TH75729A - Chemical compound - Google Patents

Abstract

DC60 (18/07/48) Compound formula (I) (chemical formula) (I) A mixture containing these substances, a method for preparing these substances, and their use in medical treatment (e.g., modifying the activity of CCR5 receptors in mammals). Compound formula (I) (chemical formula) (I) A mixture containing these substances, a method for preparing these substances, and their use in medical treatment (e.g., modifying the activity of CCR5 receptors in mammals).

Claims (14)

1. A compound with formula (I) (chemical formula) (I) in which: A is none or is (CH2)2; L is CH or N; M is NR1, O, S, S(O) or S(O)2; R1 is hydrogen, C1-6 alkyl [selectively substituted for phenyl {which group is selectively substituted for halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)} or heteroaryl {which group is selectively substituted for halo, Replaced by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(O)NH, S(O)2 NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}], phenyl {selectively replaced by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}, heteroaryl {selectively replaced by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O) (C1-4 alkyl) or S(O)2(C1-4 alkyl)}, S(O)2R5, S(O)2NR6R7, C(O)R8, C(O)2(C1-6 alkyl) (e.g., tert-butoxycarbonyl), C(O)2(phenyl(C1-2 alkyl)) (e.g., benzyloxycarbonyl) or C(O)NHR11; R2 is phenyl (optionally replaced by halo, CN or C1-4 haloalkyl), thienyl or halothianyl; R3 is hydrogen or methyl; Rb is hydrogen C1-3 alkyl; R4 is a five or six-carbon heterocycle. At least one atom, one to four nitrogen atoms, and, optionally, one oxygen or sulfur atom, - the carbon ring of the aforementioned heterocycle R4 is optionally replaced by oxo, C1-6 alkyl [which i.e., optionally replaced by halogen, CN, OH, C1-4 alkoxy, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl) or heterocyclyl. {These groups are selectively substituted with C1-6 alkyl [which is selectively substituted with oxo, halogen, OH, C1-4 alkoxy, OCF3, C(O)(C1-4 alkoxy), CN, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NH2, NH(C1-4 alkyl) or N(C1-4 alkyl)2], C(O)C1-4 alkyl) [which alkyl is selectively substituted with C1-4 alkoxy or fluoro], benzyl [which is selectively substituted with halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)], C (O)C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2 or S(O)2 (C1-4 alkyl) [which is selectively replaced by alkyl]}], C2-6 alkenyl, C3-6 cycloalkyl, CN, C(O)NH2, C(O)NH(phenylC1-2 alkyl), phenyl [which is selectively replaced by a halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)] or benzyl [which is selectively replaced by a halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, Cyanone, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2C1-4 alkyl)]; - This is possible, the nitrogen ring of the aforementioned heterocycle R4 is selectively replaced by the halogen C1-6 alkyl [selectively replaced by oxo, halogen, OH, C1-4 alkoxy, OCF3, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)2(C1-4 alkyl), C(O)(C1-4 alkoxy), CONH2, CONH(C1-4 alkyl), CON(C1-4 alkyl)2, cyano, aryl { selectively replaced by halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}, heteroaryl {selectively replaced by C1-4 oxo, halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}, heterocyclyl {Selected to be replaced by C1-4 alkyl, aryl [Selected to be replaced by halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)], SO2NH(C1-4 alkyl), SO2N(C1-4 alkyl)2, CONH(C1-4 alkyl), CON(C1-4 alkyl)2, CO(C1-4 alkyl), CO(aryl) [Selected to be replaced by halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)], SO2(aryl) [selectively replaced by halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)]}], C3-6 cycloalkyl, CO(C1-4 alkyl) [selectively replaced by halogen], CO(aryl) [selectively replaced by halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)]}], SO2(aryl) [selectively replaced by halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, Cyano, Nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)], SO2(C1-4 alkyl) [optionally replaced by fluorine], COO(C1-6 alkyl), aryl [optionally replaced by heterogen], C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, Cyano, Nitro, S(C1-4 alkyl),S (O)(C1-4 alkyl) or S(O)(C1-4 alkyl)], heteroaryl [selectively replaced by oxo, halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)(C1-4 alkyl)], CONH(C1-4 alkyl), CONH(aryl) [selectively replaced by halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)], SO2NH(C1-4 alkyl) or SO2N(C1-4 alkyl)2; - The requirement is that when the nitrogen ring of the aforementioned heterocycle R4 is replaced by an alkyl group, the aforementioned alkyl group does not contain an oxo, halogen, OH, C1-4 alkoxy, OCF3, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, S(C1-4 alkyl), S(O)(C1-4 alkyl), or S(O)2(C1-4 alkyl) substrate on the carbon attached to the nitrogen ring of the aforementioned heterocycle R4; the five or six member heterocycle R4 selectively fuses with cyclohexane, piperidine, benzene, pyridine, pyridazine, pyridin, or pyrazine; The carbon atom ring of the fused cyclohexane, piperidine, benzene, pyridine, pyridazine, pyrimidine, or pyrazine mentioned above is selectively replaced by a halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano-nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl), or S(O)2(C1-4 alkyl); and the nitrogen of the fused piperidine ring mentioned above. Selectively replaced by C1-4 alkyl [which is selectively replaced by oxo, halogen, OH, C1-4 alkoxy, OCF3, C(O)(C1-4 alkoxy), CN, C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NH2, NH(C1-4 