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US 7,923,450 B2Granted
Modulators for amyloid beta
AssigneeHoffmann-La Roche Inc.
InventorsKarlheinz Baumann, Alexander Flohr, Erwin Goetschi, Helmut Jacobsen, Synese Jolidon, Thomas Luebbers
Life of this patent
Estimating the term…
Abstract
The invention relates to compounds of formula wherein R1, R2, R3, R4, X and Y are as defined herein and to pharmaceutically active acid addition salts thereof. The compounds can be used for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome.
Claims14
A compound of formula I
- wherein
- R1 is —C(O)O-lower alkyl or cyano or is selected from the group consisting of pyridine-4-yl, thiazole-5-yl, oxazol-5-yl, [1,2,4]triazol-1-yl, imidazol-1-yl, pyrazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, and [1,2,4]-thiadiazol-5-yl,
- optionally substituted by R′;
- R′ is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy or lower alkoxy substituted by halogen;
- R2 is hydrogen, lower alkoxy, lower alkyl, halogen or cyano;
- R3 is —(CH2)n—C(O)O-lower alkyl, lower alkoxy, hydroxy, —O—Si(CH3)2-lower alkyl, —C(O)—N(lower alkyl)2, —O—S(O)2-lower alkyl, C3-7-cycloalkyl, S(O)2-aryl, or is heterocyclyl or —C(O)-heterocyclyl, wherein the heterocyclyl group is pyrrolidinyl, piperidinyl, or morpholinyl, or is aryl or hetaryl, wherein aryl is phenyl, hetaryl is pyridyl or [1,2,4]oxadiazole-5-yl and wherein the aryl and hetaryl rings are optionally substituted by one or more R′;
- R4 is hydrogen, lower alkyl, hydroxy or CH2CN;
- X is S or —N═C(R5)—;
- R5 is hydrogen, lower alkyl or hydroxy,
- Y is a bond, —O—, —CH2—, —CH2—CH2—,
- or —N(R)—;
- R is hydrogen, lower alkyl, C(O)O-lower alkyl, C(O)-lower alkyl, S(O)2-lower alkyl, or benzyl;
- and
- n is 0 or 1;
- or a pharmaceutically active acid addition salt thereof.
12 more elements
A compound selected from the group consisting of
- [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(2-methoxy-phenyl)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-amine;
- [4-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-benzothiazol-2-yl]-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;
- 2-(4-methyl-imidazol-1-yl)-5-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-phenol;
- [4-(2-methyl-oxazol-5-yl)-phenyl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine;
- [3-methoxy-4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine;
- [3-methoxy-4-(2-methyl-thiazol-5-yl)-phenyl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine;
- [4-(2,4-dimethyl-thiazol-5-yl)-3-methoxy-phenyl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine;
- (4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-(4-pyridin-4-yl-phenyl)-amine;
- [4-(2-ethyl-oxazol-5-yl)-phenyl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine;
- [4-(2,4-dimethyl-oxazol-5-yl)-phenyl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine;
- and
- [4-(3-methyl-[1,2,4]thiadiazol-5-yl)-phenyl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine.
9 more elements
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
- wherein
- R1 is —C(O)O-lower alkyl or cyano or is selected from the group consisting of pyridine-4-yl, thiazole-5-yl, oxazol-5-yl, [1,2,4]triazol-1-yl, imidazol-1-yl, pyrazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]-oxadiazol-2-yl, and [1,2,4]-thiadiazol-5-yl, optionally substituted by R′;
- R′ is halogen, lower alkyl, lower alkyl substituted by halogen, lower alkoxy or lower alkoxy substituted by halogen;
- R2 is hydrogen, lower alkoxy, lower alkyl, halogen or cyano;
- R3 is —(CH2)n—C(O)O-lower alkyl, lower alkyl, lower alkoxy, hydroxy, —O—Si(CH3)2-lower alkyl, —C(O)—N(lower alkyl)2, —O—S(O)2-lower alkyl, C3-7-cycloalkyl, S(O)2-aryl, or is heterocyclyl or —C(O)-heterocyclyl, wherein the heterocyclyl group is pyrrolidinyl, piperidinyl, or morpholinyl, or is aryl or hetaryl, wherein aryl is phenyl, hetaryl is pyridyl or [1,2,4]oxadiazole-5-yl and wherein the aryl and hetaryl rings are optionally substituted by one or more R′;
- R4 is hydrogen, lower alkyl, hydroxy or CH2CN;
- X is S or —N═C(R5)—;
- R5 is hydrogen, lower alkyl or hydroxy,
- Y is a bond, —O—, —CH2—, —CH2—CH2—,
- or —N(R)—;
- R is hydrogen, lower alkyl, C(O)O-lower alkyl, C(O)-lower alkyl, S(O)2-lower alkyl, or benzyl;
- and
- n is 0 or 1;
- or a pharmaceutically active acid addition salt thereof and a pharmaceutically acceptable carrier.
11 more elements
Dependencies are inferred from the claim text.