1-n-phenylamino-1h-imidazol derivatives and pharmaceutical compositions containing them

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula (I): and to its salts with acid, where: R1 and R2 represent hydrogen; Q represents (CH2)m-X-(CH2)n-A; A represents direct bond, O, SO2, NR5; X represents direct bond, O, SO2, C(O) or NR5; Z represents group selected from : m and n represent, each independently, 0, 1, 2, 3 or 4; p represents 1, 2, 3 or 4; q represents 0, 1 or 2; dotted line means that R8 and/or R9 can be situated in any position of benzothiophene ring; R3 and R8 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11 or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10; when Q-Z represents n 0, 1 or 2 and p represents 1, one of R3 and R8 represents hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, and the other represents hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11 OSO2NR10R11, NR12SO2NR10R11, CO2R10; R4 and R9 represent, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alcoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CHO; when p represents 2, 3 or 4, R9 can be similar or different; R6 and R7 represent hydrogen; each R5, R10, R11 and R12 represents hydrogen; when Z represents and p represents 1, then R8 and R9 can also together with phenyl ring form benzoxathiazine dioxide. Invention also relates to pharmaceutical composition and to application of derivatives by any of ii.1-25.

EFFECT: obtaining novel biologically active compounds which possess inhibiting activity with respect to aromatase and/or steroid-sulfatase and/or carboanhydrase.

36 cl, 67 ex, 5 tbl

 

The present invention relates to derivatives of 1-N-phenylamino-1H-imidazole and containing pharmaceutical compositions.

The invention generally relates to the field of hormone-dependent and gormonozawisimogo cancer and endocrine disorders.

Aromatase is a physiological enzyme responsible for the specific conversion of androgens, such as Androstenedione or testosterone, estrogens such as follikulin and estradiol, respectively (Simpson ER et al., Endocrine Reviews, 1994, 15: 342-355). Inhibition of aromatase is, therefore, the chosen strategy impact on normal or pathological estrogeninduced or estrogenzawisimy biological processes, such as female sexual differentiation, ovulation, implantation, pregnancy, cell proliferation in the breast and endometrium, as well as regulation of spermatogenesis or proliferation of the cells of the prostate in men or preproductive functions, such as osteogenesis or the balance of T cells and cytokines (see Simpson ER et al., Recent Progress in Hormone Research, 1997, 52: 185-213 and all Endocrine Related Cancer (1999, volume 6, n 2) and Breast Cancer Research Treatment (1998, volume 49, supplement No. 1)).

The enzyme asteroidsurfaces (E.C. 3.1.6.2., STS) catalyzes the hydrolysis of sulfate follikulina to follikulina and sulfate DHEA to DHEA (Dibbelt L, Biol. Chem Hoppe-Seyler, 1991, 372, 173-185, and Stein C, J. Biol. Chem., 1989, 264, 13865-13872).

The way asteroidsurfaces was in the focus of recent is their research in the field of breast cancer, relative to the local interstitial formation of estrogens from abundant circulating pool of sulfate follikulina (E1S) (Pasqualini JR, J. Steroid Biochem. Mol. Biol., 1999, 69, 287-292 and Purohit A, Mol. Cell. Endocrinol., 2001, 171, 129-135).

Inhibition of this enzyme would prevent the formation of E1S free follikulina (E1), which can be converted into estradiol (E2) enzymatic recovery. In addition to the way sulfatase follikulina, now it is believed that another potent estrogen, androstenediol (adiol), resulting from DHEA in the hydrolysis of DHEA-s with can be another important component that supports the growth and development of hormone-dependent tumors of the breast.

The formation of estrogen in women is schematically presented in figure 1.

For the treatment of patients with hormone-dependent cancer currently using aromatase inhibitors to prevent the synthesis of estrogen. However, clinical trials have shown a relative lack of efficacy for patients with tumors positive estrogen receptor (Castiglione-Gertsch M, Eur. J. Cancer, 1996, 32A, 393-395 and Jonat W, Eur. J. Cancer, 1996, 32A, 404-412). As explanation, the path asteroidsurfaces can be another important way for the formation of estrogen in breast cancer tumors.

EMATE (Ahmed S, Curr. Med. Chem., 2002, 9, 2, 263-273), follikulin-3-su is Hamat, is the traditional standard steroid inhibitor sulfatase, but has a major drawback, namely that it has estrogenic nature because of its mechanism of inhibition: sulphamate part is cleaved during the process of inactivation of enzymes, resulting in the E1not formed from E1S, and directly from the EMATE (Ahmed S, J. Steroid Biochem. Mol. Biol., 2002, 80, 429-440).

Other non-steroidal sulphamate compounds that lead to derived without estrogenic properties, were presented as acceptable potential drugs, such as 6,6,7-COUMATE, a standard nestrogannye inhibitor sulfatase known from the literature (Purohit A, Cancer Res, 2000, 60, 3394-3396).

The human carbonic anhydrase to catalyze the conversion of carbon dioxide (CO2in bicarbonate ion (HCO3-) and are involved in physiological and pathological processes. These processes include hormone-dependent and gormononezawisimy carcinogenesis, metastatic invasive process and hypoxic tumors expressing these enzymes, which are less sensitive to classical chemo/radiotherapy inhibitors. In particular, it was found that the EMATE has the activity of carbonic anhydrase inhibitor man, such activity ACET zalameda, known sulfonamidnuyu inhibitor of human carbonic anhydrase (Winum J and al., J. Med. Chem. 2003, 46, 2197-2204).

It is therefore particularly interesting to find compounds with at least one, preferably at least two of the following activities: inhibition of aromatase inhibition by asteroidsurfaces and inhibition of carbonic anhydrase.

Recently B. Potter et al. (J. Med. Chem., 46, 2003, 3193-3196) reported that sulamericana derivatives aromatase inhibitor YM 511 inhibited sulfatase and aromatase activity in cells JEG-3.

Connection represented as suitable for treatment estrogenzawisimy diseases described in US 2003/0008862A. Imidazole derivatives with antiaromatase properties described in WO 2004/054983.

At the present time found that imidazole derivatives, which contain 1-N-phenylaminopropyl, show unexpectedly high potential in relation to inhibition of aromatase and/or asteroidsurfaces and/or carbonic anhydrase.

Accordingly, one of the objectives of the present invention to provide derivatives of 1-N-phenylamino-1H-imidazole, which would be a very powerful aromatase inhibitors and/or asteroidsurfaces and/or carbonic anhydrase.

Another objective of the present invention to provide a pharmaceutical composition containing as an active ingred the enta derived 1-N-arylamino-1H-imidazole, as depicted below.

The next task of the present invention is the use of derivatives of 1-N-phenylamino-1H-imidazole for the manufacture of a medicinal product for the treatment or prevention of various diseases and for the regulation of reproductive functions in women, males, and females and males of wild or domestic animals.

Derivatives of 1-N-phenylamino-1H-imidazole according to the invention is represented by the following General formula (I):

and their salts with acid and stereoisomeric forms, where:

R1andtheR2denote, each independently, hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl; or R1and R2together form a saturated or unsaturated 5-, 6 - or 7-membered carbocyclic ring;

Q represents(CH2)m-X-(CH2)n-A;

A denotes a direct bond, O, S, SO, SO2, NR5;

X denotes a direct bond, CF2, O, S, SO, SO2C(O)NR5or CR6R7;

Z denotes a group chosen from:

m and n denote, each independently, 0, 1, 2, 3 or 4;

p denotes 1, 2, 3 or 4;

q denotes 0, 1 or 2;

the dotted line means that R8and/or R9can be in any position benzothiophene ring;

R3and R8denote, each independently researched the mo, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, OPO(OR10)2,

NR10R11, SO2NR10R11, OSO2NR10R11, OSO2OR10, SO2OR10SSO2NR10R11, CF2SO2OR10, CF2SO2NR10R11, CF2-tetrazolyl or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, OCHO, OCONR10R11, OCSNR10R11, SCONR10R11, SCSNR10R11, tetrazolyl, NR12CONR10R11, NR10-CHO;

when Q-Z means

n denotes 0, 1 or 2 and p represents 1, one of R3and R8denotes hydroxy, nitro, OPO(OR10)2, NR10R11, OSO2NR10R11, OSO2OR10, SO2OR10SSO2NR10R11, CF2SO2OR10, CF2SO2NR10R11, CF2-tetrazolyl, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, OCHO, OCONR10R11, OCSNR10R11,

SCONR10R11, CSNR 10R11, tetrazolyl, NR12CONR10R11, NR10-CHO and the other denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, SO2NR10R11, OSO2OR10, SO2OR10SSO2NR10R11, CF2SO2OR10, CF2SO2NR10R11, CF2-tetrazolyl, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, OCHO, OCONR10R11, OCSNR10R11, SCONR10R11, SCSNR10R11, tetrazolyl, NR12CONR10R11, NR10-CHO;

R4and R9denote, each independently, hydrogen or hydroxy, cyano, halogen, nitro, OPO(OR10)2, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, SO2NR10R11,SO2NR10R11, OSO2OR10, SO2OR10SSO2NR10R11, CF2SO2OR10, CF2SO2NR10R1 , CF2-tetrazolyl, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, SNO, CONR10R11, OCHO, OCONR10R11, OCSNR10R11, SCONR10R11, SCSNR10R11, tetrazolyl, NR12CONR10R11, NR10-CHO;

when p represents 2, 3 or 4, R9may be the same or different;

R6and R7denote independently hydrogen, halogen, (C1-C6)alkyl or (C3-C8)cycloalkyl;

R5, R10, R11and R12denote, each independently, hydrogen, hydroxy, (C1-C6)alkyl or (C3-C8)cycloalkyl; R10can also be salt; R10and R11can also form, together with the nitrogen atom to which they are attached, a 5-7 membered heterocycle containing one or two heteroatoms selected from O, S and N;

when Z represents

and p denotes 1,

then R8and R9can also form together with the phenyl ring dioxide benzoxadiazole dioxide dihydroisocodeine dioxide of benzoxazinone dioxide benzoxadiazole, tetroxide benzoxadiazole, tetroxide benzodithiophene or tetroxide benzodioxathiepin;

when Z represents

R3and R4together with the phenyl what olicom, to which they are attached, can also form benzofuran or N-methylbenzotriazole, provided that when p represents 1 and Q denotes (CH2)nthen R8and R9denote independently hydroxy, nitro, OPO(OR10)2, NR10R11, SO2NR10R11, OSO2OR10, SO2OR10SSO2NR10R11, CF2SO2OR10, CF2SO2NR10R11, CF2-tetrazolyl, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10, CONR10R11, OCHO, OCONR10R11, OCSNR10R11, SCONR10R11, SCSNR10R11, tetrazolyl, NR12CONR10R11or NR10-CHO.

The present invention also relates to salts of the compounds according to the invention or their stereoisomeric forms, if they exist.

In the description and the claims, the term “(C1-C6)alkyl” means a straight or branched hydrocarbon chain having 1-6 carbon atoms. (C1-C6)alkyl represents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl. Preferred alkyl radicals are those which have 1, 2 or 3 carbon atoms.

The term "halogen" denotes chlorine, bromine, iodine or fluorine.

The term “(C 3-C8)cycloalkyl” means a saturated monocyclic hydrocarbon having 3 to 8 carbon atoms. (C3-C8)cycloalkyl represents, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

The term “(C1-C6)alkoxy” means the group OR in which R is a (C1-C6)alkyl, as defined above. (C1-C6)alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, n-pentyloxy or isopentane. Preferred alkoxy radicals are those which have 1, 2 or 3 carbon atoms.

The term "acyl" means a group,

in which R' denotes hydrogen or (C1-C4)alkyl, where the term "alkyl" is defined above. Acyl is, for example, formyl, acetyl, propionyl, butyryl or valeryl. Preferred acyl radicals include formyl and acetyl.

In the definition of R10"salt" means a salt of an alkali metal or alkali earth metal salt, such as sodium, potassium, magnesium or calcium, or ammonium salts or organic amine, such as triethylamine, ethanolamine or Tris-(2-hydroxyethyl)amine. In the context of this invention refers to groups that have a balance OR10.

5-7-Membered heterocycle may be saturated with the th or unsaturated, and includes, for example, tetrazole, triazole, pyrazole, pyrazolidine, imidazole, imidazolidine, piperidine, piperazine, morpholine, pyrrolidine.

The compounds of formula (I) form salts with acids, for example, with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with organic carboxylic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid and the like, Especially preferred salts are salts which are pharmaceutically acceptable.

Among the compounds of formula (I), compounds that satisfy at least one of the following conditions are preferred:

R3and R8denote, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11,

SO2NR10R11, OSO2NR10R11, OSO2NR12SO2NR10R11, OCHO, NR12SOsub> 2NR10R11;

R4and R9denote, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, OSO2NR10R11, CO2R10CHO, NR12SO2NR10R11;

R1and R2denote, each independently, hydrogen or (C1-C6)alkyl;

R10, R11and R12denote, each independently, hydrogen or (C1-C6)alkyl.

Especially preferred compounds of formula (I)in which:

one of R3and R8denotes hydroxy, nitro, NR10R11, OSO2NR10R11or

NR12SO2NR10R11; and

another denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, OSO2NR10R11NR12SO2NR10R11.

Especially preferred group of these compounds are represented by the compounds in which:

one of R3and R8denotes hydroxy, cyano, (C -C6)alkoxy or OSO2NR10R11; and

another denotes hydrogen or hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy,

NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR10SO2NR11R12.

Preferably, the compounds of formula (I) are compounds in which:

one of R3and R8denotes cyano; and

another denotes hydrogen or hydroxy, halogen, nitro, (C1-C6)alkoxy, trifluoromethyl, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11.

Other preferred compounds are compounds in which:

one of R4and R9denotes hydrogen or hydroxy, cyano, OSO2NR10R11; and

another denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl,

(C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10CHO, NR12SO2NR10R11.

Another group of preferred compounds represented by the compounds in which:

R4denotes hydrogen, hydroxy, cyano, or OSO2NR10R11;

R9denotes hydrogen or hydroxy, cyan is, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10CHO.

Especially preferred compounds of formula (I) are compounds where:

R4denotes hydrogen; and

R9denotes hydroxyl, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10CHO or NR12SO2NR10R11.

Especially preferred compounds of formula (I) are compounds in which Z represents:

in which R8and R9have the above specified values.

In the above defined compounds R8and R9preferably have the following meanings:

R8denotes hydrogen, hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11or OSO2NR10SO2NR11R12;

R9denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10CHO, NR12SO2NR10R11.

p and q have the above specified values.

Among the compounds of formula (I), compounds in which Q is selected from a direct link, C(O), SO2, CONH, C(O)(CH2)n, (CH2)n(O) or (CH2)nwhere n denotes 0, 1 or 2, are also particularly preferred.

Especially preferred are the compounds of formula (II)

in which:

Q represents (CH2)nwhere n denotes 0, 1 or 2;

one of R3and R8denotes hydroxy, nitro, NR10R11, OSO2NR10R11or NR12SO2NR10R11and the other denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, OSO2NR10R11or NR12SO2NR10R11;

R4and R9denote, each independently, hydrogen, hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, OSO2NR10R11or NR12SO2NR10R11.

R10and R11about the mean, each independently hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl;

p denotes 1, 2, 3 or 4;

R8and R9together with the phenyl ring to which they are attached, can also form dioxide benzoxadiazole or dioxide dihydroisocodeine;

R3and R4together with the phenyl ring to which they are attached, can also form benzofuran or N-methylbenzotriazole.

Among these compounds of formula (II), compounds that correspond to at least one of the following conditions are preferred:

Q represents (CH2)nwhere n denotes 0, 1 or 2;

R8denotes hydroxy, halogen, nitro, cyano or (C1-C6)alkoxy,

NR10R11, SO2NR10R11, OSO2NR10R11or NR12SO2NR10R11;

R9denotes hydrogen, hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11;

p denotes 1, 2, 3, or 4.

The most preferred compounds of the formula (II) are compounds in which:

n denotes 0 or 1;

R1and R2denote, each independently, hydrogen or (C1-C6)alkyl;

R4and R9denote, each independently, hydrogen, ha is oven, (C1-C6)alkoxy, acyl, NR10R11, OSO2NR10R11or NR12SO2NR10R11.

Particularly preferred compounds of the formula (II) are compounds in which:

n denotes 0 or 1;

R1, R2and R4denote each hydrogen;

R9denotes hydrogen, halogen, (C1-C6)alkoxy or OSO2NR10R11.

