Title:
NITROGEN-CONTAINING TRICYCLIC COMPOUND AND PHARMACEUTICAL USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2023/032940
Kind Code:
A1
Abstract:
The present invention provides a compound which has PDHK inhibitory activity and which is useful for treating or preventing diabetes (type 1 diabetes, type 2 diabetes, etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactatemia, diabetes complications (diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, cataract, etc.), heart failure (acute heart failure, chronic heart failure), cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral arterial disease, intermittent claudication, chronic obstructive pulmonary disease, brain ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, pulmonary hypertension, Alzheimer's disease, vascular dementia, glaucoma, retinopathy of diabetes, retinopathy of prematurity, retinal vein occlusion, ischemic optic neuropathy, or chronic kidney disease. The present invention relates to a compound represented by formula [I], formula [II], or formula [III] or a pharmaceutically acceptable salt thereof. [In the formula, each symbol has the same meaning as in the description.]
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Inventors:
YAMAKAWA MAKI (JP)
SUZAWA KOICHI (JP)
YAMASHITA TOMOYA (JP)
UENO HIROSHI (JP)
MANABE TOMOYUKI (JP)
SUZAWA KOICHI (JP)
YAMASHITA TOMOYA (JP)
UENO HIROSHI (JP)
MANABE TOMOYUKI (JP)
Application Number:
PCT/JP2022/032483
Publication Date:
March 09, 2023
Filing Date:
August 30, 2022
Export Citation:
Assignee:
JAPAN TOBACCO INC (JP)
International Classes:
C07D471/14; A61K31/424; A61K31/437; A61K31/4985; A61K31/5025; A61K31/5377; A61K31/5386; A61P3/00; A61P3/06; A61P3/10; A61P9/00; A61P9/04; A61P9/10; A61P9/12; A61P11/00; A61P21/00; A61P25/00; A61P25/02; A61P25/28; A61P27/06; A61P35/00; A61P43/00; C07D487/14; C07D498/04; C07D498/14; C07D519/00
Domestic Patent References:
| WO2019151274A1 | 2019-08-08 | |||
| WO2017020981A1 | 2017-02-09 | |||
| WO2014142290A1 | 2014-09-18 | |||
| WO2001017956A1 | 2001-03-15 | |||
| WO2021177330A1 | 2021-09-10 | |||
| WO2019151274A1 | 2019-08-08 |
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SUGDEN MCHOLNESS MJ: "Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs", AM J PHYSIOL ENDOCRINOL METAB., vol. 284, no. 5, May 2003 (2003-05-01), pages E855 - 62, XP008101778, DOI: 10.1152/ajpendo.00526.2002
BOWKER-KINLEY MM, DAVIS WI, WU P, HARRIS RA, POPOV KM.: "Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex", BIOCHEM J., vol. 329, 1 January 1998 (1998-01-01), pages 191 - 6
KIM JWTCHERNYSHYOV ISEMENZA GLDANG CV: "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia", CELL METAB., vol. 3, no. 3, March 2006 (2006-03-01), pages 177 - 85
MORINO KPETERSEN KFDUFOUR SBEFROY DFRATTINI JSHATZKES N ET AL.: "Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents", J CLIN INVEST., vol. 115, no. 12, December 2005 (2005-12-01), pages 3587 - 93
CATERSON IDFULLER SJRANDLE PJ: "Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid on pyruvate dehydrogenase complex activity in starved and alloxan-diabetic rats.", BIOCHEM J., vol. 208, no. 1, 15 October 1982 (1982-10-15), pages 53 - 60
BODEN GCHEN XSTEIN TP: "Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus", AM J PHYSIOL ENDOCRINOL METAB., vol. 280, no. 1, January 2001 (2001-01-01), pages 23 - 30
SHANGRAW REFISHER DM: "Pharmacokinetics and pharmacodynamics of dichloroacetate in patients with cirrhosis", CLIN PHARMACOL THER., vol. 66, no. 4, October 1999 (1999-10-01), pages 380 - 90
STACPOOLE PWMOORE GWKORNHAUSER DM: "Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia", NENGL J MED., vol. 298, no. 10, 9 March 1978 (1978-03-09), pages 526 - 30
