Title:
CHIRAL HETEROCYCLIC COMPOUND WITH HEDGEHOG PATHWAY ANTAGONIST ACTIVITY, METHOD AND USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2018/006756
Kind Code:
A1
Abstract:
A chiral heterocyclic compound with hedgehog pathway antagonist activity, method and use thereof are provided. The chiral heterocyclic compound with hedgehog pathway antagonist activity has the structure represented by formula I. A pharmaceutical composition and combined application composition are also provided. Novel molecules of formula II that inhibit hedgehog pathway signaling and therapeutic applications for the treatment of malignancies, prevention of tumor regrowth, sensitization of radio-chemo therapies, and other diseases related to hedgehog signaling are also provided.
Inventors:
ZHANG XIAOHU (CN)
Application Number:
PCT/CN2017/091130
Publication Date:
January 11, 2018
Filing Date:
June 30, 2017
Export Citation:
Assignee:
SUZHOU KINTOR PHARMACEUTICALS INC (CN)
International Classes:
C07D471/04; A61K31/395; A61K31/519; A61K33/24; A61K33/243; A61P35/00
Domestic Patent References:
| WO2014113191A1 | 2014-07-24 | |||
| WO2014113191A1 | 2014-07-24 |
Foreign References:
| CN103588771A | 2014-02-19 | |||
| EP1183040A1 | 2002-03-06 |
Other References:
GULAMHUSSEN, A.M. ET AL.: "Highly efficient preparation of R-1-methyl- tetrahydroisoquinoline using chiral Ru(II)-catalyst", REACTION KINETICS AND CATALYSIS LETTERS, vol. 97, no. 2, 11 July 2009 (2009-07-11), pages 335 - 340, XP019733397, DOI: doi:10.1007/s11144-009-0036-y
JIANGHUI, DEV. CELL REVIEW, vol. 15, 2008, pages 801 - 812
XIE ET AL., NATURE, vol. 391, 1998, pages 90 - 92
BAR ET AL., STEM CELLS, vol. 25, no. 10, 2007, pages 2524 - 33
FILBIN ET AL., NATURE MEDICINE, vol. 19, 2013, pages 1518 - 1523
SANCHEZ ET AL., PNAS, vol. 101, no. 34, 2004, pages 12561 - 566
BERMAN,D.M.;KARHADKAR,S.S.;MAITRA,A.;MONTES DE OCA,R.;GERSTENBLITH,M.R.;BRIGGS,K.;PARKER,A.R.; SHIMADA,Y.;ESHLEMAN,J.R.;WATKINS,D.: "Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumors", NATURE, vol. 425, 2003, pages 846 - 851, XP002554661, DOI: 10.1038/nature01972
KUBO ET AL., CANCER RES, vol. 64, 2003, pages 6071 - 6074
SIMS-MOURTADA ET AL., ONCOGENE, vol. 26, 2007, pages 5674 - 1055
SCALES ET AL., TRENDS PHARMACOL. SCI., vol. 30, 2009, pages 303 - 312
PEUKERTMILLER-MOSLIN, CHEMMEDCHEM, vol. 5, 2010, pages 500 - 512
HU ET AL., ACTA PHARMACOL. SIN., vol. 28, 2007, pages 1224 - 30
MIMEAULT ET AL., INT. J. CANCER, vol. 118, 2006, pages 1022 - 31
SIM-MOURTADA ET AL., CLIN. CANCER RES., vol. 12, 2006, pages 6565 - 6572
COOPER ET AL., SCIENCE, vol. 280, 1998, pages 1603 - 1607
CHEN ET AL., GENES. DEV., vol. 16, 2002, pages 2743 - 2748
TREMBLEY ET AL., J. MED. CHEM., vol. 52, 2009, pages 4400 - 4418
ROBARGE ET AL., BIOORG. MED. CHEM. LETT., vol. 19, 2009, pages 5576 - 5581
YAUCH ET AL., SCIENCE, vol. 326, 2009, pages 572 - 574
GULAMHUSSEN, A.M. ET AL.: "Highly efficient preparation of R-1-methyltetrahydroisoquinoline using chiral Ru(ll)-catalyst", REACTION KINETICS AND CATALYSIS LETTERS, vol. 97, no. 2, 11 July 2009 (2009-07-11), pages 335 - 340, XP019733397, DOI: 10.1007/s11144-009-0036-y
JEMAL,A.SIEGEL,R.WEINGERG.R.A.: "Cancer statistics", CA..CANCERJ CLI., vol. 144, 2010, pages 277 - 300, XP055137643, DOI: 10.3322/caac.20073
WORKMAN,P.;COLLINS,I.: "Cancer Drug Design and Discovery", 2008, ELSEVIER, article "Modern Cancer Drug Discovery:Integrating Targets, Technologies and Treatments.", pages: 3 - 38
