Treating primary or idiopathic hyperoxaluria with small molecule inhibitors of lactate dehydrogenase

Patent metadata

Field	Value
Publication number	US-11752138-B2
Application number	US-202117322260-A
Country	US
Kind code	B2
Filing date	May 17, 2021
Priority date	May 18, 2020
Publication date	Sep 12, 2023
Grant date	Sep 12, 2023

Abstract

The disclosure provides methods of treating a patient having primary hyperoxaluria or idiopathic hyperoxaluria comprising administering a therapeutically effective amound of compound of the formula

and pharmaceutically acceptable salts, solvates, and hydrates thereof to the patient. The variables, e.g. ring A, n, R, R 3 , R 10 , X, Y, and Z are defined herein. These compounds act as lactate dehydrogenase inhibitors and are useful inhibiting the conversion of glyoxylate to oxalate. When administered to a patient having a disease or disorder associated with elevated oxalate levels, such as PH type 1, type 2, or type 3 or idiopathic hyperoxaluria the compounds prevent or substantially reduce the amount and buildup of oxalate the patient's kidneys, bladder, urinary tract and other parts of the patient's body.

First claim

What is claimed is:

1. A method of treating a disease or disorder associated with elevated oxalate levels in a patient comprising, administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, or hydrate thereof to the patient:

wherein
the A ring,

 is phenyl or pyridyl;
X is hydrogen or a halogen;
Y is hydrogen or C 1 -C 2 alkyl;
Z is —CO 2 H, —CONH 2 , —CONH(CN), —CONHSO 2 CH 3 , —CONH(OH), —COCF 3 , CH(OH)CF 3 ,

—CH 2 OH, or —B(OH) 2 ;
n is 0, 1, 2, or 3;
R is independently chosen at each occurrence from halogen, hydroxyl, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy;
R 3 is a —C(O)CH 3 , a substituted or unsubstituted phenyl group, a substituted or unsubstituted indanyl group, a substituted or unsubstituted tetrahydronaphthyl group, a substituted or unsubstituted cyclohexenyl group, a substituted or unsubstituted indenyl group, substituted or unsubstituted 2,6-diazaspiro[3.3]heptanyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted dihydrofuranyl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted spiro[2.5]oct-5-enyl, a substituted or unsubstituted benzimidazolyl group, or
R 3 is -L-Q, wherein L is an C 2 -C 4 alkynyl group, an ethylenylene group, a cyclopropylene group, or a cyclobutylene group, and wherein Q is hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 3 -C 6 cycloalkyl group, or a substituted or unsubstituted five-membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S; or
R 3 is —NR 5 C(O)R 4 or —C(O)NR 5 R 6 , wherein R 4 is hydrogen, C 1 -C 5 alkyl, or substituted or unsubstituted phenyl, and R 5 and R 6 are each independently hydrogen or C 1 -C 5 alkyl, wherein R 5 and R 6 optionally form a ring, and wherein R 4 and R 5 optionally form a ring; and R 10 is hydrogen or (cyclopropyl)C 0 -C 4 alkyl, which cyclopropyl is optionally substituted with methyl or cyclopropyl or fused to a cyclopropyl group in spiro orientation, or R 10 is (cyclopropyl)C 1 -C 4 alkyl in which the C 1 -C 4 alkyl is substituted with cyclopropyl.

2. The method of claim 1 , wherein in the compound of Formula I or salt, solvate, or hydrate thereof, wherein
X is hydrogen or fluoro;
Y is hydrogen; and
Z is —CO 2 H, and
R 10 is (cyclopropyl)C 0 -C 2 alkyl.

3. The method of claim 1 , wherein in the compound of Formula I or salt, solvate, or hydrate thereof:
the A ring is phenyl;
R is halogen and n is 0 or 1; and
R 3 is phenyl, which is unsubstituted or substituted with one or two substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, or
R 3 is -L-Q, wherein L is an ethynyl group; and
Q is a 2-thienyl, 2-thiazolyl, or cyclopentyl, each of which is unsubstituted or substituted with 1 or two substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

4. The method of claim 1 , wherein in the compound of Formula I or salt, solvate, or hydrate thereof:
the A ring is phenyl;
R is halogen and n is 0 or 1; and
R 3 is -L-Q, wherein L is an ethynyl group; and
Q is a 2-thienyl, 2-theaxolyl, or cyclopentyl, each of which is unsubstituted or substituted with 1 or two substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy.

