HIV protease inhibitors

Details HIV protease inhibitors HIV protease inhibitors

2000-11-02

2003-03-04

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S227500, C514S252100, C514S256000, C514S269000, C514S314000, C514S397000, C544S060000, C544S298000, C544S315000, C544S374000, C546S001000, C546S268400, C548S304400, C548S304700, C548S311100, C549S029000, C549S292000, C549S417000

Reexamination Certificate

active

06528510

ABSTRACT:

BACKGROUND OF THE INVENTION
The HIV-protease enzyme is absolutely essential for the replication and dissemination of HIV throughout the body (Navia M. A. and McKeever B. M.,
Ann. New York Acad. Sci.,
1990;616:73-85) and has become an extremely important target for the design and development of anti-HIV therapeutic agents (von der Helm K.,
Biol. Chem.
1996;377:756-774). Several peptidomimetic HIV protease inhibitors have been successfully developed (such as indinavir, saquinavir, ritonavir, and nelfinavir), which demonstrate significant clinical success in lowering plasma viral load. reducing the onset to AIDS. and decreasing the frequency of opportunistic infections (Deeks S. G., Smith M., Holodniy M., and Kahn J. O.,
JAMA.,
1997;277: 145-153).
Yet the current HIV protease inhibitors by their peptidomimetic nature have relatively poor solubility, high biliary excretion, limited bioavailabilities and significant liver metabolism. These drawbacks in turn increase the need for high doses of drug which increases the frequency of various side effects and multiple drug interactions (Barry M., Gibbons S., Back D., and Mulcahy F.,
Clin Pharmacokinet.,
1997;32: 194-209). More importantly, resistance to the current HIV protease inhibitors has emerged (Shock H. B.. Garsky V. M., and Kuo L.,
J. Biol Chem,
1996;27 1:31957-31963) resulting in treatment failures (Fatkenheuer G., Theisen A., Rockstroh J., Grabow T., et at.,
AIDS,
1997;11:F113-F1 16). From this discussion, it is apparent that while HIV protease is an excellent antiviral target for the treatment of HIV infection and AIDS, there is a critical need to identify non-peptide inhibitors with improved pharmacological properties and which are not cross resistant with the current drugs (Wallace R. W.,
DDT,
1997;2:83-84).
U.S. Pat. No. 5,789,440 recites non-peptidic HIV protease inhibitors of formula A
The patent application is hereby incorporated by reference. Excellent HIV protease inhibition was achieved, but the antiviral activity at the cellular level was in some cases less than desired for an ideal therapeutic agent due to poor overall pharmacological properties (Tummino P. J., Vara Prasad J. V. N., Ferguson D., Nauhan C., et al.,
BioOrganic and Med. Chem.,
1996;4:1401-1410). These efforts however led to a core structure B where R
1
and R
2
were alkyl groups filling the
S
1
′ and S
2
′ pockets, respectively, and the phenyl of the phenethyl group at C
6
filled the S
2
pocket very efficiently. This core structure was recognized as a valuable platform for additional study (Tait B. D., Hagen S., Domagala J. M., Ellsworth E. L., et al.,
J. Med. Chem.,
1997;40:3781-3792).
Additional dihydropyrones C were reported when it was unexpectedly discovered that certain polar groups judiciously placed at R
1
-R
5
led to greatly
improved antiviral cellular activity. See U.S. patent application Ser. No. 08/883,743. The patent application is hereby incorporated by reference. Among the preferred compounds were those where R
1
and R
5
were OH, NH
2
, or CH
2
OH. In such cases, the preferred R
4
included a small alkyl chain or ring and R
6
was methyl. In addition to improved cellular antiviral activity, the compounds also showed good pharmacokinetics in animals relative to the non-polar substituted compounds. These compounds were also not cross resistant with current HIV Protease inhibitors (Hagen S. E., Vara Prasad J. V. N., Boyer F. E., Domagala J. M., et al.,
J. Med.,
1997;40:3707-3711; Vander Roest S., Wold S., and Saunders J., 37
th
Interscience Conference on Antimicrobial Agents and Chemotherapy,
Sep. 28-Oct. 1, 1997, Toronto, Canada. Abstract I-84; Domagala J. M., Boyer F., Ellsworth E., Gajda C., et al., 5
th
Conference on Retroviruses and Opportunistic Infections,
Feb. 1-5, 1998, Chicago, Ill. Abstract 638).
