Type iv phosphodiesterase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

 

The text descriptions are given in facsimile form.

1. The compound of structural Formula I

and its pharmaceutically acceptable salts, where
X represents oxygen;
Y represents oxygen;
Y1, Y2, R7and R4represent H;
X1and X2selected independently from the group consisting of hydrogen, alkyl groups containing from 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group may be substituted with halogen, aryl group containing from 6 to 10 carbon atoms, or cycloalkyl group containing from 3 to 9 carbon atoms, or 5 to 9 membered heterocyclic group with 2 heteroatoms selected from N and O, or cycloalkyl group containing from 5 to 9 carbon atoms;
R1represents an alkyl group of 1-2 carbon atoms or-CH2-CO-Rp,
where Rpis optionally substituted 5-7-membered heterocyclic ring containing 1 to 2 nitrogen atoms, where the substituents are selected from the group consisting of C1-C6of alkyl, hydroxyl, -CO-C1-C5of alkyl, -COO-C1-C5of alkyl, C1-C5alkyl-phenyl, phenyl, where C1-C5alkyl group or phenyl can be substituted by a hydroxyl group or a halogen,
R2replaced by-CO-Rp,
where Rpis optionally substituted 5-7-membered heterocyclic ring containing 1 to 2 nitrogen atoms, where the substituents are selected from the group consisting of C1-C5of alkyl, -CO-C1-C5alkyl is, -COOH, 6-membered heterocyclyl containing 1 nitrogen atom, oxo, -COO-C1-C5of alkyl, -CONH2, -CONH-C1-C5of alkyl, -CON(C1-C5the alkyl)2, (3 cyclopentyloxy-4-methoxyphenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanone, hydroxyl, C1-C5alkyl-phenyl, phenyl, where C1-C5alkyl or phenyl group may be further substituted by hydroxyl, methoxy group, With3-C7cycloalkyl or halogen group, provided when Deputy is (3-cyclopentyloxy-4-methoxyphenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl)-metrolina group, Rprepresents 1,4-diazepinone ring and the substitution occurs on the nitrogen atom;
alternative R1and R2can optionally form together a substituted cycloalkyl ring containing from 4 to 9 carbon atoms, where the substituents are selected from the group consisting of oxo, NH2, -NH-COO-C1-C5of alkyl, -NH-(COO-C1-C5the alkyl)2and phthalimido groups or optionally substituted 5-6 membered heterocyclyl rings containing 1 to 2 oxygen atoms and nitrogen, where the substituents are selected from the group consisting of C1-C5of alkyl, oxo, NH2(S)-C1-C5of alkyl, -CONH-SO2-phenyl, -CO-NH-phenyl, where phenyl may be substituted by a halogen group, n is and the condition, what heterocyclyl ring is not dihydrofuran ring.

2. The compound according to claim 1, where X1is selected from the group consisting of methyl, ethyl, butyl, propyl, isopropyl, isobutyl, diformate, cyclopropylmethyl and benzyl groups, and X2is selected independently from the group consisting of methyl, ethyl, butyl, propyl, isopropyl, isobutyl, morpholinylmethyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl and benzyl groups.

3. The compound according to claim 1, where Rpis selected from the group consisting of piperazinil, piperidinyl, pyrrolidinyl and Diaz-bicycloheptene rings.

4. The compound according to claim 1, where the substituents 5-6 membered heterocyclyl rings containing 1 to 2 nitrogen atoms formed by R1and R2represent-NH2differentillumination, dichlorophenolindophenol, tert-butoxycarbonyl or chlorophenylsulfonyl.

