Granted Patent
B2
US 12,649,720 · App. 18/767,083 · Granted Jun 9, 2026
Crystal forms of 2-[4-[(2,3,4-trimethoxyphenyl)methyl]piperazin-1-yl]ethyl pyridine-3-carboxylate
Inventors:
Neil Buckley (Boston, MA); Dan Belmont (Boston, MA); Sarah Bethune (Boston, MA); Krista Diaz (Boston, MA)
Assignee:
IMBRIA PHARMACEUTICALS, INC.
View Patent ↗
Loading inventors, assignments & file history…
Abstract
The invention provides polymorphs of a compound of Formula (X): The invention also provided pharmaceutical compositions containing polymorphs of the compound and methods treating conditions in a subject by providing polymorphs of the compound.
Claims (21)
1 . A method of treating a cardiovascular condition comprising providing to a subject with a cardiovascular condition a therapeutically effective amount of crystal Form A polymorph of a monohydrate hydrochloride salt of a compound of Formula (X):
wherein the Form A polymorph has an XRPD pattern as shown in FIG. 4 .
2 . The method of claim 1 , wherein the compound is provided in a pharmaceutical composition.
3 . The method of claim 2 , wherein the pharmaceutical composition is a unit dosage comprising from about 10 mg to about 1000 mg of the compound of Formula (X).
4 . The method of claim 3 , wherein the pharmaceutical composition is provided orally.
5 . The method of claim 3 , wherein the pharmaceutical composition is provided in at least one dose per day.
6 . The method of claim 3 , wherein the pharmaceutical composition is provided in multiple doses per day.
7 . The method of claim 5 , wherein the at least one dose is provided daily for at least two weeks.
8 . The method of claim 5 , wherein the at least one dose comprises about 200 mg of the compound of Formula (X).
9 . The method of claim 2 , wherein the pharmaceutical composition comprises a format selected from the group consisting of a tablet, troche, lozenge, aqueous suspension, oily suspension, emulsion, hard capsule, soft capsule, and syrup.
10 . The method of claim 2 , wherein the pharmaceutical composition comprises a mixture of the compound of Formula (X) and an erodible polymer that promotes swelling of the mixture in an aqueous environment.
11 . The method of claim 10 , wherein the erodible polymer is hydroxypropyl methylcellulose (HPMC).
12 . The method of claim 11 , wherein the mixture comprises the compound of Formula (X) and HPMC in a ratio of from about 1:10 to about 10:1.
13 . The method of claim 1 , wherein the cardiovascular condition is selected from the group consisting of aneurysm, angina, atherosclerosis, cardiomyopathy, cerebral vascular disease, congenital heart disease, coronary artery disease, coronary heart disease, diabetic cardiomyopathy, heart attack, heart disease, heart failure, hypertension, ischemic heart disease, pericardial disease, peripheral arterial disease, rheumatic heart disease, stroke, transient ischemic attacks, and valvular heart disease.
14 . The method of claim 13 , wherein the cardiovascular condition is angina.
15 . The method of claim 14 , wherein the angina is refractory to other medical interventions.
16 . The method of claim 1 , wherein the compound has an endothermic peak at about 85.3° C. (±5° C.) and at about 214.6° C. (±5° C.) in a differential scanning calorimetry (DSC) thermogram.
17 . The method of claim 1 , wherein the crystal is substantially free of polymorphs of Form B, Form C, Form D, and Form E.
18 . The method of claim 1 , wherein the compound has a DSC thermogram substantially in accordance with FIG. 5 .
19 . The method of claim 1 , wherein the compound exhibits a dehydration at about 25.9° C. to about 150.0° C. with a weight loss of about 3.46% in a thermogravimetric analysis (TGA).
20 . The method of claim 1 , wherein the compound has a TGA thermogram substantially in accordance with FIG. 5 .
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Nov 20, 2024
From: BUCKLEY, NEIL; BELMONT, DAN; BETHUNE, SARAH; DIAZ, KRISTA
To: IMBRIA PHARMACEUTICALS, INC.
