Anti-HIV (AIDS) agents

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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5142352, 514248, 514249, 514258, 514274, 514300, 514345, 514355, 514357, 514365, 514383, 514399, 514419, 514453, 514602, 514616, 544128, 544235, 544316, 544354, 544355, 546122, 546169, 546298, 546316, 546323, 548202, 5482678, 5483381, 548516, 549405, 560 27, 564 80, 564153, A61K 3147, A61K 3144, A61K 31495, A61K 31425, C07D21548, C07D24136, C07D47104, C07D47500

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active

055167845

DESCRIPTION:

BRIEF SUMMARY
SUMMARY OF THE INVENTION

This application is the national phase of PCT/US92/06525 filed on Aug. 11, 1992.
The invention relates to compounds of the formula ##STR2## or a pharmaceutically acceptable salt thereof,
wherein Ar is ##STR3##
R.sub.10 is H or OH;
J is O or an electron pair;
W is ##STR4##
Z is H or Z and Q taken together are --(CH.sub.2).sub.3 --, or --(CH.sub.2).sub.4 --;
P is H, CBZ or tBOC; ##STR5##
T is --Y--L wherein
wherein Y is --SO--, --SC.sub.2 --, S, or O
L is ##STR6##
m is0, 1 or 2;
p is 0, 1, or 2; and
qis0, 1, or 2; or an isomer thereof.
Preferred are compounds of formula I wherein Y is S.
Preferred are compounds of formula I wherein ##STR7##
Preferred are compounds of formula I wherein Ar is ##STR8## Preferred among such compounds are those wherein Ar is ##STR9##
Especially preferred among such compounds are those compounds of formula I wherein Ar is ##STR10##
Also preferred are compounds of formula I wherein Ar is ##STR11## Preferred among such compounds are those wherein Ar is ##STR12##
Preferred are compounds of formula I wherein W is CO.
Preferred are compounds of formula I wherein Z is H.
Preferred are compounds of formula I wherein Q is ##STR13##
Preferred are compounds of formula I wherein R.sub.1 is ##STR14##
Preferred are compounds of formula I wherein U is ##STR15##
Preferred are compounds of formula I wherein J is an electron pair.
Preferred are compounds of formula I wherein L is ##STR16## and R.sub.2 is --NH tBu or --NHPh.
Most preferred are those compounds as described just above wherein R.sub.2 is NH tBu.
As used herein substituted phenyl (as in substituted NHPh) denotes phenyl substituted with up to 5 substituents selected from the group consisting of alkyl, alkoxy, halogen, NH.sub.2, OH, NO.sub.2, CN, S-alkyl, --SO.sub.2 -alkyl, --CO-alkyl, COOH, COOalkyl, naphthalene, substituted naphthalene, quinoline, and substituted quinoline but no more than three of the same substituent on a given phenyl ring.
Substituted naphthalene denotes naphthalene substituted with up to 7 substituents selected from the group consisting of alkyl, alkoxy, halogen, NH.sub.2, OH, NO.sub.2, CN, S-alkyl, --SO.sub.2 -alkyl, --CO-alkyl, COOH, COOalkyl, but no more than four of the same substituent on a given naphthalene ring.
Substituted quinoline denotes quinoline substituted with up to 6 substituents selected from the group consisting of alkyl, alkoxy, halogen, NH.sub.2, OH, NO.sub.2, CN, S-alkyl, --SO.sub.2 -alkyl, --CO-alkyl, COOH, COOalkyl, but no more than four of the same substituent on a given quinoline ring.
Alkyl denotes straight or branched saturated hydrocarbons which contain from 1 to 12 carbon atoms. Representative examples include methyl, butyl, isobutyl, isoamyl, and the like. Alternatively, the number of carbon atoms in a particular alkyl may be specified. For example, C.sub.1 -C.sub.7 alkyl refers to an alkyl which may have one to seven carbon atoms.
Alkoxy denotes --O-alkyl wherein alkyl is as described above.
Cyclic alkyl denotes a cyclic alkyl having from 3 to 10 carbon atoms and which may optionally have one or more fused or bridged rings.
Ph denotes phenyl.
Halogen denotes chlorine, fluorine or bromine.
As used herein, a boldfaced line denotes a bond that comes up above the plane of the page. A dashed line denotes a bond that goes down below the plane of the page. A wavy line denotes either racemic mixture or that the stereochemistry of this bond is not known.
Exemplary compounds of the invention include: ##STR17##
as used here and below, * means that the relative stereochemistry of the two chiral centers is known, but the absolute stereochemistry is not known ##STR18##
As used herein, tBu means tert.-butyl and nBu means normal-butyl.
Preferred compounds of the invention are: ##STR19## wherein all possible epimers are present at the carbons labelled a, b, and c ##STR20##
The most preferred compound of the invention is: ##STR21##
The chemical name for this compound is: N-(1,1-Dimethyl ethyl)-2-[[[3-[N-(2-quinolinylcarbonyl)-L-asparaginyl]amino]-3(S)-phenylme thyl-2(S)-hydrox

REFERENCES:
patent: 5256677 (1993-10-01), Sham
Debouck, C. AIDS Res. Hum. Retrov., 1992 8(2) 153-164 (Original article is an order).
Roberts, N. A. et al. Science 1990, 248, 358-361 (Parent application 1449-AR).
March, J. `Advanced Organic Chemistry. Reactions, Mechanisms, and Structure` McGraw Hill, 1977. p. 360.
Yarchoan, R. and Broder S. 1992 J. Enzyme Inhibition 6, 99-111.
Science, vol. 248, pp. 358-361, Roberts et al, Rational Design of Peptide-Based HIV Proteinase Inhibitors (Apr., 1990).
Journal of Cellular Biochemistry, Keystone Symposia on Molecular and Cellular Biology (1994) Abstract S039.
J. Org. Chem., vol. 59, p. 3656 1994 Parks et al.

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