaminomethylene, lower cycloalkyl, heterocycle, lower heterocyclyl and lower aralkyl; where R4selected from lower aralkyl, aryl, lower cycloalkyl, lower cycloalkenyl and from five to decatizing heterocycle; where R4optional replaced in position capable of substitution by one or more radicals selected from halogen, lower alkylthio, lower alkylsulfonyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl, N-arylenecarborane, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylenecarborane, lower halogenoalkane, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower halogenoalkane, sulfamyl, lower N-alkylaminocarbonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five - or six-membered heterocycle, lower cycloalkenyl, nitro, acylamino,

or where R3and R4together form

where m is from 1 to 3 inclusive; where a is selected from phenyl and a five - or six-membered rings of heteroaryl; where R5is lower alkyl; R6represents one or more radicals selected from halogen, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyl cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower N-alkylaminocarbonyl, lower N-arylenecarborane, lower alkyl, lower alkenyl, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylenecarborane, lower halogenoalkane, hydrido, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower halogenoalkane, sulfamyl, lower N-alkylaminocarbonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five - or six-membered heterocycle, lower cycloalkenyl, nitro, acylamino; and where R7selected from hydrido, lower alkyl, aryl and lower aralkyl; or their pharmaceutically acceptable salts.

A more preferred class of compounds consists of those compounds of formula I, where R1represents phenyl, where R1substituted in position capable of substitution by one or more radicals selected from sulfamyl, halogen, lower alkyl, lower alkoxy, hydroxyl, lower halogenoalkane and

where R2selected from hydrido, lower alkyl, lower halogenoalkane, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, lower zainoulline, lower alkoxycarbonylmethyl, lower halogenoalkane, lower carboxyglutamate, lower alkoxycarbonylmethyl, lower aminocarbonylmethyl the sludge, lower alkylaminocarbonyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamines, lower N-alkyl-N-aralkylamines, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-acylaminoalkyl, lower N,N-dialkylamino-alkyl, lower N-alluminare, lower N-aralkylamines, lower N-alkyl-N-aralkylamines, lower N-alkyl-N-arylenecarborane, aryloxy, lower Alcoxy, lower alkoxy, lower alkylthio, aaltio, lower Uralkali, aminocarbonyl, lower aminocarbonyl, lower N-alkylaminocarbonyl, N-arylenecarborane, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylenecarborane, lower cycloalkylcarbonyl, lower carboxymethylaminomethyl, lower alcoxycarboxylates, lower hydroxyalkyl,

where R3selected from hydrido, lower alkyl, halogen, cyano, lower hydroxyalkyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower N-alkylaminocarbonyl, N-arylaminomethylene, arylsulfonyl, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylaminomethylene and lower cycloalkyl; where R4selected from lower aralkyl, aryl, lower cycloalkyl, Nissel cycloalkenyl and from five to decatizing heterocycle; where R4optional replaced in position capable of substitution by one or more radicals selected from halogen, lower alkylthio, lower alkylsulfonyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower halogenoalkane, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower halogenoalkane, sulfamyl, lower alkylaminocarbonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five - or six-membered heterocycle, lower cycloalkenyl, nitro,

or where R3and R4together form

where m is 2; where a is selected from phenyl and a five - or six-membered rings of heteroaryl; where R5is lower alkyl; R6represents one or more radicals selected from halogen, lower alkylthio, lower alkylsulfonyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower halogenoalkane, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower halogenoalkane, sulfamyl, lower N-alkylamino, lower N,N-dialkylamino, lower cycloalkenyl and nitro; and R7selected from hydrido, lower alkyl, aryl and lower aralkyl; Il is their pharmaceutically acceptable salts.

Even more preferred class of compounds consists of those compounds of formula I, where R1represents phenyl, where R1substituted in position capable of substitution by one or more radicals selected from sulfamyl, halogen, lower alkyl, lower alkoxy and

where R2selected from hydrido, lower alkyl, lower halogenoalkane, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, lower zainoulline, lower alkoxycarbonylmethyl, lower halogenoalkane, lower carboxyglutamate, lower alkoxycarbonylmethyl, lower aminocarbonylmethyl, lower alkylaminocarbonyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamines, lower N-alkyl-N-aralkylamines, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-acylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-alluminare, the lower N-aralkylamines, lower N-alkyl-N-alluminare, lower N-alkyl-N-alluminare, lower alkoxy, aryloxy, lower Alcoxy, lower alkylthio, aaltio, lower Uralkali, aminocarbonyl, lower aminocarbonyl, lower N-alkylaminocarbonyl, N-arylenecarborane, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylenecarborane, the bottom is his cycloalkylcarbonyl, lower carboxymethylaminomethyl, lower heterocyclizations, lower alcoxycarboxylates, lower hydroxyalkyl,

where R3selected from hydrido, lower alkyl, halogen, cyano, lower hydroxyalkyl, lower alkoxy, lower N-alkylamino, lower N,N-dialkylamino, lower alkylthio, lower alkylsulfonyl and lower cycloalkyl; where R4selected from lower aralkyl, aryl, lower cycloalkyl, lower cycloalkenyl and from five to decatizing heterocycle; where R4optional replaced in position capable of substitution by one or more radicals selected from halogen, lower alkylthio, lower alkylsulfonyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower halogenoalkane, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower halogenoalkane, sulfamyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five - or six-membered heterocycle, lower cycloalkenyl, nitro,

or where R3and R4together form

where m is 2; where a is selected from phenyl and a five-membered heteroaryl; where R5is lower alkyl; R6pre is ensured by one or more radicals, selected from halogen, lower alkyl, lower alkylsulfonyl, lower halogenoalkane, lower alkoxy, sulfamyl, amino or nitro; and R7selected from hydrido, lower alkyl, aryl and lower aralkyl; or their pharmaceutically acceptable salts.

Within formula I there is a subclass of compounds consists of compounds, where R1is phenyl, substituted in position capable of substitution by one or more radicals selected from halogen, lower alkyl, sulfamyl and

where R2selected from hydrido, lower alkyl, lower halogenoalkane, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, lower zainoulline, lower alkoxycarbonylmethyl, lower halogenoalkane, lower carboxyglutamate, lower alkoxycarbonylmethyl, lower aminocarbonylmethyl, lower alkylaminocarbonyl, lower N-alkylamino, lower N,N-dialkylamino, N-arylamino, lower N-aralkylamines, lower N-alkyl-N-aralkylamines, lower N-alkyl-N-arylamino, lower aminoalkyl, lower N-acylaminoalkyl, lower N,N-dialkylaminoalkyl, lower N-alluminare, the lower N-aralkylamines, lower N-alkyl-N-aralkylamines, lower N-alkyl-N-alluminare, lower alkoxy, aryloxy, lower aralex is, lower alkylthio, aaltio, lower Uralkali, aminocarbonyl, lower aminocarbonyl, lower N-alkylaminocarbonyl, N-arylenecarborane, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylenecarborane, lower cycloalkylcarbonyl, lower carboxymethylaminomethyl, lower alcoxycarboxylates, lower hydroxyalkyl,

where R3selected from hydrido, lower alkyl, halogen, cyano, lower hydroxyalkyl, lower alkoxy, lower alkylthio, lower N-alkylamino, lower N,N-dialkylamino, lower alkylsulfonyl and lower cycloalkyl; where R4selected from lower aralkyl, aryl, lower cycloalkyl, lower cycloalkenyl and from five to decatizing heterocycle; where R4optional replaced in position capable of substitution by one or more radicals selected from halogen, lower alkylthio, lower alkylsulfonyl, lower alkyl, lower alkenyl, lower alkylsulfonyl, cyano, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower halogenoalkane, hydroxyl, lower alkoxy, lower hydroxyalkyl, lower halogenoalkane, sulfamyl, lower alkylaminocarbonyl, amino, lower N-alkylamino, lower N,N-dialkylamino, five - or six-membered heterocycle, lower cycloalkenyl nitro,

where R5is lower alkyl; and R7selected from hydrido, lower alkyl, aryl and lower aralkyl; or their pharmaceutically acceptable salts.

The class of compounds of particular interest consists of those compounds of formula I, where R1is phenyl, substituted in position capable of substitution by one or more radicals selected from fluorine, chlorine, methyl, sulfamyl, and

where R2selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, hexyl, formatie, diformate, trifloromethyl, chlormethyl, dichloromethyl, trichloromethyl, pentaborate, heptafluoropropyl, diperchlorate, dichloromethyl, deperately, deferrable, dichlorethyl, dichloropropyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxide, phenoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, TRIFLUOROACETYL, cyanomethyl, ethoxycarbonylmethyl, 1,1-debtor-1-phenylmethyl, 1,1-debtor-1-phenylethyl, divorcethe, methoxycarbonylmethyl, divorcelegal, N,N-dimethylacetamide, N-phenyldiethanolamine, N-ethylamino, N-methylamino, N,N, N,N-diethylamino, N-phenylamino, N-benzylamino, N-phenylethylamine, N-methyl-N-benzylamino, N-ethyl-N-phenylamino, N-methyl-N-phenylamino, aminomethyl, N-methylaminomethyl, N,N-dimethylaminomethyl, N-phenyliminomethyl, N-benzylaminopurine, N-methyl-N-benzylaminopurine, N-methyl-N-phenyliminomethyl, methoxy, ethoxy, phenoxy, benzyloxy, methylthio, phenylthio, benzylthio, N-metalmachine, N-methylthymidine, N-methylacetamide, urea, metallocene, thiourea, methylthymidine, acetamide, N-phenylethylamine, N-benzylmethylamine, N-methylethylamine, N-phenylethylamine, N-benzylmethylamine, N-methylethylamine, N-phenylacetamide, N-benzylacrylamide, N-methylacetamide, aminocarbonyl, aminocarbonylmethyl, N-methylaminomethyl, N-ethylaminoethanol, N-isopropylaminocarbonyl, N-propylaminosulfonyl, N-butylaminoethyl, N-sibutramineherbal, N-tert-butylaminoethyl, N-intramyocardial, N-phenylenecarbonyl, N,N-dimethylaminobenzoyl, N-methyl-N-ethylaminomethyl, N-(3-forfinal)aminocarbonyl, N-(4-were)aminocarbonyl, N-(3-chlorophenyl)aminocarbonyl, N-methyl-N-(3-chlorophenyl)aminocarbonyl, N-(4-methoxyphenyl)aminocarbonyl, N-methyl-N-phenylenecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, carboxymethylaminomethyl, benzyloxycarbonylglycine, is hydroxypropyl, hydroxymethyl and hydroxypropyl; where R3selected from hydrido, methyl, ethyl, isopropyl, tert-butyl, isobutyl, hexyl, fluorine, chlorine, bromine, cyano, methoxy, methylthio, methylsulfonyl, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, cyclopropyl, cyclopentyl, hydroxypropyl, hydroxymethyl and hydroxyethyl; and

where R4selected from phenylethenyl, phenyl, naphthyl, biphenyl, cyclohexyl, cyclopentyl, cycloheptyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 4-cyclohexenyl, 1-cyclopentenyl, 4-cyclopentenyl, benzofuran, 2,3-dihydrobenzofuran, 1,2,3,4-tetrahydronaphthyl, benzothiazyl, indenyl, indanyl, indolyl, dihydroindole, Romania, benzopyrane, tigermania, benzothiophene, benzodioxolyl, benzodioxane, pyridyl, teinila, thiazolyl, oxazolyl, purile and pyrazinyl; where R4optional replaced in position capable of substitution by one or more radicals selected from fluorine, chlorine, bromine, methylthio, methylsulfonyl, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, hexyl, etilene, propenyl, methylsulfonyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxide, phenoxycarbonyl, aminocarbonyl, formatie, diformate, Tr is formatie, chlormethyl, dichloromethyl, trichloromethyl, pentaborate, heptafluoropropyl, bromodifluoromethyl, diperchlorate, dichloromethyl, deperately, deferrable, dichlorethyl, dichloropropyl, hydroxyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy, sulfamyl, methylaminomethyl, hydroxypropyl, hydroxyisopropyl, hydroxymethyl, hydroxyethyl, triptoreline, amino, N-methylamino, N-ethylamino, N-ethyl-N-methylamino, N,N-dimethylamino, N,N-diethylamino, formylamino, methylcobalamine, triptorelin, piperidinyl, piperazinil, morpholino, cyclohexylmethyl, cyclopropylmethyl, cyclopentylmethyl, nitro,

and where R7selected from hydrido, methyl, ethyl, phenyl and benzyl; or their pharmaceutically acceptable salts.

In the scope of formula I includes a second subclass of compounds which are of considerable interest, where R1is phenyl, substituted in position capable of substitution, sulfamylon; where R2selected from lower halogenoalkane, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, aminocarbonyl, lower N-alkylaminocarbonyl, N-arylenecarborane, lower N,N-dialkylaminoalkyl, lower N-alkyl-N-arylenecarborane, lower cycloalkylcarbonyl and lower hydroxyalkyl, where R3and R4together form

where m is 2; where a is selected from phenyl and a five-membered heteroaryl; and where R6represents one or more radicals selected from halogen, lower alkyl, lower alkylsulfonyl, lower halogenoalkane, lower alkoxy, amino or nitro; or their pharmaceutically acceptable salts.

The class of compounds of particular interest consists of those compounds of formula I, where R2selected from formatie, diformate, trifloromethyl, chlormethyl, dichloromethyl, trichloromethyl, pentaborate, heptafluoropropyl, diperchlorate, dichloromethyl, deperately, deferrable, dichlorethyl, dichloropropyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isobutoxide, phenoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, TRIFLUOROACETYL, aminocarbonyl, N-methylaminomethyl, N-ethylaminoethanol, N-isopropylaminocarbonyl, N-propylaminosulfonyl, N-butylaminoethyl, N-sibutramineherbal, N-tert-butylaminoethyl, N-intramyocardial, N-phenylenecarbonyl, N,N-dimethylaminobenzoyl, N-methyl-N-ethylaminomethyl, N-(3-forfinal)aminocarbonyl, N-(4-were)aminocarbonyl, N-(3-chlorophenyl)aminocarbonyl, N-(4-methoxyphenyl)aminaka is bonila, N-methyl-N-phenylenecarbonyl, cyclohexanecarbonyl, hydroxypropyl, hydroxymethyl and hydroxyethyl; where a is selected from phenyl, purile and tanila; and where R6represents one or more radicals selected from fluorine, chlorine, bromine, methylsulfonyl, methyl, ethyl, isopropyl, tert-butyl, isobutyl, formatie, diformate, trifloromethyl, chlormethyl, dichloromethyl, trichloromethyl, pentaborate, heptafluoropropyl, diperchlorate, dichloromethyl, deperately, deferrable, dichlorethyl, dichloropropyl, methoxy, methylenedioxy, ethoxy, propoxy, n-butoxy, amino or nitro; or their pharmaceutically acceptable salts.

In the scope of formula I is a third subclass of compounds which are of considerable interest, where R1selected from phenyl, naphthyl, biphenyl, and five - or six-membered rings of heteroaryl, where R1substituted at substitutable position by one or more radicals selected from halogen, lower alkyl, lower alkoxy, hydroxyl and lower halogenoalkane; where R2selected from lower halogenoalkane; where R3is hydrido; and where R4is aryl, substituted in position capable of substitution, sulfamylon; or their pharmaceutically acceptable salts.

The class of compounds of particular interest consists of those compounds of formula I, where R1selected from Enola, naphthyl, benzofuran, benzothiazyl, indolyl, benzodioxolyl, benzodioxane, pyridyl, teinila, thiazolyl, oxazolyl, purile and pyrazinyl; where R1substituted in position capable of substitution by one or more radicals selected from fluorine, chlorine, bromine, formatie, diformate, trifloromethyl, chlormethyl, dichloromethyl, trichloromethyl, pentaborate, heptafluoropropyl, diperchlorate, dichloropropyl, dichloromethyl, deperately, deferrable, dichlorethyl, methyl, ethyl, propyl, hydroxyl, methoxy, ethoxy, propoxy and n-butoxy; where R2selected from formatie, diformate, trifloromethyl, chlormethyl, dichloromethyl, trichloromethyl, pentaborate, heptafluoropropyl, diperchlorate, deperately, dichloromethyl, deferrable, dichlorethyl and dichloropropyl; where R3is hydrido; and where R4is phenyl, substituted in position capable of substitution, sulfamylon; or their pharmaceutically acceptable salts.

In the scope of formula I is a subclass of compounds of interest represented by formula II:

where R2selected from hydrido, alkyl, halogenoalkane, alkoxycarbonyl, cyano, cyanoalanine, carboxyl, aminocarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl, arylenecarborane, carboxyethyl is aminocarbonyl, carboxyethyl, alcoxycarboxylates, aminocarbonylmethyl, alkoxycarbonylmethyl and hydroxyalkyl; where R3selected from hydrido, alkyl, cyano, hydroxyalkyl, cycloalkyl, alkylsulfonyl and halogen; and R4selected from aralkyl, aryl, cycloalkyl, cycloalkenyl and heterocycle; where R4optional replaced in position capable of substitution by one or more radicals selected from halogen, alkylthio, alkylsulfonyl, cyano, nitro, halogenoalkane, alkyl, hydroxyl, alkenyl, hydroxyalkyl, carboxyl, cycloalkyl, alkylamino, dialkylamino, alkoxycarbonyl, aminocarbonyl, alkoxy, halogenoalkane, sulfamyl, heterocycle and amino; provided that R2and R3both are not hydrido; in addition, provided that R2is not carboxyla or stands, when R3is hydrido, and when R4is phenyl; in addition, provided that R4is not triazolium, when R2is methyl; in addition, provided that R4is not arukenimon, when R2is carboxyl, aminocarbonyl or etoxycarbonyl; in addition, provided that R4is not phenyl when R2represents methyl and R3is carboxyl; and in addition, provided that R4is not resumes is authorized by tanila, when R2represents trifluoromethyl; or their pharmaceutically acceptable salts.

The class of compounds of particular interest consists of those compounds of formula II, where R2selected from hydrido, lower alkyl, lower halogenoalkane, lower alkoxycarbonyl, cyano, lower zainoulline, carboxyl, aminocarbonyl, lower alkylaminocarbonyl, lower cycloalkylcarbonyl, arylenecarborane, lower carboxymethylaminomethyl, lower alcoxycarboxylates, lower aminocarbonylmethyl, lower carboxyethyl, lower alkoxycarbonylmethyl and lower hydroxyalkyl; where R3selected from hydrido, lower alkyl, cyano, lower hydroxyalkyl, lower cycloalkyl, lower alkylsulfonyl and halogen; and R4selected from aralkyl, aryl, cycloalkyl, cycloalkenyl and heterocycle; where R4optional replaced in position capable of substitution by one or more radicals selected from halogen, lower alkylthio, lower alkylsulfonyl, cyano, nitro, lower halogenoalkane, lower alkyl, hydroxyl, lower alkenyl, lower hydroxyalkyl, carboxyl, lower cycloalkyl, lower alkylamino, lower dialkylamino, lower alkoxycarbonyl, aminocarbonyl, lower alkoxy, lower halogenoalkane, sulfamyl, five - or pole which membered heterocycle, and amino; or their pharmaceutically acceptable salts.