Reel/Frame 069343/0538 →
Continuity (5)
Provisional Application
63046120
· Jun 30, 2020
References Cited (209)
US 4100285A
· Murai et al.
· 1978
[cited by applicant]
US 4140755A
· Sheth et al.
· 1979
[cited by applicant]
US 4166452A
· Generales, Jr.
· 1979
[cited by applicant]
US 4256108A
· Theeuwes
· 1981
[cited by applicant]
US 4265874A
· Bonsen et al.
· 1981
[cited by applicant]
US 4574156A
· Morita et al.
· 1986
[cited by applicant]
US 4845099A
· Ruger et al.
· 1989
[cited by applicant]
US 4876257A
· Hajos et al.
· 1989
[cited by applicant]
US 4885300A
· Press et al.
· 1989
[cited by applicant]
US 5077288A
· Lavielle et al.
· 1991
[cited by applicant]
US 5286728A
· Ferrini
· 1994
[cited by applicant]
US 5340809A
· Gaudry et al.
· 1994
[cited by applicant]
US 5380726A
· Ferrini
· 1995
[cited by applicant]
US 5384319A
· Ferrini
· 1995
[cited by applicant]
US 5397780A
· Mizuno et al.
· 1995
[cited by applicant]
US 5399557A
· Mizuno et al.
· 1995
[cited by applicant]
US 5401743A
· Rendenbach-Mueller et al.
· 1995
[cited by applicant]
US 5428038A
· Chatterjee et al.
· 1995
[cited by applicant]
US 5527800A
· Goto et al.
· 1996
[cited by applicant]
US 5591849A
· Kato et al.
· 1997
[cited by applicant]
US 5641779A
· Halazy et al.
· 1997
[cited by applicant]
US 5770735A
· Emonds-Alt et al.
· 1998
[cited by applicant]
US 5776937A
· Gante et al.
· 1998
[cited by applicant]
US 5849745A
· Wierzbicki et al.
· 1998
[cited by applicant]
US 5856326A
· Anthony et al.
· 1999
[cited by applicant]
US 5962448A
· Mizuno et al.
· 1999
[cited by applicant]
US 5977111A
· Mizuno et al.
· 1999
[cited by applicant]
US 6087346A
· Glennon et al.
· 2000
[cited by applicant]
US 6121267A
· Glase et al.
· 2000
[cited by applicant]
US 6200989B1
· De Cillis et al.
· 2001
[cited by applicant]
US 6214841B1
· Jackson et al.
· 2001
[cited by applicant]
US 6271223B1
· Mizuno et al.
· 2001
[cited by applicant]
US 6331623B1
· Mizuno et al.
· 2001
[cited by applicant]
US 6528529B1
· Brann et al.
· 2003
[cited by applicant]
US 6562978B1
· Imamura et al.
· 2003
[cited by applicant]
US 6693099B2
· Degenhardt et al.
· 2004
[cited by applicant]
US 7638531B2
· Mutahi et al.
· 2009
[cited by applicant]
US 7666866B2
· Franciskovich et al.
· 2010
[cited by applicant]
US 7772251B2
· Sturzebecher et al.
· 2010
[cited by applicant]
US 7968538B2
· Becker et al.
· 2011
[cited by applicant]
US 8016783B2
· Pastore et al.
· 2011
[cited by applicant]
US 8202901B2
· Lopaschuk et al.
· 2012
[cited by applicant]
US 8293240B2
· Newell et al.
· 2012
[cited by applicant]
US 8461117B2
· Sufi et al.
· 2013
[cited by applicant]
US 8569495B2
· Chassaing et al.
· 2013
[cited by applicant]
US 8697661B2
· Kritikou
· 2014
[cited by applicant]
US 9096538B2
· Nakamura et al.
· 2015
[cited by applicant]
US 9120801B2
· Alisi et al.
· 2015
[cited by applicant]
US 9169279B2
· Hanna et al.
· 2015
[cited by applicant]
US 20080108618A1
· Brann et al.
