Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-01
2001-09-25
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S220000, C514S008100, C424S085200, C424S085700, C544S277000
Reexamination Certificate
active
06294540
ABSTRACT:
The present invention relates to a novel salt of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1 -methanol or a solvate thereof, pharmaceutical formulations containing such a compound and their use in medicine, specifically in the treatment of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection.
(1S, 4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (‘the compound’) and its antiviral use, especially against HIV infections, is described in European patent Specification Number 0434450 which also refers to pharmaceutically acceptable derivatives specifically salts, esters and salts of such esters of the compound, and in particular describes hydrochloride salts of the compound. In addition PCT Patent Application No. 96/06844 describes the succinate salt of the above compound.
The compound (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol is currently under clinical investigation as an anti-HIV pharmaceutical agent. There exists a need for the compound to be prepared in a form suitable for ease of isolation in large scale manufacture, and for ease of formulating into an acceptable product for administration to humans. We have found that manufacture of the free base of the compound produces an amorphous solid which traps solvents and is, therefore, unsuitable for large scale purification, or for formulation, without additional purification procedures.
Whereas the succinate salt described in PCT Patent Application No. PCT/GB95/02014 has advantages in its preparation, for example, it forms the salt easily from stoichiometric ratios of the acid and base and crystallises very easily out of solution, it is not an ideal subject for pharmaceutical formulation, specifically tableting. In particular, the succinate salt of the compound agglomerates to form a ‘lumpy’ mass which will not easily pour and is thus unsuitable for use in commercial tableting machines, such that an extra processing step of high energy milling is required to give a uniform particle size. An additional complication attendent upon formulation of the succinate salt of the compound is that it can exist in several crystal forms, each form having slightly different physical properties. The preparation of the succinate salt of the compound requires close attention to avoid the preparation of undesired forms, which if formed require reworking to the desired form.
We have found that the advantages of the hemisulfate salt of the compound over the disclosed hydrochloride salts and succinate salt renders the hemisulfate salt particularly suitable and advantageous to prepare on a large scale, and in particular for use in the preparation of pharmaceutical formulations. Specifically the hemisulfate salt forms a free flowing powder, which lacks any undue tendency to agglomerate, and which is easily poured and compacted, and thus ideal for use in commercial tableting machines without the need for milling. The salt is believed to exist as a single morphic and crystalline form. The salt does not readily hydrate or solvate (e.g. on storage). The salt filters and dries readily, thereby assisting ease of preparation. A further advantage is the higher aqueous solubility of the hemisulfate as compared to the succinate, which makes the hemisulfate particularly suitable for the preparation of liquid formulations.
We have also found that where the hemisulfate salt is prepared by a ‘salt exchange’ process, that is to say by conversion of a precursor salt of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, particularly the glutarate or succinate salt, an enrichment in optical purity over that of the precursor salt is achievable. Thus, the need for any further preparative or purification steps to enhance the optical purity of the hemisulfate salt product may be reduced or eliminated.
According to the first aspect of the invention there is provided the hemisulfate salt of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol or a solvate thereof, including a hydrate thereof, hereinafter referred to as the compound according to the invention.
For the avoidance of doubt, as used herein, the hemisulfate salt of (1S,4R)-cis4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol means the salt formed between (1S,4R)-cis4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol and sulfuric acid in a stoichiometric ratio of 2:1.
Further aspects of the invention include:
a) The compound of the invention for use in medicine, particularly in the treatment of viral infections, specifically an HIV or an HBV infection.
b) A method for the treatment of a viral infection particularly an HIV or an HBV infection in a human which comprises administering to said human an effective amount of the compound according to the invention.
c) Use of a compound according to the invention in the manufacture of a medicament for the treatment of a viral infection particularly an HIV or an HBV infection.
The compound of the invention is particularly useful for the treatment of HIV infections.
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.
Examples of clinical conditions caused by HIV infections which may be treated in accordance with the invention include Acquired Immune Deficiency Syndrome (AIDS) or symptoms that frequently precede AIDS, or related clinical conditions such as AIDS-related complex (ARC), progressive generalised lymphadenopathy (PGL), Kaposis sarcoma, thrombocytopenic purpura, AIDS related neurological conditions, such as multiple sclerosis or tropical paraparesis and also anti-HIV antibody-positive and HIV-positive conditions including AIDS asymptomatic patients.
The compounds of the invention may be administered alone or in combination with other therapeutic agents suitable in the treatment of HIV infections, such as Nucleoside Reverse Transciptase Inhibitors (NRTIs) for example zidovudine, zalcitabine, lamivudine, didanosine, stavudine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine, adefovir and (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, lovaride, non-NRTIs for example nevirapine, delavuridine, &agr;-APA, HBY-1293 and efavirenz HIV protease inhibitors for example saquinavir, indinavir, nelfinavir, ritonavir and VX-478, other anti-HIV agents for example soluble CD4, immune modulators for example interleukin II, erythyropoetin, tucaresol, and interferons for example &agr;-interferon. In addition the compound of the invention may be administered in combination with other therapeutic agents suitable in the treatment of HBV infections for example lamivudine, (2R,5S)-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine, immune modulators, and interferons as described above. Such combinations may be administered together or sequentially providing that any duration between the administration of each therapeutic agent does not diminish their additive effect.
While it is possible for the compound of the invention to be administered as the raw chemical, it is preferable and advantageous to present the compound of the invention as a pharmaceutical formulation, and represents a further feature of the invention. The pharmaceutical formulation comprises the compound of the invention together with one or more acceptable carrier(s) therefor and optionally other therapeutic agents. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipients thereof.
The compounds according to the invention may be administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including transdermal, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramusc
Brodie Alastair Couper
Jones Martin Francis
Seager John Frederick
Wallis Christopher John
Berch Mark L.
Fix Amy H.
Glaxo Wellcome Inc.
LandOfFree
Carbocyclic nucleoside hemisulfate and its use in treating... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Carbocyclic nucleoside hemisulfate and its use in treating..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Carbocyclic nucleoside hemisulfate and its use in treating... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2455959