Particularly preferred compounds of the formula (II) are compounds in which:

n and p represent 1;

R8denotes hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy, NR10R11,

SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11or OSO2NR10SO2NR11R12;

R9denotes hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10or CHO;

R3denotes cyano, hydroxy, OSO2NR10R11or NR12SO2NR10R11;

R4denotes hydrogen, hydroxy, halogen, cyano or OSO2NR10R11.

Among these compounds, compounds that correspond to at least one of the following conditions are preferred:

one of R3The R 8denotes a hydroxy, cyano or OSO2NR10R11preferably cyano or OSO2NR10R11; and

the other represents hydroxy, nitro, NR10R11, OSO2NR10R11or NR12SO2NR10R11preferably hydroxy or OSO2NR10R11.

Among these compounds of formula (II), compounds in which R10and R11denote hydrogen, are preferred.

Especially preferred are also the compounds of formula (III):

in which:

Q represents (CH2)m-X-(CH2)n-A-;

A denotes a direct bond or O, S, SO, SO2, NR5;

X denotes a direct bond, CF2, O, S, SO, SO2C(O)NR5or CR6R7;

m and n denote, each independently, 0, 1, 2, 3 or 4;

R3, R4, R8and R9denote, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, benzyloxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, NR10R11, OPO(OR10)2, OCHO, COOR10, SO2NR10R11, OSO2NR10R11, SO2OR10, OSO2OR10SSO2NR10R11, CONR10R11, OCONR10 R11, OCSNR10R11, SCONR10R11, SCSNR10R11, NR12SO2NR10R11, tetrazolyl, NR10CONR11OH, NR10SO2NR11OH, NOH-CHO, NOHSO2NR10R11or OSO2NR10OH;

q denotes 0, 1 or 2.

R5, R6, R7, R10, R11and R12denote, each independently, hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl; R10can also be salt; R10and R11can also form with the nitrogen atom to which they are attached, a 5-7 membered heterocycle containing one or two heteroatoms selected from O, S and N;

The dotted line means that Q and/or R8and/or R9can be in any position benzothiophene rings.

Among the compounds of the formula (III), compounds that correspond to at least one of the following conditions are preferred:

R3denotes hydrogen, halogen or cyano;

R8means OSO2NR10R11or NR12SO2NR10R11;

R9denotes hydrogen, halogen, nitro, COOR10or cyano;

R4denotes hydrogen, halogen, cyano, (C1-C6)alkoxy, NR10R11, OSO2NR10R11or NR12SO2NR10R11;

R10, R11and R12the seat is t, each independently hydrogen or (C1-C6)alkyl.

The compounds of formula (III)in which Q represents (CH2)m-X-(CH2)n-A, where m denotes 0, 1 or 2 and X represents a direct link, SO2or, n = 0 and A denotes a direct bond, are also preferred.

Especially preferred compounds of formula (IV):

in which R1, R2, R3, R4, R8, R9and p have the meanings as defined for compounds of formula (I).

Particularly preferred compounds of the formula (IV) are compounds in which:

R3denotes cyano or OSO2NR10R11;

R4denotes hydrogen, hydroxyl, halogen, cyano, OSO2NR10R11;

R8denotes hydroxy, cyano, OSO2NR10R11, NR10R11, NR12SO2NR10R11, OCHO, tetrazolyl;

R9denotes hydrogen, halogen, nitro, cyano or CO2R10; and

Q has such meanings as defined above for compounds of formula (I).

Due to its ability to inhibit the enzymes aromatase and/or asteroidsurfaces and/or carbonic anhydrase, the compounds according to the invention can be used individually or in combination with other active ingredients for the treatment or prevention of any hormone is about or gormonozawisimogo cancer in humans, as well as in wild or domestic animals. Thanks to the activity of aromatase inhibition and/or asteroidsurfaces, the compounds according to the invention are suitable for the management of regulated estrogen reproductive functions in humans, as well as in wild or domestic animals.

For the treatment or prevention of these conditions, the compounds according to the invention can be used individually or in combination with an antiestrogen, SERM (selective modulator of estrogen receptor), an aromatase inhibitor, an inhibitor of carbonic anhydrase, antiandrogens, inhibitor asteroidsurfaces, an inhibitor of LiAZ, a progestin or agonist or antagonist of LH-RH. Compounds according to the invention can also be used in combination with radiotherapy agent; a chemotherapeutic agent, such as nitride analogue of mustard gas, such as cyclophosphamide, melphalan, ifosfamide or trofosfamide; ethylenimines, such as thiotepa; nitrosamines, such as carmustine; specific agent, such as temozolomide or dacarbazine; an antimetabolite of folic acid, such as methotrexate or raltitrexed; purine analog such as tioguanin, cladribine or fludarabine; pyrimidine analog, such as fluorouracil, tegafur or gemcitabine; Vinca alkaloid or analog, such as vinblastine, vincristine or vinorelbine; producing the tion podofillotoksina, such as etoposide, taxanes, docetaxel or paclitaxel; anthracyclines or equivalent, such as doxorubicin, epirubicin, idarubitsin or mitoxantrone; cytotoxic antibiotics such as bleomycin or mitomycin; a platinum compound, such as cisplatin, carboplatin or oxaliplatin; a monoclonal antibody, such as rituximab; anti-tumor agent, such as pentostatin, miltefosine, estramustin, topotecan, irinotecan or bikalutamid; or an inhibitor of prostaglandin (COX 2/COX-1 inhibitor).

Compounds according to the invention can also be used to monitor or control adjustable estrogen reproductive functions, such as male or female fertility, pregnancy, abortion or delivery, people, and various species of wild or domestic animals, individually or in combination with one or more other therapeutic means, such as an agonist or antagonist of LH-RH, astroprojection contraceptives, progestin, antiprogestin or inhibitor of prostaglandin.

Because breast tissue is a sensitive target stimulated by estrogen proliferation and/or differentiation, aromatase inhibitors, and/or asteroidsurfaces and/or carbonic anhydrase can be used to treat or prevented the I of benign breast diseases in women gynecomastia in males and benign or malignant breast tumors with or without metastases in men and women or in male or female animals. Compounds according to the invention can also be used for treatment or prevention of benign or malignant disease of the uterus or ovary. In each case, the compounds according to the invention can be used individually or in combination with one or more other sexual endocrine therapies such as antiandrogen, antiestrogen, progestin or agonist or antagonist of LH-RH.

Because the enzyme asteroidsurfaces transforms sulfate DHEA to DHEA, the precursor to active androgens (testosterone and dihydrotestosterone), the compounds according to the invention can be used to treat or prevent androgenozavisimaya diseases such as androgenic alopecia (male pattern hair loss) (Hoffman R et al., J. Invest. Dermatol., 2001, 117, 1342-1348), hirsutism, acne (Billich A, et al., WO 9952890), benign or malignant disease of the prostate or testis (Reed MJ, Rev. Endocr. Relat. Cancer, 1993, 45, 51-62), individually or in combination with one or more other sexual endocrine therapies such as antiandrogen, antiestrogen, SERM, antiaromatase, a progestin, an inhibitor of LiAZ or agonist or antagonist of LH-RH.

<> Inhibitors asteroidsurfaces can also be used to treat cognitive dysfunction, because they are able to enhance cognitive processes and spatial memory in rats (Johnson DA, Brain Res, 2000, 865, 286-290). Sulfate DHEA as neurosteroid affects many systems of neurotransmitters, including those that utilize acetylcholine, glutamate and GABA, leading to increased neural excitability (Wolf OT, Brain Res. Rev, 1999, 30, 264-288). Compounds according to the invention, therefore, also useful for enhancing cognitive function, especially for the treatment of senile dementia, including Alzheimer's disease, increasing the levels of DHEA in the Central nervous system.

In addition, estrogens are involved in the regulation of the balance between the predominant immune functions Th1and Th2and may therefore be useful for treating or preventing independent of sex of autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis, etc. (Daynes RA, J. Exp. Med, 1990, 171, 979-996). In addition, it was shown that inhibition of asteroidsurfaces provides protection in models of contact Allergy and induced collagen arthritis in rodents (Suitters AJ, Immunology, 1997, 91, 314-321).

Studies using 2-MeOEMATE showed that the inhibitors asteroidsurfaces have a powerful, independent of estradiol growth-inhibitory effect (MacCarthy-Moorogh , Cancer Research, 2000, 60, 5441-5450). Reduction of tumor volume was unexpectedly observed with the compounds according to the invention, with a low inhibition asteroidsurfaces tumors. Because of this, the compounds according to the invention can lead to a reduction in cell division due to the strong interaction between such new chemical structural units and microcrustacea network in cancer cells, regardless of tissue, including breast, endometrium, uterus, prostate, testis or metastasis generated from them. Compounds according to the invention may therefore be useful for treatment of estrogenozawisimah cancer.

Compounds according to the invention are of particular value for the treatment or prevention of estrogenzawisimy diseases or disorders, that is induced by estrogen or stimulated by estrogen diseases or disorders (Golob T, Bioorg. Med. Chem., 2002, 10, 3941-3953).

In addition, the compounds according to the invention are inhibitors of carbonic anhydrase (CA). This property may explain the interest in such compounds for the treatment of gormonozawisimogo cancer. Immunohistochemical studies of CA II showed that it is expressed in malignant brain tumors (Parkkila A-K, et al., Histochem. J., 1995, 27: 974-982), as well as in carcinomas of the stomach and pancreas (Parkkila S et al., Histochem. J., 1995, 27: 133-138), and recent studies have shown that CA IX and XII is also expressed in kotoryj tumors and may be functionally linked to oncogenesis. Ivanov et al. (Proc. Natl. Acad. Sci. USA, 1998, 95: 12596-12601) recently hypothesized that associated with tumor CA IX and XII may be involved in the oxidation of extracellular nutrient environment of the cancer cells, which creates a microenvironment conducive to the growth and distribution of the tumor. It is shown that acetazolamide significantly inhibited the invasive ability in four renal lines of cancer cells (Parkkila S et al., Proc. Natl. Acad. Sci. USA, 2000, 97: 2220-2224), the effect is related to CA II, IX, and XII, which are expressed in these cells. Leukemia cells can spread very easily from the bone marrow to other organs through the circulatory system, but various leukemias differ in their ability to form extramedullary tumors, i.e. metastases. If the activity of CA were essential for the invasion of other cancer cells, then one would similarly predict that the active CA can also function in leukemic cells.

In the framework of this application, the term "combination" or "combination" refers to any Protocol for joint introduction of the compounds according to the invention and one or more other pharmaceutical substances, irrespective of the nature of time of administration and dosage adjustment over time of any of the substances. Co-administration may, for example, can be performed simultaneously, sequentially, or in the period BP is like.

For the treatment/prevention of any of these diseases or disorders, compounds according to the invention can be administered, for example, orally, topically, parenterally in dosage formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and fillers. These dosage forms are provided as examples, but the expert can select other pharmaceutical forms for administration of the compounds according to the invention. The term parenteral as part of this application includes subcutaneous injections, intravenous, intramuscular, epigastric injection or infusion. In addition to the treatment of humans, the compounds according to the invention is effective in the treatment of warm-blooded animals, such as mice, rats, horses, sheep, dogs, cats, etc.

Pharmaceutical compositions containing the active ingredient(s)may be in a form suitable for oral use, for example, in the form of tablets, lozenges, candies, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be obtained according to any known specialist method for producing pharmaceutical compositions, and such compositions may contain one or more means selected from the group sotoyama is from sweetening agents, flavouring substances, dyes and preservatives, in order to obtain pharmaceutically elegant and affordable drugs. Tablets contain the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable inert excipients, which are suitable to obtain tablets. These inert excipients may constitute, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja agents such as corn starch or alginic acid; binding agents, for example starch, gelatin or gum Arabic, and lubricants, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may have a coating known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a delayed action for a long period of time. For example, there may be used material for deferred action, such as glycerol monostearate or distearate glycerin.

They may also have a coating applied by the method described in the patent US 4256108; 4166452 and 4265874 to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be p is estaline as hard gelatin capsules, in which the active ingredient(s) is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin oil or olive oil.

Aqueous suspensions contain the active ingredient(s) in a mixture with excipients suitable for receiving water suspensions. Such excipients are suspendresume agents, such as carboxymethylcellulose sodium, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth and Arabian gum; dispersing or wetting agents may be natural fosfatados, for example lecithin, or condensation products of accelerated with fatty acids such as stearate and polyethylene oxide, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as polyoxyethylenesorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit, for example polietilensorbit monooleate. Aqueous suspensions may also soda is to press one or more preservatives, for example, ethyl or n-propyl, n-hydroxybenzoate, one or more dyes, one or more flavoring agents and one or more sweetening agents such as sucrose, saccharin or aspartame.

Oil suspensions can be prepared by suspension of the active ingredient(s) in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or acetyloxy alcohol. Sweetening agents such as those mentioned above, and flavoring agents may be added to obtain an acceptable oral drug. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for obtaining aqueous suspension by the addition of water, contain the active ingredient(s) in a mixture with dispersing or wetting agent, suspenders agent and one or more preservatives. Suitable dispersing or wetting agents and suspendresume agents illustrated above. Additional excipients, for example sweetening, flavoring and dyes, may also be present. The pharmaceutical compositions according invented the Yu may also be in the form of emulsions of the type oil-in-water". The oil phase can be represented vegetable oil, for example olive oil or peanut oil, or mineral oil, for example, vaseline oil, or mixtures thereof. Suitable emulsifiers can be a natural phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and anhydrides of exit, for example, sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, for example, polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening and flavouring substances.

The pharmaceutical compositions can be in the form of a sterile aqueous or oily suspension for injection. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspendida agents which have been mentioned above. A sterile preparation for injection may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used, can be called water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are traditionally used as dissolve Italy or suspendida nutrient medium. This purpose can be any soft fixed oils, including synthetic mono - or diglycerides. In addition, when receiving injectable drugs are used fatty acids such as oleic acid.

The dosage levels of the order of approximately from 0.0001 mg to about 20 mg/kg of body weight per day is suitable for treatment of the above conditions, or alternatively, from about 0.1 mg to about 2000 mg per patient per day.

The amount of active ingredient that may be combined with materials native to obtain a single dosage form varies depending on the individual patient and the particular route of administration. In General, the dosage forms contain from about 0.1 mg to about 400 mg of the compounds according to the invention is usually 0.1 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 100 mg, 200 mg or 400 mg

It is clear, however, that the specific dose level for any particular patient will depend upon a variety of factors, including age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion, combination of drugs and the severity of the particular disease, which is directed therapy.

According to another object the invention relates to a method of treatment or before which brasenia these diseases, disorders or conditions. The method comprises the administration to a patient (human or animal) a therapeutically effective amount of the compounds according to the invention or its pharmaceutically acceptable salt with an acid.

Derivatives of 1-N-arylamino-1H-imidazole of the formula (I) and their salts with an acid can be obtained according to the General schemes Ia, Ib, IIa, IIb, IV and V in which ()mmeans (CH2)mand ()nmeans (CH2)n.

Scheme Ia

According to scheme Ia, N,N-disubstituted aniline (3) can be obtained by condensation of aniline derivative (1) with the halogenated, alkilinity derivatives, sulfanilimide derived or sulfanilimide derivatives (2) using standard conditions (March J.,Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New York). Most halogenated, alcolink derivatives, sulfanilic derivatives or sulfinyl derivatives (2) are commercially available or synthesized by conventional chemical methods (see experimental part).

The compound (3) is converted into its nitroso-derivative, using standard conditions, then restore, receiving 1,1-disubstituted hydrazine of the formula (4).

Alternatively, a 1,1-disubstituted hydrazine (4) can be obtained by selective N-alkylation of hydrazine of formula (5) with the compound is of the formula (2), using the conditions described U. Lerch and J. König (Synthesis, 1983, 2, 157-8), or conditions described by J. Chung et al. (Tetrahedron Letters, 1992, 33, 4717-20).

Then by condensation of (4) with dealkylase-alkyl-isothiocyanate derived or Ethylenedioxy-alkyl-isocyanate derivative gain thiosemicarbazide (6), which is converted into 1-aminoimidazole-2-tion (7) by treatment with acid, such as acetic acid or sulfuric acid.

