# US 10,688,095 B2 · Compounds and their use for reducing uric acid levels

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- Number: US 10,688,095 B2
- Document ID: US10688095B2
- Status: Granted
- Kind: B2
- Application number: 16/227,398
- Filed: 2018-12-20
- Published: 2019-04-25
- Granted: 2020-06-23
- Earliest claimed: 2016-07-06
- Assignees: Acquist LLC
- Applicants: Acquist LLC
- Inventors: Raymond P. Warrell, Jr.; John J. Piwinski; Alexandre Larivée; Arshad Siddiqui; Karen Thai
- Web page: https://patentgrep.com/patent/US10688095B2

## CPC

- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Bifunctional barbiturate-derivative compounds that increase uric acid excretion and reduce uric acid production, and monofunctional barbiturate-derivative compounds that either increase uric acid excretion or reduce uric acid production are provided. Methods of using these compounds for reducing uric acid levels in blood or serum, for treating disorders associated with excess uric acid, and for maintaining normal uric acid levels in blood or serum, or the whole body, 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 O, Y is OH, X, is each O, S, NR2 or N(R2)2;
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, —OCF3, —OCHF2, —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, alkynyl and cycloalkyl;
wherein each R1 is C1-C8 branched or unbranched alkyl, optionally substituted with Z;
wherein each R2 is H;
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 three of a, b, c, d and e are nitrogen, and Z is not connected directly to nitrogen or oxygen; and
b) tautomers of any of the foregoing compounds.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein three of a, b, c, d, and e are nitrogen.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R1 is—CH3.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein—XR1 is—SCH3 or —OCH3.

### Claim 5 (depends on 4)

The compound according to claim 4, wherein A is substituted phenyl.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein A is—CF3 substituted phenyl.

### Claim 7 (depends on 6)

The compound according to claim 6, which has a structure represented by

### Claim 8 (depends on 1)

The compound according to claim 1, which is selected from the group consisting of compounds having a structure represented by
and tautomers thereof.

### Claim 9

A compound selected from the group consisting of
a) compounds having a structure represented by Formula (I):
wherein
W is O, Y is OH, X is O, S, NR2 or N(R2)2;
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 H;
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 three of a, b, c, d and e are nitrogen, and Z is not connected directly to nitrogen or oxygen; and
b) tautomers of any of the foregoing compounds.

### Claim 10 (depends on 9)

The compound according to claim 9, wherein A is thiazole or isothiazole.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein three of a, b, c, d, and e are nitrogen.

### Claim 12 (depends on 11)

The compound according to claim 11, which has a structure represented by Formula (Io).

### Claim 13

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

### Claim 14 (depends on 13)

The pharmaceutical composition according to claim 13, which comprises a compound having a structure represented by Formula (IId) or a tautomer thereof.

### Claim 15

A method for reducing uric acid levels in blood, serum or a whole body of a subject, or for reducing elevation of uric acid levels in blood, serum or a whole body of a subject, or for treating a disorder associated with excess uric acid, comprising administering to a subject in need thereof a compound having a structure represented by Formula (II); a tautomer or Formula (II), or a combination thereof, in an amount effective to reduce blood or serum uric acid levels.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the disorder associated with excess uric acid is selected from gout, hyperuricemia, tumor lysis syndrome, kidney disease, arthritis, kidney stones, kidney failure, urolithiasis, plumbism, hyperparathyroidism, psoriasis, inborn genetic errors of metabolism such as Lesch-Nyhan syndrome, sarcoidosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), cardiovascular disease, atherosclerosis, hypertension, obesity, diabetes, insulin resistance, metabolic syndrome, and transplantation of blood, bone marrow or solid organs.

### Claim 17 (depends on 15)

The method according to claim 15, which comprises administration of a compound having a structure represented by Formula (IIdd).

### Claim 18 (depends on 15)

The method according to claim 15, wherein the compound, tautomer or combination thereof is administered parenterally, intraperitoneally, intravenously, intranasally, intrarectally, or orally.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the compound, tautomer or combination thereof is administered by injection, infusion, or oral administration.

### Claim 20 (depends on 15)

The method according to claim 15, wherein the compound, tautomer or combination thereof is administered intermittently.