Patent EA-005289-B1 (EA)
Title: Tetrahydropyridino or piperidino heterocyclic derivatives as crf receptor antagonists
Inventor: NAKAZATO ATSURO
IPC: C07D401/04
Filed: 2001-07-04
Abstract: 1. A tetrahydropyridino or piperidino derivative represented by the formula [I]: A-Het [I] wherein A is a group represented by the following formula [II] or [III]: wherein the position of substitution by the Y-(CH2)n- group of the group represented by the formula [II] is 4-position or 5-position, the position of substitution by the Y-C(R<0>)=group of the group represented by the formula [III] is 3-position or 4-position, R<0> is a hydrogen atom, a C1-5alkyl group, a C3-8cycloalkyl group or a C3-8cycloalkyl-C1-5alkyl group, n is an integer of 0 to 5, and Y is a cyano group, a group represented by the formula -CONR<1>R<2> (wherein each of R<1> and R<2>, which may be the same or different, is a hydrogen atom, a C1-5alkyl group, a C3-8cycloalkyl group, a C3-8cycloalkyl-C1-5alkyl group, a C1-5alkoxy-C1-5alkyl group, a C3-8cycloalkyloxy-C1-5alkyl group or a phenyl group, or R<1> and R<2>, when taken together with the adjacent nitrogen atom, represent a 5- to 8-membered saturated heterocyclic group represented by the formula: (wherein B is CH2, NH, N-C1-5alkyl, N-C3-8cycloalkyl, N-C1-5alkyl-C3-8cycloalkyl, O or S) or a group represented by the formula -CO2R<3> (wherein R<3> is a hydrogen atom, a C1-5alkyl group, a C3-8cycloalkyl group, a C3-8cycloalkyl-C1-5alkyl group, a C1-5alkoxy-C1-5alkyl group, a C3-8cycloalkyloxy-C1-5alkyl group or a phenyl group), and Het is any of heterocyclic groups represented by the following formulas form (01) to form (20): wherein E is CH or N, R<4> is a hydrogen atom, a C1-5alkyl group, a C3-8cycloalkyl group, a C3-8cycloalkyl-C1-5alkyl group, a hydroxyl group, a C1-5alkoxy group, a C3-8cycloalkyloxy group, or a group represented by the formula -N(R<10>)R<11> (wherein each of R<10> and R<11>, which may be the same or different, is a hydrogen atom, a C1-5alkyl group, a C3-8cycloalkyl group or a C3-8cycloalkyl-C1-5alkyl group), each of R<5>, R<6>, R<7> and R<8>, which may be the same or different, is a hydrogen atom, a halogen atom, a C1-5alkyl group, a C3-8cycloalkyl group, a C3-8cycloalkyl-C1-5alkyl group, a hydroxyl group, a C1-5alkoxy group, a C3-8cycloalkyloxy group, a group represented by the formula -N(R<12>)R<13> (wherein each of R<12> and R<13>, which may be the same or different, is a hydrogen atom, a C1-5alkyl group, a C3-8cycloalkyl group or a C3-8cycloalkyl-C1-5alkyl group), a group represented by the formula -CO2R<14> (wherein R<14> is a hydrogen atom, a C1-5alkyl group, a C3-8cycloalkyl group, a C3-8cycloalkyl-C1-5alkyl group, a C1-5alkoxy-C1-5alkyl group, a C3-8cycloalkyloxy-C1-5alkyl group or a phenyl group), a cyano group, a nitro group, a C1-5alkylthio group, a trifluoromethyl group or a trifluoromethoxy group, R<9> is a hydrogen atom, a C1-5alkyl group, a C2-5alkenyl group, a C2-5alkynyl group, a C3-8cycloalkyl group or a C3-8cycloalkyl-C1-5alkyl group, and Ar is an aryl or heteroaryl group unsubstituted or substituted with 1 to 3 substituents which may be the same or different and are selected from halogen atoms, C1-5alkyl groups, C1-5alkoxy groups, C1-5alkylthio groups, trifluoromethyl group, trifluoromethoxy group and groups represented by the formula -N(R<15>)R<16> (wherein each of R<15> and R<16>, which may be the same or different, is a hydrogen atom or a C1-5alkyl group); or a pharmaceutically acceptable salt thereof or its hydrate. 2. The tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to claim 1, which is a compound represented by the formula [IV]: wherein Het is as defined above, and m is 0 or 1 3. The tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to claim 2, which is a compound represented by the formula [V]: wherein R<4>, R<5>, R<6>, R<7>, Ar and m are as defined above. 4. The tetrahydropyridino heterocyclic derivative or a pharmaceutically acceptable salt thereof or its hydrate according to claim 3, wherein m in the formula [V] is 0. 5. The tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to claim 4, which is a compound represented by the formula [VI]: wherein each of R<18>, R<19> and R<20>, which may be the same or different, is a hydrogen atom, a methyl group, a fluorine atom or a chlorine atom, and each of X<5>, X<6> and X<7>, which may be the same or different, is a hydrogen atom, a methyl group, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group. 6. The tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to claim 5, which is a compound represented by the formula [VII]: wherein R<18>, R<19> and R<20> are as defined above, and each of X<8> and X<9>, which may be the same or different, is a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group. 7. The tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to claim 6, which is a compound represented by the formula [VIII]: wherein X<9> is as defined above, and R<21> is a hydrogen atom, a chlorine atom or a methyl group. 8. The tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to claim 2, which is a compound represented by the formula [IX]: wherein R<4>, R<5>, R<6>, Ar and m are as defined above. 9. The tetrahydropyridino heterocyclic derivative or a pharmaceutically acceptable salt thereof or its hydrate according to claim 8, wherein m in the formula [IX] is 0. 10. The tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to claim 9, which is a compound represented by the formula [X]: wherein each of R<22> and R<23>, which may be the same or different, is a hydrogen atom or a methyl group, and each of X<10>, X<11> and X<12>, which may be the same or different, is a hydrogen atom, a chlorine atom, a bromine atom, a methoxy group, a methylthio group or a trifluoromethyl group. 11. The tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to claim 9, which is a compound represented by the formula [XI]: wherein X<13> is a chlorine atom or a bromine atom, X<14> is a chlorine atom, a bromine atom or a trifluoromethyl group, and X<15> is a hydrogen atom, a chlorine atom, a bromine atom, a methoxy group, a methylthio group or a trifluoromethyl group. 12. An antagonist against CRF receptors, comprising a tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to any one of claims 1 to 11, as an active ingredient. 13. Use of a tetrahydropyridino heterocyclic derivative, a pharmaceutically acceptable salt thereof or its hydrate according to any one of claims 1 to 11, as an antagonist against CRF receptors.