Indasoles, benzisoxazoles and benzisotiazoles, method of their obtaining, pharmaceutical compositions and application as estrogenic medications

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess qualities to estrogen modulators, of general formula (1) or its pharmaceutically acceptable salt, where R1 represents hydrogen atom or (C1-C6)alkyl, -SO2NR7R8, phenyl (C1-C3)alkyl or (C1-C3)alkyl, substituted with 5-8-member heterocyclic radical, containing nitrogen atom; R2 and R3 each independently represents hydrogen atom or hydroxyl, halogen atom or (C1-C6)alkoxy; X represents O, S, SO, SO2 or NR4; R4 represents hydrogen atom or (C1-C6)alkyl, phenyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted with 5-8-member saturated heterocyclic radical, containing one nitrogen atom, or group -COR7, -CO2R7 or -SO2NR7R8, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom or phenyl(C1-C3)alkoxy; Y represents direct bond, -(CR10R11)n- or -R10C=CR11-; R7 and R8 each independently represents hydrogen atom or (C1-C6)alkyl group; R10 and R11 each independently represent hydrogen atom or cyano, or group CONR7R8; n equals 1 or 2; A represents (C3-C12)cycloalkyl or phenyl, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom, (C1-C3)alkyl, (C1-C3)alkoxy; when X represents NR4, Y and R2 together with containing them indazole cycle can also form 1H-pyrano[4,3,2-cd)indazole; on condition that: 1) when X represents O, S or NR4, R1 represents hydrogen atom or (C1-C6)alkyl, and Y stands for direct bond, then A is not optionally substituted phenyl; 2) when X represents O, R1O represents 6-OH or 6-OCH3, Y represents direct bond and A represents cyclopeptyl, then (R2, R3) or (R3, R2) are different from (H, CI) in position 4, 5; 3) when X stands for O, R1O represents 6-OH, R2 and R3 represent H, and Y represents CH=CH, then A is not phenyl or methoxyphenyl; 4) when X represents SO2, A represents phenyl and R1O represents 5-or 6-OCH3, then (R2, R3) or (R3, R2) are different from (H, OCH3) in position 6- or 5-, compound not being one of the following: 3-phenyl-5-(phenylmethoxy)-1H-indazole; n-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5]isoxazole; 3-(4-chlorphenylmethyl)-6-hydroxy-7-(n-propyl)-benz[4,5]isoxazole; 6-hydroxy-3-(2-phenylethyl)-7(n-propyl)-benz[4,5]isoxazole; 3-cyclopropyl-6-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5|isoxazole; 3-cyclohexylmethyl-6-hydroxy-3-phenylmethyl-7-propyl-benz[4,5]isoxazole. Invention also relates to pharmaceutical composition, application and method of prevention and treatment of disease, where modulation of estrogen receptors is required.

EFFECT: obtaining novel compounds, which possess qualities of estrogen receptors modulators.

18 cl, 7 dwg, 8 tbl, 97 ex

 

The technical field to which the invention relates

The present invention relates to non-steroidal compounds having affinity to estrogen receptors. In particular, the present invention relates to the derivatives of indazole, benzisoxazole and benzisothiazole as modulators of subtypes of estrogen receptor and/or selective modulators of estrogen receptor (SERM). The present invention relates also to pharmaceutical compositions containing these compounds and to the use of such compounds in the treatment of diseases caused by estrogen.

The level of technology

The end of the reproductive period of a person's life can often be accompanied causing inconvenience and destructive symptoms, and one of the most common are hot flashes. Perimenopause, or preclimax represents ongoing for several years the period during which the normal cycle of ovulation is followed by the cessation of menstruation. This period is characterized by irregular menstrual cycles. The duration of the cycles begins to increase, and ovulation and fertility decline. Menopause is usually defined as the point in time, after the loss of ovarian activity, when menstruation stops completely. In addition, estrogens are involved in various other Phi is Biologicheskie processes, such as modulation of the immune response and the development of cancer (breast cancer, endometrial, colon, prostate). It was shown that ERα is involved in several diseases such as breast cancer and osteoporosis.

Reliably established that estrogens play an important role in the development and homeostasis reproductive, Central nervous, skeletal and cardiovascular systems in both men and women. Currently found in the brain, many estrogen receptors, which are involved in various processes such as the regulation of mood and temperature, sleep, susceptibility to epileptic seizures, the propagation mechanisms of pain and cognitive function (Toran-Allerand, Endocrinology, 2004, 145, 1069-1074).

It is now known that estrogen receptor (ER) is a nuclear receptor with two known different subtypes. Recently was discovered (Mosselman et al., FEBS Letters, 1996, 392, 49-53) new ERβ subtype that is different from the known subtypes ERα (Green, Nature, 1986, 320, 134-139). These subtypes have different biological role and can find selective and effective clinical use (Harris H.A., Endocrinology, 2002, 143, 11, 4172-4177). The ligand-binding region of the ER subtypes are approximately 50% identical (Kuiper et al., Endocrinology, 1998, 139(10), 4252-4263), they have similar affinity binding to estradiol (E2and capable of hetero - and homodimerization (Cowley, J. Biol. hem., 1997, 272, 19858-19862) with the formation of the signaling complex (Kuiper et al., Endocrinology, 1997, 138(10), 863-870; Kuiper, Proc. Natl. Acad. Sci. USA, 1996, 93, 5925-5930). ERβ with high levels is expressed in several tissues, including the epithelium of the prostate (Z. Weihua, Proc. Natl. Acad. Sci. USA, 2001, 98, 6330-635), sinteticheskie ganglia (Zoubina E.V., J. Urol., 2003, 169, 382-385), the colon (Witte D., Hum. Pathol., 2001, 32, 940-944), the bladder, the granular cells of the ovary (Nilsson, S., Physiol. Rev., 2001, 81, 1535-1565), bone marrow (Shim G.J., Proc. Natl. Acad. Sci. USA, 2003, 100, 6694-6699), stroma of the mammary gland (Cunha G.R., J. Mammary Gland Biol. Neoplasia, 1997, 2, 393-402), lung, bowel, vascular endothelium of the dorsal line splicing, part of the brain (Mitra S.W., Endocrinology, 2003, 144, 2055-2067, Krel W., Proc. Natl. Acad. Sci. USA, 2001, 98, 12278-12282). ERα is expressed in the epithelium of the breast (Palmieri C., Endocr. Relat. Cancer, 2002, 9, 1-13), bone, tech cells (J. Couse, Endocr. Rev., 1999, 20, 358-417), stroma of the prostate (Chu, S., Mol. Cell Endocrinol., 1997, 132, 195-199), liver, testes. The fact that the detected compounds with specific activity to one or the other subtype, can provide selective treatment estrogenzawisimy diseases such as Alzheimer's disease, climacteric complaints in the period (in particular, hot flashes, vaginal dryness, atrophy), impaired cognitive functions (in particular, fear, depression, dementia, osteoporosis, estrogenzawisimy tumors (cancer of the uterus, breast, colon or prostate cancer), benign is prostatic hyperplasia, the function of the bladder, disorders of hearing, stroke, leukemia, hypertension, obesity, syndrome level becomes too low intestinal, or reproductive aspects, such as contraception or fertility. ERβ-selective ligands may be therapeutically useful in the treatment of chronic inflammation of the intestines and joints (Harris et coll., Endocrinology, 2003, 144, 4241-4249).

According Warembourg M. and Leroy D. (Brain Res., 2004, 26; 55-56) ERβ was detected only in the spinal cell line splicing in rats. On the contrary, only immunoactivity ERα was detected in the septum and in the magnocellular supraopticus, paraventrikulyarnoe, arched and prelimilary nuclei. These observations demonstrate the presence of different neuro-anatomical pattern for the two subtypes of estrogen receptors. Localization of ERβ in serotonergic cells proves the link between ERβ and serotonergic pathway. Finally, Cyr M. et al. report (J. Psychiatry Neurosci., 2002, 27, 12-27) effect of selective modulators of estrogen receptor (SERM), such as raloxifene, on the receptor 5-NTA.

Therefore, it is reasonable to develop modulators ERβ as compounds of interest for the treatment of schizophrenia, neurodegenerative diseases such as Alzheimer's and Parkinson's disease. For the same reasons modulators ERβ should be of interest as Nar is protective, antidepressant or anti-fobia sedatives.

However, two of the receptor, which act as ligand-activated transcription factors were detected in different tissues, and their binding pocket differs by only two amino acids: Leu and Met in ERα, Met and Ile in ERβ. These similarities can be explained by the fact that the regulation subtype of alpha or beta leads to the same pharmacological effect as is the case preclinical model of the phenomenon of the tides. While the modulator of ERα reduces the occurrence of “tides” in preclinical models in rats (Harris et al., Endocrinology, 2002, 143, 4172-4177), selective modulators of estrogen receptor, such as derivatives of spyroidea, which have affinity to both subtypes have the same effect on “tides” (Watanabe et al., J. Med. Chem., 2003, 46, 3961-3964).

It was also shown that estrogen receptors are able to suppress NFKB-mediated transcription as ligand-dependent and ligand-independent manner (Quaedackers et al., Endocrinology 2001, 142: 1156-1166; br et al., Journal of Steroid Biochemistry & Molecular Biology 1998, 67: 233-240; Pelzer et al., Biochemical &Biophysical Research Communications 2001, 286: 1153-7). These data suggest a link between selective modulators of estrogen receptor and NFKB, which is involved in apoptosis and immune/inflammatory response.

Many of the compounds described in ka is este agonists or antagonists of the estrogen receptor, because they respectively have similar activity or block the activity of estradiol. Such compounds agonists can be used as a contraceptive for women in the premenopausal period. Antagonists are widely used as therapeutic agents in the treatment of breast cancer (Vogel, Anticancer Drugs, 2003, 14, 265-273), whereas agonists are used to perform HRT (hormone replacement therapy) in women postclimacteric period (Burkman, Minerva Ginecol, 2003, 55, 107-116) for treatment of hot flashes, vaginal atrophy. SERMs are compounds that, depending on the tissues have mixed activity (McDonnell, J. Soc. Gynecol. Invest., 2000, 7, S10-S15). SERMs can be useful in the treatment of osteoporosis, cardiovascular diseases and diseases related to estrogen receptor.

Upon binding with the ligands of the estrogen receptors adopt different conformations. Decoding three-dimensional structures of ERα and ERβ conducted by joint crystallization with different ligands (Pike, A. C. W., EMBO J. 1999, 18, 4608-4618; Shiau, A. K., Cell, 1998, 95, 927-937). Each of the ligands affects the conformation of the receptor ERα or ERβ and leads to the manifestation of different biological activity.

Various compounds, represented as estrogenic tools described in US 2003/0207927 A1 and US 2003/0171412 A1. Derivatives indazole, presents the s as blockers of potassium channels, described in WO 2004/043354 and WO 2004/043933. The synthesis of various isoxazoles described in Ind. J. Chem. 1980, 19B: 571-575. Intermediate benzisoxazole connection used in receiving diuretics, described in Chem. Pharm. Bull. 1991, 39(7): 1760-1772. The synthesis of various benzisothiazole described in Tetrahedron 1988, 44(10): 2985-2992.

The invention

One aspect of the present invention relates to derivatives of indazole, benzisoxazole and benzisothiazole, which have affinity to estrogen receptors.

Another aspect of the invention relates to pharmaceutical compositions containing the above derivative indazole, benzisoxazole and benzisothiazole.

Another aspect of the invention concerns the application of the derived indazole, benzisoxazole and benzisothiazole for the preparation of drugs for treatment or prevention of various diseases mediated by estrogen receptors.

Derivatives indazole, benzisoxazole and benzisothiazole of the present invention can be represented by the following General formula (I):

where:

- R1means a hydrogen atom or (C1-C6)alkyl, (C3-C6)cycloalkyl, trifluoromethyl group,- N=CR5R6, -SO2NR7R8, phenyl, phenyl(C1-C3)alkyl or (C1-C3)alkyl, substituted saturated hetero is ilicheskom radical, where the phenyl is not substituted or is substituted by at least one Deputy, selected from the group which consists of hydroxyl, halogen atom, nitro, cyano, (C1-C3)alkyl, (C1-C3)alkoxy and trifluoromethyl; R1can also be salt;

- R2and R3each independently means a hydrogen atom or a hydroxyl, a halogen atom, nitro, cyano, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, trifluoromethyl, a group-NR7R8, -CONR7R8, -COR9or-CO2R9; R2can also be a phenyl or a saturated or unsaturated heterocycle, where the phenyl is not substituted or is substituted by at least one Deputy, selected from the group which consists of hydroxyl, halogen atom, nitro, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, trifluoromethyl and saturated heterocyclic radical;

- X means O, S, SO, SO2or NR4;

- R4means a hydrogen atom or (C1-C6)alkyl, (C3-C6)cycloalkyl, phenyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted saturated heterocyclic radical, a group-COR7, -CO2R7or-SO2NR7R8where the phenyl is not substituted or is substituted by at least one Deputy, selected from the group which includes hydro the forces, halogen atom, nitro, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, trifluoromethyl, phenyl(C1-C3)alkyl or phenyl(C1-C3)alkoxy;

Y represents a direct bond, O, S, SO, SO2, NR4WITH, -(CR10R11)nor R10C=CR11-;

- R5, R6, R7and R8each independently represent a hydrogen atom or (C1-C6)alkyl or (C3-C6)cycloalkyl group;

- R9means a hydrogen atom, (C1-C6)alkyl, phenyl or a saturated or unsaturated heterocyclic radical, where the phenyl is not substituted or is substituted by at least one Deputy, selected from the group which consists of hydroxyl, halogen atom, nitro, cyano, (C1-C3)alkyl, (C1-C3)alkoxy, trifluoromethyl and saturated heterocyclic radical;

- R10and R11each independently represent a hydrogen atom or a cyano, (C1-C6)alkyl, -CO-phenyl,- (unsaturated heterocyclic radical or a group-ONR7R8where the phenyl is not substituted or is substituted by at least one Deputy, selected from the group which consists of hydroxyl, halogen atom, nitro, cyano, (C1-C3)alkyl, (C1-C3)alkoxy and trifluoromethyl;

- n is 1 or 2;

- Means (C3-C15)cycloalkyl, (C3 -C15)cycloalkyl, phenyl or naphthyl, where cycloalkyl or cycloalkyl not substituted or is substituted by at least one (C1-C6)alkyl, and where phenyl or naphthyl are not substituted or is substituted by at least one Deputy, selected from the group which consists of hydroxyl, halogen atom, nitro, cyano, (C1-C3)alkyl, (C1-C3)alkoxy and trifluoromethyl;

- when X is NR4then the Y and R2together with the containing indazol cycle can also form 1H-pyrano[4,3,2-cd]indazol.

Claimed compounds of the formula (I), except:

1) when X is O, S or NR4, R1denotes a hydrogen atom or (C1-C6)alkyl, (C3-C6)cycloalkyl or trifluoromethyl, and Y represents a direct bond, a is not optionally substituted phenyl or optionally substituted naphthyl;

2) when X is NR4where R4is a hydrogen atom or (C1-C6)alkyl, and R1Means 6-och3then Y does not denote WITH;

3) when X is O, R1Means 6-HE-or 6-och3, Y represents a direct link, and means cyclopentyl (R2,R3) or (R3,R2) different from (H, Cl) at position 4,5;

4) when X is O, R1Means 6 HE, R2and R3means a hydrogen atom, and Y represents CH=CH, a is not phenyl is m or 4-methoxyphenyl;

5) when X is SO2And means phenyl and R1Means 5 - or 6-och3(R2,R3) or (R3,R2) different from (H, och3) at position 6 or 5.

In the description and in the claims should be understood that the term “(1-C6)alkyl” means linear or branched hydrocarbon chain containing from 1 to 6 carbon atoms. For example, (C1-C6)alkyl radical means methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, tert-boutigny, pentelenyi, isopentenyl or sexily radicals. Preferred alkyl radicals are those radicals which contain 1, 2 or 3 carbon atoms.

It should be understood that the term “halogen” means chlorine atom, bromine, iodine or fluorine.

It should be understood that the term “(3-C15)cycloalkyl” means rich, condensed or bridged, mono-, bi - or tricyclic hydrocarbon containing from 3 to 15 carbon atoms. Monocyclic radical is, for example, cyclopropyl, cyclopentyl, tsiklogeksilnogo, cycloheptenyl, cyclooctyl or cyclododecyl radicals. Condensed, bridged or spiranovic bicyclic or tricyclic radical, for example, is norbornylene, bonnily, isobornylic, noradrenaline, adamantly Spiro[5,5]uncannily radical. The preferred cycloalkyl are cycloalkyl containing from 5 to 12 carbon atoms, the most preferred are cyclopentenyl, tsiklogeksilnogo, cycloheptenyl and adamantly radicals. Examples (C3-C6)cycloalkyl radical are cyclopropyl, cyclobutyl, cyclopentyl or tsiklogeksilnogo radicals.

It should be understood that the term “(3-C15)cycloalkyl” means unsaturated (C3-C15)cycloalkyl, and the value of this term above.

It should be understood that the term “(1-C6)alkoxy” means the group OR in which R means (C1-C6)alkyl, the value of which is indicated above. Example (C1-C6)CNS radical is metaxylene, amoxilina, propoxyphenyl, isopropoxyphenyl, butoxyphenyl, isobutoxy, tert-butoxyphenyl, p-pentylaniline, isopentylamine radicals. Preferred CNS radicals are those radicals which contain 1, 2 or 3 carbon atoms.

In the definition of R1it should be understood that the “salt” means a salt of an alkali metal or salt of the alkaline-earth metal such as sodium, potassium, magnesium or calcium, or a salt with ammonia or with organic amines, such as triethylamine, ethanolamine or Tris-(2-hydroxyethyl)amine.

<> It should be understood that the term “heterocycle” or “heterocyclic” means a saturated or unsaturated 5 - to 8-membered monocyclic radical containing one or two heteroatoms selected from O, N or S.

Examples of unsaturated heterocyclic radicals include, but are not limited to, purely, imidazolylalkyl, imidazolidinyl, peredelnyj, personilnya, personilnya, pyridazinyl, pyrimidinyl, pyrrolidinyl, finalininkiu, izohinolinove, diazolidinyl, thienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indaily and industrily radicals.

