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US 2018/0002275 A1Published application
Hypdh inhibitors and methods of use for the treatment of kidney stones
AssigneesWake Forest University Health Sciences, The UAB Research Foundation
InventorsW. Todd Lowther, Ross P. Holmes, Daniel Yohannes
Life of this patent
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Abstract
Provided herein are compounds of Formula (I), Formula (II), and Formula (III), and compositions comprising the same, as well as methods of use thereof for controlling or inhibiting the formation of calcium oxalate kidney stones, inhibiting the production of glyoxylate and/or oxalate, and/or inhibiting hydroxyproline dehydrogenase (HYPDH).
Claims25
A method of inhibiting the formation of oxalate kidney stones, comprising:
- administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, a compound of Formula II, or a compound of Formula III:
- wherein:
- X is O, S, NH, NMe or CRxRy, wherein Rx and Ry are each independently selected from H, alkyl and halo;
- n is 0, 1, 2, 3, 4, 5 or 6;
- m is 0, 1, 2, or 3;
- R1 is selected from the group consisting of:
- alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, amine and carboxy;
- R2 is selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R2 is R2aR2b, wherein R2a and R2b are each independently selected from alkyl and hydroxy;
- R3 is selected from the group consisting of:
- H, hydroxy, amine, and ═O;
- or R3 is R3aR3b, wherein R3a and R3b are each independently selected from alkyl and hydroxy;
- R4 is selected from the group consisting of:
- H, alkyl, and hydroxy;
- or R4 is R4aR4b wherein R4a and R4b are each independently selected from alkyl, hydroxy, and halo, wherein said alkyl may be unsubstituted or substituted 1, 2 or 3 times with hydroxy;
- and
- each R5 is independently selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R5 is R5aR5b wherein R5a and R5b are each independently selected from alkyl and hydroxy;
- or R2 and an adjacent R5 are taken together to form an aryl or heteroaryl,
- or a pharmaceutically acceptable salt or prodrug thereof.
19 more elements
A method of inhibiting the production of glyoxylate and/or oxalate in a subject in need thereof, comprising:
- administering to said subject a therapeutically effective amount of a compound of Formula I, a compound of Formula II, or a compound of Formula III:
- wherein:
- X is O, S, NH, NMe or CRxRy, wherein Rx and Ry are each independently selected from H, alkyl and halo;
- n is 0, 1, 2, 3, 4, 5 or 6;
- m is 0, 1, 2, or 3;
- R1 is selected from the group consisting of:
- alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, amine and carboxy;
- R2 is selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R2 is R2aR2b, wherein R2a and R2b are each independently selected from alkyl and hydroxy;
- R3 is selected from the group consisting of:
- H, hydroxy, amine, and ═O;
- or R3 is R3aR3b, wherein R3a and R3b are each independently selected from alkyl and hydroxy;
- R4 is selected from the group consisting of:
- H, alkyl, and hydroxy;
- or R4 is R4aR4b wherein R4a and R4b are each independently selected from alkyl, hydroxy, and halo, wherein said alkyl may be unsubstituted or substituted 1, 2 or 3 times with hydroxy;
- and
- each R5 is independently selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R5 is R5aR5b wherein R5a and R5b are each independently selected from alkyl and hydroxy;
- or R2 and an adjacent R5 are taken together to form an aryl or heteroaryl,
- or a pharmaceutically acceptable salt or prodrug thereof.
19 more elements
A method of inhibiting hydroxyproline dehydrogenase (HYPDH) in a subject in need thereof, comprising:
- administering to said subject a therapeutically effective amount of a compound of Formula I, a compound of Formula II, or a compound of Formula III:
- wherein:
- X is O, S, NH, NMe or CRxRy, wherein Rx and Ry are each independently selected from H, alkyl and halo;
- n is 0, 1, 2, 3, 4, 5 or 6;
- m is 0, 1, 2, or 3;
- R1 is selected from the group consisting of:
- alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, amine and carboxy;
- R2 is selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R2 is R2aR2b, wherein R2a and R2b are each independently selected from alkyl and hydroxy;
- R3 is selected from the group consisting of:
- H, hydroxy, amine, and ═O;
- or R3 is R3aR3b, wherein R3a and R3b are each independently selected from alkyl and hydroxy;
- R4 is selected from the group consisting of:
- H, alkyl, and hydroxy;
- or R4 is R4aR4b wherein R4a and R4b are each independently selected from alkyl, hydroxy, and halo, wherein said alkyl may be unsubstituted or substituted 1, 2 or 3 times with hydroxy;
- and
- each R5 is independently selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R5 is R5aR5b wherein R5a and R5b are each independently selected from alkyl and hydroxy;
- or R2 and an adjacent R5 are taken together to form an aryl or heteroaryl,
- or a pharmaceutically acceptable salt or prodrug thereof.
19 more elements
A compound of Formula I, a compound of Formula II, or a compound of Formula III:
- wherein:
- X is O, S, NH, NMe or CRxRy, wherein RxRy are each independently selected from H, alkyl and halo;
- n is 0, 1, 2, 3, 4, 5 or 6;
- m is 0, 1, 2, or 3;
- R1 is selected from the group consisting of:
- alkyl, alkenyl, alkynyl, aryl, halo, hydroxy, amine and carboxy;
- R2 is selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R2 is R2aR2b, wherein R2a and R2b are each independently selected from alkyl and hydroxy;
- R3 is selected from the group consisting of:
- H, hydroxy, amine, and ═O;
- or R3 is R3aR3b, wherein R3a and R3b are each independently selected from alkyl and hydroxy;
- R4 is selected from the group consisting of:
- H, alkyl, and hydroxy;
- or R4 is R4aR4bwherein R4a and R4b are each independently selected from alkyl, hydroxy, and halo, wherein said alkyl may be unsubstituted or substituted 1, 2 or 3 times with hydroxy;
- and
- each R5 is independently selected from the group consisting of:
- H, alkyl, hydroxy, amine, and ═O;
- or R5 is R5aR5b wherein R5a and R5b are each independently selected from alkyl and hydroxy;
- or R2 and an adjacent R5 are taken together to form an aryl or heteroaryl,
- or a pharmaceutically acceptable salt or prodrug thereof.
18 more elements
-26. (canceled)
Dependencies are inferred from the claim text.