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Last Updated: March 28, 2024

Claims for Patent: 8,999,969


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Summary for Patent: 8,999,969
Title:Anti-RSV compounds
Abstract: The present invention relates to anti-RSV compounds of Formula (I) and methods for use of the compounds in the treatment and prevention of RSV infection. ##STR00001##
Inventor(s): Mackman; Richard L. (Millbrae, CA), Sperandio; David (Palo Alto, CA), Yang; Hai (San Mateo, CA)
Assignee: Gilead Sciences, Inc. (Foster City, CA)
Application Number:13/383,180
Patent Claims:1. The present invention provides a compound of Formula I: ##STR00108## wherein A is aryl or heteroaryl; R.sub.1 is selected from alkyl, alkoxy, haloalkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl, said heterocyclyl is optionally substituted by one to three substituents independently selected from the group consisting of halo, hydroxyl, haloalkyl, alkoxy, alkyl, alkoxy-alkyl-, hydroxyl-alkyl-, CN, and alkyl-NH--: said aryl or heteroaryl is optionally substituted by one to three substituents independently selected from the group consisting of halo, cyano, nitro, hydroxyl, alkyl, alkoxy, and alkyl-NH--, with the proviso that when A is aryl, R.sub.1 is not unsubstituted aryl; R.sub.2 is selected from hydrogen, alkyl, alkoxy, amino, alkyl-NH--, CN, alkyl-SO.sub.2--, and halo; R.sub.3 is selected from hydrogen, alkyl, heterocyclyl, heteroaryl, heteroaryl-alkyl- and cycloalkyl, wherein said alkyl is optionally substituted by one substituent selected from the group consisting of NH.sub.2--C(O)--, halo, hydroxyl, NH.sub.2--SO.sub.2--, alkoxy-alkyl-, heterocyclyl; aryl, heteroaryl, CN, and alkyl-NH--; R.sub.4 is selected from hydrogen, alkyl and haloalkyl; R.sub.3 and R.sub.4 taken together with the nitrogen atom to which they are attached optionally form a 3- to 7-membered ring; R.sub.5 is selected from hydrogen, alkyl, alkoxy, haloalkyl, and halo; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein A is C.sub.6-C.sub.10 aryl or monocyclic 6-membered heteroaryl.

3. The compound of claim 1 wherein A is monocyclic 5-membered heteroaryl or bicyclic 8- to 10-membered heteroaryl.

4. The compound of claim 1 wherein A is a monocyclic 5-membered heteroaryl; R.sub.1 is alkyl, or aryl; R.sub.2 is hydrogen, or alkyl; R.sub.3 is cycloalkyl, or alkyl; R.sub.4 is hydrogen; R.sub.5 is hydrogen, or halo.

5. The compound of claim 4 wherein A is thienyl or pyrazolyl group.

6. The compound of claim 1 wherein A is a bicyclic 8- to 10-membered heteroaryl; R.sub.1 is alkyl; R.sub.2 is hydrogen, or alkyl; R.sub.3 is cycloalkyl, or alkyl; R.sub.4 is hydrogen; R.sub.5 is hydrogen, or halo.

7. The compound of claim 6 wherein A is indolyl, indazolyl, or quinoxalinyl group.

8. A compound of Formula IA: ##STR00109## wherein X, Y and Z are independently N or CH; R.sub.1 is selected from alkyl, alkoxy, haloalkyl, aryl, heteroaryl, and heterocyclyl, said heterocyclyl is optionally substituted by one to three substituents independently selected from the group consisting of halo, hydroxyl, haloalkyl, alkoxy, alkyl, alkoxy-alkyl-, and hydroxyl-alkyl-, said aryl is optionally substituted by one to two substituents independently selected from the group consisting of halo, cyano, nitro and hydroxyl, with the proviso that when X and Y are simultaneously CH, R.sub.1 is not unsubstituted aryl; R.sub.2 is selected from hydrogen, alkyl, alkoxy, and halo; R.sub.3 is hydrogen, alkyl, heterocyclyl, heteroaryl, heteroaryl-alkyl-, or cycloalkyl, said alkyl is optionally substituted by one substituent selected from the group consisting of NH.sub.2--C(O)--, halo, hydroxyl, NH.sub.2--SO.sub.2 alkoxy-alkyl-, and heterocyclyl; R.sub.4 is hydrogen, or alkyl; R.sub.3 and R.sub.4 taken together with the nitrogen atom to which they are attached optionally form a 3- to 7-membered ring; R.sub.5 is selected from hydrogen, alkyl, alkoxy, haloalkyl, and halo; or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 wherein X and Z are CH, and Y is N.

10. The compound of claim 8 wherein X, Y and Z are CH.

11. The compound of claim 8 wherein X and Z are N, Y is CH.

12. The compound of claim 8 wherein X and Z are CH; Y is N; R.sub.1 is haloalkyl, or heterocyclyl, said heterocyclyl is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, alkoxy-alkyl-, alkyl, haloalkyl, and hydroxyl-alkyl-: R.sub.2 is hydrogen; R.sub.3 is selected from hydrogen, alkyl, heteroaryl, heteroaryl-alkyl-, and cycloalkyl, said alkyl is optionally substituted by one substituent selected from the group consisting of NH.sub.2--C(O)--, halo, hydroxyl, NH.sub.2--SO.sub.2--, alkoxy-alkyl-, and heterocyclyl; R.sub.4 is hydrogen, or alkyl; R.sub.3 and R.sub.4 taken together with the nitrogen atom to which they are attached optionally form a 3- to 7-membered ring; R.sub.5 is hydrogen, or halo; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

