SUBSTITUTED TETRA HYDRO NAPHTHALINES, METHOD FOR THEIR MANUFACTURE AND THEIR USE AS DRUGS

摘要

Substituted benzene compounds (I) and their salts, are new. Substituted benzene compounds of formula (I) and their salts, are new. Either R 1>, R 2>H, (1-8C)-alkyl, (1-4C)-alkoxy-(1-4C)-alkyl, (3-8C)-alkenyl, (3-8C)-alkynyl, CO(R 9>), (C(R 1> 0>)(R 1> 1>)) q-R 1> 2>, CO(C(R 1> 3>)(R 1> 4>)) rR 1> 5>, COO(1-8C)-alkyl or CO(C(R 1> 3>)(R 1> 4>)) rN(R 1> 6>)(R 1> 7>); and L 1>C(R 3> 4>)(R 3> 5>), C(R 3> 6>)(R 3> 7>)C(R 3> 8>)(R 3> 9>) or (3-6C)-cycloalkyl; and R 3> 4>-R 3> 9>H or (1-8C)-alkyl; or R 1>R 2>N : 4-10-membered mono-, bi- or spiro-cyclic ring (which additionally contains 0-3 heteroatoms except N, preferably O, N or S), where the heterocyclic ring system is additionally substituted by F, Cl, Br, CF 3, CN, (1-6C)-alkyl, (3-8C)-cycloalkyl, O-(1-8C)-alkyl, (1-4C)-alkoxy-(1-4C)-alkyl, hydroxy-(1-6C)-alkyl, oxo, CO(R 1> 8>), CON(R 1> 9>)(R 2> 0>), OH, COO(R 2> 1>), N(R 2> 2>)CO(1-6C)-alkyl, N(R 2> 3>)(R 2> 4>) or SO 2(1-6C)-alkyl; or R 1>R 3> 4>, R 1>R 3> 5>, R 1>R 3> 6>, R 1>R 3> 7>, R 1>R 3> 8>, R 1>R 3> 9>5-6-membered ring; R 1> 0>, R 1> 1>H, (1-6C)-alkyl, hydroxy-(1-2C)-alkyl, F or OH; either R 9>, R 1> 3>, R 1> 4>, R 1> 6>, R 1> 7>-R 2> 4>H or (1-6C)-alkyl; or R 1> 6>R 1> 7>N, R 2> 3>R 2> 4>N : 5-6 membered ring, which can include further 0-1 heteroatoms except N, which are NH, N-(1-6C)-alkyl, O or S; q, r : 0-6; R 1> 2>, R 1> 5>H, OH, F, O-(1-6C)-alkyl, S-(1-6C)-alkyl, O-phenyl, CN, COO(R 2> 5>), N(R 2> 6>)CO(1-6C)-alkyl, N(R 2> 7>)(R 2> 8>), CON(R 2> 9>)(R 3> 0>), SO 2(1-6C)-alkyl, 3-12-membered mono-, bi- or spiro-cyclic ring (containing 4 heteroatoms of N, O or S, and further substituted by F, Cl, Br, OH, CF 3, NO 2, CN, OCF 3, oxo, O-(1-6C)-alkyl, (1-4C)-alkoxy-(1-4C)-alkyl, S-(1-6C)-alkyl, (1-6C)-alkyl, (2-6C)-alkenyl, (3-8C)-cycloalkyl, O-(3-8C)-cycloalkyl, (3-8C)-cycloalkenyl, O-(3-8C)-cycloalkenyl, (2-6C)-alkynyl, N(R 3> 1>)(R 3> 2>), COO(R 3> 3>), SO 2(1-6C)-alkyl or COOH); either R 2> 5>-R 3> 3>H or (1-8C)-alkyl; or R 2> 7>R 2> 8>N, R 2> 9>R 3> 0>N, R 3> 1>R 3> 2>N : 5-6-membered ring, which includes 0-1 heteroatoms except N, which are NH, N-(1-6C)-alkyl, O or S; R 3>-R 5>H, F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O-(1-6C)-alkyl, S-(1-6C)-alkyl, O-(1-4C)-alkoxy-(1-4C)-alkyl, (1-6C)-alkyl, CON(R 4> 0>)(R 4> 1>) or CO(R 4> 2>); either R 4> 0>-R 4> 2>H or (1-8C)-alkyl; or R 4> 0>R 4> 1>N : 5-6-membered ring further