Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Para-n-benzene - sulfoxy-n containing doai – and said benzene...
Patent
1996-08-21
1998-03-03
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Para-n-benzene - sulfoxy-n containing doai, and said benzene...
558413, 558418, A61K 3163, C07C25534
Patent
active
057234523
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB95/00375, filed Feb. 23, 1995.
The present invention relates to certain arylthiobenzonitrile compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy, particularly for the prophylaxis or treatment of vital infections and inflammation.
In the field of antiviral chemotherapy, few drugs exist which effectively combat the virus per se, owing to the difficulty of attacking the virus while leaving uninfected host cells unimpaired. It has been established that certain stages in the virus replicative cycle offer possible targets for antiviral therapy. These stages may prove susceptible to attack where they differ sufficiently from any corresponding host-cell function. However, owing to great similarity between vital and host functions, effective treatments have proved very difficult to identify.
One group of viral pathogens which has assumed a particular importance is the retroviruses. Retroviruses form a sub-group of RNA viruses which, in order to replicate, must first `reverse transcribe` the RNA of their genome into DNA (`transcription` conventionally describes the synthesis of RNA from DNA). Once in the form of DNA, the vital genome my be incorporated into the host cell genome, allowing it to take advantage of the host cell's transcription/translation machinery for the purposes of replication. Once incorporated, the viral DNA is virtually indistinguishable from the host's DNA and, in this state, the virus introducing mechanism may persist for the life of the cell.
A species of retrovirus, Human Immunodeficiency Virus (HIV), 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. Characteristically, AIDS is associated with a progressive depletion of T-cells, especially the helper-inducer subset bearing the OKT.sup.4 surface marker. HIV is cytopathic and appears to preferentially infect and destroy T-cells bearing the OKT.sup.4 marker. It is now generally recognised that HIV is the aetiological agent of AIDS.
PCT patent application WO 92/06683 discloses certain diphenylsulfides having anti-retrovirus activity. However, there is no disclosure of the compounds of formula (I) infra. 2-Amino-6-(phenylthio)benzonitrile is disclosed as a chemical intermediate (Ashton, W. T. et al., J. Med. Chem., 1973, 16(11) 1233-7 and Harris, N. V. et al., J. Med. Chem. 1990, 33(1), 434-4).
We have now identified certain arylthiobenzonitrile compounds and salts thereof which have unexpectedly been found suitable for use in medical therapy and in particular as antiviral and antiinflammatory agents.
According to the first aspect of the present invention there is provided a compound of formula (I) ##STR2## wherein, R is hydrogen, C.sub.1-4 alkyl (for example methyl), C.sub.1-4 alkoxy (for example methoxy), hydroxyl, mercapto, or a group of formula NR.sup.1a R.sup.2a or SR.sup.1a (wherein R.sup.1a and R.sup.2a, which may be the same or different, are hydrogen, C.sub.1-4 alkyl (for example methyl) or phenyl C.sub.1-4 alkyl (for example benzyl)); C.sub.1-4 alkyl (for example methyl) or phenyl C.sub.1-4 alkyl (for example benzyl); provided that when R.sup.1 and R.sup.2 are both hydrogen and m is 0, R is not hydrogen; or a physiologically functional derivative thereof.
Preferably both R.sup.1 and R.sup.2 are hydrogen or C.sub.1-4 alkyl, or R.sup.1 is hydrogen and R.sup.2 is C.sub.1-4 alkyl.
Preferred compounds of formula (I) include those wherein n is 1 or 2, ring A is 3-substituted or 3,5-disubstituted and m is 2.
Preferred compounds of formula (I) include:
A preferred physiologically functional derivative of a compound of formula (I) is
A particularly preferred compound of formula (I) is
The compounds of formula (I) and also the known compound, 2-amino-6-(phenylthio)benzonitrile, and their physiologically functional derivatives thereof are hereinaf
REFERENCES:
patent: 4829058 (1989-05-01), Seydel et al.
Harris, N.V. et al., "Antifolate and Antibacterial Activities of 5-Substituted 2,4-Diamonoquinazolines", J. Med Chem, vol. 33, No. 1, 1990, pp. 434-444.
Ashton, W.T. et al., "Synthesis of 5-Substituted Quinazolines as Potential Antimalarial Agents", J. Med. Chem., vol. 16, No. 11, 1973, pp. 1233-1237.
DeWitt LaVonda R.
Glaxo Wellcome Inc.
Richter Johann
Sackey Ebenezer
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