Desulfuromonas (7) in acetic acid under the conditions described S.Grivas and E.Ronne inActa Chemica Scandinavia, 1995, 49, 225-229, gives the final 1-N-phenylamino-1H-imidazole (8), which, if necessary, converted into one of its salts with an acid.

Alternatively, the above compound (8), where R3or R4denote electron-withdrawing group can be obtained by condensation of N-imidazolinone (9) with one, alkilinity derivatives, sulfanilimide derived or sulfanilimide derivatives (2) using standard conditions (March J.,Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New York).

If R8is an ester, saponification of the compound (8) gives the carboxylic acid derivative in the usual way.

If R8is a sulphonamide, it can be directly obtained using the appropriate substituted Alcolea derived or halogenerator the tion (2).

If R8denotes cyano, reaction with sodium azide gives tetrazolyl group (Kiyoto K.,Synthesis, 1998, 910-14).

Compound (9) are obtained in a manner similar to the way opened above to obtain compound (8), based on the compound (4).

Scheme Ib

According to the scheme Ib, removal of the protection methoxy or benzyloxy derivatives (8) using tribromsalan (McOmie. J.F.W,Tetrahedron, 1968, 24, 2289-92) or piperidine (Nishioka H.Synthesis, 200, 2, 243-46), or by hydrogenation (Felix A.,J Org Chem, 1978, 43, 4194-97) gives hydroxyl compound (10). Recovery nitrocompounds (8) douglasites tin or ruthenium and hydrazine (WO 02051821) gives aminosidine (12) (V. Matassa,J Med Chem,1990, 33, 2621-29).

These compounds are converted into the corresponding sulfamate (11) or aminosulphonylphenyl (13) by treatment with sodium hydride and sulfhemoglobin (Nussbaumer. P,J Med Chem, 2002, 45, 4310-20) or interaction with sulfhemoglobin in dimethylacetamide (DMAc) (Makoto O,Tetrahedronletters, 2000, 41, 7047-51).

These hydroxyl compounds can be converted into formatnya derivatives by treatment with formylacetate (E. Schreiner,Bioorg Med Chem Lett,2004, 14, 4999-5002) or 1H-imidazole-1-carboxylate derivatives by treatment with N,N'-carbonyl diimidazol (Fischer, W.,Synthesis, 2002, 1, 29-30).

Compound (10) or (12)having amino and hydroxyl, position ortho, can be converted into the corresponding benzoxadiazole in the terms proposed by K. K. Andersen (J Org Chem, 1991, 56, 23, 6508-6516).

When X is CO or CS, recovery ketone, thioketone, amide, thioamide performed under standard conditions (March J.,Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New York). This stage of recovery can be effective at any stage of the synthesis process.

Scheme IIa

According to the scheme IIa, compound (15) can be obtained by the same procedure as the compound (3) in scheme Ia, based on the compounds (1) and (14), or by condensation of N-imidazolinone (9) with one, alkilinity derivatives, sulfanilimide derived or sulfanilimide derivative (14) using standard conditions (March J.,Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New York). Most halogenated, alcolink derivatives, sulfanilic derivatives or sulfinyl derivatives (14) are commercially available or synthesized by conventional methods (see experimental part).

If R8is an ester, saponification of the compound (15) gives the carboxylic acid derivative in the usual way.

If R8is a sulphonamide, it can be directly obtained using the appropriate substituted Alcolea production is wow or halogenated (14).

If R8denotes cyano, interaction with sodium azide gives tetrazolyl group (Kiyoto K.,Synthesis, 1998, 910-14).

Removing protection methoxy - or benzyloxybenzoate (15) using tribromsalan (McOmie. J.F.W,Tetrahedron, 1968, 24, 2289-92) or by hydrogenation (Felix A.,J Org Chem, 1978, 43, 4194-97) gives hydroxybenzamide (16). Recovery nitrobenzothiazole connection (15) douglasites tin gives aminobenzamide (18) (V. Matassa,J Med Chem, 1990, 33, 2621-29).

These compounds (16) and (18) is converted into the corresponding sulfamate (17) or aminosulphonylphenyl (19) using the same conditions as in the synthesis of compounds (11) or (13).

Oxidation of sulfur in benzothiophene hydrogen peroxide in triperoxonane acid under the conditions described Grivas S. and E. Ronne (Acta Chemica Scandinavia, 1995, 49, 225-229), or meta-chloroperbenzoic acid in methylene chloride gives the oxidized benzothiophene. (Ong, H. H., J Med Chem, 1987, 30, 12, 2295-2303).

Recovery amide, thioamide, ketone, thioketone, when X is CO or CS, or repair of oxidized sulfur group carried out under the conditions described C. Ellefson (J Med Chem, 1981, 24, 1107-10), Hajos J. (Complex Hydrides, Elsevier, New York, 1979) or Drabowicz S. (Org Prep Proced Int, 1977, 9, 63-83) and J. Bordwell (J Am Chem Soc, 1951, 73, 2251-53), or in standard conditions (March J.,Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New York). These stages of oxidation and reduction can b shall be effective at any stage of the synthesis process.

Scheme IIb

According to the scheme IIb, compound (21) synthesized by the same methods of synthesis of compounds (3), based on the compounds (1) and (20) or (9) and (20).

3-Halogenbenzonitriles derivative (21) is treated with an aqueous metal hydroxide (Svoboda J.,Collect Czech Chem comm, 2000, 65, 7, 1082-92 or Sall D.,J Med Chem,2000, 43, 4, 649-63), getting 3-hydroxybenzophenone derivative (22), or treated with an aqueous ammonia in acetone or ethanol (Bordwell F.,J. A. C. S., 1948, 70, 1955-58), getting 3-aminobenzophenone derivative (24).

2-Hydroxybenzophenone derivative (22) or 2-aminobenzothiazole derivative (24) are respectively the unprotect 2-methoxybenzothiazole derivative (21) using pyridine hydrochloride (Cannizzo S.,J Heterocyclic Chem, 1990, 27, 2175-79) and by restoring 2-nitrobenzothiazole connection (21) douglasites tin (Matassa V,J Med Chem,1990, 33, 2621-29).

These compounds (22) and (24) can be sulfanilamide obtaining (23) and (25), using the same conditions as for the synthesis of compounds (11) or (13).

The deprotonation of 2-H-benzothiophene derivative (21) using the lithium amides or Akilov leads to litoraneo in the C-2 position. Adding sulfurylchloride gives chlorosulfonyl, which is treated with an aqueous ammonia in acetone (Graham S.,J Med Chem, 1989, 32, 2548-54), getting 2 Sul is parametrisations derivative (21), or adding dry ice, followed by hydrolysis gives benzothiophene derived 2-carboxylic acid (21) (D. Matecka,J Med Chem,1997, 40, 705-16).

Benzothiophene derived 3-carboxylic acid or carboxamide (21) is obtained by treatment of 3-H-benzothiophene derived by trichloroacetamido/aluminum chloride, followed by hydrolysis with water (R. Bonjouklian,Synth Comm, 1985, 15, 8, 711-13) or aqueous ammonia (K. Turnbull,J Heterocycl Chem, 2000, 37, 2, 383-88).

3-Sulfonamidnuyu derivative (21) are obtained under the conditions described N. Chapman (J. Chem. Soc., 1970, 18, 2431-35) or Hageman W. (Ger. Offen., 3435173, 11 April 1985).

Oxidation of sulfur in benzothiophene and recovery carboxamide, thioamide, ketone, thioketone, oxidized sulfur group can be carried out at any stage of the synthesis conditions, already presented in the present description.

Scheme III

According to scheme III, compound (27) obtained by condensation of N-imidazolinone (9) with the isocyanate derivative (26)using standard conditions (March J.,Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New York). Most of the isocyanate derivative (26) are commercially available or synthesized by conventional methods.

Connection (28) and (30) are synthesized by the same methods of synthesis of compounds (10) and (12) in scheme Ib.

Compounds (29) and (31) are synthesized by the same synthesis methods, and the unity (11) and (13) in scheme Ib.

Scheme IV

According to scheme IV, bi-aryl compounds (33) can be synthesized by the same methods of synthesis of compound (8) with derivative (32). Derivatives (32) are commercially available or synthesized by conventional methods (as ex Buraway S, J Chem Soc, 1955, 2557; Tilley J W, J Med Chem, 1989, 32, 8, 1814).

Scheme V

According to scheme V, compound (35) synthesized by the same methods of synthesis of compound (8) with heterocycles (34) (one or two nitrogen atom in any of the provisions). Heterocycles (34) are commercially available or synthesized by conventional methods (see the following examples). Halogenated pyridine (34) can be obtained in accordance with publications (Biorg Med Chem Lett, 1996, 6, 21, 2613; A G Myers, J Org Chem 1996, 61, 813; Tetrahedron, 1993, 49, 19, 4085) or carboxylic acid (WO 0177078). Halogenated pyrimidine (34) can be obtained from alkylpyridine (Budesinsky, Collect, Czech, Chem Commun, 1968, 33, 7, 2266; Kunieda T, J Am Chem Soc, 1971, 93,3487) normal halogenoalkanes (Isoda S, Chem pharm Bull, 1980, 28, 5, 1408; March J.,Advanced Organic Chemistry, Fourth edition, Wiley Interscience, New York) or from carbaldehyde (Bredereck, Chem Ber, 1967, 100, 11, 3664; Adams J L, Bioorg Med Chem Lett, 1998, 8, 22, 3111), and carboxylic acid (Huffman K R, J Org Chem, 27, 1962, 551; Daves J Org Chem, 1961, 26, 2755) can be converted to the acid chlorides of the acids (34). Halogenated pyrazine (34) can be obtained from alkali is of azines (Lutz W B, J Org Chem, 1964, 29, 415) bromirovanii or carbaldehyde (US 3558625), and carboxylic acids (Sato N, J Heterocycl Chem, 19, 1982, 407-408; Felder P, Helv Chim Acta, 1964, 47, 873) can be converted to the acid chlorides of the acids (34). Halogenated pyridazine (34) can be obtained according Piras S (Farmaco, 1993, 48, 9, 1249) Yanai, (Heterocycles, 1976, 4, 1331) or halogenoalkanes alkylpyridine (Becker, J Prakt Chem, 1970, 312, 591; DE 1950491), and carboxylic acid (Boger D, L, J Am Chem Soc 1987, 109, 9, 2717) can be converted to the acid chlorides of the acids (34).

For all schemes IIa, IIb, IV, V carboxylate derivative, a sulfa derivative and tetrazole derivative synthesized by the methods already described for scheme Ia and R8and (R9)p and is made in the same conditions already presented in the present description.

The group described for R3, R4, R8and R9can be obtained in the usual ways (see review sulfatase (Nussbaumer P,Medecinal Research, 2004, 24, 4, 529-76), carbonic anhydrase (Supuran C T,Carbonic anhydrase, 2004, C R C press) and articles from Park J D (J Heterocycl Chem, 2000, 37, 2, 383-88), Schreiner E P (Bioorg Med Chem Lett, 2004, 14, 4999-5002) and Taylor S D (BioorgMed Chem Lett, 2004, 14, 151-155).

The following examples are intended to illustrate but not to limit the scope of the invention.

OBTAINING N,N-DISUBSTITUTED of HYDRAZINES (4)

Example 1

N1-(4-Cyanovinylene)-N1-(4-methoxyphenyl)hydrazine

Chloro evententry (25 g, 164,90 mmol) was introduced with stirring in a flask containing toluene (200 ml) and triethylamine (46,40 ml, 329,80 mmol). Hydrochloride 4-methoxyphenylhydrazine (28,80 g, 164,90 mmol) was added in portions and the reaction mixture was stirred 3 hours at the boil under reflux. After cooling, the mixture was filtered, washed with toluene (50 ml) and water (200 ml)to give a solid white color (27,20 g, 65%); MP: 115°C.

1H-NMR (DMSO-d6): the 3.65 (s, 3H), 4,30 (s, 2H), 4,57 (s, 2H), 6,77 (d, 2H), 6,94 (d, 2H), of 7.48 (d, 2H), 7,76 (d, 2H).

GETTING IMIDAZOLES (9)

Example 2

4-[N-(1H-Imidazol-1-yl)amino]benzonitrile

a) 4-[N-(2,3-dihydro-1H-imidazol-1-yl-2-tion)amino]benzonitrile

To a suspension of the hydrochloride of 4-cyanopyridine (6,00 g, 35,40 mmol) in ethanol (60 ml) was added dropwise 2,2-dimethoxymethylsilane (6.25 g, 42,4 mmol) and the reaction mixture was heated under reflux for 2 hours. After cooling, the solvent is evaporated in vacuo, the resulting oil was diluted with a mixture of acetic acid/water (9/1, 32 ml) and the suspension was heated under reflux for 1.5 hours and at room temperature over night. The obtained residue was poured into water (300 ml) and collected a brown precipitate. After homogenization in ethanol from the solid brown color obtained solid white (4,60 g, 58%).

1H-NMR (DMSO-d6): is 6.54 (d, 2), of 7.00 (t, 1H), 7.23 percent (t, 1H), 7.62mm (d, 2H), 9,83 (s, 1H), 12,40 (s, 1H).

b) 4-[N-(1H-imidazol-1-yl)amino]benzonitrile

35%hydrogen peroxide (4,90 ml of 55.5 mmol) was added dropwise to ice suspension of 4-[N-(2,3-dihydro-1H-imidazol-1-yl-2-tion)amino]benzonitrile (4,00 g, 18,50 mmol) in acetic acid (20 ml). When TLC showed completion of the reaction, the reaction mixture was diluted with water, was established pH 11 with sodium hydroxide, treated with hydrosulfite sodium and were extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuum. Flash chromatography on silica gel (toluene/dioxane: 6/4) received net oil and crystallization from ethanol was obtained white crystals (4,40 g, 58%), MP: 162°C.

1H-NMR (DMSO-d6): 6,50 (d, 2H), was 7.08 (s, 1H), 7,30 (s, 1H), 7,66 (d, 2H), 7,83 (s, 1H).

OBTAINING DERIVATIVES of BENZOTHIOPHENE (14) AND (20)

Example 3

1-Chloro-3-(3-methoxyphenyl)sulfanitran-2-he

To a stirred solution of 1,3-dichloro-2-propanone (12,70 g, 0.1 mol) in methanol/water (100 ml, 1:3) at 0°C was added a suspension of 3-methoxybenzamide (14,02 g, 0.1 mol) and sodium hydroxide (4,00 g, 0.10 g) in water (100 ml). The mixture was stirred at 0°C for 7 hours and at room temperature for 10 hours. The precipitated product was extracted with dichloromethane (100 ml), washed with water (80 ml) and dried with sodium sulfate. After removal of solvent which was alocale the desired product (oil, 18,70 g).

1H-NMR (CDCl3): of 3.80 (s, 3H), 3,83 (s, 2H), 4,29 (s, 2H), 6,78 (DD, 1H), 6,98 (d, 1H), 6.90 to (DD, 1H), 7,21 (t, 1H).

Example 4

3-Chloromethyl-6-methoxybenzamide

The solution above tizaidine (17,50 g, 75,85 mmol) in CH2Cl2(1700 ml) was added dropwise to a solution of BF3·Et2O (or 10.60 ml, 83,44 mmol) in CH2Cl2(100 ml) at room temperature under nitrogen atmosphere. The mixture was stirred over night and after hydrolysis in an aqueous solution of NaHCO3the reaction mixture was stirred until both phases were not transparent. Layer CH2Cl2was separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum, obtaining oil (18,00 g). Flash chromatography on silica gel (toluene/petroleum spirit 40-60°C: 5/5) gave a mixture of 1:10 3-chloromethyl-4-methoxybenzamide:3-chloromethyl-6-methoxybenzamide in the form of oil (12,35 g, 58%).

The main isomer1H-NMR (CDCl3): the 3.89 (s, 3H), 4,82 (s, 2H), was 7.08 (DD, 1H), 7,30 (s, 1H), 7,35 (d, 1H), 7,78 (d, 1H).

Example 5

3-Bromo-6-benzyloxybenzoate

N-Bromosuccinimide (15,70 g, 83,92 mmol) and p-toluensulfonate acid (2.70 g, 15,68 mmol) was added to a solution of 6-benzyloxybenzoate (Zhengying C., computer network 1370533 A and 21.2 g, 88,33 mmol) in 1,2-dichloroethane (120 ml). The mixture was stirred at 80°C for 35 minutes, cooled naidanow bath and succinimide was removed by filtration. The solution was extracted with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuum, obtaining oil. Crystallization from pentane received solid white (21,60 g, 92%; MP: 68°C).

