Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2001-08-14
2003-02-25
Bernhardt, Emily (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06525195
ABSTRACT:
FIELD OF THE ART
This invention relates to a process for the preparation of the polymorph A of doxazosin mesylate. This polymorph is crystalline and is named Form A.
PRIOR ART REFERENCE
Doxazosin is the generic name (INN) of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]-piperazine, of formula
which is used as described in The Merck Index, article 3422 of the XI Edition (1989) and article 3489 of the XII Edition (1996), as the equimolar salt thereof with methanesulfonic acid (monomethanesulfate or monomesylate), as a antihypertensive drug marketed under the following brand names, among others: Aldafil®, Cardura®, Carduran®, Diblocin®, Supressin®, etc.
U.S. Pat. No. 4,188,390, of which ES-A474 805 is the equivalent, describes both doxazosin and, generically, the pharmaceutical salts thereof and although doxazosin mesylate is not explicitly described in these documents, it is indicated therein that the pharmaceutical salts may include the addition salts with sulfonic acids.
In the article published by Xu Liying et al., in
Zongguo Yaowu Huaxue Zazhi,
1995, Vol. 5, part 4, pages 266-270, summarized in Chemical Abstracts, ref. CA 124:325182, there is described for the first time the crystalline polymorphism proper to doxazosin mesylate. Three polymorphs, designated A, B and C are identified in the above article, with the use of differential thermal analysis, infra red spectroscopy and X-ray diffraction techniques, although extremely superficial instructions are given for the preparation thereof, limited to stating that the form A is prepared by recrystallization of the commercial product in ethanol. It should be pointed out that the above article speaks of doxazosin, without specifying that it is a question of the mesylate thereof, although it is clearly explained therein that the “doxazosin” used is the commercial product used for the treatment of high blood pressure, which allows it to be deduced without any doubt that the study described in the article relates to doxazosin mesylate, which is the only doxazosin salt which has been marketed as a pharmaceutical up to date.
Subsequently, M. Grcman et al., in
Farm. Vestn
1997, 48:292-293 also described up to five different crystalline polymorphs of doxazosin mesylate, although with much less precision and data than in the Xu Liying et al. article, in spite of which it seems quite probable that the polymorph called A in the Grcman article is the same as the polymorph A described in the Xu Liying article. The Grcman article offers still fewer details on the processes for preparing the different crystalline polymorphs of doxazosin mesylate, since the authors go no further than stating that all are prepared by crystallization.
European patent applications EP-A-0 848 001, EP-A-0 849 264 and EP-A-0 849 265 disclose three different crystalline polymorphs of doxazosin mesylate, as well as processes for the preparation thereof, but none of them coincides with the polymorph A described by Xu Liying et al.
Finally, European patent application EP-A-0 849 266 discloses a crystalline polymorph of doxazosin mesylate, which is designated Form III in the said application, and which is characterized mainly by the 2&thgr; diffraction angles in the X-ray powder diffractogram. If the infra red spectrum, the 2&thgr; diffraction angles and the complete X-ray powder diffractogram described in EP-A-0 849 266 for the so-called Form III of doxazosin mesylate are compared with the same data given in the Xu Liying article for polymorph A, the obvious conclusion is reached that the so-called Form III is in reality the Form A of doxazosin mesylate previously described by Xu Liying et al.
The said EP-A-0 849 266 also discloses a process for the preparation of the said Form III of doxazosin mesylate consisting, in the essential aspects thereof, of the following steps:
(a) starting out from doxazosin base and reacting it with acetic acid, to form the acetate salt dissolved in an organic solvent as intermediate,
(b) reacting the thus obtained solution with methanesulfonic acid,
(c) crystallizing the product at reflux temperature of the solvent and removing the adduct formed by filtration,
(d) adding the moist adduct to a low molecular weight alcohol and boiling under reflux for a certain time, and
(e) cooling the thus obtained solution and collecting the product crystals by filtration.
As will be observed, it is a complex, time-consuming process which requires the prior formation of a salt other than the doxazosin mesylate, i.e., the acetate, to displace it subsequently with the methanesulfonic acid.
There remains, therefore, the need to have simpler, cheaper alternative processes allowing the industrial preparation of Form A of doxazosin mesylate.
OBJECT OF THE INVENTION
The object of the present invention is a process for the preparation of Form A of doxazosin mesylate, the industrial application of which is easy and cheap, starting out from easily industrially accessible intermediates and without the need for preparing intermediate salts other than the mesylate.
REFERENCES:
patent: 4188390 (1980-02-01), Campbell
patent: 6130218 (2000-10-01), Mörsdor et al.
patent: 6133269 (2000-10-01), Mörsdor et al.
patent: 6140334 (2000-10-01), Mörsdor et al.
patent: 849266 (1996-12-01), None
patent: 0 848 001 (1998-06-01), None
patent: WO 96/39406 (1996-12-01), None
patent: WO 99/35143 (1999-07-01), None
Chem Abstract Plus 1997-724496, M. Groman, et al., in “Farm. Vestn” 1997, 48:292-293.
Chem Abstract 124-325182, Xu Liying, et al., in “Zongguo Yaowu Huaxue Zazhi”, 1995, vol. 5, part 4, pp. 266-270.
Aguilar Carmen Arnalot I
Bosch I Lladó Jordi
Miguel Ma Carmen Onrubia
Bernhardt Emily
Medichem S.A.
Scully Scott Murphy & Presser
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