5. A method of preventing the symptoms of primary hyperoxaluria, reducing the severity of the symptoms of primary hyperoxaluria in a patient, comprising determining the patient has a mutation in a gene encoding an enzyme, the mutation causing a loss of enzyme function or a reduction in enzyme activity, where the enzyme is selected from:
(a) alanine-glycolate aminotransferase (AGXT);
(b) glyoxylate reductase/hydroxypyruvate reductase (GPHPR); and
(c) 4-hydroxy-2-oxoglutarate aldolase 1 (HOGA1);

and administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate, or hydrate, thereof to the patient:

wherein
the A ring,

 is phenyl or pyridyl;
X is hydrogen or a halogen;
Y is hydrogen or C 1 -C 2 alkyl;
Z is —CO 2 H, —CONH 2 , —CONH(CN), —CONHSO 2 CH 3 , —CONH(OH), —COCF 3 , CH(OH)CF 3 , —CH 2 OH, or —B(OH) 2 ;
n is 0, 1, 2, or 3;
R is independently chosen at each occurrence from halogen, hydroxyl, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy;
R 3 is a —C(O)CH 3 , a substituted or unsubstituted phenyl group, a substituted or unsubstituted indanyl group, a substituted or unsubstituted tetrahydronaphthyl group, a substituted or unsubstituted cyclohexenyl group, a substituted or unsubstituted indenyl group, substituted or unsubstituted 2,6-diazaspiro[3.3]heptanyl group, a substituted or unsubstituted imidazolyl group, a substituted or unsubstituted dihydrofuranyl group, a substituted or unsubstituted pyrrolidinyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted thiazolyl group, a substituted or unsubstituted spiro[2.5]oct-5-enyl, a substituted or unsubstituted benzimidazolyl group, or
R 3 is -L-Q, wherein L is an C 2 -C 4 alkynyl group, an ethylenylene group, a cyclopropylene group, or a cyclobutylene group, and wherein Q is hydrogen, a C 1 -C 5 alkyl group, a substituted or unsubstituted C 3 -C 6 cycloalkyl group, or a substituted or unsubstituted five-membered heterocycle having 1 to 3 heteroatoms selected from N, O, and S, or
R 3 is —NR 5 C(O)R 4 , —C(O)NR 5 R 6 , wherein R 4 is hydrogen, C 1 -C 5 alkyl, or substituted or unsubstituted phenyl, and R 5 and R 6 are each independently hydrogen or C 1 -C 5 alkyl, wherein R 5 and R 6 optionally form a ring, and wherein R 4 and R 5 optionally form a ring; and
R 10 is hydrogen or (cyclopropyl)C 0 -C 4 alkyl, which cyclopropyl is optionally substituted with methyl or cyclopropyl or fused to a cyclopropyl group in spiro orientation, or R 10 is (cyclopropyl)C 1 -C 4 alkyl in which the C 1 -C 4 alkyl is substituted with cyclopropyl.

6. A method of treating a disease or disorder associated with elevated oxalate levels in a patient comprising, administering a therapeutically effective amount of a compound of Formula II to the patient:

or a pharmaceutically acceptable salt thereof, wherein:
Y is O or S;
Q is thienyl;
R x is halogen, C 1 -C 4 alkyl, CHF 2 , CF 3 , cyclopropyl or cyclobutyl;
R y is C 1 -C 4 alkyl;
R 10 is (cyclopropyl)C 0 -C 3 alkyl optionally substituted with one or two groups independently selected from methyl and cyclopropyl;
R is hydrogen or fluoro; and
m is 0 or 1.

7. The method of claim 6 comprising administering a therapeutically effective amount of a compound, salt, solvate, or hydrate thereof of Formula II having the Formula II-A:

Assignees

• Univ Vanderbilt
• Uab Res Found
• Us Health

Inventors

• Hall Matthew
• Urban Daniel J
• Knight John
• Holmes Ross
• Wood Kyle David
• Waterson Alex
• Darley-Usmar Victor M
• Neckers Leonard M

Classifications

• A61K31/427 Primary

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title