DI MAGLIANO,M.P.HEBROK,M.: "Hedgehog signalling in cancer formation and maintenance", NAT.REV. CANCER, vol. 3, 2003, pages 903 - 911, XP002591182, DOI: 10.1038/NRC1229
BEACHY,P.A.KARHADKAR,S.S.BERMAN,D.M.: "Tissue repair and stem cell renewal in carcinogenesis", NATURE, vol. 432, 2004, pages 324 - 331
DAHMANE,N.LEE,J.ROBINS,P.HELLER,P.RUIZI ALTABA,A.: "Activation of the transcription factor Gli 1 and the sonic Hedgehog signaling pathway in skin tumours", NATURE, vol. 389, 1997, pages 876 - 881
HUTCHIN,M.E.KARIAPPER,M.S.T.GRATCHTCHOUK,M.WANG,A.WEI,L.CUMMINGS,D.LI U,J.MICHAEL,L.R.GLICK,A.DLUGOSZ,A.A.: "Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: Conditional skin tumorigenesis recapitulates the hair growth cycle", GENES DEV, vol. 19, 2004, pages 214 - 224
KUBO,M.;NAKAMURA,M.;TASAKI,A.;YAMANAKA,N.;NAKASHIMA,H.;NOMURA,M.;KUROKI,S.;KATANO,M.: "Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer", CANCER RES, vol. 64, 2004, pages 6071 - 6074
GOODRICH,L.V.SCOTT,M.P.: "Hedgehog and Patched in neural development and disease", NEURON, vol. 21, 1998, pages 1243 - 1257
STECCA,B.;MAS.,C.;CLEMENT,V.;ZBINDEN,M.;CORREA,R.;PIGUET,V.;BEERMANN,F.;RUIZ,A.: "Melanomas require Hedgehog-Gli signaling regulated by interactions between Glil and the RAS-MEK/AKT pathways", PROC.NATL.ACAD.SCI. US.A., vol. 104, 2007, pages 5895 - 5900
THAYER,S.P.;PASCADIMAGLIANO,M.;HEISER,P.W.;NIELSEN,C.M.;ROBERTS,D.J.;LAUWERS,G.Y.;QI,Y.P.;GYSIN,S.;FERNANDEZ-DELCASTILLO,C.;YAJNIK: "Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis", NATURE, vol. 425, 2003, pages 851 - 856, XP002987278, DOI: 10.1038/nature02009
LUM,L.BEACHY,P.A.: "The Hedgehog response network:sensors,witches,and routers", SCIENCE, vol. 304, 2004, pages 1755 - 1759
PASCADIMAGLIANO,M.HEBROK,M.: "Hedgehog signalling in cancer formation and maintenance", NAT. REV. CANCER, vol. 3, 2003, pages 903 - 911, XP002591182, DOI: 10.1038/NRC1229
ROMER,J.T.KIMURA,H.MAGDALENO,S.SASAI,K.FULLER,C.BAINES,H.CONNELLY,M.STEW ART,C.F.GOULD,S.RUBIN,L.L.: "Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptcl(+/-)p53(-/-) mice", CANCER CELL, vol. 6, 2004, pages 229 - 240
DMD, vol. 34, 2006, pages 1310 - 1316
REMINGTON: "The Science and Practice of Pharmacy", 1995, MACK PUBLISHING COMPANY
HOOVERJOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS
See also references of EP 3478685A4
JIANGHUI, DEV. CELL REVIEW, vol. 15, 2008, pages 801 - 812
XIE ET AL., NATURE, vol. 391, 1998, pages 90 - 92
BAR ET AL., STEM CELLS, vol. 25, no. 10, 2007, pages 2524 - 33
FILBIN ET AL., NATURE MEDICINE, vol. 19, 2013, pages 1518 - 1523
SANCHEZ ET AL., PNAS, vol. 101, no. 34, 2004, pages 12561 - 566
BERMAN,D.M.;KARHADKAR,S.S.;MAITRA,A.;MONTES DE OCA,R.;GERSTENBLITH,M.R.;BRIGGS,K.;PARKER,A.R.; SHIMADA,Y.;ESHLEMAN,J.R.;WATKINS,D.: "Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumors", NATURE, vol. 425, 2003, pages 846 - 851, XP002554661, DOI: 10.1038/nature01972
KUBO ET AL., CANCER RES, vol. 64, 2003, pages 6071 - 6074
SIMS-MOURTADA ET AL., ONCOGENE, vol. 26, 2007, pages 5674 - 1055
SCALES ET AL., TRENDS PHARMACOL. SCI., vol. 30, 2009, pages 303 - 312
PEUKERTMILLER-MOSLIN, CHEMMEDCHEM, vol. 5, 2010, pages 500 - 512
HU ET AL., ACTA PHARMACOL. SIN., vol. 28, 2007, pages 1224 - 30
MIMEAULT ET AL., INT. J. CANCER, vol. 118, 2006, pages 1022 - 31
