US 9,006,187 B2Granted

Thiophene derivative as SGLT2 inhibitor and pharmaceutical composition comprising same

AssigneeThe Green Cross Corporation

InventorsJinhwa Lee, Kwang-Seop Song, Suk Ho Lee

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Abstract

The present invention relates to a novel compound with thiophene ring having an inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) being present in the intestine and kidney, and a pharmaceutical composition comprising the same as an active ingredient, which is useful for preventing or treating metabolic disorders, particularly diabetes. The prevention also provides a method for preparing same, a pharmaceutical composition containing same, and a method for preventing or treating metabolic disorders, particularly diabetes.

Claims16

Dependent claims

A compound of formula (I), or a pharmaceutically acceptable salt, carboxylate, or aminoacetate thereof:

wherein,
ring A is thiophene;
and
ring B is benzene, 5 to 10-membered heterocycloalkyl, or 5 to 13-membered heteroaryl,
in which said ring A is substituted with at least one substituent selected from the group consisting of hydroxy, mercapto, cyano, carboxy, nitro, guanidino, ureido, amino, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy-C1-7 alkyl, C1-7alkoxy, C1-7alkoxy-C1-7 alkoxy, C2-7 alkenyloxy, C2-7 alkynyloxy, 5 to 10-membered heterocycloalkyloxy, C3-10 cycloalkyl, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, phenyl-C1-7 alkoxy, mono- or di-C1-7 alkylamino, aminocarbonyl, C2-8 acylamino, C2-8 acyl, C1-7 alkoxycarbonyl, mono- or di-C1-7 alkylcarbamoyl, C1-7alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfanyl, C1-7alkylsulfinyl, C1-7alkylsulfonyl, C6-14 arylsulfanyl, C6-14 alkylsulfonyl, C-6-14 aryl, C7-15 aroyl, 5 to 13-membered heteroaryl, 6 to 14-membered heteroaroyl, C7-15 aroyloxy, C2-8 acyloxy, 6 to 14-membered heteroaroyloxy, and 5 to 10-membered heterocycloalkyl,
in which said ring B is substituted with at least one substituent selected from the group consisting of halogen, hydroxy, mercapto, cyano, carboxy, nitro, guanidino, ureido, amino, C1-7alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkoxy, C2-7 alkenyloxy, C2-7 alkynyloxy, 5 to 10-membered heterocycloalkyloxy, C3-10 cycloalkyl, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, phenyl-C1-7 alkoxy, mono- or di-C1-7 alkylamino, aminocarbonyl, C2-8 acylamino, C2-8 acyl, C1-7 alkoxycarbonyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfanyl, C1-7 alkylsulfinyl, C1-7 alkylsulfonyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, C7-15 aroyl, 5 to 13-membered heteroaryl, 6 to 14-membered heteroaroyl, C7-15 aroyloxy, C2-8 acyloxy, 6 to 14-membered heteroaroyloxy, and 5 to 10-membered heterocycloalkyl,
in which
said alkyl, alkenyl, alkynyl, alkoxy, or acyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, and mercapto;
said cycloalkyl, cycloalkenyl, aryl, aroyl, heteroaryl, heteroaroyl, or heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy;
and
said heterocycloalkyl, heteroaryl, and heteroaroyl each independently contains at least one heteroatom selected from the group consisting of N, O and S.

8 more elements

A compound of Formula (I), or a pharmaceutically acceptable salt, carboxylate, or aminoacetate thereof:

