Sulfamate derivatived of benzothiophene as steroid sulfatase inhibitors

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to sulfamate derivatives of benzothiophene, obtained by method including stages: 1) conversion of 6-methoxybenzothiophene (3); , where R3 represents monobromine-derivative using N-bromosuccinimide and APTS in standard conditions; 2) conversion of said monobromine-derivative by interaction with Mg in Et2O in argon atmosphere into magnesium-organic bromide and its further condensation with ketone or aldehyde selected from group, consisting of cyclopentanone, cyclohexanone, cycldecanone, 4-methylcyclohexanone, 2-methylcyclohexanone, 2,2-dimethylcyclopentanone, 2-adamantanone, propanal, hexanal, cyclohexane carboxaldehyde, cycloheptancarboxaldehyde in Et2O obtaining corresponding hydroxyl-substituted methoxybenzothiophene in standard conditions; 3) processing said hydroxy-substituted methoxybenzothiophene with triethylsilane in argon atmosphere in dichlomethane obtaining corresponding substituted methoxybenzothiophene; 4) optional alkylating of corresponding substituted methoxybenzothiophene using standard conditions obtaining corresponding substituted methoxybenzothiophene, carrying (C1-C6)alkyl or (C3-C12)cycloalkyl; removal of protective group from substituted methoxybenzothiophene, obtained at stage 3) or stage 4) in presence of tribromborane in standard conditions; conversion of obtained hydroxy-compound into corresponding sulfamate by processing with sodium hydrate and amidochlorsulfonic acid, or interaction with sulfamoylchloride in dimethylacetamide; 7) optional oxidation of obtained compound with hydrogen peroxide in trifluoracetic acid in standard conditions. Compounds can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders. Also described are pharmaceutical composition based on compounds I and application of the latter.

EFFECT: obtaining compounds which can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders.

43 cl, 1 dwg, 10 tbl, 67 ex

 

The technical field to which this invention

This invention generally relates to steroid hormones and, more precisely, to the new sulfonatophenyl of benzothiophene that are ingabire enzyme steroid sulfatase. The invention also relates to pharmaceutical compositions containing these derivative, and methods of use thereof.

The level of technology

The enzyme steroid sulfatase (Y.S. 3.1.6.2., STS) catalyzes the hydrolysis of etranslate to estrone and DHEA-sulfate to DHEA (Dibbelt l., Biol. Chem., Hoppe-Seyler, 1991, 372, 173-185; C. Stein, J. Biol. Chem., 1989, 264, 13865-13872).

The way of the metabolism of steroid sulfatase until recently attracted interest from the point of view of the study of breast cancer due to the local interstitial formation of estrogens from a rich pool of circulating etranslate (E1S) (J.R. Pasqualini, J. Steroid Biochem. Mol. Biol., 1999, 69, 287-292; Purohit, A., Mol. Cell. Endocrinol., 2001, 171, 129-135).

Inhibition of this enzyme would prevent the transformation of E1S free estrone (E1), which, in turn, can be converted into estradiol (E2) enzymatic recovery. Currently, it is believed that in addition to the metabolic pathway istranslated another strong estrogen - androstenediol (adiol)formed from DHEA after hydrolysis of DHEA-S may be another important route, sostavlyauschuu growth and development of hormone-dependent breast tumors.

The formation of estrogens in humans schematically represented in the drawing.

At the present time to prevent the synthesis of estrogen in patients with hormone-dependent cancer use aromatase inhibitors. However, clinical trials showed a relative decrease in the efficiency in patients with tumors positive for estrogen receptors (Castiglione-Gertsch, M., Eur. J. Cancer, 1996, 32A, 393-395; Jonat W., Eur. J. Cancer, 1996, 32A, 404-412). As explained, the metabolic pathway involving steroid sulfatase can be another important route to the formation of estrogen in breast tumors.

EMATE (Ahmed, S., Curr. Med. Chem., 2002, 9, 2, 263-273), estrone-3-sulpham, is a traditional standard inhibitor of steroid sulfatase, but has a significant drawback, as estrogen due to its mechanism of inhibition: sulphamate fragment is cleaved in the process of inactivation of the enzyme, which releases the E1not E1S, but from EMATE (Ahmed, S., J. Steroid Biochem. Mol. Biol., 2002, 80, 429-440).

Other non-steroidal sulfonatophenyl, which releases derivatives without estrogenic properties presented in the literature as a suitable candidate drugs, for example 6,6,7-COUMATE, a standard nestrogannye inhibitor sulfatase (Purohit A., Cancer Res., 2000, 60, 3394-3396).

Thus, there is a need for inhibitors of steroid sulfatase to ensure, in particular, estrogenzawisimy diseases.

The invention

The subject of this invention is the provision of sulfomethylation of benzothiophene that are potent inhibitors of steroid sulfatase.

Another object of this invention is to provide pharmaceutical compositions containing as active ingredient sulfonethylmethane of benzothiophene described above.

Another object of this invention is the use of sulfomethylation of benzothiophene for the manufacture of a medicinal product for the treatment or prevention of various diseases and control of reproductive functions in women, males, and females and males of wild and domestic animals.

Derivatives sulfamethazine of this invention can be represented by the following General formula (I):

where

- R1represents hydrogen, (C1-C6)alkyl, (C2-C6)alkene, (C3-C12)cycloalkyl or (C3-C12)cycloalken where cycloalkyl and cycloalkyl are optionally mono - or disubstituted by (C1-C4)alkyl;

- R2represents hydrogen, (C1-C6 )alkyl or C3-C12)cycloalkyl;

- R3represents hydrogen, (C1-C6)alkoxy or halogen;

- m is 0, 1, 2;

n is 0, 1, 2;

when m is 0, R1and R2together can also form a group -(CH2)p-where p is 3, 4 or 5;

a dotted line shows that the sulphamate group (OSO2(NH2)) is in position 5 or 6 benzothiophene rings.

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

- R1represents hydrogen, (C1-C6)alkyl or (C3-C12)cycloalkyl, optionally mono - or disubstituted by (C1-C4)alkyl, preferably R1is a (C3-C10)cycloalkyl, optionally mono - or disubstituted by (C1-C4)alkyl;

- m is 0 or 1;

- R2represents hydrogen;

- R3represents hydrogen;

n is 0 or 2;

- sulphamate group is in position 6 benzothiophene group.

In the description and the accompanying claims is meant that the term "(1-C4)or(C1-C6)alkyl" means a linear or branched saturated hydrocarbon chain containing from 1 to 4, or from 1 to 6 ATO is s carbon respectively. This alkyl radical is, for example, methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, tert-boutigny, pentelenyi, isopentenyl or sexily radical.

It is implied that the term "(1-C6)alkoxy" means the group-OR where R is a (C1-C6)alkyl, which is defined above.

It is also understood that the term "(3-C12)cycloalkyl" means a saturated mono - or bicyclic hydrocarbon containing from 3 to 12 carbon atoms. (C3-C12)cycloalkyl radical is, for example, cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptenyl, cyclooctyl, cyclodecyl or adamantly radical.

The term "halogen" means chlorine atom, bromine, fluorine or iodine.

The term "(2-C6)alkene" means a linear or branched unsaturated hydrocarbon chain containing from 2 to 6 carbon atoms. (C2-C6)alkanoyl radical is, for example, ethylene, propenoic, butenova, pentanoyl or hexenoic radical.

The term "(3-C12)cycloalkyl" means unsaturated mono - or bicyclic hydrocarbon containing from 3 to 12 carbon atoms. (C3-C12)cycloalkenyl radical is, for example, cyclopropene, qi is lobotomy, cyclopentenone, cyclohexenone, cyclooctanone, cyclodecanone or adamantinoma radical.

Taking into account when comparing compounds of this invention with aromatase inhibitors for their ability to inhibit steroid sulfatase and, thus, lead to the spending of other sources of endogenous estrogen, the compounds of this invention can be used by themselves or in combination with one or more other sexual endocrine therapies such as antiestrogens and selective estrogen receptor modulators (Selective Estrogen Receptor Modulators - SERM), antiaromatase, antiandrogens, inhibitors LiAZ, progestins or LH-RH agonists or antagonists, for the treatment or prevention estrogenzawisimy disorders or diseases. The compounds of this invention can also be applied to control or influence on estrogenrelated reproductive function, such as male or female fertility, pregnancy, miscarriage or childbirth in humans and wild and domestic animals, by themselves or in combination with one or more other therapeutic means, such as LH-RH agonists or antagonists, astroprojection contraceptives, progestins, antiprogestins or prostaglandins.

Breasts are sensitive targets estrogens wiremay proliferation and/or differentiation, and the compounds of this invention can be used in the treatment or prevention of benign breast diseases in women, gynecomastia in males and benign or malignant tumors of the breast with metastasis or without men and women or male and female animals. The compounds of this invention can also be applied in the treatment or prevention of benign or malignant diseases of the uterus or ovaries. In each case the compounds of this invention can be used by themselves or in combination with one or more other sexual endocrine therapies listed above.

Because the enzyme steroid sulfatase transforms DHEA-sulfate (DHEA, the precursor to active androgens (testosterone and dihydrotestosterone), the compounds of this invention can be used for the treatment or prevention of androgen-dependent diseases, such as androgenic alopecia (male pattern hair loss in women male type) (R. Hoffman et al., J. Invest. Dermatol., 2001, 117, 1342-1348) or acne (Billich A. et al., 1999, WO 9952890), benign or malignant disease of the prostate or testis (Reed M.J., Rev. Endocr. Relat. Cancer, 1993, 45, 51-62), by themselves or in combination with one or more other sexual endocrine therapies such as ancient the genes antiestrogens, SERM, antiaromatase, progestins, inhibitors LiAZ or LH-RH agonists or antagonists.

Inhibitors of steroid sulfatase also potentially involved in the treatment of disorders of cognitive abilities, because they are able to improve memory, learning and spatial memory in rats (Johnson D.A., Brain Res., 2000, 865, 286-290). DHEA-sulfate as neurosteroid affects several neurotransmitter systems, including systems involving acetylcholine, glutamate and GABA, which leads to increased neural excitability (O.T. Wolf, Brain Res. Rev., 1999, 30, 264-288).

In addition, estrogens are involved in the regulation of the balance between the predominant immune functions Th1and Th2and, therefore, can be used in the treatment or prophylaxis depend on the sex of autoimmune diseases such as lupus, multiple sclerosis, rheumatoid arthritis, etc. (R.A. Daynes, J. Exp. Med., 1990, 171, 979-996). Inhibition of steroid sulfatase, as shown, is protection in models of contact Allergy and collagen-induced arthritis in rodents (Suitters A.J., Immunology, 1997, 91, 314-321).