A family of specific compounds of particular interest, of the formula I consists of compounds and their pharmaceutically acceptable salts, are presented below:

4-[5-(4-(N-ethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-methyl-4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N,N-dimethylamino)-3-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N,N-dimethylamino)-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N-ethyl-N-methylamino)-3-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N-ethyl-N-methylamino)-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N,N-diethylamino)-3-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(3-chloro-4-(N,N-diethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzo is sulfonamid;

4-[5-(4-(N,N-diethylamino)-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-forfinal]-N-methylacetamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-chlorophenyl]-N-methylacetamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-were]-N-methylacetamide;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-forfinal]-N-metalmachine;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-chlorophenyl]-N-metalmachine;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-were]-N-metalmachine;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-forfinal]-N-methylthymidine;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-chlorophenyl]-N-methylthymidine;

N-[4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-3-were]-N-methylthymidine;

4-[5-(3-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-(N-ethyl-N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chloro-3-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methyl-3-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(triptime who yl)-1H-pyrazole-5-yl]phenyl]-N-methylacetamide;

N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-4-forfinal]-N-methylacetamide;

N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-4-were]-N-metalmachine;

N-[3-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-4-forfinal]-N-methylthymidine;

4-[5-(2-(N-ethyl-N-methylamino)-4-were)-3-(trifluoromethyl)1H-pyrazole-1-yl]benzosulfimide;

N-[2-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-4-were]-N-metalmachine;

N-[2-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]-4-forfinal]-N-methylthymidine;

4-[5-(1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(7-fluoro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1-ethyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(7-methyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(7-chloro-1-methyl-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3-dihydro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(7-fluoro-1-methyl-2,3-dihydro-1H-indol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-aminomethyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(N-methylamino)methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(N,N-dimethylamino)methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide

4-[5-phenyl-3-(N-phenylamino)methyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(N-benzylamino)methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(N-benzyl-N-methylamino)methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(N-methyl-N-phenylamino)methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]ndimethylacetamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-methylacetamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-phenylacetamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-benzylated;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]urea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-metalmachine;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-phenylacetone;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-benzyladenine;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]thiourea;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-methylthymidine;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-phenyltoloxamine;

N-[[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]methyl]-N-benzyltoluene;

4-[4-methoxy-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-methylthio-5-phenyl-3-(trifluoromethyl)-1H-p is razol-1-yl]benzosulfimide;

4-[4-(N-methylamino)-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-(N,N-dimethylamino)-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-methoxy-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-ethoxy-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-phenoxy-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-benzyloxy-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-methylthio-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-benzylthio-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(N-methylamino)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(N,N-dimethylamino)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(N-benzyl-N-methylamino)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]ndimethylacetamide;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-N-methylacetamide;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-N-benzylated;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]urea;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-N-metalmachine;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-N-benzyladenine;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]thiourea;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-N-methylthymidine;

N-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-N-benzylthio Cavina;

4-[5-phenyl-3-(1,1-debtor-1-phenylmethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-phenyl-3-(1,1-debtor-2-phenylethyl)-1H-pyrazole-1-yl]benzosulfimide;

1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-DIPEROXY acid;

methyl 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-deflorated;

1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-deflorated;

N,N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-deflorated;

N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-deflorated;

1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-acetic acid;

1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-DIPEROXY acid;

1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-DIPEROXY acid;

1-[4-(aminosulfonyl)phenyl]-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-3-acetic acid;

1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-acetic acid;

(R)-2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]propanoic acid;

(S)-2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]propanoic acid;

(R)-2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-yl]propanoic acid;

(S)-2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-yl]propanoic acid;

(R)-2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-yl]propanoic acid;

(S)-2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-Fe is Il-1H-pyrazole-3-yl]propanoic acid;

2-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-3-H-pyrazole-3-yl]-2-methylpropanoate acid;

2-[1-[4-(aminosulfonyl)phenyl]-4-chloro-5-phenyl-1H-pyrazole-3-yl]-2-methylpropanoate acid;

2-[1-[4-(aminosulfonyl)phenyl]-4-bromo-5-phenyl-1H-pyrazole-3-yl]-2-methylpropanoate acid;

2-fluoro-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

3-fluoro-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

2-methyl-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

3-methyl-4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

ethyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

ethyl 1-[4-(aminosulfonyl)phenyl]-5-(4-were)-1H-pyrazole-3-carboxylate;

isopropyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-AMINOPHENYL)-1H-pyrazole-3-carboxylate;

1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid;

tert-butyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

propyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

butyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

isobutyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

pentyl 1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosol who were radioactive)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-were)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-nitrophenyl)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazole-3-carboxylate;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(3,5-debtor-4-methoxyphenyl)-1H-pyrazole-3-carboxylate;

N-[4-were]-1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxamide;

N-[3-chlorophenyl]-1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxamide;

N-[3-forfinal]-1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxamide;

N-[3-forfinal]-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

phenylmethyl N-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carbonyl]glycinate;

1-[4-(aminosulfonyl)phenyl]-5-(4-bromophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxamide;

N-(4-methoxyphenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxamide;

N-(4-were)-1-[4-(aminosulfonyl)phenyl]-5-(4-CHL is henyl)-1H-pyrazole-3-carboxamide;

N,N-dimethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-phenyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-ethyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-isopropyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-propyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-isobutyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-tert-butyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-pentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-cyclohexyl-1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxamide;

N-cyclopentyl-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

4-[5-(4-chlorophenyl)-3-(pyrrolidinecarboxamido)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(piperidinecarboxylic)-1H-pyrazole-1-yl]benzosulfimide;

N-(3-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-harfe who yl)-1H-pyrazole-3-carboxamide;

N-(2-pyridyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

N-methyl-N-(3-chlorophenyl)-1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-nitrophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(3-chloro-4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-methylthiophenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(4-were)-1H-pyrazole-3-carboxamide;

N-methyl-1-[4-(aminosulfonyl)phenyl]-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

N-[[1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carbonyl]glycine;

1-[4-(aminosulfonyl)phenyl]-5-(3-bromo-4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

1-[4-(aminosulfonyl)phenyl]-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazole-3-carboxamide;

4-[5-(4-bromophenyl)-3-cyano-1H-pyrazole-1-yl]benzosulfimide;

4-[3-cyano-5-(4-forfinal)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-cyano-1H-pyrazole-1-yl]benzosulfimide;

4-[3-cyano-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-cyano-5-(4-were)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-cyano-5-(4-methylthiophenyl)-1H-p is razol-1-yl]benzosulfimide;

4-[5-(3-chloro-4-methoxyphenyl)-3-cyano-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-cyano-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-bromo-4-methoxyphenyl)-3-cyano-1H-pyrazole-1-yl]benzosulfimide;

4-[3-cyano-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-nitrophenyl)-3-(cyano)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-forfinal)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-chlorophenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-bromo-5-(4-chlorophenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-bromo-5-(4-were)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-were)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-bromo-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-cyano-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(3,5-debtor-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-fluoro-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-4-methylsulphonyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-feast of the ol-1-yl]benzosulfimide;

4-[4-ethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-4-ethyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-ethyl-5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-ethyl-5-(4-methoxy-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-ethyl-5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-ethyl-5-(3-fluoro-4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-forfinal)-4-methyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-methyl-5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-bromo-5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-3-(deformity)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-bromo-3(deformity)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-3-(deformity)-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-3-cyano-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-chlorophenyl)-3-cyano-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-3-cyano-5-(4-forfinal)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-bromo-3-cyano-5-(4-forfinal)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-bromo-3-cyano-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

ethyl [1-(4-aminosulphonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate;

methyl [1-(4-aminosulphonylphenyl)-4-chloro-5-phenyl-1H-pyrazole-3-yl]carboxylate;

methyl [1-(4-aminosulphonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate;

ethyl [1-(4-aminosulphonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate;

methyl [1-(4-aminosulphonylphenyl)-4-chloro-5-(4-forfinal)-1H-pyrazole-3-yl]carboxylate;

methyl [1-(4-aminosulphonylphenyl)-4-bromo-5-(4-forfinal)-1H-pyrazole-3-yl]carboxylate;

methyl [1-(4-aminosulphonylphenyl)-4-chloro-5-(3-chloro-4-methoxyphenyl)-1H-pyrazole-3-yl]carboxylate;

methyl [1-(4-aminosulphonylphenyl)-4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazole-3-yl]carboxylate;

methyl [1-(4-aminosulphonylphenyl)-5-(3-bromo-4-methoxyphenyl)-4-chloro-1H-pyrazole-3-yl]carboxylate;

[1-(4-aminosulphonylphenyl)-4-chloro-5-phenyl-1H-pyrazole-3-yl]carboxamide;

[1-(4-aminosulphonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxamide;

1-(4-aminosulphonylphenyl)-4-chloro-5-(4-forfinal)-1H-pyrazole-3-yl]carboxamide;

[1-(4-aminosulphonylphenyl)-4-bromo-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxamide;

[1-(4-aminosulphonylphenyl)-4-bromo-5-phenyl-1H-pyrazole-3-yl]carboxamide;

[1-(4-aminosulphonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-

3-yl]carboxylic acid;

[1-(4-aminosulphonylphenyl)-4-chloro-5-phenyl-1H-pyrazole-3-yl]carboxylic acid;

[1-(4-aminosulphonylphenyl)-4-chloro-5-(3,5-dichloro-4-methoxyphenyl)-1H-pyrazole-3-yl]carboxylic acid;

4-[4-chloro-3-isopropyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-3-methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-3-hydroxymethyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-chlorophenyl)-3-hydroxymethyl-1H-pyrazole-1-yl]benzosulfimide;

[1-(4-aminosulphonylphenyl)-4-chloro-5-(4-chlorophenyl)-1H-pyrazole-3-yl]propanoic acid;

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-[2,4-differenl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,6-differenl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]bansilal foamed;

4-[5-(4-bromophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,4-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-triptoreline)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-trifloromethyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-AMINOPHENYL)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-fluoro-2-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-ethoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,5-dimethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide is;

4-[5-(4-chloro-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-ethylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,4-dimetilfenil)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methoxy-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-bromo-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-hydroxy-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4-acid)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-methoxy-5-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-fluoro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-hydroxymethylene)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methoxy-3-(1-propenyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,4-acid)-3-(trifluoromethyl)-1H-pyrazole-1-yl]Ben is alcolholic;

4-[5-(3-chloro-4-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methoxy-3-propylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,5-debtor-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-cyclopropylmethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzoic acid;

4-[5-(3-methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(N-methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-amino-4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

methyl 4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzoate;

4-[1-[4-(aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzamide;

4-[5-(3,5-differenl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,4,6-tryptophanyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-[2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-and the]benzosulfimide;

4-[5-(2,4,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4-dimetilfenil)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-chloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methylsulfinylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-fluoro-4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-fluoro-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-chloro-4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chloro-2-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,dihydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-isopropylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

N-[4-[1-[4-(aminosulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl]ndimethylacetamide;

N-[4-[1-[4-(aminosulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl]formamide;

N-[4-[1-[4-(aminosulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl]triptorelin;

4-[5-(4-[N-methylaminomethyl]phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,5-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-n-butoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-[aminosulfonyl]phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3-differenl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,5-differenl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3,4-tryptophanyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4,5-tryptophanyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,4,5-tryptophanyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-[2,5,6-tryptophanyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3,4,5-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3,4,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3,5,6-tetrafluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide is;

4-[5-(pentafluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3,4-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,4,5-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,5,6-trichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3,4,5-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1,2,4,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3,5,6-tetrachlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3,4,5,6-pentachlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-tert-butylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-isobutylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-triptoreline)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methylthiophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(1-morpholino)phenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-were)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-phenyl-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-and the]benzosulfimide;

4-[5-(3,4-dimetilfenil)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[1-[4-(aminosulfonyl)phenyl]-3-(deformity)-1H-pyrazole-5-yl]benzoic acid;

methyl 4-[1-[4-(aminosulfonyl)phenyl]-3-(deformity)-1H-pyrazole-5-yl]benzoate;

4-[1-[4-(aminosulphonylphenyl]-3-(deformity)-1H-pyrazole-5-yl]benzamide;

4-[5-(2-fluoro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-cyanophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-were)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chloro-3-were)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4-acid)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,5-debtor-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-bromo-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methylsulfinylphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-bromo-2-thienyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-chloro-2-thienyl)-3-(WPPT is ormetal)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1-cyclohexenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(cyclohexyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(biphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1,4-benzodioxan-6-yl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(4-methylcyclohexyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(methyl-1-cyclohexenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-methyl-1-cyclopentenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(benzofuran-2-yl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1,3-benzodioxol-5-yl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-pyrazinyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-(morpholino)phenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,5-dimethyl-3-furyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-methyl-2-furyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1-chloro-1-methyl-4-cyclohexyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4-dibromo-4-methylcyclohexyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-methoxycyclohexyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-thienyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,4-dimethyl-3-thienyl)-3-(deformity)-1H-feast of the evils-1-yl]benzosulfimide;

4-[5-(2,5-dichloro-3-thienyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(benzofuran-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-bromo-2-thienyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-chloro-2-thienyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-indanyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-methyl-2-thienyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2,3-dihydrobenzofuran-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-benzothiazyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4-dihydro-2H-1-benzopyran-6-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,4-dihydro-2H-1-benzothiophen-6-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-phenylethenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methyl-1,3-benzodioxol-6-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-pyrazinyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(biphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1,2,3,4-tetrahydronaphtyl-6-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-naphthyl)--(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-thiazolyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-oxazolyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(cyclohexyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(cyclopentyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(cycloheptyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(1-cyclopentenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-furyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(2-pyridyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-pyridyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(6-methyl-3-pyridyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-pyridyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-cyclohexenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-methylcyclohex-4-EN-1-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-chloro-2-furyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(5-bromo-2-furyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(6-methoxy-2-naphthyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(hardif ormetal)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(pentafluoroethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-methoxyphenyl)-3-(chloromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(chlorodifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(phenyl)-3-(permitil)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(bromodifluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(permitil)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(chloromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(dichloromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(dichloromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-forfinal)-3-(trichloromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(1,1-dottorati)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(1,1-deferror)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(1,1-dichloroethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(1,1-dichloropropyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-nitro-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(amidino)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(methylsulphonyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-methyl-aminosulfonyl)-spirutal-1-yl]benzosulfimide;

4-[5-(4-forfinal)-3-(imidazolyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-forfinal)-3-(2-pyridyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-cyanoimino)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(tetrazolyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(phenylsulfonyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-phenylenesulfonyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N,N-dimethylaminomethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-methyl-N-phenylenesulfonyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-ethylaminomethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-isopropylaminocarbonyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-methyl-N-ethylaminomethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-methyl-N-(3-chlorophenyl)aminosulfonyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(N-methyl-N-(2-pyridyl)aminosulfonyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-methyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-isobutyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(3-hydroxypropyl)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-forfinal)-3-(3-hydroxypropyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxypropyl)-N-pyrazole-1-yl]benzosulfimide;

4-[5-(4-were)-3-(2-hydroxyisopropyl)-1H-pyrazole-1-yl]benzosulfimide;

1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-propanoic acid;

1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-propanoic acid;

1-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-propanamide;

methyl 1-[4-(aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-propanoate;

4-[3-(3-hydroxymethyl)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(3-hydroxymethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(3-hydroxymethyl)-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(3-hydroxymethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-methoxyphenyl)-3-(3-hydroxymethyl)-1H-pyrazole-1-yl]benzosulfimide;

ethyl 3-[1-(4-aminosulphonylphenyl)-5-(phenyl)-1H-pyrazole-3-yl]-2-cyano-2-propenoate;

4-[5-(4-chlorophenyl)-3-(chloro)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(bromo)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(fluoro)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-4,5-dihydro-7-methoxy-1H-benzo[g]indazol-1-yl]benzosulfimide;

4-[3-(deformity)-4,5-dihydro-7-methyl-1H-benzo[g]indazol-1-yl]benzosulfimide;

4-[4,5-dihydro-7-methoxy-3-(trifluoromethyl)-1H-benzo[g]indazol-1-yl]benzosulfimide;

4-[4,5-dihydro-3-(trifluoromethyl)-1H-benzo[g]indazol-1-yl]benzosulfimide;

4-[4,5-dihydro-7-methyl-3-(trifluoromethyl)-1H-benzo[g]indazol-1-yl]benzosulfimide;

4-[4,5-dihydro-6,8-dimethyl-3-(trifluoromethyl)-1H-benzo[g]indazol-1-yl]benzosulfimide;

4-[4,5-dihydro-6,8-dimethoxy-3-(trifluoromethyl)-1H-benzo[g]indazol-1-yl]benzosulfimide;

methyl [1-(4-aminosulphonylphenyl)-4,5-dihydro-7-methoxy-1H-benzo[g]indazol-3-yl]carboxylate;

4-[4,5-dihydro-3-trifluoromethyl-1H-thieno[3,2,g]indazol-1-yl]benzosulfimide;

4-[1-phenyl-3-(deformity)-1H-pyrazole-5-yl]benzosulfimide;

4-[1-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-5-yl]benzosulfimide;

4-[1-(4-forfinal)-3-(deformity)-1H-pyrazole-5-yl]benzosulfimide;

4-[1-(4-methoxyphenyl)-3-(deformity)-1H-pyrazole-5-yl]benzosulfimide;

4-[1-phenyl-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzosulfimide;

4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzosulfimide;

4-[1-(4-forfinal)-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzosulfimide and

4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzosulfimide.

A family of specific compounds of particular interest within formula II consists of compounds and their pharmaceutically acceptable salts, are presented below:

4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-forfinal)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzene is sulfonamid;

4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(4-were)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-cyano-5-(4-forfinal)-1H-pyrazole-1-yl]benzosulfimide;

4-[3-(deformity)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide;

4-[4-chloro-5-phenyl-1H-pyrazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazole-1-yl]benzosulfimide and

4-[5-(4-(N,N-dimethylamino)phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide.

The term "hydrido" denotes a single hydrogen atom (H). This hydrographical can be attached, for example, the oxygen atom with the formation of a hydroxyl radical or two hydrographical can be attached to the carbon atom with the formation of a methylene (-CH2-)radical.

