Adamantane derivatives, method of production thereof, pharmaceutical composition and method for producing pharmaceutical compositions

 

Describes the adamantane derivatives of General formula (I)where x is 1 or 2, a represents the group CH2In represents a hydrogen atom or halogen, R is phenyl, pyridyloxy or indolenine group, each of which may be substituted with halogen atom, amino group, nitro, C1-C6-alkyl, 3-8-membered heterocyclic, C1-C6- alkylsulfanyl group1-C6- alkoxy, C1-C6- alkylamino, benzyl, C1-C6- alkylthiophene, phenylthiourea and others, as well as the method of obtaining the compounds of formula (I). Represented a pharmaceutical composition having an antagonistic activity against receptor RH7and how you can get it. The technical result consists in the development of compounds useful as antagonists of the receptor RH7for use in the treatment of inflammatory, immune and cardiovascular disease. 4 C. and 5 C.p. f-crystals.

Description text in facsimile form (see graphic part).

Claims

1. Adamantane derivatives of General formula (I)where x is 1 Il the th phenyl, pyridyloxy or indolenine group, each of which may be optionally substituted by one or more substituents independently selected from (i) halogen atom or amino, hydroxyl, nitro, C1-C6-alkyl, halogen-C1-C6-alkyl, -NR5R6, 3-8-membered heterocyclyl, C1-C6-alkylsulfonyl or C1-C6-alkylsulfonyl group, or (ii) C1-C6-alkoxy, C1-C6-alkylamino, benzyl, C1-C6-alkylthio or phenylthiourea, optionally substituted by one or more substituents, independently selected from a halogen atom or amino, cyano, carboxyl, hydroxyl, 1-pyrrolidinyl, 1-piperidinyl, C1-C6-alkyl, C1-C6-alkoxy, (di)1-C6-alkylamino, C1-C6-alkoxycarbonyl or one of the following groups: -O-(CH2)y-CO2N, y is 1-6,

y is 2-6,

R5represents a hydrogen atom or a C1-C6-alkyl or C3-C6-cycloalkyl group;
R6represents a C3-C8-cycloalkyl group and, in addition, C1-C6-alcoda or C1-C6-alkyl or C3-C8-cycloalkyl group;
R8represents a C1-C6-alkyl or C3-C8-cycloalkyl group,
R9represents a hydrogen atom or a hydroxyl group;10represents a hydrogen atom or a phenyl or imidazolidinyl group,
provided that R is not unsubstituted pyridyloxy group when a represents a group CH2and represents a hydrogen atom,
or their pharmaceutically acceptable salt or solvate.

2. Connection on p. 1, where R is a phenyl, pyridyloxy or indolenine group, each of which may be optionally substituted by one or two substituents, independently selected from (i) an atom of fluorine, chlorine, bromine or iodine, or amino, hydroxyl, nitro, aziridinyl, pyrrolidinyl,1-C4-alkyl, trifloromethyl, -NR5R6With1-C4-alkylsulfonyl or C1-C4-alkylsulfonyl group, or (ii)1-C4-alkoxy, C1-C4-alkylamino, benzyl,1-C4-alkylthio or phenylthiourea, optionally substituted by one or two substituents, independently selected from the à ylamino, With1-C4-alkoxycarbonyl or one of the following groups:
-O-(CH2)y-CO2N, y is 1-3,
the equals 2-3,

3. Connection under item 1 or 2, where R5represents a hydrogen atom or a C1-C4is an alkyl group.

4. The compound according to any one of paragraphs.1-3, where R6represents a C1-C4is an alkyl group, when R5is not a hydrogen atom.