5. The compound according to claim 1, which is selected from the following groups of compounds:
[3-(3-cyclopentyloxy-4-methoxyphenyl)-5-(tert-butilovyi piperazine-1-yl-carbonyl-4-carboxylic acid)-4,5-dihydroisoxazole-5-yl)-(tert-butyl ether piperazine-1-yl-4-carboxylic acid)alanon (Compound 1),
1-{1-[5-(4-acetyl-4-phenyl-piperidine-1-carbonyl)-3-(3-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-4-acetyl-4-phenyl-piperidine-4-yl]-Etalon (Connect the tion 2),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-(pyrrolidin-1-carbonyl)-4,5-dihydro-isoxazol-5-yl]-pyrrolidin-1-yl-Etalon (Compound 3),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-(piperidine-1-carbonyl)-4,5-dihydro-isoxazol-5-yl]-piperidine-1-yl-Etalon (Compound 4),
3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-(methyl ether 1-carbonyl-pyrrolidin-2-carboxylic acid)-4,5-dihydro-isoxazol-5-yl)-[methyl ether pyrrolidin-5-yl-2-carboxylic acid]alanon (Compound 5),
[5-[4-(4-chlorophenyl)-4-hydroxy-piperidine-1-carbonyl]-3-(3-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-[4-(4-chlorophenyl)-4-hydroxy-piperidine-1-yl]-Etalon (Compound 6),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-(hydroxymethyl-piperidine-1-carbonyl)-4,5-dihydro-isoxazol-5-yl]-(4-hydroxymethyl-piperidine-1-yl)-Etalon (Compound 7),
[5-(5-benzyl-2,5-diazabicyclo[2.2.1]heptane)-2-(carbonyl)-3-(3-cyclopentyloxy-4-methoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-5-benzyl-2,5-diazabicyclo-[2.2.1]hept-2-yl-Etalon (Compound 8),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-piperidine-1-yl-methanon (Compound 9),
tert-butyl ester 4-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-piperazine-1-carboxylic acid (Compound 10),
1-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-carbonyl]-pyrrolidin-2-carboxylic acid (Compound 1),
methyl ether of 1-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-pyrrolidin-2-carboxylic acid (Compound 12),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-pyrrolidin-1-yl-methanon (Compound 13),
[1,4]-bipiperidine-1-yl-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanon (Compound 14),
1-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-4-phenyl-piperidine-4-yl}-Etalon (Compound 15),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-methyl-piperazine-1-yl)-methanon (Compound 16),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-piperazine-1-yl-methanon (Compound 17),
[4-(4-chloro-phenyl)-4-hydroxy-piperidine-1-yl]-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydroisoxazole-5-yl]-methanon (Compound 18),
{4-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-[1,4]diazepan-1-yl}-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanon (Compound 19),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-cyclopropylmethyl-piperazine-1-yl)-methanon (Compound 20),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-isobutyl-1-piperazine-1-yl)-methanon (Compound 21),
[3-hydroxymethyl-piperidine-1-the l]-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanon (Compound 22),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(4-hydroxy-piperidine-1-yl)-methanon (Compound 23),
(4-benzyl-piperidine-1-yl)-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanon (Compound 24),
1-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-piperidine-4-one (Compound 25),
[4-(4-bromophenyl)-4-hydroxy-piperidine-1-yl]-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanon (Compound 26),
(5-benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-methanon (Compound 27),
(4-benzyl-piperazine-1-yl)-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl)-methanon (Compound 28),
methylamide 1-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-pyrrolidin-2-carboxylic acid (Compound 29),
diethylamid 1-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-pyrrolidin-2-carboxylic acid (Compound 30),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl]-(2-hydroxymethyl-pyrrolidin-1-yl)-methanon (Compound 31),
methyl ether of 1-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydroisoxazole-5-carbonyl]-piperidine-2-carboxylic acid (Compound 32),
amide [3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-IU the Il-4,5-dihydro-isoxazol-5-carboxyl]-pyrrolidin-2-carboxylic acid (Compound 33),
3-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-carbonyl]-bicyclo[2.2.1]heptane-2-on (Compound 34),
3-(3-cyclopentyloxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-EN-6-he (Compound 35),
3-(3-cyclopentyloxy-4-methoxy-phenyl)-7-methyl-1-oxa-2,7-diaza-Spiro[4.4]non-2-ene-6,9-dione (Compound 36),
[3-(3-cyclopentyloxy-4-methoxy-phenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl-(2-methoxymethyl-pyrrolidin-1-yl)-methanon (Compound 37),
3-(3-cyclopentyloxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 38),
3-(3-cyclopropylmethoxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 39),
3-(4-deformedarse-3-propoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 40),
3-(4-deformedarse-3-butoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 41),
3-(4-deformedarse-3-isobutoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 42),
3-(3-cyclopropylmethoxy-4-deformedarse-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 43),
3-(3-benzyloxy-4-deformedarse-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 44),
3-(4-deformedarse-3-cyclopentyloxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 45),
3-(3,4-bis-deformedarse-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 46),
3-[3-(bicyclo[2.2.1]hept-2-yloxy)-4-deformedarse-phenyl]-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 48),
3-(4-deformedarse-3-methoxy-f the Nile)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 49),
3-(4-benzyloxy-3-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 50),
3-(3-cyclohexyloxy-4-deformedarse-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 51),
4-(1,7-dioxa-2-Aza-Spiro[4.4]non-2-EN-3-yl)-2-methoxy-phenol (Compound 52), 3-[3-(indan-2-yloxy)-4-methoxy-phenyl]-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 53),
3-(4-ethoxy-3-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 54), 3-(3-methoxy-4-propoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 55),
3-(4-isopropoxy-3-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 56), 3-(4-butoxy-3-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 57),
3-(4-cyclopentyloxy-3-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 58),
3-(4-isobutoxy-3-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 59), 3-(4-cyclohexyloxy-3-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 60),
3-(4-cyclopropylmethoxy-3-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 61),
3-(3,4-dimethoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4,4]non-2-ene (Compound 62), 3-(3-ethoxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 63),
3-(4-methoxy-3-propoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 64), 3-(3-isopropoxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 65),
3-(3-butoxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 66), 3-(3-isobut the C-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 67),
3-[4-methoxy-3-(3-methyl-butoxy)-phenyl-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 68),
3-(3-cyclohexyloxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 69),
3-(3-cyclohexyloxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 70),
3-[4-methoxy-3-(2-morpholine-4-yl-ethoxy)-phenyl]-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 71),
3-(3-benzyloxy-4-methoxy-phenyl)-1,7-dioxa-2-Aza-Spiro[4.4]non-2-ene (Compound 72),
5-(1,7-dioxa-2-Aza-Spiro[4.4]non-2-EN-3-yl)-2-methoxy-phenol (Compound 73), tert-butyl ester 3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2,8-diaza-Spiro[4.5]Dec-2-ene-8-carboxylic acid (Compound 74),
hydrochloride 3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2,8-diaza-Spiro[4.5]Dec-2-ene (Compound 75),
4-chloro-N-[3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2,8-diaza-Spiro[4.5]Dec-2-ene-8-carbonyl]-benzosulfimide (Compound 76),
(2,6-debtor-phenyl)-amide 3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2,8-diaza-Spiro[4.5]Dec-2-ene-8-carboxylic acid (Compound 77),
(2,4-dichloro-phenyl)-amide 3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2,8-diaza-Spiro[4.5]Dec-2-ene-8-carboxylic acid (Compound 78),
isopropyl ester [3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2-Aza-Spiro[4.5]Dec-2-EN-8-yl]-carbamino acid (Compound 79),
hydrochloride salt of 3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2-Aza-Spiro[4.5]Dec-2-EN-8-ylamine (Compound 80),
2-[3-(3-qi is opentrace-4-methoxy-phenyl)-1-oxa-2-Aza-Spiro[4.5]Dec-2-EN-8-yl]-isoindole-1,3-dione (Compound 81),
7-(3-cyclopentyloxy-4-methoxy-phenyl)-5-oxa-6-Aza-Spiro[3.4]Oct-6-ene (Compound 82),
3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2-Aza-Spiro[4.5]Dec-2-ene (Compound 83),
tert-butyl ether 3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2,7-diaza-Spiro[4.4]non-2-ene-7-carboxylic acid (Compound 84),
hydrochloride salt of 3-(3-cyclopentyloxy-4-methoxy-phenyl)-1-oxa-2,7-diaza-Spiro[4.4]non-2-ene (Compound 85)
applicable pharmaceutically acceptable salt.

