Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-07-18
2003-09-09
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S019300, C514S466000, C514S469000, C514S603000, C536S063000, C536S063000, C549S361000, C549S438000, C549S462000, C564S086000
Reexamination Certificate
active
06617310
ABSTRACT:
FIELD OF THE INVENTION
This invention relates generally to phosphate esters of bis-amino acid sulfonamides containing substituted benzyl amines, pharmaceutical compositions comprising the same, and methods of using the same for treating viral infection.
BACKGROUND OF THE INVENTION
Compounds of Formula A are known HIV Protease
In the above formula, R
1
is F, R
2
is F or H, and R
3
is selected from the group: 4-aminophenyl, 3-aminophenyl, 2,3-dihydrobenzofuran-5-yl, and 1,3-benzodioxol-5-yl. The presence of the hydroxyl group in Formula A is expected to contribute to variable plasma levels following oral administration of these compounds. Since consistent plasma levels following oral administration are a desirable characteristic of drugs, it is desirable to discover new compounds that address the potential plasma level variability of the compounds of Formula A.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel HIV protease inhibitors.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
It is another object of the present invention to provide pharmaceutical compositions with protease inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide novel HIV protease inhibitors for use in therapy.
It is another object of the present invention to provide the use of novel HIV protease inhibitors for the manufacture of a medicament for the treatment of a HIV.
It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample that comprises treating the body fluid sample with an effective amount of a compound of the present invention.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV protease, HIV growth, or both.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formula I:
wherein R
1
, R
2
, R
3
, and R
4
are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are expected to be prodrugs of HIV protease inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[1] Thus, in an embodiment, the present invention provides a novel compound of Formula I:
or a pharmaceutically acceptable salt form thereof, wherein:
R
1
is F or H;
R
2
is F or H;
R
3
is selected from the group: 4-aminophenyl, 3-aminophenyl, 2,3-dihydrobenzofuran-5-yl, and 1,3-benzodioxol-5-yl; and,
R
4
is selected from the group PO
3
H
2
, PO
3
HNa, PO
3
HK, PO
3
Na
2
, and PO
3
K
2
.
[2] In a preferred embodiment, the present invention provides a novel compound of Formula II:
[3] In another preferred embodiment, the present invention provides a novel compound of Formula IIa:
[4] In another preferred embodiment, the present invention provides a novel compound of Formula IIa, wherein:
R
3
is 3-aminophenyl.
[5] In another preferred embodiment, the present invention provides a novel compound of Formula IIa, wherein:
R
3
is 4-aminophenyl.
[6] In another preferred embodiment, the present invention provides a novel compound of Formula IIa, wherein:
R
3
is 2,3-dihydrobenzofuran-5-yl or 1,3-benzodioxol-5-yl.
[7] In another preferred embodiment, the present invention provides a novel compound of Formula IIb:
[8] In another preferred embodiment, the present invention provides a novel compound of Formula IIb, wherein:
R
3
is 3-aminophenyl.
[9] In another preferred embodiment, the present invention provides a novel compound of Formula IIb, wherein:
R
3
is 4-aminophenyl.
[10] In another preferred embodiment, the present invention provides a novel compound of Formula IIb, wherein:
R
3
is 2,3-dihydrobenzofuran-5-yl or 1,3-benzodioxol-5-yl.
[11] In another preferred embodiment, the present invention provides a novel compound of Formula IIc:
[12] In another preferred embodiment, the present invention provides a novel compound of Formula IIc, wherein:
R
3
is 3-aminophenyl.
[13] In another preferred embodiment, the present invention provides a novel compound of Formula IIc, wherein:
R
3
is 4-aminophenyl.
[14] In another preferred embodiment, the present invention provides a novel compound of Formula IIc, wherein:
R
3
is 2,3-dihydrobenzofuran-5-yl or 1,3-benzodioxol-5-yl.
[15] In another preferred embodiment, the present invention provides a novel compound of Formula III:
[16] In another preferred embodiment, the present invention provides a novel compound of Formula IIIa:
[17] In another preferred embodiment, the present invention 5 provides a novel compound of Formula IV:
[18] In another preferred embodiment, the present invention provides a novel compound of Formula IVa:
In another embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating HIV infection that comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:
(a) a compound of formula I; and,
(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.
In another preferred embodiment, the reverse transcriptase inhibitor is selected from the group AZT, ddC, ddI, d4T, 3TC, delavirdine, efavirenz, nevirapine, Ro 18,893, trovirdine, MKC-442, HBY 097, ACT, UC-781, UC-782, RD4-2025, and MEN 10979, and the protease inhibitor is selected from the group saquinavir, ritonavir, indinavir, amprenavir, nelfinavir, palinavir, BMS-232623, GS3333, KNI-413, KNI-272, LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392, U-140690, and ABT-378.
In an even more preferred embodiment, the reverse transcriptase inhibitor is selected from the group AZT, efavirenz, and 3TC and the protease inhibitor is selected from the group saquinavir, ritonavir, nelfinavir, and indinavir.
In a still further preferred embodiment, the reverse transcriptase inhibitor is AZT.
In another still further preferred embodiment, the protease inhibitor is ritonavir.
In another preferred embodiment, component (b) is a HIV reverse transcriptase inhibitor and a HIV protease inhibitor.
In another preferred embodiment, component (b) is two different HIV reverse transcriptase inhibitors.
In another embodiment, the present invention provides a pharmaceutical composition useful for the treatment of HIV infection, which comprises a therapeuticall
Kaltenbach Robert F.
Trainor George L.
Bristol-Myers Squibb Pharma Company
Covington Raymond
Rotman Alan L.
VanAtten Mary K.
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