Retroviral protease inhibitors

The present invention provides novel HIV protease inhibitors, pharmaceutical formulations containing those compounds and methods of their use.

BACKGROUND OF THE INVENTION 
A retrovirus designated human immuno-deficiency virus (HIV) is the 
causative agent of the complex disease termed Acquired Immune Deficiency 
Syndrome (AIDS), and is a member of the lentivirus family of retroviruses 
(M. A. Gonda, F. Wong-Staal NR. C. Galo, "Sequence Homology and 
Morphological Similarity of HTLV III And Visna Virus, A Pathogenic 
Lentivirus", Science, 227, 173, (1985); and P. Sonigo and N. Alizon, et 
al., "Nucleotide Sequence of the Visna Lentivirus: Relationship to the 
AIDS Virus", Cell, 42, 369, (1985)). The complex disease AIDS includes 
progressive destruction of the immune system and degeneration of the 
central and peripheral nervous systems. The HIV virus was previously known 
or referred to as LAV, HTLV-III, or ARV. 
A common feature of retrovirus replication is the post-translational 
processing of precursor polyproteins by a virally encoded protease to 
generate mature viral proteins required for viral assembly and function. 
Interruption of this processing appears to prevent the production of 
normally infectious virus. Unprocessed structural proteins also have been 
observed in clones of non-infectious HIV strains isolated from human 
patients. The results suggest that inhibition of the HIV protease 
represents a viable method for the treatment of AIDS and the prevention or 
treatment of infection by HIV. 
The HIV genome encodes structural protein precursors known as gag and pol, 
which are processed to afford the protease, reverse transcriptase and 
endonuclease/integrase. The protease further cleaves gag and gag-pol 
polyproteins to yield mature structural proteins of the virus core. 
Considerable efforts are being directed toward the control of HIV by means 
of the structural protein precursors which are processed to yield the 
retroviral protease, reverse transcriptase and endonuclease/integrase. For 
example, the currently used therapeutic, AZT, is an inhibitor of the viral 
reverse transcriptase (H. Mitsuya, NS. Broder, "Inhibition of the In Vitro 
Infectivity in Cytopathic Effects of HTLV III", Proc. Natl. Acad. Sci. 
USA, 83, 1911 (1986). 
Research efforts have also been directed toward HIV protease inhibitors. 
For example, EPA 361 341; EPA 346 847; EPA 402 646; and EPA 337 714 all 
disclose compounds which are said to be useful as HIV protease inhibitors. 
Unfortunately, many of the known compounds suffer from toxicity problems, 
lack of bioavailability or are short lived in vivo. 
Despite the recognized therapeutic potential associated with a protease 
inhibitor and the research efforts expended thus far, a viable therapeutic 
agent has not yet emerged. 
Accordingly, a primary object of the present invention is to provide novel 
HIV protease inhibitors which are useful in the treatment of AIDS. 
A further object of the present invention is to provide therapeutic 
compositions that are of value in the prevention and/or treatment of 
infection by HIV and the treatment of the resulting acquired immune 
deficiency syndrome. 
Still another object is to provide methods for the prevention and/or 
treatment of infection by HIV and the resulting acquired immune deficiency 
syndrome. 
Other objects, features, and advantages will become apparent to those 
skilled in the art from the following description and claims. 
SUMMARY OF THE INVENTION 
The present invention relates to compounds and pharmaceutically acceptable 
salts thereof that inhibit the protease encoded by human immunodeficiency 
virus (HIV) type 1 (HIV-1) and type 2 (HIV-2). These compounds are useful 
in the prevention of infection by HIV, the treatment of infection by HIV 
and/or the treatment of the resulting acquired immune deficiency syndrome 
(AIDS) either as compounds, pharmaceutically acceptable salts, 
pharmaceutical composition ingredients, whether or not in combination with 
other anti-virals, immunomodulators, antibiotics or vaccines. Methods of 
treating AIDS, methods of preventing infection by HIV and methods of 
treating infection by HIV are also disclosed. 
