Benzazepine derivatives, process for the preparation of the same and uses thereof
View Patent ↗Compounds of the general formula (I): or salts thereof, which exhibit CCR5 antagonism and exert preventive and therapeutic effects against HIV infections: wherein R 1 is a 5- to 6-membered aromatic ring which bears a substituent represented by the general formula: R-Z 1 -X-Z 2 - (wherein R 1 is hydrogen or optionally substituted hydrocarbyl; X is optionally substituted alkylene; and Z 1 and Z 2 are each a heteroatom) and may be further substituted, with R being optionally bonded to the aromatic ring to form another ring; Y is optionally substituted imino; and R 2 and R 3 are each optionally substituted aliphatic hydrocarbyl or an optionally Substituted hetero-alicyclic group.
1. A compound of the formula (I):
wherein R 1 is a 5- to 6-membered aromatic ring which has a group of the formula: R-Z 1 -X-Z 2 - wherein R is a hydrogen atom or a substituted or unsubstituted hydrocarbon group, X is a substituted or unsubstituted alkylene chain, and Z 1 and Z 2 are respectively hetero-atoms, and which may have a further substituent, the group R may bind to the 5- to 6-membered aromatic ring to form a ring, Y is a substituted or unsubstituted imino group, R 2 and R 3 are respectively a substituted or unsubstituted aliphatic hydrocarbon group or a substituted or unsubstituted alicyclic heterocyclic group; or a salt thereof.
2. The compound according to claim 1 , wherein the 5- to 6-membered aromatic ring is benzene, furan or thiophene.
3. The compound according to claim 1 , wherein the 5- to 6-membered aromatic ring is benzene.
4. The compound according to claim 1 , wherein R is a halogenated or unhalogenated lower alkyl group.
5. The compound according to claim 1 , wherein X is —(CH 2 ) n — wherein n is an integer of 1-4.
6. The compound according to claim 1 , wherein Z 1 and Z 2 are respectively —O—, —S(O) m — wherein m is an integer of 0-2 or —N(R 4 )— wherein R 4 is a hydrogen atom or a substituted or unsubstituted lower alkyl group.
7. The compound according to claim 1 , wherein Z 1 is —O— or —S(O) m — wherein m is an integer of 0-2.
8. The compound according to claim 1 , wherein Z 1 is —O—.
9. The compound according to claim 1 , wherein Z 2 is —O— or —N(R 4 )— wherein R 4 is a hydrogen atom or a substituted or unsubstituted lower alkyl group.
10. The compound according to claim 1 , wherein Z 2 is —O—.
11. The compound according to claim 1 , wherein Y is —N(R 5 )— wherein R 5 is a hydrogen atom, a substituted or unsubstituted hydrocarbon group or a substituted or unsubstituted acyl group.
12. The compound according to claim 11 , wherein R 5 is C 1-4 alkyl, formyl or C 2-5 alkanoyl.
13. The compound according to claim 11 , wherein R 5 is a group represented by the formula —(CH 2 ) k —R 6 ; wherein k is 0 or 1, and R 6 is a substituted or unsubstituted 5- to 6-membered monocyclic aromatic group.
14. The compound according to claim 1 , wherein R 2 is a substituted or unsubstituted straight chain hydrocarbon group.
15. The compound according to claim 1 , wherein R 2 is a substituted or unsubstituted lower alkyl group.
16. The compound according to claim 1 , wherein R 3 is a substituted or unsubstituted alicyclic hydrocarbon group or a substituted or unsubstituted alicyclic heterocyclic group.
17. The compound according to claim 16 , wherein the alicyclic hydrocarbon group is a lower cycloalkyl group.
18. The compound according to claim 16 , wherein the alicyclic hydrocarbon group is cyclohexyl.
19. The compound according to claim 16 , wherein the alicyclic heterocyclic group is a saturated alicyclic heterocyclic group.
20. The compound according to claim 16 , wherein the alicyclic heterocyclic group is tetrahydropyranyl, tetrahydrothiopyranyl or piperidyl.
21. The compound according to claim 16 , wherein the alicyclic heterocyclic group is tetrahydropyranyl.
22. A compound selected from the group consisting of 7-(4-ethoxyethoxyphenyl)-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-ethyl-7-(4-propoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-ethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-ethoxyethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-formyl-7-(4-propoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-formyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide, N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-1-propyl-2,3-dihydro-1-benzazepine-4-carboxamide, 1-benzyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-cyclopropylmethyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-phenyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(3,4-methylenedioxy)phenyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(2-methyloxazol-5-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-allyl-7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(3-thienyl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-2-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(1-methylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(3-methylisothiazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-(1-ethylpyrazol-4-yl)methyl-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide, 1-isobutyl-N-[4-[[N-methyl-N-(tetrahydropyran-5-yl)amino]methyl]phenyl]-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(thiazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(1-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide, 7-(4-butoxyethoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1-(2-methyltetrazol-5-yl)methyl-2,3-dihydro-1-benzazepine-4-carboxamide and salts thereof.
23. A method for producing a compound of the formula I:
wherein R 1 is a 5- to 6-membered aromatic ring which has a group of the formula: R-Z 1 -X-Z 2 - wherein R is a hydrogen atom or a substituted or unsubstituted hydrocarbon group, X is a substituted or unsubstituted alkylene chain, and Z 1 and Z 2 are respectively hetero-atoms, and which may have a further substituent, the group R may bind to the 5- to 6-membered aromatic ring to form a ring, Y is a substituted or unsubstituted imino group, R 2 and R 3 are respectively a substituted or unsubstituted aliphatic hydrocarbon group or a substituted or unsubstituted alicyclic heterocyclic group; or a salt thereof, which comprises subjecting a compound of the formula:
wherein R 1 and Y are as defined above, a salt or a reactive derivative thereof to a condensation reaction with a compound of the formula:
wherein R 2 and R 3 are as defined above, or a salt thereof;
and then optionally isolating said compound of formula I or a salt thereof.
24. A pharmaceutical composition which comprises the compound according to claim 1 or a salt thereof and a pharmaceutically acceptable carrier, excipient, binder or diluent.
25. A method for treating infectious diseases of HIV comprising administering a pharmaceutically effective amount of a compound of claim 1 or a salt thereof in combination with a protease inhibitor, a reverse transcriptase inhibitor or a combination thereof to a mammal in need thereof.
26. A method for treating AIDS comprising administering a pharmaceutically effective amount of a compound of claim 1 or a salt thereof to a mammal in need thereof.
27. A method for treatment of infectious diseases of HIV comprising administering an effective amount of a compound of claim 1 or a salt thereof to a mammal in need thereof.