1H-NMR (DMSO-d6): 5,14 (s, 2H), was 7.08 (DD, 1H), 7,25-of 7.55 (m, 6H), the 7.65 (d, 1H), 7,76 (d, 1H).

Example 6

3-Bromo-6-benzyloxybenzoate-1,1-dioxide

To a solution of 3-bromo-6-benzyloxybenzoate (2.00 g, 6,27 mmol) in dichloromethane (50 ml) and triperoxonane acid (1.5 ml) was added 35%aqueous hydrogen peroxide (2.00 ml, 19,54 mmol). After 8 hours at 50°C the mixture is hydrolyzed with saturated aqueous NaHCO3, was extracted with dichloromethane, dried over Na2SO4, filtered and concentrated in vacuum to give crude product. Flash chromatography on silica gel (toluene/ethyl acetate: 9/1) received a clear oil (1.10 g, 55%).

1H-NMR (DMSO-d6): 5,20 (s, 2H), 7,20-of 7.60 (m, 7H), 7,72 (d, 1H), 7,83 (s, 1H).

Example 7

(6-Benzyloxybenzoate-2-yl)methanol

To a solution of 6-benzyloxybenzoate-2-carbaldehyde (described Nomura Y., WO 9635688 A1, 6.50 g, 24,20 mmol) in THF (50 ml) was added dropwise cooled to -30°C suspension of LiAlH4(0.85 grams, 22,26 mmol). After heating to room temperature, the mixture was stirred overnight, cooled to -10°C, hydrolyzed with ice water, was extracted with dichloromethane, su is or over Na 2SO4, filtered and concentrated in vacuum to give crude product. Flash chromatography on silica gel (toluene/ethyl acetate: 7/3) received a clear oil (4,50 g, 69%).

1H-NMR (DMSO-d6): and 4.68 (s, 2H), 5,13 (s, 2H), ceiling of 5.60 (s, 1H), 7,00 (DD, 1H), 7,14 (s, 1H), 7,25-7,80 (m, 7H).

Example 8

6-Benzyloxy-2-(chloromethyl)benzothiophen

Sulphonylchloride (20 ml) was added to a solution of (6-benzyloxybenzoate-2-yl)methanol (4,20 g, 15,50 mmol) in dichloromethane (40 ml). The mixture was stirred at the boil under reflux for 2 hours, cooled to room temperature, then was concentrated in vacuum, obtaining 4,20 g in the form of oil.

1H-NMR (CDCl3): of 4.75 (s, 2H), 5,04 (s, 2H), 6,95 (DD, 1H), 7,10 (s, 1H), 7,20-of 7.60 (m, 7H).

GETTING IMIDAZOLES of the FORMULA (8, 33, 35)

Using the same method as described in example 2, but replacing the hydrochloride of 4-cyanobenzylidene on:

- N1-(4-cyanovinylene)-N1-(4-methoxyphenyl)hydrazine,

received the following connection:

Example 9

4-[N-(1H-Imidazol-1-yl)-N-(4-methoxyphenyl)amino]methylbenzonitrile

1H-NMR (DMSO-d6): 3,70 (s, 3H), of 4.90 (s, 2H), 6,60-7,00 (m, 5H), 7,40 (s, 1H), 7,55 (d, 2H), of 7.70 (s, 1H), 7,78 (d, 2H).

Crystallization from ether ethanol with hydrochloric acid was obtained white crystals (5,70 g, 66%).

TPL: 207°C

1H-NMR (DMSO-d6): 3,70 (s, 3H), equal to 4.97 (s, 2H), 6,93 (d, 2H), 7,13 (d, 2H), 7,45 (d, 2H), of 7.70 (s, 1H), 7,84 (who, 2H), 8,04 (s, 1H), 8,18 (s, 1H), of 9.55 (s, 1H).

Example 10

4-[N-(4-Hydroxyphenyl)-N-(1H-imidazol-1-yl)amino]methylbenzonitrile

The solution tribromide boron (60 ml, 60,00 mmol) in 20 ml of dichloromethane was added to a cold (0-5°C) solution of 4-[N-(1H-imidazol-1-yl)-N-(4-methoxyphenyl)amino]methylbenzonitrile (4,60 g, 15,11 mmol). After 1 hour at room temperature, the mixture is hydrolyzed with saturated aqueous NaHCO3that was filtered, washed with water (50 ml) and dichloromethane (20 ml)to give a solid brown color (4,00 g). Crystallization from acetone received solid brown (3.00 g, 68%). TPL: 150°C.

1H-NMR (DMSO-d6): 4,84 (s, 2H), 6,70 (s, 4H), 6.90 to (s, 1H), 7,45 to 7.62 (m, 3H), 7,62-of 7.90 (m, 3H), 9,25 (s, 1H).

Example 11

4-[N-(4-Hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

4-Hydroxybenzamide (15.6 g, of 84.3 mmol, obtained according to A. Wissner et al., J. Med. Chem. 1992, 35, 1650), was added to a mixture of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (10,00 g, 54,30 mmol) and K2CO3(8,20 g, 59,70 mmol) in dry THF (150 ml) at room temperature. The mixture was then stirred at room temperature for 2 hours and then was poured into water and was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuum to give crude product (16,00 g as solids). Crystallization from ethyl acetate with ethanol received expected the th product (6.50 g, 41%, MP: 180°C).

1H-NMR (DMSO-d6): 4,80 (s, 2H), 6,65 (d, 2H), 6,91 (s, 1H),? 7.04 baby mortality (d, 1H), 7,20 (s, 1H), 7,56 (s, 1H), 7,63 (d, 2H).

Using the same method, but replacing 4-hydroxybenzamide on:

- 3-chloro-4-hydroxybenzamide

- 3-bromo-4-hydroxybenzamide

- 4-hydroxy-3-methoxybenzylamine

- 2,3,5,6-titrator-4-hydroxybenzylidene (obtained according to S.J. Angyal et al., J. Chem. Soc. 1950, 2141)

- 3-formyl-4-hydroxybenzylidene (obtained according to S.J. Angyal et al., J. Chem. Soc. 1950, 2141)

- 1-benzyloxy-4-(2-bromoethoxy)benzene (obtained according to Brinkman J. and al. Bioorg. Med. Chem. Lett., 1996, 6, 21, 2491-94)

- 2-chloro-5-chloromethylpyridine

- 4-(methyl bromide)benzosulfimide (obtained according Colescott R. and all. J. Chem. Soc., 1957, 79, 4232-35)

- 4-(chloromethyl)-2-NITROPHENOL (obtained according to the Bayer patent: DE 132475)

- 5-chloromethyl-2-methoxybenzoic acid (obtained according to Leonard F. and all. J. Med. Chem., 1965, 8, 812-15),

received, respectively, the following connections:

Example 12

4-[N-(3-Chloro-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

TPL 195°C

1H-NMR (DMSO-d6): 4,88 (s, 2H), to 6.67 (d, 2H), to 6.88 (d, 2H), 6,98 (s, 1H), 7,05 (DD, 1H), 7,24 (d, 1H), 7,33 (s, 1H), of 7.70 (s, 1H), 7,72 (d, 2H), 10,28 (s, 1H).

Example 13

4-[N-(3-Bromo-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

TPL 198°C

1H-NMR (DMSO-d6): the 4.90 (s, 2H), 6,65 (d, 2H), 6,85 (d, 1H), 6,99 (s, 1H), 7,07 (d, 1H), 7,30 (s, 1H), 7,40 (s, 1H), 7,6 (s, 1H), to 7.67 (d, 2H), the 10.40 (s, 1H).

Example 14

4-[N-(4-Hydroxy-3-methoxyphenethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

TPL 215°C

1H-NMR (DMSO-d6): 3,70 (s, 3H), 4,89 (s, 2H), of 6.68 (s, 2H), 6,70 (d, 2H), 6,80 (s, 1H), 6,99 (s, 1H), 7,30 (s, 1H), 7,63 (s, 1H), 7,72 (d, 2H), 9,20 (s, 1H).

Example 15

4-[N-(2,3,5,6-Titrator-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

TPL 243°C

1H-NMR (DMSO-d6): 5,09 (s, 2H), 6,72 (d, 2H), 7,00 (s, 1H), 7,32 (s, 1H), 7,69 (d, 2H), to 7.77 (s, 1H), RS 11.80 (s, 1H).

Example 16

4-[N-(3-Formyl-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

TPL 160°C

1H-NMR (DMSO-d6): of 4.95 (s, 2H), 6,70 (d, 2H), 6.90 to (s, 1H), of 6.96 (d, 1H), 7,35 (s, 1H), 7,44 (DD, 1H), 7,58 (d, 1H), to 7.67 (s, 1H), 7,71 (d, 2H), and 10.20 (s, 1H), 10,75 (s, 1H).

Example 17

4-{N-[2-(4-Benzyloxy-phenoxy)ethyl]-N-(1H-imidazol-1-yl)amino]}benzonitrile

1H-NMR (DMSO-d6): 3,95-4,10 (m, 2H), 4,11-to 4.28 (m, 2H), free 5.01 (s, 2H), 6,60 (d, 2H), PC 6.82 (d, 2H), 7,95 (d, 2H), 7.03 is is 7.50 (m, 7H), of 7.69 (d, 2H), 7,88 (s, 1H).

Example 18

4-{N-[(6-Chloropyridin-3-yl)methyl]-N-(1H-imidazol-1-yl)amino}benzonitrile

TPL 156°C

1H-NMR (DMSO-d6): 5,10 (s, 2H), of 6.71 (d, 2H), 7,00 (s, 1H), 7,42 (s, 1H), 7,49 (d, 1H), 7,55-of 7.90 (m, 4H), to 8.34 (d, 1H).

Example 19

4-{[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}benzosulfimide

TPL 150°C

1H-NMR (DMSO-d6): of 5.15 (s, 2H), 6,62 (d, 2H), 7,00 (s, 1H), was 7.36 (s, 2H), 7,45 (s, 1H), 7,55 (d, 2H), 7,65-of 7.90 (m, 5H).

Example 20

4-[N-(4-G is droxy-3-nitrophenylamino)-N-(1H-imidazol-1-yl)amino]benzonitrile

TPL 205°C

1H-NMR (DMSO-d6): to 4.98 (s, 2H), 6,72 (d, 2H), 7,00 (s, 1H), 7,06 (d, 1H), 7,39 (s, 1H), of 7.48 (d, 1H), 7,60 for 7.78 (m, 3H), of 7.82 (s, 1H).

Example 21

5-{[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}-2-methoxybenzoic acid

TPL 187°C

1H-NMR (DMSO-d6): 3,79 (s, 3H), of 5.00 (s, 2H), 6,69 (d, 2H), 6,98 (s, 1H), 7,05 (d, 1H), 7,31 (s, 1H), 7,39 (DD, 1H), 7,55 (d, 1H), 7,62-a 7.85 (m, 3H).

Example 22

4-[N-(1H-Imidazol-1-yl)-N-(4-nitrophenyl)amino]benzonitrile

4-[N-(1H-Imidazol-1-yl)amino]benzonitrile (10,00 g, 54,30 mmol) was added in portions to a suspension of tert-butoxide potassium (6,69 g, 59,73 mm) in DMSO (100 ml) at 10-15°C) with agitation. The mixture was stirred for 30 minutes at room temperature and then was added dropwise 4-nitrofurant (7,60 g 54,00 mm) in DMSO (15 ml), keeping the temperature below 30°C. After 2 h the mixture was poured into water (800 ml), the precipitate was collected by filtration and purified by crystallization from ethanol (1,00 g, 48%, MP: 188°C).

1H-NMR (DMSO-d6): 7,00 (d, 2H), 7,17 (s, 1H), 7,26 (d, 2H), 7,65 (s, 1H), of 7.90 (d, 2H), to 8.20 (s, 1H), 7,22 (d, 2H).

Using the same method, but replacing 4-nitro-torbenson on:

- 6-chloronicotinoyl

- 4-perforazione

- 4-hydroxyphenylacetate

- 4-hydroxyphenylpropionic (obtained according to Elias H. and all. Macromol. Chem. Phys., 1981, 182, 681-86)

- 4-phenylmethanesulfonyl (obtained according Toja E. and all. Eur. J. Med. Chem. 1991,26, 403-13),

received, respectively, the following connections:

Example 23

6-Chloro-N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)nicotinamide

TPL 132°C

1H-NMR (DMSO-d6): 6,98 (s, 1H), 7,40 to 7.62 (m, 3H), of 7.70 (s, 1H), 7,95 (d, 2H), 8,00 (d, 1H), 8,19 (s, 1H), to 8.57 (d, 1H).

Example 24

N-(1H-Imidazol-1-yl)-N-(4-cyanophenyl)-2-(4-forfinal)ndimethylacetamide

TPL 131°C

1H-NMR (DMSO-d6): of 3.57 (s, 2H), 7,00-to 7.35 (m, 5H), at 7.55 (d, 2H), of 7.70 (s, 1H), to 7.93 (d, 2H), 8,19 (s, 1H).

Example 25

N-(1H-Imidazol-1-yl)-N-(4-cyanophenyl)-2-(4-hydroxyphenyl)ndimethylacetamide

1H-NMR (DMSO-d6): of 3.32 (s, 2H), 6,65 (d, 2H), 6.87 in (d, 2H), was 7.08 (s, 1H), 7,50 (d, 2H), of 7.70 (s, 1H), of 7.90 (d, 2H), 8,10 (s, 1H), of 9.30 (s, 1H).

Example 26

N-(4-Cyanophenyl)-3-(4-hydroxyphenyl)-N-(1H-imidazol-1-yl)propanamide

TPL 172°C

1H-NMR (DMSO-d6): 2,25-2,60 (m, 2H), 2,65-2,90 (m, 2H), 6,63 (d, 2H), 6.90 to (d, 2H), was 7.08 (s, 1H), 7,51 (d, 2H), to 7.61 (s, 1H), of 7.90 (d, 2H), 8,10 (s, 1H), 9,20 (s, 1H).

Example 27

N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)-4-(phenylmethoxy)benzosulfimide

1H-NMR (CDCl3): 5,14 (s, 2H), 6,93 (t, 1H), 7,00-to 7.15 (m, 3H), 7,30 was 7.45 (m, 7H), to 7.50 (s, 1H), 7,66 (d, 2H), 7,68 (d, 2H).

GETTING IMIDAZOLES of the FORMULA (15), (21)

Example 28

5-Nitro-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)]benzothiophen-2-carboxamide

5-Nitrobenzamide-2-carbonylchloride (industrial connection fee of 10.00 g, 41,00 mmol) was added to a mixture of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (of 7.55 g, 41,00 mmol), Thea 20 ml, 143,00 mmol) in dry THF (150 ml) at room temperature. The mixture was then stirred at room temperature overnight and the precipitate was filtered off, washed with THF, water, give crude product as a solid (9,26g). Crystallization from ethanol was obtained white crystals (3.50 g, MP: 221°C).

1H-NMR (DMSO-d6): 7,10 (s, 1H), 7,54 (s, 1H), of 7.70 (d, 2H), 7,82 (s, 1H), 7,98 (d, 2H), 8,15-to 8.40 (m, 3H), 8,89 (s, 1H).

Using the same method, but replacing 5-nitrobenzamide-2-carbonylchloride on:

6-methoxybenzamide-3-acetylchloride (described Sauter F., Monatshefte Fuer Chemie, 1968, 99, 2, 610-15), received the following connection:

Example 29

N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)-2-(6-methoxybenzoate-3-yl)ndimethylacetamide

TPL: 104°C

1H-NMR (DMSO-d6): 3,75-of 3.85 (m, 5H), 7,02 (DD, 1H), 7,13 (s, 1H), 7,30 (s, 1H), 7,50 to 7.75 (m, 4H), 7,80 (s, 1H), of 7.90 (d, 2H), of 8.25 (s, 1H).

