Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1992-02-20
2001-01-30
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S043000, C514S049000, C514S050000
Reexamination Certificate
active
06180639
ABSTRACT:
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 compound of formula (I)
also known as BCH-189 or NGPB-21 has been described as having antiviral activity in particular against the human immunodeficiency viruses (HIV's), the causative agents of AIDS (5th Anti-Aids Conference, Montreal, Canada Jun. 5th-9th 1989: Abstracts T.C.O.1 and M.C.P. 63: European Patent Application Publication No. 0382562). The compound of formula (I) is a racemic mixture of the two enantiomers of formulae (I-1) and (I-2):
and was described and tested in the form of its racemate. 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compound has a significant side-effect liability and thus either cannot be employed or, once employed, may have to be withdrawn in a significant number of patients.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.
We have now found that, surprisingly, enantiomers of the compound of formula (I) are equipotent against HIV but that one of the enantiomers (the (−)-enantiomer) has considerably lower cytotoxicity than the other enantiomer. There is thus provided in a first aspect of the invention the (−) (or laevorotatory) enantiomer of the compound of formula (I) and pharmaceutically acceptable derivatives thereof.
The (−) enantiomer has the chemical name (−)-cis-4-Amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (hereinafter compound (A)). It has the absolute stereochemistry of the compound of formula (I-1) which has the name (2R,cis))-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one.
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, preferably no more than about 2%, in particular 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-hydroxy-methyl group is replaced by an acyl function R—C— 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. methoxymethyl), aralkyl (e.g. benzyl), aryloxyalkyl (e.g. phenoxymethyl), aryl (e.g. phenyl optionally substituted by halogen, C
1-4
alkyl or C
1-4
alkoxy); sulphonate esters such as alkyl- or aralkylsulphonyl (e.g. methanesulphonyl); amino acid esters (e.g. L-valyl 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
1-16
alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted by at least one halogen (bromine, chlorine, fluorine or iodine), C
1-6
alkyl, C
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, benzoic, malonic, naphthalene-2-sulphonic and benzenesulphonic acids. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium), ammonium and NR
4
— (where R is C
1-4
alkyl) salts.
References hereinafter to a compound according to the invention include both the compound (A) and its pharmaceutically acceptable derivatives.
The compounds of the invention either themselves possess antiviral activity and/or are metabolizable to such compounds. In particular these compounds are effective in inhibiting the replication of retroviruses, including human retroviruses such as human immunodeficiency viruses (HIV's), the causative agents of AIDS.
There is thus provided as a further aspect of the invention compound (A) or a pharmaceutically acceptable derivative thereof for use as an active therapeutic agent in particular as an antiviral agent, for example in the treatment of retroviral infections.
In a further or alternative aspect there is provided a method for the treatment of a viral infection, in particular an infection caused by a retrovirus such as HIV, in a mammal including man comprising administration of an effective amount of compound (A) or a pharmaceutically acceptable derivative thereof.
There is also provided in a further or alternative aspect use of compound (A) or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a viral infection.
The compounds of the invention are also useful in the treatment of AIDS related conditions such as AIDS-related complex (ARC), progressive generalised lymphadenopathy (PGL), AIDS-related neurological conditions (such as dementia or tropical paraparesis), anti-HIV antibody positive and HIV-positive conditions, Kaposi's sarcoma, thrombocytopenia purpurea and associated opportunistic infections for example
Pneumocystis carinii.
The compounds of the invention are also useful in the prevention of progression to clinical illness of individuals who are anti-HIV antibody or HIV-antigen positive and in prophylaxis following exposure to HIV.
The compound (A) or pharmaceutically acceptable derivatives thereof may also be used for the prevention of viral contamination of physiological fluids such as blood or semen in vitro.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established infections or symptoms.
It will be further appreciated that the amount of a compound of the invention required for use in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general however a suitable dose will be in the range of from about 0.1 to about 750 mg/kg of bodyweight per day preferably in the range of 0.5 to 60 mg/kg/day, most preferably in the range of 1 to 20 mg/kg/day.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
The compound is conveniently administered in unit dosage form; for exa
Coates Jonathan Allan
Mutton Ian Martin
Penn Charles Richard
Storer Richard
Williamson Christopher
Biochem Pharma Inc.
Krass Frederick
Millen White Zelano & Branigan P.C.
LandOfFree
1,3-oxathiolane nucleoside analogues does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 1,3-oxathiolane nucleoside analogues, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 1,3-oxathiolane nucleoside analogues will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2463043