Examples of saturated heterocyclic radicals include, but are not limited to, imidazolidinyl, morpholinyl, thiomorpholine, piperidinyl, piperazinilnom, pyrrolidinyl, pyrazolidinone, tetrahydrofuranyl, 2-oxopiperidine, 2-oxo-piperidinyl and 2-oxopyrrolidin radicals, while morpholinyl and piperidinyl radicals are preferred.

There is no need to specify that in the case when X is NR4and Y, and R2together with the containing indazol cycle form a 1H-pyrano[4,3,2-cd]indazol, one of the carbon atoms “Pyrenophora fragment” includes Deputy And whose value specified above.

The compounds of formula (I) can about Asociate additive salts with acids. These salts, in particular salts which are pharmaceutically acceptable, are encompassed by the present invention. Examples of salts include salts which are formed, for example, with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, 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.

The present invention also encompasses the stereoisomeric forms of the compounds of formula (I).

Preferred compounds of formula (I) include compounds that satisfy at least one of the following conditions:

- R1means a hydrogen atom, (C1-C6)alkyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted saturated heterocyclic radical, or the group,- SO2NR7R8;

- R2means a hydrogen atom, hydroxyl, (C1-C6)alkyl, or halogen atom;

- R3means a hydrogen atom;

- Y represents a direct bond;

- Means (C3-C15)cycloalkyl, optionally substituted by Myung is our least one (C1-C6)alkyl;

- R1O is in the position of the 6 - ring.

The most preferred compounds are such compounds in which:

- R1means a hydrogen atom or a group-SO2NR7R8where R7and R8each independently mean a hydrogen atom or (C1-C6)alkyl;

- R2means a hydrogen atom;

- Means (C3-C12)cycloalkyl, optionally substituted from 1 to 4 (C1-C6)alkilani.

Preferred are the following compounds:

a) Compounds where X is NR4and

- R1means a hydrogen atom or (C1-C6)alkyl, phenyl(C1-C3)alkyl or the group-SO2NR7R8;

- R2and R3each mean a hydrogen atom;

- R4means a hydrogen atom or (C1-C6)alkyl, phenyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted saturated heterocyclic radical, a group-SO2NR7R8or-COR9where phenyl optionally substituted by at least one Deputy, selected from the group which consists of hydroxyl, halogen atom and phenyl(C1-C3)alkoxy;

- Y represents a direct bond, -(CR10R11)nor R10C=CR11-;

- R7and R8each independently train achut a hydrogen atom or (C 1-C6)alkyl;

- R9means a hydrogen atom or (C1-C6)alkyl;

- R10and R11each independently represent a hydrogen atom, cyano or the group-ONR7R8;

- n is 1 or 2;

- Means (C3-C15)cycloalkyl, optionally substituted by at least one (C1-C6)alkyl, or phenyl optionally substituted by hydroxyl or (C1-C3)CNS group;

- Y, and R2together with the containing indazol cycle can also form 1H-pyrano[4,3,2-cd]indazol;

provided that when R1means H or (C1-C6)alkyl, and Y represents a direct bond, a is not optionally substituted phenyl.

b) Compounds where X is O and

- R1means a hydrogen atom or (C1-C6)alkyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted saturated heterocyclic radical, or the group,- SO2NR7R8;

- R2means a hydrogen atom, halogen atom, hydroxyl or (C1-C6)alkoxy;

- R3means a hydrogen atom;

- Y represents a direct bond, -(CR10R11)nor R10C=CR11-;

- R7and R8each independently represent a hydrogen atom or (C1-C6)alkyl;

- R10and R11each independent coder who have a hydrogen atom or cyano;

- n is 1 or 2;

- Means (C3-C15)cycloalkyl, optionally substituted by at least one (C1-C6)alkyl, or phenyl, optionally substituted by at least one Deputy, selected from (C1-C3)alkoxy, hydroxyl, (C1-C3)alkyl and halogen atom;

provided that

b1) when R1means H or (C1-C6)alkyl, and Y represents a direct bond, a is not optionally substituted phenyl;

b2) when R1Means 6-HE-or 6-och3, Y represents a direct link, and means cyclopentyl (R2, R3) non (Cl, H) at position 4, 5;

b3) when X is O, R1Means 6 HE, R2and R3mean N, and Y represents CH=CH, a is not phenyl or 4-methoxyphenyl.

(C) Compounds where X is S(O)mand

- R1means a hydrogen atom or phenyl(C1-C3)alkyl or the group-SO2NR7R8;

- R2and R3each means a hydrogen atom, hydroxyl or a halogen atom;

- Y represents a direct bond, -(CR10R11)nor R10C=CR11-;

- R7and R8each independently represent a hydrogen atom or (C1-C6)alkyl;

- R10and R11each independently represent a hydrogen atom or cyano;

- Means (C3-C15)t is cloaker, optionally substituted by at least one (C1-C6)alkyl;

- m is 0, 1 or 2.

Because they are capable of acting as agonists or antagonists for estrogen receptors (in other words, as SERMs), the compounds of the present invention can be applied individually or in combination with other active ingredients for the treatment or prevention of any estrogen related diseases or to control regulated by estrogen functions in humans (Njar V.C. and A.M. Brodie, Drugs, 1999, 58: 233-255), as well as in wild and domestic animals.

Because the mammary glands are sensitive targets for stimulated estrogen proliferation and/or differentiation, SERMs are most suitable for treating or preventing flowing in the mild form of breast cancer in women, gynecomastia in men, or benign or malignant tumors of the breast with metastasis and without metastasis in both men and women (A. M. Brodie and V. C. Njar, Steroids, 2000, 65: 171-179; K.I. Pritchard, Cancer, 2000, 85, suppl. 12: 3065-3072) or in male and female animals.

Thanks to the involvement of estrogens in the mechanisms of ovulation, implantation and pregnancy SERMs of the present invention can be applied accordingly in the contraceptive, contraceptive or abortifacient purposes in females (A. M. Brodie and V. C. Njar, Drugs, 1999, 58: 233-255), and Takuo females of wild and domestic animals.

The uterus is another's reproductive organ, sensitive to estrogenic activation. Therefore, SERMs are suitable for treating or preventing endometriosis occurring in mild disease of the uterus or benign or malignant tumors of the uterus with metastasis and without metastasis in women (A. M. Brodie and V. C. Njar, Drugs, 1999, 58: 233-255) or in female animals.

Because the ovary is a physiological source of estrogen, SERMs can be used to treat abnormal or premature estrogen production in the ovary, such as polycystic ovarian syndrome, or premature puberty, respectively (Bulun et al., J. Steroid. Biochem. Mol. Biol., 1997, 61: pages 133-139). A beneficial effect on related and not related to the ovaries, but producing estrogen benign or malignant tumor with metastasis and without metastasis (Sasano H. and Harada N., Endocrine Reviews, 1998, 19: 593-607) can also provide treatment with the use of SERMs of the present invention.

Men to action estrogenic stimulation also sensitive tissue of the prostate and testicles (Abney T.O., Steroids, 1999, 64: 610-617; Carreau S. et al., Int. J. Androl., 1999, 22: 133-138). Therefore, SERMs can be used for treating or preventing benign (F. Sciarra and Toscano V., Archiv Androl., 2000, 44: 213-220) and malignant tumors of the prostate with metastases and without metastasis (Auclerc g et al, Oncologist, 2000, 5: 36-44) or for treatment, prevention or control functions or disorders of spermatogenesis in men and in male wild or domestic animals.

It is also known that estrogens are involved in the regulation of bone turnover; therefore, SERMs can be used both individually and in combination with other antiresorptive and proteogenic means, in the treatment or prevention of bone diseases using appropriate sequences and modes of introduction of therapeutic agents.

In addition, estrogens are involved in the regulation of the balance between dominant Th1and Th2functions of the immune system, and therefore may be suitable in the treatment or prevention of dependent from the floor of autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis.

Thus, another aspect of the present invention relates to a method of treating or preventing the above diseases and disorders in which the patient or animal in need of such treatment or prevention, is administered a therapeutically effective amount of the compounds of formula (I) or a therapeutically effective amount of its salts. The present invention also encompasses co-administration of compounds according to the invention together with one or more what exectly, which are active in the treatment or prevention of the above diseases or disorders.

In particular, the compounds of the present invention can be used with the following statement:

- the treatment of cognitive disorders, such as neuroprotective, antidepressant or anti-fobia sedatives;

- the treatment of schizophrenia and neurodegenerative diseases such as Alzheimer's and Parkinson's disease;

- prevention or treatment of estrogenzawisimy diseases, such as hot flashes, osteoporosis, mood during perimenopause, premenstrual syndrome, vasomotor symptoms, vaginal atrophy or dryness, sexual dysfunction such as decreased libido, urinary incontinence, itching, local infections of the genital tract. In this case, these compounds may be combined with sexually endocrine therapeutic tool;

the control or regulation of reproductive functions, such as the fertility of men and women, pregnancy, abortion, contraception, childbirth, or regulated by estrogen skin diseases. In this case, these compounds can be combined with agonist or antagonist LH-RH astroprojection contraceptive, a progestin, antiprogestins or prostaglandin;

- prevention or treatment is benign or malignant diseases of the breast, the uterus or ovaries or polycystic ovary syndrome. In this case, these compounds can be combined with the antiestrogen, a progestin or agonist or antagonist LH-RH;

- the prevention or treatment of benign or malignant diseases of the prostate or testicles. In this case, these compounds can be combined with antiandrogens, a progestin, an inhibitor of LiAZ or an agonist of LH-RH. If necessary, the compounds of the present invention can also be combined with radiotherapy agent; a chemotherapeutic agent, such as an analogue of nitrogen mustard gas, such as cyclophosphamide, melphalan, ifosfamide or trofosfamide; ethylenimines, such as thiotepa; nitrosamines, such as carmustine; subjected to lysis agent, such as temozolomide or dacarbazine; 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; a Vinca alkaloid or its analogue, such as vinblastine, vincristine or vinorelbine; derived podofillotoksina, such as etoposide, taxanes, docetaxel or paclitaxel; anthracyclines or its analogue, such as doxorubicin, epirubicin, idarubitsin or mitoxantrone; C is ototoksicskimi antibiotic, such as bleomycin or mitomycin; from a derivative of a platinum compound, such as cisplatin, carboplatin or oxaliplatin; with a monoclonal antibody, such as rituximab; antineoplastics means, such as pentostatin, miltefosine, estramustin, topotecan, Enoteca or bikalutamid; or an inhibitor of prostaglandin (inhibitor SOH/SOH);

- the prevention or treatment of irritable bowel syndrome, Crohn's disease, ulcerative proctitis, colitis or arthritis;

- prevention or treatment of cardiovascular diseases, atherosclerosis, hypertension, restenosis (in particular, to lower cholesterol, triglycerides, Lp(a) or LDL or for modulating HDL).

In this description, the term “United” or “combination” refers to any mode of the joint introduction of the compounds of formula (I) and one or more other pharmaceutical compounds, regardless of the type and time of introduction and variations in dosage over time for any of these compounds. Co-administration can, for example, be carried out in parallel, sequentially or within a longer period of time.

The compounds of formula (I) or their pharmaceutically acceptable salts can be administered, for example, orally, topically, parenterally in the form of a single dosage forms containing conventional non-toxic farm is citiesi acceptable carriers, secondary drug and/or media. These dosage forms are given in the examples, but for the introduction of compounds of formula (I) experts can develop other pharmaceutical forms. The term parenteral herein includes subcutaneous injections, methods, intravenous, intramuscular or vnutrigrudne injection or infusion. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, sheep, dogs, cats, etc., the compounds of the present invention is effective for the treatment of people.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example in the form of tablets, lozenges, pellets, suspensions, water-or oil-based, dispergiruyushchie powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compounds intended for oral use can be obtained by any known from the field of engineering methods that are used to prepare pharmaceutical compositions, and compositions can contain one or more means selected from the group that includes sweeteners, flavourings, colourings and preservatives in order to obtain pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient mixed with Neto is, or toxic pharmaceutically acceptable excipients, which are suitable for preparing tablets. These fillers can be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating means and disintegrating agents such as corn starch or alginic acid; binders, for example starch, gelatin or gum, and lubricants, for example magnesium stearate, stearic acid or talc. Tablets can be without shells or tablet known methods can be applied coating to delay their destruction or absorption in the gastrointestinal tract and thereby provide a prolonged action over a longer period. For example, there may be used a substance prolonged action, such as glycerol monostearate or distearate glycerin. The tablets can also be coated using the methods described in U.S. patent No. 4256108, 4166452 and 4265874, and get the osmotic therapeutic tablets, providing controlled release.

Compositions for oral administration can also be prepared in the form of gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which AK is active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active ingredient in a mixture with fillers, which are suitable for the preparation of aqueous suspensions. Such fillers are suspendresume means, for example sodium derivative of carboxymethylcellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone resin tragakant and gum; dispersing and wetting agents such as natural phosphatides, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters formed from fatty acids and hexitol, such as monooleate of polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters formed from fatty acids, and anhydrides of exit, such as, for example, monooleate polyethylenimine. Aqueous suspensions may also contain 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 sweeteners such to the to sucrose, saccharin or aspartame.

Suspension oil-based can be prepared by dispersing the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Suspension oil-based and may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Can be added sweeteners, such as the above sweeteners, and flavors to give the drugs a pleasant taste. In these songs you can add the preservative in the form of an antioxidant, such as ascorbic acid.

Dispergirujutsja powders and granules suitable for preparation of an aqueous suspension by adding water, are the active ingredient in a mixture with dispersing or wetting agent, suspendium means and one or more preservatives. As examples of suitable dispersing or wetting means and suspendida means you can bring those indicated above. There may be additional fillers, such as sweeteners, flavoring agents and dyes. The pharmaceutical compositions of the present invention may also be in the form of emulsions of the type oil-in-water. The oil phase may be a vegetable oil, neprimirimym butter or peanut butter or mineral oil, for example liquid paraffin or mixtures of these substances. Suitable emulsifying agents include natural gums, for example, soybean oil, lecithin, and esters or partial esters derived from fatty acids and anhydrides of exit, such as monooleate sorbitan, and condensation products of these partial esters with ethylene oxide, such as monooleate of polyoxyethylenesorbitan. The emulsion may also contain sweeteners and flavorings.

The pharmaceutical compositions can be in the form of a sterile suspension for injection, water-or oil-based. These suspensions can be formulated according to known from the field of engineering methods using a dispersing or wetting means and suspendida funds that have already been mentioned above. Suitable for injection sterile drugs can be a sterile solution or suspension for injection prepared in a non-toxic parenterally acceptable diluent or solvent, for example, can be a solution in 1,3-butanediol. Usable acceptable carriers or solvents include water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment usually apply sterile Neleus the e oil. This purpose can be any soft fixed oils, including synthetic mono - or diglycerides. In addition, for the preparation of compositions for injection are used in fatty acids such as oleic acid.

In the treatment or prevention of the above diseases or disorders, the dosage levels are in the range from about 0.001 mg to about 10 mg/kg body weight / day or, alternatively, in the range from about 0.1 mg to about 100 mg per patient per day.

The amount of active ingredient which can be combined with substances-carriers to obtain a single dosage form varies depending on the patient and the particular route of administration.

It should however be understood that the specific levels of dosage 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, therapy of which spend.

Derivatives indazole formula (I) can be obtained in accordance with the General schemes Ia, Ib, Ic.

Scheme Ia

According to scheme Ia derived toranzo is a (1) communicates with a suitable acid chloride of acid (2) by the reaction of the Friedel-in accordance with the methodology see K. L. Kees (J. Med. Chem., 29, 11, 1986, 2329-2334) c the formation of the ketone (5). The ketone (5) can also be obtained by condensation alkaline (4) with a derivative of perbenzoate (3) in accordance with H. Shaffer (J. Am. Chem. Soc., 1939, 61, 2175). Then the ketone (5) is refluxed in EtOH in the presence of a substituted hydrazine or hydrazine hydrate with the formation of the corresponding indazol cycle (6) or (7). Compound (7) can be obtained by selective N-alkylation of indazole (6) under the conditions described U. Lerch and J. König (Synthesis, 1983, 2, 157-8), or in conditions described by J. Chung and all (Tetrahedron Letters, 1992, 33, 4717-20).

The demethylation of compounds (6) and (7) (if R1denotes methyl) or with the help of tribromsalan in the terms and conditions mentioned J. F. W. McOmie (Tetrahedron, 1968, 24, 2289-92), or by using HBr/AcOH or pyridinium hydrochloride or dibenzylammonium compounds (6) and (7) (if R1denotes benzyl) using Pd/C in the presence or in the absence of Pt2in the described conditions W. H. Hartung (Org. React., VII, 1953, 263) are respectively the derivatives of hydroxyindole (8) and (12). Indazole (6) can be directly N-sulfanilamide with the formation of compound (10) by treatment with sodium hydride and sulfhemoglobin as described P. Nussbaumer (J. Med. Chem., 2002, 45, 4310-20), or by reaction with sulfhemoglobin in dimethylacetamide (DMAc), as described O. Makoto (Tetrahedron Letters, 2000, 41, 7047-51), and then the protective group is removed the gain derived sulpham (11). Indazol (8), which is released from the protective group can then be converted into desulfatohirudin derivative (9). Similarly, indazol (12) can be introduced into the reaction sulfhemoglobin and get O-sulphamate derivative (13), which removes the protective group and get a connection (14).

Scheme Ib

According to the scheme Ib 3-methylsiloxane derived indazole (15), which is obtained in accordance with the conditions set F. Dennler (Tetrahedron, 22, 1966, 3131), enter into interaction with VOS2Oh, tea and DMAP (Ishizuki, T., Tetrahedron Lett., 28, 1987, 4185) and get a connection (16). Compound (16) bromilow reaction Mens-Ziegler in the presence with NBS and benzoyl peroxide in accordance with B. R. Henke (J. Med. Chem., 1997, 40, 17, 2706-2725) and get a connection (17). The compound (18) are obtained by the reaction of the compound (17) with KCN in the conditions described by Ainsworth (J. Am. Chem. Soc., 1957, 79, 5242-5243). Then the compound (18) interacts with the aldehyde (19) NaH/DMF or KOH/EtOH to obtain the compound (20) in accordance with the method described by M. J. Meyers (J. Med. Chem., 44, 24, 2001, 4230) (during this reaction, carried out the removal of the protective group BOC). Then the compound (20) communicates with NaBH4in EtOH with the formation of compound (21). The demethylation of compounds (21) (if R1denotes methyl) or with the help of tribromsalan in the terms and conditions mentioned J. F. W.Mcmie (Tetrahedron, 1968, 24, 2289-92), or by using HBr/AcOH or pyridinium hydrochloride or dibenzylammonium connection (21) (if R1denotes benzyl) using Pd/C in the presence or in the absence of Pt2in the described conditions W.H.Hartung (Org. React., VII, 1953, 263)are derived nitrile (22). Demethylation using HBr/AcOH gives amide derivative (23).

