Antiviral therapies with phospholipase D inhibitors

1. A method for treating a subject comprising the step of co-administering an effective amount of a combination of two or more therapeutic agents to the subject;

wherein the subject has been diagnosed with a need for treatment of an influenza infection prior to the administering step; and

wherein the combination of two or more therapeutic agents comprises:

(a) an phospholipase D inhibitor; and

(b) one or more therapeutic agents selected from:

(i) a viral protein M2 ion channel inhibitor,

(ii) a neuraminidase inhibitor, and

(iii) a nucleoside analog selected from ribavirin, viramidine, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, 2′-deoxy-2′-fluoroguanosine, pyrazofurin, carbodine, and cyclopenenyl cytosine;

wherein the phospholipase D inhibitor is a compound having a structure represented by a formula:

Wherein R 21 is a phenyl or halophenyl; each of R 27 and R 28 is, independently, a hydrogen or a C1 to C6 alkyl; R 30 is an optionally substituted organic residue selected from aryl and heteroaryl, wherein the organic residue is up to C16,

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the influenza infection is caused by a type A influenza virus.

3. The method of claim 2 , wherein the type A influenza virus is of subtype H1, H5, H7 or H9.

4. The method of claim 2 , wherein the type A influenza virus is of subtype H1N1, H1N2, H2N2, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, or H10N7.

5. The method of claim 4 , wherein the type A influenza virus is of subtype H1N1, H1N2, H2N2, H3N2, H5N1, H5N3, H7N2, H7N3, H7N7, H9N2, or H10N7.

