Patent EA-001324-B1 (EA)
Title: Heterobicyclic derivatives
Inventor: SHIMAZAKI NORIHIKO
IPC: C07D471/04
Filed: 1996-12-13
Abstract: 1. A compound of the formula    wherein R<1> is pyridyl (C1-6) alkyl, N-oxidopyridyl (C1-6) alkyl or  imidazolyl (C1-6) alkyl, R<2> is aminophenyl, [protected amino] phenyl, [[[halophenyl] (C2-6) alkenoyl] amino] phenyl, [[pyridyl (C2-6) alkenoyl] amino] phenyl, [[[N-oxidopyridyl] (C2-6) alkenoyl] amino] phenyl, [[[protected aminopyridyl](C2-6)alkenoyl]amino]phenyl, [thiazolylcarbonylamino]phenyl, which may have pyridyl, naphthyl, having C1-6 alkoxy and halogen, [dihalophenyl] (C2-6) alkenyl, [N-oxidopyridyl] (C2-6) alkenyl, [aminopyridyl] (C2-6) alkenyl, [protected aminopyridyl] (C2-6) alkenyl, [carboxypyridyl] (C2-6) alkenyl, [protected carboxypyridyl] (C2-6) alkenyl, [[pyridyl (C2-6) alkenyl] pyridyl] (C2-6) alkenyl, [[carboxy (C2-6) alkenyl] pyridyl] (C2-6) alkenyl, [[protected carboxy (C2-6) alkenyl] pyridyl] (C2-6) alkenyl, [pyridyl (C2-6) alkenyl] pyridyl, C1-6 alkylbenzothiazolyl or [halopyridylcarbonyl] amino, with proviso that when R<2> is [[4-pyridyl (C2-6) alkenoyl] amino] phenyl, aminophenyl, [C1-6 alkanoylamino]phenyl or [dihalophenyl] (C2-6)alkenyl, then  R<1> is N-oxidopyridyl (C1-6) alkyl or imidazolyl (C1-6)alkyl, and a pharmaceutically acceptable salt thereof.  2. The compound of claim 1, wherein R<2> is aminophenyl, [C1-6 alkanoylamino]phenyl, [[[halophenyl] (C2-6) alkenoyl]amino]phenyl, [[pyridyl(C2-6)alkenoyl]amino]phenyl, [[[N-oxidopyridyl] (C2-6)alkenoyl]amino]phenyl, [[[acylaminopyridyl](C2-6)alkenoyl]amino]phenyl [[pyridylthiazolyl]carbonylamino]phenyl, naphthyl having C1-6 alkoxy and halogen, [dihalophenyl](C2-6)alkenyl, [N-oxidopyridyl](C2-6)alkenyl, [aminopyridyl](C2-6)alkenyl, [[acylamino]pyridyl] (C2-6)alkenyl, [carboxypyridyl](C2-6)alkenyl, [esterified carboxypyridyl](C2-6)alkenyl, [[pyridyl(C2-6)alkenyl]pyridyl](C2-6)alkenyl, [[carboxy(C2-6)alkenyl]pyridyl](C2-6)alkenyl, [[esterified carboxy(C2-6)alkenyl]pyridyl](C2-6)alkenyl, [pyridyl(C2-6)alkenyl]pyridyl, C1-6 alkylbenzothiazolyl or halopyridylcarbonylamino, with proviso that when R<2> is [[4-pyridyl(C2-6)alkenoyl] amino] phenyl, aminophenyl, [C1-6 alkanoylamino]phenyl or [dihalophenyl](C2-6)alkenyl, then R<1> is N-oxidopyridyl(C1-6)alkyl or imidazolyl(C1-6)alkyl.  3. The compound of claim 2, wherein R<2> is aminophenyl, [C1-6 alkanoylamino]phenyl, [[[halophenyl] (C2-6) alkenoyl]amino]phenyl, [[pyridyl(C2-6)alkenoyl]amino]phenyl, [[[N-oxidopyridyl] (C2-6)alkenoyl]amino]phenyl, [[[[C1-6 alkanoylamino]pyridyl](C2-6)alkenoyl]amino]phenyl, [[pyridylthiazolyl]carbonylamino]phenyl, naphthyl having C1-6 alkoxy and halogen, [dihalophenyl](C2-6)alkenyl, [N-oxidopyridyl](C2-6)alkenyl, [aminopyridyl](C2-6)alkenyl, (C1-6) [[C1-6 