Title:
OXYNITIDINE DERIVATIVES USEFUL AS INHIBITORS OF TOPOISOMERASE IB (TOP1) AND/OR TYROSYL-DNA PHOSPHODIESTERASE 1 (TDP1)
Document Type and Number:
WIPO Patent Application WO/2020/023700
Kind Code:
A3
Abstract:
Compounds and pharmaceutically acceptable salts thereof of Formula I are disclosed. Certain compounds and salts of Formula I are active as Topl and / or Tdpl inhibitors. The disclosure provides pharmaceutical compositions containing a compound of Formula I as the only active agent, or optionally containing one or more additional active agents. Methods of using compounds of Formula I to treat cancer are provided in this disclosure. The disclosed compounds of Formula I may be used alone to treat cancer, but may also be used in combination with another active agent, such as a Topl inhibitor, for example, camptothecin or a camptothecin analogue.
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Inventors:
AN LIN-KUN (CN)
ZHANG XIAORU (CN)
WANG HAOWEN (CN)
POMMIER YVES GEORGES (US)
KISELEV EVGENY A (US)
RAVJI AZHAR ALI (US)
AGAMA KELI KISSEH (US)
ZHANG XIAORU (CN)
WANG HAOWEN (CN)
POMMIER YVES GEORGES (US)
KISELEV EVGENY A (US)
RAVJI AZHAR ALI (US)
AGAMA KELI KISSEH (US)
Application Number:
PCT/US2019/043357
Publication Date:
May 07, 2020
Filing Date:
July 25, 2019
Export Citation:
Assignee:
US HEALTH (US)
UNIV SUN YAT SEN (CN)
UNIV SUN YAT SEN (CN)
International Classes:
A61P25/00; A61K31/4355; A61K31/4418; A61K31/4741; A61K31/496; A61K31/5377; A61P31/00; A61P35/00; C07D221/18; C07D491/056; C07D491/153
Domestic Patent References:
| WO2018118852A1 | 2018-06-28 | |||
| WO2000021537A1 | 2000-04-20 |
Foreign References:
| US20120172371A1 | 2012-07-05 | |||
| US20100256164A1 | 2010-10-07 | |||
| US20130345252A1 | 2013-12-26 |
Other References:
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NANDINI SHARMA ET AL: "Microwave-Assisted Ruthenium-Catalysed ortho -C-H Functionalization of N -Benzoyl [alpha] -Amino Ester Derivatives", ADVANCED SYNTHESIS & CATALYSIS, vol. 360, no. 16, 28 June 2018 (2018-06-28), DE, pages 3083 - 3089, XP055657726, ISSN: 1615-4150, DOI: 10.1002/adsc.201800458
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MIYOJI HANAOKA ET AL: "Chemical transformation of protoberberines. XVI. Regioselective introduction of an oxy functionality at the C12-position of the benzo(c)phenanthridine skeleton: A convenient synthesis of macarpine from oxychelirubine.", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 38, no. 12, 1 January 1990 (1990-01-01), JP, pages 3335 - 3340, XP055657837, ISSN: 0009-2363, DOI: 10.1248/cpb.38.3335
HISASHI ISHII ET AL: "Studies on the chemical constituents of rutaceous plants. LV. The development of a versatile method for the synthesis of antitumor-active benzo(c)phenanthridine alkaloids. 5. A new method for quaternization of the benzo(c)phenanthridine nucleus.", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 32, no. 8, 1 January 1984 (1984-01-01), JP, pages 2984 - 2994, XP055658022, ISSN: 0009-2363, DOI: 10.1248/cpb.32.2984
KISELYOV A S: "Reaction of ortho-Lithiated N-Methylbenzamide with 1,2-Diketones: A Novel Highly Efficient Route to N-Methylisoquinolin-1-ones", TETRAHEDRON LETTERS, ELSEVIER LTD, AMSTERDAM, NL, vol. 36, no. 4, 23 January 1995 (1995-01-23), pages 493 - 496, XP004028776, ISSN: 0040-4039, DOI: 10.1016/0040-4039(94)02293-K
YANG SHENG-HUI ET AL: "Isoquinoline alkaloids fromand their biological evaluation", THE JOURNAL OF ANTIBIOTICS, NATURE PUBLISHING GROUP, GB, vol. 68, no. 4, 1 October 2014 (2014-10-01), pages 289 - 292, XP036973715, ISSN: 0021-8820, [retrieved on 20141001], DOI: 10.1038/JA.2014.139
CHO W-J ET AL: "A NOVEL SYNTHESIS OF BENZOÄCÜPHENANTHRIDINE SKELETON AND BIOLOGICAL EVALUATION OF ISOQUINOLINE DERIVATIVES", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 47, no. 6, 1 January 1999 (1999-01-01), pages 900 - 902, XP001204220, ISSN: 0009-2363