Circuit IC

According to the scheme IC compound (24)obtained in the conditions described M. Kitagawa (Chem. Pharm. Bull., 39, 10, 1991, 2681), enter into reaction with hydrazine hydrate or alkyl - or arylhydrazines by boiling under reflux with the formation of compound (25). The compound (25) will Demetriou in the presence of BBr3in CH2Cl2in the described conditions J. F. W.McOmie (Tetrahedron, 1968, 24, 2289-92), and get a connection (26) and (27).

Derivatives benzisoxazole formula (I) can be obtained in accordance with the General schemes IIa, IIb, IIc.

Scheme IIa

According to the scheme IIa already described the ketone (5) or ketone (29)obtained by the reaction of the Friedel-and described in K. L. Kees (J. Med. Chem., 29, 11, 1986, 2329-2334), refluxed with hydroxylamine hydrochloride under the conditions described Y. Yamanaka (Pestic. Sci., 1998, 54, 3, 223-229), and receive the corresponding oxime (28) or (30) without closing cycle. Compound (28) then cyclist boiling under reflux the solution NaOH/EtOH, and the connection (30) cyclist using intramolecular reaction of Mitsunobu (Synthesis, 1981, 1) and receive appropriate benzisoxazol (31).

The demethylation of compounds (31) (if R1denotes methyl) or with the help of tribromsalan in the conditions described by J. F. W. McOmie (Tetrahedron, 1968, 24, 2289-92), or by using HBr/AcOH or pyridinium hydrochloride or dibenzylammonium connection (31) (if R1denotes benzyl) using Pd/C under the conditions described A. M. Felix (J. Org. Chem., 43, 1978, 4194), receive hydroxy benzisoxazole (32). The specified connection (32) can be transformed into the corresponding sulpham (33) by treatment with sodium hydride and sulfhemoglobin (P.Nussbaumer, J. Med. Chem., 2002, 45, 4310-20) or by reaction with sulfhemoglobin in dimethylacetamide (DMAc) (O.Makoto, Tetrahedron Letters, 2000, 41, 7047-51). Compound (32) can also be turned into a simple ether (34) by the reaction with 1-(2-chloro-ethyl) - piperidine in the conditions described by M. R. Tremblay (Bioorg. Med. Chem., 1999, 7, 6, 1013-1024).

Scheme IIb

According to the scheme IIb benzisoxazol (35)obtained in the conditions described H. Uno (Chem. Pharm. Bull., 24, 1976, 632), is introduced into reaction with the aldehyde (19) NaH/DMF or KOH/EtOH and get a connection (36). Then the compound (36) communicates with NaBH4in EtOH with the formation of compound (37).

The demethylation of compounds (37) or with the help of tribromsalan in terms of the s, see J. F. W. McOmie (Tetrahedron, 1968, 24, 2289-92), or by using HBr/AcOH or pyridinium hydrochloride receive hydroxy benzisoxazole (38).

Scheme IIC

According to the scheme IIC benzisoxazol (39)obtained in the conditions described by M. A. Elkasaby (Indian J. Chem. Sect. B, 1980, 19, 571), protect using tert-butyldimethylsilyloxy in the imidazole/DMF (P. M. Kendall, J. Org. Chem., 44, 1979, 1421) and the compound obtained (40) bromilow in the presence of NBS and benzoyl peroxide, receiving connection (41). Compound (41) being in communication with LDA and substituted derivatives of phenylacetonitrile and get a connection (42) according to methodology described E. Teodori (Bioorg. Med. Chem., 7, 9, 1999, 1873-1880). After removal of the hydroxyl group in the presence of n-Bu4F under the conditions described by E. J. Corey (J. Am. Chem. Soc., 94, 1972, 6190)receive connection (43).

Derivatives benzisothiazole formula (I) can be obtained in accordance with the General scheme III.

Scheme III

According to scheme III ketone (5) interacts with phenylmethanol with the formation of compound (44). The obtained compound (44) is refluxed in sulfurylchloride with subsequent treatment with ammonia and receive benzisothiazol with the closing of the cycle (45) in accordance with the methodology, given the military D. M. Fink (Tetrahedron Letters, 1993, 34, 41, 6525-6528). The demethylation of compounds (45) or with the help of tribromsalan in the conditions described by J. F. W. McOmie (Tetrahedron, 1968, 24, 2289-92), or by using HBr/AcOH or pyridinium hydrochloride receive hydroxy benzisothiazole (46). The above compound (46) can be transformed into the corresponding sulfamate (47) by treatment with sodium hydride and sulfhemoglobin (P. Nussbaumer, J. Med. Chem., 2002, 45, 4310-20) or by reaction with sulfhemoglobin in dimethylacetamide (DMAc) (O. Makoto, Tetrahedron Letters, 2000, 41, 7047-51).

The oxidation of these compounds (46) and (47) by hydrogen peroxide in triperoxonane acid in accordance with the conditions set S. Grivas and E. Ronne (Acta Chemica Scandinavia, 1995, 49, 225-229), gives, respectively, mono - and/or dookisleniya benzisothiazole (49) and (48). Compound (49) can be sulamericano and get connection (48).

General schemes I, II and III explain the synthesis of compounds (I), in which the substituent R1About is in position 6 of the heterocycle. However, it should be understood that the compounds (I), in which the substituent R1About is in position 4-, 5 - or 7 - heterocycle, can also be obtained by the above methods.

The following examples are provided for illustration, and they do not limit the present invention.

GETTING ACETOPHENONE (5)

Example 1

4-Benzyloxy-2-perbenzoate

To the mixture-fluoro-4-hydroxybenzonitrile (98 g, of 0.68 mol) and K2CO3(94 g of 0.68 mol) in acetonitrile add benzylchloride (86,6 g of 0.68 mol). The mixture is left to mix overnight at room temperature and the reaction monitored by thin layer chromatography (TLC) (toluene/AcOEt 8/2). The mixture is filtered, concentrated in vacuo and crystallized from pentane, getting 147 g of a solid (95%).

1H-NMR (DMSO-d6): 5.25 in (c, 2H), 7,05 (DD, 1H), 7,25 (DD, 1H), 7,30-of 7.60 (m, 5H), of 7.75 (t, 1H).

By the same method, but substituting 2-fluoro-4-hydroxybenzonitrile

cycloheptyl(2-fluoro-4-hydroxyphenyl)metano

1-substituted(2-fluoro-4-hydroxyphenyl)metano

receive, respectively, the following connections:

Example 2

Cycloheptyl(4-benzyloxy-2-forfinal)methanon (71%)

1H-NMR (CDCl3): 1,10-2,00 (m, 12H), 3,50 (m, 1H), 5,17 (c, 2H), 6,85 (dt, 1H), 7,20 (DD, 1H), 7,30-of 7.60 (m, 6H).

Example 3

1-Substituted(4-benzyloxy-2-forfinal)methanon (38%)

1H-NMR (DMSO-d6): 1,30-2,30 (m, 15H), 5,20 (c, 2H), 6,85 (dt, 1H), 7,12 (DD, 1H), 7,20-of 7.60 (m, 6H).

Example 4

Cyclopentyl(4-benzyloxy-2-forfinal)metano

A suspension of magnesium (19 g, of 0.79 mol) and iodine (catalytic amount) in THF (20 ml) is refluxed under nitrogen atmosphere. Slowly add a solution of cyclopentylamine (110 g, 0,738 mol) in THF (400 ml). The mixture is refluxed until then, until the entire magni is not used, then cooled to 30°C. and add a solution of 4-benzyloxy-2-perbenzoate (129 g of 0.56 mol) in THF (600 ml). The reaction mixture was allowed to mix overnight at 50°C, and then terminate the reaction by adding aqueous solution of NH4Cl and ice, extracted with ethyl acetate and washed with a saturated solution of salt. The mixture is dried over Na2SO4, filtered and concentrated in vacuo. Cleaning method flash chromatography (heptane/EtOAc 9/1) to give 60 g of the product (35% in the form of a solid substance).

1H-NMR (DMSO-d6): 1,40-2,00 (m, 8H), to 3.58 (m, 1H), 5,20 (c, 2H), 6,85-7,20 (m, 2H), 7,25-of 7.55 (m, 5H), 7,80 (t, 1H).

Using the same method, but replacing cyclopentylamine on cyclohexylurea receive the following connection:

Example 5

Cyclohexyl(4-benzyloxy-2-forfinal)methanon (35%), TPL 78°C

1H-NMR (DMSO-d6): 1,00-2,00 (m, 10H), was 3.05 (m, 1H), 5,20 (c, 2H), 6.90 to-7,10 (m, 2H), 7,20-of 7.60 (m, 5H), of 7.75 (t, 1H).

Example 6

1-Substituted(2-fluoro-4-hydroxyphenyl)metano

To a mixture of AlCl3(45 g of 0.337 mol) in 1,2-dichloroethane (DCE, 250 ml) at 0°C was added 1-adamantylamine (36,6 g, 0,228 mol) in DCE (150 ml). At a temperature of 0°C is added slowly 3-terfenol (21 g, 0,183 mol) in DCE (100 ml). Over the course of the reaction is monitored by TLC (heptane/toluene 50/50). The mixture is then poured into 2 n HCl solution, extracted with AcOEt, washed with a solution of NaHCO3and rich dissolve the Ohm salt, dried over Na2SO4, filtered and concentrated in vacuo. Cleaning method flash chromatography (heptane/toluene 8/2) to give 27 g of 1-substituted(2-fluoro-4-hydroxyphenyl)methanone (48% in the form of a solid substance).

1H-NMR (DMSO-d6): of 1.30 (m, 15H), 5,97 (c, 1H), 6,70 (d, 1H), 6,94 (DD, 1H), to 7.64 (d, 1H).

By the same method, substituting 1-adamantylamine on cycloheptaamylose receive the following connection:

Example 7

Cycloheptyl(2-fluoro-4-hydroxyphenyl)methanon (60%)

1H-NMR (DCl3): 1,20-2,00 (m, 12H), to 3.58 (m, 1H), 6,70-of 6.90 (m, 2H), of 7.90-8,10 (m, 1H), 12,45 (s, 1H).

By the same method, substituting 1-adamantylamine on cycloheptaamylose and replacing 3-terfenol 3-Floransa receive the following connection:

Example 8

Cycloheptyl(4-methoxy-2-forfinal)methanon (45%)

1H-NMR (CDCl3): 1,40-2,00 (m, 12H), 1,9 (3, 2H), 3,25 (m, 1H), 3,80 (c, 3H), of 6.50 (DD, 1H), 6,65 (DD, 1H), of 7.75 (t, 1H).

Using the same method, but substituting 3-terfenol on:

3-Floransa

3,5-dimethoxybenzoyl

receive, respectively, the following connections:

Example 9

1-Substituted(4-methoxy-2-forfinal)methanon (15%)

1H-NMR (CDCl3): 1,50-2,30 (m, 15H), 3,85 (c, 3H), 6,60 (2D, 1H), 6,70 (2D, 1H), of 7.70 (t, 1H).

Example 10

1-Substituted(2-chloro-4,6-acid)methanon (22%)

1H-NMR (CDCl3-d1): 1,60-2,10 (m, 1H), 3,75 (c, 3H), 3,80 (c, 3H), 6.35mm (c, 1H), 6,50 (c, 1H).

By the same method, substituting 3-terfenol 3.4-dimethoxyphenol and replacing 1-adamantylamine on cyclohexanecarbonitrile receive the following connection:

Example 11

Cyclohexyl(2-fluoro-4-hydroxy-5-methoxyphenyl)metano

1H-NMR (DMSO-d6): 1,00-2,00 (m, 10H), was 3.05 (m, 1H), 3,80 (c, 3H), of 6.65 (d, 1H), 7.23 percent (d, 1H), 10,50 (c, 1H).

GETTING INDAZOLS(6), (7), (8) AND (12)

Example 12

6-Benzyloxy-3-cyclopentyl-1H-indazol

The mixture cyclopentyl(4-benzyloxy-2-forfinal)methanone (40 g, 0.13 mol) in hydrazine-hydrate (50 ml) is refluxed overnight. After cooling to room temperature the solid is filtered off, dissolved in EtOAc, and then washed with aqueous solution of NH4Cl and saturated salt solution. The solution is dried over Na2SO4, filtered and concentrated in vacuo. Cleaning method flash chromatography (toluene/EtOAc 9/1) to give the expected product (13 g, 45% in the form of a solid substance).

1H-NMR (DMSO-d6): 1,40-of 2.20 (m, 8H), to 3.34 (m, 1H), 5,13 (c, 2H), 6.75 in (DD, 1H), 6.90 to (d, 1H), 7,20-7,53 (m, 5H), EUR 7.57 (d, 1H), 9,40 (c, 1H).

By the same method, but replacing cyclopentyl(4-benzyloxy-2-forfinal)metano

cyclohexyl(4-benzyloxy-2-forfinal)metano

cycloheptyl(4-benzyloxy-2-forfinal)metano

1-substituted(4-methoxy-2-forfinal)metano

the CEC is heptyl (4-methoxy-2-forfinal)metano

receive, respectively, the following connections:

Example 13

6-Benzyloxy-3-cyclohexyl-1H-indazol (58%)

1H-NMR (CDCl3): 1,10-2,10 (m, 10H), 2.95 and (m, 1H), 5,15 (c, 2H), 6.75 in (DD, 1H), 6.90 to (d, 1H), 7,20-of 7.55 (m, 5H), the 7.65 (d, 1H), 12,32 (c, 1H).

Example 14

6-Benzyloxy-3-cycloheptyl-1H-indazol (85%)

1H-NMR (CDCl3): 1,20-2,10 (m, 12H), to 2.55 (m, 1H), 5,07 (c, 2H), 6,45 (DD, 1H), 6,55 (d, 1H), 6,95 (d, 1H), 7,20 is 7.50 (m, 5H).

Example 15

3-(1-Substituted)-6-methoxy-1H-indazole (30%)

1H-NMR (CDCl3): 1,50-2,70 (m, 15H), 3,85 (c, 3H), 6,78 (DD, 1H), to 6.88 (d, 1H), EUR 7.57 (d, 1H).

Example 16

3-Cycloheptyl-6-methoxy-1H-indazole (45%)

1H-NMR (CDCl3): 1,40-of 2.30 (m, 12H), up 3.22 (m, 1H), 3,83 (c, 3H), 6.35mm (c, 1H), 6,65-of 6.90 (m, 2H), 7,58 (d, 1H).

By the same method, but replacing the hydrazine-hydrate, 1-(4-benzyloxyphenyl)hydrazine (synthesized in accordance with K.J.Duffy, J. Med. Chem., 2001, 44, 22, 3730-3745), get the following connection:

Example 17

6-Benzyloxy-3-cyclopentyl-1-(4-benzyloxyphenyl)-1H-indazol(66%)

1H-NMR (DMSO-d6): 1,15-2,05 (m, 10H), 2.95 and (dt, 1H), 3,88 (c, 3H), 5,15 (c, 2H), 6.75 in (DD, 1H), 7,12 (d, 1H), 7,25-7,58 (m, 5H), the 7.65 (d, 1H).

By the same method, but replacing cyclopentyl(4-benzyloxy-2-forfinal)methanon at cyclohexyl(4-benzyloxy-2-forfinal)methanon and replacing hydrazine hydrate to methylhydrazine or benzylpiperazine, respectively, received the following connections:

Example 18

6-Benzyloxy the-3-cyclohexyl-1-methyl-1H-indazol (66%)

1H-NMR (DMSO-d6): 1,15-2,05 (m, 10H), 2.95 and (dt, 1H), 3,88 (c, 3H), 5,15 (c, 2H), 6.75 in (DD, 1H), 7,12 (d, 1H), 7,25-7,58 (m, 5H), the 7.65 (d, 1H).

Example 19

1-Benzyl-6-benzyloxy-3-cyclohexyl-1H-indazol (76%)

1H-NMR (DMSO-d6): 1,15-2,05 (m, 10H), 2.95 and (dt, 1H), 5,10 (c, 2H), 5,15 (c, 2H), 6.75 in (DD, 1H), 7,12 (d, 1H), 7,15-the 7.65 (m, 10H), the 7.65 (d, 1H).

Example 20

tert-Butyl 6-benzyloxy-3-cyclohexyl-1H-indazol-1-carboxylate

At a temperature of 0°C. di-tert-BUTYLCARBAMATE (36,38 g, 0,166 mol) in acetonitrile (340 ml) is added to a mixture of 6-benzyloxy-3-cyclohexyl-1H-indazole (42,50 g, was 0.138 mol), tea (22 ml, 0,152 mol), acetonitrile (460 ml) and DMAP (3,40 g, or 0.027 mol).

The mixture is stirred at room temperature overnight, then concentrated in vacuo, diluted with ethyl acetate and washed with water, acidified with 2 N. HCl solution to pH 2. The mixture is dried over Na2SO4, filtered and diluted with diisopropyl ether and then crystallized expected product (44,50 g, yield 79%).

1H-NMR (DMSO-d6): 1,15-2,05 (m, 19H), to 3.00 (m, 1H), 5,19 (c, 2H), 7,03 (DD, 1H), 7,25 was 7.45 (m, 5H), of 7.69 (d, 1H), 7,78 (d, 2H).