When the term "alkyl" used either alone or within other terms such as "halogenated" and "Ala sulfonyl", it embraces linear or branched radicals having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl radicals are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having from one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like, the Term "alkenyl" embraces linear or branched radicals having at least one carbon-carbon double bond and having from two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkyl radicals are "lower alkeneamine" radicals having two to about six carbon atoms. Examples of such radicals include ethynyl, n-propenyl, butenyl, etc. the Term "halogen" means a halogen, such as fluorine atoms, chlorine, bromine or iodine. The term "halogenated" embraces radicals where any one or more of the atoms (hydrogen) alkyl defined above substituted by halogen. In particular, gateways monohalogen-, di - halogen - and POLYHALOGENATED radicals. Monologically radical, for example, may have either an atom of iodine, bromine, chlorine or fluorine atom within the radical. Dihalogen and POLYHALOGENATED radicals may have two or more of the same halogen atoms, or a combination of different halogen atoms. "Lower halogenated" embraces radicals having 1-6 carbon atoms. Examples halogenating radicals include vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, diperchlorate, dichloromethyl, defloratin, direcror, dichlorethyl and dichloropropyl. The term "hydroxyalkyl" embraces linear or branched alkyl radicals having from one to about ten carbon atoms any one of which may be substituted by one or more hydroxyl radicals. Preferred hydroxyalkyl radicals are "lower hydroxyalkyl" radicals having one to six carbon atoms and one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyhexyl. The terms "alkoxy" and "alkoxyalkyl" embraces linear or branched oxycodonesee radicals, and each is alkyl part number ATO is s carbon from one to ten, such as methoxyacetyl. More preferred alkoxy radicals are "lower alkoxy" radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The term "alkoxyalkyl" also embraces alkyl radicals having two or more alkoxyalkyl related alkyl radical, i.e. forming monoatomically and dialkoxybenzene radicals. More preferred alkoxyalkyl radicals are "lower alkoxyalkyl" radicals having one to six carbon atoms and one or two alkoxyalkyl. Examples of such radicals include methoxymethyl, methoxyethyl, ethoxyethyl, methoxybutyl and methoxypropyl. "Alkoxy" or "alkoxyalkyl" radicals may be additionally substituted by one or more halogen atoms such as fluorine, chlorine or bromine, to obtain the "halogenoalkane" or "halogenoacetyl" radicals. Examples of such radicals include formatosi, chloromethoxy, triptoreline, triptoreline, floratone, forproperty. The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be connected together as lateral suspension or may be condensed. The term "aryl" embraces aromatic radicals, that is their as phenyl, naphthyl, tetrahydronaphthyl, indan and biphenyl. The term "heterocycle" includes saturated, partially saturated and unsaturated heteroaromatics radicals in the form of a ring, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicals include saturated (3-6)-membered heterogenities group containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidine, piperazinil etc.]; rich (3-6)-membered heterogenities group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; rich (3-6)-membered heterogenities group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., diazolidinyl etc.]. Examples of partially saturated heterocyclic radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazolo. The term "heteroaryl" embraces unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals, also known by the term "heteroaryl" radicals, include unsaturated 5 to 6-membered heterogenities group containing 1 to 4 nitrogen atoms, for example pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl is so], tetrazolyl [e.g., 1H-tetrazolyl 2N-tetrazolyl etc.] etc; unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl, tetrachloropyridine [for example, tetrazolo [1,5-b]pyridazinyl etc.] etc; unsaturated (3-6)-membered heterogenities group containing an oxygen atom, such as pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heterogenities group containing a sulfur atom, for example 2-thienyl, 3-thienyl etc; unsaturated 5 to 6-membered heterogenities group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl etc.] etc; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., benzoxazolyl, benzoxadiazole etc.]; unsaturated 5 to 6-membered heterogenities group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl etc.] etc; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzac azolyl, benzothiadiazole etc.], etc. the Term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such a condensed bicyclic radicals include benzofuran, benzothiophene etc. Mentioned "heterocyclic group" may have 1 to 3 substituents such as lower alkyl, hydroxy, oxo, amino and lower alkylamino. Preferred heterocyclic radicals include from five to decatizing condensed or unfused radicals. More preferred examples of heteroaryl radicals include benzofuran, 2,3-dihydrobenzofuran, benzothiazyl, indolyl, dihydroindole, bromanil, benzopyran, thiochroman, benzothiophen, benzodioxolyl, benzodioxolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl. The term "sulfonyl", used either alone or linked to other terms such as alkylsulfonyl, denotes respectively divalent radicals-SO2-. "Alkylsulfonyl" embraces alkyl radicals associated with sulfonyl radical, where alkyl such as defined above. More preferred alkylsulfonyl radicals are "lower alkylsulfonyl" radicals having one to six carbon atoms. Examples of such lower alkylsulfonyl radicals include methylsulphonyl, ethylsulfonyl about ylsulphonyl. The term "arylsulfonyl" covers, as defined above, aryl radicals associated with sulfonyl radical. Examples of such radicals include phenylsulfonyl. The terms "sulphonamide", "aminosulfonyl" and "sulfonamides", used either as such or with terms such as "N-alkylaminocarbonyl", "N-arylamination, N,N-dialkylaminoalkyl" and "N-alkyl-N-arylamination ' denote sulfanilyl radical, substituted by aminosalicylate, forming a sulfonamide (-SO2NH2). The terms "N-alkylaminocarbonyl" and "N,N-dialkylaminoalkyl" refers to selfamily radicals substituted, respectively, with one alkyl radical, or two alkyl radicals. More preferred alkylaminocarbonyl radicals are "lower alkylaminocarbonyl" radicals having one to six carbon atoms. Examples of such lower alkylaminocarbonyl radicals include N-methylaminomethyl, N-ethylaminoethanol and N-methyl-N-ethylaminomethyl. The terms "N-arylamination" and "N-alkyl-N-arylamination" refers to selfamily radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. The preferred N-alkyl-N-arylaminomethylene radicals are "lower N-alkyl-N-arylsulfonyl" radicals having alkyl radicals who s from one to six carbon atoms. Examples of such lower N-alkyl-N-killinaskully radicals include N-methyl-phenylenesulfonyl and N-ethyl-phenylenesulfonyl. The terms "carboxy" or "carboxyl", used either alone or with other terms, such as "carboxylic", denotes-CO2N. The terms "alkanoyl" or "carboxylic" embraces radicals having the above-defined carboxylation associated with the alkyl radical. Alcoholnye radicals can be substituted or unsubstituted, such as formyl, acetyl, propionyl (propanol), butanol (butyryl), Isobutanol (isobutyl), Valerie (pentanol), isovaleryl, pivaloyl, hexanoyl or the like, the Term "carbonyl", used either alone or with other terms, such as "alkylaryl", denotes -(C=O)-. The term "alkylaryl" embraces radicals having a carbonyl radical, a substituted alkyl radical. More preferred alkylcarboxylic radicals are "lower alkylsulphonyl" radicals having one to six carbon atoms. Examples of such radicals include methylcarbamyl and ethylcarboxyl. The term "alkylcarboxylic" denotes an alkyl radical, substituted "alkylaryl" radical. The term "alkoxycarbonyl" means a radical containing alkoxyalkyl defined above connected through an oxygen atom to a carbonyl radical. Preferably the lower alkoxycarbonyl covers alkoxyalkyl, having from one to six carbon atoms. Examples of such "low alkoxycarbonyl" ester radicals include substituted or unsubstituted methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl and hexyloxybenzoyl. The term "alkoxycarbonyl" embraces radicals having "alkoxycarbonyl"defined above is substituted by an alkyl radical. More preferred alkoxycarbonylmethyl radicals are "lower alkoxycarbonyl" radicals having defined above lower alkoxycarbonyl radicals associated with one to six carbon atoms. Examples of such lower alkoxycarbonylmethyl radicals include methoxycarbonylmethyl, tert-butoxycarbonylmethyl and methoxycarbonylethyl. The term "aminocarbonyl" when used by itself or with other terms, such as aminocarbonylmethyl", "N-alkylaminocarbonyl", "N-allumination", "N,N-dialkylaminoalkyl", "N-alkyl-N-allumination", "N-alkyl-N-hydroxyaminobuteroyl" and "N-alkyl-N-hydroxyarylalkyl"denotes an amide group of the formula-C(=O)NH2. The terms "N-alkylaminocarbonyl" and "N,N-dialkylaminoalkyl" refers to aminocarbonyl radicals, which is substituted by one alkyl radical and with two alkyl radicals, respectively. Preferred "lower alkylaminocarbonyl the l radicals, having lower alkyl radicals described above, associated with aminocarbonyl radical. The terms "N-allumination" and "N-alkyl-N-allumination" refers to aminocarbonyl radicals substituted, respectively, with one aryl radical, or one alkyl and one aryl radical. The term "aminocarbonyl" embraces alkyl radicals substituted aminocarbonyl radicals. The term "N-cycloalkylcarbonyl" means aminocarbonyl radicals, which is substituted by at least one cycloalkyl radical. Preferred "lower cycloalkylcarbonyl" radicals having lower cycloalkyl radicals with three to seven carbon atoms, associated with aminocarbonyl radical. The term "aminoalkyl" embraces alkyl radicals substituted by aminosalicylate. The term "acylaminoalkyl covers aminoalkyl radicals having a nitrogen atom, a substituted alkyl radical. The term "amidino" refers to-C(=NH)-NH2the radical. The term "cyanamide" refers to-C(=N-CN)-NH2the radical. The term "heterocyclyl covers heterocyclization alkyl radicals. More preferred heteroseksualnymi radicals are "lower heterocyclyl" radicals having one to six carbon atoms and heterocyclization. Examples include such radicals, ka is pyrrolidinyl, pyridylmethyl and thienylmethyl. The term "aralkyl" embraces aryl-substituted alkyl radicals. Preferred Uralkalij radicals are "lower aralkyl" radicals having aryl radicals associated with alkyl radicals having from one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylether. Aryl in the specified aralkyl may be optionally substituted with halogen, alkyl, alkoxy, halogenation, halogenoalkane. Terms benzyl and phenylethyl interchangeable. The term "cycloalkyl" embraces radicals having from three to ten carbon atoms. More preferred cycloalkyl radicals are "lower cycloalkyl" radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "cycloalkenyl" embraces unsaturated cyclic radicals having three to ten carbon atoms, such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, linked to a divalent sulfur atom. Example "alkylthio" is methylthio, (CH3-S-). The term "alkylsulfonyl covers Radik the crystals, containing a linear or branched alkyl radical, of one to ten carbon atoms, linked with a divalent-S(=O)- atom. The term "aminoalkyl" embraces alkyl radicals substituted by aminosalicylate. More preferred aminoalkyl radicals are "lower aminoalkyl" (radicals)having from one to six carbon atoms. Examples include aminomethyl, aminoethyl and aminobutyl. The term "acylaminoalkyl covers aminoalkyl radicals having the nitrogen atom, substituted by at least one alkyl radical. More preferred acylaminoalkyl radicals are "lower acylaminoalkyl" (radicals)having from one to six carbon atoms, associated with lower aminoalkyl radical described above. The terms "N-alkylamino" and "N,N-dialkylamino" denote amino groups which are substituted with one alkyl radical and with two alkyl radicals, respectively. The preferred alkylenediamine are "lower alkylamino"having one or two alkyl radical with one to six carbon atoms linked to the nitrogen atom. Suitable "alkylamino" may be mono or dialkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino or the like, the Term "arylamino" denotes amino groups which are substituted by one or two aryl radicals which, such as N-phenylamino. "Arylamino" radicals may be further substituted on the aryl part of the ring radical. The term "aralkylamines" denotes amino groups which are substituted by one or two Uralkalij radicals, such as N-benzylamino. "Aralkylamines" radicals may be further substituted on the aryl part of the ring radical. The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" denote amino groups which are substituted one Uralkali and one alkyl radical, or one aryl and one alkyl radical, respectively, at the amino group. The terms "N-alluminati" and "N-aralkylamines" denote amino groups which are substituted with one aryl radical or one Uralkali radical, respectively, and having the amino group associated with the alkyl radical. More preferred arylaminomethylene radicals are "lower alluminati" (radicals)with killinarden associated with an alkyl radical having from one to six carbon atoms. Examples of such radicals include N-phenyliminomethyl and N-phenyl-N-methylaminomethyl. The terms "N-alkyl-M-alluminati" and "N-aralkyl-N-acylaminoalkyl" denotes N-alkyl-N-arylamino and N-aralkyl-N-alkylamino respectively, and having the amino group associated with alkyl radicals. The term "acyl"used, or one or wew and term such as "acylamino", denotes a radical which is the residue after removal of hydroxyl from an organic acid. The term "acylamino covers aminoacyl, substituted acyl group. Examples of "acylamino" radical is acetylamino or acetamido (CH3C(=O)-NH-), where the amine may be further substituted by alkyl, aryl or aralkyl. The term "aristeo" embraces aryl radicals with six to ten carbon atoms, associated with divalent sulfur atom. Example "aristeo is phenylthio. The term "Uralkali covers defined above kalkilya radicals associated with dvuhvalenten a sulfur atom. Example "Uralkali is benzylthio. The term "aryloxy" covers, as defined above, aryl radicals, linked to an oxygen atom. Examples of such radicals include phenoxy. The term "arakaki covers oxycodonesee kalkilya radicals linked through an oxygen atom to other radicals. The preferred arakomerciuli are "lower Alcoxy" radicals having phenyl radicals associated with lower above described alkoxylation. The term "halogenerator" covers, as defined above, aryl radicals associated with halogenoalkane radicals. The term "carboxyglutamic covers defined above carboxialkilnuyu radicals with halogen is haunted radicals, associated with the alkyl part. The term "alkoxycarbonylmethyl covers defined above alkoxycarbonyl radicals, substituted halogenosilanes radical. The term "aminocarbonylmethyl covers defined above aminocarbonyl radicals, substituted halogenosilanes radical. The term "alkylaminocarbonyl covers defined above alkylaminocarbonyl radicals, substituted halogenosilanes radical. The term "alkoxycarbonylmethyl covers defined above alkoxycarbonyl radicals and ceanorhaditis, both substituted alkenyl radical. The term "carboxymethylaminomethyl covers aminocarbonyl radicals, substituted carboxialkilnuyu radicals, as defined above. The term "alcoxycarboxylates covers aminocarbonyl radicals, substituted aryl-substituted alkoxycarbonyl radicals, as defined above. The term "cycloalkenyl covers cycloalkyl radicals having from three to ten carbon atoms, connected to the alkyl radical, as defined above. More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having cycloalkyl radicals associated with lower alkyl radicals, as defined above. Examples include for the sake of the materials, such as cyclopropylmethyl, cyclobutylmethyl and cyclohexylethyl. The term "aralkyl" embraces aryl radicals associated with alkenylamine radicals having from two to ten carbon atoms, such as phenylbutyl and phenylethenyl or still.

In addition, in the family of compounds of formula I include pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" embraces salts commonly used to obtain the alkali metal salts and to obtain salts of accession of free acids or free bases. The nature of salt is unimportant, provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable salts of accession of the acid compounds of formula I can be obtained from inorganic acids or organic acids. Examples of such inorganic acids are hydrochloric, Hydrobromic, itestosterone, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, analiticheskogo, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic who, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, Anthranilic, musilova, salicylic acid, 4-hydroxybenzoic, phenylacetic, almond, ammonia (AMOVA), methansulfonate, econsultancy, benzolsulfonat, Pantothenic, 2-hydroxyethanesulfonic, toluensulfonate, sulfanilic, cyclohexanesulfonyl, stearic, Allenova, β -hydroxybutiric (β -hydroxybutyrate), galactosemia and galacturonic acid. Suitable pharmaceutically acceptable salts of attaching the base of the compounds of formula I include metallic salts obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts derived from N,N’-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be obtained in the usual way from the corresponding compounds of formula I by reacting, for example, the appropriate acid or base with the compound of the formula I.

GENERAL SYNTHESIS METHODS

The compounds of this invention can be synthesized in accordance with methods presented in Schemes I-VIII, where R1-R7the substituents are as defined above for formula I, except where noted later.

CX is mA I

In the Diagram I presented the receipt of Tetra-substituted pyrazoles of the source material 1. In stage 1 Scheme of the synthesis of I, phenylmercaptan (1) is subjected to interaction with the substrate and alkylating reagent (R3X, where X is tsepliaeva group, such as tosyl), obtaining the substituted ketone (2). In stage 2 of the substituted ketone (2) is subjected to interaction with a base, such as sodium methylate, and allermuir reagent, such as an ester (R2CO2CH3), or the equivalent of ester (R2CO-imidazole), obtaining the intermediate product-diketone (3) according to the method similar to the method developed by Reid and Calvin, J. Amer. Chem. Soc., 72, 2948-2952 (1950). At stage 3 diketone (3) is subjected to interaction with substituted hydrazine in acetic acid or an alcohol solvent, obtaining a mixture of pyrazoles (4) and (5). Scroll to the desired pyrazole (4) can be achieved by chromatography or recrystallization.

Scheme II

In the scheme of synthesis II presents the formation of compounds covered by formula I, where R3is a hydrogen atom. In stage 1, the ketone (1) is subjected to interaction with the bottom, preferably NaOMe or NaH, and complex ester or the equivalent of ester from the intermediate diketone (6), which is used without further sight of the TCI. In stage 2 of the diketone (6) in anhydrous proton solvent such as absolute ethanol or acetic acid, is subjected to the interaction with the salt of hydrochloric acid or free base of the substituted hydrazine, at the boiling point under reflux for 10 to 24 hours, receiving a mixture of pyrazoles (7) and (8). Recrystallization from a mixture of diethyl ether/hexane or chromatography gives (7) usually in the form of light yellow or yellowish-brown solid.

Scheme III

The synthesis scheme III illustrates the method of obtaining compounds 4,5-dihydrobenzo[g]indazole covered by formula I. In stage 1 ethyltryptamine subjected to interaction with the bottom, such as a 25% sodium methylate in proton solvent such as methanol, and derived from 1-tetralone (9)to give the intermediate diketone (10). In stage 2 of the diketone (10) in anhydrous proton solvent such as absolute ethanol or acetic acid, is subjected to the interaction with the free base or salt of hydrochloric acid substituted hydrazine at the boiling point under reflux for 24 hours, obtaining a mixture of pyrazoles (11) and (12). Recrystallization gives 4,5-dihydrobenzo[g]industriventilation (11).

Scheme IV

The synthesis scheme IV illustrates the formation of compounds of the pyrazole (13)where R3is chlorine, from the available connections pyrazole (7)where R3represents hydrogen. Chlorination is a consequence of the pulses of gas chlorine at room temperature through a solution containing (7).

Scheme V

The synthesis scheme V shows getting substituted ketones 18, which are not commercially available for use in Scheme I. Ketones can be obtained by standard acylation according to the Friedel-Crafts original disubstituted benzene 14 chlorides or anhydrides of acids 15. Alternative ketones can be obtained from phenylcarbonylamino 16 using known ORGANOMETALLIC technologies, where M represents a metal, such as lithium, magnesium, etc. Alternative ORGANOMETALLIC way can serve as a way to get out of aldehyde 17, where M represents a metal, such as lithium, magnesium, etc. Oxidation with a suitable oxidizing agent such as CDF3that leads to the production of ketones.

Scheme VI

The synthesis scheme VI illustrates an alternative selective method of producing pyrazole 21. Commercially available enone 19 can be epoxidizing to get epoxyketone 20, which is subjected to interaction with 4-sulfonamide hydrazin hydrochloride, getting pyrazole 21.

Scheme VII

The synthesis scheme VII shows getting pyrazoles 23 (where R4is 3-amino-4-substituted phenyl) from the initial substance 22. The corresponding 5-(4-sevmeshennyj aryl)pyrazoles can be nitrified in the position adjacent to the R-group under conditions standard for nitration, and the nitro-group can be restored to the amino group preferably hydrazine and Pd/C. With amino compounds can be further manipulated, alkylating the amino group.

Scheme VIII

In Scheme VIII shows the derivation of the pyrazoles 26 of ester 24. Recovery of ester 24 to alcohol, preferably lithium aluminum hydride (LAH), with subsequent oxidation, preferably MnO2gives the aldehyde 25. Various nucleophiles (such as hydroxamate and 1,3-dicarbonyl compounds) can be condensed with the aldehyde with obtaining the required oximo or olefins 26.

The following examples contain detailed descriptions of methods of preparing compounds of formula 1-11. These detailed descriptions fall within the scope of the invention and serve to illustrate the above General Synthesis Methods, which form part of this invention.

All parts are by weight and temperatures are given in degrees Celsius, unless otherwise stated. VRMS (HMS) is an abbreviation mass spectroscopy high resolution. In the following Tables "ND" means "not determined".

Example 1

4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Getting 4,4,4-Cryptor-1-[4-(chloro)phenyl]-butane-1,3-dione

Ethyltryptamine (23,52 g, 166 mmol) was placed in a 500 ml three-neck round bottom flask and dissolved in methyl tert-butyl ether (75 ml). To the stirred solution was added 25% sodium methylate (40 ml, 177 mmol) via a dropping funnel over a 2 minute period. Then 4’-chloroacetophenone (23,21 g, 150 mmol) dissolved in tert-butyl methyl ether (20 ml) and added to the reaction mixture dropwise over 5 minutes. After stirring over night (of 15.75 hours) added 3N Hcl (70 ml). The organic layer is collected, washed with brine (75 ml), dried over MgSO4, filtered and concentrated in vacuo, getting 35,09 g of yellow-orange solid. The solid is recrystallized from isooctane, getting 31,96 g (85%) Dion: TPL 66-67° C.

Stage 2: Obtain 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

4-Sulfonamidophenylhydrazine hydrochloride (982 mg, 4.4 mmol 1.1 equivalent) is added to a stirred solution of 4,4,4-Cryptor-1-[4-(chloro)phenyl]butane-1,3-dione from Stage 1 (1,00 g, 4.0 mmol) in ethanol (50 ml). The reaction mixture is heated at the boiling temperature of the reflux and stirred for 20 hours. (HPLC area percentage shows 96:3 ratio 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide to its regional isomer (regioisomer) (4-[3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide). After cooling to room temperature the reaction mixture was concentrated in vacuo. The remainder absorb with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo, receiving light brown solid, which is recrystallized from ethyl acetate and isooctane, getting pyrazole (1.28 g, 80%, TPL 143-145°). HPLC (HPLC) shows that the purified substance is of 99.5:0.5 mixture of 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide to its regional isomer.1H NMR (CDCl3/CD3OD 10/1)d of 5.2 (s, 2H), 6,8 (s, 1 H), 7,16 (d, J=8.5 Hz, 2 H), 7,35 (d, J=8.5 Hz, 2 H), 7,44 (d, J=8, 66, 2 H), to $ 7.91 (d, J=8,66, 2 H);

13C-NMR (CDCl3/CD3OD 10/1)d 106,42 (d, J=0.03 Hz), to 121.0 (K, J=276 Hz), 125,5, 126,9, 127,3, 129,2, 130,1, 135,7, 141,5, 143,0, 143,9 (K, J=37 Hz), 144, 0mm;19F-NMR (CDCl3/CD3OD 10/1)d-62,9. EI (EI)GC-MS (GX-MS)M+ = 401.

Example 2

4-[5-(4-Were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 1-(4-were)-4,4,4-triptorelin-1,3-dione

4’-Methylacetophenone (5,26 g of 39.2 mmol) was dissolved in 25 ml of methanol under argon and added 12 ml (52,5 m is ol) of sodium methylate in methanol (25%). The mixture is stirred for 5 minutes and add 5.5 ml (46.2 mmol) of ethyltryptamine. After boiling under reflux for 24 hours the mixture is cooled to room temperature and concentrate. Add 100 ml of 10% Hcl and the mixture extracted with 4× 75 ml ethyl acetate. The extracts are dried over gSO4filter and concentrate the receiving of 8.47 g (94%) of a brown oil, which was used further without additional purification.

Stage 2: Obtain 4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

It comes from Stage 1 (4,14 g, 18.0 mmol) in 75 ml of absolute ethanol is added 4.26 deaths g (19.0 mmol) of 4-sulfonamidophenylhydrazine hydrochloride. The reaction mixture was refluxed under argon for 24 hours. After cooling to room temperature and filtration, the reaction mixture was concentrated, receiving 6,13 g orange solid. The solid is recrystallized from a mixture of methylene chloride/hexane, getting 3.11 g (8.2 mmol, 46%) of product as a pale yellow solid: TPL 157-159° C;

Elemental analysis: Calculated for C17H14N3O2SF3: C, 53,54; N, 3,70; N, 11,02. Found: C, 53,17; N, 3,81; N, 10,90.

Example 3

4-[5-(3,5-Dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 3,5-dichloro-4-IU is oxazolidinone

To a cooled solution (0° (C) 7,44 g (55,8 mmol) ll3in 25 ml of CH2Cl2under argon is added dropwise 2.5 ml of acetic anhydride. After stirring for 0.5 hours added dropwise 4,18 g (23.6 mmol) of 2,6-dichloroethane. The reaction mixture was stirred at 0° C for 1 hour, warmed to room temperature and stirred for 12 hours. The reaction mixture was poured into a mixture of 6 ml conc. hydrochloric acid/80 ml of ice water. The aqueous phase is extracted with ethyl acetate (3× 75 ml). The combined organic washing water, dried over gSO4, filtered and evaporated, obtaining the crude product as a yellow oil. NMR analysis shows that the acylation occurs only in the para-position by methoxy (group). Crude oil is used without further purification.

Stage 2 and 3: Obtain 4-[5-(3,5-dichloro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

A named connection receive the same manner as in Example 2, stage 1 and 2, and purified on prep. plate, elwira mixture 10/1 hexane/ethyl acetate, receiving a yellow solid: Elemental analysis: Calculated for C17H12N3About3SF3CL2·H2ABOUT: WITH, 42,16; N, 2.91 IN; N, 8,68. Found: C, 42,03; N, 2,54; N, 8,45.

