N-sulfonylurea-[1,3]-dioxano[5,6-b] azirine and intermediate products for their production

 

(57) Abstract:

New N-sulfonylurea- [1,3] -doxepin- [5,6-b] -azirine formula I, where R1and R2is a hydrogen atom or a C1-C4-alkyl, phenyl, or R1+ R2can represent a group of alkylidene, such as Tetra-, Penta - or hexamethylene, and R3- lower alkyl, unsubstituted or substituted by a halogen atom, a trifluoromethyl, or a group , where X is a hydrogen atom, a C1-C4alkyl or fluorine atom, chlorine, bromine or iodine, or a nitro-group, amino group, C1-C6alluminare, such as acetylamino or C1-C4alkoxygroup. The compounds I possess hypoglycemic activity. The new compounds of formula II are used as intermediates in the synthesis of compound I.

2 C. and 33 C.p. f-crystals, 5 PL.

The invention concerns new N-sulfonylurea-[1,3]-dioxano[5,6-b] -azirines and intermediate products for their preparation.

It is known that in clinical therapy of non-insulin dependent type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) currently apply only to two classes of hypoglycemic compounds: sulfonylureas and biguanidines [R. Sarges, Progr.Med.Chem. 18, the same in clinical trials on the hypoglycemic effect are representatives of many classes of compounds, such as thiazolidin (ciglitazone, pioglitazone, WED-72467), sulfanilamidnyi (CGP 11112), carboxamide (linogliride), oxyanion acid (etomoxir), pyridinedimethanol (DG 5125), polysaccharides (acarbose) and some other compounds, but none of them reaches the market because of insufficient effectiveness or other reasons [R. J. Mohrbacher et al, Ann. Rep. Med. Chem. 22 213 (1987); R. E. Larson et al, Ann.Rep.Med.Chem. 25, 205 (1989); K. E. Steiner and E. L. Lien, Prog.Med.Chem. 24,209 (1987); S. C. Stinson, Chem.Eng.News, Sept.30, 1991].

Studies prior art has shown that N-sulfonylurea-[1,3] -dioxano[5,6-b]-azirine the formula below I represent a new class of heterocyclic compounds and a new class of highly active hypoglycemic compounds.

The first object of the invention is a new N-sulfonylurea-[1,3] -dioxano[5,6-b]-azirine General formula I

< / BR>
where

R1and R2can denote a hydrogen atom, alkyl with the content of 1-4 C atoms, straight or branched chain, or phenyl;

R1+ R2can mean alkylidene group, such as group tetr is full or substituted, such as a methyl group, a halogen atom, trifluoromethyl, or para-substituted phenyl group

< / BR>
where

X can mean a hydrogen atom, alkyl with the content of 1-4 C atoms, straight or branched chain or an atom of fluorine, chlorine, bromine or iodine, or a nitro, amino or C1-C6acylamino, for example acetylamino, or group C1-C6-alkoxy, such as methoxy, obtained according to one of the following reactions (schemes 1-4),

< / BR>
already known for the synthesis of N-sulfonylation [O. C. Dermer, G. E. Ham, Ethyleneimine and Other Aziridines, Chemistry and Applications, Academic Press, New York, London, 1969; P. E. Fanta, in: A. Weissberger (Ed.), The Chemistry of Heterocyclic Compounds, vol.19, Part 1, Interscience Publishers, New York, London, Sydney, 1964, p.524], especially according to the above reaction (I) using as starting product is easily available in the market of CIS-2-butene-1,4-diol with obtaining aldehydes or ketones of General formula II

< / BR>
where

R1and R2have the specified values,

4,7-dihydro-1,3-doxepin formula III

< / BR>
where

R1and R2have the specified values,

which interact with chloride nitrile in organic NITRILES of the formula

R4CN

where

R4represents alkyl with the content of 1-4 atoms is rmula V

< / BR>
where

R1, R2and R4have the specified values,

subjected to reaction dehydrohalogenation cyclization with the formation of tetrahydro-[1,3]-dioxano[5,6-b]-azirines General formula VI.

