Heterocyclic substituted phenylmethanones as glycine transporter 1 inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

 

The text descriptions are given in facsimile form.

1. Compounds of General formula I

where
R1represents-OR1', -SR1"A 6-membered heteroseksualci containing one atom CI is the oxygen and possibly one nitrogen atom, phenyl or 5-membered heteroaryl containing two nitrogen atom, or a 6-membered heteroaryl containing one nitrogen atom;
R1'/R1”represent1-6-alkyl, C1-6-alkyl substituted by halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)xis phenyl;
R2represents-S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl or CN;
represents an aromatic or partially aromatic bicyclic amine, which may contain one or two additional N-atom selected from the group consisting of
,,,
,,,
,,
and where one additional N-atom kernel aromatic or partially aromatic bicyclic amine can be present in the form of its oxide
R3-R10represent hydrogen, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-membered heteroseksualci containing one heteroatom selected from nitrogen or oxygen, 6-membered heteroseksualci containing two oxygen atom or two nitrogen atom, 6-8-membered heteroseksualci containing one atom is zhota and one atom of oxygen or sulfur, 5-membered heteroaryl containing two or three nitrogen atom, 5-membered heteroaryl containing one sulfur atom, in which one carbon atom may be additionally substituted on the nitrogen atom or oxygen, 6-membered heteroaryl containing one or two nitrogen atom, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-membered cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted by halogen, C1-6-alkoxy substituted by halogen, C1-6-alkyl, substituted hydroxy, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2-C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)xTo 6-membered heteroseksualci containing one oxygen atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-Aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-Aza-bicyclo[3.2.1]Oct-8-yl;
R' and R'" in the group (d) together with -(CH2)2-with which they are linked, may form a six-membered ring; or
R, R', R" and R'" independently of one another represent hydrogen or C1-6-alkyl;
and where all groups are phenyl-, cycloalkyl-, cyclic amide, heteroseksualci - or 5 - or 6-membered heteroaryl as defined for R1, R1', R1”and R3-R10may be unsubstituted or replace the n in one or more than one Deputy, selected from the group consisting of hydroxy, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted by halogen, or C1-6-alkoxy;
n, m, o, p, q, r, s and t have the values 1 or 2;
x has the value 0, 1 or 2;
y has a value of 1 or 2;
and their pharmaceutically acceptable salts accession acid.

2. The compounds of formula I according to claim 1 and

where
R1represents-OR1', -SR1”A 6-membered heterocycle containing one oxygen atom and one nitrogen atom, or phenyl;
R1'/R1”represent hydrogen, C1-6-alkyl, C1-6-alkyl substituted by halogen, -(CH2)x- C3-6cycloalkyl;
R2represents-S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl;
R3represents hydrogen, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-membered heterocycle with one atom of oxygen or nitrogen, 6-membered heteroseksualci containing two oxygen atom or two nitrogen atom, 6-8-membered heteroseksualci containing one nitrogen atom and one oxygen atom or sulfur, With1-6-alkoxy, CN, NO2, NH2, phenyl, 5-membered heteroaryl containing one sulfur atom, 5-membered heteroaryl containing two heteroatoms, one of which is nitrogen and the other is oxygen, sulfur or nitrogen, a 5-membered heteroaryl containing three nitrogen atom, a 6-members of the hydrated heteroaryl, containing one or two nitrogen atom, -C(O)-5-membered cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted by halogen, C1-6-alkoxy substituted by halogen, -O-(CH2)y-C1-6-alkoxy, -C(O)-C1-6-alkyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)xTo 6-membered heteroseksualci containing one oxygen atom, -C(O)O-C1-6-alkyl, 2-oxa-5-Aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-Aza-bicyclo[3.2.1]Oct-8-yl;
R, R' independently of one another represent hydrogen or C1-6-alkyl;
and where all groups are phenyl, heteroseksualci - or 5 - or 6-membered heteroaryl as defined for R1, R1', R1”and R3may be unsubstituted or substituted by one or more than one Deputy, selected from the group consisting of hydroxy, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted by halogen, or C1-6-alkoxy;
n has values of 1 or 2;
x has the value 0, 1 or 2;
y has a value of 1 or 2;
and their pharmaceutically acceptable salts accession acid.

