Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-12-20
1999-02-02
Clardy, S. Mark
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544343, C07D48704, A61K 31495
Patent
active
058665757
DESCRIPTION:
BRIEF SUMMARY
This application has been filed under 35 USC 371 as a national stage application of PCT/SE95/00747 filed Jun. 19, 1995.
The present invention relates to use of indolo-2,3b-quinoxalines of the general formula I ##STR2## wherein R.sub.1 represents hydrogen or one or several, preferably 1 to 4, similar or different substituents in the positions 1-4 and/or 7-10, selected from halogen, preferably Br, lower alkyl/alkoxy group having not more than 4carbon atoms, trifluoromethyl group, trichloromethyl group; X is a group --(CH.sub.2).sub. n--R.sub.2 wherein R.sub.2 represents a nitrogen containing basic residue such as NH.sub.2, NHR.sub.4 or NR.sub.5 R.sub.6 wherein R.sub.4, R.sub.5 and R.sub.6 independently are lower alkyl or cycloalkyl and n is an integer of from 1 to 4 and R.sub.3 represents hydrogen, lower alkyl/cycloalkyl group having not more than 4 carbon atoms, and the physiologically acceptable addition products of the compounds with acids and halogen adducts, preferably adducts with iodine, iodine monochloride or iodine monobromide, as inhibitors of human immunodeficiency virus (HIV) integrase.
Substituted indoloquinoxalines of formula I have previously been demonstrated to possess valuable activity against several types of vira and several of the compounds also have been demonstrated to show a high anti-cancer effect, cf. our previous patents EP 0,238,459 and U.S. Pat. No. 4,990,510. However, they have also been shown to be inactive as enzyme inhibitors, cf. Harmenberg et al, Antimicrobial Agents and Chemotherapy, November 1988, pp. 1720-724. These studies included several virus polymerases.
Of the RNA viruses the retroviruses are of particular importance. Retroviruses are a sub-group of RNA viruses which in order to replicate must first "reverse transcribe" the RNA of their genome into DNA ("transcription" is a conventional description of the synthesis of RNA from DNA). Once in the form of DNA the viral genome may be incorporated into the host cell genome which allows it to take advantage of the transcription/translation of the host cell for the purposes of replication. Once incorporated in the host cell the viral DNA is virtually indistinguishable from the host's DNA and, in this state, the virus may persist for the life of the cell.
Human Immunodeficiency Virus (HIV) is a species of retrovirus which has been reproducibly isolated from humans with Acquired Immune Deficiency Syndrome (AIDS) or with the symptoms that frequently precede AIDS. AIDS is an immunosuppressive or immunodestructive disease that predisposes subjects to fatal opportunistic infections. AIDS is characteristically associated with a progressive depletion of T-cells, especially the helper-inducer subset bearing the OKT.sup.4 surface marker. HIV is cytopathic and seems to preferentially infect and destroy T-cells bearing the OKT.sup.4 marker and it is generally recognised that HIV is the etiological agent of AIDS.
The treatment of human immunodeficiency virus (HIV) is thus an increasing and important problem which needs to be solved.
It has according to the present invention unexpectedly been found that compounds of the general formula I are active against the enzyme human immunodeficiency virus integrase which was a surprising discovery in view of the fact that compounds of the same type previously had been shown to be inactive as enzyme inhibitors, cf. the article of Harmenberg et al cited above.
According to the present invention it has surprisingly been found that these indoloquinoxalines are active against the enzyme human immunodeficiency virus integrase (HIV integrase). This is evidenced from an in vitro assay in accordance with the method described by M. R. Fesen et al in Proc. Natl. Acad. Sci., USA, March 1993, Vol. 90, pp. 2399-2403.
In this test the sequental cleavage and integration reactions in the retroviral integrase assay can be illustrated by means of the following figure: ##STR3## The cleavage reaction removes a dinucleotide from the 3' end of one of the strands at the integration site, thereby converting the .sup.32
REFERENCES:
patent: 4990510 (1991-02-01), Bergman et al.
Patel et al., Eur. J. Biochem., 197, 597-604, (1991).
Harmenberg et al., Antiviral Res. 15, 193-204, (1991).
Behravan et al., Biopolymers, vol. 34, 599-609, (1994).
Harmenberg et al., Antimicribial Agents and Chemotherapy, vol. 32, No. 11, p. 1720-1724 (1988).
Fesen, et al, "Inhibitors of human immunodeficiency virus intergrase"; PNAS, USA, 90:2399-2403 (1993).
Harmenberg, et al, Antiherpesvirus Activity and Mechanism of Action of Indolo-(2,3-b)Quinoxaline and Analogs; Antimicrobial Agents and Chemotherapy, 32(11):1720-1724.
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Vink, et al, "The human immunodeficiency virus integrase protein"; TIG, 9(12):433-437, (1993).
STN International, File CA, Chemical abstracts, abstract No. 64087, vol. 115, No. 7 (Aug. 19, 1991). Patel, Naina et al., "Proton NMR studies of the interaction between a self-complementary deoxyoligonucleotide duplex and indola 2,3-b-quinoaxaline derivatives active against herpes virus."
STN International, File CA, Chemical abstracts, abstract No. 64118, vol. 115, No. 7 (Aug. 19, 1991). Patel, Naina et al., "Interaction of the deoxyoligonucleotide duplex d(CGCGATCGG)2 and anti-herpes virus active indola 2,3-b-quinoxaline derivatives."
STN International, File CA, Chemical abstracts, abstract No. 64175, vol. 115, No. 7 (Aug. 19, 1991). Harmenberg, Johan et al., "The mechanism of action of the anti-herpes virus compound 2,3-dimethyl-6 (2-dimethylaminoethyl)-6H-indolo (2,3-biquinoxaline."
Clardy S. Mark
Lundblad Leif J. I.
Qazi Sabiha N.
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