Example 4

4-[5-(3-Ethyl-4-methoxyphenyl is)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 3-ethyl-4-methoxyacetophenone

ll3(4.9 g, to 36.8 mmol)are added to a solution of 2-Atalanta (2.5 g, 18.4 mmol) in methylene chloride (50 ml). Acetylchloride (1.3 ml, 18.4 mmol) is added dropwise to the reaction mixture, which was then stirred at the boil under reflux for 0.5 hours. After cooling to room temperature the reaction mixture was poured over crushed ice and then subjected to extraction with a mixture of methylene chloride/water. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude product chromatographic 4000 micron chromatotron the plate with a mixture of 10% ethyl acetate/90% hexane as eluent, obtaining 2.3 g of the desired substance.

Stage 2 and 3: Obtain 4-[5-(3-Ethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

A named connection receive, using the method described in Example 2, stage 1 and 2: Elemental analysis: Calculated for C19H18N3About3SF3: C, 53,64; H, 4.26 DEATHS; N, 9,88. Found: C, 53,69; N, 4,36; N, 9,88.

Example 5

4-[5-(3-Methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Getting 2-methylthiazole

Methyliodide (0.5 ml, 8.1 mmol) and potassium carbonate (1.1 g, 8.1 mmol) is added to a solution of o-thiocresol (1.0 g, 8.1 mmol) in 10 ml of DMF (DMF). The reaction is th the mixture was stirred at 50° C for 4 hours and poured into hexane and water. The organic layer is separated, dried over magnesium sulfate and concentrated, obtaining 1.1 g of the desired substance.

Stage 2, 3 and 4: Obtain 4-[5-(3-methyl-4-methylthiophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

A named connection receive, using the methodology presented in Example 4, Stage 1, 2 and 3: Elemental analysis: Calculated for C18H16N3O2S2F3: C, 50,58; N, OF 3.77; N, 9,83. Found: C, 50,84; N, 3,62; N, 9,62.

Example 6

4-[5-(3-(3-Propenyl)-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Getting 3-allyl-4-methoxyacetophenone

Potassium hydroxide (3.2 g, with 56.8 mmol) is added to a solution of 3-allyl-4-hydroxyacetophenone (10 g, with 56.8 mmol) in 125 ml THF (THF). Add dimethylsulfate (excess) and the reaction mixture is stirred at 50° C for 16 hours. The reaction mixture is cooled, concentrated and poured into EtOAc and water. The organic layer is separated and washed with diluted sodium hydroxide, in order to be freed from unreacted educt. An ethyl acetate layer is dried and concentrated, obtaining of 9.2 g of 3-allyl-4-methoxyacetophenone.

Stage 2 and 3: Obtain 4-[5-(3-(3-propenyl)-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

A named connection, and the uses of the techniques, described in Example 2, Stage 1 and 2: Elemental analysis: Calculated for C20H18N3F3About3S: C, 54,92; N, 4,15; N, BEING 9.61. Found: C, 54,70; N, 4,12; N, 9,43.

Example 7

4-[5-(3-Propyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-

pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 3-n-propyl-4-methoxyacetophenone

To a solution of the product of Example 6, step 1 (3 g, 17,0 mmol) in 50 ml of ethanol is added a catalytic amount of 4% Pd/C. the Reaction mixture was stirred in a Parr the vibrator at room temperature under hydrogen pressure 0,352 kg/cm2(5 psi) for 0.5 hours. The reaction mixture was filtered and concentrated, receiving 4 grams of pure 3-propyl-4-methoxyacetophenone.

Stage 2 and 3: Obtain 4-[5-(3-n-propyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

A named connection receive, using the techniques described in Example 2, Stage 1 and 2: Elemental analysis: Calculated for C20H20N3F3O3S: C, 54,66; N, 4,59; N, 9,56. Found: C, 54,84; N And 4.65; N, 9,52.

Example 8

4-[5-(3-Cyclopropylmethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Getting 3-cyclopropylmethyl-4-methoxyacetophenone

To a solution of the product of Example 6, step 1 (3 g, 17,0 mmol), catalytic amounts of Pd(OAc)2in 20 ml of Et2/sub> O add ethereal diazomethane until then, until the original substance is not used. The reaction mixture was filtered, concentrated and chromatographic 4000 micron chromatotron plate (20% EA(EA)/80% hexane as eluent)to give 2.5 g of the desired ketone.

Stage 2 and 3: Obtain 4-[5-(3-cyclopropylmethyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

A named connection receive, using the techniques described in Example 2, Stage 1 and 2: Elemental analysis: Calculated for C21H20N3F3SO3: C, 55,87; N, TO 4.47%; N, 9,31. Found: C, 55,85; N, 4,27; N, 9 : 30 A.m.

Example 9

4-[4-Methyl-3-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

To a solution of the product of Example 2 (500 mg, 1,31 mmol) in 5 ml of sulfuric acid added nitric acid (0.6 ml, of 1.31 mmol) and the reaction mixture was stirred at room temperature for 0.5 hours. The mixture was poured on ice, the solid precipitate is filtered off and chromatographic 4000 micron plate (20% EtOAc/80% hexane as eluent)to give 410 mg of the desired substance: Elemental analysis: Calculated for C17H13N4O4SF3: C 47,89; N, OF 3.07; N, 13,14. Found: C, 47,86; N, Of 2.81; N, 13,15.

Example 10

4-[5-(3-Amino-4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide the

A catalytic amount of 10% Pd/C added to a solution of hydrazine hydrate (of 0.022 ml, 0.7 mmol) in 10 ml of ethanol. The reaction mixture is refluxed for 15 minutes until the introduction of the compound from Example 9 (100 mg, 0.23 mmol) and the reaction mixture is refluxed for another 2 hours. The reaction mixture is cooled, filtered through celite and concentrated, receiving 100 mg of these compounds are: Elemental analysis: Calculated for C17H15N4O2SF3·0,5 CO2: C, 50,24; N, 3,61; N, 13,39. Found: C, 50,49; N, 3,44; N, 13,37.

Example 11

4-[5-(4-Hydroxymethylene)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 4-[5-(4-bromomethylphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

The product from Example 2 (1.13 g, 3.0 mmol) and N-bromosuccinimide (NBS) (0.64 g, 3.6 mmol) is dissolved in 40 ml of benzene and irradiated with a UV lamp for 3 hours. The reaction mixture is cooled to room temperature and poured into 50 ml of H2O. the Organic phase was separated, washed with brine and dried over gSO4. The crude pyrazole obtained as an amber oil. The oil is purified using a circular (radial) chromatography, elwira a mixture of 30% ethyl acetate/70% hexane, receiving 4-methyl bromide compound as a yellow oil, which crystallizes at a hundred the Institute.

Stage 2: Obtain 4-[5-(4-hydroxymethylene)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Methyl bromide compound from Stage 1 are dissolved in 30 ml of acetone/4 ml H2O and refluxed for 120 hours. The reaction mixture was concentrated and the residue is dissolved in 50 ml of ethyl acetate and dried over gSO4. The crude product is obtained as an amber oil. The oil is purified using a circular (radial) chromatography, elwira a mixture of 30% ethyl acetate/70% hexane, obtaining a named connection in the form of a yellow solid: Elemental analysis: Calculated for C17H14N3About3SF3: C, 51,38; N, 3,55; N, 10,57. Found: C, 57,28; N And 3.59; N, 10,31.

Example 12

4-[1-(4-(Aminosulfonyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzoic acid

To the product from Example 11 in 2 ml of acetone add 1,33 M Jones reagent until then, until the orange color disappears. The reaction mixture was poured into 20 ml of ethyl acetate and 20 ml of H2O and the organic layer was separated, washed with saturated sodium bisulfite and dried over gSO4. The crude product is filtered through silica gel/celite, getting a named connection in the form of a yellow solid. VRMS (HRMS) m/z 411,0507 (calculated for C17H12N3O4SF3, 411,0500).

The following compounds in Table I get with the according methods similar to the methods illustrated in Examples 1-12, with substitution of the appropriate acetophenone.

Example 55

4-[5-(4-Hydroxy-3-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

To a solution of the product of Example 41 (240 mg, of 0.58 mmol) in DMF (DMF) (3 ml) was added NaSMe (205 mg, 2.9 mmol) and the mixture refluxed for 2 hours. The mixture is cooled, poured in 0,1N HCl and extracted with EtOAC (3x). The combined extracts dried over gSO4and concentrate. Flash chromatography using 1:1 mixture of hexane/ethyl acetate to give 31 mg of the named compound: Elemental analysis: Calculated for C17H14N3About3SF3·0,25 H2O: C, 50,80; N, TO 3.64; N, 10,45. Found: C, 50,71; N, 3/47; N, accounted for 10.39.

Example 56

4-[5-(4-(N-Methylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

To a solution of the product from Example 53 (431 mg, 1.0 mmol) in 10 ml of methanol added 36 mg (0,17 mmol) hydrate chloride ruthenium (III), and then 1.5 ml of 30% hydrogen peroxide (14.7 mmol) for 2 hours. The reaction is quenched with 25 ml of 1M KOH in methanol and to the will centerour, getting 1.24 g of brown solid. The solid is purified on prep. plate, elwira mixture 2/97/1 methanol/methylene chloride/ammonium chloride, receiving 52 mg (0.14 mmol, 12%) of product as a yellow solid.

Example 57

N-[4-[1-[4-(Aminosulfonyl)phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-yl]phenyl]-N-methylacetamide

19 mg (0,051 mmol) of the product from Example 56 process of 0.03 ml of acetic anhydride (0.32 mmol) and 0.03 ml of triethyl-amine (0.22 mmol)in 3 ml of methylene chloride at room temperature for 12 hours. The reaction mixture was concentrated and the residue is dissolved in 10 ml of ethyl acetate. After washing with brine (2× 10 ml), the solution is dried over MgSO4, filtered and concentrated, obtaining a named connection (to 18.4 mg, 74%) as a yellow solid: VRMS (HRMS) m/z 438,0976 (calculated for C19H17N4O3SF3, 438,0974).

Example 58

4-[5-(4-Chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 4,4-debtor-1-[4-(chloro)phenyl]-butane-1,3-dione

Hatildeparaher (24,82 g, 200 mmol) is placed in a 500 ml three-neck round bottom flask and dissolved in diethyl ether (200 ml). To the stirred solution was added 25% sodium methylate in methanol (48 ml, 210 mmol) via a dropping funnel over a 2 minute period. Then ’-chloroacetophenone (25,94 g, 200 mmol) dissolved in diethyl ether (50 ml) and added dropwise to the reaction mixture dropwise over 5 minutes. After stirring overnight (18 hours), add 1N HCl (250 ml) and ether (250 ml). The organic layer is collected, washed with brine (250 ml), dried over MgSO4, filtered and concentrated in vacuo, receiving and 46.3 g of yellow solid. The solid is recrystallized from methylene chloride and isooctane, getting 31,96 g (69%) Dion: TPL 65-66,5° C.

Stage 2: Obtain 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

4-Sulfonamidophenylhydrazine hydrochloride (1.45 g, 6.5 mmol 1/3 equivalent) and 4,4-debtor-1-[4-(chloro)phenyl]butane-1,3-dione from Stage 1 (of 1.16 g, 5 mmol) dissolved in ethanol (10 ml). The reaction mixture is heated at boiling temperature under reflux and stirred for 20 hours. After cooling to room temperature the reaction mixture was concentrated in vacuo. The remainder is absorbed by ethyl acetate (100 ml), washed with water (100 ml) and brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo, obtaining of 1.97 g of light brown solid, which is recrystallized from ethanol and water, receiving 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide (1.6 g, 83%); TPL 185-186° C.

Example 59

4-[5-(3-Fluoro-4-methoxy who enyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 3’-fluoro-4’-methoxyacetophenone

Aluminium chloride (80,0 g, 0.6 mol) and chloroform (750 ml) placed in a 2 l three-neck round-bottom flask equipped with a mechanical stirrer, and cooled using an ice bath. To the stirred solution was added dropwise acetylchloride (51,0 g to 0.65 mol), keeping the temperature between 5-10° C. the Mixture is stirred for 10 minutes at 5° before adding dropwise at 5-10° 2-fernicola (62,6 g, 0.5 mol). The mixture was stirred at 0-10° C for 1 hour and poured onto ice (1 l). The resulting layers are separated and the aqueous layer was extracted with dichloromethane (2× 250 ml). The combined organic layers washed with water (2× 150 ml), dried over anhydrous MgSO4, filtered and concentrated in vacuo to a volume of 300 ml. Add hexane, and formed a white solid, which emit filtration and air-dried. This substance is recrystallized from a mixture of dichloromethane and hexanol, receiving (77,22 g, 92%) substances suitable for use in the next stage: TPL 92-94°;1H NMR (DMSO-d6) to 7.8 (m, 2 H), and 7.3 (t, 1 H), of 3.9 (s, 3 H), and 2.5 (s, 3H).

Stage 2: Obtain 4,4-debtor-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione

Hatildeparaher (4,06 g, to 32.7 mmol) was placed in a 250 ml Erlenmeyer flask and dissolved in methyl tert-butyl ether (50 ml). To the stirred solution was added 25% methyl is tons of sodium (7,07 g, to 32.7 mmol), and then 3’-fluoro-4’-methoxyacetophenone from Stage 1 (5.0 g, 29.7 mmol). After stirring for 16 hours add 1N HCl (50 ml). The organic layer is collected, washed with water (2× 50 ml), dried over anhydrous MgSO4filter and add to hexane, precipitating a yellowish-brown solid (7.0 g, 96%): TPL 70-72°;1H NMR (DMSO-d6) 8,0 (m, 3 H), and 7.3 (t, 1 H)and 6.9 (s, 1 H), 6,5 (t, 1 H), of 3.9 (s, 3 H).

Stage 3: Obtain 4-[5-(3-fluoro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

4,4-Debtor-1-(3-fluoro-4-methoxyphenyl)-butane-1,3-dione from step 2 (7.0 g, 28.4 mmol) was dissolved in ethanol (150 ml). To a stirred mixture of 4-sulphonamido-phenylhydrazine hydrochloride (7.4 g, 33 mmol) and stirred at the boiling temperature under reflux overnight (16 hours). The mixture is cooled and water is added until, until gradually appears crystals. The product is separated by filtration and air-dried, obtaining the desired product as light yellowish brown solid (9.8 g, 87%): TPL 159-161°;1H NMR (DMSO-d6) a 7.85 (d, 2H), 7.5 (m, 6 H), 7,3 or 6.9 (m, 5 H), and 3.8 (s, 3 H). Calculated for C17H14N3SO3F3: C, 51,38; N, 3,55; N, 10,57. Found: C, 51,46; N, To 3.52; N, 10,63.

Example 60

4-[3-Deformity-5-(4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: the Floor is giving 4,4,4-trifluoromethyl-1-(4-methoxyphenyl)-butane-1,3-dione

To a stirred solution of 4-methoxyacetophenone (11,43 g, 76,11 mmol) and ethyldiethanolamine (8,4 ml, 10.4 g, 83,72 mmol)in diethyl ether (300 ml) in a 500 ml round bottom flask was added sodium methylate in methanol (18.2 ml of 25% solution, 79,91 mmol). The solution for thirty minutes becomes dark lavender and then for 1.5 hours takes the form of a grey suspension. The reaction mixture is stirred for 60 hours. Add diethyl ether (300 ml) and the mixture is acidified (pH 2) with 1N HCl. The mixture is transferred into a separating funnel, mix and share. The ether phase is washed with water, dried over magnesium sulfate and filtered. Add hexane, causing the precipitation of an orange solid (5,25 g), 4,4,4-trifluoromethyl-1-(4-methoxyphenyl)butane-1,3-dione. Additional 3,43 g of product is obtained by recrystallization of the concentrated mother liquor from the hexane:1H NMR (CDCl3) 400 MHz (15,58 SHS, 1H), 7,94 (d, J=8,87 Hz, 2H), 6,98 (d, J=8,87 Hz, 2H), OF 6.49 (S, 1H), 6,00 (t, J=54,55 Hz, 1 H)to 3.89 (s, 3 H).

Stage 2: Obtain 4-[5-(4-methoxyphenyl)-3-deformity-1H-pyrazole-1-yl]benzosulfimide

A mixture of 4,4,4-trifluoromethyl-1-(4-methoxyphenyl)butane-1,3-dione from Stage 1 (2,006 g, 8,79 mmol) and 4-sulfonamidophenylhydrazine cleaners containing hydrochloride salt (2,065 g, 9,23 mmol)dissolved in ethanol (25 ml), heated at boiling temperature under reflux for 16 hours. The reaction mixture is cooled up to matnog temperature, concentrated and recrystallized from methanol, obtaining 4-[5-(4-methoxyphenyl)-3-deformity-1H-pyrazole-1-yl]benzosulfimide in the form of a fluffy, yellowish-brown kristallov (1,49 g, 45%): TPL 133-135°;1H NMR (CDCl3) 300 MHz of 7.90 (d, J=8,863 Hz, 2H), 7,45 (d, J=8,863 Hz, 2H), 7,14 (d, J=8,863 Hz, 2 H), to 6.88 (d, J=8,863 Hz, 2H), 6,77 (t, J=56, 47 Hz, 1 H), of 6.68 (s, 1 H), 4,96 (CL, 2H), 3,83 (s, 3H);19NMR (Dl3) 300 MHz-112,70 (d, J=57,9 Hz). Mass spectrum high resolution: Calculated for C17H15F2N3About3S: 379,0802. Found: 379,0839. Elemental analysis: Calculated for C17H15F2N3About3S: C, 53,82; N, 3,99; N, 11,08. Found: C, 53,75; N, 3,99; N, 11,04.

The following compounds in Table II receive according to methods similar to the methods illustrated in the Examples 58-60, with substitution of the appropriate acetophenone.

Example 82

4-[5-(1,3-Benzodioxol-5-yl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 1-(1,3-benzodioxol-5-yl)-4,4-diformate-1, 3-dione

Hatildeparaher (1,72 g, 11 mmol) dissolved in ether (25 ml). To the stirred solution was added 25% sodium methylate (2.38 g, 11 mmol), and then 3’,4’-(methylenedioxy) acetophenone (1.64 g, 10 mmol). After stirring 16 hours, add 1N HCl (25 is l). The organic layer is collected and washed with water (2× 25 ml), dried over magnesium sulfate, filtered and concentrated. The crude dione used in the next stage without additional purification and research (specific method).

Stage 2: Obtain 5-(1,3-benzodioxol-5-yl)-4-[3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

1-(1,3-Benzodioxol-5-yl)-4,4-diformate-1,3-dione from Stage 1 (2.4 g, 10 mmol) dissolved in ethanol (100 ml). To a stirred mixture of 4-sulfonamidophenylhydrazine hydrochloride (2,46 g, 11 mmol) and heated at boiling temperature under reflux for 16 hours. The mixture is cooled and water is added until, until crystals appear. By filtering receive light yellowish-brown solid (3.3 g, 84%): TPL 214-218°;1H NMR (DMSO-d6): 7,86 (d, J=8.7 Hz, 2H), 7,51 (d, J=8.7 Hz, 2H), 7,49 (CL, 2H), 7,3-6,7 (m, 5 H), the 6.06 (s, 2 H). Elemental analysis: Calculated for C17H13N3SO4F2: C, 51,91; N, TO 3.33; N, IS 10.68. Found: C, Better Than Anticipated At 51.90; H, 3,25; N, 10,65.

Example 83

4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1-H-pyrazole-3-carboxylic acid

Stage 1: Obtain methyl 4-[4-(chloro)phenyl]-2,4-dioxaborinane

Dimethyloxalate (23,6 g, 200 mmol) is placed in a 500 ml three-neck round bottom flask and dissolved in diethyl ether (200 ml). To the mix is Astaro add 25% sodium methylate in methanol (48 ml, 210 mmol) via a dropping funnel over a 2 minute period. Then 4’-chloroacetophenone (25,94 g, 200 ml) dissolved in diethyl ether (50 ml) and added to the reaction mixture dropwise over 3 minutes. After stirring overnight (18 hours) add 1N HCl (400 ml) and ethyl acetate (750 ml). The organic layer is collected, washed with brine (350 ml), dried over MgSO4, filtered and concentrated in vacuo, obtaining of 45.7 g of yellow solid. The solid is recrystallized from ethyl acetate and isooctane, receiving 23 g (48%) Dion: TPL 108,5-110,5° C.

Stage 2: Obtain 4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1-H-pyrazole-3-carboxylic acid

4-Sulfonamidophenylhydrazine hydrochloride (1.45 g, 6.5 mmol, 1.3 equivalents) and methyl 4-[4-(chloro)phenyl]-2,4-dioxouranium (1.2 g, 5 mmol) dissolved in ethanol (50 ml). The reaction mixture is heated at boiling temperature under reflux and stirred for 20 hours. After cooling to room temperature the reaction mixture was concentrated in vacuo. The remainder is absorbed by ethyl acetate (200 ml) and washed with water (100 ml) and brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo, obtaining 1.7 g of light brown solid, which is recrystallized from methanol and water, receiving 1.6 g (85%) of white solids. This substance is dissolved is methanol (150 ml) and 3N NaOH (75 ml) and stirred at the boiling point under reflux for 3 hours. The methanol is removed in vacuo and the aqueous solution acidified with concentrated HCl. The product is extracted with ethyl acetate (200 ml), washed with brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo, obtaining 4-[4-(aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1-H-pyrazole-3-carboxylic acid, 1.4 g (74%): TPL 135° C (decomp.).