including 0-1 heteroatoms except N, which are NH, N-(1-6C)-alkyl, O or S; X : O or C(R 4> 3>)(R43a); either R 6>,R6a, R 7>, R7a, R 4> 3>, R43a : H, F, (1-8C)-alkyl, OH, O-(1-6C)-alkyl; or R 6>R6a, R 4> 3>R43a : oxo; L 2>a bond, C(R 4> 4>)(R 4> 5>) or C(O)NR 8>(which binds with A at ortho position over a bridge containing one or two elements of C or N to form 9-10-membered bicyclic ring); R 8>, R 4> 4>, R 4> 5>H or (1-8C)-alkyl; A : 5-6-membered aromatic ring (which contains up to 2 heteroatoms of N, O or S, and substituted by one or more substituents of H, F, Cl, Br, I, OH, CF 3, NO 2, CN, OCF 3, O-(1-6C)-alkyl, O-(1-4C)-alkoxy-(1-4C)-alkyl, (1-6C)-alkyl, N(R 5> 4>)(R 5> 5>), SO 2-CH 3, CON(R 5> 6>)(R 5> 7>), N(R 5> 8>)CO(R 5> 9>) or CO(R 6> 0>)); either R 5> 4>-R 6> 0>H or (1-8C)-alkyl; or R 5> 4>R 5> 5>N, R 5> 6>R 5> 7>N : 5-6-membered ring, which can include 0-1 heteroatoms except N, which are NH, N-(1-6C)-alkyl, O or S; L 3>bond or linker with 1-4 member (where: the member is O, S, SO 2, N(R 6> 1>), CO, C(R 6> 2>)(R 6> 3>) or C?=C, and the linker exhibits no OCO or COO group), or C(R 6> 2>)(R 6> 3>)O; B 1>(1-6C)-alkyl, (1-4C)-alkoxy-(1-4C)-alkyl, hydroxy-(1-6C)-alkyl, 3-10-membered mono-, bi- or spirocyclic non-aromatic ring (which includes 0-3 heteroatoms of O, N or S, and the ring system is further substituted by one or more F, CF 3, (1-6C)-alkyl, O-(1-8C)-alkyl, (1-4C)-alkoxy-(1-4C)-alkyl, hydroxy-(1-4C)-alkyl, oxo, CO(R 6> 4>) or OH), or 4-10-membered mono-, bi- or spirocyclic non-aromatic ring (which includes 1-3 heteroatoms of O, N or S, and further substituted by one or more substituents of F, CF 3, (1-6C)-alkyl, O-(1-8C)-alkyl, (1-4C)-alkoxy-(1-4C)-alkyl, hydroxy-(1-4C)-alkyl, oxo, CO(R 6> 4>) or OH); and R 6> 1>, R 6> 2>, R 6> 3>, R 6> 4>H or (1-8C)-alkyl (when X is C(R 4> 3>)(R43a)). An independent claim is included for a medicament comprising one or more (I). [Image] - ACTIVITY : Metabolic; Antidiabetic; Antilipemic; Anorectic; Antiarteriosclerotic; Cardiant; Vasotropic; Cerebroprotective; Hepatotropic; Thrombolytic; Hypotensive; Cardiovascular-Gen; Neuroleptic; Antidepressant; Tranquilizer; Hypnotic; CNS-Gen; Antiinflammatory; Gastrointestinal-Gen. - MECHANISM OF ACTION : Melamine-concentrating hormone receptor-1 modulator. The ability of (I) to modulate melamine-concentrating hormone receptor-1 was tested using an in-vitro method. The results showed that (I) exhibited an IC 5 0value of less than 1 mu m, preferably 1 nm.