Derivatives of succinic and glutaric acids and analogs thereof useful as inhibitors of phex
View Patent ↗The present invention relates to derivatives of succinic and glutaric acids and analogues thereof, having the following general formula: useful as inhibitors of PHEX. These derivatives are useful for promoting generation of bone mass and treating or preventing diseases or conditions associated with a phosphate metabolism defect. Methods for preparation and intermediates are also disclosed.
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein
A is a zinc ligand or zinc ligand bearing moiety selected from the group consisting of:
B is absent:
R is hydrogen or lower alkyl;
R 1 is hydrogen or lower alkyl;
R 2 is hydrogen, or lower alkyl;
R 3 is hydrogen or lower alkyl;
R 4 is lower alkyl, substituted lower alkyl, cycloalkyl-(CH 2 ) w —, aryl-(CH 2 ) w —, substituted aryl —(CH 2 ) w — or heteroaryl-(CH 2 ) w —;
R 5 is hydrogen, lower alkyl, substituted lower alkyl, cycloalkyl-(CH 2 ) x —, aryl-(CH 2 ) x —, substituted aryl-(CH 2 ) x —, or heteroaryl-(CH 2 ) x —;
R 8 and R 9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl-(CH 2 ) y —, substituted aryl-(CH 2 ) y —, heteroaryl-(CH 2 ) y —,
R 10 is alkyl, substituted alkyl, cycloalkyl-(CH 2 ) y , aryl-(CH 2 ) y —, substituted aryl-(CH 2 ) y — or heteroaryl-(CH 2 ) y —;
R 13 is hydrogen, lower alkyl, cycloalkyl or phenyl;
R 14 is hydrogen, lower alkyl, lower alkoxy or phenyl;
R 15 is lower alkyl or aryl-(CH 2 ) y —;
D is —COOH,
E is hydrogen, —COOH, —CONH 2 , —CONH(lower alkyl), —CON(lower alkyl) 2 , —CONH—(CH 2 ) z -aryl, —CON(—(CH 2 ) z -aryl) 2 , —CO-amino acid, —CH 2 COOH, CH 2 OH, —CH 2 CH 2 OH, or —COOR 16 ;
R 16 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl-(CH 2 ) y —, substituted aryl-(CH 2 ) y —, heteroaryl-(CH 2 ) y —,
C is carbon;
H is hydrogen;
O is oxygen;
N is nitrogen;
S is sulfur;
P is phosphorus;
v is zero;
w is zero or an integer ranging from 1 to 4;
x is an integer ranging from 1 to 4;
y is zero or an integer ranging from 1 to 6; and
z is zero, one, two, or three.
2. The compound of claim 1 , wherein R 1 and R 3 , when v=0, are connected together to form an alkylene bridge of 3 carbon atoms representing with the carbon atoms to which they are attached a cyclopentane ring.
3. The compound of claim 1 , wherein R 1 and R 3 , when v=0, are connected together to form an alkylene bridge of 4 carbon atoms representing with the carbon atoms to which they are attached a cyclohexane ring.
4. The compound of claim 1 , wherein R and R 4 are connected together to form an alkylene bridge of 3 carbon atoms representing with the nitrogen and carbon atoms to which they are attached a pyrrolidine ring.
5. The compound of claim 1 , wherein R and R 4 are connected together to form an alkylene bridge of 4 carbon atoms representing with the nitrogen and carbon atoms to which they are attached a piperidine ring.