3. The compounds of formula I b according to claim 1

where
R1represents-OR1'A 6-membered heteroseksualci with one atom of oxygen and possibly one nitrogen atom, 5-membered heteroaryl containing two nitrogen atom, a 6-membered gets roarer, containing one nitrogen atom, or phenyl;
R1'represents a C1-6-alkyl, C1-6-alkyl substituted by halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)xis phenyl;
R2represents-S(O)2-C1-6-alkyl or CN;
and where additional N-atom core bicyclic amine can be present in the form of its oxide
R4represents hydrogen, halogen, C1-6-alkyl, 6-membered heteroseksualci containing one oxygen atom, phenyl, 6-membered heteroaryl containing one nitrogen atom, C1-6-alkyl substituted by halogen;
R, R' independently of one another represent hydrogen or C1-6-alkyl;
and where all the groups phenyl or 5-membered heteroaryl as defined for R1, R1', R1”and R4may be unsubstituted or substituted by one or more than one Deputy, selected from the group consisting of hydroxy, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted by halogen, or C1-6-alkoxy;
m has the value 1 or 2;
x has the value 0, 1 or 2;
and their pharmaceutically acceptable salts accession acid.

4. The compounds of formula I according to claim 1 in

where
R1represents-OR1'A 6-membered heteroseksualci containing one atom CI is the oxygen and possibly one nitrogen atom, phenyl, 5-membered heteroaryl containing two nitrogen atom, or a 6-membered heteroaryl containing one nitrogen atom as heteroatom;
R1'represents a C1-6-alkyl, C1-6-alkyl substituted by halogen, -(CH2)x-C3-6cycloalkyl;
R2represents-S(O)2-C1-6-alkyl, or CN;
R5represents hydrogen, halogen, C1-6-alkyl, 6-membered heteroseksualci containing one oxygen atom and one nitrogen atom, phenyl, C1-6-alkyl substituted by halogen;
R, R' independently of one another represent hydrogen;
and where all the phenyl group is as defined for R1and R5may be unsubstituted or substituted by one or more than one halogen;
on the matter of 1 or 2;
x has the values 0, 1;
and their pharmaceutically acceptable salts accession acid.

5. The compounds of formula I, according to claim 1

where R1represents-OR1', phenyl;
R1'represents a C1-6-alkyl, C1-6-alkyl substituted by halogen;
R2represents-S(O)2-C1-6-alkyl;
R6represents a C1-6-alkyl, C1-6-alkyl substituted by halogen;
R, R' independently of one another represent hydrogen;
p has the value 1 or 2;
and their pharmaceutically acceptable Sol the accession acid.

6. The compounds of formula I D. according to claim 1

where
R1represents-OR1'or phenyl;
R1'represents a C1-6-alkyl, C1-6-alkyl substituted by halogen;
R2represents-S(O)2-C1-6-alkyl;
R7represents hydrogen, halogen, C1-6-alkyl, 6-membered heteroseksualci containing one oxygen atom and one nitrogen atom, C1-6-alkoxy, CN, NO2C1-6-alkyl substituted by halogen, C1-6-alkyl, substituted hydroxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -O-(CH2)x- phenyl, -C(O)O-C1-6-alkyl;
R' and R'" in the group (d) together with -(CH2)2-with which they are linked, may form a six-membered ring; or
R, R', R" and R'" independently of one another represent hydrogen or C1-6-alkyl;
q has the value 1 or 2;
x has the value 0, 1 or 2;
y has a value of 1 or 2;
and their pharmaceutically acceptable salts accession acid.

7. The compounds of formula I e according to claim 1

where
R1represents-OR1';
R1'represents a C1-6-alkyl, C1-6-alkyl substituted by halogen;
R2represents-S(O)2-C1-6-alkyl;
R8represents hydrogen, halogen, CN;
and their pharmaceutically acceptable salts etc the connections acid.

8. The compounds of formula I, W 1

where
R1represents-OR1';
R1'represents a C1-6-alkyl, C1-6-alkyl substituted by halogen;
R2represents-S(O)2-C1-6-alkyl;
R9represents halogen, NO2;
s has a value of 1 or 2;
and their pharmaceutically acceptable salts accession acid.

9. The compounds of formula I h 1

where
R1represents-OR1';
R1'represents a C1-6-alkyl, C1-6-alkyl substituted by halogen;
R2represents-S(O)2-C1-6-alkyl;
R10represents hydrogen, C1-6-alkyl;
t has a value of 1 or 2;
and their pharmaceutically acceptable salts accession acid.

10. Compounds of General formula I according to claims 1 and 2, where R1is a OR1'and R1'is the same as described in claims 1 and 2.