Example 21

6-Benzyloxy-3-cyclopentyl-1-(2-piperidine-1-retil)-1H-indazol

6-Benzyloxy-3-cyclopentyl-1H-indazol heated for 1 hour with NaOH (1.64 g, 41 mmol) and 1-(2-chloroethyl)piperidine in EtOH (60 ml) to 40°C. Over the course of the reaction is monitored by TLC (toluene/dioxane: 7/3) and after e is complete the mixture is cooled to room temperature. Terminate the reaction by adding NH4Cl, extracted with AcOEt, dried over Na2SO4, filtered and concentrated in vacuo. Cleaning method flash chromatography (toluene/1,4-dioxane 7/3) to give the expected product (600 mg, 8% in the form of a solid substance).

1H-NMR (DMSO-d6): 1,40-to 2.40 (m, 14H), 2,50 is 2.80 (m, 2H), 3,10-of 3.60 (m, 5H), 4,30 (t, 2H), 5,15 (c, 2H), 6,70 (DD, 1H), 7,10 (d, 1H), 7,40 (m, 5H), 7,60 (d, 1H).

By the same method, but replacing 1-(2-chloroethyl)piperidine for 4-bromobenzylamine receive the following connection:

Example 22

6-Benzyloxy-1-(4-bromobenzyl)-3-cyclopentyl-1H-indazol

1H-NMR (DMSO-d6): 1,50-2,20 (m, 8H), to 3.38 (m, 1H), 5,15 (c, 2H), 5,50 (c, 2H), 6,78 (DD, 1H), 7,05-of 7.55 (m, 10H), 7,60 (d, 1H).

Example 23

3-Cyclopentyl-1H-indazol-6-ol

A mixture of 6-benzyloxy-3-cyclopentyl-1H-indazole (13 g, is 0.102 mol), Pd/C (5%, 0.65 g) and Pt2On (catalytic amount) in ethanol (130 ml) was stirred at room temperature in hydrogen atmosphere. Over the course of the reaction is monitored by TLC (heptane/EtOAc 50/50). After the reaction the mixture is filtered through celite and concentrated in vacuo. Crystallized from a mixture of CH2Cl2/pentane and obtain 7.2 g of white crystals (85%), TPL 175°C.

1H-NMR (DMSO-d6): 1,40-of 2.20 (m, 8H), to 3.35 (m, 1H), 6,55 (DD, 1H), of 6.68 (d, 1H), 7,50 (d, 1H), 9,45 (c, 1H), 12,05 (c, 1H).

By the same method, but replacing 6-benzyloxy-3-cyclopentyl-1H-indazol is:

6-benzyloxy-3-cyclohexyl-1H-indazol

6-benzyloxy-3-cyclohexyl-1-methyl-1H-indazol

6-benzyloxy-3-cyclopentyl-1-(4-benzyloxyphenyl)-1H-indazol

6-benzyloxy-3-cyclopentyl-1-(2-piperidine-1-retil)-1H-indazol

6-benzyloxy-1-(4-bromobenzyl)-3-cyclopentyl-1H-indazol

1-benzyl-6-benzyloxy-3-cyclopentyl-1H-indazol

tert-butyl 6-benzyloxy-3-cyclohexyl-1H-indazol-1-carboxylate

receive, respectively, the following connections:

Example 24

3-Cyclohexyl-1H-indazol-6-ol (85%), TPL 147°C

1H-NMR (DMSO-d6): 1,10-2,10 (m, 10H), 2,90 (m, 1H), 6,55 (DD, 1H), 6,65 (c, 1H), 7,50 (d, 1H), 9,45 (c, 1H), 12,05 (c, 1H).

Example 25

3-Cyclohexyl-1-methyl-1H-indazol-6-ol (75%), TPL 205°C

1H-NMR (DMSO-d6): 1,20-2,00 (m, 10H), of 2.92 (dt, 1H), 3,80 (c, 3H), 6,60 (DD, 1H), of 6.68 (d, 1H), 7,55 (d, 1H), 9,58 (c, 1H).

Example 26

3-Cyclopentyl-1-(4-hydroxyphenyl)-1H-indazol-6-ol (54%), TPL 178°C

1H-NMR (DMSO-d6): 1,50-2,20 (m, 8H), 3,40 (t, 1H), of 6.68 (DD, 1H), 6,83 (d, 1H), 6.90 to (d, 2H), 7,38 (d, 2H), to 7.59 (d, 1H), 9,60 (c, 1H), 9,68 (c, 1H).

Example 27

3-Cyclopentyl-1-(2-piperidine-1-retil)-1H-indazol-6-ol, hydrochloride (90%), TPL 120°C

1H-NMR (DMSO-d6): 1,15-2,30 (m, 14H), 2,90 (m, 2H), 3,20-of 3.60 (m, 5H), and 4.68 (t, 2H), 6,70 (DD, 1H), to 6.88 (d, 1H), 7,52 (d, 1H), 10,80 (c, 1H).

Example 28

1-(4-Bromobenzyl)-3-cyclopentyl-1H-indazol-6-ol (90%), TPL 147°C

1H-NMR (DMSO-d6): 1,45-of 2.30 (m, 8H), to 3.35 (m, 1H), 5.40 to (c, 2H) 6,60 (d, 1H), 7,00-7,40 (m, 4H), to 7.50 (d, 1H), 7,70 (c, 1H).

Example 29

1-Benzyl-3-cyclohexyl-1H-indazol-6-ol (40%), TPL 154°C

1H-NMR (CDCl3): 1,10-to 2.40 (m, 10H), 3,03 (m, 1H), 5.40 to (c, 2H), 5,70 (c, 1H), 6,53 (d, 1H), 6,76 (DD, 1H), 7,00-to 7.35 (m, 5H), 7,60 (d, 1H).

Example 30

1-tert-Butyl-3-cyclohexyl-6-hydroxy-1H-indazol-1-carboxylate (87%), TPL 124°C

1H-NMR (DMSO-d6): 1,20-2,05 (m, 19H), 2,95 (m, 1H), 6,80 (DD, 1H), 7,40 (d, 1H), 7,65 (d, 1H).

Example 31

3-(1-Substituted)-1H-indazol-6-ol, hydrochloride

A mixture of 3-(1-substituted)-6-methoxy-1H-indazole (210 mg, 0.75 mmol) in 40%solution of HBr in acetic acid (10 ml) is heated overnight to a temperature of 70°C. the Mixture was poured on ice and neutralized with a solution of NaHCO3and then extracted with AcOEt, dried over Na2SO4, filtered and concentrated in vacuo. Cleaning method flash chromatography (heptane/EtOAc 50/50) to give 200 mg of product. The solid is crystallized from Et2About in the form of a salt with HCl. The crystals are filtered, washed with ether and dried, receiving 160 mg salt (80%), TPL 140°C.

1H-NMR (DMSO-d6): 1,00-2,60 (m, 15H), of 6.65 (d, 1H), 6.75 in (c, 1H), 7,55 (d, 1H).

Using the same method, but substituting 3-(1-substituted)-6-methoxy-1H-indazol 3-cycloheptyl-6-methoxy-1H-indazol receive the following connection:

Example 32

3-Cycloheptyl-1H-indazol-6-ol, hydrochloride (60%), TPL 95°C

1H-NMR (DMSO-d6): 1,0-2,00 (m, 12H), 3,1 (m, 1H), 6,62 (d, 1H), 6,64 (c, 1H), 7,60 (d, 1H).

OBTAINING 1H-INDAZOLINONE(9), (10), (11), (13) AND (14)

Example 33

6-Benzyloxy-3-cycloheptyl-1H-indazol-1-sulfonamide

Sulfhemoglobin (2.9 g, 25 mmol) are added to a solution of 6-benzyloxy-3-cycloheptyl-1H-indazole (6) (4 g, a 1.75 mmol) in N,N-dimethylacetamide (40 ml) at 0°C. the Mixture was stirred at 0°C for 3 hours After extraction with EtOAc the organic layer is washed with a solution of NH4Cl and saturated salt solution. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. Cleaning method flash chromatography followed by crystallization from EtOH gives 1.2 g of yellow crystals (24%).

1H-NMR (DMSO-d6): 1,20-2,00 (m, 12H), 2,58 (m, 1H), of 5.05 (c, 2H), 6,65-7,00 (m, 1H), 7,20 is 7.50 (m, 6H), 7,92 (c, 1H), 8,55 (c, 2H).

By the same method, but replacing 6-benzyloxy-3-cycloheptyl-1H-indazol on:

6-benzyloxy-3-cyclohexyl-1H-indazol

3-cyclohexyl-1H-indazol-6-ol

3-cyclohexyl-1-methyl-1H-indazol-6-ol

1-benzyl-3-cyclohexyl-1H-indazol-6-ol

tert-butyl 6-benzyloxy-3-cyclohexyl-1H-indazol-1-carboxylate

receive, respectively, the following connections:

Example 34

6-Benzyloxy-3-cyclohexyl-1H-indazol-1-sulfonamide (100%)

1H-NMR (DMSO-d6): 1,10-2,10 (m, 10H), was 3.05 (m, 1H), 5,15 (c, 2H), 7,00 (DD, 1H), 7,25-of 7.60 (m, 6H), 7,80 (d, 1H), 8,35 (c, 2H).

When is EP 35

1-(Aminosulfonyl)-3-cyclohexyl-1H-indazol-6-isalphabet (40%), TPL 213°C

1H-NMR (DMSO-d6): 1,20-2,10 (m, 10H), 3,13 (d, 1H), 7,25 (DD, 1H), 7,80 (d, 1H), 8,00 (d, 1H), 8,10 (c, 2H), 8,50 (c, 2H).

Example 36

3-Cyclohexyl-1-methyl-1H-indazol-6-sulfonamide (84%), TPL 188°C

1H-NMR (DMSO-d6): 1,20-2,10 (m, 10H), 3,03 (m, 1H), 3,95 (c, 3H), 6,98 (d, 1H), 7,45 (c, 1H), a 7.85 (d, 1H), 8,00 (c, 2H).

Example 37

1-Benzyl-3-cyclohexyl-1H-indazol-6-isalphabet (85%), TPL 188°C

1H-NMR (DMSO-d6): 1,10-2,10 (m, 10H), totaling 3.04 (m, 1H), 5,55 (c, 2H), 7,05 (d, 1H), 7,10 (m, 5H), of 5.53 (c, 1H), 7,88 (d, 1H), 8,00 (c, 2H).

Example 38

tert-Butyl-6-[(aminosulfonyl)oxy]-3-cyclohexyl-1H-indazol-1-carboxylate (46%), TPL 128°C

1H-NMR (DMSO-d6): 1,20 is 2.10 (m, 19H), 3,10 (m, 1H), 7.23 percent (DD, 1H), of 7.90-with 8.05 (m, 2H), 8,11 (c, 2H).

By the same method as in example 21, but replacing 6-benzyloxy-3-cyclopentyl-1H-indazol on:

6-benzyloxy-3-cycloheptyl-1H-indazol-1-sulfonamide

6-benzyloxy-3-cyclohexyl-1H-indazol-1-sulfonamide

receive, respectively, the following connections:

Example 39

3-Cycloheptyl-6-hydroxy-1H-indazol-1-sulfonamide, TPL 155°C

1H-NMR (DMSO-d6): 1,20-2,00 (m, 12H), 2,60 (m, 1H), 6,70 (m, 2H), 6.90 to (c, 2H), 7,05 (m, 1H), 7,80 (c, 1H).

Example 40

3-Cyclohexyl-6-hydroxy-1H-indazol-1-sulfonamide, TPL 162°C

1H-NMR (DMSO-d6): 1,10-2,10 (m, 10H)to 3.00 (m, 1H), 6,78 (DD, 1H), 7,25 (d, 1H), 7,68 (d, H), by 8.22 (c, 2H), of 10.05 (c, 1H).

Example 41

3-Cyclohexyl-1H-indazol-6-insultant

A mixture of tert-butyl-6-[(aminosulfonyl)oxy]-3-cyclohexyl-1H-indazol-1-carboxylate (4,00 g, 10,12 mmol), water (10 ml), dioxane (30 ml) and few drops of concentrated (30%) of the HCl solution is stirred overnight and poured into water. The precipitate is collected by filtration and obtain the expected product. Crystallization from toluene obtain white crystals (1.25 g, 48%).

1H-NMR (DMSO-d6): 1,10-2,10 (m, 10H), totaling 3.04 (m, 1H), 6,95 (DD, 1H), 7,35 (d, 1H), 7,83 (d, 1H), of 7.96 (c, 2H).

OBTAINING 3-methyl bromide-1H-INDAZOLS (16), (17) AND (18)

Example 42

1-[(tert-Butoxycarbonyl)oxy]-6-methoxy-3-methyl-1H-indazol

Di-tert-BUTYLCARBAMATE in acetonitrile is mixed at a temperature of 0°C With 6-methoxy-3-methyl-1H-indazole (produced according to the method described by F. Dennler, Tetrahedron, 22, 1966, 3131-3139) (26,27 g rate £ 0.162 mol), acetonitrile (200 ml), triethylamine (25 ml, 0,178 mol), DMAP (3,96 g, 0,0324 mol). The mixture is left to mix overnight at room temperature. The acetonitrile was concentrated in vacuo. The mixture is extracted with ethyl acetate and acidified to pH=2 with concentrated HCl solution, dried over Na2SO4, filtered and transferred into diisopropyl ether. Gain of 23.9 g of the expected product in the form of salts, 59%).

1H-NMR (DMSO-d6): 1,60 (c, 9H), 2,44 (c, 3H), 3,85 (c, 3H), 6,95 (DD, 1H), 7,50 (d, 1H), 7,65 (d, 1H)./p>

Example 43

1-[(tert-Butoxycarbonyl)oxy]-6-methoxy-3-methyl bromide-1H-indazol

1-[(tert-Butoxycarbonyl)oxy]-6-methoxy-3-methyl-1H-indazol of 25.2 g, 0,096 mol) is dissolved in CCl4and mixed with benzoyl peroxide (2,33 g, 9.6 mmol). To the resulting mixture is slowly added N-bromosuccinimide (NBS, 18,8 g, 0,109 mol) and refluxed overnight. The mixture is cooled to room temperature, filtered through celite, the filtrate was concentrated in vacuo and purified by the method of flash chromatography using toluene as eluent. Receive a 10.5 g of the expected product (32%, in oil).

1H-NMR (DMSO-d6): 1,65 (c, 9H), 3,85 (c, 3H), 4.95 points (c, 2H), 7,05 (DD, 1H), 7,55(c, 1H), 7,80 (d, 1H).

Example 44

{1-[(tert-Butoxycarbonyl)oxy]-6-methoxy-1H-indazol-3-yl}acetonitrile

KCN (5.73 g, 88 mmol) in 23 ml of H2About added dropwise at a temperature of 0°C to 1-[(tert-butoxycarbonyl)oxy]-6-methoxy-3-methyl bromide-1H-indazole (10.5 g, 30,08 mmol) in 80 ml of ethanol and stirred at room temperature for 1 hour 30 minutes the Mixture was poured into water and extracted with ethyl acetate. The organic layer is dried over Na2SO4. After concentration and precipitation with diisopropyl ether get the expected product (4.42 g, 50% in the form of a solid substance).

1H-NMR (DMSO-d6): 1,65 (c, 9H), 3,85 (c, 3H), 4,42 (c, 2H), 7,00 (d, 1H), 7,50 (d, 1H), of 7.75 (d, 1H).

The FLOOR IS GIVING (1H-INDAZOL-3-YL)ACETONITRILE (20), (21) and (22)

Example 45

2-(Z/E)-2-(6-Methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)prop-2-enitel

a 40%solution of KOH in water in the amount of 3.5 ml and 7.1 ml of ethanol is added dropwise to p-anisic the aldehyde (of 2.06 ml and 16.9 mmol) and {1-[(tert-butoxycarbonyl)oxy]-6-methoxy-1H-indazol-3-yl}acetonitrile in ethanol. After completion of the reaction the mixture is filtered and gain of 3.53 g of the expected product (77% in the form of a solid substance).

1H-NMR (DMSO-d6): 3,35 (c, 1H), 3,85 (c, 3H), 3,90 (c, 3H), 6,70-7,20 (m, 4H), a 7.85-8,15 (m, 4H).

Using the same method, but replacing p-anisic aldehyde to cyclohexanecarboxaldehyde receive the following connection:

Example 46

2-(Z/E)-3-Cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)prop-2-enitel (55,4%)

1H-NMR (DMSO-d6): 1,20-1,80 (m, 10H), 2,60-of 2.75 (m, 1H), 3,80 (c, 3H), 6,85 (DD, 1H), 6,95 (d, 1H), 7,15 (d, 1H), a 7.85 (d, 1H), 13,20 (c, 1H).

Example 47

2-(6-Methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)propanenitrile

To 2-(6-methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)prop-2-onitrile (3,53 g to 11.56 mmol), dissolved in ethanol, added in several portions NaBH4(0.66 g, 17 mmol). The mixture is stirred at 70°C overnight, and then poured into water, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer is dried over Na2SO4, filtered and concentrated. The oil precipitated from ethanol is diisopropyl ether and receive the expected product (3,18 g, in the form of a white powder, 85,3%).

1H-NMR (DMSO-d6): 3,56 (c, 3H), 3,60-of 3.80 (m, 2H), 3,85 (c, 3H), 4.26 deaths (t, 1H), 6.90 to-7,30 (m, 6H), of 7.97 (d, 1H), 11,13 (c, 1H).

Using the same method, but substituting 2-(Z/E)-2-(6-methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)prop-2-enitel 2-(Z/E)-3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)prop-2-enitel receive the following connection:

Example 48

3-Cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile (97,5%)

1H-NMR (DMSO-d6): 0,85-of 2.45 (m, 13H), 3,80 (c, 3H)and 4.65 (t, 11-1), to 6.75 (DD, 1H), 6.90 to (d, 1H), 7,65 (d, 1H), 12,85 (c, 1H).

Example 49

3-Cyclohexyl-2-(6-hydroxy-1H-indazol-3-yl)propanenitrile

3-Cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile (1,61 g of 5.68 mmol) dissolved in CH2Cl2and cooled in a bath with ice. To the resulting mixture are added 1M solution of BBr3/CH2Cl2(8.6 ml, charged 8.52 mmol)and then stirred the mixture at a temperature of 50°C, then poured into a saturated solution of NaHCO3, extracted with ethyl acetate, dried over Na2SO4, filtered, concentrated in vacuo and purified by the method of flash chromatography (CH2Cl2/Meon 98/2). After crystallization from EtOH obtain 780 mg of white crystals (51%), TPL 175°C.

