Heterocyclic derivatives
View Patent ↗The object of the present invention is to provide soluble β-amyloid precursor protein secretory stimulators, which are effective in treating neurodegenerative diseases as well as cerebrovascular disorder-induced neuronopathy. More specifically, the present invention provides a novel compound of the following Formula (I) or a salt or prodrug thereof: [wherein R 1 and R 2 each represent a hydrogen atom or a lower alkyl group, etc., Ar 1 and the ring B each represent an optionally substituted aromatic group, the ring A represents an optionally substituted benzene ring, the ring C represents an optionally substituted 4- to 8-membered ring which may further be condensed with an optionally substituted ring, X represents CH or N, and Y represents CH or N].
1. A compound of the following Formula (I) or a salt or prodrug thereof:
wherein R 1 and R 2 , which may be the same or different, each represent a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted hydroxy group, or R 1 and R 2 may together form a 4- to 7-membered ring together with their adjacent carbon atoms, Ar 1 represents an optionally substituted aromatic group, the ring A represents an optionally substituted benzene ring, the ring B represents an optionally substituted aromatic ring, the ring C represents an optionally substituted 4- to 8-membered ring which may further be condensed with an optionally substituted ring, X represents CH or N, and
represents a single bond or a double bond, provided that Y represents CH or N when said bond is a single bond, and Y represents C when said bond is a double bond.
2. A compound of the following Formula (I′) or a salt or prodrug thereof:
wherein R 1 and R 2 , which may be the same or different, each represent a hydrogen atom or an optionally substituted lower alkyl group, or R 1 and R 2 may together form a 4- to 7-membered ring together with their adjacent carbon atoms, Ar1 represents an optionally substituted aromatic group, the ring A represents an optionally substituted benzene ring, the ring B represents an optionally substituted aromatic ring, the ring C represents an optionally substituted 4- to 8-membered ring, X represents CH or N, and Y represents CH or N.
3. The compound of claim 1 or a salt or prodrug thereof, wherein the partial structure:
wherein the ring B, the ring C and X are as defined in claim 1 , has the following formula:
wherein R 3 represents a hydrogen atom, a halogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group, the ring B′ represents an optionally substituted benzene ring, X represents CH or N, Z represents an oxygen atom, a sulfur atom, CR 4 R 5 , NR 6 or
wherein R 4 , R 5 , R 6 and R 7 , which may be the same or different, each represent a hydrogen atom or an optionally substituted lower alkyl group), m represents 0 or 1, and n represents an integer of 1 to 4.
4. The compound of claim 1 or a salt or prodrug thereof, wherein the ring C is further condensed with a monocyclic ring in addition to the ring B.
5. The compound of claim 1 or a salt or prodrug thereof, wherein R 1 is a hydrogen atom.
6. The compound of claim 1 or a salt or prodrug thereof, wherein R 1 is a hydroxy group, an optionally substituted alkoxy group or an optionally substituted acyloxy group.
7. The compound of claim 1 or a salt or prodrug thereof, wherein R 2 is a hydrogen atom or an optionally substituted lower alkyl group.
8. The compound of claim 1 or a salt or prodrug thereof, wherein Ar 1 is an optionally substituted monocyclic aromatic group.
9. The compound of claim 1 or a salt or prodrug thereof, wherein Ar 1 is an optionally substituted phenyl, furyl, thienyl or pyridyl group.
10. The compound of claim 1 or a salt or prodrug thereof, wherein the ring A is an unsubstituted benzene ring.
11. The compound of claim 1 or a salt or prodrug thereof, wherein at least one of X and Y is N.
12. The compound of claim 1 or a salt or prodrug thereof, wherein X is N and Y is C.
13. The compound of claim 1 or a salt or prodrug thereof, wherein R 1 is a hydrogen atom, an alkyloxy group or an acyloxy group, R 2 is a hydrogen atom or an optionally substituted lower alkyl group, Ar 1 is an optionally substituted phenyl group, an optionally substituted furyl group, an optionally substituted thieny group or an optionally substituted pyridyl group, the ring A is an unsubstituted benzene ring, the ring B is an optionally substituted benzene ring, the ring C is an optionally substituted nitrogen-containing 5- to 7-membered heterocyclic ring which may be condensed with an unsubstituted benzene ring, X is N, and Y is CH.