11. Compounds of General formula I of claim 10, where connections are
(5,6-dichloro-1,3-dihydro-isoindole-2-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
rat-(5,6-dichloro-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methanon,
(5,6-di the ENT-1,3-dihydro-isoindole-2-yl)-(2-isopropylphenyl-5-methanesulfonyl-phenyl)-methanon,
[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methanon,
(5-chloro-6-methyl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(5-chloro-6-methoxy-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(5-ethylsulfanyl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(2 isobutoxy-5-methanesulfonyl-phenyl)-(5-trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methanon,
4 isopropoxy-N-methyl-3-(5-trifluoromethyl-1,3-dihydro-isoindole-2-carbonyl)-benzosulfimide,
(5-chloro-6-methyl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(5-chloro-6-methyl-1,3-dihydro-isoindole-2-yl)-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanon,
(5-chloro-6-ethylsulfanyl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-(5-methoxy-1,3-dihydro-isoindole-2-yl)-methanon,
[[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-methyl-6-trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methanon,
[[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-methoxy-6-trifluoromethyl-1,3-dihydro-isoindole-2-yl)-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-triptoreline-1,3-dihydro-isoindole-2-yl)-methane is,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(4-methyl-thiazol-2-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(2-methyl-pyridin-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(5-methyl-thiophene-3-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-thiazol-2-yl-1,3-dihydro-isoindole-2-yl)-methanon,
(5-ethylsulfanyl-6-trifluoromethyl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(5-chloro-6-methoxy-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(5-chloro-6-methoxy-1,3-dihydro-isoindole-2-yl)-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanon,
(5-fluoro-6-trifluoromethyl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(5 ethoxy-6-trifluoromethyl-1,3-dihydro-isoindole-2-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
(5-chloro-6-morpholine-4-yl-1,3-dihydro-isoindole-2-yl)-(2-isobutoxy-5-methanesulfonyl-phenyl)-methanon,
(5-chloro-6-morpholine-4-yl-1,3-dihydro-isoindole-2-yl)-(2-cyclobutylmethyl-5-methanesulfonyl-phenyl)-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((5)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(then it is carbonated the Rho-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
(2 isobutoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
(2 cyclopropylmethoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
(2 cyclobutylmethyl-5-methanesulfonyl-phenyl)-[5-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[2-(2,2-dimethyl-propoxy)-5-methanesulfonyl-phenyl]-[5-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-(3,3-debtor-piperidine-1-yl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(2,2,2-Cryptor-ethyl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[(1R,5S)-5-(3-oxa-8-Aza-bicyclo[3.2.1]Oct-8-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-methyl-6-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(tetrahydro-furan-3-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-chloro-6-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(tetrahydro-Piran-3-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-pyridin-4-yl-1,3-dihydro-from ndol-2-yl)-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-pyridin-3-yl-1,3-dihydro-isoindole-2-yl)-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-phenyl-1,3-dihydro-isoindole-2-yl)-methanon,
[5-(2-chlorophenyl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-thiophene-3-yl-1,3-dihydro-isoindole-2-yl)-methanon,
[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(4-methyl-thiophene-2-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(3-methyl-thiophene-2-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-(4-fluoro-phenyl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-(3-fluoro-phenyl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-(2-fluoro-phenyl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-(3,5-debtor-phenyl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(3-methoxy-phenyl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-thiophene-2-yl-1,3-dihydro-isoindole-2-yl)-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(4-methyl-thiophene-3-the l)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-pyrazole-1-yl-1,3-dihydro-isoindole-2-yl)-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(2,2,2-Cryptor-ethoxy)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-chloro-6-(tetrahydro-furan-3-yl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
rat-(2-isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-furan-3-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
rat-[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-[5-(tetrahydro-furan-3-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
rat-(2-isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-Piran-3-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-chloro-6-(3-oxa-8-Aza-bicyclo[3.2.1]Oct-8-yl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-methanon,
rat-[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-[5-(tetrahydro-Piran-3-yl)-1,3-dihydro-isoindole-2-yl]-methanon,
((1S,4S)-5-chloro-6-2-oxa-5-Aza-bicyclo[2.2.1]hept-5-yl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-fluoro-6-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-(3-fluoro-oxetan-3-yl)-1,3-dihydro-isoindole-2-yl]-[5-IU insulter-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-[5-(3,3,3-Cryptor-propoxy)-1,3-dihydro-isoindole-2-yl]-methanon,
(5-fluoro-6-morpholine-4-yl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
(5-fluoro-6-morpholine-4-yl-1,3-dihydro-isoindole-2-yl)-[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-[5-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-[5-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-methanon,
[5-chloro-6-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-chloro-6-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
[5-fluoro-6-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-fluoro-6-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanon,
[5-fluoro-6-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-methanon or
[5-chloro-6-(tetrahydro-Piran-4-yloxy)-1,3-dihydro-isoindole-2-yl]-[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-methanon.

