Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-02-26
2000-11-07
Stockton, Laura L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142338, 5142345, 514249, 514255, 514317, 514321, 514322, 514365, 514367, 514375, 514387, 514388, 514394, 514422, 514445, 514452, 514456, 514603, 544160, 544360, 544367, 544368, 544370, 544383, 546198, 546234, 5462701, 546293, 548163, 548164, 548178, 5483064, 5483074, 5483097, 548217, 548526, 548204, 549 65, 549366, 549438, 549467, 564 78, 564 82, A61K 3118, A61K 31496, C07D40112
Patent
active
061437476
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to retroviral protease inhibitors and, more particularly, relates to novel compounds and a composition and method for inhibiting retroviral proteases. This invention, in particular, relates to bis-sulfonamide-containing hydroxyethylamine protease inhibitor compounds, a composition and method for inhibiting retroviral proteases such as human immunodeficiency virus (HIV) protease and for treating a retroviral infection, e.g., an HIV infection. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
2. Related Art
During the replication cycle of retroviruses, gag and gag-pol gene transcription products are translated as proteins. These proteins are subsequently processed by a virally encoded protease (or proteinase) to yield viral enzymes and structural proteins of the virus core. Most commonly, the gag precursor proteins are processed into the core proteins and the pol precursor proteins are processed into the viral enzymes, e.g., reverse transcriptase and retroviral protease. It has been shown that correct processing of the precursor proteins by the retroviral protease is necessary for assembly of infectious virons. For example, it has been shown that frameshift mutations in the protease region of the pol gene of HIV prevents processing of the gag precursor protein. It has also been shown through site-directed mutagenesis of an aspartic acid residue in the HIV protease active site that processing of the gag precursor protein is prevented. Thus, attempts have been made to inhibit viral replication by inhibiting the action of retroviral proteases.
Retroviral protease inhibition typically involves a transition-state mimetic whereby the retroviral protease is exposed to a mimetic compound which binds (typically in a reversible manner) to the enzyme in competition with the gag and gag-pol proteins to thereby inhibit specific processing of structural proteins and the release of retroviral protease itself. In this manner, retroviral replication proteases can be effectively inhibited.
Several classes of compounds have been proposed, particularly for inhibition of proteases, such as for inhibition of HIV protease. Such compounds include hydroxyethylamine isosteres and reduced amide isosteres. See, for example, EP 0 346 847; EP 0 342,541; Roberts et al, "Rational Design of Peptide-Based Proteinase Inhibitors, "Science, 248, 358 (1990); and Erickson et al, "Design Activity, and 2.8 .ANG. Crystal Structure of a C.sub.2 Symmetric Inhibitor Complexed to HIV-1 Protease," Science, 249, 527 (1990). Sulfonamide-containing, aminosulfonamide-containing and urea-containing hydroxyethylamine compounds and intermediates useful as retroviral protease inhibitors have been disclosed in WO94/05639, WO94/10136, WO94/10134, WO94/04493, WO94/04492, WO 93/23368, and WO93/23379.
Several classes of compounds are known to be useful as inhibitors of the proteolytic enzyme renin. See, for example, U.S. Pat. No. 4,599,198; U.K. 2,184,730; G.B. 2,209,752; EP 0 264 795; G.B. 2,200,115 and U.S. SIR H725. of these, G.B. 2,200,115, GB 2,209,752, EP 0 264,795, U.S. SIR H725 and U.S. Pat. No. 4,599,198 disclose urea-containing hydroxyethylamine renin inhibitors. EP 468 641 discloses renin inhibitors and intermediates for the preparation of the inhibitors, which include sulfonamide-containing hydroxyethylamine compounds, such as 3-(t-butoxycarbonyl)amino-cyclohexyl-1-(phenylsulfonyl)amino-2(5)-butanol. G.B. 2,200,115 also discloses sulfamoyl-containing hydroxyethylamine renin inhibitors, and EP 0264 795 discloses certain sulfonamide-containing hydroxyethylamine renin inhibitors. However, it is known that, although renin and HIV proteases are both classified as aspartyl proteases, compounds which are effective renin inhibitors generally cannot be predicted to be effective HIV protease inhibitors.
BRIEF DESCRIPTION OF THE INVENTION
The present invention is directed to virus inhibiting compounds a
REFERENCES:
patent: H725 (1990-01-01), Gordon
patent: 4477441 (1984-10-01), Boger et al.
patent: 4514391 (1985-04-01), Gordon et al.
patent: 4548926 (1985-10-01), Matsueda et al.
patent: 4599198 (1986-07-01), Hoover
patent: 4616088 (1986-10-01), Ryono et al.
patent: 4668769 (1987-05-01), Hoover
patent: 4668770 (1987-05-01), Boger et al.
patent: 4757050 (1988-07-01), Natarajan et al.
patent: 4880938 (1989-11-01), Freidinger
patent: 4963530 (1990-10-01), Hemmi et al.
patent: 4977277 (1990-12-01), Rosenberg et al.
patent: 5157041 (1992-10-01), Hamda
patent: 5508294 (1996-04-01), Vazquez et al.
patent: 5521219 (1996-05-01), Vazquez et al.
patent: 5639769 (1997-06-01), Vazquez et al.
patent: 5760064 (1998-06-01), Vazquez et al.
Thornber, Chemical Society Reviews, vol. 8, No. 1, 1979, pp. 563-580.
Roberts et al, "Rational Design of Peptide-based Proteinase Inhibitors," Science, 248, 358 (1990).
Erickson et al, "Design Activity, and 2.8.ANG. Crystal Structure of a C.sub.2 Symmetric Inhibitor Complexed to HIV-1 Protease," Science, 249, 527 (1990).
Pearl et al, "Sequence specificity of retroviral proteases" Nature, 328, (1987).
Martin, Drugs of the Future, 16 (3), 210-212 (1991).
Meek et al, Letter To Nature, 343, 90-92 (1990).
McQuade et al, Science, 247, 454-456, 1990.
Rich et al, Peptide Inhibitors of Proteases, 511-520, 1983.
Rosenberg et al, J. Med. Chem., 30, 1224-1228 (1987).
Freskos John N.
Getman Daniel P.
Sikorski James A.
Talley John J.
G. D. Searle & Co.
Stockton Laura L.
LandOfFree
Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1641332