Xanthine oxidase inhibitors and methods of use

Patent metadata

Field	Value
Publication number	US-9580379-B2
Application number	US-201414508960-A
Country	US
Kind code	B2
Filing date	Oct 7, 2014
Priority date	Jun 9, 2014
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

Abstract

Small molecule xanthine oxidase inhibitors are provided, as well as compositions, methods for their use for treating disorders, mediated at least in part, by xanthine oxidase.

First claim

What is claimed is:

1. A method for reducing uric acid and/or reactive oxygen species production in a patient in need thereof, comprising administering to the patient an effective amount of compound of Formula III:

or a tautomer, a pharmaceutically acceptable salt and/or solvate thereof, where X and Y are independently selected from the group consisting of —OR 3 , —SR 3 , —NHR 3 , and —NHOR 3 , or X and Y are joined together to form ═O, ═S, ═NR 3 , ═NOR 3 or a cyclic ring system of the formula:

where X 1 and Y 1 are independently selected from the group consisting of —O—, —S —, —SO 2 —, and —N(R 3 )—, and L is —C(O)—or C 2 to C 4 alkylene group optionally substituted with one or two oxo; and
each R 20 is independently selected from the group consisting of hydrogen, —C(═O)R 4 , —C(═O)NHR 4 , —C(═S)R 4 , —C(═S)NHR 4 , —C(═O)OR 4 , —C(═O)SR 4 , —C(═S)OR 4 , —P(═O)R 4 , —P(═O) 2 R 4 , —P(═O)NHR 4 , —P(═O) 2 NHR 4 , —P(═S)NHR 4 , —P(═O)OR 4 , —P(═O) 2 OR 4 , —P(═O)SR 4 , —P(═O) 2 SR 4 , and —P(═S)OR 4 , wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 4 -C 7 cycloalkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, and C 5 -C 6 heteoaryl or heterocycle having 1 to 3 heteroatoms selected from O, S, SO 2 , N, NR 11 , and R 30 ; or —OR 4 is a hydroxy group esterified with a phospholipid; where is hydrogen or C 1 to C 6 alkyl, or C 5 -C 6 heteroaryl having 1 to 3 heteroatoms selected from O, S, SO 2 , N, and NR 12 ; R 12 is hydrogen or C 1 to C 6 alkyl; and R 30 is a saturated fatty chain or an unsaturated fatty chain.

2. The method of claim 1 , wherein the compound of Formula III is selected from the group consisting of:

where R 40 is hydrogen, R 30 or —COR 30 , and where R 30 , X and Y are defined as in claim 1 ;
or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

3. The method of claim 1 , wherein the compound of Formula III is selected from the group consisting of:
5-(1,3-dioxolan-2-yl)-3-nitrobenzene-1,2-diol;
3,4-bis(allyloxy)-5-nitrobenzaldehyde;
and 7-nitro-2-oxobenzo[d][1,3]dioxole-5-carbaldehyde;

or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

4. A method for treating a condition, mediated at least in part by xanthine oxidase, in a patient in need thereof, comprising administering to the patient an effective amount of a compound-of Formula III:

or a tautomer, a pharmaceutically acceptable salt and/or solvate thereof,

where X and Y are independently selected from the group consisting of —OR 3 , —SR 3 , —NHR 3 , and —NHOR 3 or X and Y are joined together to form ═O, ═S, ═NR 3 , ═NOR 3 or a cyclic ring system of the formula:

where X 1 and Y 1 are independently selected from the group consisting of —O—, —S—, —SO 2 —, and —N(R 3 )—, and L is —C(O)—or C 2 to C 4 alkylene group optionally substituted with one or two oxo; and
each R 20 is independently selected from the group consisting of hydrogen, —C(═O)R 4 , —C(═O)NHR 4 , —C(═S)R 4 , —C(═S)NHR 4 , —C(═O)OR 4 , —C(═O)SR 4 , —C(═S)OR 4 , —P(═O)R 4 , —P(═O) 2 R 4 , —P(═O)NHR 4 , —P(═O) 2 NHR 4 , —P(═S)NHR 4 , —P(═O)OR 4 , —P(═O) 2 OR 4 , —P(═O)SR 4 , —P(═O) 2 SR 4 , and —P(═S)OR 4 , wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 4 -C 7 cycloalkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, and C 5 -C 6 heteoaryl or heterocycle having 1 to 3 heteroatoms selected from O, S, SO 2 , N, NR 11 , and R 30 ; or —OR 4 is a hydroxy group esterified with a phospholipid; where R 11 is hydrogen or C 1 to C 6 alkyl, or C 5 -C 6 heteroaryl having 1 to 3 heteroatoms selected from O, S, SO 2 , N, and NR 12 ; R 12 is hydrogen or C 1 to C 6 alkyl; and R 30 is a saturated fatty chain or an unsaturated fatty chain.

