The use of inhibitors of cyclooxygenase-2 for the treatment and prevention of neoplasia

 

(57) Abstract:

Proposed: inhibitors of cyclooxygenase-2 General formula (II) for the treatment and prevention of neoplasia, in particular adenomatous polyps, cancer of the gastrointestinal tract, liver cancer, skin cancer, bladder cancer, cervical cancer, prostate cancer and lung cancer, and the drug based on them. The invention expands the Arsenal of tools specified destination. 3 N. and 17 C.p. f-crystals, 2 PL.

formula II

where R4, R2and R3such as defined in the description.

The technical field to which the invention relates.

The present invention relates to the field of prevention and treatment of neoplasia. In particular, the present invention relates to inhibitors of cyclooxygenase-2 or a derivative thereof for the prevention and treatment of neoplasia.

Background of invention

Prostaglandins play a major role in the inflammatory process, and inhibition of production of prostaglandins, in particular products PGG2, PGH2and PGE2it was common to find anti-inflammatory drugs. However, conventional non-steroidal prothiofos what I associated with inflammation, active also in the impact on other regulated by prostaglandins processes not associated with inflammation. Therefore, the use of high doses of the most common NSPs can lead to serious side effects, including life-threatening ulcers, which limits their therapeutic potential. Alternative NSPs is the use of corticosteroids, which also give harmful effects, especially when conducting long-term therapy.

It was found that NSPs prevents the production of prostaglandins by inhibiting the enzyme at the site arachidonic acid/prostaglandin in humans, including the enzyme cyclooxygenase (SOH). The recent discovery of adaptive enzyme associated with inflammation (called "cyclooxygenase-2 (SOH-2)" or "prostaglandin G/H synthase II"), makes feasible the task of inhibition with a more efficient reduction of inflammation in smaller and less dangerous side effects.

Compounds that selectively inhibit cyclooxygenase-2, already described in the U.S. patents№№5380738, 5344991, 5393790, 5434178, 5474995, 5510368 and in WO 96/06840, WO 96/03388, WO 96/03387, WO 96/25405, WO 95/15316, WO 94/15932, WO 94/27980, WO 95/00501, WO 94/13635, WO 94/20480 and WO 94/26731.

Neoplastic painful soumise rapidly progressive growth of cells, continue to be the subject of worldwide research efforts in the search for therapeutic agents that are effective in their treatment. Effective therapeutic agent lengthen the life expectancy of the patient, drove rapidly progressive growth of cells associated with neoplasms, or affect recurrence neoplasma. Search in this area have primarily focused on the identification of funds that would be therapeutically effective for humans and other mammals.

It was recently revealed the presence of MOR-2 in neoplastic disease. See Masanobu Oshima et al. (Cell, 87, 803-809 (1996); and Michelle Parret et al. (International Journal of Oncology, 10, 503-507 (1997).

As inhibitors of cyclooxygenase-2 have been described [pyrazole-1-yl]benzosulfimide, it proved to be a promising tool for the treatment of inflammation, arthritis and pain with minimal side effects in preclinical and clinical trials. In U.S. patent No. 5466823 described their use for the prevention of colon cancer. However, their use for the treatment of colon cancer or for the treatment or prevention of other neoplasms has not yet been described.

The present invention is aimed at the use of inhibitors of cyclooxygenase the natives neoplastic means results in a synergistic effect or reduces toxic side effects, associated with chemotherapy, reducing the concentration of the calling side effects remedies necessary to ensure therapeutic efficacy.

Detailed description of the invention

In accordance with this invention proposes a method of treatment or prevention of neoplasms, producing prostaglandin, the subject in need of such treatment or prevention, including treatment of the subject a therapeutically effective amount of an inhibitor of cyclooxygenase-2 or its derivative.

The term "treatment" includes partial or total inhibition of the development, spread, or metastasis of neoplasms and partial or complete destruction of the cell neoplasms.

The term "prevention" includes either preventing the onset of clinically obvious neoplasia, or preventing the onset of preclinical obvious stage neoplasia in individuals at risk. This term also covers the prevention of the formation of tumor cells, or stop, or reverse the process of transformation into tumor cells cells in a state of malignant degeneration. This includes prophylactic treatment of persons exposed to the risk of development is its goal of reducing the severity of the disease, and frequency of diseases in the treatment of each tool as such, and with capability to avoid harmful side effects that accompany alternative modes of therapy.

The term "subject" from the point of view of treatment includes any human or animal with any of the known neoplasia, preferably human. As for methods of prevention, the subject is a human or an animal, preferably human, exposed to the risk of neoplasia, derived epithelial cells.

The subject may be at risk of the disease because of exposure to carcinogens, genetic predisposition to neoplasia, and the like.

The term "neoplasia" includes neoplasia, which produces prostaglandins or expresses cyclooxygenase, including benign and malignant tumors, growths and polyps.

In the above method neoplasm that produces prostaglandins, include brain cancer, bone cancer, epithelial cell neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, cancer of the gastrointestinal tract, such as cancer of the steam muscle scloho bladder, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell (epidermoid) and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers, acting on epithelial cells throughout the body. Preferably the neoplasia selected from cancer of the gastrointestinal tract, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamous cell and basal cell cancers. Inhibitors SOH-2 can also be used to treat fibrosis resulting from radiation therapy. The method can be used to treat subjects having adenomatous polyps, including congenital familial adenomatous polyposis (FAP). Furthermore, the method can be used to prevent the formation of polyps in patients at risk of disease familial adenomatous polyposis.

Inhibitors cyclooxygenase metabolic pathways of arachidonic acid used for the prevention and treatment of epithelial-cell neoplasms, can inhibit EN zymes may block the activity of the enzyme directly, acting as a substrate for the enzyme. The use of selective inhibitors of cyclooxygenase-2 is very advantageous in that it minimizes the side effects on the stomach, which can occur when using indiscriminate NSPs, especially with long-term prophylactic treatment.