1H-NMR (DMSO-d6): 0,80-2,05 (m, 13H)and 4.65 (t, 1H), 6,70 (DD, 1H), 6,78 (d, 1H), 7,60 (d, 1H), 9,70 (c, 1H), 12,60 (c, 1H).

GETTING PROPANAMIDE (23)

By the same method as in Primera, but replacing 3-(1-substituted)-6-methoxy-1H-indazol on:

2-(6-methoxy-1H-indazol-3-yl)-3-(4-methoxyphenyl)propanenitrile

3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile

receive, respectively, the following connections:

Example 50

2-(1-Acetyl-6-hydroxy-1H-indazol-3-yl)-3-(4-methoxy-phenyl)propanamide (7,7%), TPL 152°C.

1H-NMR (DMSO-d6): 2,22 (c, 3H), 3.15 in (kV, 2H), 3,80 (c, 3H), 4,15 (m, 1H), of 6.68 (DD, 1H), 6,80 (d, 1H), 6,85-7,05 (m, 3H), 7,20 (m, 2H), 7,52 (c, 1H), 7,80 (d, 1H), 12,53 (c, 1H).

Example 51

3-Cyclohexyl-2-(6-hydroxy-1H-indazol-3-yl)propanamide (34%), TPL 199°C

1H-NMR (DMSO-d6): 0,70-2,10 (m, 13H), 3,90 (m, 1H), 6,55 (d, 1H), 6.75 in (c, 1H), 6,83 (c, 1H), 7,45 (c, 1H), 7,65 (d, 1H), 9,50 (c, 1H), 12,20 (c, 1H).

OBTAINING 1H-PYRANO[4,3,2-cd]INDAZOLS (25), (26) and (27)

Example 52

7-Methoxy-3-(4-methoxyphenyl)-1H-pyrano[4,3,2-cd]indazol

By the same method as in example 12, but replacing cyclopentyl(4-benzyloxy-2-forfinal)methanon 5-chloro-7-methoxy-3-(4-methoxyphenyl)-4H-chromen-4-one (synthesized according to KitagawaChem. Pharm. Bull., 39, 1991, 2681), you get the expected product in the form of solids, 84%).

1H-NMR (DMSO-d6): 3,60 (c, 3H), 3,80 (c, 3H), 6,60 (d, 2H), 6,80 (d, 2H), 7,10 (d, 1H), 7,30 (d, 1H), 7,80 (c, 1H).

By the same method as in example 49, but substituting 3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile 7-methoxy-3-(4-methoxyphenyl)-1H-pyrano[4,3,2-cd]indazol receive the following compounds is Oia:

Example 53

3-(4-Methoxyphenyl)-1H-pyrano[4,3,2-cd]indazol-7-ol, hydrochloride (26%), TPL 255°C

1H-NMR (DMSO-d6): 3,55 (c, 3H), 6,63 (m, 4H), 7,05 (d, 2H), 8,05 (c, 1H), 10,00 (c, 1H).

Example 54

3-(4-Hydroxyphenyl)-1H-pyrano[4,3,2-cd]indazol-7-ol, hydrochloride (15%), TPL 111°C

1H-NMR (DMSO-d6): 6,45 (c, 2H), 6,65 (d, 2H), 7,10 (d, 2H), 8,00 (c, 1H), 10,00 (c, 1H).

GETTING ASIMOV (28) and (30)

Example 55

1-Substituted(2-chloro-4,6-dihydroxyphenyl)metano

1M Solution tribromide boron in CH2Cl2added to a solution of 1-substituted(2-chloro-4,6-digiecocity)methanone (7 g, 21,0 mmol) and CH2Cl2(30 ml). The mixture is heated overnight and then poured into water, extracted with ethyl acetate, dried over Na2SO4and concentrated in vacuo, obtaining the expected product (1.9 g, 30%).

1H-NMR (DMSO-d6): 1,00-1,90 (m, 15H), and 6.25 (c, 1H), 6.30-in (c, 1H), 10,00 (c, 2H).

Example 56

The oxime of 1-substituted(2-chloro-4,6-dihydroxyphenyl)methanone

1-Substituted(2-chloro-4,6-dihydroxyphenyl)methanon (1.9 g, 6.2 mmol), hydroxylamine hydrochloride (100 g) and pyridine (50 ml) is refluxed for 4 hours the Mixture was concentrated in vacuo, poured into water, extracted with ethyl acetate, washed with 1 N. HCl solution, dried over Na2SO4and concentrated in vacuo give crude product. Cleaning method flash chromatography (AcOEt/toluene 3/7)gives the pure oxime (1 g in the form of solids, 50%).

1H-NMR (DMSO-d6): 1,50-2,00 (m, 15H), 6,24 (c, 1H), 6,28 (c, 1H).

Using the same method, but replacing 1-substituted(2-chloro-4,6-dihydroxyphenyl)metano

1-substituted(4-benzyloxy-2-forfinal)metano

cycloheptyl(4-benzyloxy-2-forfinal)metano

receive, respectively, the following connections:

Example 57

The oxime of 1-substituted(4-benzyloxy-2-forfinal)methanone (32%)

1H-NMR (DMSO-d6): 1,20-2,20 (m, 15H), 5,10 (c, 2H), 6,80 (dt, 1H), 6.90 to-7,17 (m, 2H), 7,20-of 7.60 (m, 5H), 10,55 (c, 1H).

Example 58

The oxime cycloheptyl(4-benzyloxy-2-forfinal)methanone (60%)

1H-NMR (DMSO-d6): 1,10-2,00 (m, 12H), 2,10-of 2.20 (m, 1H), 5,10 (c, 2H), 6,67-6,85 (m, 1H), 6.90 to-to 7.15 (m, 2H), 7,25 is 7.50 (m, 5H), 10,47 (c, 1H).

GETTING BENZISOXAZOLE (31), (32) and (34)

Example 59

6-Benzyloxy-3-cyclohexyl-1,2-benzisoxazol

A solution of hydroxylamine hydrochloride (11.7 g) in warm water (100 ml) was poured into a mixture of cyclohexyl(4-benzyloxy-2-forfinal)methanone (20,22 g, or 64.7 mmol) and EtOH (54 ml). Quickly add a solution of sodium hydroxide (11,13 g, 0,278 mol) in water (54 ml) and heated to boiling. The reaction mixture is heated for 12 h and then most of the EtOH is removed by distillation. To the residue add a solution of potassium hydroxide (8.7 g, 0,155 mol) in water (54 ml). The mixture is refluxed for 2 days, then cooled to about 6°C, With vigorous paramasivan is. Get a solid white color, which is thoroughly washed with water and triturated with diisopropyl ether. Benzisoxazol obtained after filtration in the form of a white powder (of 12.26 g, 62%), TPL 110°C.

1H-NMR (DMSO-d6): 1,00-2,10 (m, 10H), was 3.05 (m, 1H), 5,20 (c, 2H), 7,00 (DD, 1H), 7,25-of 7.55 (m, 6H), of 7.75 (d, 1H).

Using the same method, but replacing cyclohexyl(4-benzyloxy-2-forfinal)methanon at cyclohexyl-(2-fluoro-4-hydroxy-5-methoxyphenyl)methanon receive the following connection:

Example 60

3-Cyclohexyl-6-hydroxy-5-methoxybenzothiazole (50,5%)

1H-NMR (DMSO-d6): 1,20-2,10 (m, 10H), was 3.05 (m, 1H), 3,85 (c, 3H), 6,95 (c, 1H), 7.23 percent (c, 1H), 9,94 (c, 1H).

Example 61

3-(1-Substituted)-4-chloro-1,2-benzisoxazol-6-ol

Diethylazodicarboxylate (0,92 g, 1.7 EQ.) in THF (20 ml) is added to a mixture of the oxime of 1-substituted(2-chloro-4,6-dihydroxyphenyl)methanone (1 g, 3.1 mmol), triphenylphosphine (1.4 g, 1.7 EQ.) in THF (20 ml) at 0°C. the Mixture is stirred 2 h at 0°C., poured into water, extracted with ethyl acetate, dried over Na2SO4and concentrated in vacuo, obtaining the expected product. After cleaning method flash chromatography (AcOEt/toluene 1/9) and crystallization from EtOH get the expected product (230 mg, 23%), TPL 215°C.

1H-NMR (CDCl3): 1,50-2,10 (m, 15H), 6,23 (d, 1H), 6,32 (d, 1H).

Example 62

3-(1-Substituted)-6-benzyloxy-1,2-benzisoxazol

The oxime 1-adamantyl-benzyloxy-2-forfinal)methanone (2,3 mg, 6 mm) in DMF (30 ml) at 0°C in nitrogen atmosphere is added dropwise to a stirred suspension of NaH (0,61 g, 18 mm, 60%dispersion in oil) in DMF (10 ml). After complete addition, the reaction mixture is allowed to warm to room temperature and poured into H2O. the Precipitate is collected by filtration and receive the expected product (to 2.06 mg, 95%), TPL 132°C.

1H-NMR (DMSO-d6): 1,20-of 2.45 (m, 15H), 5,22 (c, 2H), 7,00 (d, 1H), 7,30-of 7.60 (m, 6H), 7,72 (d, 1H).

Using the same method, but replacing the oxime of 1-substituted(4-benzyloxy-2-forfinal)methanone on the oxime cycloheptyl(4-benzyloxy-2-forfinal)methanone receive the following connection:

Example 63

6-Benzyloxy-3-cycloheptyl-1,2-benzisoxazol (90%), so pl. 80°C

1H-NMR (DMSO-d6): 1,30-of 2.20 (m, 12H), of 3.25 (m, 1H), total of 5.21 (c, 2H), 7,00 (DD, 1H), 7,25-of 7.60 (m, 6H), of 7.75 (d, 1H).

By the same method as in example 23, but substituting 6-benzyloxy-3-cyclopentyl-1H-indazol on:

3-(1-substituted)-6-benzyloxy-1,2-benzisoxazol

6-benzyloxy-3-cycloheptyl-1,2-benzisoxazol

6-benzyloxy-3-cyclohexyl-1,2-benzisoxazol

receive, respectively, the following connections:

Example 64

3-(1-Substituted)-1,2-benzisoxazol-6-ol (47,5%), TPL 215°C

1H-NMR (DMSO-d6): 1,40-of 2.20 (m, 13H), 2,35 (c, 2H), 6,80 (DD, 1H), 6,92 (d, 1H), 7,58 (d, 1H), 10,28 (c, 1H).

Example 65

3-Cycloheptyl-1,2-benzisoxazol-6-ol (48%), TPL 156°C.

1N-the Mr (DMSO-d 6): 1,20-2,20 (m, 12H), 3,18 (m, 1H), 6,80 (d, 1H), 6.90 to (c, 1H), 7,65 (d, 1H), of 10.25 (c, 1H).

Example 66

3-Cyclohexyl-1,2-benzisoxazol-6-ol (37%), TPL 181°C

1H-NMR (DMSO-d6): 1,10-2,10 (m, 10H), to 3.02 (dt, 1H), 6,80 (DD, 1H), 6.90 to (c, 1H), 7,68 (d, 1H), of 10.25 (c, 1H).

Example 67

3-Cyclohexyl-1,2-benzisoxazol-5,6-diol

By the same method as in example 49, but substituting 3-cyclohexyl-2-(6-methoxy-1H-indazol-3-yl)propanenitrile 3-cyclohexyl-6-hydroxy-5-methoxybenzothiazole receive the expected product (48,4%), TPL 177°C.

1H-NMR (DMSO-d6): 1,20-2,05 (m, 10H), was 3.05 (dt, 1H), 6,92 (c, 1H), 7,05 (c, 1H), of 9.55 (users, 2H).

Example 68

3-Cyclohexyl-6-(2-piperidine-1-ylethoxy)-1,2-benzisoxazol

A mixture of 3-cyclohexyl-1,2-benzisoxazol-6-ol (2,69 g, 12 mmol), hydrochloride of 1-(2-chloroethyl)piperidine (2,39 g, 13 mmol) and K2CO3(3,59 g, 26 mmol) in CH3CN (30 ml) is refluxed for 3 h and then left to mix overnight at room temperature. The reaction mixture was poured into H2O and extracted with EtOAc. The organic layer was washed with saturated salt solution, dried over Na2SO4and focus, getting the balance (of 3.78 g). The residue is purified by the method of flash chromatography (toluene/1,4-dioxane 8/2). Crystallized from EtOH and receive crystals white (0,53 g, 13.4 per cent), TPL 69°C.

1H-NMR (DMSO-d6): 1,20-2,10 (m, 16H), 2,30-of 2.50 (m, 4H) 2,70 (t, 2H), 2.95 and was 3.05 (dt, 1H), 4,15 (t, 2H), 6,95 (DD, 1H), 7,25 (d, 1H), of 7.75 (d, 1H).

Example 69

Trihydroxybenzoic

Resorcinol (100 g of 0.91 mol) and 4-hydroxyphenylarsonic acid (138,4 g of 0.91 mol) is dissolved in BF3·Et2O (346 ml, 2,73 mol) in nitrogen atmosphere. The mixture is stirred and heated to a temperature of 50-60°C. After completion of the reaction the mixture is cooled to room temperature and poured into a large volume of ice water. The crude product is filtered and dried, obtaining trihydroxybenzoic (70%), TPL 211°C.

1H-NMR (acetone-d6): 4,12 (c, 2H), 6,78 (d, 2H), 6,91 (d, 1H), 7,13 (d, 2H), 7,54 and 7.6 (m, 2H), 8,21 (c, 1H), 8,35 (c, 1H), 8,70 (c, 1H).

Example 70

1-[2-Hydroxy-4-(tetrahydro-2H-Piran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-Piran-2-yloxy)phenyl]alanon

To a cooled (0-5°C.) suspension of trihydroxybenzene (100 g, 0.41 mol) and TsOH (0,062 g)as a catalyst in toluene (350 ml) is added slowly a solution of dihydropyran (DHP) (150 ml, of 1.64 mol). The reaction mixture becomes homogeneous, and it is stirred at room temperature for 1 h Add triethylamine and the solvent evaporated under reduced pressure. The brown oil after trituration in hot isopropanol (1.2 l) crystallizes, and thus produce the formed solid white (182 g, 90%).

1H-NMR (CDCl3): 1,40-of 2.05 (m, 12H), 3,40-of 3.60 (m, 2H), 3,65-3,90 (m, 2H), 4,05 (c, 2H), and 5.30 (t, 1H), 5.40 to (t, 1H), 6,4 (DD, 1H), is 6.54 (d, 1H), 6,94 (d, 2H), 7,10 (d, 2H), 7,68 (d, 1H), to 12.52 (c, 1H).

Example 71

The oxime of 1-[2-hydroxy-4-(tetrahydro-2H-Piran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-Piran-2-yloxy)phenyl]ethanone

A mixture of 1-[2-hydroxy-4-(tetrahydro-2H-Piran-2-yloxy)]-2-[4-(tetrahydro-2H-Piran-2-yloxy)phenyl]ethanone (5 g, 12 mmol) and H2NOH, HCl (8,59 g, 12.3 mmol) is stirred for 24 h in pyridine (65 ml) at room temperature. The reaction mixture was poured into a large amount of 99/1 mixture of N2About/triethylamine, and then extracted with EtOAc. The organic layer was washed with a saturated solution of salt. After drying over sodium sulfate EtOA evaporated. The residue is purified by the method column flash chromatography (toluene/1,4-dioxane 90/1 + Thea 1%) and receive a colorless oil (of 5.05 g, 97%).

1H-NMR (DMSO-d6): 1,30-2,00 (m, 12H), 3,40-of 3.60 (m, 2H), 3,60-of 3.80 (m, 2H), 4,12 (c, 2H), 5,38 (t, 1H), the 5.45 (t, 1H), 6.48 in (d, 1H), 6,50 (c, 1H), 6,93 (d, 2H), 7,05-7,30 (m, 3H), 7,40 (d, 1H), 11,63 (c, 1H), 11,85 (c, 1H).

Example 72

6-(Tetrahydro-2H-Piran-2-yloxy)-3-[4-(tetrahydro-2H-Piran-2-yloxy)benzyl]-1,2-benzisoxazol

By the same method as in example 61, but substituting the oxime of 1-substituted(2-chloro-4,6-dihydroxyphenyl)methanone on the oxime of 1-[2-hydroxy-4-(tetrahydro-2H-Piran-2-yloxy)phenyl]-2-[4-(tetrahydro-2H-Piran-2-yloxy)phenyl]ethanone receive the expected product (25%).

1H-NMR (DMSO-d6): 1,40-2,10 (m, 12H), 3,40-of 3.85 (m, 4H), 4.25 in (c, 2H), 5,39 (c, 1H), 5,61 (c, 1H), 6.90 to-7,10 (m, 3H), 7,20 of 7.3 (m, 3H), at 7.55 (d, 1H).

Example 73

3-(4-Hydroxybenzyl)-1,2-benzisoxazol-6-ol

In methanol (20 ml) was dissolved 6-(tetrahydro-2H-Piran-2-yloxy)-3-[4-(tetrahydro-2H-Piran-2-yloxy)benzyl]-1,2-benzisoxazol (of 3.85 mmol) and para-toluensulfonate acid (APTS, catalytic amount). Conduct the reaction at a temperature of 60-70°C for 3 h, then the reaction mixture is cooled to room temperature, poured into a saturated solution of NaHCO3and extracted with EtOAc. After washing (N2About) and drying (MgSO4) extract was concentrated. The crude product is purified by the method of flash chromatography (toluene/1,4-dioxane 8/2) and crystallized, getting whitish crystals (0,58 g, 31%), TPL 178°C.

1H-NMR (DMSO-d6): 4,11 (c, 2H), 6,69 (d, 2H), 6.75 in (DD, 1H), 6.90 to (d, 1H), 7,13 (d, 2H), of 7.48 (d, 1H), 9,80 (c, 2H).