Example 84

Methyl 1-(4-aminosulphonylphenyl)-5-(3,5-debtor-4-methoxyphenyl)-1-H-pyrazole-3-carboxylate

Stage 1: Obtain 3,5-debtor-4-methoxyacetophenone

To a stirred suspension ll3(24,05 g, 180,40 mmol) in chloroform (300 ml, dried by passing through alumina) at 4° C (ice bath) under nitrogen add acetylchloride (11,0 ml, 152,65 mmol) over 20 minutes. This cooled suspension was stirred at 0° C for 30 minutes and added dropwise 2,6-differenital for 30 minutes. The resulting suspension is warmed to room temperature and stirred over night. The reaction is quenched slowly pouring the reaction mixture into a rapidly stirred mixture of ice/water. The aqueous layer was extracted with methylene chloride (2× 50 ml) and the combined organic phases concentrated in vacuo, obtaining a transparent movable oil. In a 50 ml round bottom flask add the above-mentioned transparent oil, DMF (DMF) (25 ml), K2CO3(15 g). Doba is by methyliodide (6 ml) and the suspension stirred at 45° With under nitrogen over night. Add water (1 ml) and the mixture heated for a further 14 hours. The crude reaction mixture is cooled to room temperature, diluted with water (250 ml) and extracted with diethyl ether (3× 100 ml). The ether phase is washed with a saturated solution of sodium bicarbonate, potassium bisulfate (1,1 N solution), dried over MgSO4, filtered and concentrated in vacuo, getting a clear mobile liquid. This liquid is distilled (30° C, 1 mm)to give 12.5 g of a transparent liquid that is a mixture of 3,5-debtor-4-methoxyacetophenone and 3.5-debtor-4-acetoxystyrene at a ratio of 85:15. Output, on the basis of this ratio is 41%. This ketone is used as such.

Stage 2: Obtain methyl 1-(4-aminosulphonylphenyl)-5-(3,5-debtor-4-methoxyphenyl)-1H-pyrazole-3-carboxylate

To a stirred solution of 3,5-debtor-4-methoxyacetophenone from Stage 1 (6,46 g, 34,70 mmol) and dimethyloxalate (x 6.15 g, 52,05 mmol) in methanol (80 ml) add a solution of sodium methylate (13.4 ml 25% solution, 58,99 mmol) in one portion and the reaction mixture was stirred over night. The crude reaction mixture is diluted with methylene chloride, washed with potassium bisulfate (1,1 N solution), brine, dried over MgSO4, filtered and concentrated in vacuo, obtaining methyl 4-(3,5-debtor-4-methoxyphenyl)-2,4-dioxouranium in the form of b is Lovato crystalline solid, which is used as such. A mixture of 4-(3,5-debtor-4-methoxyphenyl)-2,4-dioxaborinane and 4-sulfonamidophenylhydrazine cleaners containing hydrochloride salt (7,76 g, 34,70 mmol), dissolved in methanol, heated at boiling temperature under reflux for 9 hours. After cooling the clear solution to room temperature formed a crystalline precipitate, which is collected by filtration under vacuum, obtaining the 5.45 g (37% 3.5-debtor-4-methoxyacetophenone)methyl 1-(4-aminosulphonylphenyl)-5-(3,5-debtor-4-methoxyphenyl)-1H-pyrazole-3-carboxylate in the form of a whitish solid: TPL 185-190° C;

1H NMR (CDCl3/300 MHz) of 7.95 (d, J=8,86 Hz, 2H), 7,49 (d, J=8,86 Hz, 2H), 7,02 (s, 1H), 6,77 (m, 2H), 4,99 (s, 2H), Android 4.04 (s, 3H), 3,98 (s, 3 H);19F NMR (Dl3/300 MHz)-126,66. Elemental analysis: Calculated for C17H13F2N3About3S: C, 51,06; N, OF 3.57; N, 9,92. Found: C, 51,06; N, Of 3.54; N, 9,99.

Example 85

Methyl [1-(4-aminosulphonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate

Stage 1: Obtain methyl 4-[4-(chloro)phenyl]-2,4-dioxaborinane

Dimethyloxalate (15,27 g, 0,129 mol) and 4’-chloroacetophenone (20,0 g, 0,129 mol) are loaded into a 500 ml round bottom flask with a stirring magnetic stirrer and diluted with methanol (300 ml). One portion add sodium methylate (25% in methanol, 70 ml). P is a promotional mixture is stirred at room temperature for 16 hours. During this time the reaction mixture becomes insoluble mass. Solid mechanically destroy, then add concentrated hydrochloric acid (70 ml) and the white suspension is vigorously stirred at room temperature for sixty minutes. The suspension is cooled to 0° C and maintained for 30 minutes. The solid is filtered off and the filter cake washed with cold water (100 ml). After drying obtain methyl 4-[4-(chloro)phenyl]-2, 4-dioxouranium (16,94 g, 54%) as enol:1H NMR (Dl3/300 MHz) 7,94 (d, J=8,66 Hz, 2H), of 7.48 (d, J=8,66 Hz, 2H),? 7.04 baby mortality (s, 1H), 3,95 (s, 3 H), 3,48 (s, 1H).

Stage 2: Obtain methyl [1-(4-aminosulphonylphenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-yl]carboxylate

a 100 ml round bottom flask, equipped with magnetic stirrer and inlet for nitrogen load methyl 4-[4-(chloro)phenyl]-2,4-dioxaborolan from Stage 1 (5.0 g, 20,78 mmol), 4-sulfonamidophenylhydrazine hydrochloride (5,11 g, 22,86 mmol) and methanol (50 ml). The reaction vessel is heated to the boiling temperature under reflux and maintained for 16 hours. The precipitate formed during the night. The suspension is cooled to 0° C, incubated for 0.5 hour, filtered and washed with cold water, providing after air drying to $ 7.91 g (91%) of the crude product. Recrystallization 3.50 g of boiling ethanol gives 3,14 g (97%) of imennogo methyl [1-(4-aminosulphonylphenyl)-5-(4-chlorophenyl)-1-H-pyrazole-3-yl]carboxylate: TPL 227°;1H NMR (Dl3/300 MHz) to $ 7.91 (d, J=8,86 Hz, 2H), 7,44 (d, J=8,86 Hz, 2H), 7,33 (d, J= 8,66 Hz, 2H), 7,14 (d, J=8,66 Hz, 2H), 7,03 (s, 1H), 3.96 points (s, 3H). Mass spectrum MH+=392. Elemental analysis: Calculated for C17H14N3O4ClS: C, Br52.11; N, Of 3.60; N, Of 10.72; Cl, 9,05; S, 8,18. Found: C, 52,07; N, Of 3.57; N, 10,76; Cl, 9,11; S, 8,27.

Example 86

Ethyl [1-(4-aminosulphonylphenyl)-5-(4-chlorophenyl)-1-H-pyrazole-3-yl]carboxylate

Methyl [1-(4-aminosulphonylphenyl)-5-(4-chlorophenyl)-1-H-pyrazole-3-yl]carboxylate (Example 85) (0.10 g) was dissolved in absolute ethanol (10 ml) and add a catalytic amount of 21% NaOEt/EtOH. The reaction mixture is stirred without temperature control within 72 hours, then add water (10 ml). The product crystallizes, the suspension is cooled to 0° C and maintained for 30 minutes. The product is filtered, washed with water (5 ml) and dried, obtaining 0,071 g (70%) of white solid: Mass spectrum: MH+=406. Elemental analysis: Calculated for C18H16N3O4ClS: C, 53,27; N, Of 3.97; N, 10,35; Cl, Total Of 8.74; S Of 7.90. Found: C, 53,04; N, 4,00; N, 10,27; Cl, 8,69; S 7,97.

The following compounds in Table III receive according to methods similar to those illustrated in the Examples 83-86, with appropriate substitution of reagents.

Example 96

4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-shall irsol-3-carboxamide

4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid (Example 83) (1.08 g, of 2.86 mmol), HOBt (0.66 g, 4.3 mmol) and EDC (0.66 g, 3.4 mmol) dissolved in dimethylformamide (DMF) (20 ml) and stirred at ambient temperature for 5 minutes. To this solution was added NH4OH (30%, to 2.9 ml) and the reaction mixture stirred for an additional 18 hours. This solution is then poured into ethyl acetate (200 ml) and 1N HCl (200 ml), shaken and separated. The organic layer was washed with saturated Panso3(150 ml) and brine (150 ml), dried over gSO4, filtered and concentrated, obtaining 0.9 g of a white solid, which is recrystallized from ethyl acetate and isooctane, receiving 4-[4-(aminosulfonyl)phenyl)-5-(4-chlorophenyl)-1-H-pyrazole-3-carboxamide of 0.85 g, 79%): TPL 108-110° C.

Example 97

[1-(Aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-carboxamide

a 250 ml three-neck round bottom flask equipped with a thermometer, a tube for ozonation gas, reflux condenser and under conditions which assure stirring with magnetic stir bar, loads of methyl [1-(aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxylate (Example 88) (3.0 g, to 7.99 mmol), methanol (100 ml) and a catalytic amount of sodium cyanide. Anhydrous gas-ammonia bubbled through the reaction vessel for 16 hours b is C temperature control. The suspension gets at this time, a deep-red color. Response defending, passing anhydrous nitrogen at room temperature for 20 minutes, cooled to 0° C and maintained for 30 minutes. The solid is filtered off and washed with cold water (50 ml)to give after drying of 1.87 g (65%) [1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxamide as a white solid: TPL 214-216°;1H NMR (CDCl3/CD3OD/300 MHz) of 7.64 (d, J=8,66 Hz, 2 H), 7,14 (d, J=8,66 Hz, 2 H), to 6.95 (m, 2 H), 6,82 is 6.67 (m, 6 H), to 6.39 (s, 1 H);19F-NMR (Dl3/CD3D/282,2 MHz) -112,00 (m). Mass spectrum MH+=361. Elemental analysis: Calculated for C16H13N4O3F3: C, 53,33; N, TO 3.64; N, 15,55; S 8,90. Found: C, 53,41; N, Of 3.69; N, 15,52; S 8,96.

Example 98

N-(3-Chlorophenyl)-[1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxamide

Stage 1. Obtain methyl 4-[4-forfinal]-2,4-dioxaborinane

Dimethyloxalate (18,80 g, strength of 0.159 mol) and 4’-peracetate (20,0 g, 0,145 mol) is loaded into a 1000 ml round bottom flask and diluted with methanol (400 ml). The reaction vessel is placed in a bath to ultrasonic treatment (Bransonic 1200) and add sodium methylate (25% in methanol, 70 ml) for 25 minutes. The reaction mixture is treated with ultrasound at 45° C for 16 hours. At this time, the reaction mixture starovishnevetskoe mass. Solid mechanically destroy, then poured into hydrochloric acid solution (1N, 500 ml). Include magnetic stirrer and the white suspension is vigorously stirred at room temperature for 60 minutes. The solid is filtered off and the filter cake is then washed with cold water (100 ml). After drying obtain methyl 4-[4-forfinal]-2,4-diketonates (22,91 g, 70.6 per cent) in the form of enol:1H NMR (Dl3/300 MHz) 8,03 (DDD, J=8,86 Hz, J= 8,66 Hz, J=5,03 Hz, 2 H), 7,19 (DD, J=8,86 Hz, J=8,66 Hz, 2 H),? 7.04 baby mortality (s, 1 H), of 3.95 (s, 3 H).19F-NMR (Dl3/282,2 MHz) -103,9 (m).

Stage 2. Obtain methyl 4-[1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxylate

500 ml odnogolosy round bottom flask, equipped with magnetic stirrer, load methyl 4-[4-forfinal]-2,4-diketonato from Stage 1 (1.00 mg, 44,61 mmol), 4-sulfonamidophenylhydrazine hydrochloride (10,98 g, 49,07 mmol) and methanol (200 ml). The suspension is heated and maintained at the boiling point under reflux for three hours, then cooled to room temperature. The suspension is cooled to 0° C, incubated for 30 minutes, filtered, washed with water (100 ml) and dried, obtaining of 14.4 g (86%) of methyl 4-[1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1-H-pyrazole-3-yl]carboxylate as a white solid:1H NMR (Dl3/300 MHz) of 7.85 (d, J=8, 66 Hz, 2 H), of 7.36 (d, J= 8,66 Hz, 2 H), 7,18 (DD is, J=8,66 Hz, J=8,46 Hz, J=4,85 Hz, 2 H), of 7.00 (DD, J=8,66 Hz, J=8,46 Hz, 2 H), 6,28 (s, 1 H), 3,90 (s, 3 H).19F-NMR (Dl3/282,2 MHz): -111,4 (m). Mass spectrum MH+=376. Elemental analysis: Calculated for C17H14N3O4FS: C, 54,40; N, 3,76; N, 11,19; S 8,54. Found: C, 54,49; N, 3,70; N, 11,25; S, 8,50.

Stage 3. Obtain [1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxylic acid

500 ml odnogolosy round bottom flask, equipped with magnetic stirrer, load methyl 4-[1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxylate from step 2 (10.0 g, 26,64 mmol) and tetrahydrofuran (200 ml). Add aqueous sodium hydroxide (2,5 N, 27 ml) and water (25 ml) and the suspension is heated to the boiling temperature under reflux and maintained for 16 hours. All solids are dissolved during this time. The reaction mixture is cooled to room temperature and add a solution of hydrochloric acid (1N, 110 ml). The aqueous suspension is extracted with methylene chloride (2× 200 ml). The combined organic solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to an oil. Rubbing with 300 ml of methylene chloride gives, after filtration and drying 9.0 g (94%) of [1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxylic acid as a white solid: TPL 138-142° C (decomp.);1H NMR (CD3D/300 MHz) of 7.93 (d, J=8,66 Hz, 2 is), 7,51 (d, J=8,66 Hz, 2 H), 7,31 (DDD, J=8,86 Hz, J=8,66 Hz, J=a 4.83 Hz, 2 H), 7,11 (DD, J=8,86 Hz, J=8,66 Hz, 2 H), 7,06 (s, 1 H).19F-NMR (CD3D/282,2 MHz): -114,01 (m).

Stage 4. Obtaining N-(3-chlorophenyl)-[1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxamide

100 ml odnogolosy round bottom flask, equipped with magnetic stirrer, load [1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxylic acid from Stage 3 (0,500 g, 1.38 mmol), 1-hydroxybenzotriazole hydrate (0,206 g 1,522 mmol), 1-(3-dimethylaminopropyl )-3-ethylcarbodiimide hydrochloride (0,318 g of 1.66 mmol) and N,N-dimethylformamide (30 ml). The solution was stirred at room temperature for forty minutes, then add 3-Chloroaniline (0,154 ml, 1,453 mmol); the reaction of the support at room temperature for sixteen hours, then poured into aqueous citric acid solution (5%, 100 ml). The aqueous solution is extracted with ethyl acetate (2× 60 ml) and the combined organic solutions washed with aqueous citric acid (60 ml), saturated sodium bicarbonate solution (2× 60 ml) and 50% saturated solution of sodium chloride (2× 60 ml). The organic solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to an oil. Rubbing with 20 ml dichloromethane give after filtration and drying, 0,439 g (67%) of N-(3-chlorophenyl)-[1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxamide is the form of a white solid: TPL-212° ;1H NMR (Dl3/CD3D/300 MHz) of 8.90 (s, 1 H), 7,86 (d, J=8,66 Hz, 2 H), 7,79 (t, J=2,01 Hz, 1 H), 7,46 (DD, J=7,05 Hz, J=a 2.01 Hz, 1 H), 7,33 (d, J=8,66 Hz, 2 H), 7,21-7,11 (m, 3 H), 7,02-6,94 (m, 4 H).10F-NMR (Dl3/CD3D/282, 2 MHz): -111,38 (m). Mass spectrum MH+=470. Elemental analysis: Calculated for C22H16N4O3ClFS: C, 56,11; N, Of 3.42; N, 11,90; Cl, For 6.81; S, 7,53. Found: C, 55,95; N, 3,50; N, 11,85; Cl, PC 6.82; S, 7,50.

The following compounds in Table IV receive according to methods similar to those shown in the Examples 96-98, with the replacement of the corresponding original substance.

Example 117

4-[3-Cyano-5-(4-forfinal-1H-pyrazole-1-yl]benzosulfimide

A dry 100 ml three-neck flask, equipped with reflux condenser, thermometer, dropping funnel to equalize pressure and magnetic stirrer, download anhydrous DMF (20 ml) and cooled to 0° C. Add oxalicacid (0,530 ml, 6,015 mmol) for twenty seconds, causing a temperature rise of 5° C. the Resulting white precipitate dissolves as soon as the reaction mixture cooled to 0° C. the Reaction support at 0° C for ten minutes, then a solution of [1-(4-aminosulphonylphenyl)-5-(4-forfinal)-1H-pyrazole-3-yl]carboxamide (Example 97) in anhydrous DMF (DMF) are added to vigorously stir Rast the oru for approximately two minutes. After fifteen minutes, add pyridine (1.0 ml, 12,21 mmol), in order to suppress the reaction. The mixture is then poured into dilute hydrochloric acid (1N, 100 ml) and extracted with ethyl acetate (2× 75 ml). The combined organic solution was washed with 1N HCl (2× 100 ml) and 50% saturated NaCl (3× 100 ml). The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo to crude oil. The oil is applied on a column of silica gel and elute ethyl-acetate and hexane (40% ethyl acetate)to give after concentration of appropriate fractions 0.66 g (69%) of 4-[3-cyano-5-(4-forfinal-1H-pyrazole-1-yl]benzosulfimide in the form of a white solid: TPL 184-185°;1H NMR (CDCl3/300 MHz) 7,94 (d, J=8,86 Hz, 2 H), 7,44 (d, J=8,66 Hz, 2 H), 7.23 percent-7,07 (m, 4 H), 6.87 in (s, 1 H), 4,88 (CL, 2 H);19F-NMR (l3/282,2 MHz)-109,90 (m). Mass spectrum MH+=343. Elemental analysis: Calculated for C16H11N4O2FS: C, 56,14; N, 3,24; N, 16,37; S, 9,36. Found: C, 56,19; N, And 3.16; N, 16,39; S, 9,41.

The following compounds in Table V receive according to the procedures similar to those described in Example 117, with the replacement of the corresponding original substance.

Example 128

4-[5-(4-Chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Getting 4,4,5,5,6,6,6-heptathlon-1-[4-(chloro)phenyl]GE the San 1,3-dione

Tilgathpilneser (5,23 g, 21.6 mmol) is placed in a 100 ml round bottom flask and dissolved in ether (20 ml). To the stirred solution was added 25% sodium methylate (4,85 g of 22.4 mmol)and then 4-chloracetophenone (3.04 from g to 19.7 mmol). The reaction mixture was stirred at room temperature over night (15,9 hours) and treated with 3N HCl (17 ml). The organic layer is collected, washed with brine, dried over MgSO4, concentrated in vacuo and recrystallized from isooctane, receiving the diketone as a white solid (4,27 g, 62%): TPL 27-30°;1H NMR (Dl3) 300 MHz: 15,20 (SHS, 1 H), 7,89 (d, J=8.7 Hz, 2 H), 7,51 (d, J=8.7 Hz, 2H), return of 6.58 (s, 1 H);19F-NMR (Dl3) 300 MHz:-80,94 (t),-121,01 (t),-127,17 (C); M+H 351.

Stage 2: Obtain 4-[5-(4-chlorophenyl)-3-(heptafluoropropyl)-1H-pyrazole-1-yl]benzosulfimide

4-Sulfonamidophenylhydrazine hydrochloride (290 mg, of 1.30 mmol) is added to a stirred solution of the diketone from Stage 1 (400 mg, to 1.14 mmol) in ethanol (5 ml). The reaction mixture is heated at boiling temperature under reflux and stirred for over night (23,8 hours). The ethanol is removed in vacuo and the residue is dissolved in ethyl acetate, washed with water and brine, dried over MgSO4and concentrated in vacuo, getting a white solid, which is passed through a column of silica gel, elwira a mixture of ethyl acetate/hexane (40%), paracrystalline is to see from a mixture of ethyl acetate/isooctane, getting the pyrazole as a white solid (0.24 g, 42%): TPL 168-71°;1H NMR (CDCl3) 300 MHz: of 7.90 (d, J=8.7 Hz, 2 H), was 7.45 (d, J=8.7 Hz, 2 H), 7,34 (d, J=8.5 Hz, 2 H), 7,19 (d, J=8.5 Hz, 2 H), 6,79 (s, 1 H), 5,20 (CL, 2 H);19F-NMR (Dl3) 300 MHz: -80,48 (t),-111,54 (t),-127,07 (s).