Example 30

4-{N-[1H-Imidazol-1-yl]-N-[(6-methoxybenzoate-3-yl)methyl]amino}benzonitrile

3-Chloromethyl-6-methoxybenzamide (12,35 g, 58,06 mmol) was added to a mixture of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (9,72 g, 52,78 mmol), K2CO3(14,60 g, 105,56 mmol) and potassium iodide (0.10 g, of 0.60 mmol) in dry DMF (70 ml) at room temperature. The mixture was then stirred at room temperature overnight and then was poured into water and was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated is in vacuum, give crude product as a solid (14,30 g). Flash chromatography on silica gel (toluene/dioxane: 6/4) received the expected product (10,50 g, 55%, powder). Crystallization from ethanol was obtained white crystals (7.30 g, MP: 164°C).

1H-NMR (DMSO-d6): of 3.80 (s, 3H), of 5.25 (s, 2H), 6,74 (d, 2H), 6,93 (s, 1H), 7,02 (DD, 1H), 7,28 (s, 1H), 7,40 (s, 1H), 7,53 (s, 1H), 7,55 (s, 1H), 7,68 (d, 1H), of 7.75 (d, 2H).

Example 31

4-[N-(6-Benzyloxy-1,1-dioxygenation-3-yl)-N-(1H-imidazol-1-yl)amino]benzonitrile

4-[N-(1H-Imidazol-1-yl)amino]benzonitrile (0.50 g, 27,14 mmol) was added in portions to a suspension of tert-butoxide potassium (0.35 g, 31,00 mmol) in THF (20 ml) at 10-15°C) with agitation. The mixture was stirred for 30 min at room temperature and then was added dropwise 3-bromo-6-benzyloxybenzoate-1,1-dioxide (1.10 g, 31,33 mm) in THF (5 ml), keeping the temperature below 30°C. After one night, the mixture was poured into water (200 ml) and was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuum to give crude product as oil (2.50 g). Flash chromatography on silica gel (toluene/1,4-dioxane: 7/3) and by crystallization in ethanol received light brown crystals (1.20 g, 95%; MP: 146°C).

1H-NMR (DMSO-d6): 5,22 (s, 2H), 6.48 in (s, 1H), of 6.49 (d, 1H), 7,05-7,20 (m, 2H), 7,25 is 7.50 (m, 8H), 7,60 (d, 1H), 7,73 (s, 1H), 7,94 (d, 2H).

Using the same method, but substituting 3-bromo-6-benzyloxybenzoate-1,-dioxide on:

6-benzyloxy-2-(chloromethyl)benzothiophen,

received the following connection:

Example 32

4-[N-[(6-Benzyloxybenzoate-2-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile

1H-NMR (DMSO-d6): 5,12 (s, 2H), and 5.30 (s, 2H), 6,72 (d, 2H), 7,00 (s, 1H),? 7.04 baby mortality (DD, 1H), 7.23 percent (s, 1H), 7,27-of 7.90 (m, 11H).

GETTING IMIDAZOLES of the FORMULA (10), (16)

Example 33

4-{N-[(6-Hydroxybenzoate-3-yl)methyl]-N-[1H-imidazol-1-yl]amino}benzonitrile

A solution of 4-{N-[1H-imidazol-1-yl]-N-[(6-methoxybenzoate-3-yl)methyl]amino}benzonitrile (0.50 g, of 1.39 mmol) in 10 ml of methylene chloride was added at room temperature to a solution of 1M tribromide boron in methylene chloride (1.50 ml, of 1.52 mmol). After 2 h at room temperature, the mixture is hydrolyzed with saturated aqueous NaHCO3, was extracted with dichloromethane, dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified flash chromatography on silica gel (toluene/dioxane: 6/4)to give the expected product (0,30 g, 62%, powder). Crystallization from ethanol was obtained white crystals (0.10 g, MP: 169°C).

1H-NMR (DMSO-d6): of 5.24 (s, 2H), 6,72 (d, 2H), 6.87 in (DD, 1H), 6,94 (s, 1H), 7,27 (d, 2H), 7,29 (s, 1H), 7,55 (s, 1H), 7,56 (d, 1H), of 7.75 (d, 2H), 9,67 (s, 1H).

Using the same method, but replacing 4-{N-[1H-imidazol-1-yl]-N-[(6-methoxybenzamide-3-yl)methyl]amino}benzonitrile on:

N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)-2-(6-methoxybenzoate-3 is)ndimethylacetamide, received the following connection:

Example 34

N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)-2-(6-hydroxybenzoate-3-yl)ndimethylacetamide

TPL 179°C

1H-NMR (DMSO-d6): and 3.72 (s, 2H), 6,85 (DD, 1H), 7,10 (d, 2H), 7,25 (d, 1H), 7,40-of 7.70 (m, 3H), 7,80 (s, 1H), to $ 7.91 (d, 2H), 8,24 (s, 1H), 9,60 (s, 1H).

Example 35

4-[N-(3-Amino-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

4-[N-(4-Hydroxy-3-nitrophenylamino)-N-(1H-imidazol-1-yl)amino]benzonitrile (2 g, 5,97 mmol) was first made over the suspension of Pd/C (10 wt.% coal, 0.2 g) in ethanol (30 ml). When TLC showed completion of the reaction, the mixture was filtered through celatum, washed with EtOH. The solvent was concentrated in vacuum. Crystallization from a mixture of EtOH/petroleum ether got orange crystals (1.1 g, 60.5 per cent, TPL: 208°C).

1H-NMR (DMSO-d6): 4,60 (s, 2H), 4,79 (s, 2H), 6,80 (d, 1H), 6,40-to 6.80 (m, 4H), of 6.99 (s, 1H), 7,25 (s, 1H), 7,50-7,80 (m, 3H), 9,07 (s, 1H).

Using the same method, but substituting 4-[N-(4-hydroxy-3-nitrobenzyl)-N-(1H-imidazol-1-yl)amino]benzonitrile on:

- 4-{N-[2-(4-benzyloxyphenyl)ethyl]-N-(1H-imidazol-1-yl)amino]}benzonitrile

- N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)-4-(phenylmethoxy)benzosulfimide,

received, respectively, the following connections:

Example 36

4-{N-[2-(4-Hydroxyphenoxy)ethyl]-N-(1H-imidazol-1-yl)amino}benzonitrile

TPL 188°C

1H-NMR (DMSO-d6): 4,99 (t, 2H), 4,17 (t, 2H), 6,40-6,85 (m, 6H), 7,10 (s, 1H), 7,40 (s, 1H), and 68 (d, 2H), 7,86 (s, 1H), of 8.95 (s, 1H).

Example 37

N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)-4-hydroxybenzenesulfonate

TPL 248°C

1H-NMR (DMSO-d6): to 6.95 (d, 2H), 7,00 (s, 1H), 7,24 (s, 1H), 7,49 (d, 2H), 7,52 (d, 2H), 7,88 (s, 1H), 7,92 (d, 2H), 10,95 (s, 1H).

Example 38

4-[N-[(6-Hydroxy-1,1-dioxygenation-3-yl)]-N-(1H-imidazol-1-yl)amino]benzonitrile

A mixture of 4-[N-[(6-benzyloxy-1,1-dioxygenation-3-yl)]-N-(1H-imidazol-1-yl)amino]benzonitrile (3.00 g, is 6.78 mmol), 10% Pd/C (0.50 g), THF (30 ml) and a solution of ammonium formate (25% in H2O, 30 ml) was stirred at ambient temperature for 6 hours and filtered. The mixture was poured into water and was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuum to give crude product (2.50 g as solids). Crystallization from ethanol was obtained white crystals (0,80 g, 26%, TPL: 260°C).

1H-NMR (DMSO-d6): of 6.25 (s, 1H), 6,29 (d, 1H), PC 6.82 (DD, 1H), 7,10 (s, 1H), 7,15 (s, 1H), 7,30 (m, 2H), of 7.70 (s, 1H), to $ 7.91 (d, 2H), of 8.25 (s, 1H).

Using the same method, but substituting 4-[N-[(6-benzyloxy-1,1-dioxygenation-3-yl)]-N-(1H-imidazol-1-yl)amino]benzonitrile on:

4-[N-[(6-benzyloxybenzoate-2-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile,

received the following connection:

Example 39

4-[N-[(6-Hydroxybenzoate-2-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile

TPL 230°C

1H-NMR (DMSO-d6): ,28 (, 2H), 6,70 (d, 2H), PC 6.82 (DD, 1H), 7,00 (s, 1H), 7,15-7,21 (m, 2H), 7,31 (s, 1H), 7,55 (d, 1H), 7,69-7,80 (m, 3H), 9,63 (s, 1H).

GETTING IMIDAZOLES of the FORMULA (12), (18)

Example 40

4-[N-(4-AMINOPHENYL)-N-(1H-imidazol-1-yl)amino]benzonitrile

Hydrazine (of 1.52 ml, 49,00 mmol) was added in portions to a suspension of 4-[N-(1H-imidazol-1-yl)-N-(4-nitrophenyl)amino]benzonitrile (3.00 g, 9,80 mm) and ruthenium, 5% wt. coal (0,30 g, 0.15 mm) in ethanol (35 ml) at boiling under reflux with stirring. When TLC showed completion of the reaction, the mixture was cooled and the catalyst was filtered. The solvent was concentrated in vacuum. The residue was poured into water and was extracted with dichloromethane, dried over Na2SO4, filtered and concentrated in vacuum to give crude product (2.50 g as solids). Crystallization from ethyl acetate with ethanol received the expected product (1.30 grams, 50%, MP: 147 °C).

1H-NMR (DMSO-d6): of 5.50 (s, 2H), 6.30-in (d, 2H), 6,69 (d, 2H), to 7.09 (s, 1H), 7,29 (d, 2H), 7,63 (s, 1H), 7,65 (d, 2H), 8,14 (s, 1H).

Example 41

5-Amino-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)]benzothiophen-2-carboxamide

Dehydrate douglasthe tin (13,10 g 58,00 mmol) was added in portions to a stirred solution of 5-nitro-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)]benzothiophen-2-carboxamide (4,50 g, 11.6 mm) in ethanol (100 ml). The mixture was heated at the boiling point under reflux. When TLC showed full the completion of the reaction, the mixture was cooled and turned into the Foundation using a saturated solution of bicarbonate. The mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuum to give crude product as a solid (3,90 g). Crystallization from methanol had been expected product (2,60 g, 63%; MP: 214°C).

1H-NMR (DMSO-d6): 6,70-6,98 (m, 3H), 7,07 (s, 1H), 7,40-7,25 (m, 4H), 7,26-of 7.96 (m, 3H).

A GENERAL METHOD of SULFANILAMIDE

GETTING SULFAMATE (11, 17, 23) AND AMINOSULFONYL (13, 19, 25)

Example 42

4-[N-(4-Cyanovinylene)-N-(1H-imidazol-1-yl)amino]phenyl ester of sulfamic acid

Sulfhemoglobin (2,39 g, 20,69 mmol) was added to a solution of 4-[N-(4-hydroxyphenyl)-N-(1H-imidazol-1-yl)amino]methylbenzonitrile (1,00 g of 3.45 mmol) in dry DMAc (36 ml) with cooling on ice. The mixture was then stirred at room temperature for 6 hours. After adding, not (3,40 ml, 24,73 ml) the mixture was poured into cold brine and extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuum to give crude product (0,70 g as solids). Crystallization from ethyl acetate had been expected product (0.40 g, 31%; MP: 60°C).

1H-NMR (DMSO-d6): 5,00 (s, 2H), 6,70 (d, 2H), 6,92 (s, 1H), 7,19 (d, 2H), 7,40 (s, 1H), 7,55 (d, 2H), 7,74 (s, 1H), to 7.77 (d, 2H), to $ 7.91 (s, 2H).

Using the same technique, but for INAA 4-[N-(4 hydroxyphenyl)-N-(1H-imidazol-1-yl)amino]methylbenzonitrile on:

- 4-[N-(4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

- 4-[N-(3-chloro-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

- 4-[N-(3-bromo-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

- 4-[N-(3-methoxy-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]

benzonitrile

- 4-[N-(2,3,5,6-titrator-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

- 4-[N-(3-formyl-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

- 4-[N-(4-AMINOPHENYL)-N-(1H-imidazol-1-yl)amino]benzonitrile

- N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)-4-hydroxybenzenesulfonate

- 4-{N-[2-(4-hydroxyphenoxy)ethyl]-N-(1H-imidazol-1-yl)amino}benzonitrile

- N-(1H-imidazol-1-yl)-N-(4-cyanophenyl)-2-(4-hydroxyphenyl)ndimethylacetamide

- N-(4-cyanophenyl)-3-(4-hydroxyphenyl)-N-(1H-imidazol-1-yl)propanamide

- 4-[N-(3-amino-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]

benzonitrile

- 5-amino-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)]benzothiophen-2-carboxamide

- 4-[N-[(6-hydroxy-1,1-dioxygenation-3-yl)]-N-(1H-imidazol-1-yl)amino]benzonitrile

- N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)-2-[(6-hydroxybenzoate-2-yl)]ndimethylacetamide

- 4-{N-[(6-hydroxybenzoate-3-yl)methyl]-N-[1H-imidazol-1-yl]amino}benzonitrile

- 4-{N-[(6-hydroxybenzoate-2-yl)methyl]-N-[1H-imidazol-1-yl]amino}benzonitrile,

received, respectively, the following connections:

Example 43

4-{[N-(4-Cyanophenyl)-N-1H-imidazol-1-yl)amino]methyl}phenyl ether sulfamic acid

TPL 172°C

1H-NMR (DMSO-d6): 5,00 (s, 2H), 6,65 (d, 2H), 7,00 (s, 1H), 7,22 (d, 2H), 7,40 (s, 1H), 7,42 (d, 2H), of 7.70 (s, 1H), of 7.75 (d, 2H), 8,00 (s, 2H).

Example 44

2-Chloro-4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}phenyl ether sulfamic acid

1H-NMR (DMSO-d6): of 5.05 (s, 2H), 6,63 (d, 2H), 7,00 (s, 1H), 7,35-7,45 (m, 3H), 7,54 (s, 1H), of 7.70 (d, 2H), 7,80 (s, 1H), 8,29 (s, 2H).

EXAMPLE 45

2-Bromo-4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}phenyl ether sulfamic acid, hydrochloride

Crystallization was carried out in EtOH/HCl (TPL 145°C).

1H-NMR (DMSO-d6): of 5.15 (s, 2H), 6.90 to (d, 2H), of 7.48 (s, 2H), 7,60 is 7.85 (s, 5H), 8,08 (s, 1H), 8,32 (s, 2H), 9,51 (s, 1H).

Example 46

2-Methoxy-4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}phenyl ether sulfamic acid

TPL 211°C

1H-NMR (DMSO-d6): of 3.77 (s, 3H), 5,02 (s, 2H), 6.75 in (d, 2H), 6,92 (d, 1H), 7,05 (s, 2H), 7,25 (d, 1H), 7,45 (s, 1H), 7,71 (d, 2H), 7,80 (s, 1H), to 7.93 (s, 2H).

Example 47

2,3,5,6-Titrator-4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}phenyl ether sulfamic acid

1H-NMR (DMSO-d6): lower than the 5.37 (s, 2H), of 5.83 (s, 2H), 6,86 (d, 2H), was 7.08 (s, 1H), 7,41 (s, 1H), 7,79 (s, 1H), 7,81 (d, 2H).

Example 48

4-[N-[(2,2-Dioxido-1,2,3-benzoxazin-6-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile

TPL 180°C

1H-NMR (DMSO-d6): of 5.17 (s, 2H), to 6.67 (d, 2H), 7,02 (s, 1H), 7,46 (s, 1H), 7,50 (d, 2H), 7,74 (d, 2H), 7,82 (DD, 1H), 7,87 (s, 1H), 8,02 (d, 1H), 9,19 (s, 1H).

Example 49

N-{4-[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]phenyl}sulphonamide

TPL 121°C

1H-NMR(DMSO-d6): 6,38 (d, 2H), to 7.09 (s, 1H), 7,20 (s, 1H), 7,22 (d, 2H), 7,51 (d, 2H), 7,63 (s, 1H), 7,69 (d, 2H), 8,19 (s, 1H).

Example 50

4-{[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]sulfonyl}phenyl ether sulfamic acid, hydrochloride

Crystallization was carried out in EtOH/HCl.

TPL 200°C

1H-NMR (DMSO-d6): EUR 7.57 (d, 2H), 7,60 (s, 1H), of 7.70 (d, 2H), 7,80-8,10 (m, 5H), 8,40 (s, 2H), of 9.30 (s, 1H).