· 2008
[cited by applicant]
US 20080161400A1
· Virsik et al.
· 2008
[cited by applicant]
US 20090197891A1
· Lecanu et al.
· 2009
[cited by applicant]
US 20100022530A1
· Schiemann et al.
· 2010
[cited by applicant]
US 20110137362A1
· Foreman et al.
· 2011
[cited by applicant]
US 20110212072A1
· Henkel et al.
· 2011
[cited by applicant]
US 20120214818A1
· Dudley
· 2012
[cited by applicant]
US 20160346397A1
· Milne et al.
· 2016
[cited by applicant]
US 20190216936A1
· Levin
· 2019
[cited by applicant]
US 20220168431A1
· Levin et al.
· 2022
[cited by applicant]
US 20220226313A1
· Levin
· 2022
[cited by applicant]
US 20220249463A1
· Levin et al.
· 2022
[cited by applicant]
CA 2170615A1
· 1995
[cited by applicant]
CA 2186010A1
· 1995
[cited by applicant]
CA 3068254A1
· 2018
[cited by applicant]
CN 101747292B
· 2011
[cited by applicant]
DE 2714996A1
· 1977
[cited by applicant]
EP 0144991A2
· 1985
[cited by applicant]
EP 0251141A1
· 1988
[cited by applicant]
EP 615855A1
· 1994
[cited by applicant]
EP 661266A1
· 1995
[cited by applicant]
EP 749967A1
· 1996
[cited by applicant]
EP 1634598A1
· 2006
[cited by applicant]
EP 1886994A1
· 2008
[cited by applicant]
EP 2727916A1
· 2014
[cited by applicant]
JP S57131777
· 1982
[cited by applicant]
JP 2000147773A
· 2000
[cited by applicant]
JP 2006113343A
· 2006
[cited by applicant]
JP 2015017236A
· 2015
[cited by applicant]
RU 2377989C2
· 2010
[cited by applicant]
WO 1995000165A1
· 1995
[cited by applicant]
WO 9626196A2
· 1996
[cited by applicant]
WO 9630054A1
· 1996
[cited by applicant]
WO 9630343A1
· 1996
[cited by applicant]
WO 9728141A1
· 1997
[cited by applicant]
WO 9746549A1
· 1997
[cited by applicant]
WO 9858638A1
· 1998
[cited by applicant]
WO 9950247A1
· 1999
[cited by applicant]
WO 2001005763A2
· 2001
[cited by applicant]
WO 2002058698A2
· 2002
[cited by applicant]
WO 2002064576A1
· 2002
[cited by applicant]
WO 2003006628A2
· 2003
[cited by applicant]
WO 2006027223A1
· 2006
[cited by applicant]
WO 2006117686A2
· 2006
[cited by applicant]
WO 2006133784A1
· 2006
[cited by applicant]
WO 2007075629A2
· 2007
[cited by applicant]
WO 2007096251A1
· 2007
[cited by applicant]
WO 2007116074A1
· 2007
[cited by applicant]
WO 2007116243A2
· 2007
[cited by applicant]
WO 2008109991A1
· 2008
[cited by applicant]
WO 2009015485A1
· 2009
[cited by applicant]
WO 2009058818A2
· 2009
[cited by applicant]
WO 2009066315A2
· 2009
[cited by applicant]
WO 2009156479A1
· 2009
[cited by applicant]
WO 2011032099A1
· 2011
[cited by applicant]
WO 2012049101A1
· 2012
[cited by applicant]
WO 2015018660A1
· 2015
[cited by applicant]
WO 2016005576A1
· 2016
[cited by applicant]
WO 2016107603A1
· 2016
[cited by applicant]
WO 2018236745A1
· 2018
[cited by applicant]
WO 2020081361A1
· 2020
[cited by applicant]
WO 2020243119A1
· 2020
[cited by applicant]
WO 2020243120A1
· 2020
[cited by applicant]
WO 2021225950A1
· 2021
[cited by applicant]
WO 2022150403A1
· 2022
[cited by applicant]
Abrahamsson, 1998, In vitro and in vivo erosion of two different hydrophilic gel matrix tablets, European Journal of Pharmaceuticals and Biopharmaceutics, 46:69-75.