The term "inhibitor of cyclooxygenase-2" means a compound capable to inhibit cyclooxygenase-2 without significant inhibition of cyclooxygenase-1. Preferably it covers compounds that have the IC50cyclooxygenase-2 is less than approximately 0.2 μm, and also have a selectivity of inhibition of cyclooxygenase-2 relative inhibition of Cox-1 of at least 50, and more preferably at least 100. Even more preferred compounds have the IC50cyclooxygenase-1 is higher than about 1 μm, and more preferably higher than 10 μm. Pyrazoles can be prepared by the methods described in WO 95/15316, WO 95/15315 and WO 96/03385. The thiophene analogues can be obtained by methods described in WO 95/00501 and WO 94/15932. The oksazolov can be obtained by methods described in PCT documents WO 95/00501 and WO 94/27980. Isoxazoles can be prepared by the methods described in WO 96/25405. The imidazoles can be received by the event, described in U.S. patent No. 5344991 and in WO 95/00501. Certanily can be obtained by methods described in WO 96/16934. Thiazole can be obtained by methods described in WO 96/03392.

Pyridine can be obtained by methods described in WO 96/24584 and WO 96/24585.

The proposed method relates to the use of inhibitors of cyclooxygenase-2 or a derivative thereof for the prevention and treatment of neoplasms arising. In preferred embodiments, the inhibitor of cyclooxygenase-2 is selected from compounds of the formula I:

where a represents a Deputy selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;

R1represents at least one Deputy, selected from heterocyclyl, cycloalkyl, cycloalkenyl or aryl, and R1is optionally substituted at substitutable position by one or more radicals selected from alkyl, halogenoalkane, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, halogenoalkane, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfonyl, halogen, alkoxy, alkylthio;

R2is methyl or amino; and

A preferred class of compounds which inhibit cyclooxygenase-2 consists of compounds of formula I, where a is selected from 5 - or 6-membered partially unsaturated heterocyclyl, 5 - or 6-membered Nanase and phenyl; R1selected from 5 - or 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, and R1is optionally substituted at substitutable position by one or more radicals selected from lower alkyl, lower halogenoalkane, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower halogenoalkane, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfonyl, halogen, lower alkoxy and lower alkylthio; R2represents methyl or amino, and R3represents a radical selected from hydrido, oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, lower zainoulline, halogen, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower halogenoalkane, 5 - or 6-membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, acyl, phenylcarbinol, lower alkoxyalkyl, 5 - or 6-membered, heteroaromatic, aminocarbonyl, lower alkylaminocarbonyl, lower alkylamino, lower aminoalkyl, lower acylaminoalkyl, phenyloxy and lower Alcoxy; or their pharmaceutically acceptable salts.

More predpochtite oxazolyl, isoxazolyl, furil, teinila, dihydrofurane, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazoline, benzofuran, cyclopentenyl, cyclopentadienyl, phenyl and pyridyl; R1selected from pyridyl, optionally substituted at substitutable position by one or more methyl radicals, and phenyl, optionally substituted at substitutable position by one or more radicals selected from methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, penttila, hexyl, formatie, diformate, trifloromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, hydroxymethyl, triptoreline, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfonyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentox and methylthio; R2represents methyl or amino, and R3represents a radical selected from hydrido, oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxybutyl, carboxymethyl, cyanomethyl, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, penttila, hexyl, diformate, trifloromethyl, pentaborate, GE is La, pyridyl, teinila, thiazolyl, oxazolyl, furil, pyrazinyl, hydroxymethyl, hydroxypropyl, benzyl, formyl, phenylcarbinol, methoxymethyl, fullmetaljacket, aminocarbonyl, N-methylaminomethyl, N,N-dimethylaminobenzoyl, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl, N,N-dimethylaminomethyl, N-methyl-N-ethylaminomethyl, benzyloxy, phenyloxy; or their pharmaceutically acceptable salts.

Family special interest specific compounds of formula I consists of the following compounds and their pharmaceutically acceptable salts:

5-(4-forfinal)-1-[4-(methylsulphonyl)phenyl]-3-(trifluoromethyl)pyrazole;

4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole;

4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-1-yl)benzosulfimide;

4-(3,5-bis(4-were)-1H-pyrazole-1-yl)benzosulfimide;

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

4-(3,5-bis(4-methoxyphenyl)-1H-pyrazole-1-yl)benzosulfimide;

4-(5-(4-chlorophenyl)-3-(4-were)-1H-pyrazole-1-yl)benzosulfimide;

4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazole-1-yl)benzosulfimide;

4-(5-(4-chlorpropamide;

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-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-Piramal-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;

4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazole-1-iphenyl)Spiro[2,4]hept-5-EN-5-yl]benzosulfimide;

6-(4-forfinal)-7-[4-(methylsulphonyl)phenyl]Spiro[3,4]Oct-6-ene;

5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulphonyl)phenyl]Spiro[2.4]hept-5-ene;

4-[6-(3-chloro-4-methoxyphenyl)Spiro[2.4]hept-5-EN-5-yl]benzosulfimide;

5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulphonyl)phenyl]Spiro[2.4]hept-5-ene;

5-(3-chloro-4-forfinal)-6-[4-(methylsulphonyl)phenyl]Spiro[2,4]hept-5-ene;

4-[6-(3,4-dichlorophenyl)Spiro[2,4]hept-5-EN-5-yl]benzosulfimide;

2-(3-chloro-4-forfinal)-4-(4-forfinal)-5-(4-methylsulfinylphenyl)thiazole;

2-(2-chlorophenyl)-4-(4-forfinal)-5-(4-methylsulfinylphenyl)thiazole;

5-(4-forfinal)-4-(4-methylsulfinylphenyl)-2-methylthiazole;

4-(4-forfinal)-5-(4-methylsulfinylphenyl)-2-cryptomaterial;

4-(4-forfinal)-5-(4-methylsulfinylphenyl)-2-(2-thienyl)thiazole;

4-(4-forfinal)-5-(4-methylsulfinylphenyl)-2-benzylimidazole;

4-(4-forfinal)-5-(4-methylsulfinylphenyl)-2-(1-propylamino)thiazole;

2-[(3,5-dichlorophenoxy)methyl)-4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl)thiazole;

5-(4-forfinal)-4-(4-methylsulfinylphenyl)-2-cryptomaterial;

1-methylsulphonyl-4-[1,1-dimethyl-4-(4-forfinal)cyclopent-2,4-Dien-3-yl]benzene;

4-[4-(4-forfinal]-[1,1 the EPTA-4,6-diene;

