Use of 1,3-oxathiolane nucleoside analogues in the treatment of

Details Use of 1,3-oxathiolane nucleoside analogues in the treatment of Use of 1,3-oxathiolane nucleoside analogues in the treatment of

1993-08-09

1996-07-02

Goldberg, Jerome D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

A61K 31505

Patent

active

055322468

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/CA92/00001 filed Jan. 3, 1992.
The present invention relates to the use of nucleoside analogues in the treatment of viral infections. More specifically it is concerned with the use of 1,3-oxathiolane nucleoside analogues in the treatment of hepatitis, in particular hepatitis B.
Hepatitis B is a viral disease transmitted orally or parenterally by contaminated material such as blood and blood products, contaminated needles, sexually and vertically from infected or carrier mothers to their off-spring. In those areas of the world where the disease is common vertical transmission at an early age results in a high proportion of infected individuals becoming chronic carriers of hepatitis B. There are an estimated 280,000,000 carriers of hepatitis B worldwide. At the present time there are no effective chemotherapeutic agents for the treatment of hepatitis B infections.
A number of nucleoside derivatives have been described as having activity against the hepatitis B virus.
EPA 0206497 describes a number of 2',3'-dideoxy purine and pyrimidine nucleosides with antiviral activity including activity against the hepatitis B virus.
EPA 0302760 describes the use of 2',3'-dideoxy purine nucleosides for the treatment of hepatitis B infections.
WO90/14079 describes the treatment of hepatitis B by administration of 2',3'-dideoxycytidine.
WO90/14091 describes the treatment of hepatitis B by administration of 2',3'-dideoxyguanosine, 2',3'-dideoxy adenosine or 2',3'-dideoxyinosine.
European patent application publication number 0 382 526 describes a series of 1,3-oxathiolane nucleoside analogues having antiviral activity, in particular activity against HIV, the causative agent of AIDS.
PCT patent application publication number WO91/17159 describes the compound (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolanes-yl)-(1H)-pyrimidin-2- one (also known as 3TC) and its use in the treatment of HIV infections. 3TC is the (-)-enantiomer of one of the compounds (BCH-189) described in EPA 0382526. We have now found that BCH-189 and its individual enantiomers, including 3TC, are active both in vitro and in vivo against the hepatitis B virus.
The invention accordingly provides, in a first aspect, a method for the treatment of an animal, including man, infected with or susceptible to infection with the hepatitis B virus comprising the administration of an effective amount of a compound of formula (I) ##STR2## or a pharmaceutically acceptable derivative thereof.
In a further or alternative aspect there is provided a compound of formula (I) as defined hereinabove or a pharmaceutically acceptable derivative thereof for use in the manufacture of a medicament for the treatment of hepatitis B.
As will be appreciated by those skilled in the art references herein to treatment extend to prophylaxis as well as to the treatment of established infections or symptoms.
As will be appreciated by those skilled in the art the compound of formula (I) is a cis compound and contains two chiral centres (shown in formula (I) by *). Thus the compound exists as two enantiomers, compounds of formulae (Ia) and (Ib) respectively. ##STR3##
The compound of formula (I) is preferably in the form of a racemic mixture or its (-)-enantiomer but a mixture of compounds of formulae (Ia) and (Ib) in any ratio may be employed in the invention.
The compound of formula (I) has the chemical name cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. It is also known as BCH-189. The (-)-enantiomer has the chemical name (-)-cis-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-o ne and has the absolute stereochemistry of the compound of formula (Ib) which has the name (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2- one. It is also known as 3TC.
Preferably when the (-)-enantiomer is employed it will be substantially free of the corresponding (+)-enantiomer, that is to say no more than about 5% w/w of the (+)-enantiomer, preferably no more than about 2%, in particular less than about 1% w/w w

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