12. Compounds of General formula I according to claims 1 and 2, where R1 represents an unsubstituted or substituted phenyl, for example, the following connections:
5-chloro-6-morpholine-4-yl-1,3-dihydro-isoindole-2-yl)-(4-methanesulfonyl-biphenyl-2-yl)-methanon,
(5-chloro-6-morpholine-4-yl-1,3-dihydro-isoindole-2-yl)-(3'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-methanon,
(5-chloro-6-morpholine-4-yl-1,3-dihydro-isoindole-2-yl)-(4'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-methanon or
(4'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-[5-(tetrahydro-Piran-4-yl)-1,3-dihydro-isoindole-2-yl]-methanon.

13. Compounds of General formula I b according to claim 3, where the compounds are 2-cyclobutylmethyl-5-methanesulfonyl-phenyl)-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl)-methanon,
(2 isobutoxy-5-methanesulfonyl-phenyl)-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl)-methanon,
[5-methanesulfonyl-2-((R)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl)-methanon,
(4'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl)-methanon,
(3',4'-debtor-4-methanesulfonyl-biphenyl-2-yl)-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl)-methanon,
[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl)-methanon,
[5-methanesulfonyl-2-(2,2,3,3-titrator-propoxy)-phenyl]-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl)-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(2-methyl-3-trifluoromethyl-5,7-dihydro-Pierre is lo[3,4-b]pyridine-6-yl)-methanon,
[3-(4-fluoro-phenyl)-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl)-methanon or
[2-(4-fluoro-phenyl)-5,7-dihydro-pyrrolo[3,4-b]pyridine-6-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon.

14. Compounds of General formula I according to claim 4, where connections are
(2 cyclobutylmethyl-5-methanesulfonyl-phenyl)-(6-trifluoromethyl-1,3-dihydro-pyrrolo[3,4-C]pyridine-2-yl)-methanon,
(4'-fluoro-4-methanesulfonyl-biphenyl-2-yl)-(6-trifluoromethyl-1,3-dihydro-pyrrolo[3,4-c]pyridine-2-yl)-methanon,
(3',4'-debtor-4-methanesulfonyl-biphenyl-2-yl)-(6-trifluoromethyl-1,3-dihydro-pyrrolo[3,4-C]pyridine-2-yl)-methanon,
[5-methanesulfonyl-2-(2,2,3,3,3-pendaftar-propoxy)-phenyl]-(6-trifluoromethyl-1,3-dihydro-pyrrolo[3,4-C]pyridine-2-yl)-methanon,
[5-methanesulfonyl-2-(2,2,3,3-titrator-propoxy)-phenyl]-(6-trifluoromethyl-1,3-dihydro-pyrrolo[3,4-C]pyridine-2-yl)-methanon,
[6-(4-fluoro-phenyl)-1,3-dihydro-pyrrolo[3,4-C]pyridine-2-yl]-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon or
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(6-morpholine-4-yl-1,3-dihydro-pyrrolo[3,4-C]pyridine-2-yl)-methanon.

15. Compounds of General formula I, according to claim 5, where connections are
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-etox is)-phenyl]-(2-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-yl)-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-(2-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-yl)-methanon,
(4-methanesulfonyl-biphenyl-2-yl)-(2-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-yl)-methanon,
(2 isopropoxy-5-methanesulfonyl-phenyl)-(2-methyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-yl)-methanon or
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(2-methyl-5,7-dihydro-pyrrolo[3,4-d]pyrimidine-6-yl)-methanon.

16. Compounds of General formula I D. according to claim 6, where connections are
1-(4-methanesulfonyl-biphenyl-2-carbonyl)-2,3-dihydro-1H-indol-4-carbonitril,
1-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoyl]-2,3-dihydro-1H-indole-4-carboxylic acid methyl ester,
1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-2,3-dihydro-1H-indole-4-carboxylic acid methyl ester or
(4-bromo-2,3-dihydro-indol-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon.

17. Compounds of General formula I according to claim 7 e, where connections are
(5-bromo-indol-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon,
1-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-benzoyl]-1H-indole-6-carbonitrile,
(6-chloro-indol-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon or
(4-bromo-indol-1-yl)-[5-methanesulfonyl-2-(2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon.

18. Compounds of General formula I W of claim 8, where the unity are:
[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-(5-nitro-indazol-1-yl)-methanon,
(5-chloro-indazol-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon or
(5,7-dichloro-indazol-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon.

19. The compound of General formula I according to claim 9 C, where the connection is a
(5,6-dimethyl-benzoimidazol-1-yl)-[5-methanesulfonyl-2-((S)-2,2,2-Cryptor-1-methyl-ethoxy)-phenyl]-methanon.

