Fused aminodihydrothiazine derivatives
A compound represented by the general formula: or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Ring A is a C 6-14 aryl group or the like, L is —NR e CO— or the like (wherein R e is a hydrogen atom or the like), Ring B is a C 6-14 aryl group or the like, X is a C 1-3 alkylene group or the like, Y is a single bond or the like, Z is a C 1-3 alkylene group or the like, R 1 and R 2 are each independently a hydrogen atom or the like, and R 3 , R 4 , R 5 and R 6 are independently a hydrogen atom, a halogen atom or the like, has an Aβ production inhibitory effect or a BACE1 inhibitory effect and is useful as a prophylactic or therapeutic agent for a neurodegenerative disease caused by Aβ and typified by Alzheimer-type dementia.
1. A compound represented by the formula (I):
or a pharmaceutically acceptable salt thereof, wherein
Ring A is a C 6-14 aryl group which may have 1 to 3 substituents selected from Substituent Group α or a 5- to 6-membered heteroaryl group which may have 1 to 3 substituents selected from Substituent Group α,
L is a single bond or a formula —NR e CO— (wherein R e is a hydrogen atom or a C 1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group α),
Ring B is a C 6-14 aryl group which may have 1 to 3 substituents selected from Substituent Group α or a 5- to 10-membered heterocyclic group which may have 1 to 3 substituents selected from Substituent Group α,
X is a C 1-3 alkylene group which may have 1 to 3 substituents selected from Substituent Group α,
Y is a single bond,
Z is a single bond or a C 1-3 alkylene group which may have 1 to 3 substituents selected from Substituent Group α,
R 1 and R 2 are hydrogen atoms,
R 3 , R 4 , R 5 and R 6 are independently a hydrogen atom, a halogen atom, a hydroxy group, a C 1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group α, a C 1-6 alkoxy group which may have 1 to 3 substituents selected from Substituent Group α, or
R 4 and R 6 together may form a ring represented by the formula (II):
wherein Y, Z, R 5 and R 3 are the same as defined above and Q is an oxygen atom, a methylene group or an ethylene group,
Substituent Group α is a halogen atom, a hydroxy group, a nitro group, a C 1-6 alkylthio group, or a cyano group, a C 1-6 alkoxy group which may have 1 to 3 substituents selected from Substituent Group β, or a C 1-6 alkyl group which may have 1 to 3 substituents selected from Substituent Group β, and
Substituent Group β is a halogen atom, a cyano group, a hydroxy group, or a C 1-6 alkoxy group.
2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein X is a methylene which may have 1 to 2 substituents selected from Substituent Group α.
3. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein Z is a C 1-3 alkylene which may have 1 to 3 substituents selected from Substituent Group α.
4. A compound selected from the following compounds:
(+)-N-{3-[(4aR*,8aS*)-2-amino-4,4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-8a-yl]-4-fluorophenyl}-5-chloropyridine-2-carboxamide,
(+)-N-{3-[(4aR*,7aS*)-2-amino-4,4-a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-7a-yl]-4-fluorophenyl}-5-chloropyridine-2-carboxamide,
N-{3-[(4aR*,7aS*)-2-amino-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl]-4-fluorophenyl}pyridine-2-carboxamide,
N-{3-[(4aR*,7aS*)-2-amino-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl]-4-fluorophenyl}-5-fluoropyridine-2-carboxamide,
N-[3-((4aR*,8aS*)-2-amino-4,4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-8a-yl)-4-fluorophenyl]-5-cyanopyridine-2-carboxamide,
N-[3-((4aR*,7aS*)-2-amino-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl)-4-fluorophenyl]-5-difluoromethoxypyrazine-2-carboxamide,
N-[3-((4aR*,7aS*)-2-amino-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl)-4-fluorophenyl]-5-fluoromethoxypyrazine-2-carboxamide,
N-[3-((4aR*,7aS*)-2-amino-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl)-4-fluorophenyl]-5-cyanopyridine-2-carboxamide,
N-[3-((4aR*,7aS*)-2-amino-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl)-4-fluorophenyl]-5-fluoromethoxypyridine-2-carboxamide,
(+)-N-[3-((4aR*,6S*,7aS*)-2-amino-6-methoxy-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl)-4-fluorophenyl]-5-cyanopyridine-2-carboxamide,
(+)-N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl)-4-fluorophenyl]-5-cyanopyridine-2-carboxamide,
(+)-N-[3-((4aR*,9aS*)-2-amino-4a,5,6,7,8,9-hexahydro-4H-cyclohepta[d][1,3]thiazin-9a-yl)-4-fluorophenyl]-5-cyanopyridine-2-carboxamide,
N-[3-((4aR*,7aS*)-2-amino-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazin-7a-yl)-4-methoxyphenyl]-5-chloropyridine-2-carboxamide,
N-[3-((4aS*,6S*,7aS*)-2-amino-6-methoxy-4,4-a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazine-7a-yl)-4-fluorophenyl]-5-difluoromethylpyrazine-2-carboxamide,
N-[3-((4aR*,6R*,7aS*)-2-amino-6-methoxy-4,4a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazine-7a-yl)-4-fluorophenyl]-5-difluoromethylpyrazine-2-carboxamide, or
N-[3-((4aR*,6S*,7aS*)-2-amino-6-fluoro-4,4a,5,6,7,7a-hexahydrocylcopenta[d][1,3]thiazine-7a-yl)-4-fluorophenyl]-5-difluoromethylpyrazine-2-carboxamide,
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to any one of claim 1 , 2 , or 3 as an active ingredient.
6. A method of treating a neurodegenerative disease, comprising administering an effective amount of the pharmaceutical composition according to claim 5 to a subject in need thereof, wherein the neurodegenerative disease is Alzheimer-type dementia or Down's syndrome.
7. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to claim 4 as an active ingredient.
8. A method of treating a neurodegenerative disease, comprising administering an effective amount of the pharmaceutical composition according to claim 7 to a subject in need thereof, wherein the neurodegenerative disease is Alzheimer-type dementia or Down's syndrome.
9. A method of treating Alzheimer's disease, comprising administering an effective amount of the pharmaceutical composition according to claim 5 to a subject in need thereof.
10. A method of treating Alzheimer's disease, comprising administering an effective amount of the pharmaceutical composition according to claim 7 to a subject in need thereof.