NAKAMURA M ET AL: "Structural development studies of anti-hepatitis C virus agents with a phenanthridinone skeleton", BIOORGANIC & MEDICINAL CHEMISTRY : A TETRAHEDRON PUBLICATION FOR THE RAPID DISSEMINATION OF FULL ORIGINAL RESEARCH PAPERS AND CRITICAL REVIEWS ON BIOMOLECULAR CHEMISTRY, MEDICINAL CHEMISTRY AND RELATED DISCIPLINES, ELSEVIER, NL, vol. 18, no. 7, 1 April 2010 (2010-04-01), pages 2402 - 2411, XP027027247, ISSN: 0968-0896, [retrieved on 20100302]
MATHEW K K ET AL: "The Benzophenanthridine ring system", CURRENT SCIENCE, INDIAN ACADEMY OF SCIENCES, IN, vol. 24, no. 6, 15 May 1955 (1955-05-15), pages 193, XP009518150, ISSN: 0011-3891
SOIZIC PRADO ET AL: "Synthesis and cytotoxic activity of benzo[c][1,7] and [1,8]phenanthrolines analogues of nitidine and fagaronine", BIOORGANIC & MEDICINAL CHEMISTRY : A TETRAHEDRON PUBLICATION FOR THE RAPID DISSEMINATION OF FULL ORIGINAL RESEARCH PAPERS AND CRITICAL REVIEWS ON BIOMOLECULAR CHEMISTRY, MEDICINAL CHEMISTRY AND RELATED DISCIPLINES, vol. 12, no. 14, 1 July 2004 (2004-07-01), NL, pages 3943 - 3953, XP055657474, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2004.04.038
CLARK R L ET AL: "Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics", BIOORGANIC & MEDICINAL CHEMISTRY : A TETRAHEDRON PUBLICATION FOR THE RAPID DISSEMINATION OF FULL ORIGINAL RESEARCH PAPERS AND CRITICAL REVIEWS ON BIOMOLECULAR CHEMISTRY, MEDICINAL CHEMISTRY AND RELATED DISCIPLINES, ELSEVIER, NL, vol. 15, no. 14, 15 July 2007 (2007-07-15), pages 4741 - 4752, XP026265739, ISSN: 0968-0896, [retrieved on 20070715], DOI: 10.1016/J.BMC.2007.05.002
TANG WEN-LIN ET AL: "Synthesis and biological evaluation of 5-aminoethyl benzophenanthridone derivatives as DNA topoisomerase IB inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 178, 30 May 2019 (2019-05-30), pages 81 - 92, XP085751602, ISSN: 0223-5234, [retrieved on 20190530], DOI: 10.1016/J.EJMECH.2019.05.074
XIAO-RU ZHANG ET AL: "Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 22, 18 October 2018 (2018-10-18), US, pages 9908 - 9930, XP055657629, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b00639
SUDA CHAKTHONG ET AL: "New alkylamide from the stems of Zanthoxylum nitidum", NATURAL PRODUCT RESEARCH, vol. 33, no. 2, 19 February 2018 (2018-02-19), GB, pages 153 - 161, XP055657721, ISSN: 1478-6419, DOI: 10.1080/14786419.2018.1440218
NANDINI SHARMA ET AL: "Microwave-Assisted Ruthenium-Catalysed ortho -C-H Functionalization of N -Benzoyl [alpha] -Amino Ester Derivatives", ADVANCED SYNTHESIS & CATALYSIS, vol. 360, no. 16, 28 June 2018 (2018-06-28), DE, pages 3083 - 3089, XP055657726, ISSN: 1615-4150, DOI: 10.1002/adsc.201800458
QI-FANG LEI ET AL: "Chemical Constituents of Plants from Tribe Chelidonieae and their Bioactivities", CHINESE HERBAL MEDICINES, vol. 6, no. 1, 1 February 2014 (2014-02-01), CN, pages 1 - 21, XP055657740, ISSN: 1674-6384, DOI: 10.1016/S1674-6384(14)60001-0
CHENG-HUI YANG ET AL: "Secondary Metabolites and Cytotoxic Activities from the Stem Bark of Zanthoxylum nitidum", CHEMISTRY & BIODIVERSITY, vol. 6, no. 6, 1 June 2009 (2009-06-01), CH, pages 846 - 857, XP055657747, ISSN: 1612-1872, DOI: 10.1002/cbdv.200800107
N. M. SAZONOVA ET AL: "Synthesis and antitumor activity of salts of O-methylfagaronine and its structural analog ? C-norbenzo[C]phenanthridine methyl chloride", PHARMACEUTICAL CHEMISTRY JOURNAL, vol. 25, no. 7, 1 July 1991 (1991-07-01), US, pages 465 - 469, XP055658945, ISSN: 0091-150X, DOI: 10.1007/BF00772000
HISASHI ISHII ET AL: "Chelirubine.", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 26, no. 3, 1 January 1978 (1978-01-01), JP, pages 864 - 873, XP055657823, ISSN: 0009-2363, DOI: 10.1248/cpb.26.864