wherein
ring A is thiophene;
and
ring B is benzene, 5 to 10-membered heterocycloalkyl, or 5 to 13-membered heteroaryl,
in which said ring A and ring B are each substituted with at least one substituent selected from the group consisting of halogen, hydroxy, mercapto, cyano, carboxy, nitro, guanidino, ureido, amino, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkoxy, C2-7 alkenyloxy, C2-7 alkynyloxy, 5 to 10-membered heterocycloalkyloxy, C3-10 cycloalkyl, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, phenyl-C1-7 alkoxy, mono- or di-C1-7 alkylamino, aminocarbonyl, C2-8 acylamino, C2-8 acyl, C1-7 alkoxycarbonyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfanyl, C1-7 alkylsulfinyl, C1-7 alkylsulfonyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, C7-15 aroyl, 5 to 13-membered heteroaryl, 6 to 14-membered heteroaroyl, C7-15 aroyloxy, C2-8 acyloxy, 6 to 14-membered heteroaroyloxy, and 5 to 10-membered heterocycloalkyl,
in which
said alkyl, alkenyl, alkynyl, alkoxy, or acyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, and mercapto;
said cycloalkyl, cycloalkenyl, aryl, aroyl, heteroaryl, heteroaroyl, or heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy;
and
said heterocycloalkyl, heteroaryl, and heteroaroyl each independently contains at least one heteroatom selected from the group consisting of N, O and S,
wherein the compound of Formula (I) is selected from the group consisting of:
(1) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-ethoxybenzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(2) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-methoxybenzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(3) (2R,3R,4S,5S,6R)-2-(5-chloro-4-((5-(4-fluorophenyl)thiophen-2-yl)methyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(4) (2R,3R,4S,5S,6R)-2-(4-(4-(allyloxy)benzyl)-5-chlorothiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(5) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-propoxybenzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(6) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-hydroxybenzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(7) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-(ethylthio)benzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(8) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-(prop-2-ynyloxy)benzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(9) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-isopropoxybenzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(10) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-(2-methoxyethoxy)benzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(11) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-(cyclopentyloxy)benzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(12) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-(methylthio)benzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(13) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-(2-ethoxyethoxy)benzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(14) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-methylbenzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(15) (2R,3R,4S,5S,6R)-2-(4-(4-(but-2-ynyloxy)benzyl)-5-chlorothiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(16) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-(tetrahydrofuran-3-yloxy)benzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(18) (2R,3R,4S,5S,6R)-2-(5-chloro-4-(4-propylbenzyl)thiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(19) (2R,3R,4S,5S,6R)-2-(4-(4-ethoxybenzyl)-5-methylthiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(20) (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-(4-methoxybenzyl)-5-methylthiophen-2-y1)-tetrahydro-2H-pyran-3,4,5-triol;
(21) (2R,3R,4S,5S,6R)-2-(4-((5-(4-fluorophenyl)thiophen-2-yl)methyl)-5-methylthiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(22) (2R,3R,4S,5S,6R)-2-(4-(4-(allyloxy)benzyl)-5-methylthiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(23) (2R,3R,4S,5S,6R)-2-(4-(4-hydroxybenzyl)-5-methylthiophen-2-yl)-6-(hydroxymethyl)-tetrahydro-2H-pyran-3,4,5-triol;
(24) (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-methyl-5-(4-propylbenzyl)thiophen-2-yl)tetrahydro-2H-pyran-3,4,5-triol;
(25) (2R,3R,4S,5S,6R)-2-(5-(4-ethylbenzyl)-4-methylthiophen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(26) (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(4-methyl-5-(4-methylbenzyl)thiophen-2-yl)tetrahydro-2H-pyran-3,4,5-triol;
(27) (2R,3R,4S,5S,6R)-2-(5-(4-tert-butylbenzyl)-4-methylthiophen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(28) (2R,3R,4S,5S,6R)-2-(5-(4-chlorobenzyl)-4-methylthiophen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(29) (2R,3R,4S,5S,6R)-2-(5-(4-fluorobenzyl)-4-methylthiophen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(30) (2R,3S,4S,5R,6R)-2-(hydroxymethyl)-6-(5-(4-methoxybenzyl)-4-methylthiophen-2-yl)tetrahydro-2H-pyran-3,4,5-triol;
(31) (2R,3R,4S,5S,6R)-2-(5-(4-ethoxybenzyl)-4-methylthiophen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(32) (2R,3R,4S,5S,6R)-2-(3-bromo-5-(4-ethylbenzyl)-4-methylthiophen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
(33) (2R,3R,4S,5S,6R)-2-(5-(4-ethylbenzyl)-3-methoxy-4-methylthiophen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol;
and
(34) (2R,3R,4S,5S,6R)-2-(5-(4-ethylbenzyl)-3,4-dimethylthiophen-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

