Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-01
2004-01-27
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S284000
Reexamination Certificate
active
06683085
ABSTRACT:
NEW SALT FORM AND POLYMORPHS
The present invention relates to a novel salt useful in therapy. More specifically the present invention relates to 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate, to processes for its preparation, to its uses, and to compositions containing it. The present invention also relates to novel non-hydrated polymorphs of the free base.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline has the formula
and is disclosed in WO 98/30560 (see Example 19) as being useful in the treatment of benign prostatic hyperplasia. The application refers in general terms to pharmaceutically acceptable salts and mentions the hydrochloride, hydrobromide and phosphate salts.
Unfortunately, 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline displays some disadvantageous physical properties. It is now known to occur in a number of different forms. In some cases, its aqueous solubility is rather low and it is difficult to prepare reproducibly in the same form, sometimes being obtained in a hydrated form. In addition, it has been found that some forms of the free base are rather hygroscopic. These properties are disadvantageous for the development of a drug substance because, in particular, a consistent grade of material must be reproducibly manufactured in order to satisfy regulatory requirements.
There is now provided the mesylate salt of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline having the formula
This substance has a number of unexpected advantages over the free base and it has surprisingly been found to have a unique combination of properties which make it ideal for development as a drug substance.
Those skilled in the art will appreciate that “mesylate” is an alternative term for “methanesulfonate”.
The mesylate salt has a high melting point, and is a crystalline solid which does not display any hydrated or solvated forms. It is isomorphic, i.e. it exists in a single polymorphic form, and exhibits good stability over a wide range of conditions, e.g. high light intensity. It has acceptable solubility and dissolution characteristics, and can be economically prepared and processed to provide suitable solid dosage forms of the drug. Its hygroscopicity is substantially lower than the free base (tested as its 198° C. melting point polymorph) over a wide range of relative humidity. The mesylate salt is mono-morphic and does not form hydrates; both of these features represent advantageous properties of the mesylate salt in particular.
Tables 1 to 3 below indicate the physical properties of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate and some free base forms.
TABLE 1
Physical properties of the mesylate salt
Hygroscopicity %
Form
Melting Point (° C.)
Crystallinity
(w/w) at 90% RH
Mesylate Salt
279
Crystalline
1.1
TABLE 2
Solubility of the mesylate salt and free base forms (micrograms/ml)
Hydrated form
Free base (mpt
of free
Solvent
198° C.)
base
Mesylate salt
Water at 22° C.
420
12
880
0.9% sodium chloride at
36
4
120
22° C.
TABLE 3
Hygroscopity of the mesylate salt and free base forms
Moisture sorption (% w/w)
Form
at 30° C. and 45% RH
Free base (mpt 198° C.)
1.39
Hydrated form of free base
11.24
Mesylate salt (mpt 279° C.)
0.56
The present invention also includes the substantially pure anhydrous crystalline forms of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (the free base). These anhydrous polymorphs are designated Form A, Form B, Form C, and Form E in Table 4 below. Form D, which is presented for comparison, is the hydrated form and exists as a dihydrate.
The term “substantially pure” used above means that a sample of the relevant anhydrous crystalline form contains more than 90% of a single polymorphic form, preferably more than 99% of a single polymorphic form.
TABLE 4
Polymorphic forms of the free base
Hygroscopity
Form
Melting point (° C.)
Crystallinity
% (w/w) at 90% RH
Form A
198
crystalline
2.2
Form B
218
crystalline
0.27
Form C
147
crystalline
—
Form E
229
crystalline
0.045
Form D
None
crystalline
12.8
On dehydration, the hydrated form (Form D) becomes amorphous.
The anhydrous polymorphic forms of the invention are also significantly less hygroscopic than the hydrated free base form. Of these, Forms B and E are preferred on account of their high melting points and low hygroscopicity. Form E is most preferred.
It is now believed that the solid form of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline produced originally following the procedure of WO 98/30560 (see Example 19) was a mixture of Forms B and E, probably in the ratio 1:1 (based on a differential scanning calorimetry experiment showing sharp endotherms at 220 and 227° C.). Following the creation of the most stable Form E in pure form, it is likely that this form will be produced predominantly in the future when repeating the above preparation of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline.
Also included within the scope of the present invention are radiolabelled derivatives, other isotopic forms and tautomers of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in one of its free base polymorphic forms or as the mesylate salt possesses pharmacological activity in animals. It may be used in the treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatic hyperplasia. The latter condition is of greatest interest. Thus, according to another aspect of the invention, there is provided a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically effective amount of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt to a patient suffering from such a disorder.
According to a further aspect of the invention, there is provided 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)-quinazoline in the form of the anhydrous free base or the mesylate salt for use as a pharmaceutical; and for use in the treatment of benign prostatic hyperplasia.
According to a further aspect of the invention, there is provided the use of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)-quinazoline in the form of the anhydrous free base or the mesylate salt in the manufacture of a medicament for the treatment of benign prostatic hyperplasia.
4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
Hence, according to a further aspect of the invention, there is provided a pharmaceutical formulation including 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The formulation will preferably contain less than 50% by weight of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in a free base polymorphic form or as the mesylate salt.
For
Basford Patricia Ann
Hodgson Paul Blaise
Benson Gregg C.
Ford John M.
Goddard Carl J.
Pfizer Inc.
Richardson Peter C.
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