1,3-oxathiolane nucleoside compounds and compositions

Details 1,3-oxathiolane nucleoside compounds and compositions 1,3-oxathiolane nucleoside compounds and compositions

1994-02-01

1996-07-23

Wilson, James O.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514 49, 514 50, 514269, 514274, 536 41, 544242, C07D41104, A61K 31505

Patent

active

055389759

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to nucleoside analogues and their use in medicine. More specifically the invention is concerned with 1,3-oxathiolane nucleoside analogues, pharmaceutical formulations thereof and the use thereof in the treatment of viral infections.
The only compound currently approved for the treatment of conditions caused by HIV is 3'-azido-3'-deoxythymidine (AZT, zidovudine, BW 509U). However, this compound has a significant side-effect liability and thus either cannot be employed or, once employed, may have to be withdrawn in a significant number of patients. There is in consequence a continuing need to provide compounds which are effective against HIV but with a concommitant significantly better therapeutic index.
The compound of formula (I) ##STR1## is a racemic mixture of the two enantiomers of formulae (I-1) and (I-2): ##STR2##
We have now found that, surprisingly, the (-)-enantiomer of the compound of formula (I) is much more active than the (+)-enantiomer, although both enantiomers show unexpectedly low cytotoxicity. There is thus provided in a first aspect of the invention the (-)(or laevorotatory) enantiomer of the compound of formula (I) and phazmaceutically acceptable derivatives thereof.
The (-)-enantiomer has the chemical name (-)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidi n-2-one (hereinafter compound (A)). This enantiomer has the absolute stereochemistry shown in formula (I-1).
Preferably compound (A) is provided substantially free of the corresponding (+)-enantiomer, that is to say no more than about 5% w/w of the (+)-enantiomer, more preferably no more than about 2%, and most preferably less than about 1% w/w is present.
By "a pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of compound (A) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) compound (A) or an antivirally active metabolite or residue thereof.
It will be appreciated by those skilled in the art that compound (A) may be modified to provide pharmaceutically acceptable derivatives thereof, at functional groups in both the base moiety and at the hydroxymethyl group of the oxathiolane ring. Modification at all such functional groups are included within the scope of the invention. However., of particular interest are pharmaceutically acceptable derivatives obtained by modification of the 2-hydroxymethyl group of the oxathiolane ring.
Preferred esters of compound (A) include the compounds in which the hydrogen of the 2-hydroxymethyl group is replaced by an acyl function ##STR3## in which the non-carbonyl moiety R of the ester is selected from hydrogen, straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl, t-butyl, n-butyl), alkoxyalkyl (e.g., methoxymethylL), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenoxymethyl), aryl (e.g., phenyl optionally substituted by halogen, C.sub.1-4 alkyl or C.sub.1-4 alkoxy); sulphonate esters such as alkyl- or aralkylsulphonyl (e.g., methanesulphonyl); amino acid esters (e.g., L-valyl or L-isoleucyl) and mono-, di- or tri-phosphate esters.
With regard to the above described esters, unless otherwise specified, any alkyl moiety present advantageously contains 1 to 16 carbon atoms, particularly 1 to 4 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
In particular the esters may be a C.sub.1-16 alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted by at least one halogen (bromine, chlorine, fluorine or iodine), C.sub.1-6 alkyl, C.sub.1-6 alkoxy, nitro or trifluoromethyl groups.
Pharmaceutically acceptable salts of the compound (A) include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicylic, succinic, toluene-p-sulphonic, tartaric, acetic, citric, methanesulphonic, formic, be

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