Studies using 2-MeOEMATE showed that inhibitors of steroid sulfatase have significant estradiolmedicationim rustinhibiting action (MacCARTHY-MOOROGH L., Cancer Research, 2000, 60, 5441-5450). Unexpectedly when using the compounds of this, and the finding of decreased tumor volume with a weak inhibition asteroidsurfaces tumors. Thus, the compounds of this invention can result in reduced cell division due to the significant interaction between these new chemicals and the network of microtubules inside the cancer cells regardless of the type of tissue, including tissues of the breast, endometrium, uterus, prostate, testis or their metastases. Therefore, the compounds of this invention can be useful in the treatment estrogenozawisimah cancer.

Accordingly, as another object, the invention provides a method of treating the above diseases or disorders, in particular estrogenzawisimy diseases or disorders, that is estrogeninduced or astroenterology diseases or disorders (GOLOB, T., Bioorg. Med. Chem., 2002, 10, 3941-3953). The method comprises the administration to a subject (human or animal)in need, a therapeutically effective amount of the compounds of formula (I).

Pharmaceutical compositions containing the active(s) ingredient(s)can be represented in a form suitable for oral administration, for example, in the form of tablets, lozenges, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs. Compositions intended for oral use can be obtained is consistent with in any way, known in the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group comprising sweetening agents, flavorant, dyes and preservatives, to get beautiful from the pharmaceutical point of view and palatable preparations. The tablets include the active(s) ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. Such excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricants, for example magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated with known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide support actions over a longer period. For example, can be used such materials for delayed release, as glycerylmonostearate or glycerylmonostearate. Coatings can also be applied to the tablets by the method described in U.S. Patent No. 4256108, 4166452 or 4265874, the La receiving osmotic therapeutic tablets for controlled release.

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

Aqueous suspensions contain the active(s) ingredient(s) in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspendresume agents, such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth resin and the Arabian gum; dispersing or wetting agents such as natural phosphated, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene, or condensation products of ethylene oxide with aliphatic alcohols with long chain, such as heptadecafluorooctane, condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as polyoxyethylenesorbitan, condensation products of ethylene oxide with partial esters, recip is nami from fatty acids, and anhydrides of exit, for example polyethylenterephthalat. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl-p-hydroxybenzoate, one or more dyes, one or more of flavorants and one or more sweetening agents such as sucrose, saccharin or aspartame.

Oil suspensions can be prepared by suspendirovanie active(s) ingredient(s) vegetable oil, for example, peanut oil, olive oil, sesame oil or coconut oil, or mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents listed above, and flavorant can be added to obtain the drug, pleasant taste when administered orally. Such compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of aqueous suspension by the addition of water, is produced by mixing the active(s) ingredient(s) with a dispersing or wetting agent, suspenders agent and one or more preservatives. Examples of suitable dipengaruhi or wetting agents or suspendida agents listed above. May also be present on the additional excipients, for example, sweetening agents, flavorant and dyes. The pharmaceutical compositions of this invention can be represented also in the form of emulsions water in oil". The oil phase may be a vegetable oil such as olive or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers can be a natural phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and anhydrides of exit, such as servicemanual, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening agents and flavorant.

The pharmaceutical compositions of this invention can be represented in the form of a sterile aqueous or oily suspension for injection. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspendida agents listed above. A sterile preparation for injection may also be a sterile solution or sterile suspension for injection in a non-toxic parenterally acceptable diluent or solvent such as 1,3-butanedioate diluents and solvents, which can be used are water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspension medium traditionally apply sterile fatty oil. For this purpose, can be used any soft fatty oils, including synthetic mono - or diglycerides. In the preparation of drugs for injection can also be used fatty acids such as oleic acid.

The compounds of this invention can be used in the treatment of the above diseases or disorders, at dose levels of from about 0,0001 mg to about 10 mg/kg of body weight per day or, alternatively, from about 0.01 mg to about 100 mg per day per patient.

The number of active(s) ingredient(s)that may be combined with the materials of the media to produce a single dosage form will vary depending on the characteristics of the host body to be treated, and the particular method of administration.

However, you should imagine that the specific dose 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, and rate of excretion, combination with other drugs and the severity of the particular disease, beside Amigo therapeutic treatment.

Derivatives sulfamethazine formula (I) can be obtained under the following General scheme 1.

Scheme 1

In accordance with scheme 1 3-methoxythiophene (1) is subjected to condensation with 2-bromo-1,1-diethoxyethane and obtained interim diprosone (2) is subjected to cyclization with different acids: polyphosphoric acid (Bioor. Med. Chem. Lett., 1999, 9, 759-64) or methanesulfonic acid to obtain 6-methoxybenzamide (3). This compound can also be obtained by the interaction of the Lewis acid, triptorelin, with compound (2) under the conditions described in the publication by S. Graham, J. Med. Chem., 1989, 32, 2548-54.

6-Methoxybenzamide (3) converted into bromine derivatives (4) using N-bromosuccinimide and APTS in the conditions described in the publication Y. Fort (Tetrahedron., 1994, 50, 11893-902). The compound (4) is converted into magnetogenesis bromide and then subjected to condensation with a ketone or aldehyde to obtain the monosubstituted of benzothiophene (5) under standard conditions.

Disubstituted benzothiophen (9) can be obtained by alkylation of monosubstituted compounds (5) under the conditions described in the publication Kano S. (Heterocycles, 1982, 19, 6, 1033-37).

Compounds in which R1and R2together form a group -(CH2)p-such as 7-methoxy-1,2,3,4-tetr hydrodimerization (p = 4), can be obtained under the conditions described in the publication Oliveira M. (Tetrahedron, 2002, 58, 1709-18).

Remove protection from methoxybenzamide, monosubstituted (5) or disubstituted (9), using tribromsalan results hydroxiapatite (5) and (10) under the conditions described in the publication McOmie, J.F.W. (Tetrahedron, 1968, 24, 2289-92). These compounds undergo transformation into the corresponding sulfamate (7) and (11) by treatment with sodium hydride and nidharshanf acid (P. Nussbaumer, J. Med. Chem., 2002, 45, 4310-20) or interaction with sulfhemoglobin in dimethylacetamide (DMAc) (Makoto O., Tetrahedron Letters, 2000, 41, 7047-51).

Oxidation of (7) and (11) by hydrogen peroxide in triperoxonane acid in accordance with the method of publication Grivas, S., E. Ronne, Acta Chemica Scandinavia, 1995, 49, 225-229 leads to the final benzothiophenes (8) and (12).

The compounds of formula (I), in which the sulphamate group is in position 5 benzothiophene cycle, can be obtained in the same way, but on the basis of 4-methoxythiophene.

The following examples are intended only to illustrate the scope of the present invention, but in no way limit it.

Obtain 3-bromo-6-methoxybenzamide (4)

Example 1: 6-Methoxybenzamide (3)

Diethylacetal of bromoacetaldehyde (16,50 ml, 0.11 mol) dropwise at room temperature is added to a mixture of m-methoxybenzamide (1) (15 ml, 0.12 mol) in order To 2CO3(16,60 g, 0.12 mol) in acetone (150 ml). The reaction mixture is stirred for 16 hours and then filtered. The solid product is washed with acetone and the combined filtrates concentrated in vacuo. The residue is diluted with water and extracted with Et2O. the Organic phase was washed with 0.5 M KOH, water and saturated salt solution, dried over Na2SO4, filtered and concentrated in vacuo, getting 27,40 g of compound (2) as a dark yellow oil.

1H-NMR (CDCl3): of 1.18 (t, 6N), 3,13 (d, 2H), 3.43 points-to 3.73 (m, 4H), of 3.77 (s, 3H), of 4.67 (t, 1H), 6,60-7,27 (m, 4H).

A solution of the compound (2) (13,00 g, 0,051 mol) in CH2Cl2(100 ml) at room temperature in nitrogen atmosphere are added dropwise to a solution of BF3·Et2O (6,70 ml, 0,054 mol) in CH2Cl2(1000 ml). After hydrolysis, the reaction mixture is stirred until until both phases is clear. CH2Cl2layer is separated and the aqueous layer was extracted with CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo, getting 8,68 g mixture of 4 - and 6-methoxybenzamide (3) (1:10) as dark brown oil. The crude product is used without further purification.

Main isomer (3)1H-NMR (CDCl3): 3,85 (s, 3H), 6,98 (DD, 1H), 7.23 percent (s, 2H), 7,35 (d, 1H), 7,68 (d, 1H).

Example 2: 3-Bromo-6-methoxybenzamide (4)

N-bromosuccinimide the (14,70 g, 82,59 mmol) and p-toluensulfonate acid (2.70 g, 15,68 mmol) are added to a solution of benzothiophene (3) (15,10 g, 92,07 mmol) in 1,2-dichloroethane (300 ml). The mixture was kept at 70°C for 35 minutes, cooled in an ice bath and succinimide removed by filtration. The solution is extracted with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo, obtaining22,00 g of the product as oil. Crystallization from pentane yields a white solid (16,50 g, 74%, so pl. 62°).

1H-NMR (CDCl3): 3,85 (s, 3H), 6,9 (DD, 1H), 7,50 (m, 2H), 7,65 (d, 1H).

Getting monosubstituted of benzothiophene (5)

Example 3: 3-Cyclohexyl-6-methoxybenzamide

In an argon atmosphere to Mg (0,22 g, 9,05 mmol) in Et2O (20 ml) added dropwise a solution of bromide (4) (2.00 g, 8,23 mmol) in Et2O (20 ml). The mixture is refluxed for 2 hours, add a solution of cyclohexanone (1,00 ml, 9,87 mmol) in Et2O (5 ml) and the resulting mixture is refluxed for 2 hours. The reaction mixture was poured into ice-cold water. The solution is extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo, obtaining8.00 g of the product as oil. Rubbing in diisopropyl ether leads to the production of 3-(1-hydroxycyclohexyl)-6-methoxybenzamide in the form of a white powder of 0.90 g, 65%).

1H-NMR (DMSO-d6): 1,20-2,00 (m, 10H), of 3.80 (s, 3H), and 5.30 (s, 1H), 6,93 (DD, 1H), 7,10 (s, 1H), 7,42 (d, 1H), 7,60 (d, 1H).

To a solution of 3-(1-hydroxycyclohexyl)-6-methoxybenzamide (0,30 g to 1.14 mmol) in dichloromethane (10 ml) in an atmosphere of argon is added dropwise triethylsilane (0,22 ml, 1.37 mmol). After this solution was stirred at 0°and add triperoxonane acid (5,00 ml, 67,31 mmol). The mixture is stirred for 2 hours at room temperature and poured into saturated aqueous solution of NaHCO3with ice, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo, obtainingof 0.30 g of the product as oil (100%). Crystallization from diisopropyl ether yields the product as a white crystalline substance (0.20 g, 70%).

1H-NMR (DMSO-d6): 1,00-of 2.20 (m, 11N), of 2.72 (m, 1H), 3,75 (s, 3H), 6,93 (DD, 1H), 7,01 (s, 1H), 7,43 (d, 1H), 7,58 (d, 1H).