20. Pharmaceutical composition having activity inhibitor vector glycine 1, containing one or more than one compound according to any one of claims 1 to 19 and a pharmaceutically suitable excipients.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel intermediate compounds - methyl 7-aryl-4,9-diaroyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]none-3,8-diene-8-carboxylates of formula III Ar1=Ar2=Ph, Ar3=C6H4Me-n (IIIa); and Ar1=C6H4Br-n, Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IIIb), for synthesis of methyl 6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-6-ene-8-carboxylates of formula IV where Ar1=Ar2=Ph, Ar3=C6H4Me-n (IVa); Ar1=C6H4Br-n Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IVb), which exhibit antimicrobial activity and are used as precursors for synthesis of novel heterocyclic systems, and a method for synthesis of said compounds.

EFFECT: compounds have high effectiveness.

5 cl, 1 tbl, 5 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: chemistry.

SUBSTANCE: invention relate to oxabispidinic compounds of formula I, ,where R1 is C1-12alkyl (where the given alky group is substituted with a group selected from phenyl, Het1, N(R5a)R6, -OR5c, -S(O)2N(R9b)R9c and -N(R9b)S(O)2R9d); R5a is H; R5c is C1-6alkyl (which is substituted with phenol) or phenyl; R6 is H or -C(O)OR10b; R10b is C1-6alkyl; R9b in each case where it is used in the given description of the invention represents H or C1-6alkyl; R9c and R9d in each case it is used in the given description of the invention independently presents C1-6alkyl (possibly substituted with one or more substitutes, selected from halogen or phenyl), phenyl or Het7, or R9c is H; R2 is H or OR13; R3 is H; R13 is H; Het1 and Het7 independently represent 5-12-member heterocyclic groups containing one or more heteroatoms, selected from oxygen and nitrogen, where these groups are possibly substituted with one or more substitutes selected from halogen and C1-6alkyl; A is a direct bond, -J-, J-S(O)2N(R19b)- or -J-N(R19c)S(O)2- (where in the last two groups -J is bonded to the nitrogen of an oxabispidinic ring); B is Z-{[C(O)]aC(H)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (where in the last six groups Z is bonded to a carbon atom, carrying R2 and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z- or -N(R20h)C(O)O-Z- (where in the last four groups Z is bonded to a phenyl group which is possibly substituted with a R4 group); J is C1-6alkylene, possibly broken by a -S(O)2N(R19d)- or -N(R19e)S(O)2- group and/or possibly substituted with a substitute selected form -OH; Z is a direct bond or C1-4alkylene, possibly broken by a -N(R20i)S(O)2- or -S(O)2N(R20j)- group; a, b and c possibly represent 0 or 1; n is 0, 1 or 2; R19b-R19e in each case where used in the given description of the invention independently represents H or C1-6alkyl; R20a is H or together with the only substitute R4 on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, represents C2-4alkylene, possibly broken or ending with O, N(H) or N(C1-6alkyl) group; R20b is H or C1-6alkyl; R20c-R20j in each case when used in the given description of the invention independently represents H or C1-6alkyl; or R20g and R20i independently represent C1-6alkyl, substituted with 3,5-dimethylisoxazolyl; G is CH; R4 is one or more possible substitutes selected from cyano, halogen, C1-4alkyl and C1-6alkoxy, possibly substituted with one or more hanogen and a R4 substitute on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, together with R20a can represent C2-4alkylene; broken or ending with O or N(H) or a N(C1-6alkyl) group; R41-R46 independently represent H; where each phenyl group is possibly substituted with one or more substitutes selected from halogen, cyano, C1-6alkyl and C1-6alkoxy (where the last two groups are possibly substituted with one or more halogen atoms); or to their pharmaceutically acceptable salts. The invention also relates to methods of producing said compounds, as well as to a pharmaceutical composition based on said compounds, with HERG-channel blocking activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for preventing and treating arrhythmia, particularly cardiac and ventricular arrhythmia.

32 cl, 1 tbl, 15 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 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

FIELD: chemistry.

SUBSTANCE: invention pertains to new layers of acidic compounds with Formula I , where R2 is C1-6alkyl (possibly substituted and/or ending with one or more substitute, chosen from -OH, halogen, cyano, nitro and aryl) or aryl, where each aryl group, if not specifically mentioned, is possibly substituted by one or more substitutes, including -OH, cyano, halogen, nitro, C1-6alkyl, C1-6alkoxy, -N(R14a)R14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14e)R14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2Rl3c and/or -OS(O)2R13d, where radicals from R13b to Rl3d independently represent C1-6alkyl; R14a and R14b independently represent H, C1-6alkyl, or jointly represent C3-6alkene, as a result, yielding a four-heptatomic nitrogen containing ring; radicals from R14c to R14m independently represent H or C1-6alkyl; A represents , where R16 represents unsubstituted C1-4alkyl, C1-4perfluoroalyl or phenyl, where the last group can be substituted with one or more substitutes, chosen from C1-6alkyl, halogen, nitro and C1-6alkoxy. The invention also relates to the method of obtaining Formula II compounds.

