Piperazinyl pyrimidine derivatives, preparation method and use thereof

Patent metadata

Field	Value
Publication number	US-9493453-B2
Application number	US-201314372710-A
Country	US
Kind code	B2
Filing date	Jan 15, 2013
Priority date	Jan 16, 2012
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

Provided are piperazinyl pyrimidine derivatives of formula I having CCR 4 antagonism, and the preparation method, pharmaceutical composition and use thereof in the preparation of a medicament. The medicament is useful for the treatment and prevention of CCR 4 -related diseases.

First claim

The invention claimed is:

1. A compound of formula I,

wherein:
any two of A, B and D are N and the other one is CH;
Z is selected from the group consisting of —C(O)— and —S(O) 2 —;
X is halogen or N, with the proviso that when X is halogen, R 1 and R 2 in formula I are absent;
R 1 and R 2 are each independently selected from the group consisting of H, linear or branched alkyl having 1 to 6 carbon atoms, linear or branched heteroalkyl having 1-6 carbon atoms in which 1 to 2 of the non-terminal carbon atoms independently are replaced by O, NH, or S;
R 3 is H;
R 4 is selected from the group consisting of aryl and fused aryl containing 5 to 10 atoms; wherein said aryl or fused aryl is optionally and independently mono-, di- or poly-substituted with halogen;
R 5 is selected from the group consisting of linear or branched alkyl having 1 to 6 carbon atoms, linear or branched heteroalkyl having 1 to 6 carbon atoms in which 1 to 2 of the non-terminal carbon atoms independently are replaced by O, NH, or S, cycloalkyl containing 4 to 8 carbon atoms, 5- to 8-membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of O, N and S;
m is 0, 1 or 2; and
n is 1,
or a racemate or a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound or a racemate or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof according to claim 1 , wherein the aryl is selected from the group consisting of phenyl and naphthyl.

3. A compound or a racemate or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of:
1-{4-{4-[(2,4-dichlorobenzyl)amino]-6-[(2,2-dimethoxyethyl)methylamino]pyrimidin-2-yl}piperazin-1-yl}propanone;
1-{4-{4-[(2,4-dichlorobenzyl)amino]-6-[(2,2-dimethoxyethyl)methylamino]pyrimidin-2-yl}piperazin-1-yl}-2-methylpropanone;
1-{4-{4-[(2,4-dichlorobenzyl)amino]-6-[(2,2-dimethoxyethyl)methylamino]pyrimidin-2-yl}piperazin-1-yl}-3-methylthiopropanone;
1-{4-{4-[bis(2-methoxyethyl)amino]-6-(2,4-dichlorobenzylamino)-pyrimidin-2-yl}piperazin-1-yl}propanone;
1-{4-{4-[bis(2-methoxyethyl)amino]-6-(2,4-dichlorobenzylamino)-pyrimidin-2-yl}piperazin-1-yl}-2-methylpropanone;
1-{4-{4-[bis(2-methoxyethyl)amino]-6-(2,4-dichlorobenzylamino)-pyrimidin-2-yl}piperazin-1-yl}-3-methylthiopropanone;
4-{4-[bis(2-methoxyethyl)amino]-6-(2,4-dichlorobenzylamino)-pyrimidin-2-yl}piperazin-1-yl}cyclohexylmethanone;
(R)-{4-{4-chloro-6-[(2,4-dichlorobenzyl)amino]pyrimidin-2-yl}piperazin-1-yl}(piperidin-2-yl)methanone; and
(R)-{4-{4-chloro-6-[(2,4-dichlorobenzyl)amino]pyrimidin-2-yl}piperazin-1-yl}(thiomorpholin-3-yl)methanone.

4. A pharmaceutical composition comprising the compound of formula I or a racemate or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof according to claim 1 , and at least one pharmaceutically acceptable carrier, diluent or excipient.

5. A method of treating a chemokine receptor 4 (CCR4)-related disease or disorder selected from the group consisting of allergic rhinitis, asthma and allergic dermatitis, the method comprising administering a therapeutically or prophylactically effective amount of the compound of formula I or a racemate or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 3 to a subject in need thereof.

6. A pharmaceutical composition comprising (R)-{4-{4-chloro-6-[(2,4-dichlorobenzyl)amino]pyrimidin-2-yl}piperazin-1-yl}(piperidin-2-yl)methanone, or a racemate or a stereoisomer or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient.

7. (R)-{4-{4-chloro-6-[(2,4-dichlorobenzyl)amino]pyrimidin-2-yl}piperazin-1-yl}(piperidin-2-yl)methanone.

8. The method of claim 5 , wherein the compound is (R)-{4-{4-chloro-6-[(2,4-dichlorobenzyl)amino]pyrimidin-2-yl}piperazin-1-yl}(piperidin-2-yl)methanone.

9. The compound of claim 1 , in which 1 to 2 of the non-terminal carbon atoms of the linear or branched heteroalkyl independently are replaced by O or S.

Assignees

• Inst Pharmacology & Toxicology Acad Military Medical Sciences Pla China
• Univ Beijing
• The Inst Of Pharmacology And Toxicology Acad Of Military Medical Science P L A China

Inventors

• Li Song
• Wang Ying
• Xiao Junhai
• Ma Dalong
• Gong Hongwei
• Qi Hui
• Wang Lili
• Ling Xiaomei
• Zheng Zhibing
• Zhang Yang
• Zhong Wu
• Li Meina
• Xie Yunde
• Xu Enquan
• Li Xingzhou
• Ma Jing
• Zhao Guoming
• Zhou Xinbo
• Wang Xiaokui
• Liu Hongying

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title