Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-29
2003-11-11
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S143000
Reexamination Certificate
active
06645979
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to a process for the preparation of (7-(3-carboxyphenyl)-4-chloroisoquinolin-1-yl)guanidine (I), intermediates thereto and new forms and formulations thereof suitable for pharmaceutical use.
International Patent Application publication no. WO 99/20608, which is herein incorporated by reference in its entirety, discloses certain isoquinolinylguanidine compounds as antagonists of urinary-type plasminogen activator (“uPA”, also known as urokinase, International Union of Biochemistry classification number EC.3.4.21.31), including the hydrochloride salt of (7-(3-carboxyphenyl)-4-chloroisoquinolin-1-yl)guanidine (I) (Example 55 therein). Compound (I) is a potent uPA antagonist and is thus likely to be useful in the treatment of conditions mediated by uPA. Such treatments are mentioned in WO 99/20608. For a number of such treatments, administration of an aqueous topical formulation which can be sterilised is desirable.
It is desirable, for the treatment of some of the conditions mediated by uPA, to formulate compound (I) as a suspension drug product. As such stability to autoclaving as the preferred method of sterilisation is important. Treatment of some of the conditions in certain ways requires stability in an aqueous environment. Also important is the shelf-life of the formulation, with a target stability of ca. 2 years at ambient temperature. The stability of the bulk form is also important as any changes in the form of the active substance may compromise the product's clinical and/or safety performance.
The hydrochloride salt of (I) has certain properties which make it particularly unsuitable for pharmaceutical formulation in a base suitable for topical administration, e.g. to a wound, such as poor physical stability at relevant pH (>4), poor crystallinity, etc. The scale-up of the process to make the hydrochloride salt of (I) disclosed in WO 99/20608 has disadvantages. In WO 99/20608, the hydrochloride salt of (I) is made from the corresponding nitrile by hydrolysis with hydrochloric acid. Acid-catalysed hydrolysis of the nitrile has been found to give rise to undesirable levels of certain side-reactions, such us under-hydrolysis of the nitrile moiety to give the corresponding carbamoyl compound, and over-hydrolysis at the guanidine moiety to give the corresponding amine. The route to the hydrochloride salt of (I) described in WO 99/20608 has a number of other disadvantages which make it undesirable for scale-up, such as handling and purification difficulties of certain intermediates. A number of alternative routes, salts and solvates were explored with a view to solving the above-mentioned problems.
SUMMARY OF THE INVENTION
The problems outlined above have been solved by the provision of a zwitterion monohydrate of (I), i.e. (IA) in the scheme below, and processes and intermediates thereto. Other aspects of the invention include formulations of the zwitterion monohydrate (IA), and uses thereof.
The invention further provides methods for the production of substances of the invention, which are described below and in the Examples. The skilled person will appreciate that the substances of the invention could be made by methods other than those herein described, by adaptation of the methods herein described in the sections below and/or adaptation thereof, and of methods known in the art.
It will be appreciated that tautomers and geometric isomers of the compounds disclosed herein are included within the scope of this invention. For example the compound referred to as the “zwitterion monohydrate” (IA) is herein also referred to (e.g. in the scheme) as the guanidine/acid hydrate, i.e. having N═C(NH
2
)
2
/CO
2
H groups. In aqueous solution at neutral or near-neutral pH, it is believed to exist mainly in the zwitterionic form, i.e. with the guanidinium moiety and a carboxylate moiety. The two tautomeric forms of the guanidine moiety are N═C(NH
2
)
2
and NHC(═NH)(NH
2
).
REFERENCES:
patent: 6248738 (2001-06-01), Dickinson
patent: 0629631 (1994-12-01), None
patent: 99/20608 (1999-04-01), None
Bruckner Anne
Butters Michael
Fish Paul Vincent
Fitzgerald Michael Paul
Macrae Julie Ann
Looney Adrian G.
Pfizer Inc.
Purchase, Jr. Claude F.
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