Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-19
2003-06-03
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252190, C514S253050, C514S253090, C514S253100, C514S254030, C514S254050, C514S254090, C514S241000, C514S242000, C514S252020, C514S252110, C514S253040, C514S253060, C544S121000, C544S295000, C544S363000, C544S364000, C544S366000, C544S367000, C544S369000, C544S370000, C544S373000, C544S180000, C544S182000, C544S179000, C544S238000, C544S357000, C544S362000, C544S371000
Reexamination Certificate
active
06573262
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with indoleoxoacetyl piperazine derivatives. These compounds possess unique antiviral activity. More particularly, the present invention relates to the treatment of HIV and AIDS.
2. Background Art
HIV-1 (human immunodeficiency virus-1) infection remains a major medical problem, with an estimated 33.4 million people infected worldwide. Currently available HIV drugs include six nucleoside reverse transcriptase (RT) inhibitors (zidovudine, didanosine, stavudine, lamivudine, zalcitabine and abacavir), three non-nucleoside reverse transcriptase inhibitors (nevirapine, delavirdine and efavirenz) as well as five peptidomimetic protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir and amprenavir). Each of these drugs can only transiently restrain viral replication if used alone. However, when used in combination, these drugs have a profound effect on disease progression. In fact, significant reductions in death rates among AIDS patients have been recently documented. Despite these results, 30 to 50% of patients ultimately fail combination drug therapies. Insufficient drug potency, non-compliance, restricted tissue penetration and drug-specific limitations within certain cell types (e.g. most nucleoside analogs cannot be phosphorylated in resting cells) may account for the incomplete suppression of sensitive viruses. Furthermore, the high replication rate and rapid turnover of HIV-1 combined with the frequent incorporation of mutations, leads to the appearance of drug-resistant variants and treatment failures when suboptimal drug concentrations are present (Larder and Kemp, Gulick, Morris-Jones, et al, Kuritzkes, Vacca and Condra, Schinazi, et al and Flexner, Ref. 6-12). Therefore, novel anti-HIV agents exhibiting distinct resistance patterns, and favorable pharmacokinetic as well as safety profiles are needed to provide more treatment options.
Currently marketed HIV-1 drugs are dominated by either nucleoside reverse transcriptase inhibitors or peptidomimetic protease inhibitors. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recently gained an increasingly important role in the therapy of HIV infections. At least 30 different classes of NNRTIs have been published in the literature (DeClercq, Ref. 13). Dipyridodiazepinone (nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl)piperazine derivatives (delavirdine) are already approved for clinical use. In addition, several indole derivatives including indole-3-sulfones, piperazino indoles, pyrazino indoles, and 5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported as HIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1, Williams et al, Ref. 2, Romero et al, Ref. 3, Font et al, Ref. 14, Romero et al, Ref. 15, Young et al, Ref. 16, Genin et al, Ref. 17, and Silvestri et al, Ref. 18). Other indole derivatives exhibiting antiviral activity useful for treating HIV are disclosed in PCT WO 00/76521, Ref. 102). Also, indole derivatives are disclosed in PCT WO 00/71535, Ref. 103. Indole 2-carboxamides have also been described as inhibitors of cell adhesion and HIV infection (Boschelli et al. in U.S. Pat. No. 5,424,329, Ref. 4). Finally, 3-substituted indole natural products (Semicochliodinol A and B, didemethylasterriquinone and isocochliodinol) were disclosed as inhibitors of HIV-1 protease (Fredenhagen et al, Ref. 19). However, nothing in these references can be construed to disclose or suggest the novel compounds of this invention and their use to inhibit viral infections, including HIV infection.
Structurally related compounds have been disclosed previously (Brewster et al, Ref. 20, Archibald et al, Ref. 21, American Home Products in GB 1126245, Ref. 5). However, the structures differ from those claimed herein in that they are symmetrical bis(3-indolylglyoxamides) rather than unsymmetrical aroyl indoleoxoacetyl piperazine derivatives, and there is no mention of use for treating viral infections. Interestingly, the indole moiety present in the compounds disclosed here is the common feature of many non-nucleoside HIV-1 reverse transcriptase inhibitors including Delavirdine from Upjohn (Dueweke et al. 1992, 1993, Ref. 22 and 23).
A recent PCT application, WO 99/55696, described substituted indoles as phosphodiester 4 inhibitors.
