Tetrahydroprotoberberine compound, preparation method therefor and uses thereof, and pharmaceutical composition

Patent metadata

Field	Value
Publication number	US-11731965-B2
Application number	US-201816639394-A
Country	US
Kind code	B2
Filing date	Aug 14, 2018
Priority date	Aug 14, 2017
Publication date	Aug 22, 2023
Grant date	Aug 22, 2023

Abstract

The present invention provides a tetrahydroprotoberberine compound represented by the formula (I), enantiomers, diastereomers, racemates and mixtures thereof, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof. The invention also provides a method for preparing the compound and the use thereof in the preparation of a medicament for preventing and/or treating central nervous system diseases.

First claim

The invention claimed is:

1. A tetrahydroprotoberberine compound of formula (I-A-1), enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, crystalline hydrates or solvates thereof,

wherein,
R2 is selected from halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, amino, C1-C6 alkyl substituted amino, C1-C6 alkanoyl substituted amino, C1-C6 alkyl sulfonyl substituted amino, cyano, carboxy, aldehyde group, amino-C1-C6 alkyl, hydroxy-C1-C6 alkyl, cyano-C1-C6 alkyl, C1-C6 alkanoyl, halo-C1-C6 alkanoyl, sulfoamido, C1-C6 alkyl substituted sulfoamido, carbamoyl, C1-C6 alkyl substituted carbamoyl, carboxy-C1-C6 alkyl, C1-C6 alkyl sulfonyl, halo-C1-C6 alkyl sulfonyl, C1-C6 alkyl substituted amino-C1-C6 alkyl, C1-C6 alkanoyl substituted amino-C1-C6 alkyl, C1-C6 alkoxycarbonyl, carbamoyl-C1-C6 alkyl, or C1-C6 alkyl substituted carbamoyl-C1-C6 alkyl; or
R2 is selected from halogen, mercapto, halo-C1-C4 alkoxy, hydroxy-C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkyl, C3-C5 cycloalkyl, C3-C5 cycloalkoxy, C2-C4 alkenyl, C2-C4 alkenyloxy, C2-C4 alkynyl, C2-C4 alkynyloxy, halo-C1-C4 alkyl, amino, C1-C4 alkyl substituted amino, C1-C4 alkanoyl substituted amino, C1-C4 alkyl sulfonyl substituted amino, cyano, carboxy, aldehyde group, amino-C1-C4 alkyl group, hydroxy-C1-C4 alkyl, cyano-C1-C4 alkyl group, C1-C4 alkanoyl, halo-C1-C4 alkanoyl, sulfoamido, C1-C4 alkyl substituted sulfoamido, carbamoyl, C1-C4 alkyl substituted carbamoyl, carboxy-C1-C4 alkyl, C1-C4 alkansulfonyl, halo-C1-C4 alkansulfonyl, C1-C4 alkyl substituted amino-C1-C4 alkyl, C1-C4 alkanoyl substituted amino-C1-C4 alkyl, C1-C4 alkoxycarbonyl, carbamoyl-C1-C4 alkyl, or C1-C4 alkyl substituted carbamoyl-C1-C4 alkyl; or
R2 is selected from fluorine, chlorine, bromine, mercapto, trifluoromethoxy, —SCH 3 , —SCH 2 CH 3 , methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, bromomethyl, chloromethyl, vinyl, amino, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, cyano, carboxyl, aldehyde group, —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CN, —CH 2 CH 2 CN, formyl, acetyl, propionyl, trifluoroacetyl, sulfo amido, carbamoyl, N-methylcarbamoyl, N, N-dimethylcarbamoyl, N-ethylcarbamoyl, N,N-diethylcarbamoyl, —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —SO 2 CH 3 , —SO 2 CF 3 , —CH 2 NHMe, —CH 2 NMe 2 , —CH 2 CONH 2 , —CH 2 CONHMe or —CH 2 CONMe 2 .