< / BR>
where

R1and R2have the above values,

which under the influence of sulfochloride formula VII

R3-SO2Cl

where

R3has the specified value,

gives new N-sulfonylurea-[1,3]-dioxano[5,6-b]-azirine formula I, in which R1and R2have the above meanings and R3is a group of 4-acylaminoalkyl, for example, group 4-acetylaminophenol, which are final catalyzed by base hydrolysis with the formation of new compounds of the formula I, in which R1and R2have the above meanings and R3is a group of 4-aminophenol (reaction scheme 5, see end of text).

Doxepin formula III is easily obtained according to reaction scheme 5 by methods known from the literature [C. E. Pawlosky, Dioxepins and Trioxepins, in: A. Weissberger, E. C. Taylor (Eds.), The Chemistry of Heterocyclic Compounds, v.26, Wiley Interscience, New York, 1972, p.319].

TRANS-acylaminoderivatives formula V are easily derived ka is">

According to research dissemination formula VI are unknown products, while their potential precursors of formula V in the reaction conditions, providing azirines (aqueous soda solution at 100oC or hot ethanolic solution of potassium hydroxide) form the vicinal acylamino-dioxanone [M. Sovak, R. Ranganathan, U.S. Patent 4389526 (June 21, 1983)] or doxepine-oxazoline [M. Dumic et al. Org. Prep. Proc. Int. (1992) in press].

Discovered that the new doxepine-aziridine formula VI can be obtained by chemical transformation of compounds of formula V in an aqueous solution of alkali metal hydroxide, such as sodium hydroxide or potassium, when ravnomyerno ratio of the reactants up to a fivefold molar ratio, preferably 1.5 to 2.5 molar excess of alkali metal hydroxide at 20-150oC, preferably 50-100oC.

The reaction of compounds of the formula VI with sulfochloride formula VII is carried out in the conditions already known from the literature, for example, when the stoichiometric molar relationship or with 1.1 to 2.0 molar excess, preferably of 1.1 to 1.3 molar excess sulfochloride V, in the presence or absence of an inert organic solution is of aricela, such as methylene chloride, chloroform or 1,2-dichloroethane, in addition, ethyl acetate, dioxane, dimethylformamide or dimethyl sulfoxide, in the presence of ravnomernogo number or 1.1 to 2.0 molar excess, preferably of 1.1 to 1.3 molar excess of an organic base, such as pyridine, triethylamine or morpholine, or base, used as a solvent. The reaction can also be carried out in 2-5, preferably 2-3 molar excess amounts azirine General formula VI used as the basis for removal of the hydrogen formed during the reaction.

Diallylamine compounds of General formula I, where R3is a group of 4-acylaminoalkyl, for example 4-acetylaminophenol, in compounds of General formula I, where R3is a group of 4-aminophenol, is carried out in an alkaline medium by conventional hydrolysis.

The next object of the invention are new tetrahydro-[1,3]-doxepin[5,6-b] azirine General formula VI used as intermediate products for the synthesis of biologically active substances, especially hypoglycemic agents.

The next object of the invention is the use of compounds of General formula I in LASS="ptx2">

The next object of the invention is the use of compounds of General formula I as active ingredients in pharmaceutical preparations possessing hypoglycemic action.

It is established that the compounds of formula I, corresponding to the invention, have a significant or quite strong hypoglycemic activity that was found on the model induced alloxan diabetes in rats and mice, regardless of the input method of the drug, such as intravenous, subcutaneous or oral. For example, after 4 h after subcutaneous input preparation Ia in mice a dose of 10 mg/kg concentration of glucose (sugar) in the blood was reduced to 37%, while the concentration of glucose in the blood is not subjected to the treatment of animals suffering from diabetes, was 63%. 40 minutes after intravenous input preparation Ia a dose of 20 mg/kg in mice, the glucose content in the blood was reached even 33% of the concentration values in untreated diabetic animals. After 6 h after oral input of the drug dose 20 mg/kg in mice Ia reduced the concentration of glucose in the blood up to 60% of the initial concentration. In similar experiments after 4 hours after subcutaneous enter the compound Ia in the body cap