alkanoylamino]pyridyl](C2-6)alkenyl, [[mono(or di or tri)halo(C1-6)alkanoylamino]pyridyl](C2-6)alkenyl, [carboxypyridyl](C2-6)alkenyl, [C1-6 alkoxycarbonylpyridyl] (C2-6)alkenyl, [[pyridyl(C2-6)alkenyl]pyridyl](C2-6)alkenyl, [[carboxy (C2-6)alkenyl] pyridyl] (C2-6)alkenyl, [[C1-6 alkoxycarbonyl(C2-6)alkenyl] pyridyl] (C2-6)alkenyl, [pyridyl(C2-6)alkenyl] pyridyl, C1-6 alkylbenzothiazolyl or  halopyridylcarbonylamino, with proviso that when R<2> is [[4-pyridyl (C2-6) alkenoyl] amino] phenyl, aminophenyl, [C1-6 alkanoylamino]phenyl or [dihalophenyl] (C2-6) alkenyl, then  R<1> is N-oxidopyridyl (C1-6) alkyl or imidazolyl (C1-6)alkyl. 4. The compound of claim 3, wherein R<2> is aminophenyl, [C1-6 alkanoylamino]phenyl, [[[halophenyl] (C2-6) alkenoyl]amino]phenyl, [[pyridyl(C2-6)alkenoyl]amino]phenyl, [[[N-oxidopyridyl] (C2-6)alkenoyl]amino]phenyl, [[[[C1-6 alkanoylamino]pyridyl](C2-6)alkenoyl]amino]phenyl, [[pyridylthiazolyl]carbonylamino]phenyl, naphthyl having C1-6 alkoxy and halogen, [dihalophenyl](C2-6)alkenyl, [N-oxidopyridyl](C2-6)alkenyl, [aminopyridyl](C2-6)alkenyl, [[alkanoylamino]pyridyl] (C2-6)alkenyl, [[trihalo(C1-6)alkanoylamino]pyridyl](C2-6)alkenyl, [carboxypyridyl] (C2-6)alkenyl, [alkoxycarbonylpyridyl](C2-6)alkenyl, [[pyridyl(C2-6)alkenyl]pyridyl](C2-6)alkenyl,  [[carboxy (C2-6)alkenyl]pyridyl] (C2-6)alkenyl, [[C1-6 alkoxycarbonyl (C2-6) alkenyl] pyridyl](C2-6)alkenyl, [pyridyl(C2-6)alkenyl]pyridyl, C1-6 alkylbenzothiazolyl or halopyridylcarbonylamino, with proviso that when R<2> is [[4-pyridyl(C2-6)alkenoyl] amino] phenyl, aminophenyl, [C1-6 alkanoylamino]phenyl or [dihalophenyl](C2-6)alkenyl, then R<1> is N-oxidopyridyl(C1-6)alkyl or imidazolyl(C1-6)alkyl. 5. The compound of claim 4, wherein R<1> is pyridyl (C1-6)alkyl, and R<2> is [[2-pyridyl(C2-6)alkenoyl]amino]phenyl, [[3-pyridyl(C2-6)alkenoyl]amino]phenyl, [[pyridylthiazolyl]carbonylamino]phenyl, [aminopyridyl](C2-6)alkenyl,  [[C1-6 alkanoylamino]pyridyl](C2-6)alkenyl, [[trihalo(C1-6)alkanoylamino]pyridyl](C2-6)alkenyl, [C1-6 alkoxycarbonylpyridyl] (C2-6)alkenyl, [[pyridyl(C2-6)alkenyl]pyridyl](C2-6)alkenyl or C1-6 alkylbenzothiazolyl. 6. The compound of claim 4,wherein  R<1> is imidazolyl (C1-6) alkyl, and R<2> is naphthyl having C1-6 alkoxy and halogen. 7. A process for preparing a compound of the formula    wherein R<1> and R<2> are each as defined in claim 1, or a salt thereof, which comprises  (1) reacting a compound of the formula   wherein R<2> is as defined above, or salts thereof with a compound of the formula   wherein R<1> is as defined above, or a salt thereof to give a compound of the formula    wherein R<1> and R<2> are each as defined above, or salts thereof, or  (2) acylation