2. The tetrahydroprotoberberine compound, enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, crystalline hydrates or solvates thereof, wherein the compound is selected from:
(1) (S)-2-methyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(2) (S)-2-n-propyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(3) (S)-2-isobutyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(4) (S)-2-cyano-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(5) (S)-2-carbamoyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(6) (S)-2-formyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(7) (S)-2-hydroxymethy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(8) (S)-2-carboxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(9) (S)-2-ethoxycarbonyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(10) (S)-2-aminomethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(11) (S)-2-acetaminomethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(12) (S)-2-acetyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(13) (S)-2-amino-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(14) (S)-2-acetylamino-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(15) (S)-2-bromo-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(16) (S)-2-chloro-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(17) (S)-2-vinyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g]quinolizine;
(18) (S)-2-hydroxyethyl-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(19) (S)-2,3,10-trimethoxy-9-cyano-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(20) (S)-2,3,10-trimethoxy-9-carbamoyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(21) (S)-2,3,10-trimethoxy-9-acetyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(22) (S)-2,3,10-trimethoxy-9-aminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(23) (S)-2,3,10-trimethoxy-9-acetylaminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(24) (S)-2,3,10-trimethoxy-9-formyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(25) (S)-2,3,10-trimethoxy-9-hydroxymethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(26) (S)-2,3,9-trimethoxy-10-methyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(27) (S)-2,3,9-trimethoxy-10-cyano-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(28) (S)-2,3,9-trimethoxy-10-carbamoyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(29) (S)-2,3,9-trimethoxy-10-formyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(30) (S)-2,3,9-trimethoxy-10-hydroxymethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(31) (S)-2,3 ,9-trimethoxy-10-aminomethyl-6, 8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(32) (S)-2,3,9-trimethoxy-10-acetaminomethyl-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(33) (S)-2,10-diamino-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(34) (S)-2,10-diacetylamido-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(35) 2,3-dicyano-9,10-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(36) 9,10-dimethoxy-5,6,13,13a-tetrahydroisoquinolino[3,2-a]pyrrolo[3,4-g]isoquinoline-1,3(2H,8H)-dione;
(37) (S)-2,10-dicyano-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(38) (S)-2,10-dicarbamoyl-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(39) 2,3-dicarbamoyl-9,10-dimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(40) (S)-4,10,11-trimethoxy-3,6,7,9,14,14a-hexahydroimidazo[4,5-h]isoquinolino [3,2-a]isoquinolin-2(1H)-one;
(41) (S)-4,10,11-trimethoxy-3,6,7,9,14,14a-Hexahydroimidazo[4,5-h] isoquinolino [3,2-a]isoquinoline-2(1H)-thione;
(42) (S)-4,10,11-trimethoxy-1,6,7,9,14,14a-hexahydroimidazo[4,5-h] isoquinolino [3,2 a]isoquinoline;
(43) (S)-4,10,11-trimethoxy-1,6,7,9,14,14a-hexahydroisoquinolino[3,2-a][1,2,3] triazolo [4,5-h]isoquinoline;
(44) 9,10-dimethoxy-1,5,6,8,13,13a-hexahydroimidazo[4,5-g]isoquinolino[3,2-a] isoquinoline;
(45) 9,10-dimethoxy-6,8,13,13a-tetrahydro-5H-isoquino[3,2-a]oxazolo[4,5-g] isoquinolin;
(46) 9,10-dimethoxy-3,5,6,8,13,13a-hexahydro-2H-isoquino[3,2-a]oxazolo[4,5-g] isoquinolin-2-one;
(47) 10,11-dimethoxy-4,6,7,9,14,14a-hexahydroisoquinolino[3,2-a][1,4]oxazino[3,2-g] isoquinolin-3(2H)-one;
(48) 10,11-dimethoxy-7,9,14,14a-tetrahydro-6H-isoquino[3,2-a]oxazolo[5,4-h] isoquinoline;
(49) 10,11-dimethoxy-6,7,14,14a-tetrahydro-1H-isoquino[3,2-a]oxazolo[5,4-h] isoquinolin-2(9H)-one;
(50) 11,12-dimethoxy-3,7,8,10,15,15a-hexahydroisoquinolino[3,2-a][1,4]oxazino [2,3-h] isoquinolin-2(1H)-one;
(51) (S)-2-(difluoromethoxy)-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(52) (S)-2-allyloxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(53) (S)-2-cyclopropoxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(54) (S)-2-cyclopentyloxy-3,9,10-trimethoxy-6,8,13,13a-tetrahydro-5H-dibenzo[a,g] quinolizine;
(55) (S)-2,10-di(hydroxyethoxy)-3,9-dimethoxy-6,8,13,13a-tetrahydro-5H-dibe

Assignees

• Shanghai Inst Materia Medica Cas
• Topharman Shanghai Co Ltd

Inventors

• He Yang
• Jiang Xiangrui
• Li Jianfeng
• Wang Yu
• Wang Zhen
• Chen Weiming
• Zhu Fuqiang
• Wu Chunhui
• Zhang Rongxia
• Shen Jingshan
• Jiang Hualiang

Classifications

• C07D455/03 Primary

  containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D471/14 Primary

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title