Crystal form of benzodiazepine derivatives

Details Crystal form of benzodiazepine derivatives Crystal form of benzodiazepine derivatives

1995-12-21

1997-06-10

Bond, Robert T.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540509, A61K 3155, C07D24324

Patent

active

056375859

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP 94/01094, filed Jul. 5, 1993 which claims the priority of Japanese Application 5/191,894, filed 5 Jul. 1993.


TECHNICAL FIELD

This invention relates to a novel form B crystal of (R)-1-[2,3-dihydro-1-(2'-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazep in-3-yl]-3-(3-tolyl)urea (to be referred to as "compound I" hereinafter).


BACKGROUND ART

The compound I represented by the following formula of chemical structure has been reported as a compound which has low affinity for benzodiazepine receptors, shows no significant actions on the central nervous system based on benzodiazepine receptors, but has strong CCK (cholecystokinin)-B receptor antagonism and/or gastrin receptor antagonism. This compound is useful for the treatment of digestive organ diseases such as gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, Zollinger-Ellison syndrome, gastrin-sensitive pancreatitis and the like and central nervous system-related diseases such as appetite controlling system disorders, pain, anxiety and the like (cf. International Publication WO 92/11246). ##STR1##
According to Example 16 of the above patent publication, crystals of compound I (to be referred to as "crystal form A" hereinafter) are obtained when compound I is crystallized from a toluene-n-hexane mixed solution or a methylene chloride-ether mixed solution. The A form crystals have following physicochemical properties.
[.alpha]sup.20.sub.D =+138.1.degree. (c=0.99, CH.sub.2 Cl.sub.2)
Melting point: 197.degree. to 199.degree. C.
Elemental analysis data (for C.sub.32 H.sub.28 N.sub.4 O.sub.3)


______________________________________ C (%) H (%) N (%) ______________________________________ calcd. 74.40 5.46 10.85 found 74.45 5.53 10.88 ______________________________________
Mass spectrometry data FAB, Pos. (m/z): 517 (M.sup.+ +1)


DISCLOSURE OF THE INVENTION

The object of the present invention is to provide the aforementioned B form crystals, as well as a process for the production of B form crystals, B form crystals obtained by said process and a pharmaceutical composition which contains B form crystals.
The inventors of the present invention have conducted extensive studies on other crystal forms of the compound I and found the novel crystal form B which can be handled markedly easily at the time of filtration for the large scale production or when they are made into pharmaceutical preparations, hence resulting in the accomplishment of the present invention. As shown in Table 1, the B form crystals of compound I according to the present invention are novel crystals whose physicochemical properties are clearly different from those of the known A form crystals.
In this connection, DSC (differential scanning calorimetry) patterns of the B form crystals of the present invention and the A form crystals are shown in FIGS. 1 and 2, their powder X-ray diffraction patterns in FIGS. 3 and 4, and their particle size distribution patterns in FIGS. 5 and 6.


TABLE 1 ______________________________________ Inventive B form crystal Form A crystal Melting point 187 to 190.degree. C. 197 to 199.degree. C. Endothermic peak at Endothermic peak at DSC around 191.degree. C. around 196.degree. C. Powder Lattice Lattice X-ray plane Relataive plane Relative diffrac- spacing intensity of spacing intensity of tion (.ANG.) diffraction (.ANG.) diffraction ______________________________________ 12.6 100 12.3 100 11.5 44 10.6 70 5.7 32 5.7 64 5.9 16 5.1 79 4.4 27 4.8 81 3.9 19 4.2 72 3.7 15 3.7 54 Form Crystalline powder or Crystalline powder crystals ______________________________________
As is evident from Table 1, DSC patterns, powder X-ray diffraction patterns and forms, the B form crystals of the present invention are novel crystals whose melting point, DSC, X-ray diffraction, form, etc. are completely different from those of the A form crystals.
While A form crystals are produced by recrystallizing compound I from an organic solvent such as a toluene-n-hexane mixe

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