Example 51

4-{2-[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]ethoxy}phenyl ether sulfamic acid

TPL 174°C

1H-NMR (DMSO-d6): 4,08 (t, 2H), 4,23 (t, 2H), 6,60 (d, 2H), 6,95 (d, 2H), 7,10 (s, 1H), 7,18 (d, 2H), 7,42 (s, 1H), of 7.70 (d, 2H), 7,88 (s, 3H).

Example 52

4-{[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)carbarnoyl]methyl}phenyl ether sulfamic acid

1H-NMR (DMSO-d6): of 3.32 (s, 2H), 7,12 (s, 1H), 7.18 in-7,32 (m, 4H), 7,50-of 7.60 (d, 2H), 7,71 (s, 1H), 7,85-with 8.05 (m, 4H), to 8.20 (s, 1H).

Example 53

4-{[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]-3-oxopropyl}phenyl ether sulfamic acid

TPL 100°C

1H-NMR (DMSO-d6): of 2.45 (t, 2H), 3,85 (t, 2H), 7,10 (s, 1H); 7,12-7,30 (m, 4H), at 7.55 (d, 2H), 7,65 (s, 1H), of 7.90 (m, 4H), to 8.12 (s, 1H).

Example 54

3-(Aminosulfonyl)amino-4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}phenyl ether sulfamic acid

TPL 197°C

1H-NMR (DMSO-d6): 5,00 (s, 2H), of 6.71 (d, 2), 6,93 (d, 1H), 7,02 (s, 2H), 7,21 (d, 1H), of 7.48 (s, 1H), to 7.61 (d, 2H), 7,74 (s, 1H), 7,92 (s, 2H), 8,10 (s, 2H).

Example 55

5-(Aminosulfonyl)amino-[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)]benzothiophen-2-carboxamide

TPL: 169°C

1H-NMR (d6): 6.87 in (d, 1H), 7,05-7,30 (m, 4H), 7,56 (s, 1H), to 7.67 (d, 2H), 7,80-8,10 (m, 4H), 7,86 (s, 1H), 9,65 (s, 1H).

Example 56

3-[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]-1,1-dioxygenation-6-silt ether sulfamic acid

TPL 172°C

1H-NMR (DMSO-d6): 6,24 (s, 1H), 6,29 (d, 1H), 6,85 (DD, 1H), 7,15 (s, 1H), 7,20 (s, 1H), 7,30 (m, 2H), 7,65 (s, 1H), 7,95 (d, 2H), with 8.05 (s, 2H), of 8.25 (s, 1H).

Example 57

3-{2-[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]-2-oxoethyl}bestien-6-silt ether sulfamic acid

1H-NMR (DMSO-d6): of 3.84 (s, 2H), 7,15 (s, 1H), 7,28-7,37 (DD, 1H), 7,51-the 7.65 (m, 3H), 7,80-7,98 (m, 5H), 8,01 (s, 2H), 8,29 (s, 1H).

Example 58

3-{[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}bestien-6-silt ether sulfamic acid

TPL 193°C

1H-NMR (DMSO-d6): and 5.30 (s, 2H), 6,80 (d, 2H), 6,97 (s, 1H), 7,30-7,40 (m, 2H), 7,56 (s, 1H), 7,68 (s, 1H), of 7.75 (d, 2H), 7,80-to 7.95 (m, 2H), with 8.05 (s, 2H).

Example 59

2-{[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}bestien-6-silt ether sulfamic acid

TPL 178°C

1H-NMR (DMSO-d6): of 5.17 (s, 2H), 6,65 (d, 2H), 6.89 in (DD, 1H), 6,94 (s, 1H), 7,20 (m, 2H), 7,27 (s, 1H), 7,45 (s, 1H), 7,58 (d, 1H), 7,72 (d, 2H), 8,00 (s, 2H).

Using the same procedure as in example 13, but replacement is I 4-[N-(4-hydroxyphenyl)-N-(1H-imidazol-1-yl)amino]methylbenzonitrile on:

- 4-[N-(3-bromo-4-hydroxyphenylethyl)-N-(1H-imidazol-1-yl)amino]benzonitrile,

received as a by-product of the following connections:

Example 60

2-Bromo-4-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}phenylenedimethylene

TPL 220°C

1H-NMR (DMSO-d6): 5,00 (s, 2H), 5,70 (s, 2H), 6,65 (d, 2H), 7,03 (s, 1H), 7,42 (DD, 1H), 7,50 (s, 1H), 7,55 (d, 1H), 7,65 (d, 1H), 7,72 (d, 2H), 7,81 (s, 1H).

For OTHER COMPOUNDS (8)

Example 61

4-[N-[(2,2-Dioxido-3,4-dihydro-1,2,3-benzoxazin-6-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile

To a suspension of 4-[N-[(2,2-dioxido-1,2,3-benzoxazin-6-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile (0.40 g, 1.05 mmol) in methanol (8 ml) was added in portions NaBH4(0.08 g, 2,11 mmol) and the reaction mixture was stirred at room temperature for 3 hours. After adding a saturated solution of NH4Cl (3 ml) and water (40 ml) the precipitate was filtered off, washed with water and dried, obtaining a solid white color. Crystallization from ethyl acetate with ethanol received the expected product (0.40 g, 82%; MP: 190°C).

1H-NMR (DMSO-d6): 4,55 (d, 2H), 5,04 (s, 2H), only 6.64 (d, 2H), 7,02 (s, 1H), 7,03 (d, 1H), 7,27 (d, 1H), 7,30 (s, 1H), 7,41 (s, 1H), of 7.70 (d, 2H), a 7.85 (s, 1H), 8,56 (t, 1H).

Example 62

5-{[N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)amino]methyl}-2-hydroxybenzoic acid

A mixture of 5-{[N-(4-cyanophenyl)-N-(1H-imidazol-1-yl)amino]IU the Il}-2-methoxybenzoic acid (1,00 g, to 2.85 mmol) and piperidine (0,42 ml, to 8.57 mmol) in dimethylacetamide (DMA) (2 ml) was heated at 150°C. When the starting material disappeared (TLC monitoring), the solvent was removed in vacuum. Flash chromatography on silica gel (MeOH/dichloromethane: 5/95) and crystallization from ethanol was obtained white crystals (53 mg, 6%; MP: 260°C).

1H-NMR (DMSO-d6): is 4.85 (s, 2H), is 6.54 (d, 1H), 6,66 (d, 2H), 6,95 (s, 1H), 7,05 (DD, 1H), 7,24 (s, 1H), 7,50-of 7.60 (m, 2H), 7,68 (d, 2H).

Example 63

4-[N-(1H-Imidazol-1-yl)-N-(phenyl)amino]benzonitrile

4-[N-(1H-Imidazol-1-yl)-N-(4-nitrophenyl)amino]benzonitrile (3,91 g, 12,80 mmol) was placed in a hydrogenation flask and was dissolved in acetic anhydride (60 ml) and acetic acid (60 ml). Added palladium (10%) C, 0.20 g) and the flask was attached to the device for hydrogenation Parra. The hydrogenation was performed with shaking for 3 hours at 25 psi H2. The catalyst was removed by filtration and the solution was cooled in a bath for 30 min sodium Nitrite (0.97 g, 14,00 mmol) was added to the mixture and the vessel was slightly covered. The flask was left in an ice bath for 2 hours and allowed to warm to room temperature over night. The mixture was poured into a mixture of ice/water and the solid was filtered, washed with water (50 ml)to give crude product. Flash chromatography (toluene/dioxane: 6/4) and crystallization from ethyl acetate with ethanol received the expected product (0.40 g, 8%, MP: 162 is C).

1H-NMR (DMSO-d6): 6,60 (d, 2H), 7,00-to 7.50 (m, 9H), of 7.69 (s, 1H).

GETTING BENZOXADIAZOLE (8)

Example 64

4-[N-(3-Tosylamide-4-hydroxybenzyl)-N-(1H-imidazol-1-yl)amino]benzonitrile

Taillored (3.5 g, 18,59 mmol) in CH2Cl2(20 ml) was added dropwise to a solution of (TX 1840) (5,4 g of 17.7 mmol) and pyridine (19,47 mmol, 1.6 ml) in CH2Cl2(50 ml) at 0°C.

The mixture was then stirred at room temperature for 4 h, then was poured into water and was extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuum to give crude product (8.1 g in a solid orange color).

Flash chromatography on silica gel (toluene/dioxane: 7/3) received a solid yellow color.

1H-NMR (DMSO-d6): 2,32 (s, 3H), around 4.85 (s, 2H), 6,60 (d, 2H), 6,62 (s, 1H), 6,80 (DD, 1H), 6,97 (s, 1H), 7,10-7,30 (m, 5H), of 7.00 (d, 2H), 7,03 (s, 1H), 7,52 (d, 2H), 9,45 (s, 2H).

Example 65

4-[N-[(2,2-Dioxido-3-tosyl-3H-1,2,3-benzoxadiazole-5-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile

Sulfurylchloride (of 0.60 ml, 7.40 mmol) in dichloromethane (50 ml) was added dropwise with stirring for 30 min to 4-[N-(3-tosylamide-4-hydroxybenzyl)-N-(1H-imidazol-1-yl)amino]benzonitrile (3,40 g, 7.40 mmol) and triethylamine (2.10 ml, 14,81 mmol) in dichloromethane (6 ml) at -78°C. After an additional 15 minutes the mixture was allowed to warm to room temperature over 4 chaison mixture was diluted with water, was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuum. Flash chromatography on silica gel (toluene/dioxane: 5/5) received net oil (1.60 g, 41%).

1H-NMR (DMSO-d6): 2,39 (s, 3H), by 5.18 (s, 2H), 6,80 (d, 2H), 7,00-to 7.50 (m, 6H), 7,60 is 7.85 (m, 5H), 8,02 (s, 1H).

Example 66

4-[N-[(2,2-Dioxido-3H-1,2,3-benzoxadiazole-5-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile

The potassium fluoride (0.36 g, 6,14 mmol) in water (5 ml) was added to 4-[N-[(2,2-dioxido-3-tosyl-3H-1,2,3-benzoxadiazole-5-yl)methyl]-N-(1H-imidazol-1-yl)amino]benzonitrile (1.60 g, of 3.07 mmol) in acetonitrile (15 ml) at room temperature. The solution was stirred over night, concentrated, was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuum. Flash chromatography on silica gel (toluene/dioxane: 5/5) received oil and crystallization from ethanol received the expected product (0.17 g, 15%, MP: 230°C).

1H-NMR (d6): 4,84 (s, 2H), 6,38 (DD, 1H), 6.42 per (d, 1H), 6,63 (d, 1H), 6,69 (d, 2H), 7,15 (s, 1H), 7,43 (s, 1H), of 7.70 (d, 2H), 8,02 (s, 1H).

GETTING PRILOCAIN (27)

Example 67

N-(4-Cyanophenyl)-N-(1H-imidazol-1-yl)-N'-prilocaine

Phenylisocyanate (3.6 ml, with a 32.6 mmol) was added to a solution of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (5 g, 27,17 mmol) in THF (50 ml). The mixture was stirred at 50°C during the night and after evaporation of the crystal is arranged in a mixture of acetone/EtOH, getting white crystals (2.5 g, 30.3 per cent, 178°C).

1H-NMR (DMSO-d6): 6,59 (s, 1H), 7,05-7,40 (m, 9H), 7,52 (d, 2H), 7,83 (s, 1H).

The RESULTS of BIOLOGICAL TESTS

INHIBITION of ASTEROIDSURFACES, AROMATASE AND carbonic anhydraseIN VITRO

Sulfate follikulina (E1S) is the major circulating plasma estrogen, which is converted by the enzyme asteroidsurfaces in follikulin (E1), which, in turn, can be converted into estradiol (E2) enzymatic recovery.

Clinically proven to inhibition of the synthesis of E2aromatase inhibitors is a good way to stop the progress of hormone-dependent breast tumors. Recently, in the alternative, appeared inhibition of the way asteroidsurfaces. Therefore, the development of compounds able to inhibit both aromatase and asteroidsurfaces seems to be new and desired approach to inhibition of tumor growth.

The human carbonic anhydrase to catalyze the conversion between carbon dioxide (CO2) and bicarbonate ion (HCO3-) and are involved in numerous physiological and pathological processes. They include hormone-dependent and gormononezawisimy carcinogenesis, metastasis process and hypoxic tumors, which are less sensitive and to classical chemo/radio-therapy. Inhibition of carbonic anhydrase person could be so valuable additional activity for the connection, which is a dual inhibitor of aromatase and sulfatase (DASI). In particular, it is found that the EMATE has the ability to inhibit carbonic anhydrase person like this ability acetazolamide known sulfonamida, which is an inhibitor of human carbonic anhydrase. The aim of these experiments was to evaluate thein vitrothe inhibitory potential of new compounds against aromatase and/or steroidsbritney activity. In addition, the inhibition of the activity of carbonic anhydrase II in humans as an example of human carbonic anhydrase) for some of them was evaluated in comparison with 6,6,7 COUMATE and acetazolamide.

Materials and methods

a) aromatase Activity

The cell line JEG-3, obtained from placental choriocarcinoma person, constitutive superexpression aromatase person and provides a good model for analysis of the alleged aromatase inhibitorsin vitro. Aromatase activity was determined by tritium water way. Briefly, cells were first sown in 96-well microplates in the environment, complemented decompencirovannah fetal calf serum (dFCS). After 24 hours, cells were washed and fresh medium, sotiriadou the 1β- 3H-Androstenedione as substrate of aromatase, was added together with the test compounds at concentrations ranging from 10-12M to 10-5M After 2 hours incubation, the fraction of the nutrient medium carried on homologous to new 96-well microplates and to each well was added a solution of coal dextranomer coating. After incubation on ice for 10 minutes, the microplate was centrifuged (1500 g; 4°C). All steroids, including radioactive substrate and biokinesiology estrogens, adsorbing on coal; only3H-water, specifically formed during aromatization 1β-3H-Androstenedione, remains in the supernatant. Radioactivity in the supernatant was measured by counting liquid scintillation. In parallel, the solubilization of the cells was performed in a solution of ethylenediaminetetraacetate. The DNA content was measured by standard fluorometrically way using fluorochrome Hoechst 33258. Finally, aromatase activity was expressed in fmol educated3H-water/2 hours/µg DNA and inhibition of aromatase as a percentage of the control activity without inhibitor. Nonlinear fitting analysis (GraphPad Prism Software) % inhibition vs concentration of inhibitor was possible to determine the 50%inhibitory concentration (IC50): lowest IC50meet the most potent inhibitors (table 1).

b) aktivnosti asteroidsurfaces

Cell line JEG-3 features a very high contents folliclesalready person, and therefore it is a useful biological system for the evaluation of new inhibitors asteroidsurfacesin vitro. Assays were performed with cells in logarithmic growth phase in 96-well microplate. 24 hours before the start of the study, the cells were sown on Wednesday, supplemented decompencirovannah fetal calf serum (dFCS). The medium was removed after 24 hours and cells were washed in PBS to remove all traces of dFCS. Then free from dFCS medium were added3H-E1S, then the test compounds at concentrations ranging from 10-12M to 10-5M After 4 hours of treatment nutrient medium were transferred to 96-well microplates and centrifuged at 200 × g for 10 minutes to obtain clusters of cells before extraction with toluene. The fraction of the environment used for the extraction of toluene to separate conjugated substrate from unconjugated products. Radioactivity in the toluene phase was measured by counting liquid scintillation. In parallel, after solubilization of the cells in a solution of ethylenediaminetetraacetate, DNA content was measured by standard fluorometrically way using fluorochrome Hoechst 33258. Finally, the activity folliclesalready expressed in pmol educated3H-E 1+3H-E2/4 hours/mg DNA and inhibition of sulfatase follikulina as a percentage of the control activity without inhibitor. Nonlinear fitting analysis (GraphPad Prism Software) inhibition % vs. the concentration of the inhibitor was possible to determine the 50%inhibitory concentration (IC50): lowest IC50meet the most potent inhibitors (table 1).

c) Dual aromatase activity and asteroidsurfaces

For evaluation of the inhibitory potential of the compounds DASI, parallel in relation to the activities of aromatase and asteroidsurfaces man, used a newinvitro model using cells JEG-3. Experimental conditions described above for the model asteroidsurfaces used with minor changes: the presence of both substrates,3-HE1S and 1β-3H-Androstenedione, in the medium and the incubation period is 2 hours. The results were expressed in pmol formed product (3H-E1+3H-E2or3H2O)/2 h/mg DNA (table 1).