6. The method of claim 4 , wherein type A influenza virus is H1N1.

7. The method of claim 1 , wherein co-administration is administration in a substantially simultaneous manner.

8. The method of claim 1 , wherein co-administration is administration in a substantially sequential manner.

9. The method of claim 1 , wherein the phospholipase D inhibitor is a phospholipase D2-selective inhibitor.

10. The method of claim 1 , wherein one of R 27 and R 28 is hydrogen and the other is methyl.

11. The method of claim 10 , the compound has the structure represented by a formula:

12. The method of claim 1 , the compound has the structure represented by a formula:

13. The method of claim 1 , wherein R 21 is selected from:

14. The method of claim 1 , wherein R 30 is selected from:

15. The method of claim 1 , wherein the phospholipase D inhibitor is selected from:

16. The method of claim 1 , wherein the phospholipase D inhibitor is a PLD1-selective inhibitor.

17. The method of claim 1 , wherein the phospholipase D inhibitor is

18. The method of claim 1 , wherein the viral protein M2 ion channel inhibitor is present and selected from the group consisting of amantadine, rimantadine, 1-amino-1,3,5-trimethylcyclohexane, 1-amino-1(trans),3(trans),5-trimethylcyclohexane, 1-amino-1 (cis),3(cis),5-trimethylcyclohexane, 1-amino-1,3,3,5-tetramethylcyclohexane, 1-amino-1,3,3,5,5-pentamethylcyclohexane(neramexane), 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, 1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane, 1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane, 1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane, 1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane, 1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane, 1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane, 1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane, N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, N-ethyl-1-amino-1,3,3,5,5-pentamethyl-cyclohexane, N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine, 3,3,5,5-tetramethylcyclohexylmethylamine, 1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane, 1 amino-1,3,3,5(trans)-tetramethylcyclohexane(axial amino group), 3-propyl-1,3,5,5-tetramethylcyclohexylamine semihydrate, 1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane, 1-amino-1,3,5-trimethylcyclohexane, 1-amino-1,3-dimethyl-3-propylcyclohexane, 1-amino-1,3(trans),5(trans)-trimethyl-3(cis)-propylcyclohexane, 1-amino-1,3-dimethyl-3-ethylcyclohexane, 1-amino-1,3,3-trimethylcyclohexane, cis-3-ethyl-1(trans)-3(trans)-5-trimethylcyclohexamine, 1-amino-1,3(trans)-dimethylcyclohexane, 1,3,3-trimethyl-5,5-dipropylcyclohexylamine, 1-amino-1-methyl-3(trans)-propylcyclohexane, 1-methyl-3 (cis)-propylcyclohexylamine, 1-amino-1-methyl-3 (trans)-ethylcyclohexane, 1-amino-1,3,3-trimethyl-5(cis)-ethylcyclohexane, 1-amino-1,3,3-trimethyl-5 (trans)-ethylcyclohexane, cis-3-propyl-1,5,5-trimethylcyclohexylamine, trans-3-propyl-1,5,5-trimethylcyclohexylamine, N-ethyl-1,3,3,5,5-pentamethylcyclohexylamine, N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, 1-amino-1-methylcyclohexane, N,N-dimethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, 2-(3,3,5,5-tetramethylcyclohexyl)ethylamine, 2-methyl-1-(3,3,5,5-tetramethylcyclohexyl)propyl-2-amine, 2-(1,3,3,5,5-pentamethylcyclohexyl-1)-ethylamine semihydrate, N-(1,3,3,5,5-pentamethylcyclohexyl)-pyrrolidine, 1-amino-1,3 (trans),5(trans)-trimethylcyclohexane, 1-amino-1,3(cis),5(cis)-trimethylcyclohexane, 1-amino-(1R,5S)trans-5-ethyl-1,3,3-trimethylcyclohexane, 1-amino-(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexane, 1-amino-1,5,5-trimethyl-3(cis)-isopropyl-cyclohexane, 1-amino-1,5,5-trimethyl-3(trans)-isopropyl-cyclohexane, 1-amino-1-methyl-3 (cis)-ethyl-cyclohexane, 1-amino-1-methyl-3(cis)-methyl-cyclohexane, 1-amino-5,5-diethyl-1,3,3-trimethyl-cyclohexane, 1-amino-1,3,3,5,5-pentamethylcyclohexane, 1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane, 1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane, N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, N-(1,3,5-trimethylcyclohexyl)pyrrolidine, N-(1,3,5-trimethylcyclohexyl)piperidine, N-[1,3(trans),5(trans)-trimethylcyclohexyl]pyrrolidine, N-[1,3(trans),5(trans)-trimethylcyclohexyl]piperidine, N-[1,3(cis),5(cis)-trimethylcyclohexyl]pyrrolidine, N-[1,3(cis),5(cis)-trimethylcyclohexyl]piperidine, N-(1,3,3,5-tetramethylcyclohexyl)pyrrolidine, N-(1,3,3,5-tetramethylcyclohexyl)piperidine, N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine, N-(1,3,3,5,5-pentamethylcyclohexyl)piperidine, N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)pyrrolidine, N-(1,3,5,5-tetramethyl-3-ethylcyclohexyl)piperidine, N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)pyrrolidine, N-(1,5,5-trimethyl-3,3-diethylcyclohexyl)piperidine, N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)pyrrolidine, N-(1,3,3-trimethyl-cis-5-ethylcyclohexyl)piperidine, N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl]pyrrolidine, N-[(1S,5S)cis-5-ethyl-1,3,3-trimethylcyclohexyl]piperidine, N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)pyrrolidine, N-(1,3,3-trimethyl-trans-5-ethylcyclohexyl)piperidine, N-[(1R,5S)trans-5-ethyl, 3,3-trimethylcyclohexyl]pyrrolidine, N-[(1R,5S)trans-5-ethyl, 3,3-trimethylcyclohexyl]piperidine, N-(1-ethyl-3,3,5,5-tetramethylyclohexyl)pyrrolidine, N-(1-ethyl-3,3,5,5-tetramethylyclohexyl)piperidine, N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)pyrrolidine, N-(1-propyl-3,3,5,5-tetramethylcyclohexyl)piperidine, N-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine, spiro[cyclopropane-1,2-adamantan]-2-amine, spiro[pyrrolidine-2,2′-adamantane], spiro[piperidine-2,2-adamantane], 2-(2-adamantyl)piperidine, 3-(2-adamantyl)pyrrolidine, 2-(1-adamantyl)piperidine, 2-(1-adamantyl)pyrrolidine, 2-(1-adamantyl)-2-methyl-pyrrolidine, 1-amino-3-phenyl adamantane, 1-amino-methyl adamantane, 1-amino-3-ethyl adamantane, 1-amino-3-isopropyl adamantane, 1-amino-3-n-butyl adamantane, 1-amino-3,5-diethyl adamantane, 1-amino-3,5-diisopropyl adamantane, 1-amino-3,5-di-n-butyl adamantane, 1-amino-3-methyl-5-ethyl adamantane, 1-N-methylamino-3,5-dimethyl adamantane, 1-N-ethylamino-3,5-dimethyl adamantane, 1-N-isopropyl-amino-3,5-dimethyl adamantane, 1-N,N-dimethyl-amino-3,5-dimethyl adamantane, 1-N-methyl-N-isopropyl-amino-3-methyl-5-ethyl adamantane, 1-amino-3-butyl-5-phenyl adamantane, 1-amino-3-pentyl adamantane, 1-amino-3,5-dipentyl adamantane, 1-amino-3-pentyl-5-hexyl adamantane, 1-amino-3-pentyl-5-cyclohexyl adamantane, 1-amino-3-pentyl-5-phenyl adamantane, 1-amino-3-hexyl adamantane, 1-amino-3,5-dihexyl adamantane, 1-amino-3-hexyl-5-cyclohexyl adamantane, 1-amino-3-hexyl-5-phenyl adamantane, 1-amino-3-cyclohexyl adamantane, 1-amino-3,5-dicyclohexyl adamantane, 1-amino-3-cyclohexyl-5-phenyl adamantane, 1-amino-3,5-diphenyl adamantane, 1-amino-3,5,7-trimethyl adamantane, 1-amino-3,5-dimethyl-7-ethyl adamantane, 1-amino-3,5-diethyl-7-methyl adamantane, 1-N-pyrrolidino and 1-N-piperidine derivatives, 1-amino-3-methyl-5-propyl adamantane, 1-amino-3-methyl-5-butyl adamantane, 1-amino-3-methyl-5-pentyl adamantane, 1-amino-3-methyl-5-hexyl adamantane, 1-amino-3-methyl-5-cyclohexyl adamantane, 1-amino-3-methyl-5-phenyl adamantane, 1-amino-3-ethyl-5-propyl adamantane, 1-amino-3-ethyl-5-butyl adamantane, 1-amino-3-ethyl-5-pentyl adamantane, 1-amino-3-ethyl-5-hexyl adamantane, 1-amino-3-ethyl-5-cyclohexyl adamantane, 1-amino-3-ethyl-5-phenyl adamantane, 1-amino-3-propyl-5-butyl adamantane, 1-amino-3-propyl-5-pentyl adamantane, 1-amino-3-propyl-5-hexyl adamantane, 1-amino-3-propyl-5-cyclohexyl adamantane, 1-amino-3-propyl-5-phenyl adamantane, 1-amino-3-butyl-5-pentyl adamantane, 1-amino-3-butyl-5-hexyl adamantane, and 1-amino-3-butyl-5-cyclohexyl adamantine.

