Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-11-30
2003-03-18
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S234000
Reexamination Certificate
active
06534505
ABSTRACT:
The present invention relates to polymorphs of a substituted triazolo-phthalazine derivative, to their use in therapy, to compositions containing them and to processes for their manufacture. The present invention also relates to a pamoate formulation of the derivative and to new uses of pamoate ions.
BACKGROUND OF THE INVENTION
We have now discovered that it is possible to obtain medicaments which have cognition enhancing effects which may be employed with less risk of proconvulsant effects previously described with benzodiazepine receptor partial or full inverse agonists. Inverse agonists which are inverse agonists for the &agr;5 receptor and are relatively free of activity at &agr;1, &agr;2 and &agr;3 receptor binding sites are preferred.
European Patent Applications 0085840 and 0134946 describe related series of 1,2,4-triazolo[3,4-a]phthalazine derivatives which are stated to possess antianxiety activity. However, there is no disclosure nor any suggestion in either of these publications of the compounds of the present invention, nor that the compounds disclosed in the Applications have any cognition enhancing properties.
BRIEF SUMMARY OF THE INVENTION
The present invention provides 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine in the form of a dihydrate.
There is also provided 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine in the dehydrated form of the dihydrate.
There is further provided 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine in the form of a pentahydrate.
These polymorphs are new and may be advantageous, for example, for ease of processing, handling or dosing of the compound. They may, in particular, have improved chemical properties such as solubility, stability or rate of solution. In particular, they may be particularly suitable for manufacture of dosage forms. Examples of dosage forms are mentioned later.
International Patent Application No. PCT/GB98/01307 discloses 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3, 4-a]phthalazine which compound is useful for enhancing cognition. There is no specific disclosure or discussion of the crystal forms of this compound.
The dihydrate may be prepared by mixing a saturating amount of 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo [3,4-a]phthalazine with 5% aqueous di-sodium pamoate for several days. The dihydrate can be isolated by filtering the product.
The dihydrate may alternatively be produced by mixing a saturating amount of 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine with USP water. The solids obtained from filtering the product are partially in dihydrate form.
A further method of producing the dihydrate is to mill (i.e. nanonise) the anhydrous form of 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine in accordance with details disclosed in U.S. Pat. No. 5,145,684.
Another method for producing the dihydrate is to dissolve the anhydrous form in glacial acetic acid and water in about a 39:9 mixture, followed by hot filtration, the addition of a large amount of water of about four times the volume of the mixture, and ageing at room temperature for from 2 to 40 hours before filtration of the final product.
The dehydrate may be prepared by gentle heating of the dihydrate or pentahydrate in a vacuum oven from 30° C. to 100° C. for about 20.5 hours generally under dry nitrogen purge.
The pentahydrate may be produced by adding excess solid 3-(5-methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl)methyloxy-1,2,4-triazolo[3,4-a]phthalazine to water or organic solvents with sufficient water present and generally stirring for several hours, such as about 12 hours, generally at room temperature. The pentahydrate can be isolated by filtering the product. Examples of water/organic solvents are ethyl acetate (saturated with water), acetonitrile (1/1 with water), acetic acid (20/80 with water), acetone (20/80 with water) and tetrahydrofuran (1/1 with water). The pentahydrate is preferably stored at humidities above 93%.
BRIEF DESCRIPTION OF THE FIGURES
REFERENCES:
patent: 4007167 (1977-02-01), Martin et al.
patent: 4237120 (1980-12-01), Ingle
patent: 4291026 (1981-09-01), Tobkes et al.
patent: 0 085 840 (1983-08-01), None
patent: 0 134 946 (1985-03-01), None
patent: 1059508 (1967-02-01), None
patent: WO 96/25948 (1996-08-01), None
patent: WO 98/50385 (1998-11-01), None
D. Cai, et al., Tetrahedron Lett., 37: 2537-2540 (1996).
W. Holzer and K. Ruso, J. Heterocyclic Chem., 29: 1203-1207 (1992).
R.G.M. Morris, Learning and Motivation, 12: 239-260 (1981).
Kaufman Michael J.
Rush Daniel J.
Lee Shu M.
McKenzie Thomas C
Merck & Co. , Inc.
Shah Mukund J.
Thies J. Eric
LandOfFree
Therapeutic polymorphs of a GABA-A alpha-5 inverse agonist... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Therapeutic polymorphs of a GABA-A alpha-5 inverse agonist..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Therapeutic polymorphs of a GABA-A alpha-5 inverse agonist... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3044114