Experimental evaluation of the hypoglycemic effect was carried out on mice strain CBA weighing 20 - 25 g) and rat strain FISCHER weighing 160-200, These animals were placed in a cage with food and water taken arbitrarily, when the time mode: 12 h light - 12 h darkness. Hyperglycemia was induced by a single injection tetrahydrate of alloxan (65 mg/kg; Merck) into the tail vein (C. C. Rerup, Pharmacol. Rev. 22, 485, 1970). Animals were tested within 48 hours after the injection of alloxan. From the tail vein took the original blood sample (0,025 ml), and test material (compound of formula I, dissolved in minimum amount of DMSO and diluted saline solution of 0.9% NaCI) was administered by a single subcutaneous injection or intravenous injection or through the gastric cannula. Additional blood samples were collected at different time intervals (1-24 h) depending on the dose and mode of entry. Blood glucose was analyzed by an enzymatic method [P. Trinder, Ann.Clin.Biochem. 6,24 (1969)]. In the calculation of results concentration of sugar in the blood was expressed in mmol/l blood volume. The original blood sample showed the reference value of 100%.

On the other hand, substances of General formula I did not reduce the concentration of the Oia Ia drug in healthy rats and mice are presented in table. 2.

From the above it is clear that N-sulfonylurea[1,3] -dioxano[5,6-b] azirine General formula I are effective hypoglycemic agents, and they can be converted by usual chemical methods customary in pharmaceutical technology in appropriate pharmaceutical preparations such as tablets, pills, powders, capsules, granules, solutions, etc. short or delayed action for the treatment of diabetes.

Example 1. A mixture consisting of 10.0 g of chloramine V (R1= R2= H, R3= CH3), 7.2 g of potassium hydroxide and 150 cm3water was boiled under reflux for 90 min, it was extracted with chloroform under cooling it to room temperature. After evaporation of the chloroform and chromatographic separation of the residual product evaporation in a column of silica gel with elution with a mixture of chloroform/methanol (ratio 25:1) was obtained dissemination VIa (R1=R2=H) with a boiling point of 90 - 93oC/2,1 KPa.

In a similar manner there were obtained the following tetrahydro-[1,3]-dioxano[5,6-b]azirine VI of the relevant chloramide V (see tab.3):

Example 2. A mixture consisting of 0,120 g doxepin-azirine VIa (R3of methylene chloride, the mixture was treated with 210 cm3solution of hydrate of sodium oxide (1:1), the organic layer was separated and washed with 10 cm3water, neutralized with diluted hydrochloric acid to achieve pH 6, was washed again with 10 cm3water and dried over anhydrous sodium sulfate. After evaporation of methylene chloride was obtained the crude product, which, after chromatographic separation (Rf= 0,57; eluent:ethyl acetate/methanol = 20:1; detection of product: UV spectroscopy at 254 nm; silikagelevye plate Merck 60 F254) gave sulfonylation la (R1=R2=H, R3= 4-acetylaminophenol). The melting point of the product 210-212oC (ethyl acetate/methanol = 1:1).

Using as a source products asirin VI and sulfochloride VII was synthesized following sulfonylation (I) (see tab. 4):

Example 3. A mixture consisting of 0,313 g sulfonylation Ia (R1=R2=H, R3= 4-acetylaminophenol), 0,140 g of potassium hydroxide and 3 cm3water was boiled under reflux for 30 min, concentrated with the formation of a thick suspension was extracted with chloroform. The chloroform was evaporated. After chromatographic separation, the mod is chromatographically pure product (Merck silica gel 60F254; eluent:ethyl acetate/methanol = 20: 1; detection of product: UV spectroscopy at 254 nm; iodine pairs: brown staining; ninhydrin solution: ciclamino-red staining; Rf=0,65) sulfonylation Iv (R1=R2=H, R3= 4-AMINOPHENYL) in the form of a yellowish-reddish oil.

Similar hydrolysis of the corresponding N-(4-acetylamino-benzazolyl)-azirines formula I gave the following N-(4-amino-benzazolyl)azirine formula I (see tab.5):

