Granted Patent B2

US 12,440,486 · App. 17/261,851 · Granted Oct 14, 2025

Inventors: Konstantin Petrukhin (New Windsor, NY); Boglarka Racz (Brooklyn, NY); Andras Varadi (Brooklyn, NY)

Assignee: THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

A61K31/4545A61K31/506A61P1/16A61P19/06

Abstract

Claims (111)

1. A method for treating gout in a subject afflicted therewith comprising administering to the subject a pharmaceutical composition comprising an amount of a compound effective to treat the subject, thereby treating the subject, wherein compound has the structure

wherein L is a linking group having the structure:

and Z is a group having the structure:

wherein

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 or C 1 -C 4 alkyl, aryl or heteroaryl;

R 6 is H, OH, or halogen or absent;

ψ is absent or present, and when present is a bond;

B is a substituted or unsubstituted heterobicycle, pyridazine, pyrazole, pyrazine, thiadiazole, or triazole, wherein the heterobicycle is other than chloro substituted indole; and

the pyrazole, when substituted, is substituted with other than trifluoromethyl;

B′ is a substituted or unsubstituted phenyl, pyridine, pyrimidine, benzyl, pyrrolidine, sulfolane, oxetane, CO 2 H or (C 1 -C 4 alkyl)-CO 2 H,

wherein the substituted phenyl is substituted with other than trifluoromethyl or 3-(methyl carboxylate), the substituted pyridine is substituted with other than trifluoromethyl and the substituted pyrrolidine is substituted with other than hydroxamic acid, and

the substituted or unsubstituted pyrrolidine is bound to the carbonyl through a carbon-carbon bond;

A is absent or present, and when present is

B 1 is substituted or unsubstituted monocycle, bicycle, heteromonocycle, heterobicycle, benzyl, CO 2 H or (C 1 -C 4 alkyl)-CO 2 H,

wherein when B 1 is CO 2 H, then A is present

and is

R 7 is alkyl;

X is N or CR 8 , wherein R 8 is H, OH, or halogen;

B 2 has the structure:

wherein

α and β are each a bond that is present or absent;

X 1 is N, NH or NR 99 ,

wherein R 99 is alkyl, alkenyl or alkynyl;

X 2 is C or N;

X 3 is CH or N;

R 9 , R 10 and R 11 are each, independently, H, halogen, alkyl, alkenyl, alkynyl, alkyl-OH, alkyl-NH 2 , alkyl-OAc alkyl-O(CO)-alkyl, alkyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN or CF 3 ,

wherein

X 1 , X 2 and X 3 are each N, α is present and β is absent; or

X 1 , X 2 and X 3 are each N, α is present and β is absent; or

X 1 , X 2 and X 3 are each N, α is present and β is absent; or

X 1 is NH or NR 99 , X 2 is C, X 3 is N, α is absent and β is present, wherein

when X 1 is NH, X 2 is C, X 3 is N, α is absent and β is present, then one of R 9 , R 10 and R 11 is other than H,

or B 2 has the structure:

wherein

R 12 , R 13 and R 14 are each, independently, H, halogen, alkyl, alkenyl, alkynyl alkyl-OH, alkyl-NH 2 , alkyl-OAc, alkyl-O(CO)-alkyl, alkyl-O-alkyl, haloalkyl, cycloalkyl, O-alkyl, NH-alkyl, C(O)OH, C(O)—NH 2 , C(O)—N(CH 3 ) 2 , C(O)—NHCH 3 , NHC(O)—N(CH 3 ) 2 , CN or CF 3 , or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein in the compound, R 1 , R 2 , R 3 , R 4 , and R 5 are each independently H, halogen, CF 3 or C 1 -C 4 alkyl.

3. The method of claim 1 , wherein the method further comprises a step of determining, or having determined, the level of RBP4 in adipose tissue or in serum in the subject and administering the pharmaceutical composition if the level of RBP4 in adipose tissue or in serum is elevated.

4. The method of claim 1 , wherein the amount of the compound is effective in reducing RBP4 levels in serum in the subject by about 90% or reducing uric acid levels in the serum of the subject to less than 7 mg/dL.

