IP Library › Granted Patent US 12,227,532
Granted Patent B2
US 12,227,532 · App. 17/741,427 · Granted Feb 18, 2025

Crystalline forms

Inventors: Daniel Leuenberger (Allschwil, CH); Stefan Reber (Allschwil, CH); Markus Von Raumer (Allschwil, CH)
Assignee: Viatris Asia Pacific Ptd. Ltd.
C07F9/65583C07B2200/13
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Quick Facts
Patent No.
US 12,227,532
App. No.
17/741,427
Granted
Feb 18, 2025
Kind
B2
Abstract

The invention relates to crystalline forms of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, processes for the preparation thereof, pharmaceutical compositions comprising said crystalline forms, pharmaceutical compositions prepared from such crystalline forms and their use as a medicament, especially as a P2Y 12 receptor antagonist.

Claims (23)

1. A method for the treatment of a disease that is responsive to the inhibition of platelet aggregation, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising as active ingredient a P2Y 12 receptor antagonist which is 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier material, wherein 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester, or the pharmaceutically acceptable salt thereof, is obtained from a crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride, wherein the crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride is characterized by:

a. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 4.0°, 5.0°, and 15.3°; or

b. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.2°, 6.8°, and 10.3°; or

c. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.5°, 11.0°, and 16.6°.

2. The method according to claim 1 , wherein the crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride is characterized by:

a. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°; or

b. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°; or

c. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, and 16.6°.

3. The method according to claim 1 , wherein the crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride is characterized by:

a. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and 20.7°; or

b. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°; or

c. the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.5°, 7.2°, 11.0°, 11.5°, 14.4°, 16.6°, 18.1°, 21.1°, and 22.0°.

4. The method according to claim 1 , wherein the crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 4.0°, 5.0°, 11.7°, 15.3°, and 19.3°.

5. The method according to claim 1 , wherein the crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.2°, 6.8°, 10.3°, 10.8°, and 15.4°.

6. The method according to claim 1 , wherein the crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 4.0°, 5.0°, 5.9°, 11.7°, 15.3°, 16.9°, 19.3°, 19.7°, and 20.7°.

7. The method according to claim 1 , wherein the crystalline form of 4-((R)-2-{[6-((S)-3-methoxy-pyrrolidin-1-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-3-phosphono-propionyl)-piperazine-1-carboxylic acid butyl ester hydrochloride is characterized by the presence of peaks in the X-ray powder diffraction diagram at the following angles of refraction 2θ: 5.2°, 6.8°, 8.0°, 10.3°, 10.8°, 12.7°, 15.4°, 16.2°, 20.3°, and 21.7°.

8. The method according to claim 1 , wherein the at least one pharmaceutically acceptable carrier material is a pharmaceutically acceptable liquid carrier material.

9. The method according to claim 2 , wherein the at least one pharmaceutically acceptable carrier material is a pharmaceutically acceptable liquid carrier material.

10. The method according to claim 3 , wherein the at least one pharmaceutically acceptable carrier material is a pharmaceutically acceptable liquid carrier material.

11. The method according to claim 4 , wherein the at least one pharmaceutically acceptable carrier material is a pharmaceutically acceptable liquid carrier material.

12. The method according to claim 5 , wherein the at least one pharmaceutically acceptable carrier material is a pharmaceutically acceptable liquid carrier material.

13. The method according to claim 6 , wherein the at least one pharmaceutically acceptable carrier material is a pharmaceutically acceptable liquid carrier material.

