Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1997-09-30
2002-07-09
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S050000, C514S261100
Reexamination Certificate
active
06417191
ABSTRACT:
This application is filed pursuant to 35 U.S.C. §371 as a United States National Phase Application of International Application No. PCT/EP96/01352 filed Mar. 28, 1996 which claims priority from GB9506490.3 filed Mar. 30, 1995 and GB9506489.5 filed Mar. 30, 1995.
The present invention relates to therapeutic combinations of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (1592U89), 3′-azido-3′-deoxythymidine (zidovudine) and (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (3TC) (or, alternatively to 3TC, (2R,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one (FTC)) which have anti-HIV activity. The present invention is also concerned with pharmaceutical compositions containing said combinations and their use in the treatment of HIV infections including infections with HIV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors.
Zidovudine is now well established as an important and useful chemotherapeutic agent for the treatment and/or prophylaxis of HIV-infections including related clinical conditions such. as AIDS, AIDS-related complex (ARC), AIDS dementia complex (ADC) and also for the treatment of patients who have an asymptomatic HIV infection or who are anti-HIV antibody-positive. Treatment with zidovudine prolongs the disease-free interval in asymptomatic patients infected with HIV and delays death in symptomatic patients.
Following the widespread clinical use of zidovudine in the treatment of such infections and conditions. It has been observed that in certain instances following prolonged treatment, the virus may develop a certain level of resistance to zidovudine and therefore a loss of sensitivity to the drug.
The therapeutic agent 1592U89 (European Specification EPO434450) is a promising anti-HIV chemotherapeutic candidate (International Conference on Antiviral Research Apr. 23rd 1995) showing potent activity against HIV, low cytotoxicity and excellent penetration into the brain, which is important for the treatment of AIDS and HIV linked central nervous system conditions such as ADC.
Nucleoside analogues containing an oxathiolane residue in place of the sugar residue, for example, nucleosides described in European Patent Specification No. 382526 particularly 4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one(BCH-189) have been found to have anti-HIV activity. BCH-189 is a racemic mixture and although the enantiomers are equipotent against HIV the (−)-enantiomer has considerably lower cytotoxicity than the (+)-enantiomer. The (−)-enantiomer has the chemical name (2R,cis)-4amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one, now known as 3TC or lamivudine.
An alternative oxathiolane nucleoside analogue is described in International Specification Number WO92/14743 (2R,cis)-4-amino-5-fluoro-1-(2-hydroxymethyl-1,3 oxathiolan-5-yl)-(1H)-pyrimidine-2-one, commonly referred to as FTC or 524W91.
To date the treatment of HIV infection has relied to a large extent upon monotherapy with nucleoside reverse transcriptase inhibitors such as zidovudine, didanosine (ddl), zalcitabine (ddC) and stavudine (D4T). However, these drugs eventually become less effective due either to the emergence of HIV resistant mutantsor becauseof toxicity. Thus, new therapies are needed.
The combination of zidovudine with either ddC or ddl has shown promising results in HIV infected patients (New Eng. J. Med. 1992, 329(9) 581-587, and Program Abstract 1993 9R International Conference on AIDS, abstract US-B25-1). The combination of zidovudine and 3TC has also been studied and widely reported. However, it should be noted that these results are surprising because drugs with the same site of action are frequently antagonistic or additive (Rev Infect Dis 1982, 4, 255-260). Unexpectedly, it has now been found that by combining 1592U89, zidovudine and 3TC a synergistic anti-HIV effect is achieved. The result is surprising since all three drugs act upon the same molecule, HIV Reverse Transcript use. It is a feature of this invention that the use of this drug combinations will provide synergistic antiviral effects, more complete viral suppression, viral suppression over a longer period, limit the emergence of drug resistant HIV mutants and allow better management of drug-rel ated toxicitie dt
As an alternative to 3TC the compound FTC may be used.
Thus, a ccording to one aspect, the present invention provides a combination comprising 1592U89 or a physiologically functional derivative thereof, zidovudine or a physiologically functional derivative thereof and 3TC (or, alternatively to 3TC, FTC) or a physiologically functional derivative thereof.
It will be appreciated that zidovudine may exist in the keto or enol tautomeric form and the use of either tautomeric form is within the scope of this invention. 3TC and 1592U89 will normally be provided substantially free of the corresponding enantiomer, that is to say no more than about 5% w/w of the corresponding enantiomer, preferably no more than about 2% w/w, in particular less than 1% w/w will be present.
As used herein, the term “physiologically functional derivative” includes any physiologically acceptable salt, ether, ester, salt of such ester of 1592U89, zidovudine or 3TC; or solvates of any thereof and their physiologically functional derivatives; or any other compound which upon administration to the recipient, is capable of providing (directly or indirectly) such a compound or an antivirally active metabolite or residue thereof.
Preferred esters in accordance with the invention are independently selected from the following group: (1) carboxylic acid esters in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl,
n
-propyl,
t
-butyl, or
n
-butyl), cycloalkyl, alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryioxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, C
1-4
alkyl, or C
1-4
alkoxy), or amino; (2) sulphonate esters, such as alkyl- or aralkylsulphonyl (for example, methanesulphonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); and (4) phosphonate esters In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group. Any reference to any of the above compounds also includes a reference to a physiologically acceptable salt thereof.
Particularly preferred esters are the mono-, di-, and tri-phosphate esters of zidovudine, 3TC (which may be optionally blocked) or FTC or any other compound which upon administration to a human subject is capable of providing (directly or indirectly) said mono-, di, or triphosphate ester.
A preferred derivative of 1592U89 is the tri-phosphate ester of (−) carbovir.
Examples of physiologically acceptable salts of 1592U89, zidovudine or 3TC and their physiologically acceptable derivatives include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX
4
+
(wherein X is C
1-4
alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids, organic sulphonic acids, such as methanesulphonic, ethanesulphonic, benzenesulphonic and p-toluenesulphonic acids and inorganic acids, such as hydrochloric, sulphuric, phosphoric and sulphamic acids. Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na
+
Barry David Walter
St. Clair Martha Heider
GlaxoSmithKline
Prus Karen L.
Travers Russell
LandOfFree
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