Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-29
2002-08-13
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S274000
Reexamination Certificate
active
06432966
ABSTRACT:
The present invention relates to therapeutic combinations comprising (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-pyrimidin-2-one (lamivudine) and BMS-200475, a cyclopentyl guanosine analogue. The present invention is also concerned with pharmaceutical compositions containing said combinations and their use in the treatment of HBV infections including infections with HBV mutants bearing resistance to nucleoside and/or non-nucleoside inhibitors of the replication of the hepatitis B virus.
Hepatitis B is a viral disease transmitted orally or parentally by contaminated material such as blood or 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. An estimated 350 million people world-wide are chronically infected with hepatitis B and as many as 150 million may die from liver disease in the absence of intervention.
Currently, the only established approach to treatment of hepatitis B is repeated injections of interferon, which may be associated with unpleasant side effects, and produces a long lasting response in only one third or less of those treated. Interferon is an immune modulator designed to boost the disease fighting ability of the immune system.
Lamivudine has been reported to be effective against HBV in a two year study, showing that most patients showed substantially reduced levels of viral replication with 52% maintaining undetectable levels of virus thorough to the end of the second year.
The structure of BMS-200475 is as shown in formula (I);
BMS-200475 has been reported to posses anti-HBV activity in vitro.
Metabolic Studies on BMS
-200475,
a New Antiviral Compound with Activity Against Hepatitis B Virus
. G Yasmanaka et al. 36
th
Interscience Conference on Antimicrobial Agents and Chemotherapy Sep. 15-18 1996, New Orleans, La. Oral BMS-200475 has also proved effective against Hepatitis B virus in woodchucks. Safety and pharmacokinetics of BMS-200475 have been studied in both single dose and 14-day multiple dose studies. Abstract 01 DeHertogh D, et al. Second International Conference on Therapies for Viral Hepatitis Kona, Big Island, Hi., Dec. 15-19, 1997.
The use of combinations of the invention may give rise to equivalent antiviral effect with reduced toxicity, or an increase in drug efficacy because synergy between compounds occurs. Lower overall drug doses will also possibly reduce the frequency of occurrence of drug resistant variants of HBV.
We have now found that lamivudine exhibits unexpected advantages when used in combination with BMS-200475. In particular the combinations shows a statistically significant synergistic anti-HBV effect. It is a feature of this invention that the use of this drug combination will provide synergistic antiviral effects, more complete viral suppression, viral suppression over longer periods, limit the emergence of drug resistant HBV mutants and allow better management of drug related toxicites. The use of these drug combinations may also result in a decrease of the number of, for example, tablets administered a day, therefore may increase patient compliance.
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 and symptoms.
Pharmaceutically acceptable salts of lamivudine, and BMS-200475 include those derived from pharmaceutically acceptable inorganic and organic acids. 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 acid, while not in themselves pharmaceutically acceptable may be useful in the preparation of salts useful as intermediates in obtaining 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.
Preferred esters of lamivudine and BMS-200475 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), aryloxyalkyl (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 triphosphate esters of lamivudine and BMS-200475 (both of which may be optionally blocked), or any other compound which upon administration to a human subject is capable of providing (directly or indirectly) said mono-, di-, or triphosphate ester.
Thus according to one aspect, the present invention provides a combination comprising (2R,cis)-4-amino-1 -(2-hydroxymethyl-1,3-oxathiolan-5-yl)-pyrimidin-2-one or a pharmaceutically acceptable derivative thereof and BMS-200475 or a pharmaceutically acceptable derivative thereof.
Combinations as described above may herein after be referred to as combinations according to the invention.
As used herein “pharmaceutically acceptable derivative” includes any pharmaceutically acceptable salt, ester or salt of such ester, of lamivudine, BMS-200475 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.
The present invention further provides combinations according to the invention for use in therapy, particularly in the treatment of an HBV infection including infections resistant to nucleoside and/or non-nucleoside inhibitors of the replication of the hepatitis B virus.
According to another aspect, the present invention provides a method for the treatment of a mammal, including a human, suffering from an HBV infection comprising administration of a therapeutically effective amount of a combination according to the invention.
It will be appreciated that the compounds of the combination may be administered simultaneously, either in the same or different pharmaceutical composition, or sequentially. If there is sequential administration, the delay in administering the second active ingredient should not be such as to lose the benefit of a synergistic therapeutic effect of the combination of the active ingredients. It will also be understood that lamivudine and BMS-200475, or the pharmaceutically acceptable derivatives thereof whether presented simultaneously or sequentially, may be administered individually or in any combination thereof. Lamivudine and BMS-200475 are preferably administered simultaneously or sequentially in separate pharmaceutical formulations, most preferably simultaneously.
Preferably the combination according to the invention is administered as a single combined formulation.
The present invention also provides the use of lamivudine in the
Brown Nathaniel A.
Condreay Lynn D.
Gray Douglas Fraser
Rubin Marc
Prus Karen L.
SmithKline Beecham Corporation
LandOfFree
Antiviral combinations does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antiviral combinations, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antiviral combinations will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2962526