3-hydroxypyrimidine-2,4-dione-5-carboxamides as potent inhibitors of HIV

Patent metadata

Field	Value
Publication number	US-10117871-B2
Application number	US-201615553508-A
Country	US
Kind code	B2
Filing date	Mar 3, 2016
Priority date	Mar 3, 2015
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

Various embodiments described herein are directed to compounds of formula (I), (II), (III) or (IV) for use as potent inhibitors of HIV integrase and for treatment of patients afflicted with AIDS. A major challenge of human immunodeficiency virus (HIV) chemotherapy continues to be the inevitable selection of resistance by the virus towards known drug regimens. Treating resistant HIV strains calls for novel antivirals with unique structural cores. Some embodiments are directed to compounds featuring a 3-hydroxypyrimidine-2,4-dione-5-carboxamide core that consistently confers low nanomolar potencies against HIV-1 in cell culture. Biochemical testing and molecular modeling results corroborate an antiviral mechanism of action of inhibiting integrase strand transfer (INST). Preliminary testing against raltegravir-resistant HIVs showed marginal cross resistance, suggesting that the chemotypes of the various embodiments described herein could fit an inhibitory profile of second generation INSTIs.

First claim

What is claimed is:

1. A compound of formula (I)

wherein R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl; R 2 is benzyl, which can be unsubstituted or can be substituted with one to three occurrences of a substituent independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylC(═O)NH, (C 1 -C 6 )alkylNHC(═O), ((C 1 -C 6 )alkyl) 2 NC(═O), (C 1 -C 6 )alkylSO 2 , (C 1 -C 6 )alkylNHSO 2 , and ((C 1 -C 6 )alkyl) 2 NSO 2 ; R 3 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl; or a pharmaceutically acceptable salt thereof; or
a compound of formula (II)

wherein R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl; R 2 is hydrogen, benzyl, which can be unsubstituted or can be substituted with one to three occurrences of a substituent independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylC(═O)NH, (C 1 -C 6 )alkylNHC(═O), ((C 1 -C 6 )alkyl) 2 NC(═O), (C 1 -C 6 )alkylSO 2 , (C 1 -C 6 )alkylNHSO 2 , and ((C 1 -C 6 )alkyl) 2 NSO 2 ; R 3 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl or R 1 and R 3 can form a five- or six-membered heterocyclic ring; and R 4 is a hydrogen or (C 1 -C 6 )alkyl; or a pharmaceutically acceptable salt thereof, In some embodiments, R 1 and R 3 can form a five- or six-membered heterocyclic ring; or
a compound of formula (III)

wherein R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl; R 2 is (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl; and R 3 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl or R 1 and R 3 can form a five- or six-membered heterocyclic ring; or a pharmaceutically acceptable salt thereof, In some embodiments, R 1 and R 3 can form a five- or six-membered heterocyclic ring; or
a compound of formula (IV)

wherein R 1 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl; R 2 is (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl; R 3 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl or R 1 and R 3 can form a five- or six-membered heterocyclic ring; and R 4 is a hydrogen or (C 1 -C 6 )alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is of formula (IA)

wherein R 1 is H, (C 1 -C 6 )alkyl or (C 3 -C 6 ) cycloalkyl, and R′ is zero to three occurrences of a substituent independently selected from the group consisting of fluoro, chloro, bromo, iodo, cyano, nitro, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylC(═O)NH, (C 1 -C 6 )alkylNHC(═O), ((C 1 -C 6 )alkyl) 2 NC(═O), (C 1 -C 6 )alkylSO 2 , (C 1 -C 6 )alkylNHSO 2 , and ((C 1 -C 6 )alkyl) 2 NSO 2 ; R 3 is H, (C 1 -C 6 )alkyl, (C 3 -C 6 ) cycloalkyl, or (C 6 -C 12 )aryl; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein R 1 is hydrogen, methyl or ethyl; or wherein R 3 is hydrogen; or both.

4. The compound of claim 3 , wherein R′ is a one or two occurrences of fluoro, or one occurrence of fluoro and one occurrence of chloro.

5. The compound of claim 1 , wherein the compound is any one of:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound has a half maximal HIV-1 integrase strand transfer inhibitory concentration (IC 50 ) of from about 1 nM to about 250 μM.

7. The compound of claim 1 , wherein the compound has a half maximal effective concentration (EC 50 ) of from about 1 nM to about 250 nM.

8. The compound of claim 1 , wherein the compound has a half maximal cytotoxic concentration (CC 50 ) of from about 10 μM to about 100 μM and a therapeutic index of from about 70 to about 2000.

9. A method of inhibiting the human immunodeficiency virus (HIV) integrase, comprising contacting the HIV integrase with an effective amount or concentration of a compound of claim 1 .

10. The method of claim 9 , wherein the contacting is in an intact virus in vivo in a human host.

11. A method of treating a patient afflicted with Acquired Immunodeficiency Syndrome (AIDS), comprising administering to the patient an effective dose of a compound of claim 1 .

12. The method of claim 11 , further comprising administering to the patient an effective dose of a second antiviral compound.

13. The method of claim 12 , wherein the second antiviral compound is a protease inhibitor or a reverse transcriptase inhibitor.

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

Assignees

• Univ Minnesota

Inventors

• Wang Zhengqiang

Classifications

• A61K31/03

  aromatic · CPC title

• A61K31/513 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title

• C12N2740/16063

  by chemical treatment · CPC title

• C07D239/557

  with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid · CPC title

• A61P31/18

  for HIV · CPC title