Patent FR-2881428-A1 (FR)
Title: New triterpenic alkaloids useful as a medicament to treat e.g. central nervous system and peripheral disorders
Inventor: GUILLOU CATHERINE
IPC: C07J63/00
Filed: 2005-02-02
Abstract: Triterpenic alkaloids (I) and their addition salts, isomers, enantiomers and/or diastereomers are new. Triterpenic alkaloids of formula (I) and their addition salts, isomers, enantiomers and/or diastereomers are new. R 1-CH 2X 1R 7, -CH=NR 5or -CH=O; X 1-X 3O, NH or S; R 7, R 8H, 1-10C alkyl, 1-10C alkyl-phenyl, 1-10C alkyl-carbonyl or SO 2R 9; R 91-10C alkyl or 1-10C alkyl-phenyl; either R ,R 3H or -C(=X)-R 10; or R 10H, 1-10C alkyl, (1-10C alkyl)phenyl, 3-10C cycloalkyl; R 4H, 10C alkyl or -X 3-R 12; R 12H (preferred), 1-10C alkylcarbonyl, 1-10C alkyl-phenyl or 1-10C alkyl-sulfonyl; R 5N-oxide-N +>OCH 3R 13or NCH 3R 13; R 13H, 3-10C cycloalkyl, 1-10C alkyl, phenyl or phthalimide (preferably CH 3); R 6=O or -OR 14; and R 14H, 1-10C alkyl, 1-10C alkylcarbonyl, 1-10C alkyl-phenyl or 1-10C alkyl-sulfonyl. Provided that: when X 1is S, R 7is not SO 2R 9; at least one of R 2and R 3is H. Provided that: when R 2is absent, then R 1is -CH 2X 1R 7, and NR 7and X 1R 7together forms -N=C(R 11)-X 1- (where R 11is H, 1= 1-C alkyl, (1-C alkyl)phenyl) or 3-10C cycloalkyl); when R 2= H, then R 1is -CH 2X 1R 7, and NR 7and X 1R 7together forms -N-CH(R 11)-X 1-. Provided that (I) is not: N-(16-Hydroxy-4-hydroxymethyl-17-isopropyl-4,13,14-trimethyl-11-oxo-tetradecahydro-cyclopropa[9,10]cyclopenta[a]phenanthren-3-yl)-isobutyramide; N-[3-(1-dimethylamino-ethyl)-2-hydroxy-10-hydroxymethyl-3a,10,12b-trimethyl-5-oxo-1,2,3,3a,4,5,5a,6,8,9,10,10a,11,12,12a,12b-hexadecahydro-benzo[4,5]cyclohepta[1,2-e]inden-9-yl]-isobutyramide; N-[17-(1-dimethylamino-ethyl)-16-hydroxy-4-hydroxymethyl-4,13,14-trimethyl-11-oxo-tetradecahydro-cyclopropa[9,10]cyclopenta[a]phenanthren-3-yl]-benzamide; acetic acid 4-acetoxymethyl-17-(1-dimethylamino-ethyl)-3-isobutyrylamino-4,13,14-trimethyl-11-oxo-tetradecahydro-cyclopropa[9,10]cyclopenta[a]phenanthren-16-yl ester; 3-(1-dimethylamino-ethyl)-2-hydroxy-10-isopropyl-3a,12a,14b-trimethyl-2,3,3a,5a,6,8,8a,12,12a,12b,13,14,14a,14b-tetradecahydro-1H,4H-11-oxa-9-aza-indeno[5',4':4,5]cyclohepta[1,2-a]naphthalen-5-one; acetic acid 3-(1-dimethylamino-ethyl)-10-isopropyl-3a,12a,14b-trimethyl-5-oxo-2,3,3a,4,5,5a,6,8,8a,12,12a,12b,13,14,14a,14b-hexadecahydro-1H-11-oxa-9-aza-indeno[5',4':4,5]cyclohepta[1,2-a]naphthalen-2-yl ester, 3-(1-dimethylamino-ethyl)-2-hydroxy-10-isopropyl-3a,12a,14b-trimethyl-2,3,3a,5a,6,8,8a,9,10,12,12a,12b,13,14,14a,14b-hexadecahydro-1H,4H-11-oxa-9-aza-indeno[5',4':4,5]cyclohepta[1,2-a]naphthalen-5-one; N-[3-(1-dimethylamino-ethyl)-2-hydroxy-10-hydroxymethyl-3a,10,12b-trimethyl-5-oxo-1,2,3,3a,4,5,6a,7,8,9,10,10a,11,12,12a,12b-hexadecahydro-benzo[4,5]cyclohepta[1,2-e]inden-9-yl]-isobutyramide; N-[16-hydroxy-4-hydroxymethyl-4,13,14-trimethyl-17-(1-methylamino-ethyl)-11-oxo-tetradecahydro-cyclopropa[9,10]cyclopenta[a]phenanthren-3-yl]-isobutyramide; methanesulfonic acid 17-(1-dimethylamino-ethyl)-3-isobutyrylamino-16-methanesulfonyloxy-4,13,14-trimethyl-11-oxo-tetradecahydro-cyclopropa[9,10]cyclopenta[a]phenanthren-4-ylmethyl ester; acetic acid 16-acetoxy-17-[1-(acetyl-methyl-amino)-ethyl]-3-isobutyrylamino-4,13,14-trimethyl-11-oxo-tetradecahydro-cyclopropa[9,10]cyclopenta[a]phenanthren-4-ylmethyl ester or alkaloid compound of formula (Ic), where all the above compounds are in their stereo isomeric form. Independent claims are included for: (1) the preparations of (I); and (2) the preparation of intermediate N-(16-hydroxy-4-hydroxymethyl-17-isopropyl-4,13,14-trimethyl-11-oxo-tetradecahydro-cyclopropa[9,10]cyclopenta[a]phenanthren-3-yl)-isobutyramide of formula (X). [Image] [Image] [Image] ACTIVITY : CNS-Gen.; Neuroprotective; Nootropic; Antiparkinsonian; Vasotropic; Tranquilizer; Vulnerary; Muscular-Gen. MECHANISM OF ACTION : Acetylcholinesterase inhibitor. The ability of (I) to inhibit acetylcholinesterase was tested using in vitro assay in human. The results showed (20S)-3beta -isobutyrylamino-9,19-cyclo-4alpha -hydroxymethyl-4beta ,14alpha -dimethyl-20-dimethylamino-5alpha ,9beta -pregnan-16alpha -ol-11-one exhibited IC 50value of 31 nM.