1 1. N-Sulfonylurea-[1,3]-dioxano[5,6-b]azirine formula I 6 1 in which R1and R2can represent a hydrogen atom, a C1- C4-alkyl straight or branched chain, phenyl, or R1+ R2can represent a group of alkylidene, such as Tetra-, Penta - or hexamethylene; 4 R3may be a lower alkyl, unsubstituted or substituted by a halogen atom, such as methyl, or trifluoromethyl, or a group of para-substituted phenyl 6 1 in which X is a hydrogen atom, a C1- C4-alkyl straight or branched chain or an atom of fluorine, chlorine, bromine or iodine, or a nitro-group, amino group, C1- C6-alluminare such as acetylamino, or C1- C4inopril. 2 3. Connection on p. 1, where R1= R2- H, R3is phenyl. 2 4. Connection on p. 1, where R1= R2- H, R3- 4-forfinal. 2 5. Connection on p. 1, where R1= R2- H, R3- 4-chlorophenyl. 2 6. Connection on p. 1, where R1= R2- H, R3- 4-bromophenyl. 2 7. Connection on p. 1, where R1= R2- H, R3- 4-were. 2 8. Connection on p. 1, where R1= R2- H, R3- 4-nitrophenyl. 2 9. Connection on p. 1, where R1= R2- H, R3- 4-methoxyphenyl. 2 10. Connection on p. 1, where R1= R2= H, R3= CH3. 2 11. Connection on p. 1, where R1= R2- H, R3- CF3. 2 12. Connection on p. 1, where R1= R2- H, R3- 4-AMINOPHENYL. 2 13. Connection on p. 1, where R1- H, R2- CH3, R3- 4-acetylaminophenol. 2 14. Connection on p. 1, where R1- H, R2- CH2CH3, R3- 4-acetylaminophenol. 2 15. Connection on p. 1, where R1- H, R2- CH(CH3)2, R3- 4-acetylaminophenol. 2 16. Connection on p. 1, where R1- H, R2- CH(CH3)2, R3- 4-nitrophenyl. 2 17. Connection on p. 1, where R1- H, R2- CH(CH3)2, R3- 4-AMINOPHENYL. 2 18. Connection on p. 1, where R1- H, R2- phenyl,openil. 2 20. Connection on p. 1, where R1= R2- CH3, R3- 4-AMINOPHENYL. 2 21. Connection on p. 1, where R1+ R2- (CH2)4-, R3- 4-acetylaminophenol. 2 22. Connection on p. 1, where R1+ R2- (CH2)5-, R3= 4-acetylaminophenol. 2 23. Connection on p. 1, where R1+ R2= -(CH2)6-, R3- 4-acetylaminophenol. 2 24. The compounds of formula I on PP.1 - 23, possess hypoglycemic activity. 2 25. Tetrahydro-(1,3)-doxepin (5,6-b)azirine formula VI 6 1 in which R1and R2have the same values as specified in paragraph 1. 2 26. Connection on p. 25, where R1= R2- H. 2 27. Connection on p. 25, where R1- H, R2- CH3. 2 28. Connection on p. 25, where R1- H, R2- CH2CH3. 2 29. Connection on p. 25, where R1- H, R2- CH(CH3)2. 2 30. Connection on p. 25, where R1- H, R2is phenyl. 2 31. Connection on p. 25, where R1- R2- CH3. 2 32. Connection on p. 25, where R1+ R2- -(CH2)4-. 2 33. Connection on p. 25, where R1+ R2- -(CH2)5-. 2 34. Connection on p. 25, where R1+ R2- -(CH2)6-. 2 35. The compound of formula VI in PP.25 - 33 as intermediate products for the Blues

 

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9 cl, 1 tbl, 83 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

FIELD: organic chemistry.

SUBSTANCE: invention describes C2-phenyl-substituted cyclic ketoenols of the general formula: wherein W means hydrogen atom, alkyl with 1-6 carbon atoms; X means alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms; Y means hydrogen atom, methyl, ethyl, isopropyl, alkenyl with 2-6 carbon atoms, ethynyl; Z means hydrogen atom, alkyl with 1-6 carbon atoms under condition that at least one of residues W, X, Y or Z means a chain with at least 2 carbon atoms but only one of residues X and Y can mean alkenyl with 2-6 carbon atoms; CKE means one of the following groups: , , and wherein A means hydrogen atom, alkyl with 1-6 carbon atoms; B means hydrogen atom, alkyl with 1-6 carbon atoms; A and B in common with carbon atom to which they are bound mean cycloalkyl with 5-6 carbon atoms wherein the ring carbon atom can be substituted with oxygen atom and can be substituted with alkyl with 1-6 carbon atoms or alkoxyl with 1-6 carbon atoms; A and B in common mean group of the formula: D means hydrogen atom or phenyl substituted with fluorine atom if CKE means group of the formula (4); G means hydrogen atom (a) or one of groups of the formula: or wherein R1 means alkyl with 1-6 carbon atoms, alkoxymethyl with 1-2 carbon atoms; R2 means alkyl with 1-4 carbon atoms; A and Q1 in common mean alkanediyl with 3-4 carbon atoms; Q2 means hydrogen atom. Invention provides preparing compound of the formula (I) possessing with insecticide, acaricide and herbicide activity.