alkyl) or N(C1-4 alkyl)2], C(O)(C1-4 alkyl) [which alkyl is selectively replaced by C1-4 alkoxy or halogen], benzyl [which is selectively replaced by halogen, C1-4 alkyl, C1-4 alkoxy, CF3, OCF3, cyano, nitro, S(C1-4 alkyl), S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)], C(O)(C1-4 alkoxy), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2 or S(O)2(C1-4 alkyl) [where the alkyl is selectively replaced by fluoro]; R5 is C1-6 alkyl [selectively replaced by halo (e.g. fluoro), C1-4 alkoxy, phenyl {where the group is selectively replaced by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)} or heteroaryl. {which are selectively replaced by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(O)NH, S(O)2NH, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}], cycloalkyl (selectively replaced by halo or C1-6 alkyl), pyranyl, phenyl {selectively replaced by halo C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}, heteroaryl {selectively replaced With halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)} or nitrogen with a heterocyclic ring having a 5- or 6- member {selectively replaced by S(O)2(C1-4 alkyl) or C(O)(C1-4 alkyl)}; R8 and R11, independently, are: hydrogen, C1-6 alkyl [selectively replaced by a halo (e.g., fluoro), C1-4 alkoxy, phenyl {which is selectively replaced by a halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)} or heteroaryl. {which are selectively replaced by halo C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}], C3-7 cycloalkyl (selectively replaced by halo or C1-6 alkyl), pyranyl, phenyl {selectively replaced by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}, heteroaryl {Optional substitution with halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C)-4 alkyl)} or nitrogen with a heterocyclic ring having a 5- or 6-member {Optional substitution with S(O)2(C1-4 alkyl) or C(O)(C1-4 alkyl)}; R6 and R7, independently, are hydrogen or C1-4 alkyl; Or R6 and R7 combined form a 5- or 6-member group, which is chosen to be replaced by C1-4 alkyl or phenyl (where the phenyl group is chosen to be replaced by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, S(O)mC1-4 alkyl, S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, NHS(O2)2(C1-4 alkyl), NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(O)NH2, C(O) NH2, C(O)NH(C1-4 alkyl), NHC(O)(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3, CHF2, CH2F, CH2CF3, or OCF3); R9 and R10, independently, are hydrogen or C1-6 alkyl; or their pharmacologically acceptable salts. 2. The compound formula (I) as claimed in claim 1, where L is CH. 3. Compound formula (I) as claimed under claim 1 or 2, where M is NR1. 4. Compound formula (I) as requested in claim 3, where R1 is C1-6 alkyl, phenyl {selectively substituted for halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)}, S(O)2 R5 or C(O)R8; R5 and R8 are C1-6 alkyl, CF3, C3-7 cycloalkyl (selectively replaced by halo or C1-6 alkyl), phenyl {selectively replaced by halo, C1-4 alkyl, C1-4 alkoxy, cyano, nitro, CF3, OCF3, (C1-4 alkyl)C(O)NH, S(O)2NH2, C1-4 alkylthio, S(O)(C1-4 alkyl) or S(O)2(C1-4 alkyl)} or nitrogen with a 5- or 6- heterocyclic ring member {selectively replaced by S(O)2(C1-4 alkyl) or C(O)(C1-4 alkyl)}. 5. Compound formula (I) as claimed in any of the preceding claims, where R2 is phenyl selectively substituted for fluoro, chloro or CF3. 6. A compound formula (I) as claimed under any of the preceding claims, where R3 is hydrogen. 7. A compound formula (I) as claimed in any of the preceding claims, where R9 is hydrogen. 8. A compound formula (I) as claimed under any of the preceding claims, where R10 is hydrogen. 9. A compound formula (I) as claimed under any of the preceding claims, where Rb is hydrogen. 10. A compound formula (I) as claimed in any of the preceding claims, in which R4 is 1,2,4-triazole, thiazolyl, 1,2,4-oxadiazolyl, propiridinyl, benzimidazolyl, 1,3-dihydro-2H-benzimidazolyl, benzotriazolyl or imidazopyridinyl (e.g., imidazo[4,5c]pyridinyl, 1,4,6,7-tetrahydro-5H-imidazo[4,5c]pyridinyl or 4,5,6,7-tetrahydro-3H-imidazo[4,5c]pyridinyl), each group which is either unsubstituted or substituted by one or two identical or different C1-6 alkyl groups (e.g., C1-4 alkyl; For example, methyl), C3-6cycloalkyl, CF3, CHF2, OH (which may tontomerize to the cheto form), oxo (which may tontomerize to the hydroxyl form), C1-4alkyl selectively substituted by heterocyclic (which itself is selectively substituted by S(O)2(C1-4alkyl)), S(O)2(C1-4alkyl), (C1-4alkyl)C(O), (C1-4haloalkyl)C(O), (C1-4alcoxi)C(O), C(O)NH, C(O)NH(C1-4alkyl), C(O)NH(phenyl(C1-2alkyl)) or phenyl (C1-2alkyl); The aforementioned phenyl group (C1-2 alkyl) phenyls were selectively replaced by halo, C1-4 alkyl, C1-4 alkoxy, cyano, or S(O)2(C1-4 alkyl). 11. Procedure for the preparation of the compounds as requested in claim 1. This procedure consists of the reductive amino reaction of compound formula (II): (chemical formula) (II) with compound formula (III): (chemical formula) (III) with NaBH(OA)3 (where Ac is C(O)CH3) and acetic acid in a suitable solvent at room temperature. 12. A pharmaceutical mixture consisting of the compounds claimed under claim 1, or their salts which are pharmaceutically acceptable, and a forming agent, diluting agent or carrier which are pharmaceutically acceptable. 13. The compounds as claimed in claim 1, or their salts, which are pharmacologically recognized for use as medicine. 14. The compounds as claimed in claim 1, or their salts, which are pharmaceutically acceptable for the manufacture of medicines for therapeutic use.