5. The method of claim 4 , wherein the compound of Formula III is selected from the group consisting of:

where R 40 is hydrogen, R 30 or —COR 30 , and where R 30 , X and Y are defined as in claim 4 ;
or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

6. The method of claim 4 , wherein the compound of Formula III is selected from the group consisting of:
5-(1,3-dioxolan-2-yl)-3-nitrobenzene-1,2-diol;
3,4-bis(allyloxy)-5-nitrobenzaldehyde;
and 7-nitro-2-oxobenzo[d][1,3]dioxole-5-carbaldehyde;

or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

7. A method for treating hyperuricemia in a patient in need thereof, comprising administering to the patient an effective amount of a compound of Formula III:

or a tautomer, a pharmaceutically acceptable salt and/or solvate thereof, where X and Y are independently selected from the group consisting of —OR 3 , —SR 3 , —NHR 3 , and —NHOR 3 or X and Y are joined together to form ═O, ═S, ═NR 3 , ═NOR 3 or a cyclic ring system of the formula:

where X 1 and Y 1 are independently selected from the group consisting of —O—, —S—, —SO 2 —, and —N(R 3 )—, and L is —C(O)—or C 2 to C 4 alkylene group optionally substituted with one or two oxo; and
each R 20 is independently selected from the group consisting of hydrogen, —C(═O)R 4 , —C(═O)NHR 4 , —C(═S)R 4 , —C(═S)NHR 4 , —C(═O)OR 4 , —C(═O)SR 4 , —C(═S)OR 4 , —P(═O)R 4 , —P(═O) 2 R 4 , —P(═O)NHR 4 , —P(═O) 2 NHR 4 , —P(═S)NHR 4 , —P(═O)OR 4 , —P(═O) 2 OR 4 , —P(═O)SR 4 , —P(═O) 2 SR 4 , and —P(═S)OR 4 , wherein R 4 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 4 -C 7 cycloalkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, and C 5 -C 6 heteoaryl or heterocycle having 1 to 3 heteroatoms selected from O, S, SO 2 , N, NR 11 , and R 30 ; or —OR is a hydroxy group esterified with a phospholipid; where R 11 is hydrogen or C 1 to C 6 alkyl, or C 5 -C 6 heteroaryl having 1 to 3 heteroatoms selected from O, S, SO 2 , N, and NR 12 ; R 12 is hydrogen or C 1 to C 6 alkyl; and R 30 is a saturated fatty chain or an unsaturated fatty chain.

8. The method of claim 7 , wherein the compound of Formula III is selected from the group consisting of:

where R 40 is hydrogen, R 30 or —COR 30 , and where R 30 , X and Y are defined as in claim 7 ;
or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

9. The method of claim 7 , wherein the compound of Formula III is selected from the group consisting of:
5-(1,3-dioxolan-2-yl)-3-nitrobenzene-1,2-diol;
3,4-bis(allyloxy)-5-nitrobenzaldehyde;
and 7-nitro-2-oxobenzo[d][1,3]dioxole-5-carbaldehyde;

or a tautomer, and/or a pharmaceutically acceptable salt and/or solvate thereof.

Assignees

• Baylor College Medicine

Inventors

• Chen Changyi
• Yao Qizhi
• Lu jian-ming

Classifications

• C07F7/1804

  Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896) · CPC title

• C07C205/37 Primary

  the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom · CPC title

• C07C207/04

  the carbon skeleton being further substituted by singly-bound oxygen atoms · CPC title

• C07C251/48

  with the carbon atom of at least one of the oxyimino groups bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07F9/12

  with hydroxyaryl compounds · CPC title