Prodrugs of HIV protease inhibitors
View Patent ↗A compound of the formula is disclosed as a prodrug of an HIV protease inhibitor. Methods and compositions for inhibiting HIV protease activity and treating HIV infection are also disclosed.
1. A compound having formula (I), (II), or (III)
wherein:
L 1 is selected from the group consisting of a bond, —C(O)—, and —C(O)O—, wherein the carbonyl of the —C(O)O— moiety is attached to A of formula (I), (II), or (III);
L 2 is —(CR 1 R 2 ) m —,
m is 1, 2, 3, 4, or 5;
R 1 at each occurrence is independently selected from the group consisting of hydrogen and C 1 -C 12 alkyl;
R 2 at each occurrence is independently selected from the group consisting of hydrogen and C 1 -C 12 alkyl;
R 3 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, and arylalkyl;
R 4 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl, and arylalkyl;
q is 1 or 2;
t is 1 or 2;
M a is selected from the group consisting of M 1 and M 2 ;
M b is selected from the group consisting of M 1 and M 2 ;
M 1 is selected from the group consisting of Na + , K + , and + N(R 5 )(R 6 )(R 7 )(R 8 );
M 2 is selected from the group consisting of Ca 2+ , Ba 2+ , Mg 2+ , Zn 2+ , and + N(R 9 )(R 10 )(R 11 )(R 12 ), as to R 5 and R 6 :
R 5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, arylalkyl, and —C(═NH)NH 2 , and
R 6 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, and arylalkyl, or, alternatively,
R 5 and R 6 , together with the nitrogen atom to which they are attached, form a piperidine ring;
R 7 is selected from the group consisting of hydrogen and alkyl;
R 8 is selected from the group consisting of hydrogen and alkyl;
as to R 9 and R 11 :
R 9 is -alkyl-N + (Z 1 )(Z 2 )(Z 3 ), and
R 11 is selected from the group consisting of hydrogen and alkyl, or, alternatively,
R 19 and R 11 , together with the nitrogen atom to which they are attached, form a piperazine ring;
R 10 is hydrogen, alkyl or arylalkyl;
R 12 is hydrogen or alkyl;
Z 1 is selected from the group consisting of hydrogen and alkyl;
Z 2 is selected from the group consisting of hydrogen and alkyl;
Z 3 is selected from the group consisting of hydrogen, alkyl, and arylalkyl; and
A is selected from the group consisting of
provided that:
when q is 1, M a is M 1 ;
when q is 2, M 3 is M 2 ;
when t is 1, M b is M 2 ;
when t is 2, M b is M 1 ; and
provided that:
when A is
L 1 is a bond, then L 2 is not —CH 2 —.
2. The compound of claim 1 , wherein:
L 1 is a bond,
m is 1,
R 1 is hydrogen, and
R 2 is hydrogen.
3. The compound of claim 1 , wherein:
L 1 is a bond,
m is 1,
R 1 is hydrogen, and
R 2 is C 1 -C 12 alkyl.
4. The compound of claim 1 , wherein:
L 1 is a bond,
m is 1,
R 1 is hydrogen,
R 2 is hydrogen,
q is 1,
M a is selected from the group consisting of Na + , K + , and NH 4 + ,
t is 2, and
M b is selected from the group consisting of Na + , K + , and NH 4 + .
5. The compound of claim 1 , wherein:
L 1 is a bond,
m is 1,
R 1 is hydrogen,
R 2 is C 1 -C 12 alkyl,
q is 1,
M a is selected from the group consisting of Na + , K + , and NH 4 + ,
t is 2, and
M b is selected from the group consisting of Na + , K + , and NH 4 + .
6. The compound of claim 1 , wherein L 1 is —C(O)—.
7. The compound of claim 1 , wherein:
L 1 is —C(O)—,
L 2 is —(CR 1 R 2 ) m —, and
m is 3.
8. The compound of claim 1 , wherein:
L 1 is —C(O)—,
L 2 is —(CR 1 R 2 ) m —,
m is 3,
q is 1,
M a is selected from the group consisting of Na + , K + , and NH 4 + ,
t is 2, and
M b is selected from the group consisting of Na + , K + , and NH 4 + .