13. The compound of claim 12 wherein R.sub.1 is (C.sub.1-C.sub.4)haloalkyl, or 4- to 7-membered heterocyclyl, said heterocyclyl is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, (C.sub.1-C.sub.4)alkoxy-(C.sub.1C.sub.4)alkyl-, (C.sub.1C.sub.4)alkyl, (C.sub.1C.sub.4)haloalkyl, and hydroxyl(C.sub.1-C.sub.4)alkyl; R.sub.3 is selected from hydrogen, (C.sub.1-C.sub.4)alkyl, 5- to 9-membered heteroaryl, 5- to 9-membered heteroaryl-(C.sub.1-C.sub.4)alkyl-, and (C.sub.3-C.sub.7)cycloalkyl, said alkyl is optionally substituted by one substituent selected from the group consisting of NH.sub.2--C(O)--, halo, hydroxyl, NH.sub.2--SO.sub.2--, (C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl-, and 4- to 7-membered heterocyclyl; R.sub.4 is hydrogen, or (C.sub.1-C.sub.4)alkyl; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

14. The compound of claim 8 wherein X, Y and Z are CH; R.sub.1 is selected from alkyl, alkoxy, and heteroaryl; R.sub.2 is hydrogen, or alkoxy; R.sub.3 is cycloalkyl; and R.sub.4 and R.sub.5 are hydrogen; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

15. The compound of claim 14 wherein R.sub.1 is (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy, or 5- to 9-membered heteroaryl; R.sub.2 is hydrogen, or (C.sub.1-C.sub.4)alkoxy; R.sub.3 is (C.sub.3-C.sub.7)cycloalkyl; and R.sub.4 and R.sub.5 are hydrogen.

16. The compound of claim 8 wherein X and Z are N, Y is CH; R.sub.1 is alkyl, alkoxy, or heteocyclyl; R.sub.2 is alkyl; R.sub.3 is cycloalkyl; and R.sub.4 and R.sub.5 are hydrogen; or a pharmaceutically acceptable salt thereof.

17. A compound of Formula IB: ##STR00110## wherein R.sub.1 is haloalkyl, or heterocyclyl, said heterocyclyl is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, alkoxy-alkyl-, alkyl, haloalkyl, and hydroxyl-alkyl-; R.sub.3 is selected from hydrogen, alkyl, heterocyclyl, heteroaryl, heteroaryl-alkyl-, and cycloalkyl, said alkyl is optionally substituted by one substituent selected from the group consisting of NH.sub.2--C(O)--, halo, and hydroxyl; R.sub.4 is hydrogen; and R.sub.5 is hydrogen, or halo; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

18. The compound of claim 17 wherein R.sub.1 is heterocyclyl that is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, alkoxy-alkyl-, alkyl, haloalkyl, and hydroxyl-alkyl-.

19. The compound of claim 17 wherein R.sub.1 is 4- to 7-membered heterocyclyl that is optionally substituted by one to two substituents independently selected from the group consisting of halo, hydroxyl, (C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl-, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)haloalkyl, and hydroxyl-(C.sub.1-C.sub.4)alkyl-; R.sub.3 is hydrogen, (C.sub.3-C.sub.7)cycloalkyl, 4- to 7-membered heterocyclyl, or (C.sub.1-C.sub.4)alkyl that is optionally substituted by one halo group or one 5- to 6-membered heteroaryl group; and R.sub.4 and R.sub.5 are hydrogen; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

20. The compound of claim 19 wherein R.sub.1 is pyrrolidinyl; R.sub.3 is selected from hydrogen, cyclopropyl, and (C.sub.1-C.sub.4)alkyl, wherein the (C.sub.1-C.sub.4)alkyl is optionally substituted by one halo group or one 5- to 6-membered heteroaryl group; and R.sub.4 and R.sub.5 are hydrogen; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

21. The compound of claim 19 wherein R.sub.1 is azetidinyl or 2-oxa-6-azaspiro[3,3]heptan-6-yl; R.sub.3 is cyclopropyl; and R.sub.4 and R.sub.5 are hydrogen; or a pharmaceutically acceptable salt thereof; or an optical isomer thereof, or a mixture of optical isomers.

22. A method of treating a subject infected with RSV, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of according to claim 1 and one or more pharmaceutically acceptable carriers.

24. The pharmaceutical composition of claim 23, further comprising a second therapeutic agent selected from the group consisting of: an anti-inflammatory agent selected from salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, tenoxicam, nabumetone, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone, nimesulide, zileuton, aurothioglucose, gold sodium thiomalate, auranofin, colchicine, allopurinol, probenecid, sulfinpyrazone, and benzbromarone; an anti-viral agent selected from zidovudine, acyclovir, ganciclovir, vidarabine, idoxuridine, trifluridine, ribavirin, foscarnet, amantadine, rimantadine, saquinavir, indinavir, and ritonavir; and palivizumab.

Details for Patent 8,999,969

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Swedish Orphan Biovitrum Ab (publ) SYNAGIS palivizumab For Injection 103770 06/19/1998 ⤷  Try a Trial 2039-03-29
Swedish Orphan Biovitrum Ab (publ) SYNAGIS palivizumab Injection 103770 07/23/2004 ⤷  Try a Trial 2039-03-29
Hoffmann-la Roche Inc. PEGASYS COPEGUS COMBINATION PACK peginterferon alfa-2a and ribavirin 125083 06/04/2004 ⤷  Try a Trial 2039-03-29
Schering Corporation A Subsidiary Of Merck & Co., Inc. PEGINTRON/ REBETOL COMBO PACK peginterferon alfa-2b and ribavirin 125196 06/13/2008 ⤷  Try a Trial 2039-03-29
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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