Malonamide derivatives as gamma-secretase inhibitors for treatment of alzheimer's disease

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel malonamide derivatives of general formula , to their pharmaceutically acceptable salts of acid bonding and to all forms of their optically pure enantiomers, racemates or diastereomers and diastereomer mixtures, possessing inhibiting activity with respect to γ-secretase, as well as to pharmaceutical preparation, containing one or more than one of claimed compounds, and to application of claimed compounds for manufacturing of drugs. Values of substituents R, R1, R2, R3, as well as X, n are given in invention formula.

EFFECT: obtaining compounds that can be applied in treatment of Alzheimer's disease.

19 cl, 6 dwg, 111 ex

 

The text descriptions are given in facsimile form.

1. Compounds of General formula

where R represents halogen, lower alkyl or lower alkyl substituted by halogen;
R1represents hydrogen, lower alkyl or lower alkyl substituted by halogen or hydroxy, or is a lower alkenyl, -(CH2)n-cycloalkyl, -(CH2)n-COR', or represents benzyl, possibly substituted by halogen, or represents -(CH2)n-morpholinyl;
R' represents a lower alkoxy, hydroxy or amino;
R2 represents hydrogen, lower alkyl or di-(lower alkyl), lower alkyl substituted by halogen or hydroxy, or represents benzyl or cycloalkyl;
R3represents a lower alkyl or lower alkyl substituted by halogen, or represents benzyl, possibly substituted by two halogen atoms, or represents -(CH2)n-cycloalkyl or -(CH2)n-pyridinyl;
X represents-CR4R4'or CR4R4'-O-;
R4/R4'represents independently from each other hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy or-CH2-2-[1,3]dioxolan-;
n is 0, 1 or 2;
their pharmaceutically acceptable salts accession acid and all forms of their optically pure enantiomers, racemates or diastereomers and diastereomeric mixtures.

2. The compounds of formula I according to claim 1, where X represents-CH2-.

3. The compounds of formula I according to claim 1, where X represents-SSN3- or-CH(CH2CH3)-.

4. Compounds according to claim 3, where R3represents lower alkyl substituted by halogen.

5. Compounds according to claim 4, which represent
2-methyl-N-((S)-9-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
2-methyl-N-((S)-9-methyl-8-oxo-4-trifluoromethyl-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-N'-(2,2,3,33-pendaftar-propyl)-malonamide-epimer 1,
2-methyl-N-((6R,7S)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-1-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-methyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-methyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-6,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-methyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-6,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-ethyl-N'-(2,2,333-pendaftar-propyl)-malonamide,
N-[(6R,7S)-9-(4-chloro-benzyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2-methyl-N-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-1-fluoro-6,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-methyl-N'-(2,2,3,353-pendaftar-propyl)-malonamide or
N-((6R,7S)-2-fluoro-6,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-methyl-N'-(2,2,3,33-pendaftar-propyl)-malonamide.

6. Compounds according to claim 3, where R3represents a benzyl, substituted by two halogen atoms.

7. Compounds according to claim 6, where this connection is a
N-(3,5-debtor-benzyl)-2-methyl-N'-((6R,7S)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-malonamic.

8. The compounds of formula I according to claim 1, where X represents-C(CH )2-.

9. Connection of claim 8, where R3represents lower alkyl substituted by halogen.

10. Compounds according to claim 9, which represent
N-((6R,7S)-1-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-[(6R,7S)-9-(4-chloro-benzyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-1-fluoro-6,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-[(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-Cryptor-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-9-cyclopropylmethyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2,2-dimethyl-N-(2,2,33,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-9-allyl-2-fluoro-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-[(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
{(6R,7S)-2-fluoro-6-methyl-7-[2-methyl-2-(2,2,3,3,3-pendaftar-propellerblades)-propionamido]-8-oxo-7,8-dihydro-6N-5-oxa-9-Aza-benzocycloheptene-9-yl}-acetic acid methyl ester,
N-((6R,7S)-6-benzyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro the-5-oxa-9-Aza-benzocycloheptene-7-yl)-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-6-cyclopropyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2,2-dimethyl-N-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-((6R,7S)-6-ethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-[(6R,7S)-6-ethyl-2-fluoro-8-oxo-9-(2,2,2-Cryptor-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2,2-dimethyl-N-(2,2,3,3,3-pendaftar-propyl)-malonamide or
N-[(6R,7S)-2-fluoro-6-(2-hydroxy-ethyl)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2,2-dimethyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide.

