Bicyclic derivatives and pharmaceutical composition including the same

Patent metadata

Field	Value
Publication number	US-9828366-B2
Application number	US-201515308435-A
Country	US
Kind code	B2
Filing date	May 8, 2015
Priority date	May 13, 2014
Publication date	Nov 28, 2017
Grant date	Nov 28, 2017

Abstract

The present invention relates to a novel bicyclic derivative that has an inhibitory activity against sodium-glucose linked transporters (SGLTs) present in the intestines and kidneys, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof, and a pharmaceutical composition including the same as an active ingredient, which effectively inhibit the SGLT activity, and thus can be used as a therapeutic agent to treat diseases caused by hyperglycemia, such as diabetes including insulin-dependent diabetes (type I diabetes mellitus) and non-insulin-dependent diabetes (type II diabetes mellitus), diabetic complications, and obesity.

First claim

What is claimed is:

1. A bicyclic derivative represented by Formula 1, or a pharmaceutically acceptable salt, isomer, hydrate or solvate thereof:

wherein
A is —O— or —CH 2 —;
the ring B is selected from the group consisting of the following Structural Formulae (i), (ii) and (iii):

R 1 , R 2 , and R 3 each independently are H, halogen, hydroxy, C 1-8 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-6 cycloalkyl, C 1-8 alkoxy, or C 3-6 cycloalkyloxy, wherein the C 1-8 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-6 cycloalkyl, C 1-8 alkoxy, and C 3-6 cycloalkyloxy may be each independently substituted with 1 to 5 fluoro groups, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy, 3- to 6-membered heterocycloalkyloxy, or C 1-3 alkylsulfonyl groups, wherein the C 1-8 alkoxy may be substituted with one to two C 1-8 alkoxy or C 3-6 cycloalkyloxy groups;
R 1 and R 2 substituted at two adjacent carbon atoms may be joined together to form C 3-5 alkylene bridge, where one to two methylene groups in the C 3-5 alkylene bridge may be each independently replaced with —O—, —S—, —S(═O)—, —S(═O) 2 —, —C(═O)—, or —N(—R 4 )—, and unreplaced methylene groups may be each independently substituted with 1 to 4 halogens or methyl groups;
R 4 is H or benzyl; and
the heterocycloalkyl includes at least one heteroatom selected from the group consisting of O, N, and S.

2. The compound of claim 1 , wherein
the ring B is represented by Structural Formula (i);
R 1 , R 2 , and R 3 each independently are H, halogen, hydroxy, C 1-8 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-6 cycloalkyl, C 1-8 alkoxy, or C 3-6 cycloalkyloxy, wherein the C 1-8 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-6 cycloalkyl, C 1-8 alkoxy, and C 3-6 cycloalkyloxy may be each independently substituted with 1 to 3 fluoro groups, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy, 3- to 6-membered heterocycloalkyloxy, or methylsulfonyl groups, wherein the C 1-8 alkoxy may be substituted with one to two C 1-8 alkoxy or C 3-6 cycloalkyloxy groups;
R 1 and R 2 substituted at two adjacent carbon atoms may be joined together to form C 3-5 alkylene bridge, where one to two methylene groups in the C 3-5 alkylene bridge may be each independently replaced with —O—, —S—, —S(═O)—, —S(═O) 2 —, —C(═O)—, or —N(—R 4 )—, and unreplaced methylene groups may be each independently substituted with one to two fluoro groups or methyl groups;
R 4 is H or benzyl; and
the heterocycloalkyl includes at least one heteroatom selected from the group consisting of O, N, and S.

3. The compound of claim 1 , wherein
the ring B is represented by Structural Formula (ii) or (iii); and
R 1 and R 2 each independently are H, halogen, hydroxy, or C 1-8 alkyl.

4. The compound of claim 1 , wherein A is —O—.

5. The compound of claim 4 , wherein
the ring B is represented by Structural Formula (i);
R 1 , R 2 , and R 3 each independently are H, halogen, hydroxy, C 1-8 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-6 cycloalkyl, C 1-8 alkoxy, or C 3-6 cycloalkyloxy, wherein the C 1-8 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-6 cycloalkyl, C 1-8 alkoxy, and C 3-6 cycloalkyloxy may be each independently substituted with 1 to 3 fluoro groups, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy, 3- to 6-membered heterocycloalkyloxy, or methylsulfonyl groups, wherein the C 1-8 alkoxy may be substituted with one to two C 1-8 alkoxy or C 3-6 cycloalkyloxy groups;
R 1 and R 2 substituted at two adjacent carbon atoms may be joined together to form C 3-5 alkylene bridge, where one to two methylene groups in the C 3-5 alkylene bridge may be each independently replaced with —O—, —S—, —S(═O)—, —S(═O) 2 —, —C(═O)—, or —N(—R 4 )—, and unreplaced methylene groups may be each independently substituted with one to two fluoro groups or methyl groups;
R 4 is H or benzyl; and
the heterocycloalkyl includes at least one heteroatom selected from the group consisting of O, N, and S.

