Forms A and B of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazol

Details Forms A and B of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazol Forms A and B of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazol

1996-07-03

1999-12-21

Gerstl, Robert

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D27748

Patent

active

060051159

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel Forms A and B of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]]amino ]methylene]-4-bromo-benzenesulfonamide-compound known as ebrotidine (WHO).


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an infrared (IR) spectrum of ebrotidine Form A.
FIG. 2 is an X-ray powder diffractogram of
FIG. 3 is a differential scanning calorimetry (DSC) thermogram of Ebrotidine Form A.
FIG. 4 is a infrared (IR) spectrum of Ebrotidine Form B.
FIG. 5 is a differential scanning calorimetry (DSC) thermogram of Ebrotidine Form B.


DETAILED DESCRIPTION OF THE INVENTION

N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]m ethylene]-4-bromobenzenesulfonamide, ebrotidine, is a compound which is active as a histamine H.sub.2 -receptor antagonist, thus becoming useful in therapy as an acid secretion inhibitor. The preparation of this compound was disclosed in European Patent No. 0159012 and U.S. Pat. No. 4728655. The applicants have found out that ebrotidine exhibits two novel forms, A and B, having a melting point in the range of 74-78.degree. C. and 142.5-146.degree. C. respectively. The present invention provides a process for obtaining selectively Forms A and B of ebrotidine. In the aforesaid patents, ebrotidine was obtained with a melting point of 107-110.degree. C. By performing the same experimental method in those patents (Example 23 in both of them), the applicants have found out in the course of different crystallization assays that if to the methanol filtrate resulting from the reaction between [4-[[(2-aminoethyl)thio]methyl]-2-thiazolyl]guanidine and ethyl 4-bromobenzene-sulfonyl-formimidate is added isopropanol and allowed to crystallize, ebrotidine isopropanolate is obtained, which is a useful intermediate for the preparation of Forms A and B of ebrotidine. Thus, the applicants have found out that Form A of ebrotidine can be obtained in a pure state by treating ebrotidine isopropanolate with a mixture of methanol and water. Treatment of the obtained Form A of ebrotidine with methanol leads to Form B of ebrotidine in a pure state. In turn, if Form B of ebrotidine is preferred to be obtained directly from the methanol solution, which is obtained according to the experimental method in the aforesaid example, the medium may be seeded with crystals of Form B, thus constituing an extremely practical variation.
Forms A and B of ebrotidine have different properties. Form A is an amorphous solid and Form B is a crystalline solid. Therefore, Form A is useful to prepare formulations that do not require any compression, such as capsules or sachets, while Form B is useful to prepare tablets. In case that the formulations to be prepared are liquid, the use of either form will be different since the proper characteristics of the solid state are lost in solution.
Forms A and B of ebrotidine mixed with pharmaceutically acceptable carriers can be administered at daily doses ranging from 50 to 2000 mg.
The following examples illustrate the preparation of Forms A and B of ebrotidine, and pharmaceutical formulations containing them. The examples are not intended to limitate the scope of the invention as defined hereinabove or as claimed below.


EXAMPLE 1



N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino]m
ethylene]-4-bromo-benzenesulfonamide isopropanolate (Ebrotidine isopropanolate)
To a suspension of 44.04 g of [4-[[(2-aminoethyl) thio]methyl]-2-thiazolyl]guanidine dihydrochloride in 100 ml of methanol, 145 ml of 2.05 M methanol potassium hydroxide are added at a temperature below 20.degree. C. To the resultant solution, 42.3 g of ethyl 4-bromobenzene-sulfonyl-formimidate are added at room temperature and the mixture is stirred for 1 hour, cooled at 0-5.degree. C. and filtered. To the filtrate, 245 ml of isopropanol are added at room temperature, and allowed to crystallize for 24 hours to yield 57.9 g of N-[[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl]thio]ethyl]amino] methylene]-4-bromo-benzenesulfonamide isopropanolate

REFERENCES:
patent: 4728655 (1988-03-01), Foguet et al.

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