4-[6-(4-forfinal)Spiro[2.4]hepta-4,6-Dien-5-yl]benzosulfimide;

6-(4-forfinal)-2-methoxy-5-[4-(methylsulphonyl)phenyl]pyridine-3-carbonitrile;

2-bromo-6-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]pyridine-3-carbonitrile;

6-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-2-phenylpyridine-3-carbonitrile;

4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

3-[1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-[1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-methyl-4-[1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-methyl-6-[1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

2-(3,4-differenl)-1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

4-[2-(4-were)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

2-(4-forfinal)-1-[4-(methylsulphonyl)phenyl]-4-methyl-1H-imidazo is)-1-[4-(methylsulphonyl)phenyl]-1H-imidazole;

2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

1-[4-(methylsulphonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole;

2-(4-were)-1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazole;

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

2-(3-fluoro-5-were)-1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

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

2-(3-were)-1-[A-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazole;

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

1-[4-(methylsulphonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazole;

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

4-[2-phenyl-4-trifluoromethyl-1H-imidazol-yl]benzosulfimide;

4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzosulfimide;

1-allyl-4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

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

N-phenyl-[4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-5-(trifluoromethyl)-1H-perator>

4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-1-(2-phenyl-ethyl)-1H-pyrazole;

4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-1-(2-phenyl-ethyl)-5-(trifluoromethyl)pyrazole;

1-ethyl-4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

5-(4-forfinal)-4-(4-methylsulfinylphenyl)-2-trifluoromethyl-1H-imidazole;

4-[4-(methylsulphonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-lH-imidazole;

5-(4-forfinal)-2-methoxy-4-[4-(methylsulphonyl)phenyl]-6-(trifluoromethyl)pyridine;

2 ethoxy-5-(4-forfinal)-4-[4-(methylsulphonyl)phenyl]-6-(trifluoromethyl)pyridine;

5-(4-forfinal)-4-[4-(methylsulphonyl)phenyl]-2-(2-PROPYNYL-oxy)-6-(trifluoromethyl)pyridine;

2-bromo-5-(4-forfinal)-4-[4-(methylsulphonyl)phenyl]-6-(trifluoromethyl) pyridine;

4-[2-(3-chloro-4-methoxyphenyl)-4,5-(differenl)benzosulfimide;

1-(4-forfinal)-2-[4-(methylsulphonyl)phenyl]benzene;

5-differenl-4-(4-methylsulfinylphenyl)-3-phenylisoxazol;

4-[3-ethyl-5-phenylisoxazol-4-yl]benzosulfimide;

4-[5-deformity-3-phenylisoxazol-4-yl]benzosulfimide;

4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzosulfimide;

4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide;

1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-triptoreline)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-forfinal)-4,4-dimethylcyclopentene-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(4-forfinal)-4,4-dimethylcyclopentene-1-yl]benzosulfimide;

1-[2-(4-chlorophenyl)-4,4-dimethylcyclopentene-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(4-chlorophenyl)-4,4-dimethylcyclopentene-1-yl]benzosulfimide;

4-[2-(4-forfinal)cyclopenten-1-yl]benzosulfimide;

4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzosulfimide;

1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(2,3-differenl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzosulfimide;

1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(3-chloro-4-forfinal)cyclopenten-1-yl]benzosulfimide;

4-[2-(2-methylpyridin-5-yl)cyclopentan-1-yl]benzosulfimide;

ethyl 2-[4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]

2-(tert-butyl)-4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]oxazol;

4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-2-phenyloxazol;

4-(4-forfinal)-2-methyl-5-[4-(methylsulphonyl)phenyl]oxazol and

4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzosulfimide.

The collection represents a greater interest specific compounds of formula I consists of the following compounds and their pharmaceutically acceptable salts:

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

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

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

3-[1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

2-methyl-5-[1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

4-[2-(5-methylpyridin-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide;

4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzosulfimide;

[2-trifluoromethyl-5-(3,4-differenl)-4-oxazolyl]benzosulfimide;

4-[2-methyl-4-phenyl-5-oxazolyl]benzosulfimide and

where R4represents the lowest halogenated; R5is hydrido and R6represents phenyl, optionally substituted at substitutable position 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 six-membered heterocyclic radical, or amino; or pharmaceutically acceptable salts or derivatives thereof.

Family special interest specific compounds of formula II consists of the following compounds and their pharmaceutically acceptable salts and derivatives:

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-tags the-1-yl]benzosulfimide;

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

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

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

The collection represents a greater interest specific compounds of formula II consists of the following compounds and their pharmaceutically acceptable salts or derivatives:

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

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

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

It is assumed that the derivatives cover all sorts of compounds structurally related inhibitors cyclooxygenase or possessing essentially equivalent biological activity. For example, such inhibitors mastasia the invention, can be represented in the form of their free bases or pharmaceutically acceptable acid additive salts. The term "pharmaceutically acceptable salts" embraces salts commonly used for the formation of salts of alkali metals and education salts accession of free acids or free bases. The nature of salt is not important provided that it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid additive salts of compounds of formula I can be obtained from inorganic acids or organic acids. Examples of such inorganic acids are chloromethane, Hydrobromic, iodomethane, 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, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, antenova, musilova, 4-hydroxybenzoic the-hydroxyethanesulfonic, toluensulfonate, sulfanilic, cyclohexanesulfonyl, stearic, alginic, ( -hydroxybutiric, salicylic, galactosemia and galacturonic acid. Suitable pharmaceutically acceptable snowmountain salts of compounds of formula I include salts of metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts derived from chloroprocaine, choline, N,N'-dibenziletilendiaminom, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts can be obtained by conventional means from the corresponding compounds of formula I through the implementation of the interaction, for example, a suitable acid or a suitable base with a compound of formula I.

Biological assessment

The effectiveness of inhibitors of cyclooxygenase-2 as an anti-neoplasia was defined by the following models.

Model of lung carcinoma Lewis in mice

Cell lung carcinoma Lewis implanted subcutaneously in the ball of the feet of male mice C57BL/6. Then mice were treated with 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide. The drug was given in drinking water at a dose of 6 mg/kg/day. In this model ispitnog permissible dose of 2 mg/kg/day. Just tested 10 mice per connection. Tumor volume was determined twice a week using plethysmograph. The effectiveness of these compounds was measured on day 32 after injection of cancer cells, as shown in the table.1. The value of inhibition percentage was determined by calculating the difference in tumor size compared to control group.