6. The compound of claim 1 , wherein
A is —CH 2 —;
R 1 , R 2 , and R 3 each independently are H, halogen, hydroxy, C 1-8 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-6 cycloalkyl, C 1-8 alkoxy, or C 3-6 cycloalkyloxy, wherein the C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy, and C 3-6 cycloalkyloxy may be each independently substituted with 1 to 5 fluoro groups, C 1-8 alkyl, C 3-6 cycloalkyl, or C 1-8 alkoxy groups; and
R 1 and R 2 substituted at two adjacent carbon atoms may be joined together to form C 3-5 alkylene bridge, where one to two methylene groups in the C 3-5 alkylene bridge may be replaced with an oxygen atom, and methylene groups which are not replaced with oxygen atom may be each independently substituted with one to two fluoro or methyl groups.

7. The compound of claim 6 , wherein
the ring B is represented by Structural Formula (i);
R 1 , R 2 , and R 3 each independently are H, halogen, hydroxy, C 1-8 alkyl, C 2-7 alkynyl, C 3-6 cycloalkyl, C 1-8 alkoxy, or C 3-6 cycloalkyloxy, wherein the C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy, and C 3-6 cycloalkyloxy may be each independently substituted with 1 to 3 fluoro groups, C 1-8 alkyl, C 3-6 cycloalkyl, or C 1-8 alkoxy groups; and
R 1 and R 2 substituted at two adjacent carbon atoms may be joined together to form C 3-5 alkylene bridge, where one to two methylene groups in the C 3-5 alkylene bridge may be replaced with an oxygen atom, and methylene groups which are not replaced with oxygen atoms may be each independently substituted with one to two fluoro or methyl groups.

8. The compound of claim 6 , wherein
the ring B is represented Structural Formula (i);
R 1 , R 2 , and R 3 each independently are H, a fluoro group, a chloro group, a hydroxy, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy may be each independently substituted with 1 to 3 C 1-6 alkyl or fluoro groups; and
R 1 and R 2 substituted at two adjacent carbon atoms may be joined together to form —O—(R 4 ) n —O— (wherein n is 1 or 2, and R 4 each independently is —CH 2 —, —CH(CH 3 )—, or —C(CH 3 ) 2 —).

9. The compound of claim 1 , which is selected from the group consisting of:
1) (2S,3R,4R,5S,6R)-2-(7-(4-ethoxybenzyl)-2,3-dihydrobenzofuran-5-yl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol;
2) (2S,3R,4R,5S,6R)-2-(7-(4-ethylbenzyl)-2,3-dihydrobenzofuran-5-yl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol;
3) (2R,3S,4R,5R,6S)-2-hydroxymethyl-6-(7-(4-n-propylbenzyl)-2,3-dihydrobenzofuran-5-yl)-tetrahydro-2H-pyran-3,4,5-triol;
4) (2R,3S,4R,5R,6S)-2-hydroxymethyl-6-(7-(4-trifluoromethylbenzyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol;
5) (2R,3S,4R,5R,6S)-2-hydroxymethyl-6-(7-(4-trifluoromethoxybenzyl)-2,3-dihydrobenzofuran-5-yl)tetrahydro-2H-pyran-3,4,5-triol;
6) (2S,3R,4R,5S,6R)-2-(7-(4-fluorobenzyl)-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
7) (2S,3R,4R,5S,6R)-2-(7-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
8) (2S,3R,4R,5S,6R)-2-(7-(4-(cyclopropylmethoxy)benzyl)-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
9) (2S,3R,4R,5S,6R)-2-(7-(4-ethoxy-3-fluorobenzyl)-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
10) (2S,3R,4R,5S,6R)-2-(7-(4-ethoxy-2-fluorobenzyl)-2,3-dihydrobenzofuran-5-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
11) (2S,3R,4R,5S,6R)-2-(7-

Assignees

• Hanmi Pharm Ind Co Ltd

Inventors

• Kim Ji Sook
• Kim Won Jeoung
• Jang Wook
• Song Ji Young
• Lee Moon Sub
• Kim Nam Du
• Suh Kwee Hyun

Classifications

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

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