[cited by applicant]
Aswathy, 2018, Formulation and Evaluaton of Mucoadhesive Buccal Tablet of Antianginal Drug, IJPPR. Human Journals, 13(1):43-71.
[cited by applicant]
Bhosle, 2006, Mutual Prodrug Concept: Fundamentals and Applications, Indian Journal of Pharmaceutical Sciences, May-June, pp. 286-294.
[cited by applicant]
Brand, 2013, The role of mitochondrial function and cellular bioenergetics in ageing and disease, British Journal of Dermatology, John Wiley, Hoboken, USA, 169:1-8.
[cited by applicant]
Cheng, 2006, Discovery of Potent and Orally Available Malonyl-CoA Decarboxylase Inhibitors as Cardioprotective Agents, J. Med. Chem. 49:4055-4058.
[cited by applicant]
Cheng, 2006, Synthesis and structure-activity relationship of small-molecule malonyl coenzyme A decarboxylase inhibitors, J. Med. Chem. 49:1517-1525.
[cited by applicant]
Das, 1995, Essential Fatty Acid Metabolism in Patients with Essential Hypertension, Diabetes Mellitus and Coronary Heart Disease, Prostaglandins Leukotrienes and Essential Fatty Acids, 52, 387-391.
[cited by applicant]
Extended European Search Report issued European Application No. 21799968.9, date of mailing: Apr. 4, 2024, 10 pages.
[cited by applicant]
Extended European Search Report issued in European Application No. 18821590.9, date of mailing: Oct. 5, 2020, 6 pages.
[cited by applicant]
Extended European Search Report issued in European Application No. 19872680.4, date of mailing: Jun. 20, 2022, 7 pages.
[cited by applicant]
Extended European Search Report issued in European Application No. 21833175.9, date of mailing: Jul. 17, 2024, 8 pages.
[cited by applicant]
Extended European Search Report issued in European Application No. 22169109.0, date of mailing: Aug. 30, 2022, 7 pages.
[cited by applicant]
Fang, 2011. Therapeutic inhibition of fatty acid oxidation in right ventricular hypertrophy: exploiting Randle's cycle, Journal of Molecular Medicine, 90:31-43.
[cited by applicant]
Fillmore, 2014, Malonyl CoA: A Promising Target for the Treatment of Cardiac Disease, Int. Union of Biochem. and Mol. Biol., 66(3):139-146.
[cited by applicant]
Fillmore, 2014, Mitochondrial fatty acid oxidation alterations in heart failure, ischemic heart disease and diabetic cardiomyopathy, Brit. J. Pharmacol. 171:2080-2090.
[cited by applicant]
Folmes, 2005, Fatty Acid Oxidation Inhibitors in the Management of Chronic Complications of Atherosclerosis, Current Atherosclerosis Reports Jul. 2005, 63-70.
[cited by applicant]
Gallaher, 1993, Viscosity and Fermentability as Attributes of Dietary Fiber Responsible of the Hypocholesterolemic Effect in Hamsters, J Nutr., 123, pp. 244-252.
[cited by applicant]
Gao, 2011, Echocardiography in Mice. Curr Protoc Mouse Biol, 1:71-83.
[cited by applicant]
Gibbs, 1995, Cardiac efficiency, Cardiovasc. Res. 30:627-634.
[cited by applicant]
Gustafsson, 1999, Characterisation of particle properties and compaction behaviour of hydroxypropyl methylcellulose with different degrees of methoxy/hydroxypropyl substitution, European Journal of Pharmaceutical Scienc…
[cited by applicant]
Handbook of Pharmaceutical Excipients, 6th Ed, 2009, pp. 326-329.
[cited by applicant]
International Search Report and Written Opinion issued in International Application No. PCT/US2020/034611, date of mailing: Oct. 14, 2020, 45 pages.
