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"Monohydrate Crystalline Form of 3-(5-(4-(3-Fluoropropyl)-Piperazin-1-YL)Benzimidazol-2-YL)-1-Azaazulen-2-- One, Preparation, and Pharmaceutical...

July 8, 2014



"Monohydrate Crystalline Form of 3-(5-(4-(3-Fluoropropyl)-Piperazin-1-YL)Benzimidazol-2-YL)-1-Azaazulen-2-- One, Preparation, and Pharmaceutical Composition Thereof" in Patent Application Approval Pro

By a News Reporter-Staff News Editor at Cancer Weekly -- A patent application by the inventors WEN, Yen-Fang (Miaoli County, TW); TSAI, Yuan-Jang (Hsinchu County, TW); CHEN, Wan-Ru (Nantou County, TW); HU, Tsan-Lin (Jhubei City, TW); TU, Chia-Mu (Taipei City, TW); LIU, Chih-Peng (Hsinchu City, TW), filed on August 15, 2013, was made available online on June 26, 2014, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also Industrial Technology Research Institute).

This patent application is assigned to Industrial Technology Research Institute.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Studies in modern molecular biology have discovered that a lot of kinases play an important role in the process of cell growth and cell division, and some other studies have proved that the overexpression of kinases involves cell oncogenesis, cancer cell over-proliferation, cell malignancy, and metastasis. As such, developing kinase inhibitors as effective anti-cancer medications has become an important aim in the field of anti-cancer drug research and development. Currently, the drug industry all over the world has invested greatly in order to develop novel kinase inhibitors, and therefore there are several kinase-inhibitor-based anti-cancer drugs on the market, such as Novartis's Gleevec, AastraZeneca's Iressa and Pfizer's Sutent which have been approved to be clinically effective and have high market share. The azaazulene compound, 3-(5-(4-(3-fluoropropyl)piperazin-1-yl)benzimidazol-2-yl)-1-azaazulen-2-o- ne, is a kind of small-molecule kinase inhibitor, which is capable of inhibiting a plurality of kinases. Therefore, it may be used as the anti-cancer drug and diagnostic reagent in the future.

"Different crystalline forms of a specific drug might result in variations of solubility, melting point, stability, bioavailability, and the like. Therefore, it is desirable that a novel crystalline form of the azaazulene compound with homogeneity, stability, reproducibility, and processability should be found for further development."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent application: "The disclosure is directed to a monohydrate crystalline form of 3-(5-(4-(3-fluoropropyl)piperazin-1-yl)benzimidazol-2-yl)-1-azaazulen-2-o- ne, possessing diffraction peaks of about 12.9.degree., 15.9.degree., 17.9.degree., 21.2.degree., 22.9.degree., 23.5.degree. and 24.5.degree.

"The disclosure also provides a method of preparing the monohydrate crystalline form of 3-(5-(4-(3-fluoropropyl)piperazin-1-yl)benzimidazol-2-yl)-1-azaazulen-2-o- ne, including: dissolving an amorphous form of 3-(5-(4-(3-fluoropropyl)piperazin-1-yl)benzimidazol-2-yl)-1-azaazulen-2-o- ne of Formula I in dimethyl sulfoxide to form a solution, wherein the weight ratio of the compound of Formula I to DMSO is between 1:2 and 1:100; adding the solution one drop at a time into water with stir at room temperature to form a suspension; collecting the crystalline product of the compound of Formula I from the suspension by filtration in reduced pressure; and obtaining a monohydrate crystalline form of the compound of Formula I after drying.

"The disclosure also provides a method of preparing the monohydrate crystalline form of 3-(5-(4-(3-fluoropropyl)piperazin-1-yl)benzimidazol-2-yl)-1-azaazulen-2-o- ne, including: dissolving an amorphous form of 3-(5-(4-(3-fluoropropyl)piperazin-1-yl)benzimidazol-2-yl)-1-azaazulen-2-o- ne of formula I in methanol to form a solution, wherein the weight ratio of the compound of Formula I to the methanol is between 1:50 and 1:500; obtaining a filtrate by filtrating off impurities from the solution; After evaporating the solvent, a monohydrate crystalline form of the compound of Formula I was formed.

"The disclosure further provides a pharmaceutical composition including an effective amount of the monohydrate crystalline form of 3-(5-(4-(3-fluoropropyl)piperazin-1-yl)benzimidazol-2-yl)-1-azaazulen-2-o- ne as claimed in claim 1, and at least one pharmaceutically acceptable excipient.

"A detailed description is given in the following embodiments with reference to the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

"The disclosure may be more fully understood by reading the subsequent detailed description and examples with references made to the accompanying drawings, wherein:

"FIG. 1 is a flowchart, showing the process of selecting crystalline forms in accordance with some embodiments;

"FIG. 2 is a XRPD diagram of the monohydrate form of Formula I in accordance with some embodiments;

"FIG. 3 is a DSC curve of the monohydrate form of Formula I in accordance with some embodiments;

"FIG. 4 is a thermogravimetric diagram of the monohydrate form of Formula I in accordance with some embodiments;

"FIG. 5 is an IR spectrum of the monohydrate form of Formula I in accordance with some embodiments;

"FIGS. 6a-6c are a series of X-ray diffractograms of the monohydrate form of Formula I, showing the results of reproducibility testing in accordance with some embodiments;

"FIGS. 7a-7d are a series of X-ray diffractograms of the monohydrate form of Formula I, showing the results of stability testing in accordance with some embodiments;

"FIGS. 8a-8d are a series of X-ray diffractograms of the monohydrate form of Formula I, also showing some results of stability testing in accordance with some embodiments;

"FIGS. 9a-9c are a series of X-ray diffractograms of the monohydrate form of Formula I, showing some other results of stability testing in accordance with some embodiments;

"FIGS. 10a-10b are a series of diagrams of the monohydrate form of Formula I, illustrating the PK profile in accordance with some embodiments;

"FIG. 11 is a X-ray diffractogram of the anhydrate form of Formula I in accordance with some embodiments;"

URL and more information on this patent application, see: WEN, Yen-Fang; TSAI, Yuan-Jang; CHEN, Wan-Ru; HU, Tsan-Lin; TU, Chia-Mu; LIU, Chih-Peng. Monohydrate Crystalline Form of 3-(5-(4-(3-Fluoropropyl)-Piperazin-1-YL)Benzimidazol-2-YL)-1-Azaazulen-2-- One, Preparation, and Pharmaceutical Composition Thereof. Filed August 15, 2013 and posted June 26, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=2356&p=48&f=G&l=50&d=PG01&S1=20140619.PD.&OS=PD/20140619&RS=PD/20140619

Keywords for this news article include: Cancer, Kinase, Oncology, Enzymes and Coenzymes, Industrial Technology Research Institute.

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Source: Cancer Weekly


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