a compound of the formula   wherein R<1> is as defined above, and  R<2>a is [aminopyridyl](C2-6)alkenyl, or its reactive derivative at the amino group, or salts thereof to give a compound of the formula   wherein R<1> is as defined above and  R<2>b is [acylaminopyridyl](C2-6)alkenyl, or salts thereof, or  (3) deacylation a compound of the formula   wherein R<1> is as defined above, R<2>c is [C1-6 alkanoylamino]phenyl,  [[[halophenyl](C2-6)alkenoyl]amino]phenyl, [[pyridyl(C2-6)alkenoyl]amino]phenyl, [[[N-oxidopyridyl](C2-6)alkenoyl]amino]phenyl, [[[protected aminopyridyl](C2-6)alkenoyl]amino]phenyl, [thiazolylcarbonylamino]phenyl which may have pyridyl, or [acylaminopyridyl](C2-6)alkenyl, or salts thereof with producing a compound of formula    wherein R<1> is as defined above, and R<2>d is aminophenyl or [aminopyridyl] (C2-6)alkenyl, or salts thereof, or (4) reacting a compound of the formula    wherein R<1> is as defined above, R<2>e is aminophenyl,  or its reactive derivative at the amino group, or salts thereof with a compound of the formula R<3>-OH, wherein R<3> is C1-6 alkanoyl, [halophenyl](C2-6) alkenoyl, pyridyl(C2-6)alkenoyl, [N-oxidopyridyl](C2-6)alkenoyl, [protected aminopyridyl](C2-6)alkenoyl or thiazolylcarbonyl, which may have pyridyl, or its reactive derivative at the carboxy group, or a salt thereof with producing a compound of the formula   wherein R<1> is as defined above, R<2>f is [C1-6 alkanoylamino] amino]phenyl, [[[halophenyl] (C2-6) alkenoyl] amino] phenyl, [[pyridyl (C2-6) alkenoyl] amino] phenyl, [[[N-oxidopyridyl] (C2-6) alkenoyl] amino] phenyl, [[[protected aminopyridyl](C2-6)alkenoyl]amino]phenyl, or [thiazolylcarbonylamino]phenyl, which may have pyridyl, or (5) removal of N-protective group from the compound of formula   wherein R<2> is as defined above, R<4> is N-protective group, A is C1-6 alkylene, and Y<-> is halide, or salts thereof with producing a compound of the formula   wherein R<2> and A are each as defined above, or salts thereof.  8.. A pharmaceutical composition which comprises, as an  active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers. 9. A use of a compound of claim 1 or a pharmaceutically  acceptable salt thereof as an inhibitor on the production of phosphodiesterase IV (PDE-IV) and an inhibitor on the production of tumor necrosis factor (TNF). 10. A method for the prophylactic or therapeutic treatment of phosphodiesterase IV (PDE-IV) and tumor necrosis factor (TNF) mediated diseases which comprises administering a compound of claim 1 or a pharmaceutically acceptable salts thereof to human or animals. 11. A process for preparing a pharmaceutical composition  which comprises admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier.