Nitroaniline derivatives and their use as anti-tumour agents

Details Nitroaniline derivatives and their use as anti-tumour agents Nitroaniline derivatives and their use as anti-tumour agents

1994-05-26

1996-11-05

Geist, Gary

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

564166, 564163, 564145, A01N 3718, C07C23365

Patent

active

055718450

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB92/02199 filed Nov. 27, 1992.
Alkylating agents are an important class of anticancer drugs, which express their cytotoxic and antitumour effects by forming adducts with cellular DNA (Garcia et al., Biochem. Pharmacol., 1988, 37, 3189).
The present invention relates to novel nitroaniline-based alkylating agents having activity as hypoxia-selective cytotoxins, reductively-activated prodrugs for cytotoxins, hypoxic cell radiosensitisers, and anticancer agents, to methods of preparing the novel compounds, and to the use of these compounds as antitumour agents.
In one aspect, the present invention relates to the class of nitroaniline derivatives represented by the general formula (I); ##STR2## where the nitro group is substituted at any one of the available benzene positions 2-6; where R and A separately represent the groups NO.sub.2, CN, COOR.sup.1, CONR.sup.1 R.sup.2, CSNR.sup.1 R.sup.2 or SO.sub.2 NR.sup.1 R.sup.2 and A is substituted at one of the available benzene positions 2-6; where B represents N(CH.sub.2 CH.sub.2 halogen).sub.2 or N(CH.sub.2 CH.sub.2 OSO.sub.2 R.sup.3).sub.2 substituted at any one of the available benzene positions; and where R.sup.1, R.sup.2 and R.sup.3 separately represent H, or lower alkyl optionally substituted with hydroxyl, ether, carboxyl or amino functions, including cyclic structures, or R.sup.1 and R.sup.2 together with the nitrogen form a heterocyclic structure.
Where R.sup.1, R.sup.2 and/or R.sup.3 represent lower alkyl, the group may contain from 1 to 6 carbon atoms.
Where R.sup.1, R.sup.2 and/or R.sup.3 represent groups containing tertiary amines, the N-oxides of those tertiary amine moieties are also included.
The compounds of formula (I) have cytotoxic and antitumour activity, and are useful as hypoxia-selective cytotoxins, reductively-activated prodrugs for cytotoxins, hypoxic cell radiosensitisers, and anticancer agents.
Some of the compounds of formula (I) form pharmaceutically-acceptable addition salts with both organic and inorganic acids, and these addition salts also form part of the present invention. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, isethionic and the like. Some of the compounds of formula (I) form pharmaceutically-acceptable addition salts with both organic and inorganic bases, and these addition salts also form part of the present invention. Examples of suitable bases for salt formation are sodium and potassium carbonate, sodium and potassium hydroxide, ammonia, triethylamine, triethanolamine and the like.
The compounds of formula (I) and the acid or base addition salts and the N-oxides thereof may be prepared by the processes outlined in the following Schemes 1 to 7.
Specific but non-limitative examples of the processes outlined in Schemes 1 to 7 are given hereinafter in Examples A to H respectively. ##STR3##
The invention also relates to the preparation of compounds of the general formula I, the acid or base addition salts and the N-oxides thereof, by a process as outlined in any one of Schemes 1-7 above or by an obvious chemical equivalent thereof. The invention includes also those forms of the preparation processes according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out, or a starting material is used in the form of a derivative or salt or, especially, is formed under the reaction conditions.
The following Table 1 sets out physiochemical data for 24 compounds within the general formula (I), representative of it, and preparable by the processes of the invention.


TABLE 1 __________________________________________________________________________ Analytical and physicochemical data for nitroaniline mustards of general formula 1. No. A NO.sub.2 B R mp (.degree.C.) formula analyses.sup.a __________________________________________________________________________

REFERENCES:
Martin et al., Remington's Practice of Pharmacy, eleventh ed., The Mack Publishing Co., 1956, pp. 445 & 734.
Palmer et al., Journal of Medicinal Chemistry, vol. 35, No. 17, "Hypoxia-Selective Antitumor Agents . . . Mammalien Cells", 1992, pp. 3214-3222.
Chemical Abstracts, vol. 66, No. 1, Jan. 1967, "Synthesis of 2,4-dinitrophenol derivatives as antineoplastic agents".
Chemical Abstracts, vol. 75, No. 7, Aug. 1971, "Alkylating Analogs of the Tumour Inhibitor".
Journal of Medicinal Chemistry, vol. 35, No. 17, Washington US, pp. 3214-3222, "Hypoxia-Selective Antitumor Agents. 5. Synthesis of Water-Soluble Nitroaniline Mustrads with Selective Cytotoxicity for Hypoxic Mammalien Cells", 1992.

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