5. The method of claim 1 , wherein the amount of the compound is effective to normalize the concentration of triglycerides in the liver of the subject, or normalize the concentration of free fatty acids in the serum of the subject, or normalize the concentration of free fatty acids in the liver of the subject, wherein normalize comprises increasing or reducing the concentration of triglycerides or free fatty acids such that the concentration of triglycerides or free fatty acids is closer to the concentration of triglycerides or free fatty acids in a subject without gout; or

wherein the amount of the compound is effective to prevent trafficking of a fatty acid by RBP4, or to prevent trafficking of a fatty acid to the liver by RBP4, or inhibit binding between RBP4 and a fatty acid.

6. The method of claim 5 , wherein the amount of the compound is effective to normalize the concentration of fatty acid in the liver.

7. The method of claim 1 , wherein the subject has elevated serum RBP4 levels; or

wherein the subject has serum RBP4 levels elevated by more than 3 microgram per ml.

8. The method of claim 1 , wherein in the compound,

L is

 and Z is

 or

wherein

L is

 and Z is

9. The method of claim 1 , wherein in the compound,

L is

Z is

two or more of R 1 , R 2 , R 3 , R 4 , or R 5 are other than H,

and

when R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is H, R 2 is CF 3 , R 3 is H, R 4 is CF 3 , and R 5 is H, or R 1 is Cl, R 2 is H, R 3 is H, R 4 is F, and R 5 is H, or R 1 is CF 3 , R 2 is H, R 3 is F, R 4 is H, and R 5 is H, or R 1 is CF 3 , R 2 is F, R 3 is H, R 4 is H, and R 5 is H, or R 1 is Cl, R 2 is F, R 3 is H, R 4 is H, and R 5 is H, then B is other than

10. The method of claim 1 , wherein in the compound,

L is

 and Z is

 or

wherein

L is

 Z is

 and

R 6 is absent or present, and when present is H, OH, or halogen

and when ψ is present, then R 6 is absent and when ψ is absent, then R 6 is present; or

wherein

L is

 and Z is

 or

wherein

L is

 and Z is

 or

wherein

L is

 Z is

 R 6 is H, and A is

 or

wherein

L is

 and Z is

11. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

12. The method of claim 1 , wherein the amount of the compound administered to the subject is 5-1000 mg, 5-800 mg, 5-200 mg, 45-200 mg, 45-1000 mg, 45-800 mg, 10-50 mg, 96 mg, 24 mg or 10 mg per day.

13. The method of claim 1 , wherein the method further comprises administering an amount of a second agent which is (R)-(+)-(5,6-dichloro 2,3,9,9a-tetrahydro 3-oxo-9a-propyl-1H-fluoren-7-yl)oxy]acetic acid (DPOFA), a Nonsteroidal Anti-inflammatory Drug (NSAID, indomethacin, colchicine, lesinurad, corticosteroids, betamethasone, prednisone, dexamethasone, cortisone, cortisone, hydrocortisone, methylprednisone, prednisolone, biologic anti-IL-1alpha/beta agents, canakinumab, rilonacept, anakinra, allopurinol, benzbromarone, forms of uricase enzymes, pegloticase, topiroxostat (FYX-051), ulodesine (BCX4208), KUX-1151, RLBN1001, RDEA3170, arhalofenate (MBX-102), levotofisopam, UR-1102, PF-06743649, BCX4208, SHR4640, Lumiracoxib, Tranilast, Topiroxostat, LC350189, Bucillamine, AC-201, HuZhen Capsules, MPC-004, FYU-981, Sodium Bicarbonate, SEL-212, SEL-037, Apremilast, TMX-67, SSS11, D-0120, febuxostat or probenecid, or esters or salts thereof effective to treat the subject, thereby treating the subject.

14. The method of claim 1 , wherein the subject is afflicted with gout; or

wherein the subject is afflicted with chronic gout or acute gout.

15. The method of claim 14 , wherein the amount of the compound is effective in reducing uric acid levels to 3.4-7.0 mg/dL in the blood of the subject.

16. The method of claim 1 , wherein in the compound,

L is a linking group having the structure:

Z is a group having the structure:

A is

 and

B 2 is

17. The method of claim 1 , wherein in the compound,

L is

 Z is

 and A is absent.

18. The method of claim 1 , wherein in the compound,

L is,

 Z is

 R 6 is H, and A is

19. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

21. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

Assignments (2)

Continuity (2)

References Cited (44)