Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Patent
1993-08-02
1996-01-30
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
514544, 514568, 514699, 514731, A61K 3578, A61K 31235, A61K 3119, A61K 3111, A61K 3105
Patent
active
054878934
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR91/00882, filed Nov. 12, 1991.
The present invention relates to a new antiviral use of compounds having Formula I below, belonging to the family of 2-6-di-t-butylphenol compounds substituted in the 4 position (alternate nomenclature: 3,5-di-t-butyl-4-hydroxybenzenes substituted in the i position), and resulting in a general manner from the oxidation of 2,6-di-t-butyl-4-methylphenol (alternate nomenclature: 3,5-di-t-butyl-4-hydroxytoluene, or 2,6-di-t-butyl-p-cresol) .
This new antiviral use notably manifests itself against lipid-capsid viruses such as the herpes viruses, but also against other viruses, notably papillomaviruses.
It is known that 2,6-di-t-butyl-4-methylphenol (abbreviated HG1) possesses antiviral properties against the herpes viruses such as HSV.sub.1, which are lipid-capsid viruses (abbreviated LCV), notably from French Patent Fr. Pat. 2,507,891; from the article of W. SNIPES et al., Sciences, 187, PP. 64-65 (1975), and the article of W. SNIPES et al., entitled "Hydrophobic Alcohols and Di-tert-butyl Phenols as Antiviral Agents" and published in the work "Symposium on the Pharmacological Effects of Lipids," pp. 63-73, The American Oil Chemists' Society, Champaign, Ill. (1978).
In particular it is known that the antiviral properties of 2,6-di-t-butyl-4-methylphenol are so weak against herpes viruses that it is worthwhile to associate it with an adjuvant to enhance these properties (see the aforesaid Fr. Pat. 2,507,891) or to obtain a synergism with propolis (to this end see French Patent Application No. 90 03 093 of 12 Mar. 1992, by the Applicant).
The aforementioned French Application No. 90 03 093 more specifically recommends a synergistic association of a phenol component belonging to the set of 2,6-di-t-butylphenols (abbreviated BHT, i.e., compounds having Formula I where R is an aliphatic hydrocarbon group with C.sub.1 -C.sub.12), with propolis in accordance with a BHT-to-propolis ratio by weight of from 100:1 to 650:1, and better from 135:1 to 560:1, for the treatment of infections caused by LCVs.
It is furthermore known-that compounds having Formula I below, where R is an oxygen residue, have already been described or seriously proposed as oxidation products of BHT compounds (notably HG1) or as metabolites of BHT compounds (notably HG1). To this end see the articles of G.R. YOHE et al., J. Org. Chem. 21, pp. 1289-1292 (1956), T. H. COFFIELD et al., J. Am. Chem. Soc. 79, 5019-5023 (1957), J. C. DACRE, Biochem. J. 78, pp. 758-766 (1961), and M. AKAGI et al., Chem. Pharm. Bull. (Tokyo) 10, pp. 101-105 and 200-204 (1962).
One finds that after oral or even injectable administration of HG1, in vivo metabolization into compounds having Formula I, where R is a residue containing oxygen such as CH.sub.2 OH, OCH.sub.3 or COOH, is slow and happens late. Consequently the quantities of biologically formed metabolites available in the organism, which are not eliminated by natural routes, are to the Applicant's knowledge insufficient to produce the beneficial antiviral effects, notably against LCVs such as the herpes viruses, on the one hand, and papillomaviruses, on the other hand.
Moreover, in the local administration of HG1 on the skin, in the case of treatment of skin conditions caused by herpes viruses, the metabolization of HG1 into compounds having Formula I, where R is CH.sub.2 OH, OCH.sub.3 or COOH, does not take place. This explains why after local administration of HG1, the beneficial antiviral properties of compounds having Formula I, where R is OCH.sub.3, CH.sub.2 OH or COOH, have never been able to manifest themselves.
Finally, it is known that 3,5-di-t-butyl-4-hydroxybenzoic acid, which is a compound having Formula I where R is COOH, has been used as an intermediate product in synthesis (see in particular Example 1 of EP-A-0 269 981) and that the halogenides of this acid, notably the bromide and chloride, have also been used as intermediate products in synthesis (see the aforementioned EP-A-0 269 981, and U.S. Pat. No. 4,708,966).
PURPOSE OF THE IN
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