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Claims for Patent: 5,413,999

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Claims for Patent: 5,413,999

Title: HIV protease inhibitors useful for the treatment of AIDS
Abstract:Compounds of formula ##STR1## where R.sup.1 and R.sup.2 are independently hydrogen or optionally-substituted C.sub.1-4 alkyl or aryl, or R.sup.1 and R.sup.2 are joined together to form a monocyclic or bicyclic ring system, are HIV protease inhibitors. These compounds are useful in the treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of treating infection by HIV are also described.
Inventor(s): Vacca; Joseph P. (Telford, PA), Dorsey; Bruce D. (Harleysville, PA), Guare; James P. (Quakertown, PA), Holloway; M. Katharine (Lansdale, PA), Hungate; Randall W. (Lansdale, PA), Levin; Rhonda B. (Lafayette Hill, PA)
Assignee: Merck & Co., Inc. (Rahway, NJ)
Application Number:08/059,038
Patent Claims: 1. A compound of the formula ##STR295## wherein V is absent or ##STR296## wherein Q is absent or --O--, --NR--, or heterocycle optionally sustituted with --C.sub.1-4 alkyl;

R.sup.1 is:

1) --C.sub.1-4 alkyl unsubstituted or substituted with one or more of

a) halo,

b) C.sub.1-3 alkoxy,

c) aryl unsubstituted or substituted with one or more of C.sub.1-4 alkyl, amino, hydroxy or aryl,

d) --W--aryl or --W--benzyl, wherein W is --O--, --S--, or --NH--,

e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of

i) halo,

ii) C.sub.1-3 alkoxy, or

iii) aryl,

f) heterocycle unsubstituted or substituted with one or more of oxo, halo, C.sub.1-4 alkoxy, C.sub.1-4 alkyl; ##STR297## or Boc, ##STR298## i) --NH--SO.sub.2 C.sub.1-3 alkyl, j) --NR.sub.2, and R is hydrogen or C.sub.1-4 alkyl;

k) --COOR, or

l) --((CH.sub.2).sub.m O).sub.n R wherein in is 2, 3, 4, or 5, and n is zero, 1,2 or 3, or

2) aryl, unsubstituted or substituted with one or more of

a) halo,

b) hydroxy,

c) --NO.sub.2 or --NR.sub.2,

d) C.sub.1-4 alkyl,

e) C.sub.1-3 alkoxy, unsubstituted or substituted with one or more of C.sub.1-3 alkoxy, ##STR299## q) --R.sup.5, as defined below; or 4) heterocycle unsubstituted or substituted with one or more of oxo, halo, amino, C.sub.1-4 alkoxy, C.sub.1-4 alkyl; or Boc;

5) carbocyclic unsubstituted or substituted with one or more of halo, amino, or C.sub.1-4 alkoxy;

R.sup.3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C.sub.1-3 alkoxy substituted with one or more of --OH or (3) ##STR300## R.sup.5 is 1) --1) --W--(CH.sub.2).sub.m --NR.sup.6 R.sup.7 wherein W is as defined above, m is 2,3,4 or 5, and R.sup.6 and R.sup.7 are independently

a) hydrogen,

b) C.sub.1-6 alkyl, unsubstituted or substituted with one or more of

i) C.sub.1-3 alkoxy, or

ii) --NR.sub.2,

c) the smile or different and joined together to form a 5-7 member heterocycle, such as morpholino, containing up to two additional heteroatoms selected from ##STR301## the heterocycle optionally substituted with C.sub.1-4 alkyl, or d) aromatic heterocycle unsubstituted or substituted with one or more of

i) C.sub.1-4 alkyl, or

ii) --NR.sub.2,

2) --(CH.sub.2)q--NR.sup.6 R.sup.7 wherein q is 1,2,3,4, or 5, and R.sup.6 and R.sup.7 are defined above, except that R.sup.6 or R 7 are not H or unsubstituted C.sub.1-6 alkyl, or

3) benzofuryl, indolyl, azacycloalkyl, azabicyclo C.sub.7-11 cycloalkyl, or benzopiperidinyl, unsubstituted or substituted with C.sub.1-4 alkyl;