9. The compound of claim 1 , wherein the compound is selected from the group consisting of
calcium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[1-(phosphonatooxy)ethoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide;
calcium [((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]methyl phosphate; and
calcium 1-[((1S,3S)-1-((15)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]ethyl phosphate.
10. Disodium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[(phosphonatooxy)methoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide.
11. Calcium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[(phosphonatooxy)methoxy]4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide.
12. The compound of claim 1 , wherein A is
13. The compound of claim 12 , wherein L 1 is a bond.
14. The compound of claim 12 , wherein:
L 1 is a bond,
L 2 is —(CR 1 R 2 ) m —,
m is 1,
R 1 is hydrogen, and
R 2 is C 1 -C 12 alkyl.
15. The compound of claim 12 , wherein:
L 1 is a bond,
L 2 is —(CR 1 R 2 ) m —,
m is 1,
R 1 is hydrogen,
R 2 is C 1 -C 12 alkyl,
q is 1,
M a is selected from the group consisting of Na + , K + , and NH 4 + ,
t is 2, and
M b is selected from the group consisting of Na + , K + , and NH 4 + .
16. The compound of claim 12 , wherein:
L 1 is —C(O)—,
L 2 is —(CR 1 R 2 ) m —, and
m is 3.
17. The compound of claim 12 , wherein:
L 1 is —C(O)—,
L 2 is —(CR 1 R 2 ) m —,
m is 3,
q is 1,
M 3 is selected from the group consisting of Na + , K + , and NH 4 + ,
t is 2 and
M b is selected from the group consisting of Na + , K + , and NH 4 + .
18. The compound of claim 12 , wherein the compound is selected from the group consisting of
disodium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[1-(phosphonatooxy)ethoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide;
disodium N 1 -((1S,3S,4S)-1-benzyl-3-{[3,3-dimethyl-4-(phosphonatooxy)butanoyl]oxy}-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide;
disodium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[1-(phosphonatooxy)butoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide; and
disodium N 1 -((1S,3S,45)-1-benzyl-3-[2-methyl-1-(phosphonatooxy)propoxy]-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide.
19. The compound of claim 1 , wherein A is
20. The compound of claim 19 , wherein L 1 is a bond.
21. The compound of claim 19 , wherein:
L 1 is a bond,
L 2 is —(CR 1 R 2 ) m —,
m is 1,
R 1 is hydrogen, and
R 2 is hydrogen.
22. The compound of claim 19 , wherein:
L 1 is a bond,
L 2 is —(CR 1 R 2 ) m —,
m is 1,
R 1 is hydrogen, and
R 2 is C 1 -C 12 alkyl.
23. The compound of claim 19 , wherein:
L 1 is a bond,
L 2 is —(CR 1 R 2 ) m —,
m is 1,
R 1 is hydrogen,
R 2 is C 1 -C 12 alkyl,
q is 1,
M 3 is selected from the group consisting of Na + , K + , and NH 4 + ,
t is 2, and
M b is selected from the group consisting of Na + , K + , and NH 4 + .
24. The compound of claim 19 , wherein:
L 1 is a bond,
L 2 is —(CR 1 R 2 ) m —,
m is 1,
R 1 is hydrogen,
R 2 is hydrogen,
q is 1,
M a is selected from the group consisting of Na + , K + , and NH 4 + ,
t is 2, and
M b is selected from the group consisting of Na + , K + , and NH 4 + .
25. The compound of claim 19 , wherein:
L 1 is —C(O)—,
L 2 is —(CR 1 R 2 ) m —, and
m is 3.
26. The compound of claim 19 , wherein:
L 1 is —C(O)—,
L 2 is —(CR 1 R 2 ) m —,
m is 3,
q is 1,
M a is selected from the group consisting of Na + , K + , and NH 4 + ,
t is 2, and
M b is selected from the group consisting of Na + , K + , and NH 4 + .
