Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1991-04-10
1992-07-21
Cintins, Marianne
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
552236, 552237, 552238, 552240, 552243, 552244, 552247, 552249, 552255, C09B 116, C07C 9721, A61K 3113
Patent
active
051323273
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel anthraquinones which are of particular value in the treatment of cancer.
A wide variety of aminoalkylamino anthraquinones (aminoalkylaminoanthracene-9,10-diones) has been described for use as chemotherapeutic agents for the treatment of cancer, perhaps the most active being the compound mitoxantrone (mitozantrone) of formula ##STR2## which is the subject of U.S. Pat. No. 4,197,249 and U.K. Patent 2,004,293B. However, in common with other cytotoxic chemotherapeutic agents the aminoalkylamino anthraquinones have the disadvantgage that their activity is not confined to neoplastic cells and they therefore exhibit various undesirable side effects including, to a greater or lesser extent among the different compounds, myelosuppression and cardiotoxicity.
It is an object of the present invention to provide a group of anthraquinone pro-drugs which are of lesser cytotoxicity than the drug itself, preferably being substantially non-cytotoxic, the pro-drugs being converted in vivo under the anaerobic conditions within neoplastic tissue to the cytotoxic drug thereby mitigating the side effects of administering that drug directly.
Accordingly the present invention comprises a compound of formula (I) ##STR3## in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are each separately selected from hydrogen, X, NH--A--NHR and NH--A--N(O)R'R" wherein X is hydroxy, halogeno amino, C.sub.1-4 alkoxy or C.sub.2-8 alkanoyloxy, A is a C.sub.2-4 alkylene group with a chain length between NH and NHR or N(O)R'R" of at least 2 carbon atoms and R, R' and R" are each separately selected from C.sub.1-4 alkyl groups and C.sub.2-4 hydroxyalkyl and C.sub.2-4 dihydroxyalkyl groups in which the carbon atom attached to the nitrogen atom does not carry a hydroxy group and no carbon atom is substituted by two hydroxy groups, or R' and R" together are a C.sub.2-6 alkylene group which with the nitrogen atom to which R' and R" are attached forms a heterocyclic group having 3 to 7 atoms in the ring, but with the proviso that at least one of R.sub.1 to R.sub.4 is a group NH--A--N(O)R'R", the compound optionally being in the form of a physiologically acceptable salt.
The compounds of formula (I) contain at least one substituent group NH--A--N(O) R'R" having the terminal, tertiary nitrogen atom in N-oxide form. Although groups of this type are not unknown, for example being described in European Patent Application A-0 145 226 as one of the various alternative forms of substituent in a group of substituted nitroacridones, it had not previously been appreciated that such a substituent confers valuable properties as compared with the compound containing the corresponding group NH--A--NR'R" in which the terminal, tertiary nitrogen atom is not in N-oxide form. Thus, such N-oxides are bioreductively activated within neoplastic tissue to form the cytotoxic compound containing an NH--A--NR'R" group thereby providing the desired anti-cancer activity of this compound but with mitigation of its undesired side effects.
It will be seen that in addition to the one or more substituents NH--A--N(O)R'R" in N-oxide form the compounds (I) may contain one or more substituents NH--A--NHR. Whilst these compounds, as compared with those containing no group NH--A--NHR, may exhibit some degree of cytotoxicity and are thus less preferred, this will nonetheless be at a lower level than the corresponding compound in which none of the aminoalkylamino groups is in N-oxide form and full cytotoxicity will only be expressed on conversion of the group(s) NH--A--N(O)R'R" to group(s) NH--A--NR'R".
As regards the groups NH--A--NHR and NH--A--N(O)R'R", A may be branched but is conveniently a straight chain alkylene group, i.e. tetramethylene, especially trimethylene, or particularly ethylene.
R, R' and R" may also have a branched carbon chain but are conveniently straight chain whether they are alkyl groups or hydroxy-substituted alkyl groups. When R, R' or R" is a monohydroxyalkyl group this is conveniently substituted terminally and when R, R' or R" is a dihydro
REFERENCES:
patent: 3174994 (1965-03-01), Sutton
patent: 4138415 (1979-02-01), Murdock et al.
patent: 4197249 (1980-04-01), Murdock et al.
patent: 4275010 (1981-06-01), Murdock
patent: 4278605 (1981-07-01), Murdock
patent: 4278689 (1981-07-01), Murdock et al.
patent: 4430501 (1984-02-01), Murdock et al.
patent: 4526989 (1985-07-01), Murdock et al.
patent: 4540519 (1985-09-01), Murdock et al.
patent: 4614618 (1986-09-01), Murdock et al.
patent: 4686218 (1987-08-01), Marinis et al.
patent: 4820738 (1989-04-01), Murdock et al.
patent: 4963554 (1990-10-01), Combs et al.
J. Het. Chem., 1969, 6, 389-392, Fujiwara et al., "N-Oxides and S-oxides of Ellipticine Analogues (1)".
Tetrahedron, 1988, 44, 3627-3631, Langendoen et al., "An approach to novel ellipticine glycosides".
Tetrahedron, 1989, 45, 1759-1762, Langendoen et al., "Regiospecific C-9 substitution of ellipticine derivatives".
Phytochemistry, 1972, 11, 3073-3075, Bruneton et al., "Alcaloides des ecorces d'Ochrosia Vieillardii".
Helvetica Chimica Acta, 1967, 50, 1885-1892, Bild et al., "Notiz uber die massenspektren von N-oxiden".
Anti-Cancer Drug Design, 1986, 1, 259-268, Jarman et al., "Analogues of tamoxifen . . . ".
Int. J. Radiation Oncology Biol. Phys., 1986, 12, 1239-1242, Zeman et al., "SR-4233: A new bioreductive agent".
The Chemistry of Antitumor Agents, Wilman (ed.), 1990, 342-369, Jenkins, "Hypoxia-selective agents . . . ".
Science, 1974, 186, 647-648, Hulbert et al., "Hycanthone Analogs: . . . ".
Structure-Activity Relationship of Anti-Tumor Agents, Reinhoudt et al. (eds.) 1983, 47-57, Connary, "Alkylating Prodrugs in Cancer Chemotherapy".
J. Med. Chem., 1989, 24, 23-30, Katzhendler et al., "Synthesis of aminoanthraquinone derivatives . . . ".
J. Med. Chem., 1989, 32, 1724-1728, Stefanska et al., "Synthesis of . . . 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones . . . ".
Progress in Medicinal Chemistry, Ellis and West (eds.), 1983, 20, 83-118, Cheng et al., "The design, synthesis and development . . . anthraquinones".
Cintins Marianne
Kestler Kimberly J.
National Research Development Corporation
LandOfFree
Anti-cancer compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Anti-cancer compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Anti-cancer compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-843622