Patent EP-2518052-A1 (EP)
Inventor: NOLTE BERND DR
IPC: A61K31/137
Filed: 2009-03-25
Abstract: Substituted 4-aminocyclohexane derivatives (I) and their stereoisomers or their mixtures, free compounds and/or salts are new, where (I) excludes 4-(dimethylamino)-1-methyl-4-p-tolylcyclohexyl acetate. Substituted 4-aminocyclohexane derivatives of formula (I) and their stereoisomers or their mixtures, free compounds and/or salts are new, where (I) excludes 4-(dimethylamino)-1-methyl-4-p-tolylcyclohexyl acetate. Either Y 1>, Y1a, Y 2>, Y2a, Y 3>, Y3a, Y 4>, Y4a : H, F, Cl, Br, I, CN, NO 2, CHO, R 0>, C(=O)R 0>, C(=O)H, -C(=O)-OH, -C(=O)OR 0>, C(=O)NH 2, C(=O)NHR 0>, C(=O)N(R 0>) 2, OH, OR 0>, -OC(=O)H, -OC(=O)R 0>, -OC(=O)OR 0>, -OC(=O)NHR 0>, -OC(=O) N(R 0>) 2, -SH, -SR 0>, -SO 3H, -S(=O) 1 - 2-R 0>, -S(=O) 1 - 2NH 2, -NH 2, -NHR 0>, -N(R 0>) 2, -N +>(R 0>) 3, -N +>(R 0>) 2O ->, -NHC(=O)R 0>, -NHC(=O)OR 0>, NHC(=O)-NH 2, -NHC(=O)-NHR 0>or -NHC(=O)N(R 0>) 2, preferably -H, -F, -Cl, -CN or 1-8C-aliphate; or Y 1>Y1a, Y 2>Y2a, Y 3>Y3a, Y 4>Y4a : (=O); Q : R 0>, -C(=O)-R 0>, -C(=O)OR 0>, -C(=O)NHR 0>, -C(=O)N(R 0>) 2or -C(=NH)-R 0>; R 0> : 1-8C-aliphate, 3-12C-cycloaliphate, aryl, heteroaryl, 1-8C-aliphate-3-12C-cycloaliphate, 1-8C-aliphate-aryl, 1-8C-aliphate-heteroaryl, 3-8C-cycloaliphate-1-8C-aliphate, 3-8C-cycloaliphate-aryl or -3-8C-cycloaliphate-heteroaryl, where the: aliphate is optionally saturated, optionally substituted aliphatic hydrocarbon, cycloaliphate is optionally saturated, optionally substituted alicyclic, mono- or multicyclic 3-8C-hydrocarbon (where the H atoms of the aliphate or cycloaliphate are one or more times substituted by F, Cl, Br, I, CN, -NO 2, -CHO, =O, -R 0>, -C(=O)R 0>, -C(=O)H, -C(=O)OH, -C(=O)OR 0>, -C(=O)NH 2, -C(=O) NHR 0>, -C(=O)N(R 0>) 2, -OH, -OR 0>, -OC(=O)H, -OC(=O)R 0>, -OC(=O)OR 0>, -OC(=O)NHR 0>, -OC(=O)N(R 0>) 2, -SH, -SR 0>, -SO 3H, -S(=O) 1 - 2-R 0>, -S(=O) 12NH 2, -NH 2, -NHR 0>, -N(R 0>) 2, -N +>(R 0>) 3, -N +>(R 0>) 2O ->, -NHC(=O)R 0>, -NHC(=O)OR 0>, -NHC(=O)NH 2, -NHC(=O)-NHR 0>, -NH-C(=O)N(R 0>) 2, -Si(R 0>) 3or -PO(OR 0>) 2), aryl is carbocyclic ring system with at least an aromatic ring and without heteroatoms (which are optionally further condensed with further saturated, partially unsaturated or aromatic ring system and optionally substituted in any position), or heteroaryl is 5-7 membered cyclic aromatic residue containing 1-5 heteroatoms of O, N or S (where the heterocycle is optionally substituted in any position and is a part of a bi or polycyclic system) (where the aryl or heteroaryl is one or more times substituted and the one or more H atoms of the ring system are substituted by F, Cl, Br, I, CN, -NO 2, -CHO, =O, -R 0>, -C(=O)R 0>, -C(=O)H, -C(=O)OH, -C(=O)OR 0>, -C(=O)NH 2, -C(=O)NHR 0>, -C(=O)N(R 0>) 2, -OH, -O(CH 2) 1 - 2O-, -OR 0>, -OC(=O)H, -OC(=O)R 0>, -OC(=O)OR 0>, -OC(=O)NHR 0>, -OC(=O)N(R 0>) 2, -SH, -SR 0>, -SO 3H, -S(=O) 1 - 2-R 0>, -S(=O) 12NH 2, -NH 2, -NHR 0>, -N(R 0>) 2, -N +>(R 0>) 3, -N +>(R 0>) 2O ->, -NHC(=O)R 0>, -NHC(=O)OR 0>, -NHC(=O) NH 2, -NHC(=O)-NHR 0>, -NH-C(=O)N(R 0>) 2, -Si(R 0>) 3or -PO(OR 0>) 2and optionally the N-atom is oxidized); either R 1>, R 2> : H or R 0>; or R 1>R 2> : -CH 2CH 2OCH 2CH 2-, -CH 2-CH 3NR 4>CH 2CH 2- or -(CH 2) 3 - 6; (hetero-)aryl : heteroaryl or aryl; R 4> : H, R 0>, or -C(=O)R 0>; X : O, S or NR1a; either R1a : -H, -R 0>, -S(=O) 0 - 2R 0>, -C(=O)R 0>, -C(=O)OR 0>, -C(=O)NH 2, -C(=O)NHR 0>or -C(=O)N(R 0>) 2; and R1b : -H, -R 0>, -C(=O)H, -C(=O)R 0>, -C(=O)OH, -C(=O)OR 0>, -C(=O)NH 2, -C(=O)NHR 0>, -C(=O)N(R 0>) 2, -S(=O) 1 - 2-R 0>, -S(=O) 1 - 2-OR 0>, -S(=O) 1 - 2-NH 2, -S(=O) 1 - 2-NHR 0>or - S(=O) 1 - 2-N(R 0>) 2; or R1a, R1b : -(CH 2) 2 - 5-, -CH 2CH 2OCH 2CH 2- or -CH 2CH 2NR 4>CH 2CH 2-; and n : 0-12. Provided that: simultaneously R 1>and R 2>are not H; and when X is O, and n is 0, then R1b is not H. An independent claim is included for a medicament comprising (I), optionally additives, auxiliary materials and/or further active agents. [Image] ACTIVITY : Analgesic; Tranquilizer; Antidepressant; Anticonvulsant; Neuroprotective; Nootropic; Antialcoholic; Antiaddictive; Endocrine-Gen.; Cardiovascular-Gen.; Hypertensive; Hypotensive; Auditory; Antipruritic; Antimigraine; Gastrointestinal-Gen.; Anabolic; Eating-Disorders-Gen.; Anorectic; Antidiarrheic; Uropathic; Muscle relaxant; Anesthetic; Antidiuretic. MECHANISM OF ACTION : mu -Opioid receptor binder; Opioid receptor-like 1 receptor binder. The binding affinity of (I) towards opioid receptor-like 1 receptor was tested in Chinese Hamster Ovary-opioid receptor-like 1 receptor cell using receptor binding assay. The results showed that N,N,N'N'-tetramethyl-1,4-diphenyl-cyclohexan-1,4-diamine exhibited an inhibition constant value of 0.006 mu M.