6. Pharmaceutical composition having the property of selective inhibitors of phosphodiesterase type IV, containing a therapeutically effective amount of a compound according to claim 1 or 5, together with a pharmaceutically acceptable carrier, excipient or diluent.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: in formula (I) V represents -N (R1) (R2) or OR4; R4 represents H, C1-6alkyl, C1-6halogenalkyl or (C1-6alkylen)0-1R4' R4' represents C3-7cycloalkyl, phenyl, pyridyl, piperidinyl; and R4' is optionally substituted with 1 or 2 identical or different substitutes chosen from group consisting of C1-4alkyl, amino, C1-3alkylamino, C1-3dialkylamino, phenyl and benzyl; and each R1 and R2 independently represents L1, where L1 is chosen from group consisting from H, C1-6alkyl, C2-6alkenyl, C2-6alkinyl, - adamantyl, pyrrolidinyl, pyridyl, or R1 and R2 together with nitrogen atom to which attached, form X, where X represents pyrrolidinyl, piperazinyl, piperidinyl, morpholino; where X is optionally substituted with Y, where Y represents dioxolanyl, C1-9alkyl, phenyl, furanyl, pyrrolyl, pyridyl, pyrrolidinyl; and where X and Y are optionally split with Z, where Z represents -C1-3alkylen-, C1-3alkylen-. Other radical values are specified in formula of invention.

