# US 10,759,784 B2 · Compounds and their use for reducing uric acid levels

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- Number: US 10,759,784 B2
- Document ID: US10759784B2
- Status: Granted
- Kind: B2
- Application number: 16/310,921
- Filed: 2017-06-21
- Published: 2020-01-16
- Granted: 2020-09-01
- Earliest claimed: 2016-06-30
- Assignees: Acquist LLC
- Applicants: Acquist LLC
- Inventors: John J. Piwinski; Ronald N. Buckle; Alexandre Larivée; Arshad Siddiqui; Raymond P. Warrell, Jr.
- Web page: https://patentgrep.com/patent/US10759784B2

## CPC

- A61P 5/18: of the parathyroid hormones
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 35/00: Antineoplastic agents
- C07D 401/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 487/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Bifunctional compounds that increase uric acid excretion and reduce uric acid production, and monofunctional compounds that either increase uric acid excretion or reduce uric acid production. Methods of using these compounds for reducing uric acid levels in blood or serum, for treating disorders of uric acid metabolism, and for maintaining normal uric acid levels in blood or serum are also provided. Pharmaceutical compositions comprising the bifunctional and monofunctional compounds are also provided.

## Claims

### Claim 1

A compound selected from the group consisting of
a) compounds having a structure represented by Formula (II):
wherein
W is selected from O, S, and NR2, Y is selected from OH and N(R2)2, X, is selected from O, S, and NR2;
A is phenyl, heteroaryl, C5-C10 branched or unbranched cycloalkyl, C6-C10 bicycloalkyl or C5-C10 spirocycloalkyl;
each Z is independently present or absent and, if present, is independently selected from one or more halogen atoms, —CN, —CF3, —OR2, —C(O)R2, SR2, —S(O)gR3 where g is 1 or 2, —N(R2)2, —NO2, —CO2R2, —OCO2R3, OC(O)R2, —CON(R2)2, —NR2C(O)R2, —SO2N(R2)2, —NR2SO2R3, NR2SO2N(R2)2 or NR2C(O)N(R2)2, —C(O)NHOR2, alkyl, aryl, alkenyl and alkynyl;
wherein each R1 is C1-C8 branched or unbranched alkyl, optionally substituted with Z;
wherein each R2 is independently H, alkyl or aryl;
wherein each R3 is independently alkyl or aryl, optionally substituted with one or more halogen atoms or OR2; and
wherein a, b, c, d, and e are each independently carbon or nitrogen, or four of a, b, c, d, and e are each independently carbon or nitrogen and one of a, b, c, d, and e is O, with the proviso that at least one of a, b, c, d and e is nitrogen, and Z is not connected directly to nitrogen or oxygen; and
tautomers thereof,
b) compounds having a structure represented by Formula (I):
wherein
W is selected from O, S, and NR2, Y is selected from OH and N(R2)2, X is selected from O, S, and NR2;
T is —CONR2—, —C(NR2)NH—, —C(NOR2)NH—, —C(N—NR2)NH—, —C(SR2)N—, or —NHC(O)—;
A is phenyl, heteroaryl, C5-C10 branched or unbranched cycloalkyl, C6-C10 bicycloalkyl or C5-C10 spirocycloalkyl;
each Z is independently present or absent and, if present, is independently selected from one or more halogen atoms, —CN, —CF3, —OR2, —C(O)R2, SR2, —S(O)gR3 where g is 1 or 2, —N(R2)2, —NO2, —CO2R2, —OCO2R3, OC(O)R2, —CON(R2)2, —NR2C(O)R2, —SO2N(R2)2, —NR2SO2R3, —NR2SO2N(R2)2 or —NR2C(O)N(R2)2, —C(O)NHOR2, alkyl, aryl, alkenyl and alkynyl;
wherein each R2 is independently H, alkyl or aryl;
wherein each R3 is independently alkyl or aryl, optionally substituted with one or more halogen atoms or OR2; and
wherein a, b, c, d, and e are each independently carbon or nitrogen, or four of a, b, c, d, and e are each independently carbon or nitrogen and one of a, b, c, d, and e is O, with the proviso that at least one of a, b, c, d and e is nitrogen, and Z is not connected directly to nitrogen or oxygen; and
tautomers thereof,
c) compounds having a structure represented by Formula (III):
wherein
W is selected from O, S, and NR2, Y is selected from OH and N(R2)2, X is selected from O, S, and NR2;
each R2 is independently H, alkyl or aryl; and
f is divalent —CR2—, —C(O)—, —SR2, —S(O)g— where g is 1 or 2, —N(R′)2—; or —C(—O(CR2)—O—)—
where n=2-3; and
tautomers thereof,
d) compounds having a structure represented by Formula (IV):
wherein
W is selected from O, S, and NR2, Y is selected from OH and N(R2)2, X is selected from O, S, and NR2;
each R2 is independently H, alkyl or aryl; and
f is divalent —CR2—, —C(O)—, —S(O)g— where g is 1-2, —N(R2)2—; or —C(—O(CR2)no-)- where n is 2-3; and
tautomers thereof,
e) compounds having a structure represented by Formula (V):
wherein
W is selected from O, S, and NR2, Y is selected from OH and N(R2)2, X is selected from O, S, and NR2; and
each R2 is independently H, alkyl or aryl; and
tautomers thereof,
and
tautomers thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the 5-member heterocyclic ring of Formula (II) is a substituted or unsubstituted triazole.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein, in Formula (II), —XR1 is —SCH3 or —OCH3.