EFFECT: valuable properties of compounds.

2 cl, 8 tbl, 32 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivatives of indolinospiropyrane of the formula (1): wherein R1 means (C1-C18)-alkyl; each among R2 and R3 mean independently (C1-C4)-alkyl; R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl formyl, (C1-C)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2. Method comprises the following steps: (i) synthesis of indoline on polymeric carrier of the formula (III): wherein R1 means (C1-C18)-alkyl; each among R2 and R means independently (C1-C4)-alkyl; (ii) treatment of indoline-carrying polymeric carrier wherein this carrier represents hydroxy-resin at temperature from 50°C to 120°C in inert atmosphere for time from 14 h to 11 days with a derivative of salicylic aldehyde of the formula (VI): wherein R4 means hydrogen atom, hydroxy-group, trichloromethyl, trifluoromethyl, formyl, (C1-C4)-alkyl, halogen atom, (C1-C4)-alkoxy-, nitro-group; x = 1 or 2 to yield indolinospiropyrane compound of the formula (I), and (iii) release of indolinospiropyrane compound of the formula (I). Invention proves synthesis of novel derivatives of indolinospiropyrane possessing photochromic properties.

EFFECT: improved method of synthesis.

8 cl, 28 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention relates to compounds of formula I , wherein W is halogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; X is hydrogen, halogen, C1-C6-alkyl; Y is hydrogen, halogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-haloalcoxy or cyano; Z is hydrogen, halogen, etc.; G is halogen or nitro; meanings of the other substituents are as defined in specification. Also disclosed are methods for production of said compounds by interaction compounds of formula II with halogenation agents in presence of solvent and optionally of radical initiator of with fumed nitric acid in presence of solvent.

EFFECT: new compounds with insecticide activity.

