Triazolothienopyrimidine compound inhibitors of urea transporters and methods of using inhibitors

Patent metadata

Field	Value
Publication number	US-9303042-B2
Application number	US-201314388645-A
Country	US
Kind code	B2
Filing date	Mar 27, 2013
Priority date	Mar 27, 2012
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

Abstract

Provided herein are small molecule triazolothienopyrimidine compounds that inhibit urea transport activity of solute transporters, particularly the UT-B transporter. The compounds described herein are useful for increasing solute clearance in states of fluid overload and for treating refractory edema associated with cardiovascular, renal, and metabolic diseases, disorders, and conditions.

First claim

We claim the following:

1. A method for treating a disease or disorder treatable by inhibiting transport of urea in a subject, said method comprising administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of structure (I):

or a single stereoisomer, a mixture of stereoisomers, tautomer or pharmaceutically acceptable salt thereof, wherein,
R 1 is optionally substituted aryl or optionally substituted heteroaryl;
R 2 is —N(R 5 )(R 6 );
R 3 and R 4 are each independently hydrogen, alkyl, halo or haloalkyl;
R 5 is hydrogen or alkyl; and
R 6 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl; or
R 5 and R 6 , together with the nitrogen atom to which they are attached, form an optionally substituted N-heterocycle, or optionally substituted N-heteroaryl.

2. The method of claim 1 wherein R 1 is optionally substituted phenyl and the compound has a structure of structure (II):

wherein,
n is 0, 1, 2 or 3;
X is an alkylene chain;
R 3 and R 4 are each independently hydrogen, alkyl, halo or haloalkyl;
R 7 is alkyl, halo, haloalkyl, or —OR 9 ;
R 8 is optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl, or —OR 9 ; and
R 9 is hydrogen, alkyl or haloalkyl.

3. The method of claim 2 wherein,
n is 1 or 2;
X is a C 1-5 alkylene chain;
each R 3 and R 4 is independently hydrogen, alkyl, halo or haloalkyl;
R 7 is alkyl, halo, haloalkyl, or —OR 9 ;
R 8 is optionally substituted heteroaryl; and
R 9 is hydrogen, alkyl or haloalkyl.

4. The method of claim 3 wherein,
n is 1 or 2;
X is a C 1-3 alkylene chain;
R 3 and R 4 are each hydrogen;
R 7 is alkyl, halo, haloalkyl, or —OR 9 ;
R 8 is optionally substituted thiophenyl; and
R 9 is hydrogen, alkyl or haloalkyl.

5. The method of claim 4 wherein the compound is
{3-[4-(1,1-difluoro-ethyl)-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine;
thiophen-2-ylmethyl-[3-(4-trifluoromethyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-amine;
thiophen-2-ylmethyl-[3-(4-trifluoromethoxy-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-amine;
{3-[4-methoxy-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine;
{3-[4-fluoro-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine;
{3-[4-bromo-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine;
{3-[4-chloro-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine;
{3-[3-chloro-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine;
{3-[4-ethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine;
{3-[4-isopropyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine; or
{3-[3,4-dimethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-thiophen-2-ylmethyl-amine.

6. The method of claim 3 wherein,
n is 1 or 2;
X is a C 1-3 alkylene chain;
R 3 and R 4 are each hydrogen;
R 7 is alkyl, halo, haloalkyl, or —OR 9 ;
R 8 is optionally substituted furanyl; and
R 9 is hydrogen, alkyl or haloalkyl.

7. The method of claim 6 , wherein the compound is
furan-2-ylmethyl[3-(4-isopropyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-amine;
furan-2-ylmethyl[3-(4-methyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-amine;
furan-2-ylmethyl-[3-(3,4-dimethyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-amine;
furan-2-ylmethyl[3-(4-chloro-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-amine;
furan-2-ylmethyl[3-(4-ethyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-amine; or
furan-2-ylmethyl[3-(2,5-dimethyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-amine.

8. The method of claim 2 wherein,
n is 1 or 2;
X is a C 1-3 alkylene chain;
each R 3 and R 4 is independently hydrogen, alkyl, halo or haloalkyl;
R 7 is alkyl, halo, haloalkyl, or —OR 9 ;
R 8 is —OR 9 ; and
R 9 is hydrogen, alkyl or haloalkyl.

9. The method of claim 8 wherein the compound is
{3-benzenesulfonyl-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-methoxypropyl-amine;
{3-[4-methyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-(1-methylethoxyl)propyl-amine;
{3-[4-methyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-2-methoxyethyl-amine;
{3-[3,4-dimethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-ethoxylpropyl-amine;
{3-[3,4-dimethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-(1-methylethoxyl)propyl-amine;
{3-[3,4-dimethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-2-methoxyethyl-amine;
{3-[4-chloro-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-2-methoxyethyl-amine;
{3-[4-chloro-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-methoxypropyl-amine;
{3-[4-isopropyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-ethoxylpropyl-amine;
{3-[4-isopropyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-2-methoxyethyl-amine;
{3-[4-ethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-2-methoxyethyl-amine;
{3-[4-ethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-methoxypropyl-amine;
{3-[4-ethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-(1-methylethoxyl)propyl-amine;
{3-[2,5-dimethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-ethoxypropyl-amine;
{3-[2,5-dimethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-(1-methylethoxyl)propyl-amine;
{3-[2,5-dimethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-2-methoxyethyl-amine; or
{3-[2,5-dimethyl-benzenesulfonyl]-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl}-3-methoxypropyl-amine.

10. The method of claim 2 wherein,
n is 1 or 2;
X is a C 1-2 alkylene chain;
each R 3 and R 4 is independently hydrogen, alkyl, halo or haloalkyl;
R 7 is alkyl, halo, haloalkyl, or —OR 9 ;
R 8 is optionally substituted aryl or optionally substituted heterocyclyl; and
R 9 is hydrogen, alkyl or haloalkyl.

11. The method of claim 10 wherein the compound is
[3-(4-isopropyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-(4-methoxy-benzyl)-amine;
[3-(4-isopropyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-naphthalen-1-ylmethyl-amine;
[3-(4-methyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-(4-methoxy-benzyl)-amine;
[3-(4-methyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-(1-phenyl-1-methyl)methyl-amine;
[3-(4-methyl-benz enesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-(3-methoxy-benzyl)-amine;
[3-(4-methyl-benzenesulfonyl)-thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidin-5-yl]-(4-fluoro-benzyl

Assignees

• Univ California

Inventors

• Anderson Marc
• Verkman Alan S

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P13/02

  of urine or of the urinary tract, e.g. urine acidifiers · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title