1-Azabicyclo[2.2.2]octan-3-one derivatives and maleimide derivatives and their use for treating cancer tumors
Patent 6921765 Issued on July 26, 2005. Estimated Expiration Date: September 19, 2021. Estimated Expiration Date is calculated based on simple USPTO term provisions. It does not account for terminal disclaimers, term adjustments, failure to pay maintenance fees, or other factors which might affect the term of a patent.
The present invention provides novel compounds, corresponding to formulae I and II, respectively, which are able to reactivate the apoptosis-inducing function of mutant p53 proteins. This reactivation is provided by restoration of sequence-specific DNA-binding activity and transcriptional transactivation function to mutant p53 proteins, and modulation of the conformation-dependent epitopes of the p53 protein. Accordingly, the substances according to the invention will be used in pharmaceutical compositions and methods for treatment of patients suffering from various types of tumors.
Other References
Chemical Abstracts, vol. 64, 1968, Abstracts No. 15837 a, Arnold T. Nielsen: “Systems with bridgehead nitrogen. Beta-Ketols of the 1-azabicyclo[2.2.2]octane series”, J. Org. Chem. 31(4), 1053-1059 (1966).
STN International, File CAPLUS, CAPLUS accession No. 1988:49287, Document No. 108:49287, Yanina, A.D. et al.: “Synthesis and pharmacological properties of 2- and 2,3- substituted quinuclidines”, & Khim.-Farm. Zh. (1987), 21(7), 808-11.
Tetrahedron, vol. 56, 2000, Janne E. Tonder et al: “Exploring the Stereo-selectivity in the Peterson Reaction of Several 2-Substituted 1-Azabicyclo[2.2.2]octan-3-ones”, pp. 1139-1146, see schema 1,2,3.
STN International, File CAPLUS, CAPLUS accession No. 1979:405093, Document No. 91:5093, Bondarenko, V. A. et al: “Reaction of 2-methylene-3-oxoquinuclidine with indoles”, & Khim. Geterotsikl. Soedin. (1979), (3), 371-4.
STN International, File CAPLUS, CAPLUS accession No. 1988:68304, Document No. 108:68304, Doukas, P.H. et al: “Suppression of acetylcholine by novel quinuclidine derivatives: comparison with acetyl-secochemicholinium and N-hydroxyethyl-naphthylvinylpyridine”, Cell. Mol. Basis Cholinergic Funct. (1987), 355-60.
STN International, File CAPLUS, CAPLUS accession No. 1969:491727, Document No. 71:91727, Begue, Jean P. et al:“Mass spectrometric fragmentation in the Cinchona alkaloid series”, & Bull. Soc. Chim. Fr. (1969), (4), 1251-4.
Chemical Abstracts, vol. 57, 1961, Abstract No. 2192 e, E. E. Mikhlina et al: “Synthesis fo 2,3-quinuclidinedi-carboxylic acid”, Zh. Obshch. Khim. 31, 3251-5 (1961).
Chemical Abstracts, vol. 60, 1964, Abstract No. 8526 g, Guenther Weitzel et al: “Further tumor inhibiting compounds I. Cytostatic effects of N-and S-hydroxymethyl compounds”, Z. Physiol. Chem. 334, 1-25.
STN International, file CAPLUS, CAPLUS accession No. 1975:588204, document No. 83:188204, Dore, Jean C. et al: “Antitumor chemotherapy. XIV. Cytotoxic activity of molecules possessing an ethylentic double bond substituted in alpha and beta positions by an electron-attracting group” & Eur. J. Med. Chem.—Chim. Ther. (1975), 10(1) 47-54.
STN International, file CAPLUS, CAPLUS accession No. 1979:569199, document No. 91:169199, Yamashita, T. et al: “Dependence on the lipophilicity of malemide derivatives in their inhibitory action upon chemotaxis in neutrophils”, & Experientia (1979), 35(8), 1054-6.
STN International, file CAPLUS, CAPLUS accession No. 1970:408481, document No. 73:8481, Feast, William J. et al: “Mass spectra of maleimides, isomaleimides, bis-maleimides, bis-isomaleimides and the intramolecular photocyclization products of bis-maleimides”, & Org. Mass. Spectrom. (1970), 3(4), 507-17.
Chemical Abstracts, vol. 65, 1966, Abstract No. 13818 a, Norma E. Sharpless et al: “The reactions of amines and amino acids with maleimides. Structure of the reaction products deduced from infrared and nuclear magnetic response spectroscopy”, Biochemistry 5(9), 2963-71.
Chemical Abstracts, vol. 55, 1961, Abstract No. 18587 b, P.O. Tawney et al: “Maleimide and derivatives. II. Malemide and N-methylolmaleimide”, J. Org. Chem. 26, 15-21.