17 cl, 20 tbl, 114 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compound of the formula (I): wherein (a) each R1 is chosen independently from hydrogen atom and alkoxy-group; (b) R2 represents hydrogen atom; (c) each R3 and R4 is chosen independently of one another from hydrogen atom, alkyl, alkynyl, heteroalkyl group, aryl; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one or more hydroxo-group, carboxyl group, keto-, thioketo-, phenyl group, alkyl, heteroalkyl group, heteroaryl, heterocycloalkyl, spirocycloalkyl and their combinations; (d) each R5 and R6 represents hydrogen atom; or optical isomers, diastereomers and enantiomers represented by above given formula, and their pharmaceutically acceptable salts also. Also, invention describes using compound of the formula (I) for preparing a pharmaceutical composition possessing antibacterial activity and antibacterial pharmaceutical composition containing the safety and effective amount of compound of the formula (I) and a pharmaceutically acceptable carrier. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): their using (variants) for preparing a drug used in treatment of diseases modulation of activity of chemokine receptors is useful, and to a pharmaceutical composition modulating chemokine receptors and comprising abovementioned compound. In compound of the formula (I) m = 0 or 1; R1 means halogen atom; X, Y and Z represent independently a bond, -CH2- or -O-, or X and Y form in common -CH=C(CH3)- or -C(CH3)=CH- under condition that only one radical among X, Y and Z can represents a bond, and under condition that X and Y both don't represent -O- simultaneously; n = 0, 1 or 2; R2 represents halogen atom, or (C1-C6)-alkyl; q = 0 or 1; R3 represents -NHC(O)R10, -C(O)NR11R12 or -COOR12a; each radical among R4, R5, R6, R7 and R8 represents independently hydrogen atom (H) or (C1-C6)-alkyl; t = 0, 1 or 2; R9 represents halogen atom, -OH, -COOH, (C1-C6)-alkoxy group, (C1-C6)-alkoxycarbonyl; R10 represents group (C1-C6)-alkyl, (C3-C6)-cycloalkyl, or R10 represents -NR14R15; each R11 and R12 represents independently (1) H; (2) 3-6-membered saturated cycloalkyl or phenyl or 5-membered unsaturated heterocyclyl comprising from 1 to 4 heteroatoms N wherein indicated cycloalkyl, phenyl and heterocyclyl are substituted possibly with one or two substitutes chosen from -OH, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl; (3) (C1-C6)-alkyl substituted possibly at least with one substitute chosen from halogen atom, -OH, -COOH, (C1-C6)-alkylcarbonylamino group, phenyl, 5-membered unsaturated heterocyclyl comprising oxygen atom (O), or from 1 to 2 N atoms, bicycloheptyl wherein this phenyl, heterocyclyl or bicycloheptyl is substituted possibly at least with one substitute chosen from halogen atom, -OH, =O, or (4) (C1-C6)-alkylsulfonyl, or R11 and R12 in common with N atoms to which they are bound form 5-membered unsaturated heterocyclyl comprising one N atom or 5-6-membered heterocyclyl comprising from 1 to 2 heteroatoms, such as S, O and N, or 5-6-membered saturated heterocyclyl, ortho-condensed with benzene ring and comprising one N atom and wherein indicated heterocyclic systems are substituted possibly with one or two substitutes chosen from halogen atom, (C1-C6)-alkyl, (C1-C6)-hyroxyalkyl, (C1-C6)-halogenalkyl, (C1-C6)-alkylamino, di-(C1-C6)-alkylamino group, phenyl, halogenphenyl and hydroxydiphenylmethyl; R12a represents H or (C1-C6)-alkyl; each radical among R14 and R15 represents independently H or (C1-C6)-alkylsulfonyl, or R14 and R15 in common with N atom to which they are bound form 5-membered saturated heterocyclyl comprising one N atom and substituted possibly with one -OH, or its pharmaceutically acceptable salt or solvate. Also, invention relates to a method (variants) for synthesis of compound of the formula (I) according to one of the following method: by one variant, compound of the formula (II): is subjected for interaction with compound of the formula (III): by other variant, compound of the formula (IV): is subjected for interaction with compound of the formula (V): by other variant, compound of the formula (VI): wherein R3 represents -NHC(O)R10 and L1 represents a leaving group is subjected for interaction with L1C(O)R10; by other variant, compound of the formula (VIII): wherein R3 represents -C(O)NR11R12 and L2 represents a leaving group is subjected for interaction with compound of the formula (IX) given in the invention description. Also, invention relates to an intermediate compound of the formula (IIA): (wherein R1a is chosen from F, Cl, -CH3 and -CF3; s = 1 or 2; q = 0 or 1; w = 0 or 1; R2a represents F, and when q and s = 1 and w = 0 then R1a can't represent chlorine atom), and to a method for synthesis of compound of the formula (IIA) (wherein s = 1) and wherein compound of the formula (XX): is subjected for interaction with compound of the formula (XXII): (wherein R20 represent a protective group) before formation of compound of the formula (XXIV): followed by carrying out the cyclization reaction and removing the protective group R20.

EFFECT: improved methods of synthesis.

25 cl, 236 ex

FIELD: chemistry, pharmaceuticals.

SUBSTANCE: invention pertains to new compounds with formula I, their pharmaceutical salts and to complex esters. The invented compounds have inhibiting propertied towards catepsin K and can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved, for example, inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis and tumorous diseases. In general formula I R represents H, R13 represents (inferior)alkyl, C3-C10cylcloalkyl or C3-C10cycloalkyl(inferior)alkyl, each of which is independently optionally substituted with a halogen atom, hydroxyl, CN, NO2 or optionally mono- or di(inferior)alkyl substituted amino group; and R14 represents H or optionally substituted phenyl, phenyl-W-, phenyl(inferior)alkyl-W-, C3-C10cycloalkyl, C3-C10cycloalkyl-W-, N-heterocyclyl, N-heterocyclyl -W-. Substitutes of the indicated values of radicals are shown in the formula of invention. The invention also relates to methods of obtaining the compounds.

EFFECT: obtaining pyrrolopyrimidines with inhibiting properties towards catepsin K, which can be used for making medicinal preparations for curing diseases and conditions, in which catepsin K is involved.

4 cl, 59 tbl, 10 ex

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