In accordance with the above procedure, but substituting cyclohexanone for

- Cyclopentanone;

- Cycloheptane;

- cyclooctane;

- cyclodecane;

- 4-methylcyclohexanone;

- 2-methylcyclohexane;

- 2.2-dimethylcyclopentane;

- 2-adamantanol;

- propanone;

- hexanon;

- cyclohexanecarboxaldehyde;

- cyclohexenecarboxaldehyde (obtained in accordance with the method of publication J.G. Traynham et al., Tetrahedron, 7, 1959, 165-72)

get that corresponds to the public, the following connections

Example 4: 3-Cyclopentyl-6-methoxybenzamide

1H-NMR (DMSO-d6): 1,40-of 2.20 (m, 8H), of 2.72 (m, 1H), 3,80 (s, 3H), 6,94 (DD, 1H), 7,13 (s, 1H), 7,45 (d, 1H), to 7.64 (d, 1H).

Example 5: 3-Cycloheptyl-6-methoxybenzamide

1H-NMR (DMSO-d6): 1,40-of 2.20 (m, N), was 3.05 (m, 1H), 3,80 (s, 3H), 6.90 to (DD, 1H), 7,00 (s, 1H), 7,41 (d, 1H), EUR 7.57 (d, 1H).

Example 6: 3-Cyclooctyl-6-methoxybenzamide

1H-NMR (DMSO-d6): 1,20-of 2.15 (m, 14N), 3,10 (m, 1H), of 3.77 (s, 3H), 6,92 (DD, 1H), 7,01 (s, 1H), 7,41 (d, 1H), 7,58 (d, 1H).

Example 7: 3-Cyclodecyl-6-methoxybenzamide

1H-NMR (DMSO-d6): 1,20-of 2.15 (m, N), of 3.12 (m, 1H), 3,75 (s, 3H), 6,92 (DD, 1H), 7,01 (s, 1H), 7,40 (d, 1H), 7,55 (d, 1H).

Example 8: 3-(4-Methylcyclohexyl)-6-methoxybenzamide

1H-NMR (DMSO-d6): 0,70-of 2.15 (m, N), of 2.72 (m, 0,5H, diastereoisomer), 2,99 (m, 0,5H, diastereoisomer), 3,76 (s, 3H), 6,92 (DD, 1H), 7,02 (s, 1H), 7,41 (d, 1H), 7,58 (d, 1H).

Example 9: 3-(2-Methylcyclohexyl)-6-methoxybenzamide

1H-NMR (DMSO-d6): 0,70-of 2.20 (m, N), 2,70 (m, 0,5H, diastereoisomer), to 3.02 (m, 0,5H, diastereoisomer in), 3.75 (s, 3H), 6,92 (DD, 1H), 7,02 (s, 1H), 7,40 (d, 1H), 7,55 (d, 1H).

Example 10: 3-(2,2-Dimethylcyclobutyl)-6-methoxybenzamide

1H-NMR (DMSO-d6): 0,70 (s, 3H), 1,10 (s, 3H), 1,45-of 2.20 (m, 6N), with 2.93 (m, 1H), of 3.78 (s, 3H), 7,02 (DD, 1H),? 7.04 baby mortality (s, 1H), 7,43 (d, 1H), 7,60 (d, 1H).

Example 11: 3-(2-Substituted)-6-methoxybenzamide

1H-NMR (DMSO-d6): 1,40-to 2.40 (m, 14N) 3,19 (ush. s, 1H), 3,79 (s, 3H), 6,92 (DD, 1H), was 7.08 (s, 1H), 7,43 (d, 1H), 7,60 (d, 1H).

Example 12: 3-Propyl-6-methoxybenzamide

1H-NMR (DMSO-d6): of 0.95 (t, 3H), by 1.68 (m, 2H), 2,78 (t, 2H), 3,79 (s, 3H), 6,92 (DD, 1H), 7,00 (s, 1H), 7,43 (d, 1H), 7,58 (d, 1H).

Example 13: 3-Hexyl-6-methoxybenzamide

1H-NMR (DMSO-d6): of 0.85 (t, 3H), 1,10-of 1.80 (m, 8H), 2,82 (t, 2H), 3,79 (s, 3H), 6,92 (DD, 1H), 7,01 (s, 1H), 7,45 (d, 1H), 7,58 (d, 1H).

Example 14: 3-Cyclohexylmethyl-6-methoxybenzamide

1H-NMR (DMSO-d6): 0,75-of 1.85 (m, 11N), 2,70 (d, 2H), 3,80 (s, 3H), 6,92 (DD, 1H), 7,00 (s, 1H), 7,42 (d, 1H), to 7.59 (d, 1H).

Example 15: 3-Cycloheptylmethyl-6-methoxybenzamide

1H-NMR (DMSO-d6): 1,00-1,90 (m, 13H), 2,71 (d, 2H), 3,80 (s, 3H), 6,93 (DD, 1H), 7,00 (s, 1H), 7,42 (d, 1H), to 7.59 (d, 1H).

Getting monosubstituted of benzothiophene (6)

Example 16: 3-Cyclohexylbenzothiazole-6-ol

A solution of 3-cyclohexyl-6-methoxybenzamide (of 4.00 g, 16.0 mmol) in 40 ml dichloromethane at room temperature are added to a solution of tribromide boron (24 ml, 24 mmol). The mixture was incubated for 2 hours and then hydrolyzing saturated aqueous NaHCO3, extracted with dichloromethane, dried over Na2SO4, filtered and concentrated in vacuo, obtainingalcohol (3,60 g in the form of oil, 97%).

1H-NMR (CDCl3): 1,10-2,10 (m, 10H), 2,80 (m, 1H), 6,78 (DD, 1H), 6,94 (s, 1H), 7,17 (d, 1H), of 7.48 (d, 1H), 9,42 (s, 1H, HE).

In accordance with the described method, but C is changing 3-cyclohexyl-6-methoxybenzamide

- 3-cyclopentyl-6-methoxybenzamide;

- 3-cycloheptyl-6-methoxybenzamide;

- 3-cyclooctyl-6-methoxybenzamide;

- 3-cyclodecyl-6-methoxybenzamide;

- 3-(4-methylcyclohexyl)-6-methoxybenzamide;

- 3-(2-methylcyclohexyl)-6-methoxybenzamide;

- 3-(2,2-dimethylcyclobutyl)-6-methoxybenzamide;

- 3-(2-substituted)-6-methoxybenzamide;

- 3-propyl-6-methoxybenzamide;

- 3-hexyl-6-methoxybenzamide;

- 3-cyclohexylmethyl-6-methoxybenzamide;

- 3-cycloheptylmethyl-6-methoxybenzamide,

receive, respectively, the following connections

Example 17: 3-Cyclopentylmethyl-6-ol

So pl. 116°

1H-NMR (DMSO-d6): 1,45-of 2.20 (m, 8H), of 3.25 (m, 1H), 6,78 (DD, 1H), of 6.96 (s, 1H), 7,15 (d, 1H), 7,47 (d, 1H), to 9.45 (s, 1H, HE).

Example 18: 3-Cycloheptatrien-6-ol

So pl. 140°

1H-NMR (DMSO-d6): 1,35-of 2.15 (m, N), to 3.00 (m, 1H), 6,79 (DD, 1H), 6,94 (s, 1H), 7,17 (d, 1H), of 7.48 (d, 1H), to 9.45 (s, 1H, HE).

Example 19: 3-Cyclooctylmethyl-6-ol

So pl. 100°

1H-NMR (DMSO-d6): 1,35-2,10 (m, 14N), of 3.07 (m, 1H), 6,78 (DD, 1H), 6,95 (s, 1H), 7,15 (d, 1H), 7,47 (d, 1H), 9,42 (s, 1H, HE).

Example 20: 3-Collateralisation-6-ol

So pl. 108°

1H-NMR (DMSO-d6): 1,30-2,10 (m, N), up 3.22 (m, 1H), 6,79 (DD, 1H), 6,99 (s, 1H), 7,15 (d, 1H), of 7.48 (d, 1H), 9,42 (s, 1H, HE).

Example 21: 3-(4-Methylcyclohexyl)benzothiophen-6-ol

So pl. 132°

<> 1H-NMR (DMSO-d6): 0,70-2,10 (m, N), 2,70 (m, 1H), 6,80 (DD, 1H), 6,92 (s, 1H), 7,15 (d, 1H), of 7.48 (d, 1H), 9,42 (s, 1H, HE).

Example 22: 3-(2-Methylcyclohexyl)benzothiophen-6-ol

So pl. 125°

1H-NMR (DMSO-d6): 0,60-of 2.20 (m, N), was 3.05 (m, 1H), 6,80 (DD, 1H), 6.90 to (s, 1H), 7,16 (d, 1H), 7,50 (d, 1H), to 9.45 (s, 1H, HE).

Example 23: 3-(2,2-Dimethylcyclobutyl)benzothiophen-6-ol

So pl. 90°

1H-NMR (DMSO-d6): 0,70 (s, 3H), of 1.09 (s, 3H), 1,45-of 2.20 (m, 6N), of 2.92 (DD, 1H), 6,80 (DD, 1H), 6,99 (s, 1H), 7,17 (d, 1H), 7,51 (d, 1H), to 9.45 (s, 1H, HE).

Example 24: 3-(2-Substituted)benzothiophen-6-ol

So pl. 184°

1H-NMR (DMSO-d6): 1,40-to 2.40 (m, 14N), and 3.16 (ush. s, 1H), 6,80 (DD, 1H), 7,00 (s, 1H), 7,17 (d, 1H), 7,50 (d, 1H), 9,43 (s, 1H, HE).

Example 25: 3-Propylbenzamide-6-ol

So pl. 56°

1H-NMR (DMSO-d6): to 0.97 (t, 3H), by 1.68 (m, 2H), and 2.79 (t, 2H), 6,80 (DD, 1H), of 6.96 (s, 1H), 7,17 (d, 1H), 7,50 (d, 1H), 9,46 (s, 1H, HE).

Example 26: 3-Hexylbenzoate-6-ol

So pl. 68°

1H-NMR (DMSO-d6): of 0.85 (t, 3H), 1,10-of 1.80 (m, 8H), 2,78 (t, 2H), 6,79 (DD, 1H), 6,95 (s, 1H), 7,16 (d, 1H), of 7.48 (d, 1H), to 9.45 (s, 1H, HE).

Example 27: 3-Cyclohexylbenzothiazole-6-ol

So pl. 97°

1H-NMR (DMSO-d6): 0,75-of 1.80 (m, 11N), 2,68 (d, 2H), 6,78 (DD, 1H), 6,91 (s, 1H), 7,16 (d, 1H), 7,49 (d, 1H), to 9.45 (s, 1H, HE).

Example 28: 3-Cycloheptylmethyl-6-ol

So pl. 82°

1H-NMR (DMSO-d6): 1,00-1,90 (m, 13H), of 2.72 (d, 2H), 6,80 (DD, 1H), 6,92 (s, 1H), 7,18 (d, 1H), 7,49 (s, 1H), 9,8 (s, 1H, HE).

