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Crystalline form of pyrimidio[6,1-A]isoquinolin-4-one compound

A technology of isoquinoline and pyrimidine, which is applied in the field of crystallization of pyrimido[6,1-A]isoquinolin-4-one compounds, and can solve problems such as narrow range

Active Publication Date: 2013-09-18
VERONA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Certain drugs exhibit a narrow range between therapeutic and lethal concentrations

Method used

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  • Crystalline form of pyrimidio[6,1-A]isoquinolin-4-one compound
  • Crystalline form of pyrimidio[6,1-A]isoquinolin-4-one compound
  • Crystalline form of pyrimidio[6,1-A]isoquinolin-4-one compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0125] At 70°C, about 50 mg of N-{2-[(2E)-2-(trimethylphenylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro- 2H-Pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea (RPL554) was dissolved in 0.5 ml of DMF. The clear yellow solution was cooled very slowly to about 30° C. over 4 days under a nitrogen atmosphere. A crystalline nature of the starting batch of material was observed in solution (ca. 0.4 ml). This step was repeated 2 times and material suitable for single crystal analysis was delivered in a solution volume of approximately 0.2 ml. Samples were analyzed unchanged in the mother liquor.

[0126] Single crystal data are at low temperature (123K) and at different wavelengths Measurement. In order to provide a graph that gives a direct comparison, manual adjustment of the wavelength values ​​is required. After various adjustments, the obtained figure 1 and shows a slit overlay between the measured data for RPL554070638 via XRPD (top) and the simulated XRPD derived from the singl...

Embodiment 2

[0132] Example 2. Starting materials

[0133] An ex-GMP stock of 9.0 g of RPL554 (070638-9) was taken and tested by XRPD ( image 3 and Table 1) and DSC ( Figure 4 ) analysis to serve as existing reference data.

[0134] Table 1

[0135]

[0136]

[0137] Other studies such as proton NMR and HPLC at this junction were not critical to the start of the protocol and the results of which had been previously collected. Solubility studies of this material using a general range of organic materials are likewise not unnecessary, as previous studies have provided strong indications of material behavior. The initiation of the study was prioritized for the presence of other forms of RPL554.

[0138] As is known, in addition to thermal decomposition, crystallization of this material begins to dissolve at 246°C for the single crystal endotherm, and no subsequent crystallization is found or transferred. An initial weight loss of about 4.2% was observed by TGA, corresponding to ...

Embodiment 3

[0140] Example 3. Antisolvent Addition

[0141] Antisolvent addition is a known method for obtaining amorphous materials, new polymorphs and mixed phases. Note that a stock solution of RPL554 in DMSO was made. DMSO was chosen due to the reasonable solubility of the material in this solvent, which is widely incompatible.

[0142] Experimental conditions (CG1099):

[0143] 30 mg of RPL554 was dissolved in hot DMSO (2 ml stock solution) and 0.15 ml of this solution was added in portions at room temperature to 12 cold test tubes containing each solvent (1.0 ml) under vigorous stirring. In most cases, immediate precipitation was observed. Isolation was performed by filtration and vacuum dried at 40°C. The results are detailed in Table 2 below:

[0144] Table 2. Solvent list and DMSO-based anti-solvent addition details

[0145] solvent initial result isolated solid Cumene sol n → Precipitation F1 wxya precipitation F1 Dioxane sol n Dry ...

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Abstract

The current invention is directed towards a polymorph of N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea, in the form of a crystalline solid consisting of greater than 99% by weight of N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinoIin-3(4H)-yl]ethyl}urea, at least 95% in the polymorphic form of a thermodynamically stable polymorph (I) of N-{2-[(2E)-2-(mesitylimino)-9,10-dimetlioxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea, wherein said polymorph is determined by single crystal X-ray structural analysis and X-ray powder diffraction pattern.

Description

Background technique [0001] The polymorphic representation of a drug is of key importance in pharmacy and pharmacology. Polymorphism is defined as crystallization of the same molecule with different physical properties resulting from the order of the molecules in the crystal lattice. Differences in physical properties exhibited by polymorphs affect pharmaceutical parameters such as storage stability, compressibility and density (important for formulation and product manufacture) and dissolution rate (for determining bio-availability ) is an important factor). Differences in stability may result from changes in chemical reactivity (such as differential oxidation, such that a dosage form decolorizes more rapidly when it includes one polymorph than when it includes another polymorph) or mechanical changes (e.g. tablet breakage on storage due to conversion of a kinetically preferred polymorph to a thermokinetically more stable polymorph) or both (e.g. a tablet of a polymorph in ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/519A61P11/00
CPCA61K31/519C07D471/04A61P11/00A61P11/02A61P11/06A61P17/00A61P17/06A61P27/02A61P27/14A61P27/16A61P29/00A61P37/00A61P37/06A61P37/08A61P9/10C07B2200/07C07B2200/13A61K45/06
Inventor M·J·A·沃克B·M·C·普克维耶J·S·诺森P·费尔南德斯
Owner VERONA PHARMA
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