### Claim 4 (depends on 1)

The compound according to claim 1 wherein, in Formula (I):
a) X and W are each independently O or S;
b) Y is OH or NH2;
c) T is —C(NH)NH—, —NHC(O)—, —C(SCH3)N—, —C(NOH)NH—, —C(N—NH2)NH—, or —CONH;
d) each R2 on the barbiturate ring is independently H or CH3;
e) A is phenyl, branched cycloalkyl, or unbranched cycloalkyl; and
f) Z, if present, is phenyl or CF3.

### Claim 5 (depends on 1)

The compound according to claim 1 wherein, in Formula (III), f is —S(O)2—.

### Claim 6 (depends on 1)

The compound according to claim 1 wherein, in Formula (IV), f is —NH—, —C(O)— or —C(—O(CH2)2O—)—.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein X on the fused ring structure is O.

### Claim 8 (depends on 1)

The compound according to claim 1 wherein, in Formula (V), each R2 is H.

### Claim 9

A pharmaceutical composition comprising a compound having a structure represented by any of Formulae (I)-(V); a tautomer of any of Formulae (I)-(V), or a combination thereof, and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 9)

The pharmaceutical composition according to claim 9 which is formulated for controlled or extended release of the compound or combination thereof.

### Claim 11 (depends on 9)

The pharmaceutical composition according to claim 9, wherein the pharmaceutically acceptable carrier is selected from the group consisting of water or saline, a solvent, a dispersing agent, a coating, a surfactant, a preservative, an emulsion, an alcohol, a polyol, and an isotonic agent.

### Claim 12

A method for reducing uric acid levels in blood or serum of a subject, comprising administering to a subject in need thereof a compound having a structure represented by any of Formulae (I)-(V); a tautomer of any of Formulae (I)-(V), or a combination thereof, in an amount effective to reduce blood or serum uric acid levels.

### Claim 13 (depends on 12)

The method according to claim 12, wherein administering the compound treats a disorder of uric acid metabolism caused by, or associated with, hyperuricemia.

### Claim 14 (depends on 13)

The method of claim 13 wherein the disorder of uric acid metabolism is selected from the group consisting of gout, hyperuricemia, tumor lysis syndrome, kidney disease, arthritis, kidney stones, kidney failure, urolithiasis, plumbism, hyperparathyroidism, psoriasis, inborn genetic errors of metabolism, Lesch-Nyhan syndrome, sarcoidosis, cardiovascular disease, atherosclerosis, and disorders of uric acid metabolism associated with transplantation of blood, bone marrow or solid organs.

### Claim 15 (depends on 12)

The method according to claim 12, wherein a daily dose of about 20 to about 1,500 mg/m2/day is administered.

### Claim 16 (depends on 12)

The method according to claim 12, wherein the compound or combination thereof is administered by injection, infusion, or oral administration.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the compound or combination thereof is administered by intravenous infusion or bolus injection.