Granted Patent
B2
US 12,263,157 · App. 18/079,904 · Granted Apr 1, 2025
Aldosterone synthase inhibitors for treating chronic kidney disease
Inventors:
Lisa V. Cronin (Grand Island, NY); Sibylle Jenny Hauske (Mannheim, DE); Hartmut Ruetten (Ingelheim am Rhein, DE)
Assignee:
Boehringer Ingelheim International GmbH
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The present invention relates to treatment of chronic kidney disease by administering to patients in need thereof a compound of formula (1): and pharmaceutically acceptable salts thereof, wherein Cy, R 1 and R 2 are as defined herein. The invention further relates to the use of the compounds of formula (1) in combination with sodium-glucose cotransporter-2 (SGLT2) inhibitors.
Claims (18)
1. A method for treating a patient with chronic kidney disease (CKD), the method comprising administering compound 29A to the patient
wherein compound 29A is administered once daily in an amount of 3 mg, 10 mg or 20 mg, and
wherein the treatment provides an improvement in albumin creatinine ratio (UACR) measured in First Morning Void (FMV) urine.
2. The method according to claim 1 , wherein the patient has diabetic chronic kidney disease.
3. The method according to any of claim 1 , wherein the patient has non-diabetic chronic kidney disease.
4. The method according to claim 1 , wherein the patient has Stage 1 CKD, or Stage 2 CKD, or Stage 3 CKD, or Stage 4 CKD, or Stage 5 CKD.
5. The method according to claim 1 , further comprising administering to the patient a pharmaceutically effective amount of a SGLT2 inhibitor, or a pharmaceutically acceptable salt thereof.
6. The method according to claim 5 , wherein the SGLT2 inhibitor is empagliflozin.
7. The method of claim 1 , wherein the patient has an estimated glomerular filtration rate (eGFR) ≥30 and <90 mL/min/1.73 m 2 .
8. The method of claim 1 , wherein compound 29A is administered to the patient in an amount of 10 mg.
9. The method of claim 6 , wherein the empagliflozin is administered to the patient once daily in an amount of 10 mg.
10. A method for improving the albumin creatinine ratio (UACR) in a chronic kidney disease (CKD) patient, the method comprising administering to the patient compound 29A
wherein compound 29A is administered once daily in an amount of 10 mg.
11. The method of claim 10 , further comprising administering empagliflozin once daily to the patient.
12. The method of claim 11 , wherein the empagliflozin is administered once daily to the patient in an amount of 10 mg.
13. The method of claim 10 , wherein the patient has an estimated glomerular filtration rate (eGFR) ≥30 and <90 mL/min/1.73 m 2 .
14. The method of claim 10 , wherein the patient has diabetic chronic kidney disease.
15. The method of claim 10 , wherein the patient has non-diabetic chronic kidney disease.
Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 7, 2023
From: HAUSKE, SIBYLLE JENNY; RUETTEN, HARTMUT
To: BOEHRINGER INGELHEIM INTERNATIONAL GMBH
Reel/Frame 064504/0468 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 7, 2023
From: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.
To: BOEHRINGER INGELHEIM INTERNATIONAL GMBH
Reel/Frame 064504/0476 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Aug 7, 2023
From: CRONIN, LISA V.
To: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.
Reel/Frame 064504/0569 →
Continuity (2)
Provisional Application
63289177
· Dec 14, 2021
References Cited (103)
US 5892065A
· Tsukamoto et al.
· 1999
[cited by applicant]
US 7807843B2
· Goto et al.
· 2010
[cited by applicant]
US 8293734B2
· Thompson et al.
· 2012
[cited by applicant]
US 9181272B2
· Balestra et al.
· 2015
[cited by applicant]
US 9334285B2
· Burke et al.
· 2016
[cited by applicant]
US 9745289B2
· Hornberger
· 2017
[cited by applicant]
US 20110130537A1
· Carlberg et al.
· 2011
[cited by applicant]
US 20110172217A1
· Fujioka et al.
· 2011
[cited by applicant]
US 20140315832A1
· Broedl et al.
· 2014
[cited by applicant]
US 20180125813A1
· von Eynatten et al.
· 2018
[cited by applicant]
CA 2761859A1
· 2010
[cited by applicant]
CN 1172806A
· 1998
[cited by applicant]
CN 1692103A
· 2005
[cited by applicant]
CN 102741259A
· 2012
[cited by applicant]
CN 109053637A
· 2018
[cited by applicant]
EP 0666256A1
· 1995
[cited by applicant]
EP 2341052A1
· 2011
[cited by applicant]
JP 2007297305A
· 2007
[cited by applicant]
JP 2011530621A
· 2011
[cited by applicant]
JP 2012526774A
· 2012
[cited by applicant]
WO 0198273A1
· 2001
[cited by applicant]
WO 2007100295A1
· 2007
[cited by applicant]
WO 2007116099A1
· 2007
[cited by applicant]
WO 2007117982A2
· 2007
[cited by applicant]
WO 2008027284
· 2008
[cited by applicant]
WO 2009135651
· 2009
[cited by applicant]
WO 2009135651A1
· 2009
[cited by applicant]
WO 2010042477A1
· 2010
[cited by applicant]
WO 2014055595
· 2010
[cited by applicant]
WO 2010107765A1
· 2010
[cited by applicant]
WO 2010129467
· 2010
[cited by applicant]
WO 2013037779
· 2013
[cited by applicant]
WO 2013041591
· 2013
[cited by applicant]
WO 2013156423
· 2013
[cited by applicant]
WO 2014055595A1
· 2014
[cited by applicant]
WO 2014130608A1
· 2014
[cited by applicant]
WO 2014179186A1
· 2014
[cited by applicant]
WO 2015101958A2
· 2015
[cited by applicant]
WO WO2016014736A1
· 2016
[cited by examiner]
WO 2016144844A1
· 2016
[cited by applicant]
Bolignano et al., Cochrane Database Syst Rev. Apr. 29, 2014;(4):CD007004. (Year: 2014).