Getting monosubstituted benzothiophenes ether sulfamic acid (7)

Example 29: 3-Cyclohexylbenzothiazole-6-silt ether sulfamic acid

Sodium hydride (0,60 g of 24.8 mmol) is carefully added to a solution of 3-cyclohexylbenzothiazole-6-ol (3,60 g, 15,50 mmol) in dry DMF (36 ml) at 0°C. the Mixture is stirred at room temperature for 30 minutes and at 50°C for 30 minutes, the mixture was then cooled (ice/water) and add aminohinolinove acid (4,45 g 38,00 mmol). The mixture was kept at room temperature for 3 hours, hydrolyzing saturated aqueous NH4Cl, extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated in vacuo, obtainingthe crude product (4,80 g) as oil. The product was then purified flash chromatography on silica gel (toluene/1,2-dioxane: 8/2) to give a clear oil which is recrystallized from ethanol, getting mentioned in the title compound (0.50 g, 10%, TPL 128°).

1H-NMR (CDCl3): 1,15-of 2.20 (m, 10H), 2,90 (m, 1H), 7,18 (s, 1H), 7,24 (DD, 1H), 7,30 (d, 1H), 7,32 (s, 1H), 7,98 (s, 2H, NH2).

In accordance with the above procedure, but replacing 3-cyclohexylbenzothiazole-6-ol

- 3-cyclopentylmethyl-6-ol;

- 3-cycloheptatrien-6-ol;

- 3-cyclooctylmethyl-6-ol;

- 3-collateralisation-6-ol;

- 3-(4-shall ethylcyclohexyl)benzothiophen-6-ol;

- 3-(2-methylcyclohexyl)benzothiophen-6-ol;

- 3-(2,2-dimethylcyclobutyl)benzothiophen-6-ol;

- 3-(2-substituted)benzothiophen-6-ol;

- 3-propylbenzamide-6-ol;

- 3-hexylbenzoate-6-ol;

- 3-cyclohexylbenzothiazole-6-ol;

- 3-cycloheptylmethyl-6-ol,

receive, respectively, the following connections:

Example 30: 3-Cyclopentylmethyl-6-silt ether sulfamic acid

So pl. 110°

1H-NMR (DMSO-d6): 1,50-of 2.30 (m, 8H), 3,39 (m, 1H), 7,20 (s, 1H), 7,72 (DD, 1H), 7,78 (d, 1H), 7,95 (s, 2H, NH2).

Example 31: 3-Cycloheptatrien-6-silt ether sulfamic acid

So pl. 132°

1H-NMR (DMSO-d6): 1,35-of 2.20 (m, N), of 3.12 (m, 1H), 7,19 (s, 1H), 7,24 (DD, 1H), of 7.75 (d, 1H), 7,80 (d, 1H), 7,95 (s, 2H, NH2).

Example 32: 3-Cyclooctylmethyl-6-silt ether sulfamic acid

So pl. 126°

1H-NMR (DMSO-d6): 0,90-of 2.20 (m, 14N), 3,18 (m, 1H), 7,17 (s, 1H), 7.23 percent (DD, 1H), 7,76 (d, 1H), 7,80 (d, 1H), 7,95 (s, 2H, NH2).

Example 33: 3-Collateralisation-6-silt ether sulfamic acid

So pl. 98°

1H-NMR (DMSO-d6): 1,30-2,10 (m, N), and 3.31 (m, 1H), 7,20 (s, 1H), 7.23 percent (DD, 1H), 7,76 (d, 1H), 7,79 (d, 1H), of 7.96 (s, 2H, NH2).

Example 34: 3-(4-Methylcyclohexyl)benzothiophen-6-silt ether sulfamic acid

So pl. 132°

1H-NMR (DMSO-d6): 0,75-of 2.15 (m, N), to 2.55 (m, 1H), 7,25 (s, 1H), 7,55 (DD, 1H, of 7.60 (d, 1H), of 7.70 (d, 1H), 8,25 (s, 2H, NH2).

Example 35: 3-(2-Methylcyclohexyl)benzothiophen-6-silt ether sulfamic acid

So pl. 110°

1H-NMR (DMSO-d6): 0,65-2,30 (m, N)and 3.15 (m, 1H), 7,05-7,35 (m, 2H), 7,70-7,89 (m, 2H), 7,97 (s, 2H, NH2).

Example 36: 3-(2,2-Dimethylcyclobutyl)benzothiophen-6-silt ether sulfamic acid

So pl. 72°

1H-NMR (DMSO-d6): 0,70 (s, 3H), 1,10 (s, 3H), 1,45-2,30 (m, 6N), to 3.02 (DD, 1H), 7,20 (s, 1H), 7.23 percent (DD, 1H), 7,78 (d, 1H), 7,80 (s, 1H), of 7.96 (s, 2H, NH2).

Example 37: 3-(2-Substituted)benzothiophen-6-silt ether sulfamic acid

So pl. 185°

1H-NMR (DMSO-d6): 1,50-to 2.40 (m, N), 3,37 (USS, 1H), 7,24 (m, 2H), 7,80 (d, 1H), 7,82 (s, 1H), 7,97 (s, 2H, NH2).

Example 38: 3-Propylbenzamide-6-silt ether sulfamic acid

So pl. 112°

1H-NMR (DMSO-d6): to 0.96 (t, 3H), of 1.70 (m, 2H), 2,88 (t, 2H), 7,19 (s, 1H), 7,24 (DD, 1H), 7,78 (d, 1H), 7,80 (s, 1H), 7,97 (s, 2H, NH2).

Example 39: 3-Hexylbenzoate-6-silt ether sulfamic acid

So pl. 125°

1H-NMR (DMSO-d6): of 0.95 (t, 3H), 1,10-of 1.80 (m, 8H), is 2.88 (t, 2H), 7,19 (s, 1H), 7,22 (DD, 1H), to 7.77 (d, 1H), 7,79 (s, 1H), of 7.96 (s, 2H, NH2).

Example 40: 3-Cyclohexylbenzothiazole-6-silt ether sulfamic acid

So pl. 115°

1H-NMR (DMSO-d6): to 0.80 and 1.80 (m, 11N), 2,78 (d, 2H), 7,16 (s, 1H), 7,24 (DD, 1H), to 7.77 (d, 1H), 7,79 (s, 1H), 7,97 (s, 2H, NH2).

Prima is 41: 3-Cycloheptylmethyl-6-silt ether sulfamic acid

So pl. 90°

1H-NMR (DMSO-d6): 1,00-2,00 (m, 13H), 2,82 (d, 2H), 7,18 (s, 1H), 7,22 (DD, 1H), 7,78 (d, 1H), 7,80 (s, 1H), 7,97 (s, 2H, NH2).

Obtaining mono - or dioxide monosubstituted derivatives (8)

Example 42: 3-Cyclohexylbenzothiazole-6-silt ether sulfamic acid, 1-oxide

To a solution of 3-cyclohexylbenzothiazole-6-silt ether sulfamic acid (1,00 g is 3.21 mmol) in dichloromethane (20 ml) and triperoxonane acid (5 ml) was added 35% aqueous hydrogen peroxide solution (0.35 ml of 3.42 mmol, of 1.05 EQ.). The mixture was incubated for 2 hours at 50°and then hydrolyzing saturated aqueous NaHCO3, extracted with dichloromethane, dried over Na2SO4, filtered and concentrated in vacuo to obtainthe crude product. The product was then purified flash chromatography on silica gel (toluene/1,4-dioxane: 6/4) to give a clear oil which crystallized from ethanol, receiving specified in the header of the product (0.25 g, 24%, TPL 110°).

1H-NMR (DMSO-d6): 1,10-of 2.15 (m, 10H), of 2.72 (m, 1H), 7,10 (s, 1H), 7,45 (DD, 1H), to 7.64 (d, 1H), to 7.84 (d, 1H), 8,16 (s, 2H, NH2).

In accordance with the described methodology, but substituting 3-cyclohexylbenzothiazole-6-silt broadcast on

- 3-collateralisation-6-silt ether sulfamic acid

receive the following connections:

Example 43: 3-Collateralisation-6-silt ether sulfamido the th acid, 1 oxide

So pl. 146°

1H-NMR (DMSO-d6): 1,35-2,10 (m, N), of 3.12 (m, 1H), 7,15 (s, 1H), 7,45 (DD, 1H), 7.62mm (d, 1H), 7,83 (d, 1H), 8,15 (s, 2H, NH2).

In accordance with the procedure described in example 43, but using 2,2 equivalent of hydrogen peroxide, receive the following connections:

Example 44: 3-Cyclohexylbenzothiazole-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 180°

1H-NMR (DMSO-d6): 1,15-of 2.15 (m, 10H), 2,52 (m, 1H), 7,30 (s, 1H), 7,53 (DD, 1H), 7,63 (d, 1H), 7,71 (d, 1H), 8,25 (s, 2H, NH2).

In accordance with the above procedure, but replacing 3-ticketsinventory-6-silt ether sulfamic acid

- 3-cycloheptatrien-6-silt ether sulfamic acid;

- 3-cyclooctylmethyl-6-silt ether sulfamic acid;

- 3-collateralisation-6-silt ether sulfamic acid;

- 3-(4-methylcyclohexyl)benzothiophen-6-silt ether sulfamic acid;

- 3-(2-methylcyclohexyl)benzothiophen-6-silt ether sulfamic acid;

- 3-(2,2-dimethylcyclobutyl)benzothiophen-6-silt ether sulfamic acid;

- 3-(2-substituted)benzothiophen-6-silt ether sulfamic acid;

- 3-propylbenzamide-6-silt ether sulfamic acid;

- 3-hexylbenzoate-6-silt ether sulfamic acid;

- 3-cyclohexylbenzothiazole-6-silt ether sulfamic acid;

3-cycloheptylmethyl-6-silt ether sulfamic acid,

receive, respectively, the following connections:

Example 45: 3-Cycloheptatrien-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 137°

1H-NMR (DMSO-d6): 1,35-of 2.15 (m, N), a 2.75 (m, 1H), 7,32 (s, 1H), 7,52 (DD, 1H), to 7.61 (d, 1H), of 7.70 (d, 1H), 8,25 (s, 2H, NH2).

Example 46: 3-Cyclooctylmethyl-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 122°

1H-NMR (DMSO-d6): 1,35-2,10 (m, 14N), of 2.81 (m, 1H), 7,32 (s, 1H), 7,52 (DD, 1H), to 7.61 (d, 1H), of 7.70 (d, 1H), they were 8.22 (s, 2H, NH2).

Example 47: 3-Collateralisation-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 102°

1H-NMR (DMSO-d6): 1,35-2,10 (m, N), of 2.97 (m, 1H), 7,38 (s, 1H), 7,52 (DD, 1H), 7,60 (d, 1H), of 7.70 (d, 1H), they were 8.22 (s, 2H, NH2).

Example 48: 3-(4-Methylcyclohexyl)benzothiophen-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 170°

1H-NMR (DMSO-d6): 0,75-of 2.20 (m, N), and 2.83 (m, 1H), 7,18 (s, 1H), 7,22 (DD, 1H), 7,78 (d, 1H), 7,80 (d, 1H), 7,95 (s, 2H, NH2).

