HIV protease inhibitors and methods of making the same

Details HIV protease inhibitors and methods of making the same HIV protease inhibitors and methods of making the same

1994-10-27

1998-02-03

Kumar, Shailendra

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

514307, 514311, 514354, 514355, 514357, 514374, 514400, 514423, 514478, 546143, 546146, 546175, 546314, 546315, 546316, 546317, 546334, 546336, 546337, 548237, 5483381, 548537, 560 13, 564156, 564158, A61K 3116, C07C23100, C07C23365

Patent

active

057145180

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 PCT/US 94/00420, filed Jan. 18, 1994.
This invention relates to a novel series of non-peptidic chemical compounds which have been found to be useful as HIV protease inhibitors and to the use of such compounds as antiviral agents.
Acquired Immune Deficiency Syndrome (AIDS) is a relatively newly recognized disease or condition. AIDS causes a gradual breakdown of the body's immune system as well as progressive deterioration of the central and peripheral nervous systems. Since its initial recognition in the early 1980's, AIDS has spread rapidly and has now reached epidemic proportions within a relatively limited segment of the population. Intensive research has led to the discovery of the responsible agent, human T-lymphotropic retrovirus III (HTLV-III), now more commonly referred to as the human immunodeficiency virus or HIV.
HIV is a member of the class of viruses known as retroviruses. The retroviral genome is composed of RNA which is converted to DNA by reverse transcription. This retroviral DNA is then stably integrated into a host cell's chromosome and, employing the replicative processes of the host cells, produces new retroviral particles and advances the infection to other cells. HIV appears to have a particular affinity for the human T-4 lymphocyte cell which plays a vital role in the body's immune system. HIV infection of these white blood cells depletes this white cell population. Eventually, the immune system is rendered inoperative and ineffective against various opportunistic diseases such as, among others, pneumocystic carini pneumonia, Karposis sarcoma, and cancer of the lymph system.
Although the exact mechanism of the formation and working of the HIV virus is not understood, identification of the virus has led to some progress in controlling the disease. For example, the drug azidothymidine (ART) has been found effective for inhibiting the reverse transcription of the retroviral genome of the HIV virus, thus giving a measure of control, though not a cure, for patients afflicted with AIDS. The search continues for drugs that can cure or at least provide an improved measure of control of the deadly HIV virus.
Retroviral replication routinely features post-tranlational processing of pre-peptides. This processing is accomplished by vitally encoded HIV protease enzyme. This yields mature polypeptides that will subsequently aid in the formation and function of infectious virus. If this molecular processing is stifled, then the normal production of HIV is terminated. Therefore, inhibitors of HIV protease may function as anti-HIV vital agents.
HIV protease is one of the translated products from the HIV structural protein pol gene. This retroviral protease specifically cleaves other structural polypeptides at discrete sites to release these newly activated structural proteins and enzymes, thereby rendering the virion replication-competent. As such, inhibition of the HIV protease by potent compounds may prevent proviral integration of infected T-lymphocytes during the early phase of the HIV-1 life cycle, as well as inhibit viral proteolytic processing during its late stage. Additionally, the protease inhibitors may have the advantages of being more readily available, longer lived in virus, and less toxic than currently available drugs, possibly due to their specificity for the retroviral protease.
In accordance with this invention, there is provided a novel class of chemical compounds that have been found to inhibit and block the activity of the HIV protease, which halts the proliferation of HIV virus, pharmaceutical compositions containing these compounds, novel intermediates for compounds which inhibit and block the activity of the HIV protease, novel methods for making such compounds, and use of the compounds as inhibitors of the HIV.
Typical examples of carbocyclic ring systems represented by A' and B| shown above include, but are not limited to, phenyl, naphthyl, anthryl, and phenanthryl, either in their aromatic or fully or partially hydrogenated states. Typical heteroc

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