Cancer of the prostate man

Were obtained (ATSS) two lines of cancer cells (PC-3 and LNCaP) prostate cancer person to determine the effectiveness of inhibitors of cyclooxygenase-2 in the suppression of tumor growth in a therapeutic model. In addition, the cell line LNCaP secretes antigen (PSA) serous fluid of the prostate gland when the overgrowth in the body devoid of hair mice.

PC-3

Cells PC-3 (106cells/0.2 ml 30% of Matrigel in medium RPMI 1640 were injected with on the back of the mice deprived of hair. On the 28th day was administered 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide (20 mg/kg/day in water). After 45 days was measured PGE2and DV2. Inhibitor SOH-2 inhibited tumor growth by 55%. The content of PGE2and DV2in animals treated with the inhibitor SOH-2, barometer)-1H-pyrazole-1-yl]benzosulfimide at a dose of 6 mg/kg/day in drinking water inhibited tumor growth by 55% at the 58th day. The evaluation by the method of Western blotting, the PSA level was reduced to approximately 50%.

Other

Cell line: we used the following cell lines: cell line NCI-H209, NCI-H345, and NCI-H510 classic small-cell lung cancer (SCLC); cell line NCI-H417 and NCI-H82 other form of SCLC; cell line NCI-N both carcinoma; cell line NCI-H23 adenocarcinoma; and cell line A broncho-alveolar carcinoma, cell line MCF-7 (American Type Tissue Culture, Rockville, MD; ATCC) breast cancer and cell lines of colon cancer, such as NCI-H630 (ATCC), HT 29, SW948, NSA-7 and others that may be tested in vivo or in vitro. All cells can be grown in medium RPMI-1640 with 5% fetal serum cows (FBS), penicillin and streptomycin (Gibco, Grand Island, NY) and stored in 5% CO2the atmosphere at 37°C. All cell lines are not contaminated with Mycoplasma.

Studies of cell-proliferation: use modification (Promega CellTiter 96®, Promega Madison, WI) semi-automated colorimetric analysis, MTT [Nakanishi, et al. .. Cell Biol., 56, 74-85 (1988)], by which to determine the number of cells on the basis of reduction of the content of tetrazole tumor cells in the determination by spectrophotometer (540 nm). Everything gma Chemicals, St. Louis, MO). The density of dissemination is approximately 2× 104cells/cell, the cells grow for 5 days. Each experiment is recorded as the average optical density adjusted source data +/- standard deviation. Inhibitors of cyclooxygenase-2 must be active in the inhibition of cancer cell lines in a dose of 20 mg/kg

Model of bladder tumors in mice performed with materials, reagents and methods, such as described by Grubs et al., [Anticancer Res., 13, 33-36 (1993)]. Inhibitor SOH-2 must be active at the dose of 20 mg/kg

Model of mammary gland tumors in rats performed with materials, reagents and methods, such as described in Grubbs et al., [Anticancer Res., 15, 709-16 (1995)]. Inhibitor SOH-2 must be active at the dose of 20 mg/kg

The model of cervical and vaginal carcinogenesis in mice performed with materials, reagents and methods, such as described in Arbeit et al., [Proc. Acad. Sci. USA., 93, 2930-35 (1996)]. Inhibitor SOH-2 must be active at the dose of 20 mg/kg

Cellular model of adenocarcinoma of the colon performed with materials, reagents and methods, essentially such, ka is ahiko Tsujii et al. (Proc. Natl. Acad. Sci. USA 94:3336-3340, 1997).

Thus, inhibitors SOH-2 reduces tumor growth in several animal models of cancer.

Combinational therapy inhibitor SOH-2 and other therapy tools

Cell lung carcinoma Lewis (2,5× 106cells) derived from C57BL/6 mice, were injected with subcutaneously into the hind paws of mice. Twice a week, groups of 10 mice were given by feeding through a stomach tube inhibitor MOR-2, 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide, at doses of 6 and 20 mg/kg For 5, 7 and 9 days after tumor implantation, the mice were administered cyclophosphamide (CTX) at a dose of 50 mg/kg during the study defined tumor volume. Animals were killed on day 26 and the results of this experiment were brought to the table.2. The inhibition percentage was calculated as described above.

The results of this experiment show that the combination of inhibitor SOH-2 and cytotoxic gave additional funds to their individual action effect in the inhibition of tumor growth.

The active compounds according to the present invention can be introduced by any suitable means, known to specialists in this field, preferably in the form F. the spent treatment. Active compounds and composition may, for example, be administered orally, vnutrisosudisto, intraperitoneally, intranasally, vnutribronhialno, subcutaneously, intramuscularly or topically (including aerosol).

Introduction compounds of the present invention can be designed either for prevention or for treatment. Used in accordance with the present invention methods and compositions can be used separately or in conjunction with additional therapies known to specialists in the prevention or treatment of neoplasia. In accordance with alternative methods and compositions disclosed herein, can be used in joint therapy. For example, an inhibitor of cyclooxygenase-2 may be introduced separately or together with other anticancer means, other means of inhibiting the growth or other drugs or food additives.

There are many anticancer agents, commercially available, clinical examination and in preclinical development, which could be selected for treatment of neoplasia through a combination of drug therapy and chemotherapy. Such antineoplastic agents share gormonalnye means, immunological assets, type of interferon and mixed funds.

You can also use other antitumor agents, such as metalmachine protease (MMP, MMP), replicas of SOD or v3the inhibitors.

