Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1994-12-09
1998-02-03
Travers, Russell
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514934, A61K 3120, A61K 3110
Patent
active
057145164
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/GB93/01109 filed May 27, 1995.
FIELD OF INVENTION
This invention relates to the treatment of diseases caused by herpesviruses, especially by varicella zoster virus.
PRIOR ART
Viruses modify the polypeptides they synthesize in a number of ways. These modifications may result in glycoproteins or lipoproteins which have a wide variety of functions within the virus lifecycle. Lipoproteins are known to play a significant role in infection with many viruses, but their mode of action is poorly understood.
Lipoproteins may arise by the post- or co-translational addition of fatty acids such as palmitic acid and myristic acid. Myristic acid is conjugated to the polypeptide by the enzyme N-myristoyl transferase. Inhibitors of this enzyme have been suggested as being of use as anti-viral agents (R. A. J. McIlhinney, Trends in Biochemical Sciences (1990), 15, 387-391 and L. A. Paige et al., Biochemistry (1990), 29, 10566-10573).
Recently several myristic acid analogue inhibitors of N-myristoyl transferase have been shown to be effective in inhibiting the release of the human immunodeficiency virus (HIV) from HIV infected cells (T. Saermark et al., AIDS (1991), 5, 951-958 and M. L. Bryant et al., Proc. Natn. Acad. Sci. USA (1989), 86, 8655-8659). The analogues shown to be effective are 13-oxamyristic acid and other derivatives wherein a methylene group between C.sub.4 and C.sub.13 is substituted by an oxygen or sulphur atom. Although effective, the best of these derivatives has been shown to be toxic to the infected cells. In all cases described the infective virus has been a retrovirus such as HIV or Rashid sarcomavirus (RSV). A non-toxic inhibitor of myristoylation would therefore be of value. The activity in HIV is in no way indicative of activity in other viruses. Viruses are categorised into a wide range of groups and retroviruses, such as HIV, have a unique replication strategy. HIV is a particularly diverse virus especially in that it is an RNA virus. Thus, few generalities can be brought from data originating from HIV experiments.
SUMMARY OF THE INVENTION
It has now been found that certain other derivatives of myristic acid are effective in inhibiting herpesviruses with minimal cytotoxic effect on the infected cells. These derivatives are also of use in inhibiting retroviruses such as HIV when dissolved in an appropriate solvent. This is the first non-retroviral effect of any myristic acid analogue to be demonstrated.
Accordingly the invention provides the use of a compound of general formula (I) ##STR2## wherein n is 11, 12 or 13 and R is bromine or hydroxy, and physiologically acceptable salts thereof, for the manufacture of a medicament for use in the treatment of herpesvirus infections, with the proviso than when n is 11, R is not bromo.
The term "herpesvirus infections" includes any infection or disease caused by a virus classified as a herpesvirus, especially herpes simplex virus (HSV), varicella zoster virus (VZV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV).
The compounds of general formula (I) when dissolved in a suitable solvent are also of use for the manufacture of a medicament for use in the treatment of retroviral infections, for example HIV.
Although the prior art discloses the use of 13-oxamyristic acid and other related derivatives of myristic acid, the compounds of use in the present invention differ in preserving the natural alkyl chain backbone of the fatty acid and placing substituents on that backbone chain. This results in compounds that are effective and non-toxic against non-retroviruses as well as retroviruses.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWING
FIG. 1 shows the effect of 2-hydroxymyristic acid on VZV (line with boxes) and HSV (line with triangles) over a range of concentrations.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The preferred compounds of use in the present invention are 2-bromopalmitic acid, 2-hydroxymyristic acid and 2-hydroxypalmitic acid, especially 2-hydroxymyristic acid and 2-hydroxypalmitic acid. All these compounds ma
REFERENCES:
Merck Index 10th Ed 1984 #211 & 212.
Is mail-Cassini et al 113 CA 208251s 1990.
Paige et al (abstract) 1990, FASEP, vol. 4 #7 A 2110.
Paige et al, 1990, Biochemistry, vol. 29, 10566-10573.
McIlhenney, 1990, Trends in Biological Science, vol. 15, pp. 387-391.
Blunt Caroline Jane
Harper David Richard
McIlhinney Robert Andrew
British Technology Group Limited
Travers Russell
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