(d) alkaline phosphatase Activity

The Ishikawa cells were planted in 96-well microplates for 48 hours prior to the study. The next day, culture medium was replaced free of phenol red medium, supplemented with 5% purified coal dFCS. After 24 hours, culture medium was renewed and the seeded cells dobavlyayte and were cultured for an additional four-day period. For each compound tested concentration ranged from 10-12M to 10-5M, and the final concentration of the medium did not exceed 0.1%. At the end of the incubation period, the activity of alkaline phosphatase (APase) was analyzed by a process comprising the hydrolysis of p-nitrophenylphosphate to p-NITROPHENOL and spectrophotometric determination of product at 405 nm.

Briefly, microplates were first washed twice with cold phosphate buffer solution and then kept at -80°C for at least 15 minutes. After thawing at room temperature, 50 μl of ice solutions containing 5 mm p-nitrophenylphosphate was added to each well. After an incubation period of 15-60 minutes at room temperature the intensity of the yellow color generated by the product p-NITROPHENOL was measured in each well at 405 nm.

For each tested concentration activity Arazi expressed by the absorption coefficient, first expressed as the fold increase compared with control (FI) and then as a percentage of the activity of E2(10-8M), taken as 100%. Were built sigmoid curves dose-response (GraphPad Prism Software), and 50%effective concentration (ESA) were calculated for each compound (table 1).

(e) the Activity of carbonic anhydrase II man

This test was performed as described in literature (J. Armsrong et al. Purification and properties of human erythrocyte carbonic anhydrases, J Biol Chem, 1966, 241: 5137-5149). Briefly, in this test, carbonic anhydrase II human catalyzes the conversion of p-nitrophenylacetate in p-NITROPHENOL. The potential inhibitory effect of the tested compounds was evaluated by the colorimetric determination of p-NITROPHENOL produced during the enzymatic reaction. Levels of optical density obtained without inhibitor, referred to as ' full activity." The levels obtained without inhibitor and without enzyme, referred to as ' control', to assess any impact on the substrate during the test (table 2).

letrozole
Table 1
Inhibition aromatase, follikullarinini activity and estrogenic potential
Aromataza activitySulfatase activityEstrogenic potential
ConnectionIC50((NM) ± S.E.M.nIC50((NM) ± S.E.M.nIC50((NM) ± S.E.M.n
0,47±0,08a8ndb6nd1
anastrozole6,93±1,07a6ndb6nd1
2,5±0,6c4ndc
A*nda32,5±0,5b4nd4
ndc43,6±10,8c4
Example 110,17±0,01a8ndb4nd4
Example 130,17±0,03a 8--nd4
0,05±0,02c4ndc4
Example 140,21±0,05a4ndb1nd4
Example 200,3a1ndb4nd4
Example 220,32±0,40a4--nd1
Example 2650,6a1ndb1--
Example 300,06c1- ---
Example 352,2±0,7c4ndc4--
Example 360,61±0,21c4ndc4--
Example 3752,0±9,6c4ndc4--
Example 400,67±0,10a8--nd3
Example 414,3c1----
Example 430,57±0,16a44nd4
Example 450,13±0,07c43,4±0,4c4nd4
Example 460,79±0,26a413,8±2,5b4nd4
Example 480,82±0,12a42657±257b4nd1
Example 510,34±0,13c4597,2±67,4c4--
Example 611,06±0,21a4ndb4nd1
Example 62 81,8c1ndc1--
A*: 3-cycloheptylmethyl-6-yl-1,1-dioxide-ether sulfamic acid(described in WO2004/101545)
nd: not detected
Materials and methods:andone aromatase activity;bone activity sulfatase;cthe dual activity of aromatase and sulfatase,destrogenic potential.

Among the tested compounds, example 43, example 45 example 46 showed strong inhibition (IC50approximately 10 nm) activity folliclesalready person. In addition, those same compounds showed strong inhibition of aromatase activity (IC50< 1 nm). Despite this dual activity, they did not possess estrogenic potentialin vitro.

Table 2
Inhibition of carbonic anhydrase II man
The activity of carbonic anhydrase II man
ConnectionIC50(nm) ± S.E.M.n
acetazolamide11,3 ± 1,94
6,6,7 COUMATE16,1 ± 1,54
Example 4516,2 ± 3,34
Example 516,5 ± 0,94

Example 45 and Example 51 inhibited carbonic anhydrase II manin vitro.

ANTI-UTEROTROPHIC/ANTI-STORIESLATINA ACTIVITYIN VIVO

Female Wistar rats were removed ovaries and left for 4 weeks. Before treatment, the absence of cycles was examined smears from the vagina. Animals were injected sulfate follikulina (E1S) in an amount of 50 mg/kg/day p/to, individually or in combination with oral introduction of potential inhibitors sulfatase in the amount of 1 mg/kg/day for 4 days. The uterus was removed, was purified from the adjacent tissue and weighed in the wet state (table 3).

Activity folliclesalready was measured according to the method described Purohit et al., with minor changes. Briefly, uteri were thawed, weighed and homogenized. An aliquot of supernatant was treated with the dextran-coated charcoal and analyzed in relation to sulfatase. Activity E1S was evaluated after 30 minutes Inka is then with 5 nm 3H-E1S and 20 μm unlabeled E1S as a substrate. Activity folliclesalready expressed as pmol/h/mg protein and presented as percent inhibition vs E1S; the ratio of the weight of the uterus results were expressed as % inhibition of E1S induced stimulation.

Table 3
Inhibition of the weight of the uterus
ConnectionInhibition %
(the weight of the uterus)
n
6,6,7 COUMATE818
Example 45708

Because there is a direct linear correlation between inhibition sulfatase and inhibition in uterine weight (WO 2004/101545), it can be concluded that this activity against cancer follows from significant inhibition of E1S (>90%). Example 45 was selected as a potential inhibitor activity folliclesalready due to the lack of estrogenic properties and significant inhibition asteroidsurfaces. These resultsin vivoconsistent with the results ofin vitroobtained in cells JEG-3.

The PEAK INHIBITION of ESTRADIOL, ASIN VIVOMO is SPRUCE inhibition of AROMATASE

The purpose of this experiment was to determine the dose-dependent activity of the tested compounds compared to anastrozole in relation to levels of 17β-estradiol 24 hours after a single oral administration to female rats. Anastrozole is a potent, non-steroidal aromatase inhibitor, which significantly inhibits the levels of estradiol and 3 mg/kg, 24 hours after a single oral administration to female rats. One hundred female rats IOPS Wistar weighing 180-200 g were placed at four in the cells of stainless steel. The animals were provided free access to standard diet pellets Harlan Teklad 2016. Swabs from the vagina were collected from each animal every morning to set the different phases of the cycle. Rats that did not have a regular estrous cycle, were excluded from the experiment. Starting from 4.00 PM, animal oral was administered compositions. After 24 hours, took samples of serum and estradiol levels were determined as described above (table 4).

Table 4
Inhibition of peak estradiol
ConnectionInhibition %
(peak estradiol)
Anastrozole56
Example 45/td> 28

Example 45 inhibited peak estradiolin vivo.

INHIBITION of TUMOR GROWTH

MCF-7 xenografts in naked mice

Cells MCF-7 derived from adenocarcinoma of the breast of man, was administered subcutaneously atipicheskim naked mice with remote ovaries, which was subcutaneously injected daily sulfate follikulina. The volume of the xenograft was determined weekly. When the volume of tumors was significantly increased, the test compound is administered orally in the amount of 1 mg/kg/day for 8 weeks. The xenografts measured, removed, weighed and deep freeze for determining the activity of sulfatase, according to the methods used for rat Queens.

ER+ tumor tissue breast man, transplanted in the form xenograft naked rats

Cells MCF-7 (ATCC)derived from adenocarcinoma of the breast of man, was administered subcutaneously atipicheskim naked mice with remote ovaries, which were daily injected subcutaneously estradiol. The volume of the xenograft was determined weekly. After 8 weeks, the tumor volumes reached 1000 mm, providing 500 mg of the sample estrogenconsisting tissue from each animal. At this time each tumor cut layers and re-transplanted naive naked rats with removed ovaries (Rnu/Rnu) Then the animals were treated with sulfate follikulina as a precursor of estradiol in steroidsources.com way. When the tumor volumes reached significant increase than placebo, animals are randomized and divided into two groups. Animals of the first group was treated using the compounds of example 45 and with an additional daily by the introduction of sulfate follikulina. Animals of the second group were injected carrier with the additional introduction of the same amount of sulfate follikulina. Example 45 oral was administered in an amount of 5 mg/kg/day for 5 weeks. The xenografts were measured weekly electronic caliper and compared with the group treated with sulfate follikulina (table 5).

Table 5
Inhibition of tumor human breast
OptionsVolume changes
(expressed as % of E1S-positive control group)
The treatmentTimeDay 7Day 28day 35Day 42
E1S + PR. 450-26-44-39

When the animals were treated with compound of example 45, the volume of tumors was not increased. On the other hand, at the same time, in the groups receiving only the sulfate follikulina (E1S), the tumor volumes were higher. At the end of the experiment, after five weeks of daily treatment, example 45 was led to a 40%increase reduction in tumor volume, demonstrating clear and stable anticarcinogenic activity.

Xenograft JEG-3 in naked mice

Cell line JEG-3 superexpression as aromatase person and folliculipalpus. It is injected subcutaneously atipicheskim naked mice with remote ovaries, which additional daily subcutaneously injected sulfate follikulina with test compounds or without them (in an amount of 5 mg/kg/day). In that special case, and according to their semi-fluid status (choriocarcinoma origin), measurement of tumor are irrelevant. However, the indirect effect of estradiol, which is primarily synthesized by tumor tissue, obtained on the basis of the mass of females. On the other hand, because of superexpression aromatase and sulfatase in such tumors enzyme levels can be measured. The enzymatic activity determined according to the above methods.

Xenograft JEG-3 bare rats with the addition of sulfate follikulina and Δ4-Androstenedione

15 days before the nycli cells JEG-3 rats, took blood samples to measure basal levels of estradiol in plasma. Then cells JEG-3 injected subcutaneously atipicheskim naked rats with removed ovaries (Rnu/Rnu). Animals additionally daily was administered subcutaneously sulfate follikulina and Δ4-Androstenedione with the test compound or without (1 mg/kg/day). After a 21-day period, blood sampling was performed after one day after the introduction malignant xenograft and in the end of the experiment. In this experiment, sulfate follikulina and Δ4-Androstenedione are precursors to estradiol. The effect of estradiol is reflected in the weight of the uterus after the killing. Plasma hormone levels analyzed at the end of the experiments according to the standard method provider (DSL, Webster, TX, USA).

1. Derived imidazole of the formula (I)

and its salts with an acid, where
R1and R2represent hydrogen;
Q represents(CH2)m-X-(CH2)n-A;
And denotes a direct bond, O, SO2, NR5;
X denotes a direct bond, O, SO2C(O) or NR5;
Z denotes a group chosen from:

m and n denote, each independently, 0, 1, 2, 3 or 4;
p denotes 1, 2, 3 or 4;
q denotes 0, 1 or 2;
the dotted line means that R8the/or R 9can be in any position benzothiophene ring;
R3and R8denote, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11,
SO2NR10R11, OSO2NR10R11or NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10;
when Q-Z means

n denotes 0, 1 or 2 and p represents 1, one of R3and R8denotes hydroxy, nitro, NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10,
CONR10R11and the other denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, CO2R10;
R4and R9denote, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1 -C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11,
SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR12SO2NR10R11, CO2R10CHO;
when p represents 2, 3 or 4, R9may be the same or different;
R6and R7represent hydrogen;
each R5, R10, R11and R12denotes hydrogen;
when Z represents

and p denotes 1,
then R8and R9can also form together with the phenyl ring dioxide benzoxadiazole.

2. The derivative according to claim 1 and salts thereof with an acid, in which:
one of R3and R8denotes hydroxy, nitro, NR10R11, OSO2NR10R11or
NR12SO2NR10R11;
another denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl,
(C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, OSO2NR10R11, NR12SO2NR10R11.

3. The derivative according to claim 1 or 2, and with whom and with acid, where:
one of R3and R8denotes hydroxy, cyano, (C1-C6)alkoxy or OSO2NR10R11;
another denotes hydrogen or hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy,
NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11, OSO2NR10SO2NR11R12.

4. The derivative according to claim 1 or 2, and salts thereof with an acid, in which:
one of R3and R8denotes cyano; and
another denotes hydrogen or hydroxy, halogen, nitro, (C1-C6)alkoxy, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11.

5. The derivative according to claim 1 or 2, and salts thereof with an acid, in which:
R4and R9denote, each independently, hydrogen, hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, OSO2NR10R11,
NR12SO2NR10R11, CO2R10or SNO.

6. The derivative according to claim 5 and its salts with acids, in which:
one of R4and R9denotes hydrogen or hydroxy, cyano or OSO2NR10R11; and
another denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl,
(C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10, SNO, NR12SO2NR10R11.

7. The derivative according to claim 6 and its salts with acids, in which:
R4denotes hydrogen, hydroxy, cyano or OSO2NR10R11;
R9denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10CHO.

8. The derivative according to claim 7 and its salts with acids, in which:
R4denotes hydrogen; and
R9denotes hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10CHO or NR12SO2NR10R11.

9. The derivative according to claim 1 or 2, and salts thereof with an acid, in which Z means:

where R8denotes hydrogen, hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy, NR10R11, SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11or OSO2NR10SO2NR11R 12;
R9denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10CHO, NR12SO2NR10R11;
p and q have the meanings given in claim 1.

10. The derivative according to claim 1 or 2, and salts thereof with an acid, in which Q is selected from a direct link, C(O), SO2, CONH, C(O)(CH2)n, (CH2)n(O) or (CH2)nwhere n denotes 0, 1 or 2.

11. The derivative according to claim 1 and salts thereof with an acid, in which:
Z denotes

Q represents (CH2)nwhere n denotes 0, 1 or 2;
one of R3and R8denotes hydroxy, nitro, NR10R11, OSO2NR10R11or
NR12SO2NR10R11and the other denotes hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, OSO2NR10R11or NR12SO2NR10R11;
R4and R9denote, each independently, hydrogen, hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)and is kiltie, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, carboxamido, NR10R11, OSO2NR10R11or NR12SO2NR10R11;
each R10and R11denotes hydrogen;
p denotes 1, 2, 3 or 4;
R8and R9together with the phenyl ring to which they are attached, can also form dioxide benzoxadiazole.

12. Derived in paragraph 11 and its salts with acids, in which:
Z denotes

Q represents(CH2)nwhere n denotes 0, 1 or 2;
R8denotes hydroxy, halogen, nitro, cyano or (C1-C6)alkoxy, NR10R11,
SO2NR10R11, OSO2NR10R11or NR12SO2NR10R11;
R9denotes hydrogen, hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11;
p has the meaning given in claim 1.

13. Derived in section 12 and its salts with acids, in which:
n denotes 0 or 1;
R4and R9denote, each independently, hydrogen, halogen, (C1-C6)alkoxy, acyl,
NR10R11, OSO2NR10R11or NR12SO2NR10R11.

14. Derivative according to any one of § § 11-13 and its salts with acids, in which
n denotes 0 or 1;
R1, R2and R4denote each hydrogen;
R9denotes hydrogen, halogen, (C1-C6)alkyl or OSO2NR10R11.

15. Derived in paragraph 11 and its salts with acids, in which:
n and p represent 1;
R8denotes hydroxy, halogen, nitro, cyano, (C1-C6)alkoxy, NR10R11,
SO2NR10R11, OSO2NR10R11, NR12SO2NR10R11or OSO2NR10SO2NR11R12;
R9denotes hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, NR10R11, OSO2NR10R11, CO2R10or SNO;
R3denotes cyano, hydroxy, OSO2NR10R11or NR12SO2NR10R11;
R4denotes hydrogen, hydroxy, halogen, cyano or OSO2NR10R11.

16. Derived in paragraph 11 and its salts with acids, in which one of R3and R8denotes a hydroxy, cyano or OSO2NR10R11and the other represents hydroxy, nitro, NR10R11, OSO2NR10R11or NR12SO2NR10R11.