The first group of anticancer agents that may be used in combination with a selective inhibitor of cyclooxygenase-2 consists of anticancer agents type of antimetabolite. Suitable antineoplastic agents type antimetabolites can be selected from the group consisting of 5-FU-fibrinogen, centifolias acid, aminothiadiazole, beginarea (brequinar) sodium, carmofur, Ciba-Geigy CGP-30694, cyclopentylamine, literalinteger, titanaugite, Lilly DATHF, Merrel Dow DDFC, deazaguanine, dideoxycytidine, dideoxyinosine, deocsa, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine, fludarabine, 5-fluorouracil, N-(2-furandi)-5-fluorouracil, Daiichi Seiyaku FO-152, isopropylpyrazine, Lilly LY-188011, Lilly LY-264618, metabasepath, methotrexate, Wellcome MZPES, nonspermicidal, NCI NCS-127716, NCI NCS-264880, NCI NCS-39661, NCI NCS-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, Tg, tesofensine, Erbamont TIF, trimet the group of anticancer agents, which can be used in combination with a selective inhibitor of cyclooxygenase-2 consists of alkylating anticancer agents. Suitable alkylating antineoplastic agents may be selected from the group consisting of Shionogi 254-S, analogues Aldo-phosphamide, altretamine, anxiron, hringer Mannheim BBR-2207, astroballe, budotitane, Wakunaga CA-102, carboplatin, carmustine, Chinoin-139, Chinoin-153, hlorambuzila, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-223, ciputat, Degussa D-19-384, Sumimoto DACHP (Myr) 2, diphenylpyraline, diplotene cytotoxic, Erba derivatives distamycin, Chugai DWA-2114R, ITI E, elastin, Erbamont FCE-24517, nutristrategy, fotemustine, Unimed G-6-M, Chinoin GYKI-17230, gasoline, ifosfamide, iproplatin, lomustina, mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NCS-264395, NCI NCS-342215, oxaliplatin, decision Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiramycin, Tanabe Seiyaku TA-077, tauromachine, deveoloped, taraxerone, tetrapedia and timelabel.

The third group of anticancer agents that may be used in combination with a selective inhibitor of cyclooxygenase-2 consists of anticancer agents type of antibiotics. Appropriate action is of inomycin D, actinoplanes, Erbamont ADR-456, derived aeroplysinin, Ajinomoto AN-201-II, Ajinomoto AN-3, Nipon of Soda anisomycin, anthracycline, sinomenine, boukabara, Bristol-Myers BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY-25551, Bristol-Myers BMY-26605, Bristol-Meyrs BMY-27557, Bristol-Myers BMY-28438, biomechanica, bryostatin-1, Taiho C-1027, calicheamicin, chromogenicity, dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-A1, Kyowa Hakko DC-92B, detasabila, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, Altamirano-a, epirubicin, erbstein, zorubicin, espiramicina-A1, espiramicina-A1b, Erbamont FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, pedobacter, gregarina, grancanaria, herbimycin, idarubitsina, illumines, kasugamycin, cesariano, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, SmithKline M-TAG, Newington, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxazoline, oxaprotiline, peplomycin, Palatine, pirarubicin, portraiting, peringamala A, Tobishi RA-I, rapamycin, rhizoxin, adorabella, sirenomelia, sevenmile, Sumitomo SM-5887, Snow Brand SN-706, Snow Brand SN-07, sarangiran-a, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS-9816B, steffimycin, Taiho 4181-2, talisayan, Takeda TAN-868A, serpentera anticancer agents, which can be used in combination with a selective inhibitor of cyclooxygenase-2 consists of anticancer agents mixed type selected from the group consisting of alpha-carotene, alpha deformalisation, azitretina, Biotec AD-5, Kyorin AHC-52, alstonia, amonafide, ampline, amsacrine, angiostatin, Antinomian, antineoplaston a10, antineoplaston A2, antineoplaston A3, antineoplaston A5, antineoplaston AS2-1, Henkel APD, epidemological, asparaginase, Avarol, Bukharin, brazilin, enflurane, benzodepa, Ipsen-Beaufour BIM-23015, bisantrene, Bristo-Myers BMY-40481, Vestar boron-10, brontophobia, Wellcome BW-502, Welicorne BW-773, caracemide, carmelitacitalolitao, Ajinomoto CDAF, chlorosulfonation, Chemes CHX-2053, Chemex CHX-100, War-ner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, clairedelune, ICN connection 1259, ICN connection 4711, Kontrakan, Yakult Honsha CPT-11, krishnalila, curaderm, cytochalasin, carabina, Cicolina, Merz D-609, DABIS maleate, dacarbazine, dateline, didemnin-In, simple dihematoporphyrin ether, dihydroindolone, dinamina, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, ethipramine, elliptinium, Tsurnura ERMTS, orthotamine, etoposide, etretin, phenetidine, Fujisawa FR-57704, gallinaria, genkwanin, Chugai GLA-43, Gl, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Orsuka K-76COONa, Kureha Chemical K-AM PLACES Corp KI-8110, American Cyanamid L-623, laborelena, lonidamine, Lundbeck LU-23-112, Lilly LY-186641, NCI (US) MAP, maritina, Merrel Dow MDL-27048, Medco MEDR-340, barbarona, derivatives of merocyanine, methylenedianiline. Molecular Genetics MGI-136, inactivity, mitonafide, methadone, mopidamol, motretinide, Zenyaku Kogyo MST-16, N-(retinol)amino acids, Nisshin Flour Milling N-021 N-acylated dehydroalanine, nafazatrom, Toisho NCU-190, derived nocodazole, Normosang, NSC NCI-145813, NSC NCI-361456, NSC NCI-604782, NSC NCI-95580, octreotide, Ono ONO-112, opisaniya, Akzo Org-10172, pancratistatin, patellifera, Warner Lambert PD-111707, Warner Lambert PD-115934, Warner Lambert PD-131141, Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyaminopropyl, polyprenol acid, Apomorphine, broumana, procarbazine, propamidine, Invitron proceedingsin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-R, realitiy, retinoic acid, Rhone-Pouienc RP-49532, Rhone-Poulenc RP-56976, Smith-Kiine SK&F 104864, Sumitomo SM-108, Kuraray SMANCS, SeaPharm SP-10004, spatola, derived spirocyclopropane, spirogermanium, Unimed, SS Pharmaceutical SS-554, lipoldino, Stipoldione, Suntory SUN 0237, Suntory SUN 2071, peroxydisulfate, Toyama T-506, Toyama T-680, Taxol, Teijin TEI-0303, teniposide, calibratin, Eastman Kodak TJB-29, tocotrienols, Topolino, Teijin TP-82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, collidine, withanolides and Yamanouchi YM-534.

