Anti-HIV compositions

Details Anti-HIV compositions Anti-HIV compositions

2002-05-03

2003-07-22

Reamer, James H (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06596720

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel anti-HIV composition.
BACKGROUND ART
In 1981, acquired immunodeficiency syndrome (AIDS) was recognized as a disease that greatly damages the human immune system and leads to patient death in many cases. Since then, more than 40 million people have been infected with the human immunodeficiency virus (HIV), and around 12 million people have died of AIDS. In 1997, about 6 million people became infected with HIV and about 2.3 million people, including 460,000 children died of AIDS (J. M. Mann et al., Scientific American Jul. 82, 1998).
In 1985, a synthetic 3′-deoxynucleoside, 3′-azide-3′-deoxythymidine (AZT), was reported effective in inhibiting HIV infection. Since then, other compounds such as 2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxycytidine (ddC), 3′-fluoro-3′-deoxythymidine (FLT) and 2′,3′-dideoxy-2′,3′-didehydrothymidine (d4T) have been proven effective as anti-HIV drugs.
However, these anti-HIV drugs have many defects. For example, anti-HIV drugs such as AZT have serious toxicity which limits the amount which can be clinically administered. Therefore, sometimes the drugs can not be administered to patients, or even if they can be used, often their administration must be stopped in many patients. In addition, drug-resistant viral strains tend to develop quickly during monotherapy with such anti-HIV drugs and there is also cross-resistance, for example, between AZT and d4T and between AZT and ddC. Moreover, patients tend to develop various complications, concomitantly with AIDS.
Trifluridine is a compound first synthesized by Heiderberger et al. (Journal of American Chemical Society, vol. 84, 3597(1962)), and known to have potent antitumor activity in vitro (Cancer Research, vol. 28, 2529(1968)). It is also known that this compound has potent antiviral activity against herpes simplex virus and vaccinia virus, which are DNA viruses (Science, vol. 145, 585(1964), Pergamon Press, New York 1990, 1182-1201).
However, trifluridine is known to be rapidly decomposed and inactivated by thymidine phosphorylase in the liver, intestinum tenue, etc. (Cancer Research, vol. 32, 247(1972); Japanese Journal of Cancer and Chemotherapy, vol. 8, 262(1981) and vol. 8, 1548(1981)). In clinical trials, trifluridine showed unsatisfactory antitumor effects (Cancer Chemotherapy Report, vol. 55, 205(1971)).
Currently approved medical use of trifluridine is limited to an ophthalmic preparation for herpes keratitis caused by herpes simplex virus (HSV) infection, which is an ophthalmic local treatment and thus free from decomposition by thymidine phosphorylase (The Lancet, vol. 21, 1189(1987); Physicians Desk Reference, 50th Ed. 1204(1996); American Journal of Ophthalmology, vol. 73, 932 (1972); Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology, vol. 12, 147(1996)).
Until now it has been completely unknown that trifluridine is useful for treating HIV infection, the cause of AIDS.
DISCLOSURE OF INVENTION
An object of the invention is to provide a novel anti-HIV composition.
Another object of the invention is to provide a novel anti-HIV activity potentiating composition.
A further object of the invention is to provide a novel method for treating syndromes after HIV infection.
Other objects and features of the invention will become apparent from the following description.
To overcome the prior art problems, the inventors of the present invention carried out intensive research on synthetic 2′-deoxynucleosides from diversified viewpoints and found that trifluridine and derivatives thereof have potent anti-HIV activity. The inventors further found that the use of a thymidine phosphorylase inhibitor in combination with trifluridine or its derivatives can reduce the side effects of trifluridine and its derivatives and also retain the in vivo concentration of trifluridine at a level effective for the treatment of HIV infection, thereby enhancing the anti-HIV activity of trifluridine and derivatives thereof. The present invention has been accomplished based on these novel findings.
The present invention provides an anti-HIV composition comprising at least one member selected from the group consisting of trifluridine and derivatives thereof, and a pharmaceutically acceptable carrier.
The present invention further provides an anti-HIV composition comprising (a) at least one member selected from the group consisting of trifluridine and derivatives thereof, (b) a thymidine phosphorylase inhibitor, and a pharmaceutically acceptable carrier.
The present invention further provides a composition for potentiating the anti-HIV activity of trifluridine and derivatives thereof, comprising a thymidine phosphorylase inhibitor and a pharmaceutically acceptable carrier.
The present invention further provides the use of at least one member selected from the group consisting of trifluridine and derivatives thereof for preparing the above anti-HIV compositions.
The present invention further provides a method for treating HIV infection, comprising administering an effective amount of one of the above anti-HIV compositions to HIV-infected mammals, including humans.
The present invention further provides the use of a thymidine phosphorylase inhibitor for preparing a composition for potentiating the anti-HIV activity of trifluridine or derivatives thereof.
The anti-HIV composition of the invention is useful for treating syndromes after HIV infection. The anti-HIV activity potentiating composition of the invention greatly enhances the anti-HIV activity of trifluridine and derivatives thereof.
The trifluridine or derivative thereof used as an active ingredient of the anti-HIV composition of the invention may be trifluridine or any compound that is converted into trifluridine in vivo.
Preferable examples of trifluridine and derivatives thereof are compounds represented by the formula
wherein R
1
and R
2
may be the same or different and are hydrogen, acyl, lower alkyl, alkoxy-lower alkyl, tetrahydrofuryl, tetrahydropyranyl, triphenylmethyl, benzyloxy-lower alkyl, tetrahydrofuryloxy-lower alkyl, lower alkylcarbamoyl, lower alkoxycarbonyl, tri-substituted silyl, di-substituted phosphoric acid group, benzyl or benzoyl; the three substituents of the tri-substituted silyl group and the two substituents of the di-substituted phosphoric acid group are selected from the group consisting of lower alkyl, phenyl and benzyl and may be the same or different from each other; R
3
represents hydrogen, tetrahydrofuryl or benzoyl; when R
1
or R
2
is benzyl, the benzyl may have one or more substituents selected from the group consisting of lower alkyl, lower alkoxy and halogen; when R
1
, R
2
or R
3
is benzoyl, the benzoyl may have one or more substituents selected from the group consisting of lower alkyl, lower alkoxy and halogen.
Among the compounds of formula (1), trifluridine is a compound in which R
1
, R
2
and R
3
are all hydrogen. The compounds of formula (1) other than this one are converted into trifluridine in vivo and thus function as prodrugs of trifluridine.
Useful trifluridine derivatives also include the antitumor compounds described in Japanese Unexamined Patent Publications Nos. 152898/1983, 36696/1984, 216899/1984, 56996/1985 and 261396/1989 and WO90/00557.
In the compound of formula (1), when R
1
or R
2
is acyl, the acyl can be a straight or branched acyl group preferably having 2 to 20 carbon atoms, particularly 2 to 10 carbon atoms. Specific examples include acetyl, n-butyryl, i-butyryl, t-butyl, hexanoyl, isohexanoyl and decanoyl.
When R
1
or R
2
is lower alkyl, the lower alkyl can be a C
1-6
straight or branched alkyl group. Specific examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, hexyl and isohexyl.
When R
1
or R
2
is alkoxy-lower alkyl, the alkoxy-lower alkyl can be a C
1-6
, particularly C
1-3
, straight or branched alkyl group substituted with a C
1-6
straight or branched alkoxy group. Examples of the substituent

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