EFFECT: obtaining of new intermediate compounds and their use in special obtaining of formula II oxabispidin compounds, which can be used in the treatment of cardiac arrhythmia.

8 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 3-aminorifampicin-S representing semi-product in synthesis of anzamycine antibiotics, such as rifabutin - an anti-tuberculosis antibiotic with prolonged effect. Invention describes a method for preparing3-aminorifampicin-S that involves interaction of 3-bromorifampicin-S with hexamethylenetetramine in the amount 2-6-fold molar excess of hexamethylenetetramine with respect to 3-bromorifampicin-S at temperature 40-65°C in organic solvent medium and isolation of the end product. Trichloroethylene is used as a solvent in preparing 3-aminorifampicin-S followed by its change for butyl acetate by addition of butyl acetate to reaction mass in the amount 2-5-fold excess with respect to trichloroethylene volume followed by distilling off trichloroethylene. Prepared 3-aminorifampicin-S butyl acetate solution is filtered through aluminum oxide layer and 3-aminorifmapicin-S is isolated by evaporation until dry. Also, invention describes variant of method for preparing 3-aminorifampicin-S. Invention provides reducing reaction time in preparing the end product, reduced cost and simplified reaction, enhanced yield and purity of the end product.

EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to methods for preparing derivatives of 3-aazidorifamycin S eliciting antibiotic properties. Method for preparing 3-azido-derivatives of rifamycin S involves interaction rifamycin S derivative with hydrazoic acid salt in solvent medium by stirring reagents at temperature from 0oC to 100oC for 0.5-2 h followed by extraction of the end product. 3-Halogen-derivative of rifamycin S is used as rifamycin S derivative. Simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 is used as a solvent. Sodium azide or potassium azide is used as hydrazoilc acid salt. Extraction of the end product is carried out by extraction with solvent not mixing with water or by dilution of reaction mixture with water followed by filtration. The claimed method provides enhancing the yield of the end product by 63-71% and to simplify the process of it isolating. Invention provides the enhancement of effectiveness of method for preparing 3-azido-derivatives of rifamycin S due to elevating yield of the end product and simplifying the process of its isolating.

EFFECT: improved preparing method.

1 tbl, 13 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-aminorifamycin S of the formula (I) , eliciting antibiotic properties wherein X means NH2; Y = Z and mean hydrogen atom (H) or (CH3)2C<, or C6H5CH<, or C6H10<. Method for preparing 3-amino-derivatives of rifamycin S involves stirring 3-halogen-derivative of rifamycin S in solvent medium wherein solvent represents simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the following series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 with hydrazoic acid salt wherein sodium azide is used and stirring is carried out for 0.5-2 h. Then method involves the following conversion of obtained 30azido-derivative of rifamycin S to the end product using a reducing agent wherein mixture of zinc or iron with acetic acid is used, or hydrogen in the presence of palladium catalyst followed by treatment with oxidizing agent wherein ferric (III) chloride or manganese (IV) oxide is used, or hydrogen peroxide, or persulfates, or air. Extraction of the end product is carried out by extraction with organic solvent not mixing with water or by dilution of reaction mixture with water followed by crystallization of product. Invention provides the enhancement of method for preparing 3-amino-derivatives of rifamycin S due to elevating yield of the end product and process for it isolating.

EFFECT: improved preparing method.

1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel method of producing tiotropium salts of formula 1 , in which X- can denote a monovalent anion, preferably an anion selected from a group which includes chloride, bromide, iodide, methane sulphonate and trifluoromethane sulphonate, distinguished by that compounds of formula 2 , in which X-can assume values given above, are reacted in a single stage in an acceptable solvent while adding an acceptable base to form a compound of formula 3 in situ, where R is a residue selected from a group which includes N-imidazolyl, N-triazolyl, -O- C(=NR')-NHR", -O-SO2-phenyl, -O-SO2-phenylmethyl, -O-SO2-R', -O-CO-C(methyl)3, -O-CO-phenyl-NO2, chlorine, bromine, -N3 and -O-(P=O)R'" where R' denotes C1-C4alkyl or C3-C6cycloalkyl, R" denotes C1-C4alkyl, C3-C6cycloalkyl or C1-C4alkylene- N(C1-C4alkyl)2, and R'" denotes C1-C4alkyl, -O-C1-C4alkyl, phenyl or -O-phenyl, and R1 and R2 have identical or different values and can be methyl, ethyl, propyl, butyl or phenyl which can optionally be substituted with one or more C1-C4alkyl residues to obtain a compound of formula 4 , in which groups X-, R1 and R2 can assume values given above, and then without its extraction, the compound of formula 4 is reacted with an acceptable acid or with an acceptable desilylation agent with removal of the silyl group in the compound of formula 1. The invention also relates to compounds of formulae 3 and 4.

