Combinations of a pyrimidine containing NNRTI with RT inhibitors
View Patent ↗The present invention concerns combinations of a pyrimidine containing NNRTI with nucleoside reverse transcriptase inhibitors and/or nucleotide reverse transcriptase inhibitors useful for the treatment of HIV infected patients or for the prevention of HIV transmission or infection.
1. A combination comprising
(i) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, and
(ii) tenofovir or its prodrug tenofovir disoproxil fumarate, and
(iii) emtricitabine;
wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; the tenofovir or its prodrug tenofovir disoproxil fumarate; and the emtricitabine are therapeutically effective HIV inhibitors at a dose that can be administered once daily.
2. The combination according to claim 1 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile.
3. The combination of claim 1 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride.
4. The combination of claim 1 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, is 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride.
5. The combination of claim 1 , comprising tenofovir disoproxil fumarate.
6. The combination of claim 3 , comprising tenofovir disoproxil fumarate.
7. The combination of claim 1 comprising between 10 mg and 500 mg of the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile or a stereoisomeric form thereof.
8. The combination of claim 1 comprising between 10 mg and 300 mg of the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile or a stereoisomeric form thereof.
9. The combination of claim 1 comprising about 25 mg of the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile or a stereoisomeric form thereof.
10. The combination of claim 1 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof, tenofovir or its prodrug tenofovir disoproxil fumarate; and emtricitabine are together in a unitary pharmaceutically acceptable formulation.
11. The combination of claim 10 , wherein the pharmaceutically acceptable formulation is selected from the group consisting of tablets, capsules, parenteral compositions, injectable solutions, and injectable suspensions.
12. The combination of claim 11 , wherein the pharmaceutically acceptable formulation is a tablet.
13. The combination of claim 3 , wherein the E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride, tenofovir or its prodrug tenofovir disoproxil fumarate, and emtricitabine are together in a unitary pharmaceutically acceptable formulation.
14. The combination of claim 13 , wherein the pharmaceutically acceptable formulation is a tablet.
15. The combination of claim 6 , wherein the E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride, tenofovir disoproxil fumarate, and emtricitabine are together in a unitary pharmaceutically acceptable formulation.
16. The combination of claim 15 , wherein the pharmaceutically acceptable formulation is a tablet.
17. A method of treating HIV infection in a patient comprising administering to the patient the combination of claim 1 once daily.
18. A method of treating HIV infection in a patient comprising administering to the patient the combination of claim 10 once daily.
19. A method of treating HIV infection in a patient comprising administering to the patient the combination of claim 15 once daily.
20. A method of treating HIV infection in a patient comprising administering to the patient the combination of claim 16 once daily.
21. A pharmaceutical formulation comprising the combination of claim 1 and a pharmaceutically acceptable carrier.
22. The pharmaceutical formulation of claim 21 , wherein the formulation is selected from the group consisting of tablets, capsules, parenteral compositions, injectable solutions, and injectable suspension.
23. The pharmaceutical formulation of claim 22 , wherein the formulation is a tablet.
24. A pharmaceutical formulation comprising the combination of claim 3 and a pharmaceutically acceptable carrier.
25. The pharmaceutical formulation of claim 24 , wherein the formulation is a tablet.
26. A pharmaceutical formulation comprising the combination of claim 6 and a pharmaceutically acceptable carrier.
27. The pharmaceutical formulation of claim 26 , wherein the formulation is a tablet.
28. A method of treating HIV infection in a patient comprising administering to the patient the pharmaceutical formulation of claim 21 once daily.
29. A method of treating HIV infection in a patient comprising administering to the patient the pharmaceutical formulation of claim 26 once daily.
30. A method of treating HIV infection in a patient comprising administering to the patient the pharmaceutical formulation of claim 27 once daily.
31. A kit comprising the combination of claim 1 packaged with instructions for use.
32. A kit comprising the combination of claim 3 packaged with instructions for use.
33. A kit comprising the combination of claim 6 packaged with instructions for use.