Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1991-05-06
1994-10-25
Cintins, Marianne M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 16, 560 9, 560 28, 560 30, 560 41, 560 44, 562456, 562458, C07C23730, C07C30966, A61K 31165, A61K 31255
Patent
active
053591208
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATION
This application is the national stage of international application PCT/GB 89/01042 filed Sep. 5th, 1989, and claims priority to British Application 8820850.9 filed Sep. 5th, 1988.
THIS INVENTION relates to pro-drugs and is particularly concerned with novel intermediates for the production of enzyme activatable pro-drugs.
Over the years, many cytotoxic compounds have been discovered which are of potential use in cancer chemotherapy. Nitrogen mustards form 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 pro-drugs 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 pro-drugs to patients under regimes whereby the pro-drug is only converted to the cytotoxic drug in the region of the intended site of action.
One particularly promising approach involves the conversion of the nitrogen mustard into a reaction product with an amino acid or oligopeptide to form a pro-drug 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 pro-drug. The antibody/enzyme conjugate is one formed from an antibody to tumour associated antigen and an enzyme that will convert the pro-drug 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 pro-drug is then administered to the patient so that conversion of the pro-drug 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 co-pending International Application PCT/GB88/00181 published as W088/07378.
Specific pro-drugs that can be used in the above-mentioned International Application are those based upon benzoic acid nitrogen mustards. The cytotoxic benzoic acid nitrogen mustard is converted, in accordance with the procedures described in our above-mentioned International Application, into an amide by reaction with an alpha-amino acid, the preferred alpha-amino acid being glutamic acid. In this case, the glutamic acid is linked to the nitrogen mustard through an amide bond formed between the carboxy group of the benzoic acid nitrogen mustard and the alpha-amino group of the glutamic acid.
Other pro-drugs can be prepared based on benzoic acid nitrogen mustards where the carboxy group is converted into a derivative with an oligopeptide or other protecting group which is removed in vivo, under the influence of an enzyme localised in the region of the tumour to be treated.
Pro-drugs of the type described in our above-mentioned Application and other pro-drugs embodying the same principle are administered as pro-drugs where the carboxy groups present in the glutamic acid or analogous residue, for example of aspartic acid, are in free carboxylic acid form. These pro-drugs are prepared by synthetic methods in which the carboxy groups present in the glutamic acid or analogous reactant are protected, normally in the form of an ethylester. Once the pro-drug has been prepared in the form of the ethoxy carbonyl compound, the carboxy protecting groups are removed to release the free carboxylic acid groups. In the synthetic methods described in our above-mentioned International Application, the protecting ethyl ester groups are removed by the conventional method of alkaline hydrolysis with aqueous sodium hydroxide followed by conversion of the resulting sodium salts into the free carboxylic diacid u
REFERENCES:
S.-C. J. Fu et al., "Synthesis and biological activity of isomers of N-[Bis(2-chloroethyl)aminobenzoyl] glutamic acid", Journal of Medicinal Chemistry, vol. 7(6), pp 759-762, see table I (Nov. 1964).
S.-C. J. Fu et al., "Dipeptide nitrogen mustards of glycine and gamma-amino-butyric acid", Journal of Medicinal Chemistry, vol. 9(2), pp. 214-216, see table I (Mar. 1966).
V. Sunel et al., "Syntheses of anticancer substances. XXI. Synthesis of the diethyl ester of p-[di(.beta.-chloroethyl)amino]benzoyl-L-aspartic acid with potential anticancer action", Chemical Abstracts, vol. 92 (23), Jun. 9, 1980 (Columbus, Ohio, US), see p. 721 abstract No. 198735j, & Inst. Politeh. Iasi, Sect. 2: Chim. Ing. Chim. 1979, 25(1-2), 85-9.
V. Sunel et al., "New derivatives of N-(p-aminobenzoyl)-L-aspartic acid with potential antitumor effect", Chemical Abstracts, vol. 98(23), Jun. 6th, 1983 (Columbus, Ohio, US), see p. 702, abstract No. 198688v, & Rev. Chim. (Bucharest) 1982, 33(12), 1099-101.
Cecal et al., Journal of Radioanalytical Chemistry, vol. 78, No. 2 (1983), 247-253.
Fu et al., "Synthesis and Biological Activity of Isomers of Glutamic Acid", Journal of Medicinal Chemistry, vol. 7, No. 6 (1964) pp. 759-762.
Cancer Research Campaign - Technology Limited
Cintins Marianne M.
MacMillan Keith
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