MAYERS RMLEIGHTON BKILGOUR E.: "PDH kinase inhibitors: a novel therapy for Type II diabetes?", BIOCHEM SOC TRANS., vol. 33, April 2005 (2005-04-01), pages 367 - 70, XP003021543, DOI: 10.1042/BST0330367
JEOUNG NHRAHIMI YWU PLEE WNHARRIS RA: "Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice", BIOCHEM J., vol. 443, no. 3, 1 May 2012 (2012-05-01), pages 829 - 39
ZHOU YPBERGGREN POGRILL V: "A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse", DIABETES, vol. 45, no. 5, May 1996 (1996-05-01), pages 580 - 6
XU JHAN JEPSTEIN PNLIU YQ: "Regulation of PDK mRNA by high fatty acid and glucose in pancreatic islets", BIOCHEM BIOPHYS RES COMMUN., vol. 344, no. 3, 9 June 2006 (2006-06-09), pages 827 - 33
BENFOTIAMINE. MONOGRAPH. ALTERN MED REV., vol. 11, no. 3, September 2006 (2006-09-01), pages 238 - 42
VALLIANOU NEVANGELOPOULOS AKOUTALAS P.: "Alpha-lipoic Acid and diabetic neuropathy", REV DIABET STUD., vol. 6, no. 4, 2009, pages 230 - 6, XP055554845, DOI: 10.1900/RDS.2009.6.230
USSHER JRLOPASCHUK GD.: "The malonyl CoA axis as a potential target for treating ischaemic heart disease", CARDIOVASC RES., vol. 79, no. 2, 15 July 2008 (2008-07-15), pages 259 - 68, XP002798431, DOI: 10.1093/cvr/cvn130
WARGOVICH TJMACDONALD RGHILL JAFELDMAN RLSTACPOOLEPWPEPINE CJ: "Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary arterial disease", AM J CARDIOL., vol. 61, no. 1, 1 January 1988 (1988-01-01), pages 65 - 70, XP023276043, DOI: 10.1016/0002-9149(88)91306-9
TANIGUCHI MWILSON CHUNTER CAPEHOWICH DJCLANACHAN ASLOPASCHUK GD: "Dichloroacetate improves cardiac efficiency after ischemia independent of changes in mitochondrial proton leak", AM J PHYSIOL HEART CIRC PHYSIOL., vol. 280, no. 4, April 2001 (2001-04-01), pages 1762 - 9
STACPOOLE PWNAGARAJA NVHUTSON AD: "Efficacy of dichloroacetate as a lactate-lowering drug", J CLIN PHARMACOL., vol. 43, no. 7, July 2003 (2003-07-01), pages 683 - 91
BONNET SARCHER SLALLALUNIS-TURNER JHAROMY ABEAULIEU CTHOMPSON R ET AL.: "A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth", CANCER CELL, vol. 11, no. 1, January 2007 (2007-01-01), pages 37 - 51, XP009133827, DOI: 10.1016/j.ccr.2006.10.020
MCMURTRY MSBONNET SWU XDYCK JRHAROMY AHASHIMOTO K ET AL.: "Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis.", CIRC RES., vol. 95, no. 8, 15 October 2004 (2004-10-15), pages 830 - 40, XP003001198
SAXENA U.: "Bioenergetics breakdown in Alzheimer's disease: targets for new therapies.", INT J PHYSIOL PATHOPHYSIOL PHARMACOL., vol. 3, no. 2, 2011, pages 133 - 9
STACPOOLE PW: "The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases", AGING CELL, vol. 11, no. 3, June 2012 (2012-06-01), pages 371 - 7
MARANGOS PJTURKEL CCDZIEWANOWSKA ZEFOX AW: "Dichloroacetate and cerebral ischaemia therapeutics", EXPERT OPIN INVESTIG DRUGS., vol. 8, no. 4, April 1999 (1999-04-01), pages 373 - 82
CALVERT LDSHELLEY RSINGH SJGREENHAFF PLBANKART JMORGAN MD ET AL.: "Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease", AM J RESPIR CRIT CARE MED., vol. 177, no. 10, 15 May 2008 (2008-05-15), pages 1090 - 4
FLAVIN DF.: "Journal of Oncology", vol. 2010, J ONCOL. HINDAWI PUBLISHING CORPORATION, article "Non-Hodgkin's Lymphoma Reversal with Dichloroacetate", pages: 4
FROELICH LGOETZ MEWEINMUELLER MYOUDIM MBBARTH NDIRR AGSELL WJELLINGER KBECKMANN HRIEDERER P.: "r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia.", J NEURAL TRANSM (VIENNA)., vol. 111, no. 3, March 2004 (2004-03-01), pages 295 - 310
PARNETTI LREBOLDI GPGALLAI V: "Cerebrospinal fluid pyruvate levels in Alzheimer's disease and vascular dementia", NEUROLOGY, vol. 54, no. 3, 8 February 2000 (2000-02-08), pages 735 - 7
PASCUAL BPRIETO EARBIZU JMARTI-CLIMENT JOLIER JMASDEU JC: "Brain glucose metabolism in vascular white matter disease with dementia: differentiation from Alzheimer disease", STROKE, vol. 41, no. 12, December 2010 (2010-12-01), pages 2889 - 93
SATO KMOCHIDA STOMIMOTO DKONUMA TKIYOTA NTSUDA SSHIGA YOMODAKA KNAKAZAWA T: "A pyruvate dehydrogenase kinase inhibitor prevents retinal cell death and improves energy metabolism in rat retinas after ischemia/reperfusion injury", EXPERIMENTAL EYE RESEARCH, vol. 193, April 2020 (2020-04-01), pages 107997
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
STAHL: "Properties, Selection, and Use", 2002, WILEY-VCH
PAULEKUHN ET AL., J. MED. CHEM., vol. 50, 2007, pages 6665 - 6672
PATEL MSROCHE TE: "Molecular biology and biochemistry of pyruvate dehydrogenase complexes", FASEB J., vol. 4, no. 14, November 1990 (1990-11-01), pages 3224 - 33
SUGDEN MCHOLNESS MJ: "Recent advances in mechanisms regulating glucose oxidation at the level of the pyruvate dehydrogenase complex by PDKs", AM J PHYSIOL ENDOCRINOL METAB., vol. 284, no. 5, May 2003 (2003-05-01), pages E855 - 62, XP008101778, DOI: 10.1152/ajpendo.00526.2002
BOWKER-KINLEY MM, DAVIS WI, WU P, HARRIS RA, POPOV KM.: "Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex", BIOCHEM J., vol. 329, 1 January 1998 (1998-01-01), pages 191 - 6
KIM JWTCHERNYSHYOV ISEMENZA GLDANG CV: "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia", CELL METAB., vol. 3, no. 3, March 2006 (2006-03-01), pages 177 - 85
MORINO KPETERSEN KFDUFOUR SBEFROY DFRATTINI JSHATZKES N ET AL.: "Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents", J CLIN INVEST., vol. 115, no. 12, December 2005 (2005-12-01), pages 3587 - 93
CATERSON IDFULLER SJRANDLE PJ: "Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid on pyruvate dehydrogenase complex activity in starved and alloxan-diabetic rats.", BIOCHEM J., vol. 208, no. 1, 15 October 1982 (1982-10-15), pages 53 - 60
BODEN GCHEN XSTEIN TP: "Gluconeogenesis in moderately and severely hyperglycemic patients with type 2 diabetes mellitus", AM J PHYSIOL ENDOCRINOL METAB., vol. 280, no. 1, January 2001 (2001-01-01), pages 23 - 30
SHANGRAW REFISHER DM: "Pharmacokinetics and pharmacodynamics of dichloroacetate in patients with cirrhosis", CLIN PHARMACOL THER., vol. 66, no. 4, October 1999 (1999-10-01), pages 380 - 90
STACPOOLE PWMOORE GWKORNHAUSER DM: "Metabolic effects of dichloroacetate in patients with diabetes mellitus and hyperlipoproteinemia", NENGL J MED., vol. 298, no. 10, 9 March 1978 (1978-03-09), pages 526 - 30
MAYERS RMLEIGHTON BKILGOUR E.: "PDH kinase inhibitors: a novel therapy for Type II diabetes?", BIOCHEM SOC TRANS., vol. 33, April 2005 (2005-04-01), pages 367 - 70, XP003021543, DOI: 10.1042/BST0330367
JEOUNG NHRAHIMI YWU PLEE WNHARRIS RA: "Fasting induces ketoacidosis and hypothermia in PDHK2/PDHK4-double-knockout mice", BIOCHEM J., vol. 443, no. 3, 1 May 2012 (2012-05-01), pages 829 - 39
ZHOU YPBERGGREN POGRILL V: "A fatty acid-induced decrease in pyruvate dehydrogenase activity is an important determinant of beta-cell dysfunction in the obese diabetic db/db mouse", DIABETES, vol. 45, no. 5, May 1996 (1996-05-01), pages 580 - 6
XU JHAN JEPSTEIN PNLIU YQ: "Regulation of PDK mRNA by high fatty acid and glucose in pancreatic islets", BIOCHEM BIOPHYS RES COMMUN., vol. 344, no. 3, 9 June 2006 (2006-06-09), pages 827 - 33
BENFOTIAMINE. MONOGRAPH. ALTERN MED REV., vol. 11, no. 3, September 2006 (2006-09-01), pages 238 - 42