GETTING SULFAMATES of BENZISOXAZOLE (33)

By the same method as in example 33, but substituting 6-benzyloxy-3-cycloheptyl-1H-indazol on:

3-(1-substituted)-1,2-benzisoxazol-6-ol

3-cycloheptyl-1,2-benzisoxazol-6-ol

3-cyclohexyl-1,2-benzisoxazol-6-ol

receive, respectively, the following connections:

Example 74

3-(1-Substituted)-1,2-benzisoxazol-6-isalphabet (82%), TPL 87°C

1H-NMR (DMSO-d6): 1,50-of 2.45 (m, 15H), 7,28 (DD, 1H), 7,63 (d, 1H), of 7.96 (d, 1H), 8,15 (c, 2H).

Example 75

3-Cycloheptyl-1,2-benzisoxazol-6-isalphabet (54%), TPL 82 is

1H-NMR (DMSO-d6): 1,40-2,10 (m, 12H), of 3.32 (m, 1H), 7,30 (d, 1H), 7,60 (d, 1H), with 8.05 (d, 1H), 8,15 (c, 2H).

Example 76

3-Cyclohexyl-1,2-benzisoxazol-6-isalphabet (46%), TPL 145°C

1H-NMR (DMSO-d6): 1,20-2,20 (m, 10H), 3.15 in (dt, 1H), 7,25 (DD, 1H), 7.62mm (d, 1H), with 8.05 (d, 1H), 8,15 (c, 2H).

GETTING BENZISOXAZOLE (36), (37) and (38)

Example 77

2-(Z/E)-(6-Methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)prop-2-enitel

a 40%solution of KOH/N2About (3 ml) and EtOH (4.8 ml) at room temperature is added slowly to a heterogeneous mixture of (6-methoxy-1,2-benzisoxazol-3-yl)acetonitrile (2.4 g, 12.7 mmol), obtained in accordance with H. Uno (Chem. Pharm. Bull., 24 (4), 632-643, 1976), 4-methoxybenzaldehyde (1.1 EQ., 14 mmol, 1.8 g) and EtOH (24 ml). The mixture is stirred at room temperature for 1 hour, the precipitate is filtered under vacuum, washed with water and with EtOH and get pure 2-(Z/E)-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)prop-2-enitel (3,15 g, 81%).

1H-NMR (acetone-d6): 3,94 (c, 3H), 3,97 (c, 3H), was 7.08 (DD, 1H), 7,15 (d, 2H), 8,05-8,30 (m, 4H).

Using the same method, but replacing 4-methoxybenzaldehyde 4-hydroxybenzaldehyde receive the following connection:

Example 78

2-(Z/E)-3-(4-Hydroxyphenyl)-2-(6-methoxy-1,2-benzisoxazol-3-yl)prop-2-enitel (86%), TPL >380°C.

1H-NMR (DMSO-d6): 3,85 (c, 3H), x 6.15 (d, 2H), 7,00 (d, 1H), 7,25 (c, 1H), 7,70 (c, 3H), of 8.00 (d, 1H).

the example 79

2-(6-Methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxy-phenyl)propanenitrile

NaBH4(of 1.05 EQ., 0.2 g of 5.15 mmol) is added to a heterogeneous solution of 2-(Z/E)-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)prop-2-onitrile (1.5 g, 4.9 mmol) and EtOH (20 ml). The mixture is heated to 50°C for 1 h, acidified to pH 1 with 1 n HCl solution, extracted with AcOEt, dried over Na2SO4and concentrated in vacuo, obtaining pure 2-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)propanenitrile (1.5 g, 100%).

1H-NMR (CDCl3): 3,35 (d, 2H), 3,80 (c, 3H), 3,90 (c, 3H), of 4.45 (t, 1H), at 6.84 (d, 2H), 6,93 (DD, 1H), 7,02 (d, 1H),? 7.04 baby mortality (d, 2H), 7,50 (d, 1H).

Example 80

2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(4-hydroxyphenyl)propanenitrile

To a solution of 2-(6-methoxy-1,2-benzisoxazol-3-yl)-3-(4-methoxyphenyl)propanenitrile (1.5 g, 4.9 mmol) in CH2Cl2(100 ml) under nitrogen atmosphere add a 1M solution of BBr3in CH2Cl2(4 EQ., 20 ml). The mixture is boiled for 2 h, poured into water and extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuum to give crude product. After cleaning method flash chromatography (CH2Cl2/Meon 98/2) and crystallization from EtOH get the expected crystals (850 mg, 62%), TPL 214°C.

1H-NMR (DMSO-d6): of 3.25 (m, 2H), 5,10 (t, 1H), 6,65 (d, 2H), 6.90 to (d, 1H), 7,00 (d, 2H), 7,06 (c, 1H), of 7.70 (d, 1H), 9,35 (c, 1H), 10,50 (c, 1H).

Gametocyte, as in example 77, but replacing 4-methoxybenzaldehyde on:

3-fluoro-4-methoxybenzaldehyde

4-methoxy-2-methylbenzaldehyde

3-methoxybenzaldehyde

4-forbindelse

cyclohexanol

3,4-dimethoxybenzaldehyde

and using the same methods described in examples 79 and 80, respectively, received the following connections:

Example 81

2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(3-fluoro-4-hydroxyphenyl)propanenitrile (56%), TPL 201°C

1H-NMR (DMSO-d6): of 3.25 (m, 2H), further 5.15 (t, 1H), 6,70-7,20 (m, 5H), 7,72 (d, 1H), 9,82 (c, 1H), 10,55 (c, 1H).

Example 82

2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(4-hydroxy-2-were)propanenitrile (15%), TPL 131°C

1H-NMR (acetone-d6): 2,11 (c, 3H), of 3.28 (d, 2H), 3,80 (c, 3H), 4.72 in (t, 1H), 6,40-6,60 (m, 2H), 6,85 (DD, 1H), 7,00 (d, 1H), 7,10 (d, 1H), 8,09 (c, 1H).

Example 83

2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(3-hydroxyphenyl)propanenitrile (20%)

1H-NMR (acetone-d6): 3,25-of 3.60 (m, 2H), 4,90 (t, 1H), 6,60-7,25 (m, 6H), of 7.70 (d, 1H), 8,80 (users, 1H).

Example 84

2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(4-forfinal)propanenitrile (35%), TPL 152°C

1H-NMR (DMSO-d6): 2,40-2,70 (m, 2H), 3,95 (m, 1H), 4.25 in (c, 1H), 5,90-6,50 (m, 6H), 6,70 (d, 1H).

Example 85

2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-cyclohexylpropionate (63%), TPL 111°C

1H-NMR (acetone-d6): 0,80-2,10 (m, 13H), 4,56 (DD, 1H), 6.90 to (DD, 2H), 7,02 (d, 1H), to 7.67 (d, 1H), 9,38 (c, 1H).

p> Example 86

2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(3,4-dihydroxyphenyl)propanenitrile (56%), TPL 154°C

1H-NMR (DMSO-d6): 3,00-to 3.35 (m, 2H), is 5.06 (t, 1H), 6,50 (DD, 1H), 6,55 to 6.75 (m, 2H), 6.90 to (DD, 1H), 7,00 (DD, 1H), of 7.70 (d, 1H), 8,90 (users, 1H).

GETTING BENZISOXAZOLE(40), (41), (42) and (43)

Example 87

3-Methyl-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazol

3-Methyl-1,2-benzisoxazol-6-ol (10 g, 67 mmol) (synthesized in accordance with M.A.Elkasaby,Indian. J. Chem.,1987, 26, 620) and DMF (50 ml) is added to a mixture of tert-butyldimethylsilyloxy (of 1.05 EQ., 10.6 g), imidazole (2.5 EQ., 11.4 g) and DMF (100 ml) under nitrogen atmosphere. The mixture is then stirred at room temperature for 1 hour, poured into water and extracted with ethyl acetate, then dried over Na2SO4, filtered and concentrated in vacuum to give crude product. After cleaning method flash chromatography (AcOEt/toluene 18/85 with 0.1% tea) to obtain 6-[(tert-butyl(dimethyl)silyl)oxy]-3-methyl-1,2-benzisoxazol (17.1 g, 97%).

1H-NMR (CDCl3-d1): 0,20 (c, 6H), 1.00 m (c, 9H), 2,60 (c, 3H), to 6.80 (DD, 1H), 6,95 (d, 1H), 7,45 (d, 1H).

Example 88

3-(methyl bromide)-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazol

NBS (12.7 g, 71,5 mmol) and benzoyl peroxide (1.6 g, 6.5 mmol) are added to a mixture of 3-methyl-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole (17.1 g, 65 mmol) and CCl4(200 ml). The mixture is boiled with reverse, chilling the nick overnight and the precipitate is filtered off, washed with CCl4and purified by the method of flash-chromatography (AcOEt/toluene 1/9 with 0.1% tea)to give 3-(methyl bromide)-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazol (15,1 g, 68%).

1H-NMR (CDCl3-d1): 0,25 (c, 6H), 1.00 m (c, 9H), 4,57 (c, 2H), to 6.88 (DD, 1H), 7,02 (d, 1H), 7,55 (d, 1H).

Example 89

3-(6-[(tert-Butyl(dimethyl)silyl)oxy]-1,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl)propanenitrile

In nitrogen atmosphere 2.0 M solution of n-BuLi in THF (9.7 mmol) is added slowly to a solution of Diisopropylamine (1.3 ml, of 1.05 equiv.) in dry THF (10 ml) at a temperature of minus 20°C. the Mixture was stirred at minus 20°C for 30 min, then at minus 78°C. slowly add 4-methoxybenzonitrile (1.3 g, 8,8 mmol). The mixture is stirred at minus 78°C for 30 min, then slowly add 3-(methyl bromide)-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole (3.0 g, 8,8 mmol) and dry THF (10 ml). The mixture is stirred for 30 min at room temperature, poured into water, extracted with AcOEt, dried over Na2SO4and purified by the method of flash-chromatography (AcOEt/heptane 2/8 with 0.1% tea)to give 3-(6-[(tert-butyl)dimethylsilane)oxy]-1,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl)propanenitrile (1 g, 28%).

1H-NMR (CDCl3-d1): 0,20 (c, 6H), 1.00 m (c, 9H), 3.25 to the 3.65 (m, 2H), 3,70-4,48 (t, 1H), 6,80-of 7.60 (m, 7H).

Example 90

3-(6-Hydroxy-1,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl)propanenitrile

1 is. A solution of n-Bu4F in THF is added to a mixture of 3-(6-[(tert-butyl)silyl)oxy]-1,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl)propanenitrile (1.0 g, 2.45 mmol) in dry THF (20 ml) at room temperature. The mixture is then stirred at room temperature for 2 h, then poured into water and extracted with ethyl acetate, then dried over Na2SO4, filtered and concentrated in vacuo. The crude product is purified by the method of flash-chromatography (AcOEt/toluene 2/8) and crystallized from a mixture of Meon/cyclohexane, receiving the expected product (210 mg, 30%).

1H-NMR (DMSO-d6): 3,00-3,50 (m, 2H), of 5.05 (t, 1H), 6,60 (d, 2H), 6.90 to (DD, 1H), 7,00 (d, 2H), 7,05 (c, 1H), of 7.70 (d, 1H), 9,40 (c, 1H), 10,50 (c, 1H).

GETTING BENZISOTHIAZOLE (45) and (46)

Example 91

Cyclohexyl(4-benzyloxy-2-benzylidene)metano

The solution phenylmethanol (2.35 ml, 20 mmol) in THF (10 ml) at room temperature under nitrogen atmosphere is added slowly to a mixture of tert-butoxide potassium (2.24 g, 20 mmol) in THF (80 ml). The mixture is stirred for 15 min at room temperature and slowly add cyclohexyl(4-benzyloxy-2-forfinal)methanon (6.5 g, 20 mmol) in THF (10 ml). The mixture for 2 h, heated to a temperature of 50°C, poured into an aqueous solution of NH4Cl, extracted with ethyl acetate, dried over Na2SO4, and concentrated in vacuo. The crude product is purified by the method of flash chromatography (heptane/ AcOEt 9/10 with 0.1% tea) and get cyclohexyl(4-benzyloxy-2-benzylidene)methanon (8,3 g, 100%).

1H-NMR (DMSO-d6): 1,00-of 1.85 (m, 10H), 3,10-3,30 (m, 1H), 4,15 (c, 2H), 5,19 (c, 1H), 6,85 (DD, 1H), 7,05 (d, 1H), 7,15-of 7.60 (m, 10H), of 7.90 (d, 1H).

Example 92

6-Benzyloxy-3-cyclohexyl-1,2-benzisothiazol

Sulfurylchloride (1.77 ml, 2.2 mmol) is added slowly to a solution of cyclohexyl(4-benzyloxy-2-benzylidene)methanone (8,77 g, 21 mmol) in CH2Cl2(80 ml) at 0°C. the Mixture is stirred for 2 h at room temperature, and then concentrated in vacuo. To the mixture is added THF (80 ml), and then at a temperature of 0°C. slowly add EtOH (80 ml), saturated with ammonia. Leave the mixture was mixed overnight at room temperature, poured into water, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuum to give crude product. After cleaning method flash chromatography (heptane/AcOEt 98/2) to obtain 6-benzyloxy-3-cyclohexyl-1,2-benzisothiazol (3.55 g, 52%).

1H-NMR (DMSO-d6): 1,10-2,00 (m, 10H), of 3.25 (dt, 1H), 5,20 (c, 2H), 7,12 (DD, 1H), 7,25-of 7.55 (m, 5H), of 7.75 (d, 1H), 8,02 (d, 1H).

Example 93

3-Cyclohexyl-1,2-benzisothiazol-6-ol

1 M solution of tribromide boron in CH2Cl2(11.9 ml, with 11.9 mmol) at a temperature of 0°C is added slowly to a solution of 6-benzyloxy-3-cyclohexyl-1,2-benzisothiazole (3.5 g, 10 mmol) in CH2Cl2(50 ml). The mixture is stirred at room temperature for 15 min and the pouring out of the t in the water. The precipitate is filtered off, dried and crystallized from EtOH, getting clean 3-cyclohexyl-1,2-benzisothiazol-6-ol (940 mg, 40.3 per cent), TPL 190°C.

1H-NMR (DMSO-d6): 1,10-2,10 (m, 10H), 3,20 (dt, 1H), 6,95 (DD, 1H), 7,40 (d, 1H), to 7.93 (d, 1H), 10,18 (c, 1H).

By the same technique as the examples from 91 to 93, but replacing cyclohexyl(4-benzyloxy-2-forfinal)methanon on cyclopentyl(4-benzyloxy-2-forfinal)methanon receive the following connection:

Example 94

3-Cyclopentyl-1,2-benzisothiazol-6-ol, TPL 130°C

1H-NMR (DMSO-d6): 1,50-2,20 (m, 8H), 3,62 (m, 1H), 6,95 (DD, 1H), 7,35 (d, 1H), 7,92 (d, 1H), 10,18 (c, 1H).

GETTING SULFAMATES of BENZISOTHIAZOLE (47) and (48)

Example 95

3-Cyclohexyl-1,2-benzisothiazol-6-insultant

Sulfhemoglobin (780 mg, 6,76 mmol) at a temperature of 0°C is added in portions to a mixture of 3-cyclohexyl-1,2-benzisothiazol-6-ol (790 mg, to 3.38 mmol) and dimethylacetamide (15 ml). The mixture is stirred at 0°C for 30 min, and then left to mix overnight at room temperature, poured into water, extracted with ethyl acetate, dried over Na2SO4and concentrated in vacuo.

The crude product is purified by the method of flash chromatography (toluene/1,4-dioxane 9/1) and crystallized from a mixture of EtOH/pentane, receiving the expected product (620 mg, 59%), TPL 150°C.

1H-NMR (DMSO-d6): 1,20-2,05 (m, 10H), 3,30 (m, 1H), 7,40 (DD, 1H), 8,10 (d, 1H), 8,15 (c, 2H), of 8.25 (d, 1H).

Ispolzuete same technique, but substituting 3-cyclohexyl-1,2-benzisothiazol-6-ol 3-cyclopentyl-1,2-benzisothiazol-6-ol, get the following connection:

Example 96

3-Cyclopentyl-1,2-benzisothiazol-6-insultant, TPL 132°C

1H-NMR (DMSO-d6): 1,55-of 2.25 (m, 8H), 3,65-of 3.85 (m, 1H), and 7.4 (DD, 1H), 8,10 (c, 1H), 8,15 (c, 2H), 8,23 (d, 1H).

Example 97

3-cyclohexyl-1,1-dioxo-1,2-benzisothiazol-6-insultant

Hydrogen peroxide (0.6 ml) is added slowly at room temperature to a mixture of 3-cyclohexyl-1,2-benzisothiazol-6-silt ether sulfonovoj acid (1 g, 3.2 mmol), triperoxonane acid (2 ml) and dichloromethane (20 ml). The mixture is then stirred for 2 h and poured into water. The precipitate is filtered off and purified by the method of flash chromatography (toluene/1,4-dioxane 85/15) and after crystallization receive solid (70 mg, 6%), TPL 170°C.

1H-NMR (DMSO-d6): 1,10-2,20 (m, 10H), 7,25 (DD, 1H), 8,07 (d, 1H), 8,25 (c, 1H), 8,43 (c, 1H).

The RESULTS of PHARMACOLOGICAL TESTS

In vitrobinding subtype of estrogen receptor

This method is developed on the basis of the method described for estrogen receptors of females rats (J. Botella et al., J. Endocrinol. Invest., 1990, 13: 905-910) and cells of Ishikawa person (Botella J., J. Steroid. Biochem. Molec. Biol., 1995, 55: 77-84). The magnitude of the relative affinity of binding (RBA) is determined using an analysis on competitive binding to the full-size is recombinantly ERα and ERβ person (PanVera, Madison, Wisconsin). Receptors incubated in Tris buffer (10 mm Tris, 2 mm DTT, 1 mg/BSA, 10% glycerol, adjusted to pH 7.5 with HCl) at a temperature of 4°C for 18-20 h with 2 nm [3H]-E2in the presence or absence of increasing concentrations of test compounds in the range from 1 nm to 10 μm. The nonspecific binding determined in the presence of 500-fold excess does not contain the label E2. Separation of bound and free fractions3H-E2performed using activated charcoal (2.5 percent), the dextran-coated (0.25 per cent) in buffer Tris-etc. After shaking for a few seconds and centrifugation with acceleration 1500·g at 4°C for 10 min, 150 μl per well of scintillation fluid Optiphase “Super Mix” mixed with 50 μl of the supernatant of each sample and determine the radioactivity using a particle counter MicroBeta (Wallac, Turku, Finland). To estimate the concentration of the competitor at half of maximum specific binding (IC50make the estimation data using a sigmoid curve, depending on the dose (Prism, GraphPad Software Inc.). The RBA value of each competitor calculated as the ratio of the values of the IC50and E2for the follower, while the RBA values for E2arbitrarily take equal 100%. The selectivity with respect to ERα and ERβ is determined from the ratio R EIT is possible IC 50for ERα to the value for ERβ for each test compound.

