Glucopyranosyl derivative and use thereof

Patent metadata

Field	Value
Publication number	US-11084842-B2
Application number	US-201916960488-A
Country	US
Kind code	B2
Filing date	Jan 22, 2019
Priority date	Jan 23, 2018
Publication date	Aug 10, 2021
Grant date	Aug 10, 2021

Abstract

A glucopyranosyl derivative as a sodium-dependent glucose transporters inhibitor, especially as a SGLT1 inhibitor, a pharmaceutically acceptable salt or a stereoisomer thereof, a pharmaceutical composition thereof, and the uses of the compound and pharmaceutical composition thereof in the preparation of drugs for the treatment of diabetes and diabetes-related diseases.

First claim

What is claimed is:

1. A compound having Formula (I) or a pharmaceutically acceptable salt thereof,

wherein,
L is C 1-8 alkylene or —Y—Z—, wherein the C 1-8 alkylene is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH;
Y is —O—, —NH—, —S—, —S(═O)—or —S(═O) 2 —;
Z is C 1-8 alkylene, wherein the C 1-8 alkylene is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH;
R 1 is H, D, F, Cl, Br, I, OH, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl or C 1-6 haloalkoxy, wherein each of the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 hydroxyalkyl, C 1-6 haloalkyl and C 1-6 haloalkoxy is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH;
R 2 is H, D, CN, ═O, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or C 1-6 alkylamino, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthiol and C 1-6 alkylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH, —SH or ═O;
R 3 is H, D, CN, ═O, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio or —C 1-6 alkylamino, wherein each of the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthiol and C 1-6 alkylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH, —SH or ═O;
or R 2 and R 3 , together with the carbon atom they are attached to, form a C 3-6 carbocycle or 3-6 membered heterocyclic ring, wherein each of the C 3-6 carbocycle and 3-6 membered heterocyclic ring is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH, —SH or ═O;
R 4 is H, D or —OR 4a ;
R 4a is H, D, C 1-6 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein each of the C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH, —SH or ═O;
each of R 5 and R 6 is independently H, D, F, Cl, Br, I, OH, CN, NO 2 , NH 2 , C 1-6 alkyl or C 1-6 alkoxy, wherein each of the C 1-6 alkyl and C 1-6 alkoxy is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, OH, CN, NH 2 or ═O;
or R 5 and R 6 , together with the carbon atom they are attached to respectively, form a 5 membered heterocyclyl ring or 6 membered heterocyclyl ring, wherein each of the 5 membered heterocyclyl ring and 6 membered heterocyclyl ring is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, OH, CN, NH 2 or ═O;
R 9 is H, D, F, Cl, Br, I, CN, NO 2 , NH 2 or C 1-6 alkyl;
each of R 7 and R 8 is independently H, D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 3-8 cycloalkyl, wherein each of the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 haloalkyl, C 1-6 haloalkoxy and C 3-8 cycloalkyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , ═O, —C(═O)OH or —C(═O)NH 2 ;
or R 7 and R 8 , together with the carbon atom they are attached to respectively, form a C 3-8 carbocycle, wherein each of the C 3-8 carbocycle is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , ═O, —C(═O)OH or —C(═O)NH 2 ; and
n is 0, 1, 2 or 3.

2. The compound of claim 1 having Formula (II),

3. The compound of claim 1 , wherein
L is C 1-6 alkylene or —Y—Z—, wherein the C 1-6 alkylene is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH;
Y is —O—, —NH—, —S—, —S(═O)—or —S(═O) 2 —; and
Z is C 1-6 alkylene, wherein the C 1-6 alkylene is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH.

4. The compound of claim 1 , wherein
L is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 —, —CH 2 (CH 2 ) 2 CH 2 —, —C(CH 3 ) 2 CH 2 —, —CH 2 (CH 2 ) 3 CH 2 —, —CH 2 (CH 2 ) 4 CH 2 —or —Y—Z—, wherein each of the —CH 2 —, —CH 2 C H 2 —, —CH 2 CH 2 C H 2 − , —CH(CH 3 )CH 2 —, —C(CH 2 ) 2 CH 2 —, —C(CH 3 ) 2 CH 2 —, —CH 2 (CH 2 ) 3 CH 2 —and —CH 2 (CH 2 ) 4 CH 2 —is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH;
Y is —O—, —NH—, —S—, —S(═O)— or —S(═O) 2 —; and
Z is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 —, —CH 2 (CH 2 ) 2 CH 2 − , —C(CH 3 ) 2 CH 2 —, —CH 2 (CH 2 ) 3 CH 2 — or —CH 2 (CH 2 ) 4 CH 2 − , wherein each of the —CH 2 —, —CH 2 CH 2 − , —CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 —, —CH 2 (CH 2 ) 2 CH 2 —, —C(CH 3 ) 2 CH 2 —, —CH 2 (CH 2 ) 3 CH 2 —and —CH 2 (CH 2 ) 4 CH 2 —is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH.

5. The compound of claim 1 , wherein
R 1 is H, D, F, Cl, Br, I, OH, CN, NO 2 , NH 2 , methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, hydroxymethyl, trifluoromethyl, trifluoroethyl, monofluoromethyl, trifluoromethoxy or difluoromethoxy, wherein each of the methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, hydroxymethyl, trifluoromethyl, trifluoroethyl, monofluoromethyl, trifluoromethoxy and difluoromethoxy is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH; and
R 9 is H, D, F, Cl, Br, I, CN, NO 2 , NH 2 , methyl, ethyl, n-propyl or isopropyl.

6. The compound of claim 1 , wherein
R 2 is H, D, CN, ═O, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio or C 1-4 alkylamino, wherein each of the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio and C 1-4 alkylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH, —SH or ═O;
R 3 is H, D, CN, ═O, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio or C 1-4 alkylamino, wherein each of the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio and C 1-4 alkylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH or —SH;
or R 2 and R 3 , together with the carbon atom they are attached to, form a C 3-6 carbocycle or 5-6 membered heterocyclic ring, wherein each of the C 3-6 carbocycle and 5-6 membered heterocyclic ring is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from D, F, Cl, Br, I, CN, NO 2 , OH, NH 2 , —C(═O)OH, —SH or ═O.

7. The compound of claim 1 , wherein
R 2 is H, D, CN, ═O, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, m

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Gu Zheng
• Wu Wuyong
• Qu Tong
• Kang Panpan
• Zhang Zongyuan
• Huang Weiming
• Liu Jianyu
• Zhang Yingjun

Classifications

• A61P9/12

  Antihypertensives · CPC title

• C07H7/04 Primary

  Carbocyclic radicals · CPC title

• A61P13/12

  of the kidneys · 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

• A61P5/48

  of the pancreatic hormones · CPC title