Cycloalkyl acid derivative, preparation method thereof, and pharmaceutical application thereof

Patent metadata

Field	Value
Publication number	US-9637484-B2
Application number	US-201414889563-A
Country	US
Kind code	B2
Filing date	Apr 29, 2014
Priority date	May 13, 2013
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

Cycloalkyl acid derivatives, a preparation method thereof, and a pharmaceutical application thereof are described. In particular, a cycloalkyl acid derivative represented by general formula (I) and a medical salt thereof, a preparation method thereof, and an application of the cycloalkyl acid derivative and the medical salt thereof as URAT1 inhibitors, and particularly as therapeutic agents for diseases related to an abnormal uric acid level are described, wherein definitions of substituent groups in general formula (I) are the same as the definitions in the specification.

First claim

What is claimed is:

1. A compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:
ring A is cycloalkyl;
W 1 is N;
W 2 is CR b , wherein R b is selected from the group consisting of hydrogen and alkyl;
W 3 is CR c ;
R c is selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 4 , —S(O) m R 4 , —C(O)R 4 , —C(O)OR 4 , —C(O)NR 5 R 6 , —NR 5 R 6 and —NR 5 C(O)R 6 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —OR 4 , —S(O) m R 4 , —C(O)R 4 , —C(O)OR 4 , —C(O)NR 5 R 6 , —NR 5 R 6 and —NR 5 C(O)R 6 ;
R 1 is hydrogen or alkyl;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, haloalkyl and hydroxyalkyl;
R 4 is selected from the group consisting of hydrogen, alkyl, halogen, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more groups selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, alkoxycarbonyl, —C(O)NR 5 R 6 , —NR 5 R 6 and —NR 5 C(O)R 6 ;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and
m is 0, 1, or 2.

2. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein ring A is cyclopropyl, cyclobutyl or cyclopentyl.

3. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R c is selected from the group consisting of hydrogen, halogen, cyano, alkyl, cycloalkyl, aryl, —OR 4 , —NR 5 R 6 and —NR 5 C(O)R 6 , wherein the alkyl, cycloalkyl and aryl are each independently optionally substituted with one or more groups selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl and heterocyclyl.

4. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R c is selected from the group consisting of hydrogen, halogen, alkyl and haloalkyl.

5. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is hydrogen.

6. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is hydrogen or halogen.

7. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

8. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (III) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

9. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (IV) or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

10. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is selected from the group consisting of:

11. A process of preparing the compound of formula (I) according to claim 1 , or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof, comprising a step of:

reacting a compound of formula (IA) with a compound of formula (IB) via a substitution reaction, and optionally hydrolyzing the resulting product under an alkaline condition to obtain the compound of formula (I);
wherein: X is a leaving group; and Y is a hydrogen or sodium atom.

12. A compound of formula (I-A), or a tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:
Y is a hydrogen or sodium atom;
W 1 is N;
W 2 is CR b ;
W 3 is CR c ;
R b is hydrogen;
R 2 and R 3 are each independently hydrogen;
R c is alkyl or alkoxy, wherein the alkyl and alkoxy are each independently substituted with one or more groups selected from the group consisting of cyano and —OR 4 ; and
R 4 is selected from the group consisting of hydrogen and alkyl.

13. The compound of formula (IA), or the tautomer, mesomer, racemate, enantiomer, or diastereomer thereof, or mixture thereof, or the pharmaceutically acceptable salt thereof acc

Assignees

• Shanghai hengrui pharmaceutical co ltd
• Jiangsu Hengrui Medicine Co

Inventors

• Peng Jianbiao
• Sun Piaoyang
• Lan Jiong
• Gu Chunyan
• Li Xiaotao
• Liu Bonian
• Han Chunzhou
• Hu Qiyue
• Jin Fangfang
• Dong Qing
• Cao Guoqing

Classifications

• A61P39/02

  Antidotes · CPC title

• A61P5/18

  of the parathyroid hormones · CPC title

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title