[cited by examiner]
Ménard et al., J Transl Med. Dec. 10, 2014;12:34 (Year: 2014).
[cited by examiner]
Yang et al., Current Opinion in Pharmacology, vol. 27, 2016, p. 78-85 (Year: 2016).
[cited by examiner]
Frimodt-Møller M, Persson F, Rossing P. Mitigating risk of aldosterone in diabetic kidney disease. Curr Opin Nephrol Hypertens. Jan. 2020;29(1):145-151. doi: 10.1097/MNH.0000000000000557. PMID: 31599747; PMCID: PMC69033…
[cited by examiner]
Frampton, J.E. Drugs 78, 1037-1048 (2018) (Year: 2018).
[cited by examiner]
Herrington, the potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease, Clin. Kidney Journal, 2018, 13 pages.
[cited by applicant]
Kdigo, 2020 clinical practice guideline for diabetes managment in chronic kidney disease, Kidney Int. supplement, vol. 98, 2020, p. S1-S115.
[cited by applicant]
Birge, Pharmaeutical Salts, J. Pharm. Sci, vol. 66, 1977, p. 1-19.
[cited by applicant]
Kdigo, Clinical Practice guifeline for acute kidney injury, Kidney Int. Supplement, vol. 2, 2012, p. 1-138.
[cited by applicant]
Jardine, Renal, cardiovascular and Safety outcomes of canagliflozin by baseline kidney function, J. of amer. nephrological society, vol. 31, 2020, p. 1128-1139.
[cited by applicant]
Farxiga, DAPA-CKD Phase III trial reduced worsening of kidney function, risk of cardiovacular or renal death in patients with chronic kidney disease, AstraZeneca Press Release, Oct. 23, 2020.
[cited by applicant]
Tuttle, Efficacy and safety of aldosterone synthase inhibition with and without empagliflozin for chornoic kidney disease, Lancet, Published online Dec. 15, 2023, https://doi.org/10.1016/S0140-6736(23)02408-x,).
[cited by applicant]
International Search Report, PCT/ISA/210, mailed Aug. 8, 2014, for PCT/US2014/035596.
[cited by applicant]
International Search Report, Mailed Feb. 16, 2016, PCT/ISA220, for PCT/US2015055421.
[cited by applicant]
Lucas, J. Med. Chem., vol. 51, “In Vivo Active aldosterone synthase inhibitors with improved selectivity: Lead optimization providing a series of Pyridine substituted 3,4 Dihydro-1H quinolin-2-one derivatives”, 2008.
[cited by applicant]
Anderson, Aldosterone Synthase Inhibition in Hypertenstion, Curr. Hypertens Rep., 2013, 15, p. 484-488.
[cited by applicant]
Hu, Aldosterone Synthase Inhibitors as Promising Treatments for Mineralocorticoid Dependent Cardiovascualr and renal Diseases, J. Med Chem, 2014, 57, p. 5011-5022.
[cited by applicant]
Banki, Aldosterone Antagonists in Monotherapy are Protective against Streptozotocin-Induced Diabetic Nephropathy in Rats, PLOS plus One, 2012, 7, e39938.
[cited by applicant]
Dorrance, Interfering with mineralcortocid receptor activation: the past, present and future, Prime Reports, 2014, p. 6-61.
[cited by applicant]
Hargovan, Aldoesterone Synthase Inhibitors in hypertension: current status and future possibilities, Journal of the Royal Society of Medicine, 2014, 0, p. 1-9.
[cited by applicant]
Heim, Overcominh undesirable CYP1A2 Inhibition of Pyridylnaphthaline-Type Aldoesterone Synthase Inhibtiors: Influence of Heteroaryl Derivatization on Potency and Selectivity Journal of Medicinal Chem, 2008, 501, p. 5011…
[cited by applicant]
Azzizi, Nephrol Dial Transplant 2013, 28, p. 36-43.
[cited by applicant]
International Report on Patetability for PCT/US2017038440 mailed Jan. 10, 2019.