[cited by applicant]
International Search Report and Written Opinion issued in International Application No. PCT/US2020/34608, date of mailing: Oct. 14, 2020, 28 pages.
[cited by applicant]
International Search Report and Written Opinion issued in International Application No. PCT/US2020/34609, date of mailing: Oct. 14, 2020, 22 pages.
[cited by applicant]
International Search Report and Written Opinion issued in International Application No. PCT/US2021/039303, date of mailing: Nov. 26, 2021, 19 pages.
[cited by applicant]
International Search Report and Written Opinion mailed Nov. 5, 2018, for International Patent Application PCT/US2018/038067 with International filing date Jun. 18, 2018 (11 pages).
[cited by applicant]
International Search Report issued in an International Application No. PCT/US2021/030450, date of mailing: Sep. 27, 2021, 9 pages.
[cited by applicant]
Kantor, 2000, The Antianginal Drug Trimetazidine Shifts Cardiac Energy Metabolism From Fatty Acid Oxidation to Glucose Oxidation by Inhibiting Mitochondrial Long-Chain 3-Ketoacyl Coenzyme A Thiolase, Circulation Researc…
[cited by applicant]
Kotreka, 2011, Gastroretentive Floating Drug-Delivery Systems: A Critical Review, Critical Reviews in Therapeutic Drug Carrier Systems, 28(1):47-99.
[cited by applicant]
Leriche, 2012, Cleavable linkers in chemical biology, Bioorg. Med. Chem. 20:571-582.
[cited by applicant]
Levy, 2014, Vasodilators in Acute Heart Failure: Review of the Latest Studies, Curr Emerg Hosp Med Rep, 2(2):126-134.
[cited by applicant]
Lopaschuk, 2010, Myocardial Fatty Acid Metabolism in Health and Disease, Phys. Rev. 90:207-258.
[cited by applicant]
Maskova, 2020, Hypromellose—A traditional pharmaceutical exipient with modern applications in oral and oromucosal drug delivery, Journal of Controlled Release, 324:695-727.
[cited by applicant]
Morin, 1998, Evidence for the existence of [3H]-trimetazidine binding sites involved in the regulation of the mitochondrial permeability transition pore, Brit. J. Pharmacol. 123:1385-1394.
[cited by applicant]
Narokha, 2014, Antioidant effect of nicotinic acid on experimental doxorubicin-induced chronic heart failure, Current Topics in Pharmacology, 18:105-111.
[cited by applicant]
Non-Final Office Action issued in U.S. Appl. No. 16/722,691, date of mailing: Aug. 19, 2020, 12 pages.
[cited by applicant]
Pubchem, CID 2223657, Jul. 15, 2005, pp. 1-14.
[cited by applicant]
Pubchem, CID-57503849, Create Date: Aug. 8, 2012, 16 pages.
[cited by applicant]
Reddy, 2006, Lipid Metabolism and Liver Inflammation. II. Fatty liver disease and fatty acid oxidation, Am J Physiol Gastrointest Liver Physiol, 290: G852-G858.
[cited by applicant]
Sabbah, 2005, Metabolic Therapy for Heart Disease: Impact of Trimetazidine, Heart Failure Reviews, 10, 281-288.
[cited by applicant]
Sannino, 2009, Biodegradable Cellulose-based Hydrogels: Design and Applications, Materials, 2:353-373.
[cited by applicant]
Schipke, 1994, Cardiac efficiency, Basic Res. Cardiol. 89:207-40.
[cited by applicant]
Spiekerkoetter, 2010, Mitochondrial fatty acid oxidation disorders: clinical presentation of long-chain fatty acid oxidation defects before and after newborn screening, J Inherit Metab Dis, 33:527-532.
[cited by applicant]
Steggall, 2017, Targeting Metabolic Modulation and Mitochondrial Dysfunction in the Treatment of Heart Failure, Diseases, 5(14):1-18.
[cited by applicant]
Tang, 2009, The Metabolic Approach in Patients with Heart Failure: Effects on Left Ventricle Remodeling, 15(8):850-856.