VALLIANOU NEVANGELOPOULOS AKOUTALAS P.: "Alpha-lipoic Acid and diabetic neuropathy", REV DIABET STUD., vol. 6, no. 4, 2009, pages 230 - 6, XP055554845, DOI: 10.1900/RDS.2009.6.230
USSHER JRLOPASCHUK GD.: "The malonyl CoA axis as a potential target for treating ischaemic heart disease", CARDIOVASC RES., vol. 79, no. 2, 15 July 2008 (2008-07-15), pages 259 - 68, XP002798431, DOI: 10.1093/cvr/cvn130
WARGOVICH TJMACDONALD RGHILL JAFELDMAN RLSTACPOOLEPWPEPINE CJ: "Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary arterial disease", AM J CARDIOL., vol. 61, no. 1, 1 January 1988 (1988-01-01), pages 65 - 70, XP023276043, DOI: 10.1016/0002-9149(88)91306-9
TANIGUCHI MWILSON CHUNTER CAPEHOWICH DJCLANACHAN ASLOPASCHUK GD: "Dichloroacetate improves cardiac efficiency after ischemia independent of changes in mitochondrial proton leak", AM J PHYSIOL HEART CIRC PHYSIOL., vol. 280, no. 4, April 2001 (2001-04-01), pages 1762 - 9
STACPOOLE PWNAGARAJA NVHUTSON AD: "Efficacy of dichloroacetate as a lactate-lowering drug", J CLIN PHARMACOL., vol. 43, no. 7, July 2003 (2003-07-01), pages 683 - 91
BONNET SARCHER SLALLALUNIS-TURNER JHAROMY ABEAULIEU CTHOMPSON R ET AL.: "A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth", CANCER CELL, vol. 11, no. 1, January 2007 (2007-01-01), pages 37 - 51, XP009133827, DOI: 10.1016/j.ccr.2006.10.020
MCMURTRY MSBONNET SWU XDYCK JRHAROMY AHASHIMOTO K ET AL.: "Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis.", CIRC RES., vol. 95, no. 8, 15 October 2004 (2004-10-15), pages 830 - 40, XP003001198
SAXENA U.: "Bioenergetics breakdown in Alzheimer's disease: targets for new therapies.", INT J PHYSIOL PATHOPHYSIOL PHARMACOL., vol. 3, no. 2, 2011, pages 133 - 9
STACPOOLE PW: "The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases", AGING CELL, vol. 11, no. 3, June 2012 (2012-06-01), pages 371 - 7
MARANGOS PJTURKEL CCDZIEWANOWSKA ZEFOX AW: "Dichloroacetate and cerebral ischaemia therapeutics", EXPERT OPIN INVESTIG DRUGS., vol. 8, no. 4, April 1999 (1999-04-01), pages 373 - 82
CALVERT LDSHELLEY RSINGH SJGREENHAFF PLBANKART JMORGAN MD ET AL.: "Dichloroacetate enhances performance and reduces blood lactate during maximal cycle exercise in chronic obstructive pulmonary disease", AM J RESPIR CRIT CARE MED., vol. 177, no. 10, 15 May 2008 (2008-05-15), pages 1090 - 4
FLAVIN DF.: "Journal of Oncology", vol. 2010, J ONCOL. HINDAWI PUBLISHING CORPORATION, article "Non-Hodgkin's Lymphoma Reversal with Dichloroacetate", pages: 4
FROELICH LGOETZ MEWEINMUELLER MYOUDIM MBBARTH NDIRR AGSELL WJELLINGER KBECKMANN HRIEDERER P.: "r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia.", J NEURAL TRANSM (VIENNA)., vol. 111, no. 3, March 2004 (2004-03-01), pages 295 - 310
PARNETTI LREBOLDI GPGALLAI V: "Cerebrospinal fluid pyruvate levels in Alzheimer's disease and vascular dementia", NEUROLOGY, vol. 54, no. 3, 8 February 2000 (2000-02-08), pages 735 - 7
PASCUAL BPRIETO EARBIZU JMARTI-CLIMENT JOLIER JMASDEU JC: "Brain glucose metabolism in vascular white matter disease with dementia: differentiation from Alzheimer disease", STROKE, vol. 41, no. 12, December 2010 (2010-12-01), pages 2889 - 93
SATO KMOCHIDA STOMIMOTO DKONUMA TKIYOTA NTSUDA SSHIGA YOMODAKA KNAKAZAWA T: "A pyruvate dehydrogenase kinase inhibitor prevents retinal cell death and improves energy metabolism in rat retinas after ischemia/reperfusion injury", EXPERIMENTAL EYE RESEARCH, vol. 193, April 2020 (2020-04-01), pages 107997
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
STAHL: "Properties, Selection, and Use", 2002, WILEY-VCH
PAULEKUHN ET AL., J. MED. CHEM., vol. 50, 2007, pages 6665 - 6672
Attorney, Agent or Firm:
TAKASHIMA, Hajime (JP)
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