6. The compound of claim 1 , wherein the compound is further defined as: 3-(2-Biphenyl-4-yl-ethylcarbamoyl)-4-hydroxycarbamoyl-butyric acid; 3-[2-(4′-Cyano-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid; 4-Hydroxycarbamoyl-3-[2-(4-pyridin-2-yl-phenyl)-ethylcarbamoyl]-butyric acid; 4-Hydroxycarbamoyl-3-(4-phenyl-butylcarbamoyl)-butyric acid; 4-Hydroxycarbamoyl-3-(2-phenoxy-ethylcarbamoyl)-butyric acid; 3-[2-(4′-Hydroxy-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid; 3-(2,2-Diphenyl-ethylcarbamoyl)-4-hydroxycarbamoyl-butyric acid; 3-[2-(4′-Dimethylamino-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid; 4-Hydroxycarbamoyl-3-(5-hydroxy-pentylcarbamoyl)-butyric acid; 3-[(Biphenyl-4-ylmethyl)-carbamoyl]-4-hydroxycarbamoyl-butyric acid; N-[1-carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-phenyl-1-phosphono-propylamino)-succinic acid; or 3-(2-Naphthalen-2-yl-ethylcarbamoyl)-pentanedioic acid.
7. The compound of claim 6 , wherein the compound is 3-(2-Biphenyl-4-yl-ethylcarbamoyl)-4-hydroxycarbamoyl-butyric acid.
8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a physiologically acceptable carrier or excipient.
9. The pharmaceutical composition of claim 8 , wherein the compound is further defined as: 3-(2-Biphenyl-4-yl-ethylcarbamoyl)-4-hydroxycarbamoyl-butyric acid; 3-[2-(4′-Cyano-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid; 4-Hydroxycarbamoyl-3-[2-(4-pyridin-2-yl-phenyl)-ethylcarbamoyl]-butyric acid; 4-Hydroxycarbamoyl-3-(4-phenyl-butylcarbamoyl)-butyric acid; 4-Hydroxycarbamoyl-3-(2-phenoxy-ethylcarbamoyl)-butyric acid; 3-[2-(4′-Hydroxy-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid; 3-(2,2-Diphenyl-ethylcarbamoyl)-4-hydroxycarbamoyl-butyric acid; 3-[2-(4′-Dimethylamino-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid; 4-Hydroxycarbamoyl-3-(5-hydroxy-pentylcarbamoyl)-butyric acid; 3-[(Biphenyl-4-ylmethyl)-carbamoyl]-4-hydroxycarbamoyl-butyric acid; N-[1-carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-phenyl-1-phosphono-propylamino)-succinic acid; or 3-(2-Naphthalen-2-yl-ethylcarbamoyl)-pentanedioic acid.
10. The pharmaceutical composition of claim 8 , wherein the compound is 3-(2-Biphenyl-4-yl-ethylcarbamoyl)-4-hydroxycarbamoyl-butvric acid.
11. The compound of claim 1 , wherein A is
12. The compound of claim 1 , wherein A is
13. The compound of claim 1 , wherein A is
14. The compound of claim 1 , wherein A is
15. The compound of claim 1 having the formula:
16. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 3-[2-(4′-Cyano-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid.
17. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 4-Hydroxycarbamoyl-3-[2-(4-pyridin-2-yl-phenyl)-ethylcarbamoyl]-butyric acid.
18. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 4-Hydroxycarbamoyl-3-(4-phenyl-butylcarbamoyl)-butyric acid.
19. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 4-Hydroxycarbamoyl-3-(2-phenoxy-ethylcarbamoyl)-butyric acid.
20. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 3-[2-(4′-Hydroxy-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid.
21. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 3-(2,2-Diphenyl-ethylcarbamoyl)-4-hydroxycarbamoyl-butyric acid.
22. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 3-[2-(4′-Dimethylamino-biphenyl-4-yl)-ethylcarbamoyl]-4-hydroxycarbamoyl-butyric acid.
23. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 4-Hydroxycarbamoyl-3-(5-hydroxy-pentylcarbamoyl)-butyric acid.
24. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 3-[(Biphenyl-4-ylmethyl)-carbamoyl]-4-hydroxycarbamoyl-butyric acid.
25. The pharmaceutical composition of claim 9 , wherein the compound is further defined as N-[1-carboxy-2-(1H-indol-3-yl)-ethyl]-3-(3-phenyl-1-phosphono-propylamino)-succinic acid.
26. The pharmaceutical composition of claim 9 , wherein the compound is further defined as 3-(2-Naphthalen-2-yl-ethylcarbamoyl)-pentanedioic acid.