Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-11-04
1997-10-21
Datlow, Philip I.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546169, A61K 3147, C07D21514
Patent
active
056796889
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This application is a national stage under 35 USC 371 of PCT/AU93/00103 filed Mar. 11, 1993.
The invention relates to certain amine derivatives and their use in the inhibition of human immunodeficiency virus (HIV) proteases and thus in the treatment of HIV viral infections such as acquired immunodeficiency syndrome (AIDS).
BACKGROUND ART
Human immunodeficiency virus (HIV) is a pathogenic retrovirus causing AIDS and its related disorders. The development of antiviral chemotherapy against AIDS has been the subject of an intense research effort since the discovery of HIV. (For a recent review on molecular targets for AIDS therapy see Mitsua et al, Science, 1990, pp 1533-1544). The HIV Proteases (HIV PR), and aspartyl proteases, were first suggested as a potential target for AIDS therapy by Kramer et al. (Science, 231, 1580, 1986). Since that time the potential usefulness of HIV PR inhibitors as effective agents in treatment of AIDS has been widely recognized (for a review of the HIV PR as a therapeutic target see Tomaselli et al. (Chimica Oggi, May 1991, pp 6-27 and Huff J. R., J.Med.Chem., 1991,. 34, 2314-2327). Of the classical transition state mimics for aspartyl proteases, the hydroxyethylene, dihydroxyethylene, hydroxyethylamine and phosphinic acid isosteres appear to provide the greatest affinity for HIV PR. Many inhibitors of HIV PR have been shown to have an antiviral activity at concentrations in the nanomolar range in the different cell systems and are described as such in the patent literature.
SUMMARY OF THE INVENTION
The invention provides a new class of compounds which are useful as inhibitors of retroviral proteases, particularly aspartyl proteases and more particularly HIV proteases, and which are effective in treating conditions characterized by unwanted activity of these enzymes, in particular acquired immune deficiency syndrome.
A first embodiment of the invention is directed to compounds of the general formula (I): ##STR2## or pharmaceutically acceptable salts thereof, wherein: R.sup.1 is a group R, wherein R is selected from the group consisting of hydrogen, --R'H, --R'C(O)OR", --R'C(O)NH.sub.2, --R'C(O)NHR", --R'C(O)NR"R'", --R'NHC(O)R", --R'NR'"C(O)R" or --R'C(O)R", where R" and R'" are independently optionally substituted (C.sub.1 -C.sub.18)alkyl, typically (C.sub.1 -C.sub.12)alkyl; (C.sub.3 -C.sub.18)cycloalkyl, typically (C.sub.3 -C.sub.12)cycloalkyl; (C.sub.3 -C.sub.18)cycloalkyl(C.sub.1 -C.sub.18)alkyl, typically (C.sub.3 -C.sub.12)cycloalkyl(C.sub.1 -C.sub.6)alkyl; (C.sub.6 -C.sub.24)aryl, typically (C.sub.6 -C.sub.16)aryl; (C.sub.7 -C.sub.25)aralkyl, typically (C.sub.7 -C.sub.16)aralkyl; (C.sub.2 -C.sub.18)alkenyl, typically (C.sub.2 -C.sub.12)alkenyl; (C.sub.8 -C.sub.26)aralkenyl, typically (C.sub.8 -C.sub.16)aralkenyl; (C.sub.2 -C.sub.18)alkynyl, typically (C.sub.2 -C.sub.12)alkynyl; (C.sub.8 -C.sub.26)aralkynyl, typically (C.sub.8 -C.sub.16)aralkynyl; or heterocyclic, and where R' is an optionally substituted divalent radical derived from (C.sub.1 -C.sub.18)alkyl, typically (C.sub.1 -C.sub.12)alkyl; (C.sub.3 -C.sub.18)cycloalkyl, typically (C.sub.3 -C.sub.12)cycloalkyl; (C.sub.3 -C.sub.18)cycloalkyl(C.sub.1 -C.sub.18)alkyl, typically (C.sub.3 -C.sub.12)cycloalkyl(C.sub.1 -C.sub.6)alkyl; (C.sub.6 -C.sub.24)aryl, typically (C.sub.6 -C.sub.16)aryl; (C.sub.7 -C.sub.25)aralkyl, typically (C.sub.7 -C.sub.16)aralkyl; (C.sub.2 -C.sub.18)alkenyl, typically (C.sub.2 -C.sub.12)alkenyl; (C.sub.8 -C.sub.26)aralkenyl, typically (C.sub.8 -C.sub.16)aralkenyl; (C.sub.2 -C.sub.18)alkynyl, typically (C.sub.2 -C.sub.12)alkynyl; (C.sub.8 -C.sub.26)aralkynyl, typically (C.sub.8 -C.sub.16)aralkynyl; or heterocyclic, ##STR3## where R.sup.4, R.sup.5 and R.sup.6 are independently a group R as defined above, or R.sup.4 has the meaning of R as defined above and R.sup.5 and R.sup.6 taken together are .dbd.O, .dbd.S, .dbd.NH or .dbd.NR; ##STR4## where R is as previously defined; D is O or S; Y is hydrogen, --R or --OR, where R is as previously defined, or is an amino acid, aza-amino
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Datlow Philip I.
Narhex Limited
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