REFERENCES CITED
Patent Documents
1. Greenlee, W. J.; Srinivasan, P. C., Indole reverse transcriptase inhibitors. U.S. Pat. No. 5,124,327.
2. Williams, T. M.; Ciccarone, T. M.; Saari, W. S.; Wai, J. S.; Greenlee, W. J.; Balani, S. K.; Goldman, M. E.; Theohrides, A. D., Indoles as inhibitors of HIV reverse transcriptase. European Patent 530907.
3. Romero, D. L.; Thomas, R. C., Preparation of substituted indoles as anti-AIDS pharmaceuticals. PCT WO 93/01181.
4. Boschelli, D. H.; Connor, D. T.; Unangst, P. C., Indole-2-carboxamides as inhibitors of cell adhesion. U.S. Pat. No. 5,424,329.
5. Therapeutic bis(indolyl) compounds. British Patent 1126245 (American Home Products Corp.).
Other Publications
6. Larder B. A & Kemp S. D., Multiple mutations in the HIV-1 reverse transcriptase confer high-level resistance to zidovudine (AZT),
Science
1989, 246,1155-1158.
7. Gulick R. M., Current antiretroviral therapy: an overview.,
Quality of Life Research
1997, 6, 471-474.
8. Kuritzkes D. R., HIV resistance to current therapies,
Antiviral Therapy
1997, 2(Supplement 3), 61-67.
9. Morris-Jones S, Moyle G & Easterbrook P. J., Antiretroviral therapies in HIV-1 infection,
Expert Opinion on Investigational Drugs
1997, 6(8), 1049-1061.
10. Schinazi R. F, Larder B. A & Mellors J. W., Mutations in retroviral genes associated with drug resistance,
International Antiviral News
, 1997, 5, 129-142.
11. Vacca J. P & Condra J. H., Clinically effective HIV-1 protease inhibitors,
Drug Discovery Today
1997, 2, 261-272.
12. Flexner D., HIV-protease inhibitors,
Drug Therapy
1998, 338, 1281-1292.
13. De Clercq E., The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection,
Antiviral Research
1998, 38,153-179.
14. Font, M.; Monge, A.; Cuartero, A.; Elorriaga, A.; Martinez-Irujo, J. J.; Alberdi, E.; Santiago, E.; Prieto, I.; Lasarte, J. J.; Sarobe, P. and Borras, F., Indoles and pyrazino[4,5-b]indoles as nonnucleoside analog inhibitors of HIV-1 reverse transcriptase,
Eur. J. Med. Chem
. 1995, 30, 963-971.
15. Romero, D. L.; Morge, R. A.; Genin, M. J.; Biles, C.; Busso, M,; Resnick, L.; Althaus, I. W.; Reusser, F.; Thomas, R. C and Tarpley, W. G., Bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships of novel substituted indole analogues and the identification of 1-[(5-methanesulfonamido-1H-indol-2-yl)-carbonyl]-4-[3-[1-methylethyl)amino]-pyridinyl]piperazine momomethansulfonate (U-90152S), a second generation clinical candidate,
J. Med. Chem
. 1993, 36, 1505-1508.
16. Young, S. D.; Amblard, M. C.; Britcher, S. F.; Grey, V. E.; Tran, L. O.; Lumma, W. C.; Huff, J. R.; Schleif, W. A.; Emini, E. E.; O'Brien, J. A.; Pettibone, D. J. 2-Heterocyclic indole-3-sulfones as inhibitors of HIV-reverse transcriptase,
Bioorg. Med. Chem. Lett
. 1995, 5, 491-496.
17. Genin, M. J.; Poel, T. J.; Yagi, Y.; Biles, C.; Althaus, I.; Keiser, B. J.; Kopta, L. A.; Friis, J. M.; Reusser, F.; adams, W. J.; Olmsted, R. A.; Voorman, R. L.; Thomas, R. C. and Romero, D. L., Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs,
J. Med. Chem
. 1996, 39, 5267-5275.
18. Silvestri, R.; Artico, M.; Bruno, B.; Massa, S.; Novellino, E.; Greco, G.; Marongiu, M. E.; Pani, A.; De Montis, A and La Colla, P., Synthesis and biological evaluation of 5H-indolo[3,2-b][1,5]benzothiazepine de
Fang Haiquan
Meanwell Nicholas A.
Pearce Bradley C.
Qiu Zhilei
Wallace Owen B.
Bernhardt Emily
Bristol-Myers Sqibb Company
DuBoff Samuel J.
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