Example 129

4-[5-(4-Chlorophenyl)-3-(chlorodifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 4-chloro-4,4-debtor-1-[4-(chloro)phenyl]butane-1,3-dione

Methyl 2-chloro-2,2-deflorated (4,20 g, 29 mmol) is placed in a 100 ml round bottom flask and dissolved in ether (10 ml). To the stirred solution was added 25% sodium methylate (6,37 g, 29 mmol)and then 4’-chloroacetophenone (4,10 g of 26.5 mmol). The reaction mixture was stirred at room temperature over night (to 20.4 hours), then poured into a separating funnel and washed with 3N HCl (15 ml), brine (20 ml), dried over MgSO4and concentrated in vacuo and recrystallized from isooctane, receiving the diketone as a yellow solid (of 3.78 g, 53%): TPL 53-55°;1H NMR (CDCl3) 300 MHz 14,80 (SHS, 1 H), 7,87 (d, J=8.7 Hz, 2 H), 7,50 (d, J=8.7 Hz, 2 H), of 6.49 (s, 1 H);19F-NMR (CDCl3) 300 MHz:-66,03 (C); M+267.

Stage 2: Obtain 4-[5-(4-chlorophenyl)-3-(chlorodifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

4-Sulfonamidophenylhydrazine hydrochloride (1.39 g, 6.2 mmol) is added to a stirred solution of the diketone from Stage 1 (1,43 g, 5,7 the mol) in ethanol (10 ml). The reaction mixture is heated at boiling temperature under reflux and stirred for over night (of 15.75 hours). The ethanol is removed in vacuo and the residue is dissolved in ethyl acetate, washed with water and brine, dried over MgSO4and concentrated in vacuo, getting a white solid, which is recrystallized from a mixture of ethyl acetate/isooctane, receiving the pyrazole as a white solid (0.32 g, 41%): TPL 130-133°;1H NMR (CDCl3) 300 MHz: of 7.90 (d, J=8,9 Hz, 2 H), 7,47 (d, J=8.7 Hz, 2 H), 7,35 (d, J=8.5 Hz, 2 H), 7,19 (d, J=8.7 Hz, 2 H), 6,76 (s, 1 H), 5,13 (CL, 2 H);19F-NMR (CDCl3)300 MHz; -48,44 (C); M+ 417/419.

Example 130

4-[3-(Dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 3’-fluoro-4’-methoxyacetophenone

Aluminium chloride (80,0 g, 0.6 mol) and chloroform (750 ml) placed in a 2 l three-neck round-bottom flask equipped with a mechanical stirrer, and cooled using an ice bath. To a stirred solution add acetylchloride (51,0 g to 0.65 mol)dropwise, keeping the temperature between 5-10° C. the Mixture allow to mix for 10 minutes at 5° before adding dropwise 2-fernicola (63,06 g, 0.5 mol) at 5-10° C. the Mixture was stirred at 0-10° C for 1 hour and poured into ice (1 l). The resulting layers are separated and the aqueous layer was extracted with IU what eltharion (2× 250 ml). The combined organic layers washed with water (2× 150 ml), dried over magnesium sulfate and concentrated to 300 ml Add hexane, and white solid (77,2 g, 92%) crystallized from this mixture: TPL 92-94°;1H NMR (d6-DMSO) to 7.8 (m, 2H), and 7.3 (t, J=8.7 Hz, 1 H), of 3.9 (s, 3 H), and 2.5 (s, 3 H).

Stage 2: Obtain 4,4-dichloro-1-(3-fluoro-4-methoxyphenyl)butane-1,3-dione

Methyldichlorosilane (1,57 g, 11 mmol) dissolved in ether (25 ml). To the stirred solution was added 25% sodium methylate (2.38 g, 11 mmol), and then 3’-fluoro-4’-methoxyacetophenone from Stage 1 (1.68 g, 10 mmol). After stirring for 16 hours add 1N HCl (25 ml). The organic layer is collected and washed with water (2× 25 ml), dried over magnesium sulfate and concentrated. The resulting crude Dion is used in the next stage without additional purification or research.

Stage 3: Obtain 4-[3-(dichloromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide

4,4-Dichloro-1-(3-fluoro-4-methoxyphenyl)butane-1,3-dione from step 2 (2.8 g, 10 mmol) dissolved in ethanol (100 ml). To a stirred mixture of 4-sulphonamido-phenylhydrazine hydrochloride (2,46 g, 11 mmol) and heated at boiling temperature under reflux for 16 hours. The mixture is cooled and water is added until, until crystals appear. Filtering produces a light yellowish-brown firmly the substance (2.7 g, 63%); TPL 190-193°;1H NMR (DMSO-d6): to 7.84 (d, J=8,4 Hz, 2 H), 7,53 (s, 1 H), of 7.48 (d, J=8,4 Hz, 2 H), 7,47 (CL, 2 H), 7.3 to a 7.0 (m, 3 H), to 6.95 (s, 1 H), 3,85 (s, 3 H). Elemental analysis: Calculated for C17H14N3SO3FCl2: C, 47,45; N, OR 3.28; N, 9,76. Found: C, 47,68; N, Of 3.42; N, 10,04.

Example 131

4-[3-Vermeil-5-phenyl-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain methyl 4-phenyl-2,4-dioxaborinane

To a solution of diethyloxalate (11,81 g, 100 mmol) in ether (200 ml) is added 24 ml of 25% sodium methylate in methanol and then a solution of acetophenone (12,02 g, 100 mmol) in ether (20 ml) and the mixture is stirred over night at room temperature. The mixture was partitioned between 1N HCl and EtOAc and the organic layer washed with brine, dried over MgSO4and concentrate, getting to 18.4 g of crude butanoate.

Stage 2: Obtain methyl 1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-carboxylate

Ester is obtained from butanoate in Stage 1, using the technique described in Example 2, stage 2.

Stage 3: Obtain 4-[3-hydroxymethyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide

To a solution of ester in step 2 (4.0 g, 10.4 mmol) in 50 ml THF added portions LiAlH4(0,592 g, 15.6 mmol) and the mixture is refluxed over night. The reaction mixture is cooled and the reaction quenched with 1N NaHSO4and extracted with ether (3x). Merge is installed extracts dried over gSO 4and concentrated, obtaining 3.5 g of the crude alcohol. Flash chromatography using a mixture of 1:1 hexane/EtOAc gives a named connection.

Stage 4: Obtain 4-[3-Vermeil-5-phenyl-1H-pyrazole-1-yl]benzosulfimide

To a mixture of alcohol from Stage 3 (212 mg, 0.64 mmol) in dichloromethane (4 ml) add diethylaminoethyl TRIFLUORIDE (of 0.13 ml, 1.0 mmol). The reaction mixture was stirred at room temperature for 3 hours and partitioned between water and dichloromethane. The aqueous solution is extracted with dichloromethane. The organic solution was washed with brine and concentrated. The remainder chromatographic on silica gel (1:1 hexane:ethyl acetate)to give the desired product (72 mg, 34%): TPL 162-163° C. Elemental analysis: Calculated for C16H14N3O2SF: C, 58,00; H, 4.26 DEATHS; N, 12,68. Found: C, 57,95; N, A 4.03; N, 12,58.

The following compounds in Table VI receive according to the procedures similar to those described in Examples 128-131, with substitution of the appropriate starting substances - substituted acetyl, and acetate.

Example 137

4-[5-(2-Pyrazinyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 4,4-debtor-1-(2-pyrazinyl)butane-1,3-dione

Hatildeparaher (2,23 g, 18 mmol) is placed in a 100 ml round bottom flask and dissolved in ether (10 ml). To stir the mu solution was added 25% sodium methylate (4.68 g, 22 mmol), and then acetylpyrazine (2.00 g, 16 mol). After two hours stirring at room temperature, a precipitate and the reaction mixture is added THF (10 ml). The reaction mixture is stirred for an additional 25,9 hours, then treated with 3N HCl (10 ml). The organic layer is collected, washed with brine (20 ml), dried over gSO4and concentrated in vacuo and recrystallized from a mixture of methylene chloride/isooctane, receiving the diketone as a brown solid (2,23 g, 68%); TPL pp. 103 -- 110°;1H NMR (CDCl3) 300 MHz: 14,00 (SHS, 1 H), 9,31 (d, J=1.4 Hz, 1 H), 8,76 (d, J=2.4 Hz, 1 H), 8,68 (DD, J=1.4 Hz, J=2.4 Hz, 1 H), 7,20 (s, 1 H), 6,03 (t, J=54,0 Hz, 1H);19F-NMR (CDCl3) 300 MHz:-127,16 (l); M+200.

Stage 2: Obtain 4-[5-(2-pyrazinyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

4-Sulfonamidophenylhydrazine hydrochloride (0,37 g of 1.65 mmol) is added to a stirred suspension of the diketone from Stage 1 (0,30 g, 1.50 mmol) in ethanol (10 ml). The reaction mixture is heated at boiling temperature under reflux and stirred for 5,3 hours. The ethanol is removed in vacuo and the residue is dissolved in ethyl acetate, washed with water (20 ml), brine (20 ml), dried over MgSO4and concentrated in vacuo, obtaining a brown solid (0.36 g)which is recrystallized from a mixture of ethyl acetate/ethanol/isooctane, receiving the pyrazole as a brown solid which CSOs substances (0.20 g, 38%): TPL 191-94°;1H NMR (acetone d6) 300 MHz to 8.94 (d, J=1.4 Hz, 1 H), to 8.62 (d, J=2.4 Hz, 1 H), charged 8.52 (DD, J=1.4 Hz, J=2.4 Hz, 1 H), 7,95 (d, J=8.7 Hz, 2 H), to 7.61 (d, J=8.7 Hz, 2 H), 7,30 (s, 1 H), 7,02 (t, J=54,6 Hz, 1 H), 6.73 x (CL, 2 N),19F-NMR (acetone d6) 300 MHz: -113,67 (l); M+ 351.

Example 138

4-[5-(4-Methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 4-methyl-1,3-benzodioxole

11.6 g Adogen 464 and 7 ml of dibromomethane refluxed in 50 ml of N2O for 0.5 hours under argon. 3-Methylcatechol (8,89 g, 71,6 mmol) is added over 2 hours and the mixture is refluxed for an additional 1 hour. Distillation of the product from the reaction mixture gives the named compound as a yellow oil: VRMS m/e 136, 0524 (calculated for C8H8About2, 136,0524).

Stage 2: Obtain 5-acetyl-4-methyl-1,3-benzodioxole (a) and 6-acetyl-4-methyl-1,3-benzodioxole (In)

13.8 g of polyphosphoric acid and 5 ml of acetic anhydride is heated to 45° With drying tube with CaSO4up until the mixture becomes liquid. Add the product from Stage 1 and the reaction mixture stirred at 45° C for 4.5 hours. The reaction mixture is cooled to room temperature and the reaction quenched with 150 ml of ice water. The aqueous phase is washed with ethyl acetate (4× 50 ml). United organically the extracts dried over gSO 4and filtered, obtaining the crude product as a red oil. Oil chromatographic on silica gel, elwira a mixture of 10% ethyl acetate/90% hexane, receiving two products:: Elemental analysis: Calculated for C10H10About3: C 67,07; N, 5,66. Found: C, 67,41; N, 5,75; and: MS, M+ 178.

Stages 3 and 4: 4-[5-(4-methyl-1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

The named compound is obtained from the productusing the techniques described in Example 2, Stage 1 and 2: White solid: Elemental analysis: Calculated for C18H14N3O4SF3: C, 50,82; N, UP 3.22; N, 9,88. Found: C, 50,71; N, To 3.34; N, Of 9.55.

The following compounds in Table VII receive according to the procedures similar to those illustrated in the Examples 137-138, with the replacement of the corresponding original substance.

Example 170

4-[5-(1-Cyclohexyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide

4-[5-(1-Cyclohexenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide (Example 142) (0.31 g, 0.88 mmol) was dissolved in ethanol (15 ml), add 10% palladium on carbon and the suspension peremeci is up at room temperature under hydrogen (2,531 kg/cm 2, 36 psi) for 18,25 hours. The reaction mixture was filtered through celite and the ethanol removed in vacuo, getting a white solid, which is recrystallized from a mixture of methylene chloride/isooctane (0.31 g, 99%): TPL 199-203°;1H NMR (acetone-d6) 300 MHz with 8.05 (d, J=8.7 Hz, 2 H), 7,60 (d, J=8.5 Hz, 2 H), 6,69 (t, J=55,0 Hz, 1 H), 6,47 (s, 1 H), 5,02 (CL, 2 H), to 2.67 (m, 1 H), 1,71-of 1.88 (m, 5 H), 1,24 was 1.43 (m, 5 H);19F-NMR (acetone-d6) 300 MHz -112,86 (d).

Example 171

4-[5-(4-Chlorophenyl)-3-hydroxymethyl-1H-pyrazole-1-yl]benzosulfimide

4-[4-(Aminosulfonyl)phenyl]-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid (Example 83) (3.8 g, 10 mmol) and tetrahydrofuran (100 ml) was stirred at room temperature by adding dropwise at this time of 1.0 M borane-tertrahydrofuran ring complex (30 ml, 30 mmol). The mixture is heated at the boiling point under reflux for 16 hours. The solution is cooled and added dropwise methanol until then, until there is no further gas evolution. Add ethyl acetate (100 ml) and the mixture is washed successively 1N hydrochloric acid, brine, saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate, filtered and concentrated. The resulting product is recrystallized from a mixture of ethanol:water, obtaining 2.6 g (71%) of white solids: TPL 192-194°;1H NMR (DNSO-d6/300 M is C) 7,81 (d, J=8.7 Hz, 2 H), 7,46 (d, J=8,4 Hz, 2 H), 7,42 (CL, 2 H), 7,40 (d, J=8.7 Hz, 2 H), 7,26 (d, J=8,4 Hz, 2 H), 6,63 (s, 1 H), was 5.35 (t, J=8.0 Hz, 1 H), 4,50 (d, J=8.0 Hz, 2 H). Elemental analysis: Calculated for C16H14N6SO2Cl: C, 52,82; N, 3,88; N, 11,55.

Found: C, 52,91; N, 3,88; N, 11,50.

Example 172

4-[5-Phenyl-3-(3-hydroxypropyl-1H-pyrazole-1-yl]benzosulfimide

60% dispersion of sodium hydride in mineral oil (4.0 g, 100 mmol) is washed twice with hexane (100 ml each time) and dried in a stream of nitrogen. Add ether (300 ml) and then added dropwise to ethanol (0.25 ml) and γ -butyrolactone (4 ml, 52 mmol). The mixture is cooled to 10° and dropwise within 1 hour add the acetophenone (5.8 ml, 50 mmol) in ether. The mixture is heated to 25° C and stirred overnight. The mixture is cooled to 0° and quenched with ethanol (5 ml)and then 10% aqueous ammonium sulfate (100 ml). The organic solution is separated, dried over Na2SO4and concentrate. The remainder chromatographic on silica gel with a mixture of 1:1 hexane/ethyl acetate, obtaining the desired diketone (3.4 g) as oil. To a suspension of 4-sulfonamidophenylhydrazine-Hcl (750 mg, 3.4 mmol) in methanol (8 ml) is added pyridine (of 0.34 ml, 4.2 mmol) and diketone (700 mg, 3.4 mmol)in methanol (3 ml). The mixture is stirred at 25° C overnight and concentrated in vacuo. The residue is dissolved in methylene chloride and the solution washed with 1N HCl. Organically the solution is separated, dry and concentrate. The remainder chromatographic on silica gel using ethyl acetate to obtain the desired pyrazole (435 mg) as a solid. Elemental analysis: Calculated for C18H19N3O3S: C, 60,49; N, ARE 5.36; N, 11,75. Found: C, 60,22; N, 5,63; N, 11,54.

Example 173

4-[5-(4-Forfinal)-3-(3-hydroxypropyl)-1H-pyrazole-1-yl]benzosulfimide

Following the procedure of Example 172, but replacing the acetophenone 4-peracetate receive 4-[5-(4-forfinal)-3-(3-hydroxypropyl}-1H-pyrazole-1-yl]benzosulfimide. Elemental analysis: Calculated for C18H18N3O3SF. O 25 N2O: C, 56,90; N, 4,91; N, 11,05 Found: C, 56,80; N, Of 4.67; N, 11,02.

Example 174

4-[4-(Aminosulfonyl)phenyl]-5-(4-forfinal)-1H-pyrazole-3-propanoic acid

Jones reagent (0,64 2 ml,M solution) is added dropwise to a solution of 4-[5-(4-forfinal)-3-(3-hydroxypropyl)-1H-pyrazole-1-yl]benzosulfimide from Example 173 (295 mg, 0.78 mmol) in acetone (8 ml). The mixture is stirred at 25° C for 2 hours. The solution is filtered and the filtrate concentrated in vacuo. The residue is dissolved in ethyl acetate and washed with water (3x). The organic solution is dried over MgSO4and concentrate. The oily residue is crystallized from a mixture of ether/hexane, obtaining the desired acid (149 mg): TPL 180-182° C. Elemental analysis: Calculated the C 18H16N3O4SF: C, 55,52; N, 4,14; N, 10,79. Found: C, 55,47; N, 4,22; N, 10,50.

Example 175

4-(3-Isobutyl-5-phenyl-1H-pyrazole-1-yl)benzosulfimide

Stage 1: Obtain 2,3-epoxy-5-methyl-1-phenyl-3-hexanone

To a solution of 5-methyl-1-phenyl-1-HEXEN-3-one (2.0 g, 10.6 mmol) in 15 ml EtOH and 5 ml of acetone is added dropwise a mixture of 30% hydrogen peroxide (2 ml) and 4N NaOH (1.5 ml) and the mixture was stirred at 25° C for 1-3 hours. Add water (50 ml) and the precipitate is filtered and dried at 40° in vacuum, obtaining 1.9 g of the epoxide as a white solid: Elemental analysis: Calculated for C13H16O2·0.1 g2ABOUT: WITH, 75,77; N, 7,92. Found: C, 75,47; N, 7,56.

Stage 2: Obtain 4-(3-isobutyl-5-phenyl-1H-pyrazole-1-yl)benzosulfimide

Epoxide obtained above in Stage 1 (1.26 g, 6,11 mmol) and 4-sulfonamidophenylhydrazine hydrochloride (1,38 g of 6.17 mmol) is stirred in 20 ml of EtOH with Asón (0.5 ml) and the mixture refluxed for 3 hours, cooled and quenched with 50 ml of N2O. the Aqueous layer was extracted with ethyl acetate (3× 50 ml), the combined extracts dried over MgSO4and concentrate. Flash chromatography using a mixture of 70:30 hexane/ethyl acetate gives a named connection (0,41 g, 19%) as white solids: Calculated for C19H21N3O2S:C, 64,20; N, 5,96; N, 11,82. Found: C, 64,31 N, of 6.29; N, 11,73.

Example 176

Ethyl 3-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-2-cyano-2-propenoate

Stage 1: Obtain 4-[3-formyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide

To a solution of the alcohol obtained in Example 131, step 3 (1.1 g, 3.3 mmol)in ethyl acetate (20 ml) is added MnO2(5 g, 60 mmol) and the mixture is stirred at room temperature overnight. The mixture is filtered through celite and the solution concentrated, obtaining the crude aldehyde.

Stage 2: Obtain ethyl 3-[1-[4-(aminosulfonyl)phenyl]-5-phenyl-1H-pyrazole-3-yl]-2-cyano-2-propenoate

To a solution of the aldehyde obtained in Stage 1 (1.2 g, 3.6 mmol) in benzene (18 ml), add ethylcyanoacrylate (0,38 ml, 3.6 mmol), ammonium acetate (50 mg, 0.7 mmol) and glacial acetic acid (0.17 ml, 2.8 mmol). The solution is refluxed for 18 hours, cooled and partitioned between water and ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate, water and brine. The organic solution is dried and concentrated. The remainder chromatographic on silica gel (40% hexane in ethyl acetate)to give the desired product (1.0 g, 66%): Elemental analysis: Calculated for C21H18N4O4S: FROM, TO 59.82; H, 4,30; N, 13,22. Found: C, 59,70 N, The 4.29; N, 13,26.

Example 177

4-[5-(4-Chlorophenyl)-3-[[(is, teletaxi)imino]methyl]-1H-pyrazole-1-yl)benzosulfimide

To a suspension of 220 mg (of 0.58 mmol) 4-[5-(4-chlorophenyl)-3-formyl-1H-pyrazole-1-yl]benzosulfimide (obtained as described in Example 176, step 1) in dichloromethane (3 ml) is added pyridine (of 0.12 ml, 1.3 mmol) and O-benzylhydroxylamine hydrochloride (110 mg, of 0.68 mmol) and the reaction mixture was stirred at room temperature for 18 hours. The mixture is partitioned between buffer with pH 7 and dichloromethane and the organic layer washed with water, dried and concentrated. Flash chromatography on silica gel (2:1 hexane/EtOAc) gives the titled compound (151 mg, 56%): TPL 158-159° C. Elemental analysis: Calculated for C23H19N4O3SCl· 0,25 H2O: C, 58,59; N, TO 4.17; N, 11,88. Found: C, 58,43 N, A 4.03; N, 11,85.

The following compounds in Table VIII receive according to methods similar to the methods illustrated in the Examples 171-177, with the replacement of the corresponding original substance.