Table 1
Analysis of the binding of estrogen receptor α and β
ConnectionERIC50(nm)RBA (%)nR (IC50)
E2Average±The standard deviationAverage±The standard deviationαβ
α1,6±0,1100,0±590,8
β2,1±0,1100,0±59
Example 23α1332,0±of 267.80,2±0,05431,9
β41,8±7,110,4±4,04
Example 24α159,1±23,71,2±0,29the 15.6
β10,2±0,924,6±4,39
Example 31α119,0±45,23,1± 43,3
β36,2±18,717,7±5,14
Example 35α2686,0±593,00,1±0,02410,8
β248,0±48,70,9±0,14
Example 40α1483,0±1177,60,1±0,0257,9
β187,6±34,0 1,0±0,25
Example 65α75,3±of 5.42,5±0,643,7
β20,2±4,213,2±3,14
Example 66α260,0±40,11,1±0,245,8
β44,6±7,79,4±3,14
Example 73α2912,3 ±317,80,1±0,036,0
β484,8±157,71,0±0,34
Example 80α67,5±5,03,4±0,489,0
β7,5±0,743,0±7,88
Example 81α139,3±33,92,4±0,74the 9.7
β14.4V±5,335,9±14,04
Example 84α2300,8±445,60,1±0,03418,7
β122,9±25,92,5±0,44
Example 86α1894,0±and 364.80,2±0,03414,1
β134,8±31,02,4±0,44
Example 93α88,6±11,71,3±0,242,3
βof 37.8±of 5.45,1±0,84
n = number of analyses

Estrogenic and antiestrogenic activity ofin vitro

Potential estrogenic and antiestrogenic activity of new compounds judged by the initiating activity of alkaline phosphatase (APase), specific estrogenic response of endometrial cells of adenocarcinoma Ishikawa person (Botella J., J. Steroid. Biochem. Molec. Biol., 1995, 55: 77-84; Littlefield et al., Endocrinology, 1990, 127: 2757-2762).

Cells of Ishikawa grow normally in the form of monolayers in a modified method of Dulbecco environment Needle (DMEM)containing 4 mm Glutamax I and supplemented with 10% fetal serum of cows with a remote complement (dFCS) and antibiotics. They are kept in a humid atmosphere containing 5% CO2and 95% air at ambient temperature is re 37±0,1°C. Reserves fill up once a week to maintain continuous exponential growth.

For research of Ishikawa cells are placed in 96-well microplates. The next day the medium is changed to not contain phenol red DMEM, which includes 5% dFCS and relieved of endogenous estrogens by treatment with activated charcoal coated with dextran. After another 24 hours Wednesday update and to put on the tablet cells add the appropriate controls and test compounds diluted appropriately using does not contain estrogen medium DMEM, either individually (estrogen effect)or together with 10-8M E2(antiestrogenic effect) and incubated for four days. For each connection, the range of test concentrations range from 10-12M to 10-5M, and the final concentration of the medium does not exceed 0.1%.

After an incubation period of APase activity is determined by a method that includes the hydrolysis of p-nitrophenylphosphate with the formation of p-NITROPHENOL at pH of 9.8 and spectrophotometric determination of product at a wavelength of 405 nm.

Briefly, microplates first rinse twice in cold phosphate buffer solution, and then for 15 min, placed in conditions with a temperature of minus 80°C. After thawing at room tempera what ur in for 5-10 min tablets placed on ice and to each well was added 50 μl of ice solution, containing 5 mm p-nitrophenylphosphate. Tablets allowed to warm to room temperature, to stimulate the enzymatic process (t0). After an incubation period of from 15 to 60 min, in each well at a wavelength of 405 nm is measured, the intensity of the yellow color, resulting in the formation of p-NITROPHENOL using a microplate reader (Wallac, model 1420 Victor2). For each test concentration APase activity, which manifests itself in the form of acquisitions, first expressed as the ratio of increase compared with the control (FI), and then in the percentage of activity E2(10-8)which is taken for 100%. Build sigmoid response curves dose-response and for each connection count value EC50(estrogen effect) and IC50(antiestrogenic effect).

Table 2
Estrogenic and antiestrogenic activity ofin vitro
Connection
of
Estrogenic activityAntiestrogenic activity
EU50(nm)±The standard deviation nIC50(nm)±The standard deviationn
E20,1±0,053±
Example 231695±1684ND±1
Example 24136,3±1,24ND±1
Example 3130,8±0,54ND±1
Example 35373,8 ±43,03ND±1
Example 40131,9±the 4.74ND±1
Example 6551,7±6,24ND±1
Example 66br220.6±14,04ND±1
Example 73ND±4ND±1
Example 80147, ±39,94ND±4
Example 81ND±4ND±1
Example 84322,5±204ND±2
Example 86ND±4ND±1
Example 93123,8±8,94-±1
n =number of analyses; ND = not detected; - the value was not determined

Proliferative activityin vitro

The proliferative effect of the compounds of the present invention appreciate cell line MCF-7 breast cancer person by measuring the number of viable cells after treatment for 6 days.

Cells MCF-7 grown in the usual manner in the form of monolayers in a modified method of Dulbecco environment Needle (DMEM)containing 4 mm Glutamax and 4.5 g/l glucose and supplemented with 5% (vol./about.) serum fetal cow with a remote complement (dFCS) and antibiotics.

Cells are placed in a flask in the amount 2,106cell 75 cm2and incubated at 37°C in a humid atmosphere containing 5% CO2. Cells subcultured weekly in order to maintain a constant exponential growth. For forty-eight hours before the start of the experiment environment over almost reached the status of merge cells changed to not contain phenol red DMEM, containing 5% dFCS and free from steroids by treatment with activated charcoal coated with dextran (DCC-DMEM). On the day of experiment, cells are harvested short-term treatment with trypsin and placed in the environment DCC-DMEM in 96-well tablets with density 4,103cells per well. The next day, Wednesday update, add test compounds diluted the s accordingly do not contain estrogen DMEM, and incubated for six days. For each connection, the range of test concentrations range from 10-12M to 10-5M, and the final concentration of the medium is not more than 0.1% (vol./vol.). At the end of the incubation period, cell proliferation was quantitatively evaluate the content of cellular ATP, which signals the presence of metabolically active cells.

Analysis of ATP

Analysis based on the ATP-dependent luciferase reaction, allows you to generate a luminescent signal that is proportional to the present number of ATP. Since there is a linear relationship between the amount of ATP and the amount present in the culture of viable cells, the fluorescent signal allows you to accurately assess cell proliferation (Crouch, S.P.M. et al., J. Immunol. Meth., 1993, 160, 81; Kangas, L. et al., Med. Biol., 1984, 62, 338; Petty, R.D. et al., J. Biolum. Chemilum., 1995, 10, 29).

Briefly, microplates tilt to decant culture medium, and to each well add 100 ál of fresh medium. Microplates lead in the equilibrium state at room temperature for approximately 30 minutes In each well add 100 μl of luciferase reagent and the contents stirred for 2 min to induce lysis of the cells. To stabilize the luminescent signal, tablets incubated at ControlTemplate within 10 minutes

The luminescence is recorded by a microplate reader (Wallac, model 1420 Victor2) and the results expressed as a percentage of the luminescence of the control sample. To assess their potential proliferative capacity building sigmoid response curves dose-response and for each connection count value EC50.

Table 3
Proliferative activity in cells F-7
Connection
of
Cell proliferation
EU50(nm)±The standard deviationnEffect in 10-8M (% of control)Effect in 10-6M (% of control)
E20,01±04211,6204,7
Example 23376,5±70,1381,717,7
Example 2418,5±1,83to 89.9of 142.8
Example 313,7±0,74138,8146,3
Example 3558,2±15,0494,4162,6
Example 4011,5±2,84106,9151,7
Example 6527,6±2,04123,1259,5
Example 6625,4±4,04100,3148, 7mm
Example 73365,1±126,14a 94.2133,7
Example 8045,2±25,64109,5to 147.2
Example 81634,8±284,9486,8117,3
Example 8477,9±4,1497,0285,8
Example 86465,7±34,0485,6139,4
Example 9316,1±2,64115, 8mm155,8

Estrogenic activity ofin vivo

Female rats in the prepubertal age for 3 days injected a drug in an amount of 3 mg / day per rat. The next day after the last portion of the drug removes the uterus and determine their mass.

Results expressed as % stimulation in uterine weight compared with the introduction of the media.

Connection examples 23, 31, 35, 66, 73, 84, 86 and 93 show a marked selectivity for the recombinant receptor β person and have a weak estrogenic effect of alkaline phosphatase activity in the model of Ishikawa cells. For this reason, these compounds were selected to determine their estrogenicityin vitro. The aim of the study is to test these compounds in comparison with tamoxifen (TAM), with a standard selective ERβ agonist: DPN or 2,3-bis-(4-hydroxyphenyl)propionitrile (Meyers, M. J., J. Med. Chem., 2001, 44; 24, 4230-4251) and with standard selective ERα agonist: PPT or 1,3,5-Tris-(4-hydroxyphenyl)-4-propyl-1H-pyrazole (Stauffer, S. R., J. Med. Chem., 2000, 43; 4934-4947)as the standard for comparison using 17β-estradiol (E2) and oral dose of 3 mg / day for the rat.

Table 4
Estrogenic activity in vitro selected compounds
Connection% stimuleren the deposits compared with media The number of animals
DPN3588
E25268
Example 23128
Example 241018
Example 314686
Example 35388
Example 40418
Example 65848
Example 66318
Example 73528
Example 80708
Example 81498
Example 84248
Example 86258
Example 93888
RRT966
THERE2068

The results show that the compound from example 23 is a potential ligand for beta estrogen receptor, which has a weakin vivoestrogenic activity after oral administration.

Dose-dependent uterotrophic activityin vivo

Female rats in the prepubertal age for 3 days orally administered drug in the amount of 0.3; 1; 3 or 10 mg / day per rat. The next day after the last portion of the drug removes the uterus and determine their mass.

Results expressed as % stimulation in uterine weight in comparison with native speakers. As a standard for comparison using 17β-estradiol (E2) and oral dose of 3 mg / day for the rat.

Table 5
Dose-dependent uterotrophic activityin vivo
ConnectionDosage (mg / day in the rat % stimulation compared with mediaThe number of animals
E233338
Example 230,3-138
Example 231-58
Example 233-48
Example 2310208

Connection example 23 was selected as a potentially good candidate for treatment estrogenzawisimy diseases, because it is after oral administration has not uterotrophic activity up to a dose of 3 mg per day per animal.

The effect of compounds on the model of “tides”in vivo

According to Berendsen et al. (Eur. J. Pharmacol., 2003, 482; 329-33) skin temperature on the tail in rats with removed ovaries can serve as a tool for selection of compounds that are potentially suitable for treatment of hot flashes in women during postclimacteric the strategic period. The aim of this study is to evaluate the effect of compound from example 23 for 4 days at the temperature of the skin on the tail in rats with removed ovaries. 17β-estradiol, which is used as a standard for comparison, administered orally for 13 days with a dose of 1 mg / day for the rat (Watanabe N. et al., 2003). For research use twenty female rats IOPS Wistar from Charles River (France), the weight of which on arrival is in the range from 176 to 200, Rats are placed in groups of four rats in cages made of steel wire. After implantation of telemetry transmitters (TA10TA-F40, Data Sciences International) until the end of the research they are placed in groups of two rats in macrolone cells and support their operating 14-10 time light time/dark time. Regularly check the standard conditions of detention of these individuals. Animals provide free access to special does not contain estrogen diet in the form of granules Harlan Teklad 2016 from HARLAN. They do not restrict access to filtered and softened water. Water in abundance comes through automatic waterers in metal cages and plastic bottles in macroeonomic cells. Then rats to spay and not disturb the animals for at least 2 weeks. After a specified period of hormonal peace in the tip is of the same period of time they control the temperature of the skin at the tail and then the animals are randomly divided into 3 groups depending on the average temperature. The first group is the “control group with remote ovaries, the second group is the “group of estradiol to confirm the activity of estrogen on the temperature of the tail, and the third group is the group of example 23” to test the effects of the compounds on the temperature. Body weight is determined in the first day of treatment and at study end.

Results expressed as % stimulation masses of females in comparison with the action of the media. As a standard for comparison using 17β-estradiol (E2) with a dose of 3 mg / day for the rat.

Table 6
The effect of compound from example 23 in skin temperature on the tail (TST) in rats with removed ovaries
ConnectionDosage (mg / day per rat)TST
Change in day 1 compared with day 0 (°C)
TST
Change in day 4 compared to day 0 (°C)
TST
Change in day 7 compared with day 0 (°C)
n
Media-and-0.6and-0.6a-0.74
E23-4,8is 3.5-5,64
Example 230,3-0,8of-2.1-1,910

Connection example 23 lowers the temperature of the skin in rats with removed ovaries, without harmful side effects on the uterus, in contrast to the activity of estradiol in relation to body weight or uterine (as defined below).

Table 7
The effect of compound from example 23 on body weight and females one week after processing
ConnectionDosage
(mg / day per rat)
Mass of females (% increase compared to medium)Body weight (% increase compared to medium)n
Media---4
E23273 -104
Example 230,3-2,6+4,410

The influence of compounds on bone and parameters of the cardiovascular system in vivo.

Rats with removed ovaries are preferably model for preclinical evaluation of new compounds, which are used to prevent bone loss (osteoporosis). In female rats obtained from Wistar line OFA from IFFA CREDO (France) remove the ovaries or simulate the operation for obtaining the control group. Upon receipt of rats placed in suspended metal cages groups of 3-4 animals per cage and give them enough food and water for one week. After a week of acclimatization begin to move daily dosages of interest connection or 17β-estradiol.

In the research process take plasma samples for analysis of lipid parameters triglycerides, free cholesterol, full of cholesterol, HDL, LDL, VLDL, apolipoprotein a and B100; parameters of bone metabolism, such as DPD,

Ca2+, collagen type I and II, fragments of C-telopeptide; and markers of kidney stones, such as Ca2+and inorganic phosphate. All the tests carried out in accordance with recommended the operations of the manufacturer.

To determine the mineral density of individual lumbar segments conduct high-contrast study of the lumbar or the whole body energy x-ray absorptiometry; measuring anaesthetize animals using izoflurana.

The antidepressant activity of the compounds

The antidepressant action of estradiol was recently installed in conducting research using mice ER β TO. In addition, the above localization of ER β in cell nuclei of the dorsal line splicing in rats. The test is the “gold standard” for potential antidepressant action of any connection is to test the forced swimming, and in this experiment antidepressants can be separated from the stimulants that reduce immobility in doses that enhance overall activity. To study the proposed antidepressant activity described in this description of the compounds of the forced swimming test is carried out in accordance with the following procedure. Animals placed six individuals per cage under standard conditions of the colony with a 12-hour cycle of light/dark time and give enough food and water. Before conducting the experiments they give to acclimate in the colony, at least within 7 days. the La subcutaneous injection of the compound from example 23 is dissolved in olive oil and diluted to the desired concentration daily dose. As a positive control intraperitoneally administered desipramine. The desipramine dissolved in bidistilled water (10 mg/kg). Experiments carried out 30 min after drug administration, used as positive control (only for desipramine). Other compounds, namely estradiol and connection example 23 - daily administered to rats subcutaneously for 7 days. The data collection exercise on the 8th day (24 h after the last injection) and on the 9th day (48 h after injection of estradiol or connection example 23), respectively. Data obtained after 24 hours after the last injection, constitute “the group is not exposed to animals, and these animals have never been tested in the device. Data obtained 48 h after the last injection of the compounds that make up the “group of trained animals.”

Table 8
The effect of compound from example 23 for the duration of the state of immobilization stress conditions
ConnectionDosage (mg / day per rat)Not exposed to animals (C)Trained animals (C)n
Media-133,7±28,6178,1±25,511
The desipramine30Not investigated2,6±1,5***11
E20,00722,5%±7,1***79,2±23,0*11
Example 232,845,2±15,6*160,7±44,111
(data are obtained within 10 min, the compounds or desipramine compared with the media, p<0.05 to p<0,001)

On the 8th day test is done in forced swimming. The study was conducted on rats in accordance with the methods described Porsolt (Eur. J. Pharm., 1978). In brief, rats individually placed in glass cylinders (height: 40 cm, diameter: 18 cm)containing 25 ml of water at 25°C. after 10 min the rats extracted, dried and returned to their cells. Animals again placed in the cylinders after 24 h, the procedure is repeated and conduct surveillance for 10 minutes

Model appreciate what aktivnosti desipramine, discovered in the research process. The results confirm the antidepressant efficacy of estradiol, after 24 h and 48 h after injection. Connection example 23 shows antidepressant activity when animals were first tested after 24 h after injection, while the trained animals 48 h after administration of the antidepressant action of the compounds according to example 23 disappears.

