Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-08-14
2000-03-07
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540225, A61K 31545, C07D50136
Patent
active
060340762
DESCRIPTION:
BRIEF SUMMARY
This application is a filing under 35 U.S.C. 371 of International Application No. PCT/GB96/00373.
The present invention relates to a novel compound, to a process for its manufacture and to its use in the treatment and/or prevention of bacterial infections in humans and animals caused by a wide range of organisms.
EP-A-0416814 (Beecham Group pic) describes certain cephalosporin compounds which are described to be useful in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.
One particular compound mentioned therein, i.e., [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1-(me thylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylate (i.e., example 2) has now been prepared as crystalline carboxylic acid chloride hydrochloride mono-, di- or tri-hydrate.
This particular form of the compound has unexpectedly superior stability properties over the freeze dried material of example 2 in EP-A-0416814.
EP-A-0638573 discloses crystalline hydrates of the cephalosporin 7[(Z)-2-(2-aminothiazole-4-yl)-2-(2-carboxylprop-2-oxyimino)acetamido]-3-( 5-methyl- 1,4,6-triaminopyrimidinium-2-yl)thiomethyl-3-cephem-4-carboxylate.
U.S. Pat. No. 4146710 teaches a crystalline cephalosporin derivative which is a dihydrochloride (or dihydrobromide) which may be hydrated up to the hexahydrate.
Accordingly the present invention provides [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1-(me thylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride as a mono-, di- or tri-hydrate.
Preferably the present invention provides [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1-(me thylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride as a tri-hydrate.
The present invention further provides a process for the preparation of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1-(me thylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride as a mono, di or tri-hydrate said process comprising treating an aqueous solution of [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1-(me thylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylate with hydrogen chloride.
Suitably [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino) acetamido]-3-[1-(methylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxyl ate is dissolved in water and treated with aqueous hydrochloric acid for example a 2 molar solution thereof. The resulting solution is suitably diluted with a water soluble organic solvent to precipitate the product; for example tetrahydrofuran. The resulting mixture may then be cooled for example overnight to 0 to 5.degree. C., suitably at around 4.degree. C. The resulting crystalline product may then be isolated for example by filtration, and dried for example in vacuo at ambient temperature.
It should be appreciated that more rigorous drying conditions will remove the bound molecules of water of hydration. In this way drying conditions may be conventionally controlled to give [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)(methoxyimino)acetamido]-3-[1-(met hylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride as the mono, di or tri-hydrates.
[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1-(met hylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxy may be prepared according to the procedures mentioned in or outlined by EP-A-416 814.
It should be appreciated that [6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-[1-(me thylamino)pyridinium-4-thiomethyl]-ceph-3-em-4-carboxylic acid chloride hydrochloride mono, di or tri-hydrate is an active medicinal product and may be formulated into unit dose forms suitable for administration to humans or animals in need of treatment.
[6R,7R]-7-[2-(2-Amino-4-thiazolyl)-2-(Z)-(methoxyimino)acetamido]-3-(methyl amino)pyridinium-4-thiomethyl]-ceph-3-em-4-acid chloride hydrochloride mono, di or tri-hydrate is especially suitable for the
REFERENCES:
patent: 4035361 (1977-07-01), Wheeler
patent: 4146710 (1979-03-01), Naito
patent: 4258050 (1981-03-01), Harbridge
patent: 4888344 (1989-12-01), Sunagawa
Berch Mark L.
Ginsburg Paul H.
Ling Lorraine B.
Pfizer Inc.
Richardson Peter C.
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