Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-07
2002-02-26
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S262000
Reexamination Certificate
active
06350751
ABSTRACT:
The present invention relates to pharmaceutically acceptable anhydrous paratoluene sulphonic acid salts of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one having the formula (I):
In addition the present invention relates to pharmaceutical compositions containing anhydrous para-toluene sulphonic acid salts of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [14,3-d]pyrimidin-7-one, to processes for the preparation of (I) and uses of (I) in medicine.
3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one has been disclosed (as Example 4) and claimed in published international application WO99/54333, international publication date 28
th
Oct. 1999. As detailed in WO99/54333 compounds of this type are especially useful in the treatment of inter alia male erectile dysfunction. WO99/54333 in its entirety and in particular the description of general processes for the preparation of 3-Ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one is incorporated herein by reference.
For successful utility within the pharmaceutical industry it is critical that the properties of an active material are either known or can be reasonably predicted throughout the necessary processes during both its manufacture and pharmaceutical processing as well as during its shipping, storage and eventual therapeutic use. In some cases compounds can exhibit desirable medicinal properties which cannot be translated directly into a suitable pharmaceutical composition because the active compound itself has unsatisfactory physical properties such as for example poor processing stability or low solubility.
Thus the challenge facing the pharmaceutical chemist in the search for new and improved drug compounds is not only the manufacture, isolation and characterisation of new drug compounds as well as the determination of their particular medicinal properties but also the provision of suitable pharmaceutically acceptable salts of such compounds.
The problem addressed by the present invention is the provision of a pharmaceutically acceptable salt of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one which can be efficiently processed to provide stable and effective formulations of the drug, an in particular solid and compressible dosage forms of the drug. Such dosage forms include conventional-release oral tablets, controlled-release (matrix) tablets, fast-dissolving formulations, sub-lingual tablets, buccal tablets, oral powder, soft gel and granule filled capsules, powders for reconstituted suspensions, conventional and controlled-release multi-particulate systems filled into capsules or compressed into tablets, lozenges, dragees, suppositories, pessaries, solid implants, lyophile plugs, nanoparticles and microparticles and powder for suspension and nasal delivery, and dry inhalation systems. Additional suitable dosage forms and routes of potential administration are discussed in detail in the formulation section herein.
Important criteria to be satisfied are, inter alia, that the pharmaceutically acceptable salt should be crystalline, non-hygroscopic, of suitable melting point (preferably a melting point of at least about 100°, more preferably greater than about 150° C.), possess chemical stability across a range of temperature and humidity conditions, have acceptable solubility, have an acceptable (preferably a rapid and complete) dissolution profile, have acceptable mechanical properties such as for example exhibit good compressibility without exhibiting polymorphism.
In the search for a pharmaceutically acceptable salt of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one several potential salts have been investigated. However of these, only one salt, the para-toluene sulphonic acid salt was found to fulfil the necessary criteria for a pharmaceutically acceptable salt.
Hydrated salts can provide particular issues in processing, especially during for example the milling and/or drying stages. It has been disclosed that the tendency of organic molecules to hydrate can be predicted from their molecular structure, “Hydration in organic crystals: prediction from molecular structure”, Desiraju, Gautam R. Sch. Chem., Univ. Hyderabad, Hyderabad, 500 134, India. J. Chem. Soc., Chem. Commun. (1991), Issue 6, 426-8. CODEN: JCCCAT; ISSN: 0022-4936. (EN) CAN 114:237859. Using such a predictive method it would be predicted that the tosylate salt of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one would indeed be highly likely to hydrate. Several of the salts investigated form hydrates. Furthermore, corresponding experiments on the structurally similar besylate salt of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one have determined that in addition to at least 5 anhydrous polymorphs a hydrated polymorph of the besylate salt is indeed formed.
The problem of selecting a pharmaceutically acceptable salt form for 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one has been solved by the surprising finding that the anhydrous para-toluene sulphonate salt of formula (I) meets the above criteria for a pharmaceutically acceptable salt. Even more surprising is the finding that the para-toluenesulphonate salt of the present invention does not appear to form crystalline hydrates under a range of conditions. This is particularly surprising as initial predictions would indicate that the toslyate salt would form a hydrate, especially given the fact that the besylate salt and other salts investigated hydrated as predicted. Furthermore the anhydrous para-toluene sulphonate salt of the present invention exhibits good physical dosage form stability, demonstrates stability during drying and milling processes and has a desirable drug substance stability profile.
An additional advantage of the anhydrous para-toluenesulphonate salt of the present invention versus the corresponding besylate salt in particular is that it can be prepared in improved yield (98.5% versus 85%). A further additional advantage of the particular salt of the present invention is that ease of processing of the para toluene sulphonic acid counter ion versus for example the benzene sulphonic acid (for the besylate salt).
Thus it has now been established that because of its uniquely favourable combination of pharmaceutical properties, the anhydrous para-toluene sulphonate salt of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one is especially suitable for pharmaceutical formulation and is the preferred form for administration to humans.
The term anhydrous salt as defined herein means that there is no bound water within the crystal lattice structure i.e. the compound cannot form a crystalline hydrate. For the avoidance of doubt it is to be understood that surface water i.e. water found upon the surface of a crystal is not bound water.
The preparation of the anhydrous para-toluene sulphonate salt of 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy) pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo [
Hughes Michael L.
Storey Richard A
Benson Gregg C.
Kifle Bruck
McKenzie Thomas
Musser Arlene K.
Pfizer Inc.
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