Examples funds antiradiation protection, which can be used in combination chemotherapy of the present invention, are AD-5, adnon, the analogues of amifostine, detox, dimesna, 1-102, MM-159, N-acylated dehydroalanine, TGF-Genentech, ciprocinol, amifostine, WR-151327, FUT-187, Ketoprofen transdermal, nabumeton, peroxide dismutase (Chiron) and peroxide dismutase Enzon.

Methods of obtaining anticancer agents described above can be found in the literature. Methods for producing doxorubicin, for example, described in U.S. patent No. 3590028 and No. 4012448. Ways of getting inhibitors metallating proteases described in EP 780386. Methods of obtaining SOD simulators described in EP 524101. Methods of obtaining v3inhibitors described in WO 97/08174.

It is assumed that the phrase "co-therapy" (or "combination therapy"), used to determine the application of the inhibitor of cyclooxygenase-2 and other pharmaceuticals, covers the introduction of each means in series circuit providing the beneficial effects of the combination of drugs, but also encompasses co-administration of these funds essentially simultaneously, neotdalennyh drugs for each tool. The present invention also covers a pharmaceutical composition for the prevention and treatment of neoplasia, containing a therapeutically effective amount of the compounds of formula I together with at least one pharmaceutically acceptable carrier, adjuvant or diluent (all collectively referred to herein as "carriers") and other antineoplastic agents or other growth inhibitors, other drugs or food additives.

For oral administration the pharmaceutical composition can be manufactured in the form of a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage form containing a certain amount of the active component. Examples of such dosage forms are capsules, tablets, powders, granules or suspension with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, Arabian gum, corn starch or gelatin; disintegrating agents such as corn starch, potato starch or sodium carboxymethylcellulose;n by injection in the form of a composition, in which as a suitable carrier can be used with saline, dextrose or water.

For intravenous, intramuscular, subcutaneous or intraperitoneal administration of the compound may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient. Such preparations can be obtained by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, and the like, and having a buffered pH compatible with physiological conditions to obtain an aqueous solution, and ensure the sterility of such a solution. Drugs can be in tanks at one or more doses, such as sealed ampoules or vials.

If neoplasia localized in the gastrointestinal tract, the connection may be provided with acid resistant, but not resistant to the grounds coatings known in this field, which begin to dissolve in the small intestine with a high pH. Preferred are drugs that increase local pharmacological effects and reduce systemic absorption.

Dosage forms suitable for paren doctitle make isotonic. Preparations for injection can be made by suspension or emulsification compounds in non-aqueous solvent, such as vegetable oil, synthetic aliphatic acids glycerides, esters of higher aliphatic acids or propylene glycol.

Dosage forms for topical use include known gels, creams, ointments and the like. For aerosol introduction connections can be combined with known aerosol fillers, such as saline, and injected by using a commercially available dispensers. To increase the biological compatibility, you can use a filler in the form of fatty acids. Aerosol introduction is the preferred method of administration for the prevention of epithelial neoplasms of the lung.

For rectal injection of the active ingredient can be introduced into the dosage form in the form of suppositories using bases which are solid at room temperature and melt or dissolve at body temperature. Commonly used bases include cocoa butter, treated with glycerol gelatin, hydrogenated vegetable oil, polyethylene glycols of various maleate, based on the known schemes of treatment or prevention of neoplasia. The amount of therapeutically active compounds and regimen for the treatment of painful conditions compounds and/or compositions of the present invention depends on various factors, including the age, weight, gender and the state (from a medical point of view) of the subject, the severity of the disease, method and frequency of administration and the specific compound, the location of the neoplasia, as well as individual pharmacokinetic characteristics of the subject being treated, and can thus vary within wide limits. The dose is usually lower when the compound is administered locally rather than systemically, and for prevention, not treatment. Such doses can be entered as often as required and within the time period required in the opinion of the attending physician. Specialist in this field of medicine it is clear that regimen or a therapeutically effective amount of an inhibitor may require optimization for each specific subject. The pharmaceutical compositions may contain the active ingredient in the range of about 0.1 to 2000 mg, preferably from about 0.5 to 500 mg and most preferably from about 1 to 200 mg. a Suitable daily dose is entered in one to four times per day.

All of the above mentioned patents and documents are included in this description as a reference.

The present invention is described above in relation to specific variants of its implementation, but the details of these options should not be considered as a constraint.

1. The use of the compounds of formula II

where R4represents the lowest halogenated; R5is hydrido and R6represents phenyl, optionally substituted at substitutable position 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 six-membered heterocyclic radical, or amino; or its pharmaceutically acceptable salt or pharmaceutically acceptable derivative as the active compounds of medicinal product for the treatment of neoplasia in the subject.

2. Application under item 1, in which the compound is chosen from the group of compounds and their pharmacyonline;

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

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

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

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

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

3. Application under item 2, in which the compound is 4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide or its pharmaceutically acceptable salt.

4. Application under item 2, in which the compound is 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide or pharmaceutiquement)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide or its pharmaceutically acceptable salt.

6. The use according to claim,1 wherein the neoplasia selected from colorectal cancer, cancer of the gastrointestinal tract, liver cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, breast cancer and skin cancer.

7. The use of the compounds of formula II

where R4represents the lowest halogenated; R5is hydrido and R6represents phenyl, optionally substituted at substitutable position 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 six-membered heterocyclic radical, or amino; or its pharmaceutically acceptable salt or pharmaceutically acceptable derivative as the active compounds of medicinal product for the prevention of neoplasia selected from adenomatous polyps, cancer of the gastrointestinal tract, liver cancer, bladder cancer, cancer Osia in such prevention.

8. Application under item 7, in which the compound is chosen from the group of compounds and their pharmaceutically acceptable salts, consisting of

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

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

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

9. Application under item 8 in which the compound is 4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-inania is a 4-[5-(4-chlorophenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide or its pharmaceutically acceptable salt.

11. Application under item 8 in which the compound is 4-[5-(3-fluoro-4-methoxyphenyl)-3-(deformity)-1H-pyrazole-1-yl]benzosulfimide or its pharmaceutically acceptable salt.

12. Drug for the treatment of a subject suffering from a neoplastic disease, characterized in that it is a combination of selective regarding cyclooxygenase-2 compounds and compounds selected from the agents of type antibiotics, alkylating agents, antimetabolites, hormonal means, immunological equipment, type of interferon, mixed funds, inhibitors metallating proteases (MMP), SOD and v3inhibitors.

