Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-06-18
2000-09-05
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514250, 514287, 514297, 544338, 544343, 544347, 544348, 544361, 546 65, 546102, 546104, A01N 4358, A01N 4342, C07D24136, C07D40100, C07D21900
Patent
active
061143324
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB97/0286, filed Oct. 17, 1997.
The present invention relates to compounds useful as antitumor agents, to their production and to pharmaceutical compositions containing them.
Many compounds which bind reversibly to DNA by intercalation are known to have cellular antiproliferative properties and in vivo antitumor effects, mediated principally through their inhibition of topoisomerase enzymes. For example, the acridine derivatives amsacrine [Issell, Cancer Treat. Rev. 1980, 7, 73], asulacrine [Harvey et al., Eur. J. Cancer, 1991, 27, 1617] and acridinecarboxamide [Finlay et al., Eur. J. Cancer 1996, 32A, 708] are clinical anticancer drugs or in clinical trial, and related 9-azaacridines (phenazines) have been reported to have in vivo antitumor properties in animal models [Rewcastle et al., J. Med. Chem., 1987, 30, 843].
It has now been found that a series of bis(acridinecarboxamide) and bis(9-phenazinecarboxamide) derivatives have antitumor properties. The present invention therefore provides a compound which is a bis(acridinecarboxamide) or bis(phenazinecarboxamide) derivative of formula (I): ##STR2## wherein each X, which may be the same or different in a given molecule, is --CH.dbd. or --N.dbd.; each of R.sub.1 to R.sub.4 which may be the same or different, is H, C.sub.1 -C.sub.4 alkyl , OH, SH, NH.sub.2, C.sub.1 -C.sub.4 alkoxy, aryl, aryloxy, NHR, N(R).sub.2, SR or SO.sub.2 R wherein R is C.sub.1 -C.sub.4 alkyl, CF.sub.3, NO.sub.2 or halogen, or R.sub.1 and R.sub.2 form together with the carbon atoms to which they are attached, a methylenedioxy group; each of R.sub.5 and R.sub.6, which may be the same or different, is H or C.sub.1 -C.sub.4 alkyl; Z is (CH.sub.2).sub.n, (CH.sub.2).sub.n O(CH.sub.2).sub.n, (CH.sub.2).sub.n N(R.sub.7)(CH.sub.2).sub.n, (CH.sub.2).sub.n N(R.sub.7)(CH.sub.2).sub.m N(R.sub.7)(CH.sub.2).sub.n or (CH.sub.2).sub.n N(CH.sub.2 CH.sub.2).sub.2 N(CH.sub.2).sub.n, (CH.sub.2).sub.n CONH(CH.sub.2).sub.m or (CH.sub.2).sub.n CONH(CH.sub.2).sub.m NHCO(CH.sub.2).sub.n wherein R.sub.7 is H or C.sub.1 -C.sub.4 alkyl and n and m, which may be the same or different, are each an integer of 1 to 4; or a pharmaceutically acceptable acid addition salt or N-oxide thereof; with the exception of compounds wherein each X is N, each of R.sub.1 to R.sub.6 is H, the carboxamide moiety is attached to position 1 of each phenazine ring and Z is (CH.sub.2).sub.2 NH(CH.sub.2).sub.2, (CH.sub.2).sub.3 NH(CH.sub.2).sub.3, (CH.sub.2).sub.3 N(CH.sub.2 CH.sub.2).sub.2 N(CH.sub.2).sub.3, (CH.sub.2).sub.2 NH(CH.sub.2).sub.2 NH(CH.sub.2).sub.2 or (CH.sub.2).sub.3 NH(CH.sub.2).sub.2 NH(CH.sub.2).sub.3.
In formula (I) the ring numbering in each tricylic chromophore differs depending on whether X is --CH.dbd. (acridine derivatives) or --N.dbd. (phenazine derivatives). The numbering used in each case, with reference to one tricyclic moiety, is as follows: ##STR3##
In formula (I) the substituents R.sub.1 and R.sub.2, and R.sub.3 and R.sub.4, may occupy any one of the available ring positions in their respective tricyclic chromophores. Thus when X in a tricyclic moiety is --CH.dbd. then R.sub.1 and R.sub.2, or R.sub.3 and R.sub.4 if appropriate, may each be bonded to any one of the available ring positions 1 to 8 not occupied by the carboxamide moiety --C(O)--N(R.sub.5)--. The carboxamide moiety in turn may be bonded to any one of ring positions 1, 2, 3 and 4, preferably 1 or 4. Typically when X in a given tricyclic chromophore is --CH.dbd. one of R.sub.1 and R.sub.2, or R.sub.3 and R.sub.4 if appropriate, is hydrogen and the other is hydrogen or is a substituent as defined above for formula (I) bonded at any one of ring positions 1 to 8, and the carboxamide moiety is bonded at position 1 or 4.
When X in a tricyclic moiety is --N.dbd. then R.sub.1 and R.sub.2, or R.sub.3 and R.sub.4 if appropriate, may each be bonded to any one of the available ring positions 1 to 4 and 6 to 9 which are not occupied by the carboxamide moiety, in particular one of positions 6 to 9. The carboxamide moiety, in t
REFERENCES:
Atwell et al., "Potential antitumour agents. 50 In vivo solid-tumor activity of dericatives of N-[2-(dimethylamino)ethyl] acridine-4-carboxamide", Journal of Medicinal Chemistry, vol. 30, No. 4, 1987, Washington, U.S., pp. 664-669.
Rewcastle et al, "Potential antitumor agents. 51. Synthesis and antitumor activity of substituted phenazine-1-carboxamides", Journal of Medicinal Chemistry, vol. 30, No. 5, 1987, Washington, U.S., pp. 843-851.
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.
Atwell et al, "Potential antitumor agents.50.In vivo 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.
Baguley Bruce Charles
Denny William Alexander
Finlay Graeme John
Gamage Swarnalatha Akuritaya
Spicer Julie Ann
Raymond Richard L.
Schroeder Ben
Xenova Limited
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