MIYOJI HANAOKA ET AL: "Chemical transformation of protoberberines. XVI. Regioselective introduction of an oxy functionality at the C12-position of the benzo(c)phenanthridine skeleton: A convenient synthesis of macarpine from oxychelirubine.", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 38, no. 12, 1 January 1990 (1990-01-01), JP, pages 3335 - 3340, XP055657837, ISSN: 0009-2363, DOI: 10.1248/cpb.38.3335
HISASHI ISHII ET AL: "Studies on the chemical constituents of rutaceous plants. LV. The development of a versatile method for the synthesis of antitumor-active benzo(c)phenanthridine alkaloids. 5. A new method for quaternization of the benzo(c)phenanthridine nucleus.", CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 32, no. 8, 1 January 1984 (1984-01-01), JP, pages 2984 - 2994, XP055658022, ISSN: 0009-2363, DOI: 10.1248/cpb.32.2984
KISELYOV A S: "Reaction of ortho-Lithiated N-Methylbenzamide with 1,2-Diketones: A Novel Highly Efficient Route to N-Methylisoquinolin-1-ones", TETRAHEDRON LETTERS, ELSEVIER LTD, AMSTERDAM, NL, vol. 36, no. 4, 23 January 1995 (1995-01-23), pages 493 - 496, XP004028776, ISSN: 0040-4039, DOI: 10.1016/0040-4039(94)02293-K
YANG SHENG-HUI ET AL: "Isoquinoline alkaloids fromand their biological evaluation", THE JOURNAL OF ANTIBIOTICS, NATURE PUBLISHING GROUP, GB, vol. 68, no. 4, 1 October 2014 (2014-10-01), pages 289 - 292, XP036973715, ISSN: 0021-8820, [retrieved on 20141001], DOI: 10.1038/JA.2014.139
CHO W-J ET AL: "A NOVEL SYNTHESIS OF BENZOÄCÜPHENANTHRIDINE SKELETON AND BIOLOGICAL EVALUATION OF ISOQUINOLINE DERIVATIVES", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 47, no. 6, 1 January 1999 (1999-01-01), pages 900 - 902, XP001204220, ISSN: 0009-2363
NAKAMURA M ET AL: "Structural development studies of anti-hepatitis C virus agents with a phenanthridinone skeleton", BIOORGANIC & MEDICINAL CHEMISTRY : A TETRAHEDRON PUBLICATION FOR THE RAPID DISSEMINATION OF FULL ORIGINAL RESEARCH PAPERS AND CRITICAL REVIEWS ON BIOMOLECULAR CHEMISTRY, MEDICINAL CHEMISTRY AND RELATED DISCIPLINES, ELSEVIER, NL, vol. 18, no. 7, 1 April 2010 (2010-04-01), pages 2402 - 2411, XP027027247, ISSN: 0968-0896, [retrieved on 20100302]
MATHEW K K ET AL: "The Benzophenanthridine ring system", CURRENT SCIENCE, INDIAN ACADEMY OF SCIENCES, IN, vol. 24, no. 6, 15 May 1955 (1955-05-15), pages 193, XP009518150, ISSN: 0011-3891
SOIZIC PRADO ET AL: "Synthesis and cytotoxic activity of benzo[c][1,7] and [1,8]phenanthrolines analogues of nitidine and fagaronine", BIOORGANIC & MEDICINAL CHEMISTRY : A TETRAHEDRON PUBLICATION FOR THE RAPID DISSEMINATION OF FULL ORIGINAL RESEARCH PAPERS AND CRITICAL REVIEWS ON BIOMOLECULAR CHEMISTRY, MEDICINAL CHEMISTRY AND RELATED DISCIPLINES, vol. 12, no. 14, 1 July 2004 (2004-07-01), NL, pages 3943 - 3953, XP055657474, ISSN: 0968-0896, DOI: 10.1016/j.bmc.2004.04.038
CLARK R L ET AL: "Exploring DNA topoisomerase I inhibition by the benzo[c]phenanthridines fagaronine and ethoxidine using steered molecular dynamics", BIOORGANIC & MEDICINAL CHEMISTRY : A TETRAHEDRON PUBLICATION FOR THE RAPID DISSEMINATION OF FULL ORIGINAL RESEARCH PAPERS AND CRITICAL REVIEWS ON BIOMOLECULAR CHEMISTRY, MEDICINAL CHEMISTRY AND RELATED DISCIPLINES, ELSEVIER, NL, vol. 15, no. 14, 15 July 2007 (2007-07-15), pages 4741 - 4752, XP026265739, ISSN: 0968-0896, [retrieved on 20070715], DOI: 10.1016/J.BMC.2007.05.002
TANG WEN-LIN ET AL: "Synthesis and biological evaluation of 5-aminoethyl benzophenanthridone derivatives as DNA topoisomerase IB inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 178, 30 May 2019 (2019-05-30), pages 81 - 92, XP085751602, ISSN: 0223-5234, [retrieved on 20190530], DOI: 10.1016/J.EJMECH.2019.05.074
XIAO-RU ZHANG ET AL: "Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 22, 18 October 2018 (2018-10-18), US, pages 9908 - 9930, XP055657629, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b00639
Attorney, Agent or Firm:
GARABEDIAN, Todd E. (US)
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