Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1996-04-29
1999-03-30
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
546 23, A61K 3165, A61K 3127, C07C32357, C07D20714
Patent
active
058889922
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to certain hydrocarbon derivatives bearing polar substituents and their use in the inhibition of retroviral proteases, for example in the treatment of HIV viral infections such as acquired immunodeficiency syndrome (AIDS). The invention also relates to processes for preparing such hydrocarbon derivatives bearing polar substituents, to pharmaceutical compositions comprising them and to methods for the treatment or prophylaxis of retroviral infections. The invention also relates to a process for enhancing the water-solubility of a pharmaceutical or veterinary substance.
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. 34, 2314-2327 (1991)). 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.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide compounds useful as retroviral protease inhibitors. It is another object of the present invention to provide pharmaceutical compositions comprising compounds useful for the treatment or prophylaxis of retroviral infections. It is a further object of the present invention to provide methods for the treatment or prophylaxis of retroviral infections, in particular AIDS. Other objects of the present invention are to provide processes for preparing compounds useful as retroviral protease inhibitors, and processes for enhancing the water-solubility of pharmaceutical or veterinary substances, in particular retroviral protease inhibitors.
SUMMARY OF THE INVENTION
The invention provides 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.
In the following description of the invention, the teaching of each of the publications mentioned is incorporated herein by reference.
A first embodiment of the invention is directed to compounds of the general formula or pharmaceutically acceptable salts or prodrugs thereof: --Y*, --CN, --N.dbd.CR.sub.5 R.sub.5*, --C(R.sub.5).dbd.NR.sub.3, --C(R.sub.5).dbd.NOR.sub.3, --C(NR.sub.3 R.sub.4).dbd.NR.sub.5**, C(D)OR.sub.3, --C(D)SR.sub.3 and --C(D)NR.sub.3 R.sub.4, wherein consisting of R.sub.6 and a solubilising group Px which is labile in vivo, wherein R.sub.6 is selected from the group consisting of -C.sub.18)alkyl, -C.sub.18)alkenyl, -C.sub.18)alkynyl, independently are selected from hydrogen and R.sub.20 as previously defined, or R.sub.21 and R.sub.22 together, or R.sub.22 and R.sub.23 together form a saturated or unsaturated cyclic, bicyclic or fused ring system as defined below, unsaturated cyclic, bicyclic or fused ring system as defined below, is as defined below, R.sub.10 has the meaning of R.sub.6 as previously defined, defined, P(O)(OR.sub.7)R.sub.8, S(O).sub.z OR.sub.7 and S(O).sub.z NR.sub.7 R.sub.8, wherein z is 1 or 2 and R.sub.7 and R.sub.8 independently have the meaning of
REFERENCES:
patent: 3330857 (1967-07-01), Hess et al.
patent: 5011910 (1991-04-01), Marshall et al.
patent: 5086165 (1992-02-01), Marshall et al.
patent: 5093477 (1992-03-01), Molling et al.
patent: 5116835 (1992-05-01), Ruger et al.
patent: 5126326 (1992-06-01), Anderson et al.
patent: 5132400 (1992-07-01), Gammill et al.
patent: 5137876 (1992-08-01), MacCoss et al.
patent: 5142056 (1992-08-01), Kempe et al.
patent: 5145951 (1992-09-01), Voges et al.
patent: 5151438 (1992-09-01), Sham et al.
patent: 5162538 (1992-11-01), Voges et al.
patent: 5164300 (1992-11-01), Marshall et al.
patent: 5169952 (1992-12-01), Askin et al.
patent: 5171662 (1992-12-01), Sharma
patent: 5183826 (1993-02-01), Bills et al.
patent: 5187074 (1993-02-01), Treiber et al.
patent: 5188950 (1993-02-01), Balani et al.
patent: 5192668 (1993-03-01), Treiber et al.
patent: 5194605 (1993-03-01), Greenlee et al.
patent: 5198426 (1993-03-01), Hamby et al.
patent: 5212157 (1993-05-01), Anderson et al.
patent: 5215968 (1993-06-01), Nickel et al.
patent: 5221665 (1993-06-01), Skiles
patent: 5221667 (1993-06-01), Kaltenbronn et al.
patent: 5223633 (1993-06-01), Hoppe et al.
patent: 5231153 (1993-07-01), Talley
patent: 5235039 (1993-08-01), Heath, Jr. et al.
patent: 5235057 (1993-08-01), Kleemann et al.
patent: 5248667 (1993-09-01), Bridge et al.
patent: 5250563 (1993-10-01), Chen et al.
patent: 5254682 (1993-10-01), Dhanoa et al.
patent: 5256677 (1993-10-01), Sham et al.
patent: 5268361 (1993-12-01), Almquist
patent: 5294720 (1994-03-01), Jadhav et al.
patent: 5294737 (1994-03-01), Ojima
patent: 5296604 (1994-03-01), Hanko et al.
patent: 5461067 (1995-10-01), Norbeck et al.
Tomasseli et al., "The Complexities of AIDS: An Assessment of the HIV Protease as a Therapeutic Target," Chimica Oggi, May 1991, pp. 6-27.
Huff J.R., HIV Protease: A Novel Chemotherapeutic Target For AIDS, Journal of Medicinal Chemistry, vol. 34, No. 8, Aug. 1991, pp. 2305-2314.
Sham H. L. et al., Facile Synthesis of Potent HIV-1 Protease Inhibitors Containing a Novel Pseudo-Symmetric Dipeptide Isostere, Journal of Chemical Society, No. 13, 1993, pp. 1052-1053.
Budavri, S. et al., "The Merck Index," 11th Edition 1989 Merck & Co., Monograph Nos. 32 36 47 423 481 1507 1540 1543 1575 1591 1592 1593 1597 2785 3676 3679 3680 3681 3716 3718 3751 3755 5760 5865 5867 5868 5938 6001 6047 7809 7811 7835 7836 7837 7839 7854 7855 9247 9257 9629.
Chong, K. et al., "Peptidomimetic HIV Protease Inhibitors: Phosphate Prodrugs with Improved Biological Activities", J. Med. Chem., (1993) 36:2575-2577.
Narhex Limited
Rao Deepak R.
Shah Mukund J.
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