EFFECT: obtaining tiotropium salts of formula 1 using a simpler and more efficient method which increases output of the product.

8 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compound, namely to (1'S,5'S,9'S,10'R)-methyl-5-[2-(3-benzyl-6-carboxy-4-oxo-10-oxa-3-azatricyclo[5.2.1.01.5]deca-8-ene-9-yl)ethyl]-1,10-dimethyl-6-methylene-decahydronaphtylene-1-carboxylate of formula (I) .

EFFECT: possesses anti-oxidant, hepatoprotective and hemostimulating activity, has low toxicity, and can be applied in medicine.

1 cl, 4 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new compounds with general formula: , where R is -(CH2)n-A, where A: where each of B and C independently represent phenyl or phenyl substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, -OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl) and -NO2; or n equals an integer from 0 to 3; n1 equals an integer from 1 to 3; n2 equals an integer from 0 to 4; n3 equals an integer from 0 to 3; n4 equals an integer from 0 to 2; X1 is chosen from a chemical bond -S-, -S(O)2-, -NH-, -NHC(O)- and -C=C-, R1 is chosen from C1-C6alkyl, C1-C6fluoroalkyl, C3-C6cycloalkyl, tetrahydropyranyl, CN, -N(C1-C6alkyl)2, phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphtyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperizinyl, thiazolydinyl, thiomopholinyl, tetrazolyl, benzoxazolyl, imidazolidine-2-thionyl, 7,7-dimethylbicyclo[2.2.1]heptane-2-onyl, benzo[1.2.5]oxadiazolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl and pyrrolyl, each of which can be optionally substituted with 1-3 substitutes, independently chosen from a halogen, -CN, -CHO, -CF3, OCF3, -OH, -C1-C6alkyl, C1-C6alkoxy, -NH2, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), -NO2, -SO2(C1-C3alkyl), -SO2NH2, -SO2N(C1-C3alkyl)2, -COOH, -CH2-COOH, pyridyl, 2-methylazolyl, morpholino, 1-chloro-2-methylpropyl, phenyl, (optionally substituted with one or more halogens), benzyloxy, and , X2 selected from -O-, -CH2-, -S-, -SO-, -SO2-, -NH- and , R2 represents a ring group, chosen from a phenyl or thienyl group. Each ring group is substituted with a group with formula -(CH2)n4-CO2H; and besides that, the ring group can optionally be substituted with 1 or 2 extra substitutes, independently chosen from halogen, - C1-C6alkyl and -C1-C6alkoxy; R3 is chosen from H, halogen and -NO2; R4 is chosen from H, halogen and morpholino; or its salt form, used in pharmaceuticals. The invention also relates to pharmaceutical compositions, to methods of treatment, and to compounds with formula (A).

EFFECT: obtaining new biologically active compounds and pharmaceutical compositions based on them, which have inhibiting effect on cytosolic phospholipase A2.

45 cl, 300 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

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

8 cl, 11 tbl, 463 ex

FIELD: medicine.

SUBSTANCE: invention refers to new derivatives of dihydro-pyrroloquinoline of formula I where values of R1, R2, R3a and R3c radicals are specified in cl. 1 of the patent claim. Also the invention refers to a method for making the compound of formula I, to its application, a composite product based on the compound of formula I and a general antimicrobial agent and a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new derivatives of dihydro-pyrroloquinoline exhibiting antibacterial activity.

26 cl, 4 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 8-sulphonyl-2,3,4,5-tetrahydro-1H-γ-carbolines of general formula 1 or pharmaceutically acceptable salts thereof, which are ligands with a wider range of simultaneous activity towards alpha adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors, sigma receptors, norepiniphrine receptors and serotonin receptors. In compounds of general formula 1 R1 is an amino group substitute selected from hydrogen; C1-C3alkyl optionally substituted with phenyl; C1-C4alkyloxycarbonyl; R2 is a cyclic system substitute selected from hydrogen, C1-C3alkyl optionally substituted with phenyl, pyridin-(3- or 4-yl), (6-methylpyridin-3-yl); C1-C3alkenyl substituted with phenyl; or optionally substituted phenylsulphonyl; R3 is an optionally halogen-substituted phenyl, six member aromatic azaheterocycle, mono- or di-C1-C3alkylamino group, phenylamino group which is optionally substituted with halogen atoms on the phenyl ring, or a substituted six member azaheterocycle containing an additional nitrogen atom, substituted with C1-C3alkyl.

EFFECT: compounds can be used in treating and preventing diseases and pathological conditions of the central nervous system, such as anxiety disorders, cognitive disorders, neurodegenerative diseases and depression.