17. The derivative of the P16 and its salts with acids, in which one of R3and R8denotes cyano or OSO2NR10R11and the other seat is no hydroxy or OSO 2NR10R11.

18. The derivative according to claim 1 or 2, and salts thereof with an acid, in which:
Z denotes

where Q denotes (CH2)m-X-(CH2)n-A-;
And denotes a direct bond or O, SO2, NR5;
X denotes a direct bond, O, SO2With(O) or NR5;
m and n denote, each independently, 0, 1, 2, 3 or 4;
R3, R4, R8and R9denote, each independently, hydrogen or hydroxy, cyano, halogen, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, (C1-C6)alkylthio, (C1-C6)alkylsulfonyl, acyl, (C1-C6)alkoxycarbonyl, NR10R11, SO2NR10R11,
OSO2NR10R11or NR12SO2NR10R11;
q denotes 0, 1 or 2;
each R5, R6, R7, R10, R11and R12denotes hydrogen;
the dotted line means that R8and/or R9can be in any position benzothiophene rings.

19. Derived by p and its salts with acids, in which R8does
OSO2NR10R11or NR12SO2NR10R11.

20. The derivative according to claim 19, in which R9denotes hydrogen, halogen, nitro, COOR10or cyano.

21. Derived by p, in which R4denotes hydrogen, halogen,cyano, (C1-C6)alkoxy, NR10R11, OSO2NR10R11or NR12SO2NR10R11.

22. Derived by p, in which Q denotes (CH2)m-X-(CH2)n-A, where m denotes 0, 1 or 2 and X represents a direct link, SO2or, n represents 0 and a denotes a direct link.

23. Derived by p, in which R3denotes hydrogen, halogen or cyano.

24. The derivative according to claim 1 or 2, and salts thereof with an acid, in which:
Z denotes a group:

in which R8, R9and p have the meanings given in claim 1.

25. The derivative of the point 24 and its salts with acids, in which:
R3denotes cyano or OSO2NR10R11;
R4denotes hydrogen, hydroxyl, halogen, cyano, OSO2NR10R11;
R8denotes hydroxy, cyano, OSO2NR10R11, NR10R11, NR12SO2NR10R11;
R9denotes hydrogen, halogen, nitro, cyano or CO2R10;
Q has the meaning given in paragraph 10.

26. Pharmaceutical composition having inhibitory activity against aromatase, and/or asteroidsurfaces, and/or carbonic anhydrase containing derivative according to any one of claims 1 to 25 or its pharmaceutically acceptable salt with an acid and a pharmaceutically acceptable carrier.

27. F the pharmaceutical composition according p, containing from 0.1 to 400 mg of the indicated derivative.

28. The use of a derivative according to any one of claims 1 to 25 or its pharmaceutically acceptable salt with the acid for the manufacture of a medicinal product for the treatment or prevention of hormone-dependent or gormononezawisimy tumors.

29. The use of a derivative according to any one of claims 1 to 25 or its pharmaceutically acceptable salt with the acid for the manufacture of a medicinal product for monitoring or controlling reproductive functions.

30. The use of a derivative according to any one of claims 1 to 25 or its pharmaceutically acceptable salt with the acid for the manufacture of a medicinal product for the treatment or prevention of benign or malignant diseases of the breast, uterus or ovary.

31. The use of a derivative according to any one of claims 1 to 25 or its pharmaceutically acceptable salt with the acid for the manufacture of a medicinal product for the treatment or prevention of androgenozavisimaya diseases or benign or malignant diseases of the prostate or testis.

32. The use of a derivative according to any one of claims 1 to 25 or its pharmaceutically acceptable salt with the acid for the manufacture of a medicinal product for the treatment or prevention of disorders of cognitive function.

33. Use p for the manufacture of a medicinal product for treatment is or prevention of senile dementia.

34. Use p for the manufacture of a medicinal product for the treatment or prevention of Alzheimer's disease.

35. The use of a derivative according to any one of claims 1 to 25 or its pharmaceutically acceptable salt with the acid for the manufacture of a medicinal product for the treatment or prevention of immunological disorders.

36. The use of a derivative according to any one of claims 1 to 25 or its pharmaceutically acceptable salt with the acid for the manufacture of a medicinal product for the treatment or prevention of pathologies that require the inhibition of aromatase, and/or asteroidsurfaces, and/or carbonic anhydrase.



 

Same patents:

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

The invention relates to new heterocycles compounds, more particularly to a new heterocycles compounds which are inhibitors of the enzyme 5-lipoxygenase (5-LO)

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention is related to the compound of general formula 1 or its tautomer or pharmaceutically acceptable salt, where W selected from N and CR4; X is selected from CH(R8), O, S, N(R8), C(=O), C(=O)O, C(=O)N(R8), OC(=O), N(R8)C(=O), C(R8)-CH and C(=R8); G1 - bicyclic or tricyclic condensed derivative of azepin, selected from general formulas 2-9 , or derivative of aniline of common formula 10 , where A1, A4, A7 and A10 are independently selected from CH2, C=O, O and NR10; A2, A3, A9, A11, A13, A14, A15, A19 and A20 are independently selected from CH and N; or A5 stands for covalent connection, and A6 represents S; or A5 stands for N=CH, and A6 represents covalent connection; A8 , A12 , A18 and A21 are independently selected from CH=CH, NH, NCH3 and S; A16 and A17 both represent CH2, or one from A16 and A17 represents CH2, and the one another is selected from C=O, CH(OH), CF2, O, SOc and NR10; Y is selected from CH=CH or S; R1 and R2 are independently selected from H, F, Cl, Br, alkyl, CF3 and group O-alkyl; R3 is selected from H and alkyl; R4-R7 are independently selected from H, F, Cl, Br, alkyl, CF3, OH and group O-alkyl; R8 is selected from H, (CH2)bR9 and (C=O)(CH2)bR9; R9 is selected from H, alkyl, possibly substituted aryl, possibly substituted heteroaryl, OH, groups O-alkyl, OC(=O)alkyl, NH2, NHalkyl, N(alkyl)2, CHO, CO2H, CO2alkyl, CONH2, CONHalkyl, CON(alkyl)2 and CN; R10 is selected from H, alkyl, group COalkyl and (CH2)dOH; R11 is selected from alkyl, (CH2)dAr, (CH2)dOH, (CH2)dNH2, group (CH2)aCOOalkyl, (CH2)dCOOH and (CH2)dOAr; R12 and R13 are independently selected from H, alkyl, F, CI, Br, CH(OCH3)2, CHF2, CF3, groups COOalkyl, CONHalkyl, (CH2)dNHCH2Ar, CON(alkyl)2, CHO, COOH, (CH2)dOH, (CH2)dNH2, N(alkyl)2, CONH(CH2)dAr and Ar; Ar is selected from possibly substituted heterocycles or possibly substituted phenyl; a is selected from 1, 2 and 3; b is selected from 1, 2, 3 and 4; c is selected from 0, 1 and 2; and d is selected from 0, 1, 2 and 3. Besides, the invention is related to pharmaceutical compound and to method for activation of vasopressin receptors of type 2.

EFFECT: compounds according to invention represent agonists of receptor of vasopressin V2, which stipulates for their application (another object of invention) for preparation of medicine for treatment of condition selected from polyuria, including polyuria, which is due to central diabetes insipidus, nocturnal enuresis of nocturnal polyurea, for control of enuresis, to postpone bladder emptying and for treatment of disorders related to bleeds.

21 cl, 228 ex

FIELD: chemistry.

SUBSTANCE: invention refers to Sertaconasole mononitrate process by reaction of 1-(2,4-dichlorphenyl)-2-(1H-imidazole-1-yl)ethanol and 3-bromomethyl-7-chlorbenzo[b]thiophene with tetrabutylammonium hydrosulphate and sodium hydroxide in toluene at 30-45°C. Produced free base of Sertaconasole is transferred into Sertaconasole mononitrate monohydrate with the latter being transferred into Sertaconasole mononitrate. There is disclosed and characterised intermediate Sertaconasole mononitrate monohydrate.

EFFECT: method allows simplifying process technology considerably.

6 cl, 5 dwg, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with general formula I, where R1 represents -(CHR')q-aryl or -(CHR')q-thiophen, which are unsubstituted or mono-, di- or tri-substituted with (inferior)alkyl, (inferior)alkoxy, CF3 or haloid, or represents (inferior)alkyl, (inferior)alkenyl, -(CH2)n-Si(CH3)3, -(CH2)n-O-(inferior)alkyl, -(CH2)n-S- (inferior)alkyl, -(CH2)q-cycloalkyl, -(CH2)n-[CH(OH)]m-(CF2)p-CHqF(3-q), or represents -(CH2)n-CR2-CF3, where two radicals R together with a carbon atom form a cycloalkyl ring; R' represents hydrogen or (inferior)alkyl; n is 1, 2 or 3; m is 0 or 1; p is 0, 1,2, 3, 4, 5 or 6; q is 0, 1, 2 or 3; R2 represents hydrogen or (inferior)alkyl; R3 represents hydrogen, (inferior)alkyl, CH2F, aryl, optionally mono-, di- or tri-substituted with a haloid, or represents -(CH2)nNR5R6, where R5 and R6 independently represent hydrogen or (inferior)alkyl; R4 represents one of the following groups a) or b), where R7 represents inferior)alkyl or -(CH2)ncycloalkyl; R8 and R9 independently represent hydrogen, (inferior)alkyl, -(CH2)n-cycloalkyl or -C(O)-phenyl. The invention also relates to pharmaceutically used acid addition salts of these compounds, optically pure enantiomers, racemates or diastereomeric mixtures, as well as compounds with general formula I-1, and medicinal agent.

EFFECT: obtaining new biologically active compounds, designed for inhibiting γ-secretase.

16 cl, 83 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel compound represented by formula I, where R1 and R2 are similar or different and each represents: (I) C1-10alkyl group optionally substituted with 1-3 substituents selected from C3-10cycloalkyl group, C1-6alkoxycarbonyl group b C1-6alkoxygroup; (2) C6-14aryl group optionally substituted with 1-3 substituents selected from halogen atom, carboxyl group, C1-6alkoxycabonyl group b carbamoyl group; or (3) C7-13aralkyl group; R3 represents C6-14aryl group optionally substituted with 1-3 substituents selected from C1-6alkyl group, optionally substituted with 1-3 halogen atoms, halogen atom, C1-6alkoxycarbonyl group, carboxyl group, hydroxy group, C1-6alkoxygroup, optionally substituted with 1-3 halogen atoms; R4 represents amino group; L represents C1-10alkylene group; Q represents bond, C1-10alkylene group or C2-10alkenylene group; and X represents: (1) hydrogen atom; (2) cyanogroup; (3) (3a) carboxyl group; (3b) carbamoyl group; and further as presented in invention formula. Invention also describes medication for treating diabetes, peptidase inhibitor, application of formula I compound, method of prevention or treatment of diabetes, method of peptidase inhibiting and method of obtaining formula I compounds.

EFFECT: obtaining novel compounds which have peptidase-inhibiting activity and are useful as medication for prevention and treatment of diabetes.

16 cl, 433 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds satisfying general formula (I): where: R1 stands for direct or branched (C1-C7)alkyl, X stands for hydrogen atom, R2 stands for the group chosen from naphthalenyl, pyridinyl, isoquinoleinyl, thienyl, imidazolyl, benzothienyl, benzimidazolyl, indolyl, benzotriazolyl and optionally substituted with one or more substitutes chosen from halogen atoms and following groups: (C1-C4)alkyls, thio(C1-C4)alkyls or phenyls, optionally substituted with one or more substitutes chosen from halogen atoms or trifluoromethyl, as free base or additive salt with acid. Additionally, the invention concerns medical product, pharmaceutical composition, and application.

EFFECT: production of new biologically active compounds active to specific inhibitors of glycine glyt 1 and/or glyt 2 carriers.

6 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns enantiomers of thiophene hydroxami acid derivatives of general formula I and their pharmaceutically acceptable salts. , where Ar is aryl or heteroaryl group selected out of thiophene, morpholine, which can be non-substituted or mono-, di- or trisubstituted by halogen, phenyl, alkyl, -O-alkyl, -OH; R1 is hydrogen, phenyl or alkyl; together with Ar-group R1 forms tetrahydronaphthaline or indane cycle; R2 is hydrogen or alkyl; and their pharmaceutically acceptable salts.

EFFECT: application as histondesacetylase inhibitors in obtaining medicine for neoplasm treatment in hemopoietic and lymphatic system.

29 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new 2-pyridone derivatives of formula (I): where R1, R2, R4, R5, G1, G2, L, Y and n are as specified in the invention formula, and their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy. These compounds have neutrophil elastase inhibition effect.

EFFECT: new compounds with useful biological properties.

7 cl, 1 tbl, 150 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) , where R1 is phenyl optionally substituted by halogen, cyano, C1-4alkyl or C1-4haloalkyl; R2 is hydrogen, C1-6alkyl or C3-6cycloalkyl; and R3 is a group with NH or OH and calculated or measured pKa from 1.0 to 8.0, selected out of: 2-oxo-thiazol-5-yl with C1-4fluoroalkyl, optionally substituted phenyl group, optionally substituted heterocyclyl group or CH2S(O)2(C1-4alkyl) group in position 4; 2-oxo-oxazol-5-yl with C1-4fluoroalkyl or CH2S(O)2(C1-4alkyl) in position 4; 1H-1,2,3-triazol-4-yl with C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, S-R4 (where R4 is C1-4alkyl, C1-4fluoroalkyl or C3-6cycloalkyl), NHS(O)2(C1-4alkyl), N(C1-4alkyl)S(O)2(C1-4alkyl), phenyl group, heterocyclyl group or CH2S(O)2C1-4alkyl) group in position 5; 4-oxo-1H-1,4-dihydropyridine-3-yl with C1-4fluoroalkyl in position 2; 2,6-dioxo-1H-1,2,3,6-tetrahydropyrimidine-4-yl with C1-4alkyl, C3-6cycloalkyl or CH2(C1-3fluoroalkyl) in position 3 and optionally substituted in one or more other ring positions; 6-oxo-1H-1,6-dihydropyridine-3-yl with C1-4fluoroalkyl, cyano or phenyl in position 2 and/or in position 5 and optionally substituted in one or more other ring positions; 6-oxo-1H-1,6-dihydropyridine-3-yl with CH2CO2H at ring nitrogen atom and optionally substituted in one or more other ring positions; 2H-tetrazol-5-yl; CO2H, CH2CO2H or OCH2CO2H group at optionally substituted phenyl, optionally substituted CH2O phenyl or optionally substituted naphtyl ring or optionally substituted acylated dihydroisoquinolinyl ring; or group NHS(O)2(C1-4alkyl) at optionally substituted aromatic heterocyclic ring; or their tautomer where possible; in indicated positions where heterocyclyl ring in R3 can be optionally substituted, it can be optionally substituted by fluoro, chloro, bromo, C1-4alkyl, C3-6cycloalkyl, C1-4fluoroalkyl, S-R4 (where R4 is C1-4alkyl, C1-4fluoroalkyl or C3-6cycloalkyl), cyano, S(O)2(C1-4alkyl); in indicated positions where phenyl or naphtyl ring in R3 can be optionally substituted, it can be optionally substituted by halogen, cyano, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, OCF3, SCF3, nitro, S(C1-4alkyl), S(O)(C1-4alkyl), S(O)2(C1-4alkyl), S(O)2NH(C1-4alkyl), S(O)2N(C1-4alkyl)2, NHC(O)(C1-4alkyl) or NHS(O)2(C1-4alkyl); or its pharmaceutically acceptable salts. Also invention concerns compounds of formula (I), method of obtaining compounds of any of claims 1-12, as well as pharmaceutical composition.

EFFECT: obtaining novel bioactive compounds with chemokine receptor activity modulation effect.

16 cl, 51 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

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

25 cl, 1 tbl, 14 ex

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new amino acid derivatives and their pharmaceutically acceptable salts, specifically to new amino acid derivatives and their pharmaceutically acceptable salts, which have an inhibiting activity against renin, to methods for their preparation, to pharmaceutical compositions containing them and to a method for the treatment of hypertension and heart failure in humans or animals

The invention relates to the separation and purification of 2-methylimidazole, which is an intermediate for the synthesis of antitrichomonas, protivoallergennogo drug metronidazole and accelerator curing epoxy resins
The invention relates to methods for C-alkylimidazole, in particular 2-substituted imidazoles
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