11. Compounds according to claim 1, where X represents-C(lower alkyl)(hydroxy).

12. Compounds according to claim 11, where R3represents lower alkyl substituted by halogen.

13. Connection 12, which are
N-(6R,7S)-6-cyclopropyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-hydroxy-2-methyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-[(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2-(R or S)-hydroxy-2-methyl-N-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-[(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-Cryptor-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2-(R or S)-hydroxy-2-methyl-N'-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-[(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-Cryptor-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2-(R or S)-hydroxy-2-ethyl-N'-(3,3,3-Cryptor-propyl)-malonamide,
N-[(6R,7S)-2-fluoro-6-methyl-8-oxo-9-(2,2,2-Cryptor-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2-(R or S)-hydroxy-2-methyl-N'-(2,2,2-Cryptor-ethyl)-malonamic,
(S or R)-2-ethyl-N-((6R,7S)-6-ethyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-hydroxy-N-(2,2,2-Cryptor-ethyl)-malonamic,
(R or S)-2-ethyl-N-((6R,7S)-6-ethyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-hydroxy-N-(2,2,3,3,3-pendaftar-propyl)-malonamide,
(R or S)-2-ethyl-N-((6R,7S)-6-ethyl-2-fluoro-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-hydroxy-N-(3,3,3-Cryptor-propyl)-malonamide,
(R or S)-2-ethyl-N-[(6R,7S)-6-ethyl-2-fluoro-8-oxo-9-(2,2,2-Cryptor-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2-hydroxy-N-(2,2,2-Cryptor-ethyl)-malonamic,
(R or S)-2-ethyl-N-[(6R,7S)-6-ethyl-2-fluoro-8-oxo-9-(2,2,2-Cryptor-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2-hydroxy-N-(2,2,3,3,3-pendaftar-propyl)-malonamide,
N-[(6R,7S)-2-fluoro-6-(2-hydroxy-ethyl)-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-2-(R or S)-hydroxy-2-methyl-N'-(2,2,2-Cryptor-ethyl)-malonamic,
N-[(6R,7S)-6-ethyl-2-fluoro-8-oxo-9-(2,2,2-Cryptor-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl]-(R or S)-2-hydroxy-2-methyl-N'-(2,2,2-Cryptor-ethyl)-malonamic.

14. The compounds of formula I according to claim 1, where X represents-C(CH3)2-O-.

15. The compounds of formula I according to claim 1, where X represents-C(F)(CH2CH2CH3)-.

16. Connections § 15, where R3represents a benzyl, substituted by two halogen atoms.

17. Join on clause 16, which are
N-(3,5-debtor-benzyl)-2-fluoro-N'-((6R,7S)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-propyl-malonamic or
N-(3,5-debtor-benzyl)-N'-((6R,7S)-6,9-dimethyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-Aza-benzocycloheptene-7-yl)-2-fluoro-2-propyl-malonamic.

18. Pharmaceutical drug that has inhibitory activity against γ-secretase containing one or more than one compound according to any one of claims 1 to 17 in a therapeutically effective amount and a pharmaceutically acceptable excipients.

19. The use of compounds according to any one of claims 1 to 17 for the manufacture of drugs having inhibitory activity against γ-secretase.



 

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1 tbl, 1 ex

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26 cl, 12 dwg, 4 tbl, 14 ex

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5 ex

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37 cl, 1 tbl, 141 ex

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2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-alkylsulfanyl-3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. In general formula 1 , R1 and R3 independently denote optionally identical C1-C3 alkyl, and R2 is a -(CH2)nX group or R1 and R3 independently denote different substitutes selected from C1-C3 alkyl or a -(CH2)nX group, and R2 is a hydrogen atom or C1-C3 alkyl; R4 is C1-C3 alkyl; Ri5 is a hydrogen atom, one or two identical or different halogen atoms, C1-C3 alkyl; equals 0, 1 or 2; n equals 0, 1, 2 or 3; X is a carboxyl CO2H, C1-C3 alkyloxycarbonyl, aminocarbonyl CONR6R7 or amino group NR6R7; except compounds in which R3 is a -(CH2)nX group, where X is an amino group NR6R7 and n equals 0; R6 and R7 are optionally identical and denote a hydrogen atom, optionally substituted C1-C5 alkyl or R6 and R7 together with the nitrogen atom with which they are bonded form an optionally substituted 6-member azaheterocyclyl containing 1-2 nitrogen atoms in the ring, where the substitute is selected from C1-C3 alkyl.

EFFECT: obtaining compounds which can be used in treating diseases of the central nervous system during prevention or treatment of cognitive disorders, neurodegenerative diseases, psychiatric disorders, have anxiolytic and nootropic effect and can be used to prevent and treat anxiety disorders and enhance mental capacity.

25 cl, 2 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines of general formula 1, their pharmaceutically acceptable salts and/or hydrates having serotonin 5-HT6 receptor antagonist properties. The compounds can be used in treating and preventing various diseases of the central nervous system, pathogenesis of which is associated with 5-HT6 receptors, particularly cognitive disorders, neurodegenerative diseases and psychiatric disorders. The compounds have anxiolytic and nootropic effect and can also be used for preventing and treating anxiety disorder and for enhancing metal capacity. In formula 1 , R1 is a hydrogen atom, C1-C3 alkyl, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R2 is a hydrogen atom, halogen atom, C1-C3 alkyl, phenyloxy or pyridyloxy; R3 is a hydrogen atom, C1-C3 alkyl, C1-C3 alkyloxy, (C1-C3)alkyloxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, pyridyl; R4 is C1-C3 alkyl; R5 is a hydrogen atom, one or two halogen atoms, C1-C3 alkyl, C1-C3 alkyloxy or hydroxyl; X is a sulphur atom or thionyl group (SO).

EFFECT: obtaining compounds which can be used in treating and preventing various diseases of the central nervous system.

24 cl, 9 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

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