SIM-MOURTADA ET AL., CLIN. CANCER RES., vol. 12, 2006, pages 6565 - 6572
COOPER ET AL., SCIENCE, vol. 280, 1998, pages 1603 - 1607
CHEN ET AL., GENES. DEV., vol. 16, 2002, pages 2743 - 2748
TREMBLEY ET AL., J. MED. CHEM., vol. 52, 2009, pages 4400 - 4418
ROBARGE ET AL., BIOORG. MED. CHEM. LETT., vol. 19, 2009, pages 5576 - 5581
YAUCH ET AL., SCIENCE, vol. 326, 2009, pages 572 - 574
GULAMHUSSEN, A.M. ET AL.: "Highly efficient preparation of R-1-methyltetrahydroisoquinoline using chiral Ru(ll)-catalyst", REACTION KINETICS AND CATALYSIS LETTERS, vol. 97, no. 2, 11 July 2009 (2009-07-11), pages 335 - 340, XP019733397, DOI: 10.1007/s11144-009-0036-y
JEMAL,A.SIEGEL,R.WEINGERG.R.A.: "Cancer statistics", CA..CANCERJ CLI., vol. 144, 2010, pages 277 - 300, XP055137643, DOI: 10.3322/caac.20073
WORKMAN,P.;COLLINS,I.: "Cancer Drug Design and Discovery", 2008, ELSEVIER, article "Modern Cancer Drug Discovery:Integrating Targets, Technologies and Treatments.", pages: 3 - 38
DI MAGLIANO,M.P.HEBROK,M.: "Hedgehog signalling in cancer formation and maintenance", NAT.REV. CANCER, vol. 3, 2003, pages 903 - 911, XP002591182, DOI: 10.1038/NRC1229
BEACHY,P.A.KARHADKAR,S.S.BERMAN,D.M.: "Tissue repair and stem cell renewal in carcinogenesis", NATURE, vol. 432, 2004, pages 324 - 331
DAHMANE,N.LEE,J.ROBINS,P.HELLER,P.RUIZI ALTABA,A.: "Activation of the transcription factor Gli 1 and the sonic Hedgehog signaling pathway in skin tumours", NATURE, vol. 389, 1997, pages 876 - 881
HUTCHIN,M.E.KARIAPPER,M.S.T.GRATCHTCHOUK,M.WANG,A.WEI,L.CUMMINGS,D.LI U,J.MICHAEL,L.R.GLICK,A.DLUGOSZ,A.A.: "Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: Conditional skin tumorigenesis recapitulates the hair growth cycle", GENES DEV, vol. 19, 2004, pages 214 - 224
KUBO,M.;NAKAMURA,M.;TASAKI,A.;YAMANAKA,N.;NAKASHIMA,H.;NOMURA,M.;KUROKI,S.;KATANO,M.: "Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer", CANCER RES, vol. 64, 2004, pages 6071 - 6074
GOODRICH,L.V.SCOTT,M.P.: "Hedgehog and Patched in neural development and disease", NEURON, vol. 21, 1998, pages 1243 - 1257
STECCA,B.;MAS.,C.;CLEMENT,V.;ZBINDEN,M.;CORREA,R.;PIGUET,V.;BEERMANN,F.;RUIZ,A.: "Melanomas require Hedgehog-Gli signaling regulated by interactions between Glil and the RAS-MEK/AKT pathways", PROC.NATL.ACAD.SCI. US.A., vol. 104, 2007, pages 5895 - 5900
THAYER,S.P.;PASCADIMAGLIANO,M.;HEISER,P.W.;NIELSEN,C.M.;ROBERTS,D.J.;LAUWERS,G.Y.;QI,Y.P.;GYSIN,S.;FERNANDEZ-DELCASTILLO,C.;YAJNIK: "Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis", NATURE, vol. 425, 2003, pages 851 - 856, XP002987278, DOI: 10.1038/nature02009
LUM,L.BEACHY,P.A.: "The Hedgehog response network:sensors,witches,and routers", SCIENCE, vol. 304, 2004, pages 1755 - 1759
PASCADIMAGLIANO,M.HEBROK,M.: "Hedgehog signalling in cancer formation and maintenance", NAT. REV. CANCER, vol. 3, 2003, pages 903 - 911, XP002591182, DOI: 10.1038/NRC1229
ROMER,J.T.KIMURA,H.MAGDALENO,S.SASAI,K.FULLER,C.BAINES,H.CONNELLY,M.STEW ART,C.F.GOULD,S.RUBIN,L.L.: "Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptcl(+/-)p53(-/-) mice", CANCER CELL, vol. 6, 2004, pages 229 - 240
DMD, vol. 34, 2006, pages 1310 - 1316
REMINGTON: "The Science and Practice of Pharmacy", 1995, MACK PUBLISHING COMPANY
HOOVERJOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS
See also references of EP 3478685A4
Attorney, Agent or Firm:
UNITALEN ATTORNEYS AT LAW (CN)
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