14. The compound of claim 1 or a salt or prodrug thereof, wherein R 1 is a hydrogen atom or an acyloxy group, R 2 is an unsubstituted C 1-6 alkyl group, Ar 1 is a phenyl group which may be substituted with an optionally halogenated C 1-6 alkoxy group, the ring A is an unsubstituted benzene ring, the ring B is an unsubstituted benzene ring, the ring C is tetrahydropyrrole, hexahydropyridine, hexahydropyrazine, tetrahydro-1,4-oxazine, tetrahydro-1,4-thiazine, perhydroazepine or pyrrole, X is N, and Y is CH.
15. The compound of claim 1 , which is any one of the following compounds or salts or prodrugs thereof:
(−)-2,4-cis-1-(3,4-dimethoxybenzoyl)-2-methyl-4-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline;
(−)-2,4-cis-4-(3,4-dihydro-2H-1,4-benzoxazin-4-yl)-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinoline
2,4-cis-1-(3,4-dimethoxybenzoyl)-2-methyl-4-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline;
2,3-trans-2,4-cis-3-acetoxy-1-(3,4-dimethoxybenzoyl)-2-methyl-4-(1,2,3,4-tetrahydroquinolin-1-yl)-1,2,3,4-tetrahydroquinoline;
2,4-cis-4-(3,4-dihydro-2H-1,4-benzothiazin-4-yl)-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinoline;
2,4-cis-4-(1-benzyl-1,2,3,4-tetrahydroquinoxalin-4-yl)-1-(3,4-dimethoxybernzoyl)-2-methyl-1,2,3,4-tetrahydroquinoline;
2,4-cis-1-(3,4-dimethoxybenzoyl)-2-methyl-4-(2,3,4,5-tetrahydro-1H-1-benzazepinyl)-1,2,3,4-tetrahydroquinoline;
2,3-trans-2,4-cis-3-{[(benzylamino)carbonyl]oxy}-1-(3,4-dimethoxybenzoyl)-2-methyl-4-(2,3,4,5-tetrahydro-1H-1-benzazepinyl)-1,2,3,4-tetrahydroquinoline;
2,4-cis-4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinoline;
(−)-2,4-cis-4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquin; and
2-butyl-4-(9H-9-carbazolyl)-1-(3,4-dimethoxybenzoyl)-1,2-dihydroquinoline.
16. The compound of claim 1 or a salt or prodrug thereof, wherein the 2- and 4-positions of the Formula (I) is formed the cis(−)-configuration.
17. A method for preparing a compound of the following formula or a salt or prodrug thereof:
wherein R 1 , R 2 , Ar 1 and the rings A, B and C are as defined below, which comprises reacting a compound of the following formula or a salt thereof:
wherein R 1 and R 2 , which may be the same or different, each represent a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted hydroxy group, or R 1 and R 2 may together form a 4- to 7-membered ring together with their adjacent carbon atoms, Ar 1 represents an optionally substituted aromatic group, the ring A represents an optionally substituted benzene ring, and Q 1 represents a reactive substituent, with a compound of the following formula or a salt thereof:
wherein the ring B represents an optionally substituted aromatic ring, and the ring C represents an optionally substituted 4- to 8-membered ring which may further be condensed with an optionally substituted ring.
18. A pharmaceutical composition comprising the compound of claim 1 or a salt or prodrug thereof.
19. The pharmaceutical composition of claim 18 , which is a double β-amyloid precursor protein secretion stimulator and/or an apoptosis inhibitor.
20. The pharmaceutical composition of claim 18 , which is a therapeutic agent for Alzheimer's disease, Parkinson's disease, neuropathy, senile dementia, cerebrovascular disorder-induced neuronopathy or cerebrovascular dementia.