EFFECT: effective application for treatment of migraine and other headache mediated by action of CGRP-receptors.

34 cl, 11 dwg, 6 tbl, 201 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

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes novel spiroazacyclic compounds of the general formula: wherein X means -CH2, -CH2O, -OCH2 or oxygen atom (O); Y represents O; Z means -CH or nitrogen atom (N); R1 means (C1-C6)-alkyl optionally substituted with morpholinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, 2-oxoimidazolidinyl, imidazolidinyl, 2-oxooxazolidinyl, oxazalidinyl or (C3-C6)-cycloalkyl, (C2-C8)-alkyl ester or benzyl ester; m is chosen from group comprising 0 or 1; R4 means hydrogen atom or benzyl optionally substituted with halogen atom or (C1-C4)-alkyl; R5 means hydrogen atom or benzyl optionally substituted with halogen atom, (C1-C4)-alkyl or (C1-C4)-alkoxy-group; R6 means hydrogen atom or benzyl optionally substituted with (C1-C4)-alkoxy-, cycloalkyl-(C1-C4-alkoxy)- or halogen-(C1-C4-alkoxy)-group; R2 and R3 mean hydrogen atom and at least two radicals among R4, R5 and R6 mean optionally substituted benzyl. Also, invention relates to a method for inhibition of activity of serotonin 5-HT2A receptors, a method for treatment of state mediated by serotonin 5-HT2A receptors, and using spiroazacyclic compounds proposed.

EFFECT: improved method of treatment, valuable medicinal properties of compounds.

35 cl, 3 tbl, 2 dwg, 45 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to substituted derivatives of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I in form of racemates, pure stereoisomers, particularly enantiomers or diastereomers in any ratio in mixture, in form of acids, or bases, or salts thereof, preferably physiologically acceptable salts, more preferably in form of hydrochlorides or solvates, in particular hydrates, wherein R1 and R2 are independently H, C3-C10-cycloalkyl, optionally substituted with O-alkylaryl, (C1-C12-alkyl)aryl, with the proviso, that at least one R1 and R2 is not H; R3 is H, SOR12 or COR13; R12 and R13 are independently C1-C10-alkyl, monocyclic 5-membered heterocyclic group having at least one heteroatom selected from sulfur atoms, optionally substituted with halogen; OR20, wherein R20 represents H, C1-C10-alkyl. Invention also relates to method for production of 1-oxa-2,8-diazaspiro[4,5]dec-2-ene of general formula I including a) compound of formula II interaction with methylenation agent, preferably with Ph3PCH3Br in presence of potassium tert-butylate in tetrahydrofuran (THF) to produce compound of formula III; d) compound of formula III interaction with ethylchloroximidoacetate of formula IV in presence of base, preferably of sodium hydrocarbonate or lithium hydroxide, preferably in organic solvent such as methanol, dichloromethane or TGF to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula V; c) compound of formula V interaction, directly or after previous saponification of functional group presenting in formula V (namely carboxylic acid ethyl ester) and optionally after activation of formed functional group (namely carboxylic acid) with amine of formula HNR1R2 wherein R1 and R2 are as defined above, to produce 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula VI; d) protective group removing from compound of formula VI to produce compound of formula I, wherein R3 is H; and optionally e) converting of compound of formula I, wherein R3 is H, by treatment with acid chloride of formula R12SO2Cl to compound of formula I, wherein R3 is SO2R12 or converting by treatment with carboxylic acid chloride of formula R13COCl to compound of formula I, wherein R3 is COR13. Moreover disclosed is drug having analgesic action and containing at least one substituted 1-oxa-2,8-diazaspiro[4,5]dec-2-ene derivative of general formula I.

EFFECT: new drug with analgesic action.

11 cl, 6 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

EFFECT: improved preparing method, valuable biochemical and medicinal properties.

10 cl, 6 tbl, 337 ex

The invention relates to new derivatives of oxazolidinones General formula (I) listed in the description, as well as their salt

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

FIELD: medicine.

SUBSTANCE: there are described new diazabicyclic aryl derivatives of general formula (I), where A', A", L and B, n possess the values as specified in the description which are cholinergic ligands to nicotinic acetylcholine receptors, as well as a based pharmaceutical composition. Owing to their pharmacological profile, the compound according to the invention, can be effective in treating such various diseases or disorders, as those associated with the cholinergic system of central nervous system (CNS), peripheral nervous system (PNS), as those associated with plain muscle contraction, endocrine diseases or disorders, neurodegenerative diseases or disorders, diseases or disorders involving inflammation, pain and abstinence symptoms caused by termination of abusing the chemical substances.

