Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-07
1998-11-10
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546261, C07D40102, A61K 3144
Patent
active
058344926
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US95/08519, filed Jul. 10, 1995.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the synthesis, isolation and novel pharmaceutical formulation of a chemically distinct and pharmaceutically unique class of compounds, namely pyridoxal isonicotinoyl hydrazone polyprotic salts, that have heretofore been unattainable due to the complex chemical characteristics of the free base precursor, pyridoxal isonicotinoyl hydrazone (PIH). These compounds are generally crystalline and generally free of associated water. The solubility and stability properties of these salts makes them particularly suitable as orally administered chelators that can complex and remove pharmacologically significant levels of iron at dosages that are pharmaceutically meaningful.
2. Discussion of the Prior Art
The synthesis of pyridoxal isonicotinoyl hydrazone (PIH; 3-hydroxy-5-hydroxy- methyl-2-methyl-4-pyridinylcarboxaldehyde 4' pyridinecarboxylic acid hydrazone) was first reported by Sah in 1953 {P. P. T. Sah, J. Am. Chem. Soc. 76:300 (1953)}. The very low water solubility of PIH as a pale yellow solid was noted at that time. There appeared subsequently in the literature evidence of complex behavior of PIH by virtue of its ability to form, under similar synthetic approaches, various hydrates and fractional or monohydrochlorides, all described with similar melting points but differing in their physical appearance.
The varied spectral properties of hydrates and salts reported to date were accompanied by comments about differing and limited water solubilities (S. Avramovici-Grisaru, S. Sarel, G. Link and H. Hershko. J. Med. Chem. 26:298-302 (1983).
Literature reports have specifically referred to the dihydrate (D. Libermann, N. Rist, F. Grumbach, M. Moyeux, B. Gauthier, A. Rouaix, J. Maillard, J. Himbert and S. Cals. Bull. Soc. Chim. Fr. 1430-43 (1954)), a monohydrate (H. C. Beyerman, J. S. Bontekoe, W. J. Van der Burg and W. L. C. Veer. Recl. Trav. Chim. Pays-Bas. 73:109-17 (1954)), (S. Avramovici-Grisaru, supra) the monohydro-chloride hydrate and the 0.5 hydrochloride and the monohydrochloride (J. Webb and M. L. Vitolo, Birth Defects. 23 (5B):63-70 (1988)). A patented process for making PIH as the free base (S. Archer and M. E. Auerbach, U.S. Pat. No. 2,775,598; Dec. 25, 1956) in addition to other reported syntheses of PIH required the use of appreciable amounts of water, thus generating complex and often differing products with respect to metal ion chelation, protonation, solvation and compound colors (which can range from white to yellow to green to orange) (T. B. Murphy, N. J. Rose, V. Schomaker and A. Aruffo. Inorg. Chim. Acta. 108:183-194 (1985)).
There appears in the patent literature (J. Bernstein, U.S. Pat. No. 2,810,725, Oct. 22, 1957), reference to an intermediate monosulfate from water as an insoluble orange solid which is stated to have been converted to the free base under aqueous conditions. The patent further refers to the conversion of a PIH to monohydrochloride and to the dihydrochloride (Example 6 of the patent). Attempts to repeat this work by applicants has not been successful.
The procedures to form the free base (PIH) as disclosed by Sah supra. have been found operative. Moreover, Archer et al, in U.S. Pat. No. 2,775,598, disclose another procedure for making PIH via a manganous complex which was also found operative, both with respect to production of the intermediate manganous complex and the subsequent conversion to the free base.
It is interesting to note that Example 1 of Bernstein et al supra patent closely parallels, but is not totally identical with the Archer et al supra method which yields the intermediate manganous complex. An attempted repetition of the aforesaid Example 1 by applicants, yielded the Archer manganous complex but not the Bernstein sulfate.
The stability and solubility of the isolated PIH products reported to date, by others, which includes demonstrable interconversion of one form (and color) to another in the presence of moistu
REFERENCES:
patent: 2810725 (1957-10-01), Bernstein
Bliss Robert
Lewis Neil
Patel Vithal
Terpinski Jacek
Behr Esq. Omri M.
Davis Zinna Northington
Jacobus Pharmaceutical Co.
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