1. The compound of formula (I)

or its pharmaceutically acceptable salt,
where R1means a hydrogen atom or (C1-C6)alkyl, -SO2NR7R8, phenyl (C1-C3)alkyl or (C1-C3)alkyl, substituted 5-8-membered saturated heterocyclic radical containing a nitrogen atom;
R2and R3each independently means a hydrogen atom or a hydroxyl, a halogen atom or (C1-C6)alkoxy;
X is O, S, SO, SO2or NR4;
R4means a hydrogen atom or (C1-C6)alkyl, phenyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted 5-8-membered saturated heterocyclic radical containing one nitrogen atom, or a group-COR7, -CO2R7or-SO2NR7R8where the phenyl is not substituted or is substituted by at least one Deputy, selected from the group which includes the t hydroxyl, the halogen atom and phenyl(C1-C3)alkoxy;
Y represents a direct bond, -(CR10R11)nor R10C=CR11-;
R7and R8each independently represent a hydrogen atom or (C1-C6)alkyl group;
R10and R11each independently represent a hydrogen atom or a cyano, or a group-CONR7R8;
n is 1 or 2;
And means (C3-C12)cycloalkyl or phenyl, where the phenyl is not substituted or is substituted by at least one Deputy, selected from the group which consists of hydroxyl, halogen atom, (C1-C3)alkyl, (C1-C3)alkoxy;
when X is NR4then the Y and R2together with the containing indazol cycle can also form 1H-pyrano[4,3,2-cd]indazol;
provided that:
1) when X is O, S or NR4, R1denotes a hydrogen atom or (C1-C6)alkyl, a Y indicates a direct relationship, a is not optionally substituted phenyl;
2) when X is O, R1O is 6-HE-or 6-och3, Y represents a direct link, and means cyclopentyl (R2, R3) or (R3, R2) different from (N, Cl) at position 4, 5;
3) when X is O, R1O means 6 HE, R2and R3mean N, and Y represents CH=CH, a is not phenyl or 4-methoxyphenyl;
4) when X is SO2And means fenili R 1O means 5-or 6-och3(R2, R3) or (R3, R2) different from (H, och3) at position 6 or 5, and the connection is not one of the following:
3-phenyl-5-(phenylmethoxy)-1H-indazol;
6-hydroxy-3-phenylmethyl-7-(n-propyl)-benzo[4,5]isoxazol;
3-(4-chloroformate)-6-hydroxy-7-(n-propyl)-benzo[4,5]isoxazol;
6-hydroxy-3-(2-phenylethyl)-7-(n-propyl)-benzo[4,5]isoxazol;
3-cyclopropyl-6-hydroxy-3-phenylmethyl-7-(n-propyl)-benzo[4,5]isoxazol;
3-cyclohexylmethyl-6-hydroxy-3-phenylmethyl-7-propyl-benzo[4,5]isoxazol.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R3means a hydrogen atom.

3. The compound according to any one of claims 1 or 2, or its pharmaceutically acceptable salt, where Y represents a direct link.

4. The compound according to any one of claims 1 or 2, or its pharmaceutically acceptable salt, where As means (With3-C12)cycloalkyl.

5. The compound according to any one of claims 1 to 2, or its pharmaceutically acceptable salt, where R10is the position of the 6-ring.

6. The compound according to claim 1 or its pharmaceutically acceptable salt, where
R1means a hydrogen atom or-SO2NR7R8in which R7and R8independently represent hydrogen or (C1-C6)alkyl;
R2means a hydrogen atom;
And means (C3-C12)cycloalkyl.

7. The compound according to claim 1 or farmacevtichesky acceptable salt:
3-Cyclopentyl-1H-indazol-6-ol;
3-Cyclohexyl-1H-indazol-6-ol;
1-(Aminosulfonyl)-3-cyclohexyl-1H-indazol-6-insultant;
3-Cyclohexyl-6-hydroxy-1H-indazol-1-sulfonamide;
2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(4-hydroxyphenyl)propanenitrile;
2-(b-Hydroxy-1,2-benzisoxazol-3-yl)-3-(3-fluoro-4-hydroxyphenyl)propanenitrile;
2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(4-forfinal)propanenitrile;
2-(6-Hydroxy-1,2-benzisoxazol-3-yl)-3-(3,4-dihydroxyphenyl)propanenitrile.

8. The compound according to any one of claims 1 and 2, 6, or 7, or its pharmaceutically acceptable salt for use as an active therapeutic substance modulating the estrogen receptors, for the manufacture of a medicinal product.

9. Connection to any one of claims 1 and 2, 6, or 7, or its pharmaceutically acceptable salt for use as active substances modulating the estrogen receptors.

10. Pharmaceutical composition having the properties of the modulator of estrogen receptors containing (i) an effective amount of a compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt and (11) of the pharmaceutically acceptable filler.

11. The use of the compounds of formula (I) according to any one of claims 1 to 7 or its pharmaceutically acceptable salts for the preparation of drugs for the treatment of diseases that require modulation of receptors es is of Rogen.

12. The use of the compounds of formula (I) according to claim 11 for the preparation of drugs for treatment of cognitive dysfunction.

13. The use of the compounds of formula (I) according to claim 11 for the preparation of medicines for the prevention or treatment estrogenzawisimy diseases.

14. The use of the compounds of formula (I) according to claim 11 for the preparation of drugs for the control or regulation of reproductive functions.

15. The use of the compounds of formula (I) according to claim 11 for the preparation of medicines for the prevention or treatment of benign or malignant diseases of the breast, uterus, or ovaries or polycystic ovary syndrome.

16. The use of the compounds of formula (I) according to claim 11 for the preparation of medicines for the prevention or treatment of benign or malignant diseases of the prostate or testicles.

17. The way to prevent or treat diseases that require modulation of estrogen receptors, which includes the introduction of therapeutically effective amounts of compounds of formula (I)according to any one of claims 1 to 7, or its pharmaceutically acceptable salt.

18. The compound of formula (I),
where R3means a hydrogen atom;
Y represents a direct link;
And means (C3-C12)cycloalkyl;
R1O is at position 6 is the number of the CA for the manufacture of a medicinal product, as specified in § § 11-16, or for the prevention or treatment, as indicated at 17.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of galantamine hydrobromide, which includes a method of purifying galantamine through precipitation of galantamine hydrobromide from a mixture of alkaloids obtained from Amaryllidaceae plants which contain galantaminem, with subsequent treatment of hydrobromide with an alkali, extraction and crystallisation of galantamine using a solvent of general formula , in which R1 is hydrogen or methyl, and R2 is selected from n-butyl, isobutyl, fluoro-butyl and tert-butyl.

EFFECT: obtained pure galantamine can be used to obtain galantamide hydrobromide suitable for pharmaceutical applicaion using a conventional method.

11 cl, 5 ex

The invention relates to a method for producing derivatives 4A,5,9,10,11,12-hexahydro-6H-benzofuro/3a,3,2-ef//2/benzazepine General formula (I)

< / BR>
or its salts, where R2, R4X1X2, Y1, Y2identical or different and denote hydrogen, fluorine, chlorine, bromine, iodine, hydroxy - or alkoxygroup; lowest, if necessary, branched and, if necessary, replaced, for example, at least one halogen alkyl group, a lower, if necessary branched alkenylphenol group; lower, if necessary branched alkylamino group; if necessary, substituted aryl, aracelio or aryloxyalkyl group, the alkyl chain of which, if necessary, branched and aromatic nucleus which, if necessary substituted; formyl, and unsubstituted or substituted by one or more halogen, linear or branched alkylaryl, arylcarbamoyl, aralkylamines, allyloxycarbonyl, aryloxyalkyl, Uralelectromed, alkylsulfonyl, aralkylamines, arylsulfonyl, or Y1and Y2together represent =O and where A stands for a benzene nucleus, in the case neobmennoe alkyl group; at least one lower, if necessary, the branched alkinoos group; at least one lower, if necessary branched alkyne group; at least one lower if need extensive alkoxygroup; fluorine, chlorine, bromine, iodine or more identical or different halogen, at least one substituted with one halogen or two or more identical or different halogen alkyl group, such as chlorochilon and trifluoromethyl; at least one, if necessary substituted aranceles group and/or at least one hydroxy-group; primary, secondary or tertiary amino group, the nitro-group, a nitrile group, alkylaminocarbonyl, killingray, aldehyde group, carboxyl group, all derivatives of carboxyl groups, for example esters, inorganic salts, halides

The invention relates to compounds of formula (1)

< / BR>
in which

R1is a hydrogen atom;

R2is a hydrogen atom, (C3-C12) alkenylboronic, (C3-C12)cycloalkylcarbonyl, (C3-C12)cycloalkylcarbonyl, (C3-C12)alkylcarboxylic, (C3-C12)cycloalkyl (C1-C12)alkylcarboxylic, pyridyloxy, morpholinoethoxy or tetrahydropyranyloxy, halogen(C1-C6)alkylsulfonate, (C1-C6)alkylsilane;

R3is a hydrogen atom or halogen;

R4is a hydrogen atom or a (C1-C6)alkyl, or geometric, optical or stereoisomers, or pharmaceutically acceptable additive salts, which are useful for the treatment of various memory disorders characterized by a decrease cholinergic function such as Alzheimer's disease

The invention relates to a derivative of galantamine, in particular a derivative of galantamine General formula (II)

< / BR>
in which R1represents hydrogen, (C1-C12)alkylsulphonyl, (C1-C12)alkoxycarbonyl, mono-(C1-C12)alkylaminocarbonyl or di-(C1-C12)alkylaminocarbonyl; R2represents a mono-(C1-C18)alkylaminocarbonyl or di-(C1-C8)alkylaminocarbonyl group; R3represents hydrogen or halogen; or pharmaceutically acceptable acid additive salts

The invention relates to compounds of the formula

< / BR>
where

R1is hydrogen, (C1C12) alkylsulphonyl, (C1-C12) alkoxycarbonyl,

R2- (C1-C12) alkylcarboxylic-, (C1-C12) alkoxycarbonyl-, hydroxy-, (C1-C6) alkoxycarbonyl (C1-C6) alkoxy or hydroxy (C1-C10) alkoxy - and phenylcarbonylamino, where the phenyl part is unsubstituted or substituted C1-C6the alkyl or trifluoromethyl

The invention relates to compounds corresponding to the following formula I:

< / BR>
where R1- represents a group of formula

< / BR>
where n = 1 or 2, R3represents hydroxyl, lower alkoxygroup, aryl (lower) alkoxygroup, amino group, lower alkylamino or di (lower alkyl) amino group, R4represents hydrogen, lower alkyl or aryl (lower) alkyl , R5represents hydrogen, lower alkyl, aryl (lower) alkyl or lower alkylsulphonyl, R6represents hydrogen or lower alkyl, provided that when R6is lower alkyl, then R6replaces one of the methylene hydrogen atoms, R2represents a group of formula

< / BR>
where X is hydrogen, halogen, lower alkyl or lower alkoxygroup,

R7represents lower alkyl or aryl (lower) alkyl,

R8represents hydrogen or lower alkyl,

R9represents hydrogen, lower alkyl, lower alkenyl, lower quinil, aryl (lower) alkyl, formyl, lower alkyl carbonyl, aryl (lower alkyl) carbonyl Il is kilcarbery,

R11represents hydrogen, lower alkyl or aryl (lower) alkyl,

and such compounds are applicable for alleviating various memory disorders, characterized by a cholinergic deficit such as disease Alzheimer

The invention relates to new chemical compound, specifically to 5H-3,4,6,7-tetrahydro-10-methoxy-5-methyl-6-(1', 1'-dioxide)-3'- metalorigin-4'-methoxy-benzo[B] thiophene-7 yl)-furo-[4.3.2

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of diaryl compounds with formulae given below ,

.

, in which M is S(O)2, Rx represents alkyl, R1, R2, R3 and R4 are each independently selected from OH and -NR7S(O)2R8, R5 and R7 each independently represents hydrogen or alkyl, R8 is alkyl; and their pharmaceutically acceptable derivatives, as well as to pharmaceutical compositions containing said compounds and their use in making a medicinal agent with inhibitory activity on Aβ, IAPP amyloid fibrils or synuclein fibrils.

EFFECT: substituted n-arylbenzamide and related compounds for treating amyloid diseases and synucleinopathy are disclosed.

11 cl, 19 ex, 6 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel soluble pharmaceutical salts formed from salt-forming active compound of the general formula (I) or (II) and sugar substitute that can be used in preparing medicinal agents useful in pain and enuresis treatment. Salt-forming active substance represents a salt-forming compound among 1-phenyl-3-dimethylaminopropane compounds of the general formula (I) wherein X means -OH, F, Cl, H or group -OCOR6; R1 represents (C1-C4)-alkyl group; R2 represents H or (C1-C4)-alkyl group; R3 represents H or (C1-C4)-alkyl group with a direct chain, or R2 and R3 form in common (C4-C7)-cycloalkyl group and if R5 means H then R4 represents group O-Z in meta-position wherein Z means H,(C1-C3)-alkyl, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl), -CONH-C6H4-(C1-C3-alkyl), -CO-C6H4-R7 wherein R7 represents -OCO-C1-C3-alkyl in ortho-position or group -CH2N(R8)2 in meta- or para-position and wherein R8 means (C1-C4)-alkyl or 4-morpholino-group, either R4 represents S-(C1-C3)-alkyl in meta-position, meta-Cl, meta-F, group -CR9R10R11 in meta-position wherein R9, R10 and R11 mean H or F, group -OH in ortho-position, O-(C2-C3)-alkyl in ortho-position, para-F or group -CR9R10R11 in para-position wherein R9, R10 and R11 mean H or F, or if R5 means Cl, F, group -OH or O-C1-C3-alkyl in para-position then R4 means Cl, F, group -OH or O-(C1-C3)-alkyl in meta-position, or R4 and R5 form in common group 3,4-OCH=CH- or OCH=CHO-; R6 means (C1-C3)-alkyl, or salt-forming active substance represents a salt-forming compound among 6-dimethylaminomethyl-1-phenylcyclohexane compounds of the general formula (II) wherein R1' represents H, -OH, Cl or F; R2' and R3' have similar or different values and represent H, (C1-C4)-alkyl, benzyl, -CF3, -OH, -OCH2-C6H5, O-(C1-C4)-alkyl, Cl or F under condition that at least one among radicals R2' either R3' means H; R4' represents H, -CH3, -PO-(O-C1-C4-alkyl)2, -CO-(O-C1-C5-alkyl, -CO-NH-C6H4-(C1-C3)-alkyl, -CO-C6H4-R5', CO-(C1-C5)-alkyl), -CO-CHR6'-NHR7' or unsubstituted either substituted pyridyl, thienyl, thiazolyl or phenyl group; R5' represents -OC(O)-(C1-C3)-alkyl in ortho-position or -CH2N(R8')2 in meta- or para-position and wherein R8' means (C1-C4)-alkyl, or both radicals R8' in common with nitrogen atom (N) form 4-morpholino-group, and R6' and R7' have similar or different values and represent H or (C1-C6)-alkyl under condition that if both radicals R2' and R3' represent H then R4' doesn't mean -CH3 when R1' represents additionally H, -OH or Cl, either R4' doesn't mean H when R1' represents additionally -OH. Also, invention relates to a medicinal agent based on indicated salts.

EFFECT: valuable medicinal properties of salts and drug.

14 cl, 1 tbl, 8 ex

The invention relates to a derivative of sulfoaluminate and sulphoniumhydroxide acid of formula I, its pharmaceutically acceptable salts, where W is-HE-or-NHOH; X denotes (a) a heterocyclic radical selected from the group comprising imidazolines, dihydrobenzofuranyl and so on, b) -NR1SO2R2where R1denotes a hydrogen atom, R2denotes an unsubstituted phenylalkyl and so on; Y represents carbon or sulfur, with the proviso that when Y represents carbon, n is equal to 2; Z represents phenyl, optionally substituted with halogen, unsubstituted alkoxy, phenyloxy, optionally substituted with halogen, phenylacetonitrile, 4-methylpiperazine, 4-phenylpiperidine, pyridyloxy, -NR'1COR'2, -SO2R'2where R'1denotes a hydrogen atom, R'2denotes phenyl, optionally substituted by hydroxy or phenyl, pyridinyl, substituted-CF3; m denotes an integer from 1 to 4, n represents an integer of 1 or 2

The invention relates to new derivatives of saccharin of formula I

< / BR>
in which the substituents have the following meanings: L, M denote hydrogen, alkyl, alkyloxy, alkylthio, chlorine, cyano, methylsulphonyl, nitro or trifluoromethyl, J denotes hydrogen, alkyl, cycloalkyl, alkenyl, quinil, acyl, phenyl, optionally substituted with halogen or alkyl, benzyl, means connected in position 2 optional substituted cyclohexane-1,3-diNovo ring of formula II

< / BR>
in which R1- R6mean hydrogen or methyl, or, if R1, R2, R3, R5and R6mean hydrogen, R4mean 2-ethylthiophen, tetrahydrothiopyran-3 or metaltitlepane, or R1, R4, R5mean hydrogen, and R6means methyl, R2and R3form a three-membered ring, which is formed connected in position 2 bicyclo-(4.1.0)heptane ring of formula III

< / BR>
and they are usually used in agriculture salt

The invention relates to new derivatives shinkareva acid of General formula I, in which L, M denote hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, alkylthiols with 1-4 carbon atoms, chlorine, methylsulphonyl, Z denotes hydrogen, alkyl with 1-4 carbon atoms, benzyl or phenyl, R is hydrogen, alkyl with 1-6 carbon atoms, provided that Z does not mean methyl, phenyl or hydrogen and 5-carboxy-7-metalshark and 5-carboxy-4-hariharan excluded

The invention relates to the derivatives of saccharin General formula 1, where L denotes 0 or N; when L is 0, R1- 2,6-dichloro-3-[2-(4-morpholinyl)ethoxy] benzoyl, when L is N, then L together with R1represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl, R2primary or secondary alkyl of 2-4 carbon atoms, R3- lower alkoxy at any of the 5-, 6 - or 7-positions, or their pharmaceutically acceptable additive salts of acids or bases, which inhibit the activity of proteolytic enzymes

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula

, where R1 is a

or or or group, R2 is morpholine or OR' or N(R")2; R' is a lower alkyl, a lower alkyl substituted with a halogen, or -(CH2)n-cycloalkyl; R" is a lower alkyl; R is NO2 or SO2R'; R4 is hydrogen, hydroxy, halogen, NO2, lower alkoxy, SO2R' or C(O)OR"; R5/R6/R7 denote hydrogen, halogen, lower alkyl; X'/X1 denote CH or N, provided that X1 /X1' are not CH at the same time; X2 is O or S; n equals 0 or 1, and to their pharmaceutically active acid-addition salts. The invention also relates to a drug.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter 1 inhibitors.

11 cl, 24 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

The invention relates to new chemical compounds derived from anthra[2,1-d]isothiazol-3,6,11-trione General formula I, where a is the lowest alkylene, R1and R2(independent) - lower alkyl, or R1and R2together with the nitrogen atom form a six-membered saturated, a heterocycle, which may optionally contain a heteroatom such as oxygen atom, and their pharmaceutically acceptable salts
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