13. Drug under item 12, in which a selective inhibitor SOH-2 is a compound of formula I

where a represents a Deputy selected from partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic rings;

R1represents at least one Deputy, selected from heterocyclyl, cycloalkyl, cycloalkenyl or aryl, and R1is optionally substituted at substitutable position one is oxyl, hydroxyalkyl, halogenoalkane, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfonyl, halogen, alkoxy, alkylthio;

R2is methyl or amino;

R3represents a radical selected from hydrido, halogen, alkyl, alkenyl, quinil, oxo, cyano, carboxyl, cyanoalanine, heterocyclics, alkyloxy, alkylthio, alkylsulphonyl, cycloalkyl, aryl, halogenoalkane, heterocyclyl, cycloalkenyl, aralkyl, geterotsiklicheskikh, acyl, alkylthiomethyl, hydroxyalkyl, alkoxycarbonyl, arylcarbamoyl, aralkylamines, aralkyl, alkoxyalkyl, alltoall, aryloxyalkyl, kalkiliya, alcoxialchil, alkoxylalkyl, alkoxycarbonylmethyl, aminocarbonyl, aminocarbonylmethyl, alkylaminocarbonyl, N-arylenecarborane, N-alkyl-N-arylenecarborane, alkylaminocarbonyl, carboxyethyl, alkylamino, N-arylamino, N-aralkylamines, N-alkyl-N-aralkylamines, N-alkyl-N-aralkylamines, aminoalkyl, acylaminoalkyl, N-alluminare, N-aralkylamines, N-alkyl-N-aralkylamines, N-alkyl-N-alluminare, aryloxy, Alcoxy, aaltio, Uralkali, alkylsulfonyl, alkylsulfonyl, aminosulfonyl, alkylaminocarbonyl, N-arylamino the>14. Drug under item 13, in which a is selected from 5 - or 6-membered partially unsaturated heterocyclyl, 5 - or 6-membered unsaturated heterocyclyl, 9 - or 10-membered unsaturated condensed heterocyclyl, lower cycloalkenyl and phenyl; R1selected from 5 - or 6-membered heterocyclyl, lower cycloalkyl, lower cycloalkenyl and aryl selected from phenyl, biphenyl and naphthyl, and R1is optionally substituted at substitutable position by one or more radicals selected from lower alkyl, lower halogenoalkane, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower halogenoalkane, amino, lower alkylamino, phenylamino, lower alkoxyalkyl, lower alkylsulfonyl, halogen, lower alkoxy and lower alkylthio; R2represents methyl or amino, and R3represents a radical selected from hydrido, oxo, cyano, carboxyl, lower alkoxycarbonyl, lower carboxyethyl, lower zainoulline, halogen, lower alkyl, lower alkyloxy, lower cycloalkyl, phenyl, lower halogenoalkane, 5 - or 6-membered heterocyclyl, lower hydroxyalkyl, lower aralkyl, acyl, phenylcarbinol lowest alkoxyl the th aminoalkyl, lower acylaminoalkyl, phenyloxy and lower Alcoxy; or their pharmaceutically acceptable salts.

15. Drug under item 14, in which a is selected from oxazolyl, isoxazolyl, furil, teinila, dihydrofurane, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, isothiazoline, benzofuran, cyclopentenyl, cyclopentadienyl, phenyl and pyridyl; R1selected from pyridyl, optionally substituted at substitutable position by one or more methyl radicals, and phenyl, optionally substituted at substitutable position by one or more radicals selected from methyl, ethyl, isopropyl, butyl, tert-butyl, isobutyl, penttila, hexyl, formatie, diformate, trifloromethyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, hydroxyl, hydroxymethyl, triptoreline, amino, N-methylamino, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, phenylamino, methoxymethyl, methylsulfonyl, fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, n-butoxy, pentox and methylthio; R2represents methyl or amino, and R3represents a radical selected from hydrido, oxo, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, carboxypropyl, carboxymethy antila, exile, diformate, trifloromethyl, pentaborate, heptafluoropropyl, deperately, deferrable, methoxy, ethoxy, propoxy, n-butoxy, pentox, cyclohexyl, phenyl, pyridyl, teinila, thiazolyl, oxazolyl, furil, pyrazinyl, hydroxymethyl, hydroxypropyl, benzyl, formyl, phenylcarbinol, methoxymethyl, fullmetaljacket, aminocarbonyl, N-methylaminomethyl, N,N-dimethylaminobenzoyl, N,N-dimethylamino, N-ethylamino, N,N-dipropylamino, N-butylamino, N-methyl-N-ethylamino, aminomethyl, N,N-dimethylaminomethyl, N-methyl-M-ethylaminomethyl, benzyloxy, phenyloxy; or their pharmaceutically acceptable salts.

16. Drug under item 15 in which the compound is chosen from the group of compounds and their pharmaceutically acceptable salts, consisting of

5-(4-forfinal)-1-[4-(methylsulphonyl)phenyl]-3-(trifluoromethyl)pyrazole;

4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole;

4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazole-1-yl)-benzosulfimide;

4-(3,5-bis(4-were)-1H-pyrazole-1-yl)benzosulfimide;

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

4-(3,5-bis(4-methoxyphenyl)-1H-pyrazole-1-yl)benzosulfimide;

4-razol-1-yl)benzosulfimide;

4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazole-1-yl) benzosulfimide;

4-(4-chloro-3,5-diphenyl-1H-pyrazole-1-yl)benzosulfimide;

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

5-(4-forfinal)-6-[4-(methylsulphonyl)phenyl]Spiro[2,4]-hept-5-ene;

4-[6-(4-forfinal)Spiro[2,4]hept-5-EN-5-yl]benzosulfimide;

6-(4-forfinal)-7-[4-(methylsulphonyl)phenyl]Spiro[3,4] Oct-6-ene;

5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulphonyl)phenyl]-Spiro[2,4]hept-5-ene;

4-[6-(3-chloro-4-methoxyphenyl)Spiro[2,4]hept-5-EN-5-yl]-benzosulfimide;

5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulphonyl)phenyl]Spiro[2,4]hept-5-ene;

5-(3-chloro-4-forfinal)-6-[4-(methylsulphonyl)phenyl]Spiro-[2,4]hept-5-ene;