Example 49: 3-(2-Methylcyclohexyl)benzothiophen-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 92°

1H-NMR (DMSO-d6): 0,70 at 2.45 (m, N), 2,85 (m, 1H), 7,25 (s, 1H), 7,52 (m, 3H), of 8.25 (s, 2H, NH2).

Example 50: 3-(2,2-Dimethylcyclobutyl)benzothiophen-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 172°

1H-NMR (DMSO-d6): of 0.90 (s, 3H), of 1.16 (s, 3H), 1,50-of 2.15 (m, N), of 2.66 (t, 1H), 7,49 (s, 1H), 7,52 (DD, 1H), to 7.61 (d, 1H), of 7.70 (d, 1H), 8,24 (s, 2H, NH2).

Example 51: 3-(2-Substituted)benzothiophen-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 230°

1H-NMR (DMSO-d6): 1,45-of 2.45 (m, 14N), 3.04 from (USS, 1H), 7,38 (s, 1H), 7,53 (d, 1H), to 7.64 (d, 1H), of 7.70 (d, 1H), 8,25 (s, 2H, NH2).

Example 52: 3-propylbenzamide-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 159°

1H-NMR (DMSO-d6): 0,99 (t, 3H), of 1.70 (m, 2H), 2.49 USD (t, 2H), 7,29 (s, 1H), 7,52 (DD, 1H), 7,63 (d, 1H), 7,73 (d, 1H), and 8.50 (s, 2H, NH2).

Example 53: 3-Hexylbenzoate-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 98°

1H-NMR (DMSO-d6): of 0.85 (t, 3H), 1,10-of 1.80 (m, 8H), of 2.50 (t, 2H), 7,30 (s, 1H), 7,52 (DD, 1H), 7.62mm (d, 1H), 7,73 (d, 1H), 8,27 (s, 2H, NH2).

Example 54: 3-Cyclohexylbenzothiazole-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 132°

1H-NMR (DMSO-d6): 0,80-of 1.95 (m, 11N), is 2.40 (d, 2H), 7,30 (s, 1H), 7,53 (DD, 1H), 7.62mm (d, 1H), 7,72 (d, 1H), 8,25 (s, 2H, NH2).

Example 55: 3-Cycloheptylmethyl-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 135°

1H-NMR (DMSO-d6): 1,00-of 2.15 (m, 13H), a 2.45 (d, 2H), 7,29 (s, 1H), 7,53 (DD, 1H), 7.62mm (d, 1H), 7,73 (d, 1H), 8,25 (s, 2H, NH2).

Getting disubstituted 6-methoxybenzamide (9)

Example 56: 3-Cycloheptyl-6-methoxy-2-methylbenzamide

To a solution of 3-Cyclohe the Il-6-methoxybenzamide (2.00 g, of 7.69 mmol) in dry THF (20 ml) at -70°With added dropwise a 2.5 M solution of n-utility in hexane (5 ml, 12,16 mmol). After that, the mixture is heated to -30°C for 10 minutes and cooled to -70°to add iodomethane (1.0 ml, 15,38 mmol). The mixture is heated to room temperature overnight, and then hydrolyzing with a saturated aqueous solution of NH4Cl, extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated in vacuo to obtain 2.1 g of oil. The oil is purified flash chromatography on silica gel (heptane/ethyl acetate: 1/1)to give product as a clear oil (1.50 g, 72%), which is used without further purification.

1H-NMR (DMSO-d6): 1,35-of 2.15 (m, N), to 2.29 (s, 3H), of 3.00 (m, 1H), 3,80 (s, 3H), 7,00 (s, 1H),? 7.04 baby mortality (d, 1H), 7,49 (d, 1H).

In accordance with the described methodology, but substituting logmean

- rambutan

get the following connection:

Example 57: 3-Cycloheptyl-6-methoxy-2-butylbenzamide

1H-NMR (DMSO-d6): of 0.90 (t, 3H), 1,10-2,20 (m, N), a 2.75 (t, 2H), 3.04 from (m, 1H), 3,80 (s, 3H), 7,00 (s, 1H), 7,05 (d, 1H), 7,51 (d, 1H).

Example 58: 7-Methoxy-1,2,3,4-tetrahydrolipstatin

This connection receive in accordance with the method described in the publication Oliveira M. (Tetrahedron, 2002, 58, 1709-18).

1H-NMR (CDCl3): of 1.92 (m, 4H), of 2.72 (m, 2H), and 2.83 (m, 2H), with 3.89 (s, 3H), 6,97 (DD, 1H), 7,30 (d, 1H), 7,47 (d, 1H).

Obtain the disubstituted benzothia the Enola (10)

In accordance with the methodology used for the monosubstituted derivatives, but substituting 3-cyclohexyl-6-methoxybenzamide

- 3-cycloheptyl-2-methyl-6-methoxybenzamide;

- 3-cycloheptyl-6-methoxy-2-butylbenzamide;

- 7-methoxy-1,2,3,4-tetrahydrolipstatin

receive, respectively, the following connections:

Example 59: 3-Cycloheptyl-2-methylbenzofuran-6-ol

So pl. 96°

1H-NMR (DMSO-d6): 1,30-of 2.15 (m, N), is 2.44 (s, 3H), 3,01 (m, 1H), 6.87 in (d, 1H), 6,97 (s, 1H), 7,34 (d, 1H), 9,31 (s, 1H, HE).

Example 60: 3-Cycloheptyl-2-butylbenzofuran-6-ol

Transparent oil.

1H-NMR (DMSO-d6): to 0.92 (t, 3H), 1,15-of 2.20 (m, N), 2,80 (t, 2H), to 3.02 (m, 1H), 6,85 (d, 1H), 6,95 (s, 1H), 7,32 (d, 1H), which 9.22 (s, 1H, HE).

Example 61: 1,2,3,4-Tetrahydrolipstatin-7-ol

So pl. 116°

1H-NMR (CDCl3): 1,90 (m, 4H), 2,68 (m, 2H), and 2.79 (m, 2H), 4,98 (USS, 1H, HE), to 6.88 (DD, 1H), 7,20 (m, 1H), 7,42 (d, 1H).

Getting disubstituted benzothiophenes ether sulfamic acid (11)

In accordance with the methodology used to obtain the monosubstituted derivatives, but replacing 3-cyclohexylbenzothiazole-6-ol

- 3-cycloheptyl-2-methylbenzofuran-6-ol;

- 3-cycloheptyl-2-butylbenzofuran-6-ol;

- 1,2,3,4-tetrahydrolipstatin-7-ol

receive, respectively, the following connections:

Example 62: 3-Cycloheptyl-2-methylbenzofuran-6-silt ether Sul is feminova acid

So pl. 107°

1H-NMR (DMSO-d6):1,40-of 2.20 (m, N), the 2.46 (s, 3H), 3,14 (m, 1H), 7,20 (s, 1H), 7,30 (DD, 1H), 7,60 (d, 1H), 8,00 (s, 2H, NH2).

Example 63: 3-Cycloheptyl-2-butylbenzofuran-6-silt ether sulfamic acid

Transparent oil.

1H-NMR (DMSO-d6): of 0.91 (t, 3H), 1,15-of 2.20 (m, N), 2,77 (t, 2H), 3,11 (m, 1H), 7,15 (s, 1H), 7,32 (d, 1H), to 7.59 (d, 1H), 8,04 (s, 2H, NH2).

Example 64: 1,2,3,4-Tetrahydrolipstatin-7-silt ether sulfamic acid

So pl. 165°

1H-NMR (DMSO-d6): to 1.87 (m, 4H), 2,70 (m, 2H), 2,82 (m, 2H), 7,28 (DD, 1H), 7,66 (d, 1H), 7,72 (d, 1H).

Getting disubstituted deoxidation (12)

In accordance with the methodology used to obtain the monosubstituted derivatives, but replacing 3-cycloheptatrien-6-silt ether sulfamic acid

- 3-cycloheptyl-2-methylbenzofuran-6-silt ether sulfamic acid;

- 3-cycloheptyl-2-butylbenzofuran-6-silt ether sulfamic acid;

- 1,2,3,4-tetrahydrolipstatin-7-silt ether sulfamic acid

receive, respectively, the following connections:

Example 65: 3-Cycloheptyl-2-methylbenzofuran-6-silt ether sulfamic acid, 1,1-dioxide

So pl. 90°

1H-NMR (DMSO-d6): 1,30-of 2.20 (m, N), 2,48 (s, 3H), was 2.76 (m, 1H), 7,28 (s, 1H), 7,41 (d, 1H), 7,52 (d, 1H), 8,27 (s, 2H, NH2).

Example 66: 3-Cycloheptyl-2-butylbenzofuran-6-yl is the first broadcast of sulfamic acid, 1,1-dioxide

Transparent oil.

1H-NMR (DMSO-d6): of 0.91 (t, 3H), 1,15-of 2.15 (m, N), a 2.75 (m, 1H), 2,90 (t, 2H), 7,25 (s, 1H), 7,40 (d, 1H), 7,56 (d, 1H), 8,31 (s, 2H, NH2).

Example 67: 1,2,3,4-Tetrahydrolipstatin-7-silt ether sulfamic acid, 1,1-dioxide

So pl. 229°

1H-NMR (DMSO-d6): of 1.78 (m, 4H), 2,30 - 2,70 (m, 4H), 7,54 (DD, 1H), to 7.61 (d, 1H), 7,74 (d, 1H).

The RESULTS of BIOLOGICAL TESTS

Inhibition of steroid sulfatasein vitro

Astrosolar (E1S) represents the main circulating plasma estrogen, which under the action of the enzyme steroid sulfatase converted into estrone (E1), which, in turn, can undergo transformation into estradiol (E2) enzymatic recovery. The activity of steroid sulfatase presents in most tissues (uterus, liver, mammary gland, and so on) and significantly higher in malignant than in normal breast tissue. The close relationship of estrogen to accelerate the growth and development of breast cancer has long been recognized, therefore, steroidna sulfatase is a potential target for inhibition ofin situthe formation of estrogens.

Were synthesized highly effective inhibitors of this enzyme containing sulphamate fragment, which is believed to be involved in the irreversible Engibarov the e steroid sulfatase. To date the most active compound in this class was EMATE, estrone-3-sulpham, but estrogenic activity of this compound makes it unsuitable for use in the treatment of hormone-dependent tumors. Described a large number of different in the structure of inhibitors of steroid sulfatase, which is 6,6,7-COUMATE, used as a standard non-steroidal inhibitor, does not possess estrogenic properties.

The test results arein vitro

Use twoin vitromodel tests on whole cells. JEG-3 cell line, derived from placental choriocarcinoma, initially contains a significant number of istranslated person, so can be used as a practical biological systems for screening in the format of a 96-well microplate, a significant number of compounds and assessment of suspected inhibitors of steroid sulfatasein vitro. Despite the lower activity of steroid sulfatase, MCF-7 cells constitute another suitable model for testing inhibitors of steroid sulfatase cell adenocarcinoma of the breast of man. In addition, these cells are used inin vivomodels of hormone-dependent induced xenografts.