EFFECT: effective with regard to various diseases.

16 cl, 3 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,4-diazabicyclo[3,2,1]octanecarboxamide with general formula (1) , in which X is a nitrogen atom, P and W each independently represent a nitrogen atom or a group with general formula C-R3, Q and R each independently represent a group with general formula C-R3, R1 is a hydrogen atom, R3 is a hydrogen atom or halogen or C1-C6-alkyl, C1-C6-alkoxy, O-Ms. The invention also relates to a medicinal preparation and pharmaceutical composition based on these compounds for treating or preventing disorders, related to malfunction of nicotinic receptors.

EFFECT: obtaining new compounds and a pharmaceutical composition based on the said compounds, which can be used for treating cognition failure and attention failure, or for treating motor, neurological or alerting symptoms related to dependency on different addictive substances.

5 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to quinobenzoxazin analogues with general formula (1) where V represents H, halo-, or NR1R2; NH2, or NR1-(CR12)n-NR3R4; A represents H, fluoro-, or NR12; Z represents O, S, NR1 or CH2; U represents NR1R2; X represents NR1R2 or halo-; n=1-6; where in NR1R2, R1 and R2 can form 5-7-member heterocyclic ring which is optionally substituted and has 1-2 heteroatoms, selected from group consisting of N, O and S; R1 represents H or C1-6alkyl; R2 represents C1-10alkyl optionally including one or more non-adjacent heteroatoms N or O and is optionally substituted with if necessary substituted 3-6-member carbocyclic or 5-14-member heterocyclic ring; or R2 is 5-14-member heterocyclic ring, which has 1-2 heteroatoms, selected from group consisting of N, O or S, 6-member aryl or 5-7member heteroaryl ring, which contains 1-3 heteroatoms, selected from group consisting of N, O and S, each of which can be, if necessary, substituted; R3 represents H or C1-6alkyl; R4 represents H, C1-6alkyl, optionally substituted with 3-6 carbocyclic or 5-14-member heterocyclic ring, or 6-member aryl, R4 and R3, if necessary, can form optionally 5-7-member substituted heterocyclic ring, which contains 1-2 heteroatoms selected from N and O; W represents substituent, such as described in i.1 of invention formula, where Q, Q1, Q2, and Q3 represents independently CH or N; Y represents independently O or CH; R5 represents substituent in any position of closed ring in form of H or OR2; on condition that U is not morpholinyl or 2,4-difluoroaniline, when X represents F or pyrrolidinyl, A is F, Z represents O, and W represents phenylene; each obligatorily substituted fragment being substituted with one or more halogen, C1-6-alkoxy, amino, carbamate, C1-10alkyl, C2-10alkenyl, each of which is optionally substituted with halogen, =O, 6-member aryl or one or more heteroatom, selected from N and O; 6-member aryl, 3-6-member carbocyclic ring or 5-7-member heterocyclic ring containing 1-2 heteroatoms, selected from group, consisting of N and O; or its pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition based on formula (1) compound and to method of treatment of proliferative cell diseases using formula (1) compounds.

EFFECT: obtaining novel quinobenzoxazin analogues possessing useful biological properties.

48 cl, 3 tbl, 50 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

Chemical method // 2386636

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of a compound of formula I , in which X1 is selected from O; and X2 is N; involving successive reaction of a formula II compound with (i) methyl- or optionally substituted aryl-lithium; then (ii) n-butyl-, sec-butyl-, tert-butyl- or n-hexyl-lithium; and then (iii) borate ester. The invention also relates to a method of obtaining formula IV compounds: , which involves combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a formula III compound, in which P is a nitrogen protecting group, and to a formula IV compound, where P is C1-6alkoxycarbonyl.

EFFECT: design of an efficient method of obtaining the said compound.

9 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 3,3'-bis-(3,4-dihydro-3-phenyl-2H-1,3-benzoxazin-6-yl)-1(3H)-isobenzofuranone and analogues based on phenolphthalein, formaldehyde and a primary amine of formula 1: , in which R independently represents allyl or phenyl, and to a method of synthesising the said compounds. The invention also pertains to a method of making a refractory cast or layered material based on the said compounds and laminating compositions since through thermal hardening, these compounds form a net which does not catch fire easily and is resistant to high temperatures. The said compounds can be particularly useful in making printed circuit boards.

EFFECT: obtaining fire-resistant compounds.

5 cl, 4 tbl, 1 ex

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