R.sup.12 is ##STR302## or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, of the formula ##STR303## wherein V is absent;

R.sup.1 is:

1) --C.sub.1-4 alkyl unsubstituted or substituted with one or more of

a) halo,

b) C.sub.1-3 alkoxy,

c) aryl unsubstituted or substituted with one or more of C.sub.1-4 alkyl, amino, hydroxy or aryl,

d) --W--aryl or --W--benzyl, wherein W is --O--, --S--, or --NH--,

e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of

i) halo.

ii) C.sub.1-3 alkoxy, or

iii) aryl,

f) heterocycle unsubstituted or substituted with one or more of oxo, halo, C.sub.1-4 alkoxy, C.sub.1-4 alkyl; ##STR304## or Boc, ##STR305## i) --NH--SO.sub.2 C.sub.1-3 alkyl, j) --NR.sub.2, and R is hydrogen or C.sub.1-4 alkyl;

k) --COOR, or

l) --((CH.sub.2).sub.m O).sub.n R wherein m is 2, 3, 4, or 5, and n is zero, 1,2or3,

R.sup.3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C.sub.1-3 alkoxy substituted with one or more of --OH or (3) ##STR306## or pharmaceutically acceptable salt thereof.

3. The compound of claim 2 of the formula ##STR307## wherein V is absent;

R.sup.1 is:

1) --C.sub.1-4 alkyl unsubstituted or substituted with one or more of

c) aryl unsubstituted or substituted with one or more of C.sub.1-4 alkyl, amino, hydroxy or aryl,

e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of

i) halo,

ii) C.sub.1-3 alkoxy, or

iii) aryl,

f) heterocycle unsubstituted or substituted with one or more of oxo, halo, C.sub.1-4 alkoxy, C.sub.1-4 alkyl; ##STR308## or Boc, R.sup.3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C.sub.1-3 alkoxy substituted with one or more of --OH or (3) ##STR309## or pharmaceutically acceptable salt thereof.

4. The compound of claim 3 of the formula ##STR310## wherein V is absent

R.sup.1 is:

1) --C.sub.1-4 alkyl unsubstituted or substituted with one or more of

c) aryl unsubstituted or substituted with one or more of C.sub.1-4 alkyl, amino, hydroxy or aryl,

e) a 5-7 membered cycloalkyl group unsubstituted or substituted with one or more of

i) halo,

ii) C.sub.1-3 alkoxy, or

iii) aryl,

f) heterocycle, said heterocycle being piperidinyl, pyridyl, thienyl, pyrrolyl, thiazolyl, imidazolyl, furyl benzimidazolyl, pyrazinyl, isoxazolyl, pyridazinyl,or quinolinyl, said heterocycle unsubstituted or substituted with one or more of oxo, halo, C.sub.1-4 alkoxy, C.sub.1-4 alkyl; ##STR311## Boc, R.sup.3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C.sub.1-3 alkoxy substituted with one or more of --OH or (3) ##STR312## or pharmaceutically acceptable salt thereof.

5. The compound of claim 4, of the formula ##STR313## wherein V is absent;

R .sup.1 is C.sub.1-4 alkyl substituted with pyridyl or aryl;

R.sup.3 is benzyl, unsubstituted or substituted with one or more of (1) hydroxy, (2) C.sub.1-3 alkoxy substituted with one or more of-OH or (3) ##STR314## or a pharmaceutically acceptable salt thereof.

6. The compound of the formula ##STR315## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is selected from ##STR316##

7. A compound of the formula: ##STR317## or pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to claims 3, 4, 5 , or 6 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8 for use in the treatment of AIDS, in the treatment of infection of HIV, or in the inhibition of HIV protease.

10. A pharmaceutical composition comprising the compound ##STR318## or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. A method of treating AIDS comprising administering to a mammal in need of such treatment an effective amount of a compound according to claims 5 or 7.

12. A method of treating infection by HIV comprising administering to a mammal in need of such treatment an effective amount of a compound according to claims 5 or 7.

13. A method of inhibiting HIV protease comprising administering to a mammal in need of such treatment an effective amount of a compound according to claims 5 or 7.
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