Test istranslated on cells

IP is itania on whole cells is carried out in accordance with the original method, described in the publication Duncan et al., (Cancer Res., 1993, 53:298-303), in monolayers of intact MCF-7 cells. The test is carried out on cells in the logarithmic growth phase in 96-well (JEG-3) or 24-hole (MCF-7) microplate. 24 hours (JEG-3) or 72 hours (MCF-7) prior to study cells were seeded in medium supplemented decompencirovannah fetal calf serum (dFCS). Then driven medium is removed and cells are washed with PBS to remove any traces of dFCS. Then add3H-E1S followed by the addition of the test compounds with a concentration in the range from 10-12M to 10-5M After 4 hours (JEG-3) or 20 hours (MCF-7) after processing environment is transferred or deep 96-well microplates (JEG-3) or in plastic tubes (MCF-7) and centrifuged at HD for 10 minutes to obtain a precipitate of cells before extraction with toluene. For toluene extraction using a fraction of the environment for the Department of conjugate substrate and the non-coupled products. Radioactivity toluene phase determine the liquid scintillation method. Finally, the activity istranslated expressed in polach3H-E1+3H-E2formed in 4 hours and 20 hours, µg DNA, and inhibition of istranslated - in percentage of the control activity without inhibitor. To determine the concentration of 50% inhibition (IC50) using nonlinear analysis of compliance (GraphPad Prim Software) depending on the % of inhibition against the concentration of inhibitor: lowest value of the IC 50corresponds to the most active inhibitors (table 1).

Table 1< / br>
Inhibition of istranslated in the test on whole cells
JEG-3 cellsMCF-7 cells
ConnectionIC50(nm)±S.E.M.nIC50(nm)±S.E.M.n
EMATE3,2±0,240,06±0,0118
6,6,7-COUMATE4,5±0,6370,33±0,0624
Example 3078,8±39,85
Example 31101,8±58,05
Example 32433,7±94,85
Example 33743,8±139,65
Example 34317,7±42,95
Example 35146,8±16,34
Example 36128,5±14,24
Example 3792,4±the 15.65
Example 427,0±1,250,16±0,034
Example 4410,9±2,650,24±0,054
Example 4752,1±4,450,08±0,014
Example 487,6±1,350,09±0,024
Example 492,6±0,44
Example 502,5±0,54
Example 5224,7±5,05
Example 5312,5±3,35
Example 5410,0±1,240,10±0,034
Example 557,7±0,440,05±0,016
Example 64565,8±of 129.65
Example 6531,7±9,94

Among the tested compounds, the compounds of examples 42, 44, 48, 49, 50, 54 and 55 showed a significant inhibition (IC50about 10 nm) activity istranslated person in JEG-3 cells.

These connections are checked for residual estrogenic activity ofin vivoclassic uterotrophic test after 3-day oral administration to female rats prepubertal age.

Inhibition of steroid sulfatasein vivo

Residual estrogenic activity ofin vivo

Female rats prepubertal age for three days orally administered 1 mg/rat/day connection. The next day after the last injection of the uterus are removed and determine the mass in wet state.

The results are presented as % stimulation in uterine weight compared to control.

Table 2< / br>
Residual estrogenic activity
Connection% stimulationThe number of animals
6,6,7-COUMATE3%16
Example 420%8
The use of the 44 0%8
Example 474%8
Example 483%8
Example 498%8
Example 5024%8
Example 546%8
Example 553%8

Antiuterotrophic/antisulfatide activity

To assessin vivonestroganyh inhibitors of steroid sulfatase developed a stripped down model method Purohit.

Female rats (Wistar) were ovariectomy and leave to rest for 4 weeks. Before treatment no cycle check vaginal smears.

Animals injected only astrosolar (E1S) in a dose of 50 mg/kg/day subcutaneously or astrosolar in combination with oral introduction of potential inhibitors sulfatase dose of 1 mg/kg/day for 4 days. The uterus is removed, freed from surrounding tissue and determine the mass in wet state.

The results are expressed as % inhibition of E1S induced stimulation.

Table 3< / br>
Antiuterotrophic activity
Connection% inhibition The number of animals
6,6,7-COUMATE86%48
Example 4238%8
Example 4470%8
Example 4762%8
Example 4860%8
Example 5449%8
Example 5581%16

The compound of example 55 is chosen as a potential inhibitor of the activity of steroid sulfatase due to the lack of estrogenicity and significant inhibition of E1S stimulated growth in uterine weight. These test resultsin vivogood agreement with test resultsin vitroon whole cells.

Evaluation of the effectiveness of the compound of example 55

The potency of the compound of example 55 in relation to E1S stimulated growth in uterine weight assessed in comparison with a standard inhibitor 6,6,7-COUMATE in doses ranging from 0.03 to 1 mg/kg/day orally.

In this study 24 hours after the last injection conduct an autopsy to determine the content of the E1S and E2in the serum. The uterus is removed, freed from surrounding tissue, determine the mass of wet and immediately subjected to deep freezing to determine the population sulfatase activity.

Inhibition of E1S stimulated the growth of the mass of the uterus

Table 4
Dose< / br>
mg/kg/day
6,6,7-COUMATEThe compound of example 55
0,030%0%
0,113%0%
0,352%36%
184%72%

The activity determination istranslated in the uterus

Activity istranslated determined in accordance with the method described in the publication Purohit et al., with minor modifications. Briefly, uteri thawed, weighed and homogenized. Aliquots of the supernatant is treated with activated charcoal coated with dextran, and evaluate the activity sulfatase. E1's activity assessed after incubation for 30 minutes with 5 nm3H-E1S and 20 μm unlabeled E1S as a substrate. Radioactivity define a liquid-scintillation method.

Activity istranslated expressed as pmol/h/mg protein and are converted to percentage inhibition depending on the E1S.

Table 5
Dose < / br>
mg/kg/day
6,6,7-COUMATEThe compound of example 55
0,0336%19%
0,178%64%
0,396%96%
197%97%

The estrogen serum

The content of the E1S and E2determined in accordance with the method of the provider (DSL, Webster, TX, USA).

Table 6< / br>
The content of the E1S (ng/ml)
Dose< / br>
mg/kg/day
6,6,7-COUMATEThe compound of example 55
06,3±0,3
0,0324±3,117±2,5
0,126±2,621±2,4
0,359±6,469±5,9
180±5,783±2,5

Table 7< / br>
The content of the E2(PG/ml)
Dose< / br>
mg/kg/day
6,6,7-COUMATEThe compound of example 55
0 7,8±0,7
0,0333±5,831±2,8
0,128±2,528±1,3
0,318±1,122±1,2
116±1,515±0,9

Hormone induced xenografts

MCF-7 cells isolated from mammary adenocarcinoma person, injected subcutaneously Nude, naked mice with remote ovaries with astranslator (sediment cells the rate of release of 0.5 mg/90 days). The volume of xenografts determined once a week. When the volumes of the tumors significantly increased, begin oral to enter 6,6,7-COUMATE and the compound of example 55 in doses of 0.1 mg/kg/day and the introduction is carried out within 6 weeks.

Xenotransplantation measure, removed, weighed and subjected to a deep freeze before determining the activity of steroid sulfatase.

Table 8< / br>
The volume of xenografts (mm3)
The treatmentThe volume of xenograft after treatment for 6 weeks
Control - placebo71±8,2
E1S sediment cells(you shall order his 0.5 mg/

90 days)
1816±337
E1S+6,6,7-COUMATE

0.1 mg/kg/day
1854±243
E1S + Conn. example 55

0.1 mg/kg/day
1488±233

6,6,7-COUMATE not inhibited E1S induced stimulation after 6 weeks of oral administration at a dose of 0.1 mg/kg/day. At the same time, when applied to the same dose of the compound of example 55 see 18% inhibition.

Table 9< / br>
Weight xenografts (mg)
TreatmentWeight xenograft after treatment for 6 weeks
Control - placebo31±3,8
E1S sediment cells (release 0.5 mg/90 days)1350±277
E1S+6,6,7 - COUMATE

0.1 mg/kg/day
1467±191
E1S + Conn. example 55

0.1 mg/kg/day
877±185

6,6,7 COUMATE not inhibited mass xenograft, while when using the compounds of example 55 receive 35% inhibition.

td align="center"> Treatment
Table 10< / br>
The activity of steroid sulfatase xenografts (pmol/h/mg protein)
The volume of xenograft after treatment for 6 weeks
E1S sediment cells (release 0.5 mg/

90 days)
1653±101
E1S+6,6,7 - COUMATE

0.1 mg/kg/day
540±54
E1S+Conn. example 55

0.1 mg/kg/day
263±17

A significant increase in inhibition of the activity of intratumoral steroid sulfatase observed when applying the compound of example 55 (84%) compared with the use of 6,6,7 COUMATE (67%).

1. Sulphamate derived benzothiophene obtained by the process comprising the stages:

1) conversion of 6-methoxybenzamide (H):

where R2represents hydrogen, corresponding monobromobimane using N-bromosuccinimide and APTS in standard conditions;

2) convert the specified monobromobimane interaction with Mg in Et2O in an argon atmosphere in magnetogenesis bromide and subsequent condensation with a ketone or aldehyde selected from the group consisting of Cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone, cyclodecanone, 4-methylcyclohexanone series, 2-methylcyclohexanone series, 2,2-dimethylcyclopentane, 2-adamantanone, propanal, hexanal, Ziklag is cannabalised, cyclohexenecarboxaldehyde in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide with triethylsilane in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) optional alkylation of the corresponding substituted methoxybenzamide using standard conditions to obtain the corresponding substituted methoxybenzamide bearing (C1-C6)alkyl or (C3-C12) cycloalkyl;

5) removing the protective group of the substituted methoxybenzamide, obtained in stage 3 or stage 4) in the presence of tribromsalan in standard conditions;

6) convert the received hydroxycodone in the appropriate sulpham treatment with sodium hydride and aminohinolinove acid, or interaction with sulfhemoglobin in dimethylacetamide;

7) optional oxidation of the obtained compound with hydrogen peroxide in triperoxonane acid under standard conditions.

2. Sulphamate derived benzothiophene according to claim 1, having a melting point 128°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the corresponding mo is promproizvodstve interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclohexanone in Et2O to obtain the corresponding replacement of methoxybenzylidene in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

3. Sulphamate derived benzothiophene according to claim 1, having a melting point 110°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclohexanone in Et2O with what rucenim appropriate replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 1.05 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

4. Sulphamate derived benzothiophene according to claim 1, having a melting point 98°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclodecanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement by methoxybenzonitrile in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

5. Sulphamate derived benzothiophene according to claim 1, having a melting point of 146°obtained as follows:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclodecanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) prevremeni the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 1.05 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

6. Sulphamate derived benzothiophene according to claim 1, having a melting point of 180°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclohexanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of peroxide is odorata in triperoxonane acid and dichloromethane.

