High purity N-(4-[N,N-bis(2-iodoethyl)amino]phenoscycarbonyl)-L-

Details High purity N-(4-[N,N-bis(2-iodoethyl)amino]phenoscycarbonyl)-L- High purity N-(4-[N,N-bis(2-iodoethyl)amino]phenoscycarbonyl)-L-

1997-06-23

1999-11-09

Killos, Paul J.

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

Organic compounds

Carboxylic acid esters

560160, 560163, 514548, C07C26100

Patent

active

059817917

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a known prodrug useful in Antibody Directed Enzyme Prodrug Therapy (ADEPT) in a new highly purified form and a new salt of the prodrug, pharmaceutical compositions thereof and processes for making the salt.
The prodrug N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid was disclosed on Feb. 3, 1994 in international patent application WO 94/02450; see Example 33 therein which describes a trifluoroacetic acid (TFA) salt which is produced as a gum. The known gum form of the prodrug was not able to be very highly purified because of the known difficulties of handling gum type compounds. There has been no disclosure whatsoever of a hydrogen iodide salt of the prodrug or of the prodrug per se in highly pure form.
According to one aspect of the present invention there is provided N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid in substantially pure form.
The term "in substantially pure form" means that the prodrug is at least 95% pure (preferably at least 96% pure, more preferably at least 97% pure, more preferably at least 98% pure) in relation to reaction contaminants, including solvents, carried over from any synthesis of the prodrug. These high levels of purity have only become possible by the invention disclosed herein of the hydrogen iodide salt of the prodrug which can be produced in crystalline form. The crystalline form of the prodrug allows the prodrug to be easily obtained in a highly purified state because the salt can be efficiently collected from the reaction mixture and washed with solvent to remove contaminants, including solvents, from the synthetic procedure. Preferably the substantially pure prodrug is in a dry form mixed with a buffer suitable for intravenous administration after reconstitution.
According to another aspect of the present invention there is provided a hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid. Preferably the salt is in substantially pure form. Preferably the hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid is in crystalline form. Preferably the crystalline form has a melting point of 142-145.degree. C. Preferably the crystalline form has an X-ray powder diffraction spectrum substantially as shown in FIG. 3.
The salt has the following advantages: good thermal stability; easier synthesis and purification because it can be collected efficiently from the reaction mixture; increased purity and reduced hygroscopic/deliquescence properties which further facilitate handling.
Whilst not wishing to be bound by theoretical considerations it is believed that the presence of HI somehow helps to reverse any degradation of the prodrug in the region of the mustard alkylating arms. It is believed that products derived from an aziridene intermediate may be produced on storage or heat stress when the prodrug is stored in the dry state. The HI salt of the prodrug is advantageously stable when dissolved in aqueous solution possibly due to in situ generation of iodide counter ion. A person skilled in the art would not be likely to add the likes of high concentration NaI to this prodrug for its pharmaceutical use (the only known use) because of pharmaceutical effects per se in such compounds.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid in substantially pure form and a pharmaceutically acceptable excipient.
Preferably the composition is supplied as a dry form. Preferably the excipient is a buffer, especially sodium bicarbonate. Preferably the composition is reconstituted shortly before use as an ADEPT component preferably with a sterile diluent.
According to another aspect of the present invention there is provided a two component pharmaceutical composition comprising a first component of hydrogen iodide salt of N-(4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid in dry form and a second component of sterile di

REFERENCES:
patent: 5405990 (1995-04-01), Burke et al.
patent: 5587161 (1996-12-01), Burke et al.
patent: 5660829 (1997-08-01), Burke et al.

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