Sulphonamide derivatives as prodrugs of aspartyl protease...

Details Sulphonamide derivatives as prodrugs of aspartyl protease... Sulphonamide derivatives as prodrugs of aspartyl protease...

2000-06-23

2003-05-06

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S101000, C514S347000, C514S475000, C514S601000, C514S604000, C514S605000, C549S475000, C546S293000, C564S084000, C564S086000, C564S096000, C564S098000, C564S099000

Reexamination Certificate

active

06559137

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to prodrugs of a class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of prodrugs of HIV aspartyl protease inhibitors characterized by favorable aqueous solubility, high oral bioavailability and facile in vivo generation of the active ingredient. This invention also relates to pharmaceutical compositions comprising these prodrugs. The prodrugs and pharmaceutical compositions of this invention are particularly well suited for decreasing the pill burden and increasing patient compliance. This invention also relates to methods of treating mammals with these prodrugs and pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Aspartyl protease inhibitors are considered the most effective current drug in the fight against HIV infection. These inhibitors, however, require certain physicochemical properties in order to achieve good potency against the enzyme. One of these properties is high hydrophobicity. Unfortunately, this property results in poor aqueous solubility and low oral bioavailability.
U.S. Pat. No. 5,585,397 describes a class of sulfonamide compounds that are inhibitors of the aspartyl protease enzyme. These compounds illustrate the drawbacks concomitant to pharmaceutical compositions comprising hydrophobic aspartyl protease inhibitors. For example, VX-478 (4-amino-N-((2-syn,3S)-2-hydroxy-4-phenyl-3((S)-tetrahydrofuran-3-yl-oxycarbonylamino)-butyl-N-isobutyl-benzenesulfonamide) is an aspartyl protease inhibitor disclosed in the '397 patent. It has a relatively low aqueous solubility. While the oral bioavailability of this inhibitor in a “solution” formulation is excellent, the dosage of VX-478 in this form is severely limited by the amount of liquid present in the particular liquid dosage from, e.g., encapsulated into a soft gelatin capsule. A higher aqueous solubility would increase drug load per unit dosage of VX-478.
Currently, the solution formulation of VX-478 produces an upper limit of 150 mg of VX-478 in each capsule. Given a therapeutic dose of 2400 mg/day of VX-478, this formulation would require a patient to consume 16 capsules per day. Such a high pill burden would likely result in poor patient compliance, thus producing sub-optimal therapeutic benefit of the drug. The high pill burden is also a deterrent to increasing the amount of the drug administered per day to a patient. Another drawback of the pill burden and the concomitant patient compliance problem is in the treatment of children infected with HIV.
Furthermore, these “solution” formulations, such as the mesylate formulation, are at a saturation solubility of VX-478. This creates the real potential of having the drug crystallize out of solution under various storage and/or shipping conditions. This, in turn, would likely result in a loss of some of the oral bioavailability achieved with VX-478.
One way of overcoming these problems is to develop a standard solid dosage form, such as a tablet or a capsule or a suspension form. Unfortunately, such solid dosage forms have much lower oral bioavailability of the drug.
Thus, there is a need to improve the drug load per unit dosage form for aspartyl protease inhibitors. Such an improved dosage form would reduce the pill burden and increase patient compliance. It would also provide for the possibility of increasing the amounts of the drug administered per day to a patient.
SUMMARY OF THE INVENTION