19. The method of claim 1 , wherein the neuraminidase inhibitor is present and selected from the group consisting of oseltamivir, oseltamivir phosphate, oseltamivir carboxylate zanamivir, peramivir, laninamivir octanoate, 2,3-didehydro-2-deoxy-N-acetylneuraminic acid (DANA), 2-deoxy-2,3-dehydro-N-trifluoroacetylneuraminic acid (FANA), N-[(1R,2S)-2-methoxy-2-methyl-1-[(2R,3S,5R)-5-(2-methylpropanoyl)-3-[(Z)-prop-1-enyl]pyrrolidin-2-yl]pentyl]acetamide (A-322278), and (2R,4S,5R)-5-[(1R,2S)-1-acetamido-2-methoxy-2-methylpentyl]-4-[(Z)-prop-1-enyl]pyrrolidine-2-carboxylic acid (A-315675).

20. The method of claim 1 , wherein the phospholipase D inhibitor is

and wherein the one or more therapeutic agents comprises ribavirin and/or oseltamivir.

21. A method for treating a subject comprising the step of co-administering an effective amount of a combination of two or more therapeutic agents to the subject;

wherein the subject has been diagnosed with a need for treatment of an influenza infection prior to the administering step; and

wherein the combination of two or more therapeutic agents comprises:

(a) an phospholipase D inhibitor; and

(b) one or more therapeutic agents selected from:

(i) a viral protein M2 ion channel inhibitor,

(ii) a neuraminidase inhibitor, and

(iii) a nucleoside analog selected from ribavirin, viramidine, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, 2′-deoxy-2′-fluoroguanosine, pyrazofurin, carbodine, and cyclopenenyl cytosine;

wherein the phospholipase D inhibitor is a compound having a structure represented by a formula:

 or a pharmaceutic acceptable salt thereof.