Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1996-09-09
1999-10-19
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
530321, C07D27300
Patent
active
059691328
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
A great deal of research is currently underway to develop treatments and cures for viral infections in humans and in animals. Notably the incidence of AIDS and ARC in humans is increasing at an alarming rate. The five year survival rate for those with AIDS is dispiriting and AIDS patients, whose immune systems have been seriously impaired by the infection, suffer from numerous opportunistic infections including Kaposi's sarcoma and Pneumocystis carninii pneumonia. No cure for AIDS is known and current treatments are largely without adequate proof of efficacy and have numerous untoward side effects. Fear of the disease has resulted in social ostracism of and discrimination against those having or suspected of having the disease.
The present invention relates to compounds that are useful as antiviral agents. More specifically this invention relates to macrocyclic difluorostatone derivatives that are useful as inhibitors of retroviral proteases required for replication, such as the HIV-1 and HIV-2 viral proteases, the prevention or treatment of infection by the human immunodeficiency virus (HIV), and the treatment of consequent pathological conditions such as the acquired immunodeficiency syndrome (AIDS) in mammals capable of being infected with HIV virus.
SUMMARY OF THE INVENTION
The present invention relates to compounds having the following general formula I: ##STR1## and the stereoisomers, hydrates, and pharmaceutically acceptable salts thereof wherein benzyl or 3-tetrahydrofuryl; --CH(CH.sub.3).sub.2, --CH.sub.2 CH(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2 CH.sub.3), --CH.sub.2 SH, --CH.sub.2 CH.sub.2 SCH.sub.3, --CH.sub.2 OH, --CH(CH.sub.3)OH, --CH.sub.2 (CH.sub.2).sub.3 NH.sub.2, --CH.sub.2 (CH.sub.2).sub.2 NHC (.dbd.NH) NH.sub.2, --CH.sub.2 CO.sub.2 H, --CH.sub.2 CH.sub.2 CO.sub.2 H, --CH.sub.2 CONH.sub.2, --CH.sub.2 CH.sub.2 CONH.sub.2, benzyl, ##STR2## R.sub.1 is hydrogen, C.sub.1-15 alkyl, hydroxy C.sub.1-15 alkyl, CH([(CH.sub.2).sub.d -O--CH.sub.2 ].sub.f -R.sub.7).sub.2, CH.sub.2 Si(CH.sub.3).sub.2 (R.sub.8), PDL, --(C.sub.1-6 alkylene)--OR.sub.4, CH(Y)(Z), ##STR3## wherein PDL is --(CH.sub.2).sub.a -2-, 3- or 4-pyridyl, Y is hydroxy C.sub.1-15 alkyl, C.sub.1-6 alkyl or (CH.sub.2).sub.e -C.sub.6 H.sub.4 -(V).sub.e' ; Z is (CH.sub.2).sub.d -O--CHO, C.sub.1-6 alkylene-O-(CH.sub.2).sub.d -(O--CH.sub.2 --CH.sub.2).sub.e -O--C.sub.1-6 alkyl, CHO, CO.sub.2 R.sub.4, CONHR.sub.4, (CH.sub.2).sub.d -O--(CH.sub.2).sub.d' -R.sub.5, (CH.sub.2).sub.e -OR.sub.4 or ##STR4## wherein V is OR.sub.4 or hydroxy C.sub.1-6 alkylene; provided that d'=2 when R.sub.5 is piperazinyl, substituted piperazinyl, piperidyl or morpholinyl; than hydrogen when R.sub.1 is hydrogen, or R.sub.1 and R.sub.2 taken together with the nitrogen atom to which they are attached are selected from the group consisting of; ##STR5## R.sub.3 is CH.sub.2 OR.sub.4, C(O)NHR.sub.4 or CHO; R.sub.4 is hydrogen, C.sub.1-6 alkyl, phenyl or benzyl; pyridyl, pyrazinyl, pyrimidinyl or phenyl, wherein substituted piperazinyl is piperazinyl substituted on one nitrogen atom thereof with CHO, C(O)NHR.sub.4, C.sub.1-4 alkyl or CO.sub.2 R.sub.4 ; C.sub.1-6 alkyl, C.sub.1-6 alkyl, or OH;
The present invention further provides a method of treating a patient suffering from a viral infection comprising administering to said patient an effective antiviral amount of a compound of formula (I).
In addition the present invention provides a method of inhibiting HIV protease in a patient in need thereof comprising administering to said patient an effective inhibitory amount of a compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
The term "halogen", "halo" or "halide" refers to a chlorine, bromine or iodine atom. The term "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three dimensional structures are called configurations. The term "diastereomer" refers to those stereoisomers with more than one chiral cente
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Schirlin, et al., Bioorganic & Med. Chem. Letters, vol. 4, No. 2, pp. 241-246 (1994).
Farr Robert A.
Podlogar Brent L.
Ford John M.
Merrell Pharmaceuticals Inc.
Nelligan Mark C.
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