The present invention provides novel prodrugs of a class of sulfonamide compounds that are inhibitors of aspartyl protease, in particular, HIV aspartyl protease. These prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. The present invention also provides pharmaceutical compositions comprising these prodrugs and methods of treating HIV infection in mammals using these prodrugs and the pharmaceutical compositions thereof.
These prodrugs can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antibiotics, immunomodulators or vaccines, for the treatment or prophylaxis of viral infection.
It is a principal object of this invention to provide a novel class of prodrugs of sulfonamide compounds that are aspartyl protease inhibitors, and particularly, HIV aspartyl protease inhibitors. This novel class of sulfonamides is represented by formula I:
wherein:
A is selected from H; Ht; —R
1
—Ht; —R
1
—C
1
-C
6
alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, C
1
-C
4
alkoxy, Ht, —O—Ht, —NR
2
—CO—N(R
2
)
2
or —CO—N(R
2
)
2
; —R
1
—C
2
-C
6
alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C
1
-C
4
alkoxy, Ht, —O—Ht, —NR
2
—CO—N(R
2
)
2
or —CO—N(R
2
)
2
; or R
7
;
each R
1
is independently selected from —C(O)—, —S(O)
2
—, —C(O)—C(O)—, —O—C(O)—, —O—S(O)
2
, —NR
2
—S(O)
2
—, —NR
2
—C(O)— or —NR
2
—C(O)—C(O)—;
each Ht is independently selected from C
3
-C
7
cycloalkyl; C
5
-C
7
cycloalkenyl; C
6
-C
10
aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R
2
), O, S and S(O)
n
; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, —OR
2
, SR
2
, —R
2
, —N(R
2
)(R
2
), —R
2
—OH, —CN, —CO
2
R
2
, —C(O)—N(R
2
)
2
, —S(O)
2
—N(R
2
)
2
, —N(R
2
)—C(O)—R
2
, —C(O)—R
2
, —S(O)
n
—R
2
, —OCF
3
, —S(O)
n
—Q, methylenedioxy, —N(R
2
)—S(O)
2
(R
2
) , halo, —CF
3
, —NO
2
, Q, —OQ, —OR
7
, —SR
7
, —R
7
, —N(R
2
)(R
7
) or —N(R
7
)
2
;
each R
2
is independently selected from H, or C
1
-C
4
alkyl optionally substituted with Q;
B, when present, is —N(R
2
)—C(R
3
)
2
—C(O)—;
each x is independently 0 or 1;
each R
3
is independently selected from H, Ht, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
3
-C
6
cycloalkyl or C
5
-C
6
cycloalkenyl; wherein any member of said R
3
, except H, is optionally substituted with one or more substituents selected from —OR
2
, —C(O)—NH—R
2
, —S(O)
n
—N(R
2
)(R
2
), Ht, —CN, —SR
2
, —CO
2
R
2
, NR
2
—C(O)—R
2
;
each n is independently 1 or 2;
G, when present, is selected from H, R
7
or C
1
-C
4
alkyl, or, when G is C
1
-C
4
alkyl, G and R
7
are bound to one another either directly or through a C
1
-C
3
linker to form a heterocyclic ring; or
when G is not present (i.e., when x in (G)
x
is 0), then the nitrogen to which G is attached is bound directly to the R
7
group on —OR
7
;
D and D′ are independently selected from Q; C
1
-C
6
alkyl, which is optionally substituted with one or more groups selected from C
3
-C
6
cycloalkyl, —OR
2
, —R
3
, —O—Q or Q; C
2
-C
4
alkenyl, which is optionally substituted with one or more groups selected from C
3
-C
6
cycloalkyl, —OR
2
, —R
3
, —O—Q or Q; C
3
-C
6
cycloalkyl, which is optionally substituted with or fused to Q; or C
5
-C
6
cycloalkenyl, which is optionally substituted with or fused to Q;
each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)
n
or N(R
2
); wherein Q is optionally substituted with one or more groups selected from oxo, —OR
2
, —R
2
, —N(R
2
)
2
, —N(R
2
)—C(O)—R
2
, —R
2
—OH, —CN, —CO
2
R
2
, —C(O)—N(R
2
)
2
, halo or —CF
3
;
E is selected from Ht; O—Ht; Ht—Ht; —O—R
3
; —N(R
2
)(R
3
); C
1
-C
6
alkyl, which is optionally substituted with one or more groups selected from R
4
or Ht; C
2
-C
6
alkenyl, which is optionally substituted with one or more groups selected from R
4
or Ht; C
3
-C
6
saturated carbocycle, which is optionally substituted with one or more groups selected from R
4
or Ht; or C
5
-C
6
unsaturated carbocycle, which is optionally substituted with one or more groups selected from R
4
o

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