# US 9,751,882 B2 · Diaryl[A, G]quinolizidine compound, preparation method therefor, pharmaceutical composition, and uses thereof

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- Number: US 9,751,882 B2
- Document ID: US9751882B2
- Status: Granted
- Kind: B2
- Application number: 14/400,203
- Filed: 2013-05-09
- Published: 2015-05-21
- Granted: 2017-09-05
- Earliest claimed: 2012-05-09
- Assignees: Kingsound & Partner
- Applicants: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
- Inventors: Hong Liu; Xuechu Zhen; Haifeng Sun; Liyuan Zhu; Wangke Qian; Leiping Yu; Zeng Li; Shengbin Zhou; Wenxian Cai; Hualiang Jiang; Kaixian Chen
- Web page: https://patentgrep.com/patent/US9751882B2

## CPC

- C07D 471/14: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/24: Antidepressants
- A61P 25/30: for treating abuse or dependence
- A61P 25/36: Opioid-abuse
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 455/03: 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
- C07D 491/147: the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
- C07D 491/22: in which the condensed system contains four or more hetero rings
- C07D 495/14: Ortho-condensed systems
- C07D 495/22: in which the condensed system contains four or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a diarylo[a,g]quinolizidine compound of formula (I), enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof; the preparation method thereof, and uses thereof in preparing an experimental model drugs related to dopamine receptors and 5-HT receptors or a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors.

## Claims

### Claim 1

A diarylo[a,g]quinolizine compound of formula (I), an enantiomer, a diastereoisomer, a racemate, a mixture, a pharmaceutically acceptable salt, a crystalline hydrate or a solvate thereof:
wherein
ring A is one selected from the group consisting of benzene ring, pyrrole ring, furan ring, thiophene ring, pyridine ring, benzoxazole ring, benzofuran ring and indole ring;
ring D is one selected from the group consisting of benzene ring, pyrrole ring, furan ring, thiophene ring, pyridine ring, benzoxazole ring and benzofuran ring; the rings A and D are not simultaneously benzene ring, and ring A is not an indole ring when ring D is a benzene ring;
R5 and R10 each independently represent 1 to 4 substituents selected from the group consisting of halogen, C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens, C3-C6 cycloalkyl unsubstituted or substituted with 1-3 halogens, C1-C6 straight or branched alkyl substituted with a C 1-C6 alkoxy, C1-C6 straight or branched alkyl substituted with a C3-C6 cycloalkyl, —OR6, —NR6R7, —OR9OR6, —OR9NR6R7, —R9COOR6, —R9CONR6R7, —R9OR6, —R9NR6R7, and —N(R6)SO2R7,
alternatively, any two adjacent R5s or adjacent R10s, together with the carbon atom or the heteroatom to which they are adjacent, may form a 5-7 membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O and S;
R1, R2and R3 are each independently hydrogen, halogen, hydroxy, oxo (═O), or C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens,
R4 is hydrogen, halogen, hydroxy, or C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens,
R6 and R7 are each independently hydrogen, or C1-C6 straight or branched alkyl unsubstituted or substituted with 1-3 halogens or hydroxys,
R9 is C1-C6 straight or branched alkylene;
the halogen is F, Cl or Br; and
the chiral carbon atom in the compound of formula (I) may be on R- or S- configuration.

### Claim 2

A diarylo[a,g]quinolizine compound, enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof, wherein the diarylo[a,g]quinolizine compound is

### Claim 3 (depends on 1)

A process of preparing the diarylo[a,g]quinolizine compound, enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof according to claim 1, wherein the process is carried out as any one of the following methods:
the method A comprises:
a) reacting a1 with a2 through an amino-ester exchange reaction in a polar protic solvent to give a3,
b) reacting a3 with an acylating agent through an acylation reaction in the presence of a base to give a4;
c) dehydrlating and cyclizing a4 in the presence of a condensing agent to give a5;
d) asymmetrically reducing a5 in the presence of a hydrogenation reagent and a chiral catalyst to give a6;
e) hydrolyzing a6 in the presence of a base to give a7;
f) halogenating a7 with a halogenating reagent, and then directly cyclizing it in the presence of a base to give a8;
g) optionally, when a8 has a protective group to be removed, a8 is deprotected to remove the protective group;
the method B comprises:
1) reacting a1 with b2 by a condensation reaction in the presence of a condensing agent to give b3;
2) dehydrlating and cyclizing b3 in the presence of a condensing agent to give b4;
3) asymmetrically reducing b4 in the presence of a chiral catalyst and a hydrogenation reagent to give b5; and
4) reacting b5 with a substituted aldehyde R4CHO through a Pictet-Spengler reactionunder an acidic condition to give b6;
In the above methods A and B, rings A and D as well as the substituents are defined the same as those in claim 1.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of one or more selected from the group consisting of the diarylo[a,g]quinolizine compound, enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof according to claim 1, and one or more pharmaceutically acceptable carriers.

### Claim 5 (depends on 1)

A method for treating a disease related to dopamine receptors and 5-HT receptors in a subject, wherein the disease related to dopamine receptors and 5-HT receptors is schizophrenia, Parkinson's disease, mania, depression, drug addiction or migraine, comprising:
administering to the subject an effective amount of the diarylo[a,g]quinolizine compound, enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof according to claim 1.