18 cl, 2 dwg, 6 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula: I, where R1 is selected from hydrogen or methoxy; R2 is selected from a group consisting of hydroxy, lower alkoxy, provided that R2 does not denoe methoxy when R1 denotes methoxy, lower alkoxy, mono- or di-substituted with a hydroxy group, benzyloxy, amino, alkylamino, dialkylamino, cyano group, unsubstituted phenyl or tetrazolyl, -O-(CH2)m-C(O)-NR8R9, where m equals 1 or 2, and where R8 and R9 are independently selected from hydrogen, lower alkyl or tetrazolyl, or R8 and R9 together with the nitrogen atom with which they are bonded form morpholinyl or piperazinyl, -O-(CH2)n-COOR10, where n equals 1 or 2 and R10 denotes hydrogen or lower alkyl, -O-(CH2)p-NH-C(O)-OR11, where p equals 1 or 2,and where R11 denotes lower alkyl, -O-SO2-R12, where R12 denotes lower alkyl, -NR13R14, where R13 denotes hydrogen or lower alkyl, and R14 denotes lower alkyl or benzyl, and -NH-CO-(CH2)q-R15, where q equals 1 or 2, and where R5 denotes tetrazolyl; R3 is selected from a group consisting of hydrogen, hydroxy, lower alkoxy, lower alkoxy which is mono- or di-substituted with a hydroxy group, alkoxy or unsubstituted phenyl, and -O-(CH2)m-C(O)-NR8R9, where m equals 1 or 2, and where R8 and R9 are independently selected from hydrogen or lower alkyl, or R8 and R9 together with the nitrogen atom with which they are bonded form morpholinyl or piperazinyl, which can be substituted with lower alkyl; R4 is or , where R5 is selected from lower alkyl; or R5 can also denote hydrogen when selected from a group consisting of -(CH2)m-C(O)-NR8R9, -O-(CH2)p-NH-C(O)-OR11, -O-SO2-R12, -NR13R14, -NH-CO-(CH2)q-R15 and lower alkoxy which is mono- or di-substituted with a group selected from hydroxy, benzyloxy, amino or cyano; R6 is selected from a group consisting of hydrogen and lower alkyl; R7 is selected from a group consisting of lower alkyl and lower halogenalkyl; and to pharmaceutically acceptable salts of said compounds. The invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having DPP-IV enzyme inhibiting activity.

22 cl, 50 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives of general formula , where R is an optional ortho- or meta-substitute selected from halogen and (C1-4)alkyloxy; R1 is halogen or CF3; R2 is H, (C1-4)alkyloxy or halogen; R3 is H or (CH2)n-NR5R6; R4 is H or (C1-6)alkyl, optionally substituted COOR7 or NR8R9; R5 and R6 independently denote H, (C3-8)cycloalkyl, quinuclidin-3-yl, (C2-6)alkenyl or (C1-6)alkyl, optionally substituted mono-substituted with CF3, (C3-8)cycloalkyl, (C6)aryl, a 5- or 6-member heteroaryl group, OH, (C1-6)alkyloxy, (C6-10)aryloxy, CONR11R12, NR13R14 or NR13SO2(C1-4)alkyl; or R5 and R6 together with a nitrogen atom to which they are bonded form a 4-8-member saturated heterocyclic ring which also contains 1 heteroatom selected from O, SO2 and NR15, where the ring is optionally mono-substituted or di-substituted with oxo, (C1-4)alkyl, (C3-8)cycloalkyl, NR16R17 or CONR18R19; R7 is H or (C1-4)alkyl; R8 and R9 independently denote H, (C1-4)alkyl (optionally substituted di(C1-4)alkylamino) or (C3-8)cycloalkyl; or R8 and R9 together with a nitrogen atom with which they are bonded form a 4-8-member saturated heterocyclic ring which also contains one heteroatom which is O; R11 and R12 independently denote H or (C1-4)alkyl; R13 and R14 independently denote H or (C1-4)alkyl; R15 is H, (C1-4)alkyl (optionally mono-substituted OH, (C1-4)alkyloxy or di(C1-4)alkylamino), phenyl, pyridyl or COR20; R16 and R17 denote (C1-4)alkyl; or R16 and R17 together with a nitrogen atom with which they are bonded from a 4-8-member saturated heterocyclic ring; R18 and R19 denote H; R20 is (C1-4)alkyl, (C3-8)cycloalkyl or furyl; and n equals 0 or 1; or its pharmaceutically acceptable salt. The invention also relates to use of formula I compounds to prepare a medicinal agent and to a pharmaceutical composition based on formula I compound.

EFFECT: novel derivatives have catepsin S and K inhibitory activity.

9 cl, 20 ex

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