Example 187

4-[4,5-Dihydro-3-(trifluoromethyl)-1-H-benzo[g]indazol-1-yl]benzosulfimide

Stage 1: Getting 2-TRIFLUOROACETYL-1-tetralone

In a 250 ml odnogolosy round bottom flask, equipped with reflux condenser, the input of nitrogen and a magnetic stirrer, download ethyltryptamine (28.4 g, 0.2 mol) and 75 ml of ether. To this solution was added 48 ml of 25% sodium methylate in methanol (0.21 mol). During the roughly 5 minutes, add a solution of 1-tetralone (29,2 g, 0.2 mol) in 50 ml of ether. The reaction mixture was stirred at room temperature for 14 hours and diluted with 100 ml of 3N HCl. The phases are separated and the organic layer was washed with 3N HCl and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The remainder absorb 70 ml boiling mixture of ethanol/water and cooled to room temperature, after which the formed crystals of 2-TRIFLUOROACETYL-1-tetralone, which is separated by filtration and dried in the air, receiving a pure compound (32 g, 81%): TPL 48-49°;1H NMR CDCl3δ 2,8 (m, 2 H), 2,9 (m, 2 H), 7,2 (d, J=3.0 Hz, 1 H), of 7.36 (m, 1 H), 7,50 (m, 1 H), 7,98 (m, 1 H);19F NMR CDCl3δ -72,0. EI GC-MS M+=242.

Stage 2: Obtain 4-[4,5-dihydro-3-(trifluoromethyl)-1-H-benzo[g]indazol-1-yl]benzosulfimide

In 100 ml odnogolosy round bottom flask, equipped with reflux condenser, the input of nitrogen and a magnetic stirrer, download 2-TRIFLUOROACETYL-1-tetralone from Stage 1 (1,21 g, 5.0 mmol), 4-sulfonamidophenylhydrazine hydrochloride (1.12 g, 5.0 mmol) and 25 ml of absolute ethanol. The solution is refluxed for 15 hours and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with water and brine, dried over anhydrous gSO4, filtered and concentrated in vacuo. The residue is recrystallized from a mixture of ethyl acetate and isooctane, getting 1.40 g, 71% of pure product: TPL 257-258° ;1H NMR (CDCl3/CD3OD 4:1) δ to 2.7 (m, 2 H), 2,9 (m, 2 H), and 6.6 (m, 1 H), 6,9 (m, 1 H), and 7.1 (m, 1 H), 7,16 (m, 1 H), 7,53 (m, 2 H), 7,92 (m, 2 H);19F NMR (CDCl3): δ -62,5. The Belarusian library Association-MS (FAB-MS) M+N=394.

Example 188

4-[4,5-Dihydro-7-methyl-3-(trifluoromethyl)-1 H-benzo[g]indazol-1-yl]benzosulfimide

Stage 1: Obtain 6-methyl-2-(TRIFLUOROACETYL)tetralone

Ethyltryptamine (5,33 g, 37.5 mmol) dissolved in ether (50 ml) and treated with a solution of sodium methylate (25% in methanol, 9,92 g, at 45.9 mmol), and then 6-methyltetrazol (5,94 g, 37,1 mmol). The reaction mixture was stirred at room temperature for 6.1 hours, then treated with 3N HCl (20 ml). The organic layer is collected, washed with brine, dried over MgSO4and concentrated in vacuo, obtaining a brown oil (8,09 g), which is used in the next stage without additional purification.

Stage 2: Obtain 4-[4,5-dihydro-7-methyl-3-(trifluoromethyl)-1 H-benzo[g]indazol-1-yl]benzosulfimide

To a stirred solution of the diketone from Stage 1 (1.86 g, 7,3 mmol) in ethanol (10 ml) is added 4-sulfonamidophenylhydrazine hydrochloride (1.80 g, 8.0 mmol). The reaction mixture is heated at boiling temperature under reflux and stirred for of 14.8 hours. The reaction mixture is cooled and filtered. The filtrate was concentrated in vacuo, dissolved in ethyl acetate, washed with water and R is SOLOM, dried over MgSO4and again concentrated in vacuo, receiving the pyrazole as a brown solid (1.90 g, 64%): TPL 215-218°;1H NMR (acetone-d6) 300 MHz: 8,10 (d, 2 H), 7,80 (d, 2 H), 7,24 (s, 1 H), 6,92 (d, 1 H), 6,79 (CL, 2 H), to 6.88 (d, 1 H), to 3.02 (m, 2 H), 2,85 (m, 2 H), of 2.30 (s, 3 H).19F NMR (acetone-d6) 282 MHz-62,46 (C). The mass spectrum of high resolution, calculated for C19H17F3N2O2S: 408,0994. Found: 408,0989.

The following compounds in Table IX receive according to methods similar to the methods illustrated in the Examples 187-188, with the replacement of the corresponding original substance.

Example 196

4-[4,5-Dihydro-3-(trifluoromethyl)-1 H-thieno[3,2-g]indazol-1-yl]benzosulfimide

Stage 1: Obtain 4-keto-4,5,6,7-tetrahydroindene

5-(2-Thienyl)butyric acid (28,42 g, 167 mmol) was placed in a round bottom flask with acetic anhydride (30 ml) and phosphoric acid (0.6 ml) and refluxed for 3.2 hours. The reaction mixture was poured into 100 ml of water, extracted with ethyl acetate, washed with brine, dried over MgSO4and concentrated in vacuo, obtaining a brown oil (22,60 g), which is distilled under vacuum (1 mm Od, 107-115° (C)to give white solid (13,08 g, 51%): TPL 34-40°;1H NMR (Dl3) 300 MHz: 7,29 (d, J=5,2 Hz, H), of 6.99 (d, J=5,2 Hz, 1 H), 2.95 points (t, J=6.0 Hz, 2 H), 2,47 (m, 2 H), to 2.13 (m, 2 H). M+N=153.

Stage 2: Obtain 4-keto-4,5,6,7-tetrahydro-5-(TRIFLUOROACETYL)tianeptine

Ethyltryptamine (11,81 g, 83.1 mmol) dissolved in ether (50 ml) and treated with a solution of sodium methylate (25% in methanol, 18,35 g, 84,9 mmol)and then 4-keto-4,5,6,7-Tetra-hydrocannabinol from Stage 1 (12,57 g of 82.6 mmol)dissolved in ether (25 ml). The reaction mixture is stirred for 69.4 hours at room temperature, then treated with 3N HCL (40 ml). The organic layer is collected, washed with brine, dried over gS4and concentrated in vacuo, getting a brown solid, which is recrystallized from a mixture of ether/hexane, getting diketone (10,77 g, 52%) as brown needles; TPL 54-64°;1H NMR (Dl3) 300 MHz: 15,80 (s, 1 H), 7,41 (d, J=5,2 Hz, 1 H), 7,17 (d, J=5,2 Hz, 1 H), 3.04 from (m, 2 H), 2.91 in (m, 2 H);19F NMR (Dl3) 282 MHz-70,37 (C). M+N=249.

Stage 3: Obtain 4-[4,5-dihydro-3-(trifluoromethyl)-1 H-thieno[3,2-g]indazol-1-yl]benzosulfimide

To a stirred solution of the diketone from step 2 (2.24 g, 9.0 mmol) in ethanol (20 ml) is added 4-sulfonamidophenylhydrazine hydrochloride (2,36 g, 10.6 mmol). The reaction mixture is refluxed and stirred for 14.7 hours. The reaction mixture was filtered and washed with ethanol and water, getting the desired pyrazole as a white solid (2,69 g, 75%): TPL 288-290° ;1H NMR (acetone-d6) 300 MHz to 8.12 (d, J=8.7 Hz, 2 H), 7,83 (d, J=8.7 Hz, 2 H), 7,27 (d, J=5,2 Hz, 1 H), for 6.81 SHS, 2 H, 6,59 (s, J=5.4 Hz, 1 H), 3,18 (m, 2 H), 3,01 (m, 2 H);19F NMR (acetone-d6) 282 MHz-62,46 (C). The mass spectrum of high-resolution computed for C16H12F3N3O2S: 399,0323. Found: 399,0280.

Example 197

4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 3-[4-(chloro)phenyl]-propane-1,3-dione

Ethyl formate (8,15 g, 0.11 mol) and 4’-chloroacetophenone (to 15.4 g, 0.1 mol) is stirred in ether (150 ml) at room temperature. Added dropwise to the sodium methylate (25%) (23,77 g, 0.11 mol). The mixture is stirred at room temperature for 16 hours and then treated with 150 ml of 1N hydrochloric acid. The phases are separated and the ether solution washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, getting to 18.3 g of a yellow oil. The crude mixture was used directly in the next stage without purification.

Stage 2: Obtain 4-[5-(4-chlorophenyl)-1H-pyrazole-1-yl]benzosulfimide

3-[4-(Chloro)phenyl]-propane-1,3-dione from Stage 1 (18.3 g, 0.1 mol) and 4-sulfonamidophenylhydrazine hydrochloride (a 22.4 g, 0.1 mol) is dissolved in 150 ml of absolute ethanol and heated at boiling temperature under reflux for 16 hours. The solution is cooled to room t is mperature, diluted with 100 ml of water and allowed to stand, whereupon crystals are formed pyrazole, which emit filtering, receiving of 8.4 g (25%) of a white solid: TPL 185-187°;1H NMR (Dl3/300 MHz) 7,89 (d, J=8.7 Hz, 2 H), 7,76 (d, J=1.8 Hz, 1 H), the 7.43 (d, J=8.7 Hz, 2 H), 7,34 (d, J=8.7 Hz, 2 H), 7,17 (d, J=8.7 Hz, 2 H), 6,53 (d, J=1.8 Hz, 1 H), 4,93 (CL, 2 H). Elemental analysis: Calculated for C15H12N3SO2Cl: C, 53,97; N, 3,62; N, 12,59. Found: C, 54,08; N, Of 3.57; N, 12,64.

Stage 3: Obtain 4-[5-(4-Chlorophenyl)-4-chloro-1H-pyrazole-1-yl]benzosulfimide

4-[5-(4-Chlorophenyl)-1H-pyrazole-1-yl]benzosulfimide from Stage 2 (3.0 g, 9 mmol) is dissolved in 50 ml of acetic acid and added dropwise 9 ml of 1M chlorine in acetic acid. The mixture is stirred for 16 hours, at the same time, slowly add a solution of sodium bicarbonate until then, until the mixture becomes neutral pH indicator paper. The mixture is extracted with ethyl acetate (3× 50 ml), combined and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated. The resulting product is recrystallized from isopropanol, obtaining 2.6 g (78%) of white solids: TPL 168-171° C (decomp.);1H NMR (DMSO-d6/300 MHz) 8,08 (s, 1 H), 7,83 (d, J=8.7 Hz, 2 H), 7,55 (d, J=8.7 Hz, 2 H), 7,46 (CL, 2 H), 7,44 (d, J=8.7 Hz, 2 H), 7,35 (d, J=8.7 Hz, 2 H). Elemental analysis: Calculated for C15H11N3 SO2Cl2: C, 48,93; N, A 3.01; N, 11,41. Found: C, 49,01; N, Of 2.97; N, 11,41.

Example 198

4-(4-Fluoro-5-phenyl-1H-pyrazole-1-yl)benzosulfimide

Stage 1: Getting 2-fortetienne

To a solution of 2-hydroxyacetophenone (2.5 g, 18.4 mmol) in 100 ml of CH2Cl2at -78° add triplify anhydride (anhydride triftormetilfullerenov acid) (10 g, of 35.4 mmol), and then 2,6-lutidine (4,1 ml of 35.4 mmol) and the mixture was stirred at -78° C for 50 minutes. The mixture is then poured into CH2Cl2and water and CH2Cl2layer was separated, washed with brine, dried over Na2SO4and concentrate to a solid peach color. To a solution of the crude triflate in 100 ml of THF, add 35 ml of 1N fluoride tetrabutyl of ammonia in THF. The mixture is refluxed for 15 minutes, cooled and poured into ether and water. The ether layer was separated, washed with brine, dried over Na2SO4and concentrate. Using flash chromatography on silica gel using a mixture of 20:1 hexane/EtOAc, get α -forcecon (0,852 g, 33.5 per cent).

Stage 2: Obtain 4-(4-fluoro-5-phenyl-1H-pyrazole-1-yl)benzosulfimide

A solution of 2-fortetienne (200 mg, 1,45 mmol) in 2 ml of dimethylformamide-dimethylacetal refluxed for 18 hours. The mixture is cooled and concentrated, obtaining the crude enaminoketone. the ez additional purification of the enaminoketone handle 4-sulfonamidophenylhydrazine hydrochloride (0.34 g, of 1.52 mmol) in 10 ml EtOH boiling under reflux for 17 hours. The mixture is cooled, filtered and the filtrate concentrated to a yellow resin. Using flash chromatography using a gradient from 5:1 to 2:1 GEK-San/EtOAc, obtain 0.11 g of a yellow solid. After recrystallization from a mixture of ether/hexane receive the product as a pale yellow solid, TPL 194-194,5° C; Elemental analysis: Calculated for C15H12N3O2SF· 0,2 H2ABOUT: WITH, 56,14; N, TO 3.89; N, TO 13.09. Found: C, 55,99; N, The 3.65; N, 12,92.

Example 199

4-[5-(4-Chlorophenyl)-3-(trifluoromethyl)-4-chloro-1H-pyrazole-1-yl]benzosulfimide

100 ml three-neck round-bottom flask equipped with a reflux condenser, a tube for dispersing gas and magnetic stirrer, load 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide (Example 1) (500 g, 1.2 mmol) and 50 ml of glacial acetic acid. The solution was stirred at room temperature and processed, passing a current of gas chlorine for 15 minutes. Then the solution was stirred at room temperature for 1.25 hours and then diluted with 100 ml of water. Then the solution is extracted three times with ether and the combined ethereal phase was washed with brine, dried over gSO4, filtered and concentrated in vacuo, getting a white solid, which PE is crystallizability from a mixture of ether/petroleum ether, getting 390 mg (75%) of 4-[5-(4-chlorophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide: TPL 180-182°;1H NMR (Dl3/300 MHz) of 7.97 (d, J=6.6 Hz, 2H), 7,49 (d, J=6.3 Hz, 2 H), was 7.45 (d, J=6.3 Hz, 2 H), 7,25 (d, J=6.6 Hz, 2 H), 5,78 (CL, 2 H).

Example 200

4-[4-Fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Getting 4,4,4-Cryptor-1-phenyl-butane-1,3-dione

To a solution of 2-fortetienne of Stage 1 of Example 198 (0,48 g, 3.4 mmol) in 25 ml THF at -78° add 1N bis(trimethylsilyl)amide lithium (4 ml) and the mixture was stirred at -78° C for 45 minutes. Add 1-(TRIFLUOROACETYL)imidazole (0,65 ml, 5.7 mmol) and the mixture was stirred at -78° C for 30 minutes and at 0° C for 30 minutes. The mixture is quenched 0,5N HCl, poured into ether and water and the ether layer was separated, washed with brine, dried over Na2SO4and concentrate. Using flash chromatography on silica gel using a gradient from 10:1 to 4:1 hexane/EtOAc, receive 1,3-diketone (0.34 g, 43%).

Stage 2: Obtain 4-[4-fluoro-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Diketone from Stage 1 (0.34 g, 1,45 mmol) is treated with 4-sulfonamidophenylhydrazine hydrochloride (0.35 g, 1.56 mmol) in 15 ml EtOH boiling under reflux for 15 hours. The mixture is cooled, filtered and the filtrate concentrated to a yellow resin. Using flash chromatograph and, using 3:1 hexane/EtOAc, obtain 0.28 g of yellow solid. Recrystallization from a mixture of CH2CL2/hexane gives the product as a pale yellow solid: Elemental analysis: Calculated for C16H11N3O2SF4: C, 49,87; N, IS 2.88; N, 10,90. Found: C, Of 49.79; H, Is 2.88; N, 10,81.

Example 201

4-[4-Methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 2-methyl-1-phenyl-4,4,4-triptorelin-1,3-dione

To a solution of propylene (965 mg, 7.2 mmol) in THF (20 ml) at -78° add bis(trimethylsilyl)amide, sodium (7,9 ml of 1 M solution in THF). The solution is maintained at -78° C for 0.5 hour and then heated to -20° C for 1 hour. The solution is cooled to -78° and added by cannula to 1-(TRIFLUOROACETYL)imidazole (1.5 g, 9.1 mmol) in THF (4 ml). The solution is heated to room temperature and stirred over night. The mixture was partitioned between 1N HCl and ether. The organic solution is dried (Na2SO4) and concentrated, obtaining the crude diketone (1.9 grams).

Stage 2: Obtain 4-[4-Methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Diketone from Stage 1 are dissolved in absolute ethanol (25 ml) and add 4-sulfonamidophenylhydrazine hydrochloride (2.0 g, 9.0 mmol). The mixture is heated at boiling point with the reverse you can see what these lamps for 19 hours. Volatile components are removed under vacuum and the residue is dissolved in ethyl acetate. The organic solution was washed with water and brine, dried and concentrated. The remainder chromatographic on silica gel (2:1 hexane/ethyl acetate), obtaining the above pyrazole (1.52 g, 49%): TPL 145-146° C; Calculated for C17H14N3About2SF3: C, 53,54; N, 3,70; N, BR11.01. Found: C, 53,41; N, 3,66; N, 10,92.

Example 202

4-[4-Ethyl-5-(3-methyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

Stage 1: Obtain 4-methoxy-3-methylbutyrate

To a suspension of aluminium chloride (10.3 g, 77.2 mmol) in dichloromethane (40 ml) at 0° C is added dropwise a solution of 2-methylanisole (5.0 ml, was 35.3 mmol) and butyric acid anhydride (5.8 ml, was 35.3 mmol). The reaction solution was kept at 0° C for 2 hours and then warmed to room temperature and stirred over night. The reaction solution was poured in conc. HCl (9 ml) and ice water (80 ml). The reaction mixture is extracted with dichloromethane and the organic layer washed with 2N NaOH and brine, dried and concentrated. The remainder chromatographic on silica gel (9:1 hexane:ethyl acetate)to give the desired product (5.2 g, 77%).

Stage 2 and 3: Obtain 4-[4-ethyl-5-(3-methyl-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

The named compound is obtained from butrageno is in Stage 1, using the method described in Example 201, Stage 1 and 2: TPL 135-136° C; Calculated for C20H20N3O3SF3: C, 54,66; N, 4,59; N, 9,56. Found: C, 54,11; N, To 4.38; N, 9,43.

Example 203

4-[4-Cyclopropyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide stage 1: Getting 2-cyclopropylethanol

To a suspension of sodium cyanide (1.8 g, 37,0 mmol) in dimethyl sulfoxide (20 ml) at 60° With added dropwise (methyl bromide) cyclopropane (5.0 g, 37,0 mmol). The addition is carried out at such a rate to maintain the reaction temperature at 60° C. After complete addition, the reaction mixture is heated at 80° C for 15 minutes. The mixture is cooled and partitioned between ether and water. The organic solution was washed with 1N HCl and water, dried and concentrated. The residue is dissolved in ether (5 ml) and added to a solution of phenylmagnesium (25 ml of 3 M solution in ether) in ether (20 ml) and benzene (25 ml). The reaction mixture was stirred at room temperature for 20 hours, then poured into 1N HCl solution and stirred for 1.5 hours. The organic solution was separated and the aqueous solution extracted with dichloromethane. The organic solution is dried and concentrated. The remainder chromatographic on silica gel (9:1 hexane:ethyl acetate)to give the desired product (2.0 g, 34%).

Stage 2 and 3: Obtain 4-[4-qi is sapropel-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide

The named compound is obtained from acetophenone in Stage 1, using the method described in Example 201, Stage 1 and 2: TPL 173-174° C; Calculated for C19H16N3O2SF3: C 56,01; N, 3.96 POINTS N, 10,31. Found: C, 55,85; N, Of 3.78; N, 10,19.

Example 204

4-[4-Hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]]benzosulfimide

Stage 1: Obtain 4-[4-methyl bromide-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]]benzosulfimide

To a solution of 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide obtained in Example 201 (500 g, 1.3 mmol)in carbon tetrachloride (9 ml) and benzene (4 ml) is added N-bromosuccinimide (285 mg, 1.6 mmol). The mixture is irradiated with the lamp "mountain sun" (sunlamp) for 3.5 hours. The reaction mixture was partitioned between dichloromethane and water and the organic solution is dried and concentrated, obtaining the desired product, 412 mg (69%).

Stage 2: Obtain 4-[4-formyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]]benzosulfimide

To a solution of compound obtained in Stage 1 (362 mg, of 0.79 mmol)in dimethylsulfoxide (7 ml) add kallidin (of 0.14 ml, 1.0 mmol). The solution is heated at 120° C for 3 hours and then incubated over night at room temperature. The reaction solution was distributed between ethyl acetate and water and the organic solution washed with water, dried the concentrate. The remainder chromatographic (1:1 hexane:ethyl acetate)to give the desired product (205 mg, 66%). Stage 3: Obtain 4-[4-hydroxymethyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole-1-yl]]benzosulfimide

To a solution of the aldehyde obtained in Stage 2 (165 mg, 0.41 mmol), in methanol (3.5 ml) at 0° add sodium borohydride (16 mg, 0.41 mmol). The reaction solution was kept at 0° C for 2.5 hours. The reaction is quenched by addition of aqueous 1 M KHSO4solution (3 ml). The mixture is extracted with dichloromethane and the organic solution is dried and concentrated. The remainder chromatographic on silica gel (1:1 hexane:ethyl acetate)to give the desired product (36 mg, 46%): TPL 179-180°;1H NMR d to $ 7.91 (m, 2 H), 7,53-7,40 (m, 5 H), 6.75 in (s, 2 H), 4.53-in (d, 2 H, J=5.0 Hz), 4,30 (t, 1 H, J=5.0 Hz).