[cited by applicant]
Sonegawa, Regioselective Alkylation of 2-Alkyl-5.6.7.8-tetrahydro-3H-cycloheptimidazol-4ones and 2-Alkyl-3H-cycloheptimidazol-4-ones, Chem and pharm Bulletin, 2006, vol. 54, p. 706-710.
[cited by applicant]
Mityanov, Regioselective synthesis of 2-unsubstituted 1-aryl-4-and 1-aryl-5 acylimiazoles″ Tetrahedron, 2014, vol. 70, p. 3545-3552.
[cited by applicant]
Bornstein, Phase 1C study of the aldosterone synthase inhibitor BI 690517 in diabetic patients with kidney disease, Journal of the American Society of Nephrology, vol. 32, 2021, p. 264-265.
[cited by applicant]
International Search Report for PCTUS2020030337 mailed Aug. 10, 2020.
[cited by applicant]
Abstract for JP2007297305 cited herein.
[cited by applicant]
International Search Report and Written Opinion, PCT, US 2015/041648, PCT/ISA/220, mailed Oct. 26, 2015.
[cited by applicant]
Hartmann, et al., “Discovery of selective CYP11B2 (aldosterone synthase) inhibitors for the therapy of congestive heart failure and myocardial fibrosis”, Euro. Journal of Medicinal Chamistry, vol. 38, No. 4, 2003.
[cited by applicant]
International Search Report and Written Opinion, Form ISA220, mailed Feb. 22, 2016, for PCT/US2015063064.
[cited by applicant]
International Preliminary Report on Patentability, Form PCT.IB/373, mailed Jun. 6, 2017.
[cited by applicant]
Martin, Synthesis of annulated pyridines as inhibitors of aldosterone synthase, Organic Biomol. Chemistry, vol. 14, 2016, 2016.
[cited by applicant]
Azizi, Aldosterone synthase inhibitors in humans, Nephrol Dial Translplant, vol. 28, p. 36-43. 2012.
[cited by applicant]
Hu, Aldosterone Synthase Inhibitors as promising treatments for mineralocorticoid dependent cardiovascular and renal diseases, Phamraceutical and Medicinal chem, vol. 57, 2014, p. 5011-5022.
[cited by applicant]
Banki, Aldosterone Antagonists in Monotherapy are protective against Streptozotocin-induced diabetic Neuropathy in rats, PLOS One, vol. 7, e39938, 2012.
[cited by applicant]
Andersen, Aldosterone Synthase Inhibitors in Hypertension, Current Hypertens Rep., vol. 15, 2013, p. 484-488.
[cited by applicant]
Hargovan, Aldosterone synthase inhibitors in hypertension: current status and future possibilities, Journal of the Royal Society of Medicine Cardiovascular Disease, 2014, p. 1-9.
[cited by applicant]
Dorrance, Interfering with mineralcorticoid receptor activation: the past, present and future, F1000 Prime Reports, 2014, p. 6-61.
[cited by applicant]
Shen, Synthesis of 2-(phenoxymehyl)oxirane derivatives through unexpected rearrangment of oxiran-2-ylmethyl benzenesulfomates, Synthetic Cimmuications, vol. 47, 2017, 6 pages.
[cited by applicant]
Evans, A narrative review of chronic kidney disease inclinical practice, Adv. Ther., vol. 9, 2022, 11 pages.
[cited by applicant]
Gilligan, Hyperkalemia and Hypokalemia in CKD, ACKD, vol. 24, 2017, p. 315-318.
[cited by applicant]
Neuen, Sodium-Glucose Cotransporter 2 inhibitors and Risk of Hyperkalemia in People with type 2 diabetes, Circulation, vol. 10, 2011, 11 pages.
[cited by applicant]
Verma, Aldosterone in chronic kidney disease and renal outcomes, ESC, vol. 43, 2022, 11 pages.
[cited by applicant]
Xiao, Phenylsulfone directed diasteroselective cyclization of an epoxy aalysilane system, J. of Organic Chem., vol. 53, 1988, p. 4869-4872.
[cited by applicant]
Mikleusevic, Oxazolidinone Synthesis through Halohydrin Dehalogenese Catalyzed dynamic kinetic resolution, Advanced Synthesis and Catalysis, vol. 357, 2015, p. 1709-171.
[cited by applicant]
Mende, Chronic Kidney Disease, and SGLT2 Inhibitors, Adv. Thera, vol. 10, 2022, p. 148-164.
[cited by applicant]
Wanner, Empa and Progression of Kidney Disease in Type 2 diabetes, The N. England J of Med., vol. 39, 2022, p. 148-164.
[cited by applicant]
International Search Report and Written Opinion for PCT/US2022/052631, mailed Mar. 23, 2023.
[cited by applicant]
Frimodt-Moller, Mitigating Risk of Aldosterone in Diabetic Kidney Disease, Current Opinion, vol. 29, 2020, 7 pages.
[cited by applicant]
Klunder, Arenesulfonate Derivatives of Homochiral Glycidol, J. Org. Chem, vol. 54, 1989, p. 1254-1304.
[cited by applicant]
Mitsuhiko, Gas and liquid purification technology, Electrochemistry, vol. 33, 1965, p. 458-462.
[cited by applicant]