Patent DE-102004035978-A1 (DE)
Title: New aminoadamantane derivatives useful for treating e.g. viral diseases, Parkinson's disease, Huntington's chorea, Alzheimer's disease, autism, tinnitus, Tourette syndrome, hypertension, sleep disorders and psychosis
Inventor: SCHREINER PETER R
IPC: C07C229/50
Filed: 2004-07-23
Abstract: Aminoadamantane derivatives (I) are new. Aminoadamantane derivatives of formula (I) are new. R 1>, R 2>H, F, Cl, Br, I, L, OH, O ->, OL, SH, S ->, SL, SOH, SO 2H, SO 3H, SOL, SO 2L, NO, NO 2, CN, C=NL, NC, N=CL, NH 2, NHL, NH 2L +>, NYZ, NHYZ +>, CHO, COL, COOH, COO ->, COOL, OCHO, OCOL, CONH 2, CONHL, CONYZ, NHCOOH, NLCOOH, NLCOOL, NHCOOL, NHCOL, NHC(NH)NH 2, NHC(NH)NYZ, NYC(NZ)NHL, NHC(NH)NHL, SO 2NHL, SO 2NH 2, SO 2NYZ, NYSO 2Z, O(C pH 2p) xOL, (C pH 2p) xOL, O(C pH 2pO) xL, (C pH 2pO) xL (where terminal amines are optionally present as hydrohalogenides, acetamides, mono-, di- or trihaloacetamides) CH 2(C rH 2r-a)COOH (or its 1-adamantyl ester), or R 6>(side chain of amino acid); L, Y and Z : 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, 3-20C cycloalk(en)yl, 1-20C heterocycloalk(en)yl, 5-20C (hetero)aryl, alkyl(hetero)aryl, alkyl(hetero)cycloalkyl, or alkenyl(hetero)cycloalkyl (heterocycles contain 1-5 N, O, S and/or P) (all optionally substituted with 1-3 F, Cl, Br, I, OH, OR, SH, SR, SO 3H, CN, COOH, COOR, OCOR, CONH 2, CONHR, CONRR, NH 2, NHR or NRR); R : 1-10C alkyl; p : 1-4; x : 1-10; r : 10-18; a : 0, 2, 4, 6, 8; R 3>H or L; A : bond, CO(AA) mor D 1>; AA : alpha , beta , gamma or delta -amino acid; m : 0-10; either R 4>R 4>' when A is CO(AA) mor R 1>when A is a bond; R 4>' : H, L or 1-adamantyl (optionally substituted by 1-3 F, Cl, Br, I, OH, OR, SH, SR, SO 3H, CN, COOH, COOR, CONH 2, CONHR, CONRR, NH 2, NHR or NRR); B : bond, (AA) sor D 1>; s : 0-10; R 5>R 4>', SO 2L, COL, COOL, (C pH 2p) xOL or (C pH 2pO) xL; n : 1-40; or R4 and R5 : absent; n : 1-25; B : (AA) zor 1-25-membered depsipeptide containing AA and 1-10C (cyclo)aliphatic, aromatic or araliphatic carboxylic acid (optionally substituted by 1-3 OH, CO, COOH, F Cl, Br, I, NH 2,SH or S-S); z : 3-25 (when n = 1) or 2-25 (when n = 2); or B : 3-aminoadamantanecarboxylic acid (when n=1); and R6 : benzyl, 4-hydroxybenzyl, 1H-indolylmethyl, 1H-imidazolylmethyl, 4-aminobutyl, 3-guanidylpropyl, 2-methylthioethyl, hydroxymethyl, 1-hydroxyethyl, 2-carboxyethyl, 2-carbamoyl-1-methylethyl, carboxymethyl, thiomethyl, 2-carbamoylethyl, carbamoylmethyl, selenomethyl, 3-aminopropyl or 2-aminophenyl-2-oxoethyl; and D 1>2-10-membered depsipeptide containing AA and 1-10C (cyclo)aliphatic, aromatic or araliphatic carboxylic acid (optionally substituted by 1-3 OH, CO, COOH, F Cl, Br, I, NH 2,SH or S-S). Provided that the following compounds are excluded when n = 1 and A and B are bonds: compounds where R 1>, R 2>and R 3>are H, R 4>is COOH and R 5>is H or acetyl; compounds where R 1>, R 2>and R 3>are H, R 4>is CH 2COOH and R 5>is acetyl; compounds where R 1>and R 2>are Me and R 3>, R 4>and R 5>are H; compounds where R 1>and R 2>are H, halo, CN, COOH, Me, Et, OMe, OEt, n-Pr, i-Pr, COOMe or COOEt, R 3>is H, R 4>is COOH and R 5>is 3-NHQ-2-hydroxybenzoyl (Q = formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or isopropoxycarbonyl); compounds where R 3>and R 5>are H, aryl or heteroaryl, or 1-10C (cyclo)alkyl, (cyclo)alkenyl or (cyclo)alkynyl optionally substituted with halo, aryl or heteroaryl, and R 1>, R 2>and R 4>are H, aryl or heteroaryl, or 1-10C (cyclo)alkyl, (cyclo)alkenyl or (cyclo)alkynyl optionally substituted with halo, aryl or heteroaryl, or NR 19>R 20>where R 19>and R 20>are H, aryl or heteroaryl, or 1-10C (cyclo)alkyl, (cyclo)alkenyl or (cyclo)alkynyl optionally substituted with halo, aryl or heteroaryl or NR 19>R 20>is a heterocyclic group; compounds where R 1>and R 2>are lower alkyl, R 3>is H or lower (cyclo)alkyl and R 5>is H or Me. Independent claims are also included for the following: (1) preparation of (I); and (2) preparation of 3,5-disubstituted 1-aminoadamantane derivatives by suspensing a 1,3-disubstituted adamantane derivative in nitric acid and sulfuric acid, adding oleum, reacting with a nitrile and reacting with an alcohol or water. [Image] ACTIVITY : Virucide; Antiparkinsonian; Neuroprotective; Anticonvulsant; Nootropic; Neuroleptic; Hypotensive; Tranquilizer; Antidepressant; Antimanic; Protozoacide. MECHANISM OF ACTION : Gamma-aminobutyric acid (GABA) uptake inhibitor. t-Butyl 3-(3-amino-1-adamantylcarboxamido)-1-adamantanecarboxylate (Ia) inhibited mGAT1-mediated uptake of GABA in Xenopusoocytes in a dose dependent manner at concentrations of 0-1000 mu M.