Example 205

4-[4-Chloro-3-isobutyl-5-phenyl-1H-pyrazole-1-yl]benzosulfimide

To a solution of pyrazole obtained in Example 175 (0.15 g, 0.42 mmol)in CH2Cl2(10 ml) is added slowly at room temperature the excess Sulfuryl chloride. The mixture is stirred at room temperature for 2 hours, quenched with water and the aqueous layer was extracted three times with methylene chloride. The combined organic layers dried over MgSO4and concentrate, receiving the oil, which is purified flash chromatography on silica gel using a mixture of 70:30 hexane/ethyl acetate as eluent,obtaining the required connection: VRMS m/C 389,0970 (calculated for C 19H20lN3SO2, 389,0965).

The following compounds in Table X receive according to methods similar to the illustrated in the Examples 197-205, with the replacement of the corresponding original substance.

Example 259

4-[4-Chloro-3-cyano-5-[4-(fluoro)phenyl]-1H-pyrazole-1-yl]-N-[(dimethylamino)methylene]benzosulfimide

Increasing the polarity of the elution solvent used for purification in Example 234, up to 60% ethyl acetate after concentration of the appropriate fractions gives 4-[4-chloro-3-cyano-5-[4-(fluoro)phenyl]-1H-pyrazole-1-yl-N-[(dimethylamino)methylene]benzosulfimide (0,485 g, 15%): Mass spectrum high resolution (MLi+)Calculated: 438,0779. Found: 438,0714. Elemental analysis: Calculated for C19H15N5O2FClS: With, Of 52.84; H, 3,50 N, 16,22; Cl, 8,21; S,7,42. Found: C, 52,76; N, To 3.52; N, 16,12; Cl, 8,11; S, 7,35.

Example 260

4-[4-Bromo-3-cyano-5-phenyl-1H-pyrazole-1-yl]-N-[(dimethylamino)methylene]benzosulfimide

Similarly, 4-[4-bromo-3-cyano-5-phenyl-1H-pyrazole-1-yl]-N-[(dimethylamino)the ethene]benzosulfimide emit when cleaning (product) of Example 235 (0,153 g, 28%): Mass spectrum high-resolution (M+) calculated: 457,0208. Found: 457,0157. Elemental analysis: Calculated for C19H16N5O2BrS: With, Of 49.79; H, 3,52 N, 15,28; VG, 17,43; S 6,99. Found: C, 49,85; N, Of 3.56; N, 15,10; Br, 17,52; S, 6.87 In.

Example 261

4-[1-(4-Forfinal)-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzosulfimide

Stage 1: Obtaining N,N-bis(4-methoxybenzyl)-4-(aminosulfonyl)of acetophenone

To a solution of 4-(aminosulfonyl)acetophenone (2.0 g, 9.0 mmol) in dimethyl sulfoxide (25 ml) is added sodium hydride (450 mg, 19.0 mmol). The reaction mixture is stirred for 45 minutes and then using a cannula add 4-methoxybenzyl bromide (3.5 g, 19.0 mmol) in dimethyl sulfoxide (5 ml). The mixture is stirred at room temperature for 24 hours and distributed between ethyl acetate and pH 7 buffer. The aqueous solution is extracted with ethyl acetate. The organic solution is dried over gSO4and concentrate. The remainder chromatographic on silica gel (2:1 hexane:ethyl acetate)to give the desired product (815 mg, 21%).

Stage 2: Obtaining N,N-bis(4-methoxybenzyl)-4-[1-(4-forfinal)-3-trifluoromethyl-1H-pyrazole-5-yl]benzosulfimide

To 25% solution of sodium methylate in methanol (0.2 ml) add ethyltryptamine (75 mg, of 0.53 mmol) and protected acetophenone from Stage 1 (235 mg, of 0.53 mmol). Add THF (0.5 ml) and the reaction mixture is heated when the temperature is e boiling under reflux for 2 hours and then stirred at room temperature over night. The mixture is partitioned between ether and 1N HCl solution. The organic solution is dried and concentrated, obtaining the crude diketone (279 mg), which was diluted with absolute ethanol (2.5 ml). To this suspension add pyridine (49 mg, of 0.62 mmol) and 4-forfamilies hydrochloride (80 mg, 0.50 mmol). The mixture is stirred at room temperature for 24 hours and concentrated in vacuo. The residue is dissolved in methylene chloride and washed with 1N HCl. The organic solution is dried and concentrated. The remainder chromatographic on silica gel (3:1 hexane:ethyl acetate)to give the protected pyrazole (159 mg, 51%).

Stage 3: Obtain 4-[1-(4-forfinal)-3-(trifluoromethyl)-1H-pyrazole-5-yl]benzosulfimide

To a solution of the protected pyrazole (50 mg, 0.08 mmol) in acetonitrile (1 ml) and water (0.3 ml) was added cerium (4) ammonium nitrate (360 mg, of 0.65 mmol). The reaction solution was kept at room temperature for 16 hours. The solution was poured into water (15 ml) and extracted with ethyl acetate (2× 25 ml). The combined extracts dried (MgSO4) and concentrate. The remainder chromatographic on silica gel (2:1 hexane:ethyl acetate)to give the desired product (13 mg, 42%):1H NMR (CD3OD) 7,88 (d, 2 H), 7,46 (d, 2 H), 7,39 (DD, 2 H), 7,21 (t, 2 H), 7,06 (s, 1 H).

Example 262

4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-yl]]benzosulfimide

A named connection receive the Ute, using the procedure described in Example 261: VRMS (HRMS) m/z 397,0702 (calculated for C17H14N3About3SF3, 397,0708).

BIOLOGICAL ASSESSMENT

Test for swelling pads carraginanous foot in rats

Test swelling pads carraginanous foot exercise with substances, reagents and techniques, mainly described by Winter, et al., (Proc. Soc. Exp. Biol. Med., 111, 544 (1962)). Sprague-Dawley rats males are selected in each group so that the average body weight as possible little different. Rats deprived of food, leaving access to water for sixteen hours before the test. Rats dosed orally (1 ml) of the compounds suspended in the filler containing 0.5% methylcellulose and 0.025% surfactant, or just filler. After one to two hours, do subplantar (pomodorino) injection of 0.1 ml of 1% solution carragenan/sterile 0,9% saline solution and the volume of the injected foot was measured using plethysmometer (plethysmograph) offset (offset)associated with the pressure sensor digital display. Three hours after injection of carrageenan, the volume of the foot again measured. The average swelling (swelling) of the foot in the group of animals treated with the medication, compared with the group of animals treated with placebo, and determine the percent inhibition of edema (Otterness and Bliven, Laboratory Models for Teting NSAIDs, in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed. 1985)). The percentage of inhibition shows the percentage reduction from control volume paws defined in this procedure and the data for the selected compounds in this invention are summarized in Table XI.

Test for analgesia caused by carrageenan rats

Test for analgesia, using rat carrageenan, carried out with substances, reagents and methods described Hargreaves, et al., (Pain, 32, 77 (1988)). Sprague-Dawley rats (males) treated as described previously for test swelling pads carraginanous foot. Three hours after the carrageenan injection, the rats are placed in a special Plexiglas container with a transparent floor, with the lamp high intensity source of heat radiation, located under the floor. After the initial twenty-minute time period start thermal stimulation on either injected foot, or on the opposite (contralateral) penjelasannya foot. Photovoltaic relay turns the lamp off and timer, when the light is interrupted when OTDELENIE foot. Time before the rat will hold out his foot, then measure. Delay otdergivanija in seconds is determined for the control group and groups treated with the medicinal product, and determine the percentage of inhibition of otdergivanija hyperalgesia (verbalizing) feet. The results is redstavleny in Table XI.

Table XI
 EDEMA of the RAT PAW

% Inhibition of 10 mg/kg of body weight
ANALGESIA

% Inhibition at 30 mg/kg of body weight
Examples  
14494
23538
583665
592541
604939
8222* 
8642* 
982* 
11732 
12947* 
17018* 
1711437
18832* 
19745*27
19935 
*Analysis carried out at 30 mg/kg of body weight

Evaluation of YEAR I and YEAR II activity in vitro

The compounds of this invention exhibit inhibition of in vitro COX II. AK is Yunosti inhibition of MOR II compounds of the present invention, illustrated in the Examples, define the following ways :

A. The preparation of recombinant MOR baculoviruses

2,0 TB (kb)fragment containing the coding region of either human or murine COX-I or human or murine COX-II, clone into the BamHI site of the vector pVL1393 (Invitrigen) baculovirus transfer to generate the transfer vectors and baculovirus for COX-I and COX-II in a manner analogous to the way D.R. O'reilly et al. (Baculovirus Expression Vectors: A Laboratory Manual (1992)). Recombinant baculoviruses are transfection of 4 μg DNA vector transfer baculovirus in SF9 cells insects (2× 10 E8) along with 200 ng of linearized baculovirus plasmid DNA by calcium phosphate method. Cm. M.D.Summers and G.E.Smith, A Manual of Methods for Baculovirus Vectors and Insect Cell Culture Procedures, Texas Agric. Exp. Station Bull. 1555 (1987). Recombinant viruses purified by three cycles of cleaning plaque and get the virus strains of high titer (E-E PFU/ml (pfu/ml)). For large-scale production of SF9 cells infect insects in 10 liter fermentors (0,5× 106ml) recombinant baculoviruses strain so that the multiplicity of infection was 0.1. After 72 hours the cells are centrifuged and the precipitate of cells in the test tube after centrifugation of homogenized in Tris/sucrose (50 mm: 25%, pH 8.0)containing 1% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS). The homogenate was centrifuged at 10000× G for 30 minutes and the resulting supernatant stored at -80° before using it for analysis on MOR activity.

b. Analysis SOKH I and YEAR II activity:

MOR activity analyze formed as the G2/µg protein/time using an ELISA to detect the release of prostaglandin. CHAPS-solubilization cell membrane insects containing the corresponding MOR enzyme, incubated in potassium phosphate buffer (50 mm, pH 8.0)containing epinephrine, phenol and hem with the addition of arachidonic acid (10 μm). Connection pre-incubated with the enzyme for 10 to 20 minutes before the addition of arachidonic acid. Any reaction between the arachidonic acid and the enzyme was stopped after ten minutes at 37° C/room temperature by transfection with 40 μl of the reaction mixture in 160 ál of ELISA buffer and 25 μm indomethacin. Formed PGE2measured using standard ELISA technology (Cayman Chemical). The results are presented in Table XII.

4
Table XII
ExampleSOKH II person ID50mcmSOKH I person ID50mcm
1<.118
2<.115.0
3<.1>100
.637.5
5<.16.3
6.278.7
714>100

Table XII (cont.)
ExampleSOKH II person ID50mcmSOKH I person ID50mcm
837.7>100
9.155.2
102.7>100
1220>100
552277.9
56<.111.7
5747.9>100
58<.15.7
59<.126.8
60<.1.8
82<.11.1
84<.165.5
8573.6>100
86.5>100
966.5>100
9796>100
98 <.11.7
117.3>100
1281.1>100
129<.113.5
1303.612.5
131.2>100
138.6<.l
170.1>100
171.8>100
1724.2>100
1734.7>100
1743.5100
17566.9>100
176.3>100
1871.113.6
188.219.8
196.64.1
197<.13.4

Table XII (cont.)
ExampleSOKH II person ID50mcmCOX 1 person ID50mcm
1984.256.5
199<.1<.1
200<1 .5
201<.12.2
202<.191
20327>100
2046.7>100
205<.12.1
2591.1>100
2601.1>100
261<.1<.1
262<.1<.1

Scope of the present invention also encompasses a class of pharmaceutical compositions comprising the active compounds of this combination therapy in combination with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (here called substances-“holders”) and, if desired, other active ingredients. The active compounds of this invention can be applied in any suitable way, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the intended treatment. Active compounds and composition may, for example, be applied orally, untriangulated, administered intraperitoneally, subcutaneously, intramuscularly or topically.

For oral administration Pharma is eticeskaja the composition may be in the form for example, tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably prepared in the form of a unit dose containing a specific amount of the active ingredient. Examples of such unit doses are tablets or capsules. The active ingredient may also be administered by injection in the form of a composition in which, for example, saline, dextrose or water can be used as a suitable carrier.

The amount of therapeutically active compounds that are injected, and the regimen of medicines to treat the disease with the compounds and/or compositions of this invention depends on a number of factors, including age, weight, sex and medical condition of the subject, the severity of the disease, the path and the frequency of use, and specific applicable connection, and therefore can vary widely. The pharmaceutical compositions may contain the active ingredients in the range of from about 0.1 to 2000 mg, preferably in the range of from about 0.5 to 500 mg and most preferably from about 1 to 100 mg. Daily dose of from about 0.01 to 100 mg/kg body weight, preferably from about 0.5 to 20 mg/kg body weight and most preferably from about 0.1 to 10 mg/kg body weight, may be appropriate.

Therapeutically active compounds can be applied as needed. Al is ternative therapeutically active compounds can be applied once a week, once a month, or another appropriate frequency based on the composition, period of existence, connection, introduction, basically, during a meal, the age of the animal and other related properties. The daily dose can be administered by smashing it on for one to four doses per day.

In case of skin diseases, it is preferable to apply the local preparation of the compounds of the present invention to the affected area two to four times a day.

Inflammation of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied in the form of local ointments or creams, or in the form of a suppository, containing the active ingredients in a total amount, for example from 0,075% to 30% weight./weight., preferably 0.2 to 20 wt%./weight. and most preferably 0.4 to 15% wt./weight. In the preparation of ointment, the active ingredients can be used either with a paraffin-based or water-soluble oil base. Alternative active ingredients can be put in the cream with an oil-in-water or oil-based. If required, the aqueous phase of the cream base may include, for example, at least 30% wt./weight. a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerin, polyethylene glycol and mixtures thereof. Local composition may, if required, to include a compound which enhances absorption or permeable is the terrain of the active ingredient through the skin or other affected area. Examples of such substances that increase skin permeability, are dimethyl sulfoxide and related analogues. The oil phase of the emulsions of this invention can be from known ingredients in a known manner. Although the phase may include only the emulsifier, it may include a mixture of at least one emulsifier with a fat or oil, or with both (and fat, and butter). Preferably, the hydrophilic emulsifier is included together with a lipophilic emulsifier, which acts as a stabilizer. Also preferably, the inclusion of both oils and grease. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat is the so-called emulsifying materials, which forms an oily-dispersible phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the preparation of the compositions of this invention include, among others, tween 60, span (Span) 80, cetosteatil alcohol, ministerului alcohol, glycerylmonostearate and sodium laurylsulfate.

The choice of suitable oils or fats for the technology of preparation of medicines is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils to be used etc the preparation of pharmaceutical emulsions, is very low. Thus, the cream should preferably be a low-fat, necroshade and washable product with suitable consistency to avoid leakage from tubes or other containers. Can be used mono - or dienone alkyl esters of straight or branched chain, such as digitariat, isolatedstore, propylene glycol diesters of coconut fatty acids, isopropylmyristate, decillia, isopropyl, butilstearat, 2-ethylhexylamine or mixture of esters with branched chain. They can be used as such or in combination depending on the desired properties. An alternative can be used lipids with high melting point, such as white soft paraffin and/or liquid paraffin, or mineral oil.

Formulations suitable for topical application to the eye also include eye drops, in which the active ingredients are dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredients. Anti-inflammatory active ingredients are preferably present in such formulations in a concentration of from 0.5 to 20%, mostly from 0.5 to 10% and, in particular, about 1.5% wt./weight.

For therapeutic purposes, the active compounds of this invention - the combination is usually combined with the ne or more adjuvants, suitable for the chosen path of the application. When applied per os, the compounds are usually mixed with lactose, sucrose, starch powder, esters of cellulose and alkanovykh acids, cellulose alkylamino esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, Arabic gum, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tabletirujut or capsulebuy for ease of use. Such capsules or tablets may contain a controlled release composition, which may be provided in the form of a dispersion of active compound in the hypromellose. The compositions for parenteral administration can be in the form of aqueous and non-aqueous isotonic sterile solutions for injection or suspensions. These solutions or suspensions can be obtained from sterile powders or granules having one or more carriers or diluents mentioned for use in the formulations for oral administration. The compounds can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and/or various buffers. Other adjuvants and methods of application are well known in the pharmaceutical of the region.

1. A method of treating inflammation or associated with inflammation of the disease in dogs, which consists in the introduction of the dog a daily dose of from about 0.1 mg/kg to 10 mg/kg of body weight 4-[3-(deformity)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-yl]benzosulfimide or its pharmaceutically acceptable salt.

2. The method according to claim 1, characterized in that it is intended for the treatment of inflammation.

3. The method according to claim 1, characterized in that it is designed to treat the associated with inflammatory diseases.

4. The method according to claim 1, characterized in that it is designed for the treatment of pain.

5. The method according to claim 4, characterized in that the compound or its pharmaceutically acceptable salt is administered in the form of pharmaceutical compositions.



 

Same patents:

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 medicine, in particular to a solid dosage form, based on sulfamethoxazole and trimethoprim, which is a compressed granules, coated outrivals layer of starch, magnesium stearate and polyplasdone

The invention relates to the field of pharmaceutical industry and relates to antimicrobial pharmaceutical composition for the treatment of pneumonia, infections of the respiratory tract, gastrointestinal tract, etc. containing as active ingredient co-trimoxazole and special additive: sodium carboxymethylcellulose, cellulose, sorbitol food, glycerin, parable, tween-80, food flavors and is made in the form of a suspension for oral administration

-converting enzyme)" target="_blank">

The invention relates to novel ortho-sulfonamidophenylhydrazine heteroaryl hydroxamic acids of the formula

< / BR>
where W and X are both carbon, T is nitrogen, U represents CR1where R1represents hydrogen, or alkyl containing 1-8 carbon atoms, R represents-N(CH2R5)-SO2Z, Q represents -(C=O)-NHOH, with

< / BR>
is a benzene ring, or is a heteroaryl ring of 5 to 6 atoms in the cycle, which may contain 0-2 heteroatoms selected from nitrogen, oxygen and sulfur, in addition to the heteroatom of nitrogen, denoted as W, where benzene or heteroaryl ring may optionally contain one or two substituent R1where permissible; Z is phenyl, which is optionally substituted by phenyl, alkyl with 1-8 carbon atoms, or a group OR2; R1represents halogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbon atoms, perfluoroalkyl from 1 to 4 carbon atoms, phenyl, optionally substituted by 1-2 groups OR2group-NO2group -(CH2)nZ, where Z is a phenyl which allows an alkyl with 1-8 carbon atoms, phenyl, optionally substituted with halogen, or heteroaryl radical containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; R5represents hydrogen, alkyl with 1-8 carbon atoms, phenyl, or heteroaryl containing 5 to 6 atoms in the cycle, including 1-2 heteroatoms selected from nitrogen, oxygen and sulfur; or their pharmaceutically acceptable salts

The invention relates to the field of medicine
The invention relates to the production of pharmaceutical preparations, effective for infections of the respiratory tract, urinary tract, gastrointestinal tract, surgical infection and other infectious diseases

The invention relates to medicine, specifically to medicines with antimicrobial activity

The invention relates to medicine

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 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

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

The invention relates to new compounds of the formula (I)

in which Ar1means pyrazole which may be substituted by one or more groups R1, R2or R3; Ar2means naphthyl, tetrahydronaphthyl, each of which is optionally substituted by 0-1 groups R2; X means5-C8cycloalkenyl, phenyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, furan, pyridinoyl, pyrazolyl, pyridinyl, optionally substituted by a hydroxy-group or1-C4alkoxygroup, piperidinyl; Y represents a bond or a saturated branched or unbranched1-C4the carbon chain, with one methylene group is optionally replaced with NH, or and Y is optionally independently substituted by oxopropoxy; Z means morpholine, group, pyridinyl, furanyl, tetrahydrofuranyl, thiomorpholine, pentamethylbenzene, pentamethylbenzene, secondary or tertiary amine, the nitrogen atom of the amino group covalently linked to the following groups selected from a range that includes the C1-C3alkyl and C1-C5alkoxyalkyl; R1means31-C6alkyl which is optionally partially or fully galogenidov, halogen; R3means phenyl, pyrimidinyl, pyrazolyl, which is substituted by one branched or unbranched1-C6the alkyl, and pyridinyl, optionally substituted C1-C3alkoxygroup or amino group, W denotes O and its pharmaceutically acceptable salts

The invention relates to chemical-pharmaceutical industry, in particular to the creation and production of tools for the treatment of skin diseases

The invention relates to the field of creation of a combined preparation on the basis of metamizol sodium and Campidano with analgesic, antipyretic and antispasmodic activity

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

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