4-amino-fluorobenzamides and their use as cytotoxic prodrugs

Details 4-amino-fluorobenzamides and their use as cytotoxic prodrugs 4-amino-fluorobenzamides and their use as cytotoxic prodrugs

1995-12-21

1998-09-22

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514533, 558 47, 558 48, 562565, A61K 31235, C07C22914

Patent

active

058114548

DESCRIPTION:

BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS

This application is filed under 35 U.S.C. .sctn.371(c) as a continuation of International Application PCT/GB94/00941, filed May 3, 1994, which is based on U.K. Application No. 9308957.1, filed on Apr. 30, 1993 the priority of which is claimed.
This invention relates to prodrugs, their use in therapy and a process for their preparation.


TECHNOLOGY REVIEW

Over the years, many cytotoxic compounds have been discovered which are of potential use in cancer chemotherapy. Nitrogen mustards from one important family of such cytotoxic compounds. The clinical use of cytotoxic compounds in general and nitrogen mustards in particular has been limited because of the poor selectivity in the cytotoxic effect between tumour cells and normal cells.
One approach to overcome this problem has involved the development of so-called prodrugs which are derivatives of the cytotoxic drug, often a relatively simple derivative, whose cytotoxic properties are considerably reduced compared to those of the parent drug. Numerous proposals have been made for the administration of such prodrugs to patients under regimes whereby the prodrug is only converted to the cytotoxic drug in the region of the intended site of action.


SUMMARY OF THE INVENTION

One particularly promising approach involves the conversion of the nitrogen mustard into a reaction product with an amino acid or oligopeptide to form a prodrug which can be converted to the parent nitrogen mustard at the site of intended action under the influence of an enzyme. This approach can be put into practice by the utilization of an antibody/enzyme conjugate in association with a prodrug. The antibody/enzyme conjugate is one formed from an antibody to a tumour-associated antigen and an enzyme that will convert the prodrug to the cytotoxic drug. In clinical practice, the antibody/enzyme conjugate is first administered to the patient and is allowed to localise in the region of the tumour to be treated. The prodrug is then administered to the patient so that conversion of the prodrug to the cytotoxic drug is also localised in the region of the tumour to be treated under the influence of the localised enzyme. Such a system is described in our WO-A-88/07378, and is now called "antibody-directed enzyme prodrug therapy" (ADEPT).
Specific prodrugs that can be used in ADEPT are those based upon benzoic acid nitrogen mustards (WO-A-88/07378). The cytotoxic benzoic acid nitrogen mustard is a bifunctional alkylating agent and the activating effect of the ionised carboxyl group is masked in the prodrug by converting the carboxyl group into an amide by reaction with an .alpha.-amino acid, the preferred .alpha.-amino acid being glutamic acid. The relatively inactive prodrug can be activated to its corresponding benzoic acid at a tumour site by prior administration of a monoclonal antibody coupled to the enzyme carboxypeptidase G2 (CPG2). Benzoic acid nitrogen mustard prodrugs and their cytotoxic drugs are also described in Springer et al., J. Med. Chem., (1990) 33, 677-681 and Springer et al., Anti-Cancer Drug Design (1991) 6, 467-479.
It is desirable to release a very reactive drug at the tumour in ADEPT. It is therefore an advantage to have prodrugs and corresponding active drugs of high reactivities, so that high efficacy in vivo may be obtained.


DETAILED DESCRIPTION OF THE INVENTION

I have now synthesized 2- and 3-fluoro ring substituted benzoic acid nitrogen mustards of general formula (A') ##STR3## wherein R-NH is the residue of an .alpha.-amino acid R-NH.sub.2 or oligopeptide R-NH.sub.2, and M is a nitrogen mustard group of the formula ##STR4## wherein Y and L, which may be the same or different in a molecule, are leaving groups; and pharmaceutically acceptable salts thereof. The F group may be at the 2- or 3-position relative to the --CONH-R group.
I have found that these compounds have surprising reactivities. Due to the strong inductive effect of fluorine, it would have been expected that a fluorine in the ring at position 2 or 3 would cause d

REFERENCES:
Springer, Caroline J., "Novel Prodrugs Which are Activated to Cytotoxic Alkylating Agents by Carboxypeptidase G2", J. Med. Chem. 33:677-681, 1990.

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