The compounds of the present invention are those having the Formula: 
##STR1## 
where: 
R is C.sub.5 -C.sub.7 cycloalkyl, heterocycle, aryl or unsaturated 
heterocycle; 
X i s a bond, (--CH.sub.2 -).sub.q, --O--(--CH.sub.2 --) q--, --(--CH.sub.2 
--).sub.q --, --(--CH.sub.2 --).sub.q --O-- or --N(R.sup.5) (CH.sub.2 
--).sub.m --; 
n is 0, 1, or2; 
q is 1, 2, 3or 4; 
R.sup.1 is aryl or C.sub.5 -C.sub.7 cycloalkyl; 
R.sup.2 is an amino acid side chain, unsaturated heterocycle, unsaturated 
heterocycle (C.sub.1 -C.sub.4 alkanediyl), C.sub.1 -C.sub.4 
alkylaminocarbonyl (C.sub.1 -C.sub.4 alkanediyl), or a group having the 
structure --CH.sub.2 --C(O)--NR.sup.4 --X--R or --CH.sub.2 --R; 
Y is an aryl or unsaturated heterocycle; 
R.sup.3 is a group having the structure: 
##STR2## 
where: 
1 is 3, 4 or 5; 
m at each occurrence is independently 0, 1, 2, or 3; 
p is 4 or 5; 
R.sup.4 at each occurrence is independently hydrogen, C.sub.1 -C.sub.6 
alkyl or hydroxy(C.sub.1 -C.sub.4)alkanediyl; 
R.sup.5 and R.sup.6 are independently selected from hydrogen, hydroxy, 
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, amino, C.sub.1 -C.sub.4 
alkylamino, hydroxy (C.sub.1 -C.sub.4)alkanediyl, carboxy, (C.sub.1 
-C.sub.4 alkoxy)carbonyl, aminocarbonyl, C.sub.1 -C.sub.4 
alkylaminocarbonyl, aryl, heterocycle or unsaturated heterocycle; or a 
pharmaceutically acceptable salt or solvate thereof. 
This invention also provides pharmaceutical formulations which comprise a 
compound of Formula I, or the pharmaceutically acceptable salt or solvate 
thereof, in association with a pharmaceutically acceptable carrier, 
diluent or excipient. 
A further embodiment of the present invention is a method for inhibiting 
HIV protease. More particularly, the present invention contemplates a 
method for treating infection by HIV comprising administering to a mammal 
in need of HIV inhibition, an HIV inhibiting dose of a compound of Formula 
I or a pharmaceutically acceptable salt or solvate thereof. 
A further embodiment of the present invention is a class of novel 
intermediates useful for preparing compounds of Formula I and a process 
for preparing said intermediates. The intermediates have the Formula 
##STR3## 
where 
R.sup.1 is aryl or C.sub.5 -C.sub.7 cycloalkyl; 
R.sup.b is hydrogen or an amino protecting group; 
Y is aryl or unsaturated heterocycle; 
R.sup.3 is a group selected from: 
##STR4## 
where R.sup.4, R.sup.5, R.sup.6, l and p are as defined above for Formula 
I or a pharmaceutically acceptable salt or solvate thereof. 
The process aspect of the present invention is a process for preparing the 
ketone intermediates of Formula II which comprises: 
a) reacting a compound having the formula: 
##STR5## 
where R.sup.3 and Y are as defined above for Formula I with a C.sub.1 
-C.sub.4 alkyl lithium or lithium di(C.sub.1 -C.sub.4 alkyl) amide base 
either in the presence or absence of a tetramethyl (C.sub.1 -C.sub.4 
alkylene) diamine catalyst in an aprotic solvent to afford the 
corresponding anion; and 
b) reacting the anion from (a) with an amide having the Formula 
##STR6## 
where R.sup.b and R.sup.1 are as defined above for Formula I in an aprotic 
solvent to afford said ketone intermediate.