27. The compound of claim 19 , wherein the compound is selected from the group consisting of
disodium[((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]methyl phosphate;
disodium 1-[((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]ethyl phosphate;
disodium 3-[((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2.5)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxycarbonyl]-2,2-dimethylpropyl phosphate; and
disodium 3-[((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxycarbonyl]-3,3-dimethylpropyl phosphate.
28. A pharmaceutical composition comprising:
a therapeutically effective amount of a compound or combination of compounds of claim 1 , and
a pharmaceutically acceptable carrier.
29. The pharmaceutical composition of claim 28 , wherein the compound of claim us disodium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[1-(phosphonatooxy)ethoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide.
30. A pharmaceutical composition comprising:
a therapeutically effective amount of disodium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[(phosphonatooxy)methoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide, and
a pharmaceutically acceptable carrier.
31. The pharmaceutical composition of claim 28 , wherein the compound of claim 1 is disodium 1-[((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]ethyl phosphate.
32. The pharmaceutical composition of claim 28 , wherein the compound of claim 1 is disodium[((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]methyl phosphate.
33. A pharmaceutical composition comprising:
a therapeutically effective amount of a compound or combination of compounds of claim 1 , and one, two, three, four, five or six agents independently selected from the group consisting of a second HIV protease inhibitor, a HIV reverse transcriptase inhibitor, an HIV entry/fusion inhibitor, an HIV integrase inhibitor, and an HIV budding/maturation inhibitor, and
a pharmaceutically acceptable carrier.
34. The pharmaceutical composition of claim 33 , wherein the second HIV protease inhibitor is selected from the group consisting of ritonavir, lopinavir, saquinavir, amprenavir, fosamprenavir, nelfinavir, tipranavir, indinavir, atazanavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X.
35. The pharmaceutical composition of claim 33 , wherein the HIV reverse transcriptase inhibitor is selected from the group consisting of lamivudine, stavudine, zidovudine, abacavir, zalcitabine, didanosine, tenofovir, emtricitabine, amdoxovir, elvucitabine, alovudine, MIV-210, Racivir (±-FTC), D-D4FC (Reverset, DPC-817), SPD754, nevirapine, delavirdine, efavirenz, capravirine, emivirine, calanolide A, GW5634, BMS-56190 (DPC-083), DPC-961, MIV-150, TMC-120, and TMC-125.
36. The pharmaceutical composition of claim 33 , wherein the HIV entry/fusion inhibitor is selected from the group consisting of enfuvirtide (T-20), T-1249, PRO2000, PRO542, PRO140, AMD-3100, BMS-806, FP21399, GW873140, Schering C (SCH-C), Schering D (SCH-D), TNX-355, and UK-427857.
37. The pharmaceutical composition of claim 33 , wherein the HIV integrase inhibitor is selected from the group consisting of 5-1360, zintevir (AR-177), L-870812, and L-870810.
38. The pharmaceutical composition of claim 33 , wherein the HIV budding/maturation inhibitor is PA-457.
39. The pharmaceutical composition of claim 33 , wherein the compound of claim 1 is disodium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[1-(phosphonatooxy)ethoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide.
40. A pharmaceutical composition comprising:
a therapeutically effective amount of disodium N 1 -((1S,3S,4S)-1-benzyl-5-phenyl-3-[(phosphonatooxy)methoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N 2 -{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valinamide, and one, two, three, four, five or six agents independently selected from the group consisting of a second HIV protease inhibitor, a HIV reverse transcriptase inhibitor, an HIV entry/fusion inhibitor, an HIV integrase inhibitor, and an HIV budding/maturation inhibitor, and
a pharmaceutically acceptable carrier.
41. The pharmaceutical composition of claim 33 , wherein the compound of claim 1 is disodium 1-[((1S,3S)-1-((15)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxo tetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]ethyl phosphate.
42. The pharmaceutical composition of claim 33 , wherein the compound of claim 1 is disodium[((1S,3S)-1-((1S)-1-{[(2,6-dimethylphenoxy)acetyl]amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxo tetrahydropyrimidin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]methyl phosphate.