42 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/821,863Filed 9 Sep 2011 · us provisional application
Priority: 10 Sep 2010
Published: US 2013/0172278 A14 Jul 2013
Granted: 14 Apr 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
C07H 17/00
Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
C07D 409/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 409/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms: containing three…

Family

Application61/381,613Us provisional application · filed 10 Sep 2010
US 2013/0172278 A1Pre-grant publication · published 4 Jul 2013
US 9,006,187 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I), or a pharmaceutically acceptable salt, carboxylate, or aminoacetate thereof:

wherein,
ring A is thiophene;
and
ring B is benzene, 5 to 10-membered heterocycloalkyl, or 5 to 13-membered heteroaryl,
in which said ring A is substituted with at least one substituent selected from the group consisting of hydroxy, mercapto, cyano, carboxy, nitro, guanidino, ureido, amino, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy-C1-7 alkyl, C1-7alkoxy, C1-7alkoxy-C1-7 alkoxy, C2-7 alkenyloxy, C2-7 alkynyloxy, 5 to 10-membered heterocycloalkyloxy, C3-10 cycloalkyl, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, phenyl-C1-7 alkoxy, mono- or di-C1-7 alkylamino, aminocarbonyl, C2-8 acylamino, C2-8 acyl, C1-7 alkoxycarbonyl, mono- or di-C1-7 alkylcarbamoyl, C1-7alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfanyl, C1-7alkylsulfinyl, C1-7alkylsulfonyl, C6-14 arylsulfanyl, C6-14 alkylsulfonyl, C-6-14 aryl, C7-15 aroyl, 5 to 13-membered heteroaryl, 6 to 14-membered heteroaroyl, C7-15 aroyloxy, C2-8 acyloxy, 6 to 14-membered heteroaroyloxy, and 5 to 10-membered heterocycloalkyl,
in which said ring B is substituted with at least one substituent selected from the group consisting of halogen, hydroxy, mercapto, cyano, carboxy, nitro, guanidino, ureido, amino, C1-7alkyl, C2-7 alkenyl, C2-7 alkynyl, C1-7 alkoxy-C1-7 alkyl, C1-7 alkoxy, C1-7 alkoxy-C1-7 alkoxy, C2-7 alkenyloxy, C2-7 alkynyloxy, 5 to 10-membered heterocycloalkyloxy, C3-10 cycloalkyl, C5-10 cycloalkenyl, C3-10 cycloalkyloxy, phenyl-C1-7 alkoxy, mono- or di-C1-7 alkylamino, aminocarbonyl, C2-8 acylamino, C2-8 acyl, C1-7 alkoxycarbonyl, mono- or di-C1-7 alkylcarbamoyl, C1-7 alkylsulfonylamino, phenylsulfonylamino, C1-7 alkylsulfanyl, C1-7 alkylsulfinyl, C1-7 alkylsulfonyl, C6-14 arylsulfanyl, C6-14 arylsulfonyl, C6-14 aryl, C7-15 aroyl, 5 to 13-membered heteroaryl, 6 to 14-membered heteroaroyl, C7-15 aroyloxy, C2-8 acyloxy, 6 to 14-membered heteroaroyloxy, and 5 to 10-membered heterocycloalkyl,
in which
said alkyl, alkenyl, alkynyl, alkoxy, or acyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, and mercapto;
said cycloalkyl, cycloalkenyl, aryl, aroyl, heteroaryl, heteroaroyl, or heterocycloalkyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, nitro, amino, mercapto, C1-4 alkyl, and C1-4 alkoxy;
and
said heterocycloalkyl, heteroaryl, and heteroaroyl each independently contains at least one heteroatom selected from the group consisting of N, O and S.

8 more elements

Facts

Application

13/821,863Filed 9 Sep 2011 · us provisional application

Priority

10 Sep 2010

Published

US 2013/0172278 A14 Jul 2013

Granted

14 Apr 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification7 codes

A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
C07H 17/00
Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
C07D 409/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 409/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms: containing three…