While the compounds C were notable for their improved pharmacological properties relative to the non-polar substituted core molecules B, these highly favorable properties were conferred directly by the use of OH, NH
2
and NR
2
groups placed on the lipophilic rings. The rings themselves were important for binding to the enzyme “pockets” and for holding the t-butyl group and the groups R
1
-R
3
and R
5
in their proper places within the enzyme's active site.
It is well-known in the pharmacological sciences that OH and NH
2
groups, especially phenols and anilines, offer distinct metabolic sites resulting in deactivation of the drug and more rapid clearance. In particular, phenols may be glucuronidated and amines and anilines are substrates for rapid acetylation (Goodman L. S. and Gilman A.,
The Pharmacological Basis of Therapeutics,
Permagon Press, New York, N.Y. 1985:13-16). Such modifications generally inactivate the drug by preventing its binding to the structurally stringent active site of the enzyme. The modifications also reduce the plasma level of the active agent (Caldwell J., in
Concepts in Drug Metabolism,
edited by Jenner P. and Testa B., Marcel Dekker, New York, N.Y., Part A, 1980:235-238). Another suggested problem with amines and anilines is their possible oxidation to electropositive nitrogen species which have mutagenic potential (Sobels F. H.,
Mut. Res.,
1985;157:107-110; Bus J. S. and Popp J. A.,
Fd Chem. Toxic,
1987:25:619-626; Rodrigues-Amaiz R. and Aranda J. H.,
Env. Mol. Mutagenesis,
1994;24:75-79). Thus, while the polar groups are vital for good antiviral efficacy, solubility, and oral absorption, they also present sites for metabolism and possible mutagenesis.
This hereby incorporates by reference 5888L1-01-TMC filed on even date herewith now United States Patent Application Serial Number 60/099,944 filed Sep. 11, 1998, entitled “A Method of Making Dihydropyrone HIV Protease Inhibitors” by Victor Fedij, et al.
SUMMARY OF THE INVENTION
The present invention relates to the extraordinary discovery that the phenyl groups bearing the important polar groups (especially the OH and NH
2
groups) in formula C above, the very polar groups that improved cellular antiviral activity and improved pharmacokinetics in animals relative to compounds of formula B, can themselves be replaced by certain selected heterocycles. These heterocycles bind to the enzyme in the manner of the phenyls to preserve essential enzymatic activity, but additionally present the polar atoms of the heterocycle in such a way as to maintain cellular antiviral activity without requiring peripheral OH and NH
2
groups. Since these compounds have fewer peripheral OH and NH
2
groups. they have even greater pharmacokinetic improvements and less potential for amine based toxicity.
The dihydropyrones with selected heterocycles replacing the phenyls bearing polar substituents are useful in the development of treatments for infections caused by viruses, especially by retroviruses that rely on aspartyl protease activities for replication and infectivity. One such virus is HIV. These dihydropyrones provide higher plasma levels in animals and man due to reduced metabolism and/or clearance, and they provide less toxicity risk due to the removal of certain reactive anilino functionalities. For these reasons, the compounds of this invention are very useful for lowering viral load in individuals infected with HIV. Furthermore, the compounds reduce diseases and syndromes associated with viral pathogenesis. One such syndrome is AIDS.
The compounds of the instant invention will be useful according to: Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents, supplement to the
J. of the International Association of Physicians in AIDS Care,
Supp. No. 1, Vol. 5, pp 4-26 and David A. Katzenstein, Antiretroviral Therapy for HIV: What to do in 1999.
The Journal of Critical Illness,
April 1999; 14(4):196.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to compounds or pharmaceutically acceptable salts thereof, of Formula I
R
1
is H, a straight or branched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons;
R
2
is H, a straight or branched alkyl of 1-5 carbons;

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