7. Sulphamate derived benzothiophene according to claim 1, having a melting point 132°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cycloheptanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

8. Sulphamate derived benzothiophene according to claim 1, having a melting point 137°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the corresponding mo is promproizvodstve interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cycloheptanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

9. Sulphamate derived benzothiophene according to claim 1, having a melting point 126°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane vzaimodeistvie Mg in argon atmosphere in Et 2O magnetogenesis bromide and subsequent condensation with cyclooctanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

10. Sulphamate derived benzothiophene according to claim 1, having a melting point 122°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclooctanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

11. Sulphamate derived benzothiophene according to claim 1, having a melting point 102°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclodecanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide obtained by CT the Hai 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

12. Sulphamate derived benzothiophene according to claim 1, having a melting point 132°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with 4-methylcyclohexanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in place the existing sulpham treatment with sodium hydride and nidharshanf acid.

13. Sulphamate derived benzothiophene according to claim 1, having a melting point 170°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with 4-methylcyclohexanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

14. Sulphamate derived benzothiophene according to claim 1, having the temperature is ru melting point 110° With that obtained by the process comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with 2-methylcyclohexanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

15. Sulphamate derived benzothiophene according to claim 1, having a melting point 92°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate KIS the Auteuil;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with 2-methylcyclohexanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

16. Sulphamate derived benzothiophene according to claim 1, having a melting point 72°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction is the influence of Mg in an argon atmosphere in Et 2O magnetogenesis bromide and subsequent condensation with 2,2-dimethylcyclopentane in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

17. Sulphamate derived benzothiophene according to claim 1, having a melting point of 172°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with 2,2-dimethylcyclopentane in Et2O to obtain the corresponding replacement of methoxybenzamide in the standard is s;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

18. Sulphamate derived benzothiophene according to claim 1, having a melting point 185°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with 2-adamantanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement methoxybenzamide what triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

19. Sulphamate derived benzothiophene according to claim 1, having a melting point 230°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with 2-adamantanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) p is avramania specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

20. Sulphamate derived benzothiophene according to claim 1, having a melting point 112°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with propanal in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

21. Sulphamate derived benzothiophene according to claim 1, having a temperature of prawle the Oia 159° With that obtained by the process comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with propanal in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

22. Sulphamate derived benzothiophene according to claim 1, having a melting point 125°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzo the thiophene (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with geksanalem in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

23. Sulphamate derived benzothiophene according to claim 1, having a melting point 98°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with geksanalem in Et2O with getting the appropriate replacement of methoxybenzamide in standard conditions;

3) processing the specified hydroseeding of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

24. Sulphamate derived benzothiophene according to claim 1, having a melting point 115°obtained as follows:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclohexanecarboxaldehyde in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamido the s-triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

25. Sulphamate derived benzothiophene according to claim 1, having a melting point 132°obtained as follows:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclohexanecarboxaldehyde in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

26. Sulphamate derived benzothiophene according to claim 1, having a melting point of 90°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclohexenecarboxaldehyde in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone are the s sulpham treatment with sodium hydride and nidharshanf acid.

27. Sulphamate derived benzothiophene according to claim 1, having a melting point 135°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cyclohexenecarboxaldehyde in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

6) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

28. Sulphamate derived benzothiophene according to claim 1, having a t is mperature melting 107° With that obtained by the process comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cycloheptanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) alkylation of the corresponding substituted methoxybenzamide by adding iodomethane to the mixture specified monosubstituted of methoxybenzamide in a solution of n-utility in hexane to obtain the corresponding methoxybenzamide;

5) adding a substituted methoxybenzamide obtained in stage 4) in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

6) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

29. Sulphamate derived benzo is iofina according to claim 1, having a melting point of 90°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cycloheptanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) alkylation of the corresponding substituted methoxybenzamide by adding iodomethane to the mixture specified monosubstituted of methoxybenzamide in a solution of n-utility in hexane to obtain the corresponding methoxybenzamide;

5) adding a substituted methoxybenzamide obtained in stage 4), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

6) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

7) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

30. Sulphamate derived benzothiophene according to claim 1 in the form of a clear oil obtained by the process comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cycloheptanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) alkylation of the corresponding substituted methoxybenzamide by adding bromobutane to the mixture specified monosubstituted of methoxybenzamide in a solution of n-utility in hexane to obtain the corresponding methoxybenzamide;

5) adding a substituted methoxybenzamide obtained in stage 4), in a solution of dichloromethane to a solution of tribromide boron with obtaining the appropriate hydroxybenzo open;

6) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid.

31. Sulphamate derived benzothiophene according to claim 1 in the form of a clear oil obtained by the process comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with cycloheptanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) alkylation of the corresponding substituted methoxybenzamide by adding bromobutane to the mixture specified monosubstituted of methoxybenzamide in a solution of n-utility in hexane to obtain the corresponding methoxybenzamide;

5) adding a substituted methoxybenzamide obtained in stage 4), in a solution of dichloromethane to a solution of tribromide boron with getting soo is such hydroxybenzamide;

6) convert the specified hydroxycodone in the appropriate sulpham treatment with sodium hydride and nidharshanf acid;

7) oxidation of the compounds of 2.2 equivalents of hydrogen peroxide in triperoxonane acid and dichloromethane.

32. Sulphamate derived benzothiophene according to claim 1, having a melting point 110°obtained by the method comprising the stages:

1) conversion of 6-methoxybenzamide (3) in the appropriate monobromobimane interaction with N-bromosuccinimide and n-toluensulfonate acid;

2) convert the specified monobromobimane interaction with Mg in argon atmosphere in Et2O magnetogenesis bromide and subsequent condensation with Cyclopentanone in Et2O to obtain the corresponding replacement of methoxybenzamide in standard conditions;

3) processing the specified replacement of methoxybenzamide triethylsilanol in the atmosphere of argon in dichloromethane to obtain the corresponding substituted methoxybenzamide;

4) adding a substituted methoxybenzamide, obtained in stage 3), in a solution of dichloromethane to a solution of tribromide boron to obtain the corresponding hydroxybenzamide;

5) convert the specified hydroxycodone in sootvetstvuyuschemu treatment with sodium hydride and nidharshanf acid.

33. The compound of formula (I):

where R1and R2together form a group -(CH2)p-, in which R is 4;

R3represents hydrogen;

n is 0, 1, 2;

m is 0;

the dotted line shows that the sulphamate group is in position 6-benzothiophene rings.

34. Connection p, which represents a 1,2,3,4-tetrahydrolipstatin-7-silt ether sulfamic acid.

35. Connection p, which represents a 1,2,3,4-tetrahydrolipstatin-7-silt ether sulfamic acid, 1,1-dioxide.

36. Pharmaceutical composition, useful as an inhibitor of steroid sulfatase containing compound according to one of claims 1 to 35 and a pharmaceutically acceptable carrier.

37. The connection according to one of claims 1 to 35 for use as an inhibitor of steroid sulfatase.

38. The use of compounds according to one of claims 1 to 35 in the production of pharmaceuticals for the treatment or prevention estrogenzawisimy disorders.

39. The use of compounds according to one of claims 1 to 35 in the production of drugs to control or influence on reproductive function.

40. The use of compounds according to one of claims 1 to 35 in the production of pharmaceuticals for the treatment or prevention of Dobrota the natural enemy or malignant diseases of the breast, the uterus or the ovary.

41. The use of compounds according to one of claims 1 to 35 in the production of pharmaceuticals for the treatment or prevention of androgen-dependent diseases, benign or malignant diseases of the prostate or testis.

42. The use of compounds according to one of claims 1 to 35 in the production of pharmaceuticals for the treatment or prevention of disorders of cognitive ability.

43. The use of compounds according to one of claims 1 to 35 in the production of pharmaceuticals for the treatment or prevention of immune functions.



 

Same patents:

FIELD: organic chemistry, analytical chemistry.

SUBSTANCE: invention relates to synthesis of novel analytical reagents of chelate-forming type. Synthesized compounds represent chelate-forming dibenzo-containing five-membered cyclic compounds comprising two symmetric β-dicarbonyl substitutes bound covalently with fluorine-containing radicals of the general formula (1): , wherein X means -CH2, oxygen (O), sulfur (S) atom, -NR; if X means -CH2 then R means hydrogen atom (H); R2 means -C(O)CH2C(O)Rf wherein Rf means -(CF2)nY wherein n = 1-6, and at n = 1 Y means H, F, Cl, Br, -OCF3, -OCH3, -OC3F7, -OCF2-CF2-OCF3, -C6F5, -C(O)OAlk wherein Alk means hydrocarbon radical; at n = 2 Y means H, F, Cl, Br, -OCF3, -OC3F7, -OCF2-CF2-OCF3, -C(O)OAlk; at n = 3, 5 or 6 Y means F, -C(O)OAlk; at n = 4 Y means H, F, Cl, -C(O)OAlk; if X means O, S or -NR then R means H or Alk, R2 means H, R1 means -C(O)CH2C(O)Rf. Invention can be used in field of luminescent-spectral analysis, in particular, for clinical diagnosis of object of biogenic origin, and in technique field for using as extractants of heavy and rare-earth metal ions for their extraction and/or purifying from their impurities of sewage and contour waters.

EFFECT: valuable medicinal and technical properties of compounds.

1 cl, 19 dwg, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of heterocyclic ketones of formula or or their mixes, wherein R1 and R2 are hydrogen, alkyl, C6-C10 aryl; or R1 and R2 together form cyclic ring system;R3 C1-C40 alkyl; X sulfur; by interaction of heterocyclic compound of the formula (II) with α, β-unsaturated carboxylic acid or with anhydride of an acid in a liquid reactionary medium which includes a strong organic acid selected from the group includingC1-C8 alkylsulfonic acid and a water absorber selected from the group including phosphorus pentoxide, a strong organic acid possessing higher acidity, compared to carbolyxic acid; the process is effected by adding simultaneously the compounds of formula (II), acids or anhydride to the reactionary medium specified above, at temperature from 50 to 110°C. Replaced heterocyclic ketones make the important initial compounds on receiving heterocyclic metallocene catalysts for polymerization of α-olefines.

EFFECT: new compounds possess useful biological properties.

