Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-06-18
2000-08-29
Rotman, Alan L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546103, 546104, 546105, C07D21902, C07D21908, C07D21904, C07D21910
Patent
active
061111090
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a new process for the production of the anti-cancer drug N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and derivatives thereof.
The acridine derivative N-[(2-dimethylamino)ethyl]acridine-4-carboxamide, known as DACA, is a new DNA-intercalating agent with inhibitory activity against the enzymes topoisomerase I and topoisomerase II (Schneider et al, Eur. J. Cancer Clin. Oncol, 1988, 24 1783 and Finlay, et al Eur J. Cancer 1996, 32A 708). It has a wide spectrum of activity against solid tumours in animals and is relatively unaffected by P-glycoprotein-mediated multidrug resistance (Atwell et al, J. Med Chem, 1987, 30, 664, Baguley et al, Cancer Chemother. Pharmacol 1995, 36, 244 and Finlay et al Cancer Chemother. Pharmacol. 1993, 31,401). Certain analogues of DACA have been reported, and many have shown significant activity in a mouse solid tumour (Atwell et al, ibid).
The known process for producing DACA, reported by twell et al, ibid, is shown in Scheme 1. ##STR2##
Step (i) comprises reduction of the acridone (1) by treatment with aluminium/mercury amalgam in the presence of KOH in aqueous ethanol under reflux, followed by reoxidation of the resulting acridan with FeCl.sub.3, to give the intermediate acridine carboxylic acid (2). Step (ii) comprises treatment of the acid (2) with 1,1-carbonyldiimidazole (CDI) and dimethylformamide, followed by N,N-dimethylethylenediamine.
Various disadvantages are associated with this process. One is that the reductive conditions required in step (i) are harsh. This limits the scope of the process and makes it unsuitable for the production of certain analogues of DACA which bear reduction-sensitive substituents on the acridine nucleus. For instance, dechlorination has been observed when the process has been applied to the production of chloro-substituted derivatives of DACA. Another disadvantage of the known process is that the intermediate acridine carboxylic acids (2) have severe lachrymatory and sternutatory properties, which limit their use.
It has now been found that DACA and derivatives thereof can be produced by a process which comprises cyclising an aldehyde precursor which includes an esterified, rather than a free, carboxylic acid functional group and then subjecting that esterified group in the cyclised product directly to treatment with a primary alkyl amine. If desired the esterified group in the cyclised product can first be hydrolysed to generate a free carboxylic acid function, which is then treated with the primary alkyl amine in the presence of a suitable coupling agent. The aldehyde precursor is readily produced by oxidation of the corresponding alcohol, which in turn is produced by mild reduction of the corresponding carboxylic acid via an imidazolide intermediate.
Accordingly, the present invention provides a process for producing an acridine carboxamide of formula (I): ##STR3## wherein each of R.sup.1, R.sup.2, R.sup.5 and R.sup.6, which may be the same or different, is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, aryloxy, aralkyloxy, halogen, phenyl, CF.sub.3, NO.sub.2, NH.sub.2, N(R).sub.2, NHCOR, NHCOOR, NHR.sup.4, OH, SH, SR or S (R).sub.2, wherein R.sup.4 is H, COR, SO.sub.2 R, COPh, SO.sub.2 Ph or C.sub.1 -C.sub.6 alkyl unsubstituted or substituted by OH or amino, and R is C.sub.1 -C.sub.6 alkyl; or R.sup.1 and R.sub.2, or R.sub.5 and R.sub.6, together form a methylenedioxy group; x is an integer of 1 to 6 and Y is N(R).sub.2 as defined above; or a pharmaceutically acceptable salt thereof; which process comprises: ##STR4## wherein R.sup.1, R.sup.2, R.sup.5 and R.sup.6 are as defined above and R.sup.3 is C.sub.1 -C.sub.6 alkyl, aryl or aryl-C.sub.1 -C.sub.3 -alkyl, by treatment with a Lewis acid in an organic solvent, to obtain a compound of formula (III): ##STR5## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are as defined above; and a primary alkylamine of formula (IV) obtainable by hydrolysing the compound of formula (III) as defined above, under basic conditions, with a primary alkyl amine o
REFERENCES:
patent: 3686180 (1972-08-01), Sutton et al.
patent: 4590277 (1986-05-01), Atwell et al.
Potential Anti-tumor Agents ; J. Med. Chem. !987 vol. 30 pp. 664-669; Graham J. Atwell, Aug. 20, 1986.
Facile Reduction of Carboxylic Acid . . . ; Synlett Rajiv et al; pp. 839-840, Mar. 15, 1995.
Rewcastle et al, "The synthesis of 9-oxo-9, 10-dihydroacridine-4-carboxylic acids via the Jourdan-Ullman reaction of anthranilic acids and methyl 2-iodobenzoates", Synthetic Communications, vol. 17, No. 3, 1987, pp. 309-317.
Atwell et al, "Potential antitumor agents.50.Invivo solid-tumor activity of derivatives of N-[2-(dimethylamino)ethyl] acridine-4-carboxamide", Journal of Medicinal Chemistry, vol. 30, No. 4, 1987, Washington, U.S., pp. 664-669.
Sharma et al, "Facile reduction of carboxylic acid imidazolides to primary alcohols in the presence of water", Synlett, No. 8, Aug. 1995, Stuttgart, DE, pp. 839-840.
Gamage et al, "A new synthesis of substituted acridine-4-carboxylic acids and the anticancer drug N-[2-(dimethylamino)ethyl] acridine-4-carboxamide (DACA)", Tetrahedron Letters, vol. 38, No. 4, Jan. 27, 1997, Oxford, GB, pp. 699-702.
Denny William Alexander
Gamage Swarnalatha Akuratiya
Hayman David Frank
Spicer Julie Ann
Wright Michael
Desai Rita
Rotman Alan L.
Xenova Limited
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