[cited by applicant]
The Merck Manual List of Diseases https://merckmanuals.com/professional (accessed Jan. 17, 2020), 4 pages.
[cited by applicant]
Trammell, 2016, Nicotinamide riboside is uniquely and orally bioavailable in mice and humans, Nat. Commun. 7:12948, 14 pages.
[cited by applicant]
Visser, 2008, Measuring cardiac efficiency: is it clinically useful? Heart Metab. 39:3-4.
[cited by applicant]
Yuasa, 1988, Pharmacological Studies on the Actions of Trimetazidine and Its Derivatives, The Journal of Kansai Medical University, vol. 40, Issue 1, pp. 89-116.
[cited by applicant]
Zhou, 2012, Trimetazidine Protects against Smoking-Induced Left Ventricular Remodeling via Attenuating Oxidative Stress, Apoptosis, and Inflammation, PLOS One, 7:1-7.
[cited by applicant]
Lin, 2004, Hydrophilic Excipients Modulate the Time Lag of Time-Controlled Disintegrating Press-coated Tablets, AAPS PharmSciTech, 5(4)Article 54, 5 pages.
[cited by applicant]
Maggi, 1999, Formulation of biphasic release tablets containing slightly soluble drugs, European Journal of Pharmaceutics and Biopharmaceutics, 48(1):37-42.
[cited by applicant]
Masso, 2005, Trimetazidine Indcues Parkinsonism, Gait Disorders and Tremor, Therapies, 60(4):419-422.
[cited by applicant]
Boland, 2013, Mitochondrial dysfunction in cancer, Frontiers in Oncology, 3(292): 1-28.
[cited by applicant]
Camarda, 2016, Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer, Nat Med, 22:427-432.
[cited by applicant]
Celik, 2008, Metabolic agents in the management of diabetic coronary patients: A new era, International Journal of Cardiology, 127:133-134.
[cited by applicant]
Gyamfi, 2022, Cancer as a Metabolic Disorder, Int J Mol Sci, 23(3):1155, 18 pages.
[cited by applicant]
Ji, 2020, Deregulation of Lipid Metabolism: The Critical Factors in Ovarian Cancer, Frontiers in Oncology, 10(593017), 10 pages.
[cited by applicant]
Kant, 2020, Enhanced fatty caid oxidation provides glioblastoma cells metabolic plasticity to accommodate to its dynamic nutrient microenvironment, Cell Death and Disease, 11:253.
[cited by applicant]
Karwi, 2018, Loss of Metabolic Flexibility in the Failing Heart, Frontiers in Cardiovascular Medicine, 5(68).
[cited by applicant]
Koundouros, 2020, Reprogramming of fatty acid metabolism in cancer, British Journal of Cancer, 122:4-22.
[cited by applicant]
Le, 2015, Increasing Pyruvate Dehydrogenase Flux as a Treatment for Diabetic Cardiomyopathy: A Combined 13C Hyperpolarized Magnetic Resonance and Echocardiography Study, Diabetes, 64:2735-2743.
[cited by applicant]
Mcclellan, 1999, Trimetazidine A Review of its Use in Stable Angine Pectoris and Other Coronary Conditions, Drugs, 58(1):143-157.
[cited by applicant]
Pellerin, 2020, Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives, Cancers, 12(11):3147.
[cited by applicant]
Pillai, 2023, Repurposing drugs targeting metabolic diseases for cancer therapeutics, Drug Discovery Today, 28(9): 103684.
[cited by applicant]
Sisakian, 2009, Beneficial long-term effects of Vastarel MR in patients with stable coronary artery disease developing left ventricular dysfunction Heart Metab, 42:25-28.
[cited by applicant]
Stine, 2022, Targeting cancer metabolism in the era of precision oncology, Nat Rev Drug Discov, 21:141-162.
[cited by applicant]
Zhao, 2021, Reprogramming of fatty acid metabolism in breast cancer: a narrative review, Transl Breast Cancer Res, 2:5, 9 pages.
[cited by applicant]