5 cl, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase

Ethynylbenzoate // 2079495
The invention relates to light-sensitive pesticides, specifically to some ethynylbenzoate

The invention relates to heteroalicyclic alkanoyl derivatives, which have a biocidal effect, and more particularly to aminoalcohols derived molecules containing heteroalicyclic ring system, to methods of their synthesis, their new intermediates, containing pharmaceutical compositions and to their use as biocidal agents, in particular anticancer agents

The invention relates to heteroalicyclic alkanols derived, and in particular to methods of obtaining new polycyclic biocidal compounds of General formula I

ArCH2Other where Ar is 2-benzo/b/oil/2,1-d/thiophene-5-yl; 2-benzo/db/oil/2,3-d/furan-6-yl; 2-benzo/b/oil/1,2-d/furan-5-yl; 2-/7-methyl, 7H-benzo/with/carbazole-10-yl/methyl, 2-/benzo/b/oil/2,1-d/furan-5-yl; R= -H3or their salts, which can be used as anticancer agents

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to novel compounds of formula (I), its pharmaceutically acceptable salts, possessing qualities of chemokine receptor modulators. Compounds can be applied for asthma, allergic rhinitis, COLD, inflammatory intestinal disease, irritated intestine syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, psoriasis or cancer. In compound of formula (I) , R1 represents group selected from C1-8alkyl, said group is possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4 , -NR5R6 , phenyl, phenyl is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4,-NR5R6,-SR10,C1-6alkyl and trifluoromethyl; R2 represents group selected from C1-8alkyl, said group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-(C1-6alkyl)-N-(phenyl)amino; R3 represents hydrogen, R4 represents hydrogen or group selected from C1-6alkyl and phenyl, R5 and R6, independently, represent hydrogen or group selected from C1-6alkyl and phenyl, said group being probably substituted with 1, 2 or 3 substituents, independently selected from -OR14, -NR15R16, -COOR14,-CONR15R16, or R5 and R6 together with nitrogen atom, to which they are bound, form 4-7-member saturated heterocyclic ring system, possibly containing additional heteroatom, selected from oxygen and nitrogen atoms, ring possibly being substituted with 1, 2 or 3 substituents, independently selected from -OR14, -COOR14,-NR15R16,CONR15R16 and C1-6alkyl; R10 represents hydrogen or group selected from C1-6alkyl or phenyl; and each from R7, R8, R9, R14, R15, R16 independently represents hydrogen, C1-6alkyl or phenyl; X represents hydrogen, halogeno; Rx represents trifluoromethyl, -NR5 R6 , phenyl, naphtyl, heteroaryl, heteroring can be partly or fully saturated, and one or more ring carbon atoms can form carbonyl group, each phenyl or heteroaryl group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR4, -NR5R6, -CONR5R6, -COR7, -COOR7, -NR8COR9, -SR10, -SO2R10, -SO2NR5R6, -NR8SO2R9, C1-6alkyl or trifluoromethyl; or Rx represents group selected from C1-6alkyl, said group being possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6, phenyl or heteroaryl, where heteroaryl represents monocyclic or bicyclic aryl ring, containing from 5 to 10 ring atoms, from which 1, 2 or 3 ring atoms are selected from nitrogen, sulfur or oxygen. Invention also relates to methods of obtaining compounds, versions, pharmaceutical composition and application for manufacturing medications using compounds of invention.

EFFECT: obtaining novel compounds of formula (I), its pharmaceutically acceptable salts, possessing properties of chemokine receptor moduators.

25 cl, 138 ex

FIELD: medicine, oncology.

SUBSTANCE: invention can be applied in therapy for non-hematologic malignant tumours, expressing insulin-like growth factor IGF-1R. Treatment methods proposed consist in antibody injection that specifically binds IGF-1R, as well as taxane and carboplatin. Moreover the invention relates to pharmaceutical composition, containing the above antibody.

EFFECT: improvement in therapy efficiency due to antibodies capability to inhibit tumour growth and chemotherapy efficiency increase.

14 cl, 5 dwg

FIELD: medicine; oncology.

SUBSTANCE: versions of method include combined administration of 5-(5-fluoro-2-oxo-1,2-dihydroindole-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrol-3-carboxylic acid (2-diethylaminoethyl)amide and docetaxel in low doses that are ineffective in single-drug therapy.

EFFECT: synergistic anti-tumour effect, lowered doses of each drug.

2 cl, 8 dwg, 8 tbl,24 ex

FIELD: medicine; oncology.

SUBSTANCE: 4 courses of neoadjuvant polychemotherapies are carried out and at decrease of the lung primary tumour by 1/2 of its size and at absence of the remote metastasises - to brain, skeleton bones, aliver, adrenals, the surgical treatment is carried out consisting of removal of the lung primary tumour with lympho dissection of the mediastinum and the neck. In 4 weeks after the operation polychemotherapy is carried out, and at absence of a pathomorphism or pathomorphism of degree I-II in the postoperative period drugs for carrying out of polychemotherapy are replaced and at tumour pathomorphism of III degree in the postoperative period polychemotherapy is caried out with similar preparations.

EFFECT: increase of treatment efficiency of parvicellular lung cancer due to augmentation of operation ablasticity at carrying out of neoadjuvant polychemotherapy and prescrption of polychemotherapy sensitive to tumour in postoperative period by results of pathomorphism examination.

2 ex

FIELD: medicine; pharmacology.

SUBSTANCE: crystal epirubicine hydrochloride of type II has diffraction pattern of X-ray powder scattering providing average diffraction angles (2θ) and relative intensities P(%), presented in the Table indicated below:

EFFECT: effective application of new crystal form for cancer treatment in people and animals.

6 cl, 7 dwg, 4 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: new annelated asaheterocycles include pyrimidine fragment of general formula I in the form of free bases or pharmaceutically acceptable salts. Compounds of this invention possess properties of PI3 kinase inhibitors. In general formula I X represents oxygen atom or sulphur atom; Z represents oxygen atom, R1 represents hydrogen atom or optionally substituted C1-C6alkyl, or Z represents nitrogen atom together with bound carbon atom forming through Z and R1 optionally substituted annelated imidazoline cycle; R2 represents optionally substituted C1-C6alkyl, optionally substituted C3-C8cycloalkyl, optionally substituted phenyl, possibly annelated with 5-6-term heterocyclyl containing heteroatoms chosen from oxygen and nitrogen, optionally substituted 5-6-term heterocyclyl containing heteroatoms chosen from nitrogen, oxygen and/or sulphur, possibly annelated with phenyl ring. Invention also concerns method of production of compounds, pharmaceutical compositions and medical products.

EFFECT: effective application for preparation of medical products for oncologic therapy.

14 cl, 3 dwg, 1 tbl, 4 ex

FIELD: medicine; oncology.

SUBSTANCE: Xeloda is introduced in dosage 850-1000 mg/m2 from 1st to 16th day of treatment. Additionally platinum preparation is introduced singly on 8th day in amount 1/4-1/2 of single therapeutic dose. It is accompanied with gamma-ray therapy. Within 5 days single focal dose SFD of irradiation is 1.8-2.0 Gy. And then SFD is applied in dose 1.2-1.6 Gy twice a day until total focal dose TFD is 30-36 Gy. In 14-21 days therapy course is repeated with prescribed introduction of Xeloda within the whole course of gamma therapy until total focal dose TFD is 60-65 Gy.

EFFECT: higher degree of tumour regress, decreased radioreaction of gastrointestinal tract, improved life quality and survival time in patients suffering from severe cancers.

2 ex

FIELD: medicine; oncology.

SUBSTANCE: tumour and metastasises site diagnostics is preliminary carried out using hardware and software complex "Sozvezdie". Then photosensitiser chlorine e6 is introduced. After that tumour is exposure with of laser wavelength 660±20 nm during exhalation and heart diastole. Pulse repetition rate is 22.5±2 kHz, pulse duration is 70±30 ns, and power density is 0.1-0.5 Wt/cm2. Thus retention of tumour reheat temperature is controlled within 42-45°C. Method can be applied after operation and/or chemotherapy and/or radiation therapy.

EFFECT: accelerated rehabilitation and higher selectivity of laser exposure and increase of cellular immunity.

4 cl, 3 ex

FIELD: medicine; oncology.

SUBSTANCE: laser diagnostics is preliminary applied. Finger tissues are tested for microcirculation index M1 and oxygen saturation index OS1. Occlusive sample is taken. Oxygen saturation index OS2 is evaluated directly before occlusive sample is completed. Maximum microcirculation index is evaluated after occlusive sample M2. Then introduction of 25-30 mg of Prednisolone solution is followed with introduction of Perftoran at 2.5-3.5 ml/kg of patient weight. In 1-1.5 hours finger tissues are re-tested for microcirculation index M3 and oxygen saturation index OS3. Occlusive sample is taken. Oxygen saturation index OS4 is evaluated directly before occlusive sample is completed. Maximum microcirculation index is evaluated after occlusive test M4. If ratio value is within , session of radiation therapy is applied. Method allows for evaluation of tissues and bodies microcirculation, of tissue hypoxia and the most reasonable time of radiation therapy following introduction of Perftoran.

EFFECT: higher regress of tumour processes.

2 cl, 2 ex

FIELD: medicine.

SUBSTANCE: offered is application Aplydine for production of medical product for leukaemia or lymphoma treatment by means of combined therapy using Aplydine and other medical product chosen from group consisting of methotrexate, cytosine arabinoside, mythoxanthrone, vynblastine, methylprennisolone and doxyrubicine, related methods of treatment (versions), pharmaceutical composition and kit. Cancer synergism of listed agents is shown in combination with Aplydine.

EFFECT: provision of effective treatment of fumours.

34 cl, 15 dwg, 6 ex, 11 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to fluorine and trifluoralkyl-containing heterocyclic sulfonamides of general formula I , where T - CHO, COR8 and C(OH)R1R2; R1 and R2 -hydrogen, C1-6alkyl; R3 -hydrogen; R4 - (CF3)nalkyl, (CF3)nalkylphenyl, and (F)ncycloalkyl; N equals 1-2; R5 - hydrogen, halogen, dien, condensed with Y, when Y stands for C, and dien, condensed with Y, when Y stands for C and substituted with halogen; W, Y and Z - C, CR6 and N, on condition that at least one of W or Y, or Z must be C; R6 -hydrogen halogen or C1-6alkyl; X - S and NR7; R7 - C1-6alkyl; and R8 - C1-6alkyl. Also described are method of obtaining compounds I, pharmaceutical composition and application of compounds, intermediate compounds, used in synthesis.

EFFECT: obtaining compounds which can be used to inhibit beta-amyloid formation and for treatment of Alzheimer's disease.

48 cl, 5 tbl, 42 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to agonist of receptor of glucagone-like peptide-1, which can be applied for treatment of diseases, caused by disturbance of glycometabolism, such as type II diabetes, insensibility to insulin or obesity. In structural formula each of Ar1 and Ar2 independently represents substituted phenyl, and group-substituents represent one, two or three groups selected from C1-C6alkoxyl, C1-C6-alkanoylamino, which is substituted with hydroxyl (which contains groups-substituents, including hydroxyl); C3-C6-cyclolkanoylamino, C2-C6-lkenoylamino; banzoylamino, banzyloxy C1-C6-alkanoylamino, thenoyloxy, tret-butoxyformamido, adamantanformamido; and mandeloylamino; X represents O; Y represents O. Invention also relates to method of obtaining agonist, and to its application for obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

EFFECT: obtaining medication for treatment of diseases caused by disturbance of glycometabolism.

8 cl, 4 ex, 2 tbl, 2 dwg

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