5. The compound of formula (I) under item 1 or its pharmaceutically acceptable salt or MES representing
2,4-dichloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
3,5-dichloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2,6-dichloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-methoxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-bromo-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-iodine-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2,6-dimethoxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-(trifluoromethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-elmete.1.13,7]Oct-1-ylmethyl)-benzamide,
2-amino-6-fluoro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-4-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-(2-cianfanelli)-N-(tricyclo[3.3.1.l3,7]Oct-1-ylmethyl)benzamide,
2-(4-methylphenylthio)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
2-(methylthio)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-(methylthio)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)-3-pyridinecarboxamide,
3-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2,3-dichloro-N-(tricyclo[3.3.1.l3,7]Oct-1-ylmethyl)benzamide,
2,5-dimethyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-(phenylmethyl)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
Hydrochloride of 2-(2-(N, N-dimethylamino)ethyloxy)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)benzamide,
1,1-dimethylethylene ester 2-[[(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino] carbonyl] phenyl-1-exucuse acid,
2-[[(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)amino] carbonyl] phenyl-1-oxucusu acid,
2-(methylsulfonyl)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)-5-indolocarbazole,
2-amino-6-chloro-N-(2-[tricyclo[3.3.1.13,7]Oct-1-yl]ethyl)benzamide,
2-(2-metralla[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
The dihydrochloride of 2-(2-(N,N-dimethylamino)ethylamino)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
The dihydrochloride of 2-(2-(pyrrolidin-1-yl)ethylamino)-N-(tricyclo-[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
The dihydrochloride of 2-(methylamino)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
Hydrochloride of 2-(dimethylamino)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl-3-pyridinecarboxamide,
The dihydrochloride of 2-(pyrrolidin-1-yl)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
2-(2,5-dimethoxyphenylthio)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
2-chloro-5-methylthio-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-(2-(N, N-dimethylamino)ethylthio)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)benzamide,
2-(4-methoxybenzylthio)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
2-chloro-3-fluoro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-bromo-5-fluoro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-5-fluoro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-(2,5-dihydroxyphenyl)-N-(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
3-[[(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)amino] carbonyl]pyridyl-2 is cyclo[3.3.1.13,7] Oct-1-ylmethyl)amino] carbonyl]pyridyl-2-(4-phenylthio)oxucusu acid,
The dihydrochloride of 2-(4-(3-N,N-dimethylamino)proproxyphene)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)-3-pyridinecarboxamide,
(2-methylthio-6-methyl)-N-tricyclo[3.3.1.13,7] Oct-1-ylmethyl)-3-pyridinecarboxamide,
2-[[(tricyclo[3.3.1.13,7] Oct-1-ylmethyl)amino] carbonyl] phenyl-1-hydroxybutyric acid,
2-chloro-5-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)-benzamide,
2-chloro-3-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-5-nitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
3-amino-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
5-amino-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-3-(N, N-dimethylamino)ethylamino-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-5-(N, N-dimethylamino)ethylamino-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
Fumarate 2-chloro-5-(N, N-dimethylamino)ethylthio-N-(tricyclo-[3.3.1.13,7] Oct-1-ylmethyl)benzamide,
2-chloro-3-hydroxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)-benzamide,
2-chloro-5-(N,N-dimethylamino)ethyloxy-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2,5-dichloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-5-methylamino-N-(tricyclo[3.3.,
5-aziridine-1-yl-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)-benzamide,
2-methyl-3,5-dinitro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl) benzamide,
3,5-diamino-2-methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl) benzamide,
3,5-dimethoxy-2-methyl-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl) benzamide,
3,5-dimethoxy-N-(tricyclo[3.3.1.l3,7]Oct-1-ylmethyl)benzamide,
5-(N-(2-hydroxy-2-phenylethyl)-2-amino-ethyl)amino-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
Hydrochloride of 2-chloro-5-(2-(piperidine-1-yl)ethylamino)-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
The dihydrochloride of 5-(N-(2-hydroxyethyl)-2-amino-ethyl)amino-2-chloro-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-N-(2-[tricyclo[3.3.1.13,7]Oct-1-yl]ethyl)benzamide,
2,3-dichloro-N-(2-[tricyclo[3.3.1.13,7]Oct-1-yl]ethyl)benzamide,
5-amino-2-chloro-N-(2-[tricyclo[3.3.1.13,7]Oct-1-yl)benzamid,
2,5-dimethyl-N-(2-[tricyclo[3.3.1.13,7]Oct-1-yl]ethyl)benzamide,
2-chloro-N-(3-chlorotrityl[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2-chloro-3-(N-(2-[imidazol-2-yl]ethyl)-2-amino-ethyl)amino-N-(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)benzamide,
2,5-dimethyl-N-(3-chlorotrityl[3.3,1.l3,7]Oct-1-ylmethyl)benzamide,
3,5-dimethoxy-2-methyl-N-(3-chlorotrityl[3.3.1.13,7]Oct-1-ylmethyl)benzamide or
2-chloro-5-acceptable salt or MES according to any one of paragraphs.1-5 for use as an antagonist of the receptor P2X7.

7. The method of obtaining the compounds of formula (I) under item 1, characterized in that it includes the interaction of the compounds of General formula

where the values of x, a and b are such as defined for formula (I), with the compound of General formula

where the values of R such as defined for formula (I), and L represents a removable group, such as halogen, imidazolyl or ureido group, and, optionally, the formation of its pharmaceutically acceptable salt or MES.

8. Pharmaceutical composition having antagonistic activity against receptor RH7containing the compound of formula (I) or its pharmaceutically acceptable salt or MES referred to in any of paragraphs.1-6, together with a pharmaceutically acceptable adjuvant, diluent or carrier.

9. A method of obtaining a pharmaceutical composition specified in paragraph 8, which involves mixing the compounds of formula (I) or its pharmaceutically acceptable salt or MES referred to in any of paragraphs.1-6, with a pharmaceutically acceptable adjuvant, diluent or carrier.

 

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