4-[6-(3,4-dichlorophenyl)Spiro[2,4]hept-5-EN-5-yl]benzosulfimide;

2-(3-chloro-4-forfinal)-4-(4-forfinal)-5-(4-methylsulfinylphenyl)thiazole;

2-(2-chlorophenyl)-4-(4-forfinal)-5-(4-methylsulfinylphenyl)thiazole;

5-(4-forfinal)-4-(4-methylsulfinylphenyl)-2-methylthiazole;

4-(4-forfinal)-5-(4-methylsulfinylphenyl)-2-cryptomaterial;

4-(4-forfinal)-5-(4-methylsulfinylphenyl)-2-(2-thienyl)-thiazole;

4-(4-forfinal)-5-(4-methylsulfinylphenyl)-2-benzylimidazole;

4-(4-forfinal)-5-(4-methylsulfinylphenyl)-2-(1-propylamino)thiazole;

2-[(3,5-dichlorophenoxy)methyl)-4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl)thiazole;

5-(4-forfinal)-4-(4-m,4-Dien-3-yl]benzene;

4-[4-(4-forfinal]-1,1-dimethylcyclopentane-2,4-Dien-3-yl]-benzosulfimide;

5-[4-forfinal)-6-[4-(methylsulphonyl)phenyl]Spiro[2,4] hepta-4,6-diene;

4-[6-(4-forfinal)Spiro[2,4]hepta-4,6-Dien-5-yl]benzosulfimide;

6-(4-forfinal)-2-methoxy-5-[4-(methylsulphonyl)phenyl]pyridine-3-carbonitrile;

2-bromo-6-(4-forfinal)-5-[4(methylsulphonyl)phenyl]pyridine-3-carbonitrile;

6-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-2-phenylpyridine-3-carbonitrile;

4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

3-[1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-[1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-methyl-4-[1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

2-methyl-6-[1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine;

4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

2-(3,4-differenl)-1-[4-(methylsulphonyl)phenyl]-4-(ptx2">2-(4-forfinal)-1-[4-(methylsulphonyl)phenyl]-4-methyl-1H-imidazole;

2-(4-forfinal)-1-[4-(methylsulphonyl)phenyl]-4-phenyl-1H-imidazole;

2-(4-forfinal)-4-(4-forfinal)-1-[4-(methylsulphonyl)-phenyl]-1H-imidazole;

2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

1-[4-(methylsulphonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole;

2-(4-were)-1-[4-(methylsulphonyl)phenyl]-4-Cryptor-methyl-1H-imidazole;

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

2-(3-fluoro-5-were)-1-[4-(methylsulphonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole;

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

2-(3-were)-1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1-H-imidazole;

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

1-[4-(methylsulphonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazole;

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

4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzosulfimide;

4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzosulfimide;

1-allyl-4-(4-CFT is-1H-pyrazole-3-yl]benzosulfimide;

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

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

4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-1-(2-phenylethyl)-1H-pyrazole;

4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole;

1-ethyl-4-(4-forfinal)-3-[4-(methylsulphonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole;

5-(4-forfinal)-4-(4-methylsulfinylphenyl)-2-trifluoromethyl-1H-imidazole;

4-[4-(methylsulphonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole;

5-(4-forfinal)-2-methoxy-4-[4-(methylsulphonyl)phenyl]-6-(trifluoromethyl)pyridine;

2 ethoxy-5-(4-forfinal)-4-[4-(methylsulphonyl)phenyl]-6-(trifluoromethyl)pyridine;

5-(4-forfinal)-4-[4-(methylsulphonyl)phenyl]-2-(2-propenyloxy)-6-(trifluoromethyl)pyridine;

2-bromo-5-(4-forfinal)-4-[4-(methylsulphonyl)phenyl]-6-(trifluoromethyl)pyridine;

4-[2-(3-chloro-4-methoxyphenyl)-4,5-(differenl)benzosulfimide;

1-(4-forfinal)-2-[4-(methylsulphonyl)phenyl]benzene;

5-differenl-4-(4-methylsulfinylphenyl)-3-phenylisoxazole;

4-[3-ethyl-5-phenylisoxazol-4-yl]benzosulfimide;

4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide;

1-[2-(4-forfinal)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-fluoro-2-were)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-triptoreline)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(4-forfinal)-4,4-dimethylcyclopentene-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(4-forfinal)-4,4-dimethylcyclopentene-1-yl]benzosulfimide;

1-[2-(4-chlorophenyl)-4,4-dimethylcyclopentene-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(4-chlorophenyl)-4,4-dimethylcyclopentene-1-yl]benzosulfimide;

4-[2-(4-forfinal)cyclopenten-1-yl]benzosulfimide;

4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzosulfimide;

1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

1-[2-(2,3-differenl)cyclopenten-1-yl]-4-(methylsulphonyl)benzene;

4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzosulfimide;

1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1 and the-[2-(2-methylpyridin-5-yl)cyclopentan-1-yl]benzosulfimide;

ethyl-2-[4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]oxazol-2-yl]-2-benzoylacetate;

2-[4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]oxazol-2-yl]acetic acid;

2-(tert-butyl)-4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]oxazole;

4-(4-forfinal)-5-[4-(methylsulphonyl)phenyl]-2-phenyloxazole;

4-(4-forfinal)-2-methyl-5-[4-(methylsulphonyl)phenyl]oxazole

4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzosulfimide.

17. Drug under item 16, in which the compound is chosen from the group of compounds and their pharmaceutically acceptable salts, consisting of

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

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

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

3-[1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

2-methyl-5-[1-[4-(methylsulphonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine;

4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzosulfimide;

4-[5-methyl-3-phenylisoxazol-4-yl]benzosulfimide;

4-[5-hydroxymethyl-3-phenylisoxazol the ptx2">4-[2-methyl-4-phenyl-5-oxazolyl]benzosulfimide

4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzosulfimide.

18. Drug under item 16, in which the compound is 4-[5-(4-were)-3-(trifluoromethyl)-1H-pyrazole-1-yl]benzosulfimide or its pharmaceutically acceptable salt.

19. Application under item 1, in which neoplasia represents adenomatous polyps.

20. Application under item 7. in which neoplasia represents adenomatous polyps.



 

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