14. The method according to claim 7 , wherein the at least one pharmaceutically acceptable carrier material is a pharmaceutically acceptable liquid carrier material.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 6, 2024
From: IDORSIA PHARMACEUTICALS LTD.
To: VIATRIS ASIA PACIFIC PTE. LTD.
Reel/Frame 067647/0303 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 1, 2022
From: LEUENBERGER, DANIEL; REBER, STEFAN; VON RAUMER, MARKUS
To: ACTELION PHARMACEUTICALS LTD
Reel/Frame 060422/0212 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 1, 2022
From: ACTELION PHARMACEUTICALS LTD
To: IDORSIA PHARMACEUTICALS LTD
Reel/Frame 060422/0330 →
Priority Claims (1)
WO PCT/EP2016/072562 · Sep 22, 2016 · international
Continuity (3)
Continuation 16938730 · Jul 24, 2020
Continuation 16335973
Related Publication 20220275011A1 · Sep 1, 2022
References Cited (103)
US 6855715B1 · Liebeschuetz et al. · 2005 [cited by applicant]
US 8044055B2 · Caroff et al. · 2011 [cited by applicant]
US 8048881B2 · Caroff et al. · 2011 [cited by applicant]
US 8058263B2 · Caroff et al. · 2011 [cited by applicant]
US 8067419B2 · Binkert et al. · 2011 [cited by applicant]
US 8093250B2 · Caroff et al. · 2012 [cited by applicant]
US 8288385B2 · Caroff et al. · 2012 [cited by applicant]
US 8466156B2 · Caroff et al. · 2013 [cited by applicant]
US 8518912B2 · Caroff et al. · 2013 [cited by applicant]
US 8664203B2 · Caroff et al. · 2014 [cited by applicant]
US 10730896B2 · Leuenberger et al. · 2020 [cited by applicant]
US 11365209B2 · Leuenberger et al. · 2022 [cited by applicant]
US 20030060474A1 · Bryant et al. · 2003 [cited by applicant]
US 20050038037A1 · Bryant et al. · 2005 [cited by applicant]
US 20050065163A1 · Bryant et al. · 2005 [cited by applicant]
US 20210009614A1 · Leuenberger et al. · 2021 [cited by applicant]
EP 0407200 · 1991 [cited by applicant]
JP S5373586 · 1978 [cited by applicant]
JP A2008239617 · 2008 [cited by applicant]
WO WO2002098856 · 2002 [cited by applicant]
WO WO2004052366 · 2004 [cited by applicant]
WO WO2004092189 · 2004 [cited by applicant]
WO WO2006114774 · 2006 [cited by applicant]
WO WO2007046075 · 2007 [cited by applicant]
WO WO2008044217 · 2008 [cited by applicant]
WO WO2008050301 · 2008 [cited by applicant]
WO WO2008128647 · 2008 [cited by applicant]
WO WO2009069100 · 2009 [cited by applicant]
WO WO2009080226 · 2009 [cited by applicant]
WO WO2009080227 · 2009 [cited by applicant]
WO WO2009125365 · 2009 [cited by applicant]
WO WO2009125366 · 2009 [cited by applicant]
WO WO2010116328 · 2010 [cited by applicant]
WO WO2010122504 · 2010 [cited by applicant]
WO WO2018167139 · 2018 [cited by applicant]
WO WO2022013276 · 2022 [cited by applicant]
U.S. Appl. No. 16/938,730, filed Jul. 24, 2020, Leuenberger et al. [cited by applicant]
Abele, S., “Pilot Plant Production of a P2Y [cited by applicant]
Abele, S., “Pilot Plant Production of a P2Y [cited by applicant]
Amir, J., et al., “Treatment of Thrombotic Thrombocytopeniarpura With Antiplatelet Drugs,” Blood, 1973, 42(1):27-33. [cited by applicant]
Antithrombotic Trialists' Collaboration, “Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients,” British Medical Journ… [cited by applicant]
Baldoni, D., et al., “A New Reversible and Potent P2Y [cited by applicant]
Balduini, C., et al., “Platelet Aggregation in Platelet-Rich Plasma and Whole Blood in 120 Patients with Myeloproliferative Disorders,” Coagulation and Transfusion Medicine, 1991, 95(1):82-86. [cited by applicant]
Bartoli, G., et al., “Reaction of Dianions of Acyclic Beta-Enamino Ketones with Electrophiles. 3. Nitriles: Synthesis of Pyridine and Pyrimidine Derivatives,” J. Org. Chem., 1992, 57:6020-6025. [cited by applicant]
Belanger, G., et al., “New Approach to Aphidicolin and Total Asymmetric Synthesis of Unnatural (11R)-(−)-8-Epi-11-hydroxyaphidicolin by Tandem Transannular Diels-Alder/Aldol Reactions,” J. Org. Chem., 2000, 65:7070-7074. [cited by applicant]
Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., vol. 66, No. 1, pp. 1-19 (1977). [cited by applicant]
Bertrand, M.E., et al., “Randomized Multicenter Comparison of Conventional Anticoagulation Versus Antiplatelet Therapy in Unplanned and Elective Coronary Stenting,” Circulation, 1998, 98:1597-1603. [cited by applicant]
Brighton, T.A., et al., “Antiphospholipid antibodies and thrombosis,” Bailliere's Clinical Haematology, 1994, 7(3): 541-557. [cited by applicant]
Caira, et al., “Crystalline Polymorphism of Organic Compounds,” Topics in Current Chemistry, vol. 198, pp. 163-208 (1998). [cited by applicant]
CAPRIE Steering Committee, “A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE),” The Lancet, 1996, 248:1329-1339. [cited by applicant]
Caroff, E., et al., “Optimization of 2-phenyl-pyrimidine-4-carboxamides towards potent, orally bioavailable and selective P2Y [cited by applicant]
Caroff, E., et al., “4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino }-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y [cited by applicant]
Cattaneo, M., et al., “The platelet P2Y [cited by applicant]
Charette, A.B., et al., “Enantioselective Cyclopropanation of Allylic Alcohols with Dioxaborolane Ligands: Scope and Synthetic Applications,” J. Am. Chem., 1998, 120:11943-11952. [cited by applicant]
ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT00222677, “Aspirin for the Prevention of Recurrent Venous Thromboembolism,” University of Perugia, Sep. 22, 2005, 6 pages. [cited by applicant]
ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT01954615, “Single-ascending Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-281959 / ACT-246475 in Healthy Mal… [cited by applicant]
ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT03384966, “A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults with Coronary Artery Disease,” Dec. 28, 2017, 6 pages. [cited by applicant]
ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT03430661, “A Study to Investigate the Interaction Between ACT-246475 and Clopidogrel, Prasugrel, and Ticagrelor in Healthy Subjects,” Feb. 13, 2018, 8 pages. [cited by applicant]
ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT03487445, “A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults with Heart Attack,” Apr. 4, 2018, 4 pages. [cited by applicant]
ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT03593278, “A Study to Evaluate ACT-246475 Fate in Healthy Male Subjects,” Jul. 20, 2018, 5 pages. [cited by applicant]
ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT03814200, “A Study to Investigate the Effect of Rifampicin on the Uptake and Breakdown of ACT-246475 in Healthy Subjects,” Jan. 23, 2019, 5 pages. [cited by applicant]
Coller, B.S., et al., “Historical Perspective and Future Directions in Platelet Research,” J Thromb Haemost., 2011, 9 (Suppl. 1):374-395. [cited by applicant]
Collins, C.E., et al., “Review article: platelets in inflammatory bowel disease—pathogenetic role and therapeutic implications,” Aliment Pharmacol. Ther., 1997, 11:237-247. [cited by applicant]
Davies et al. “Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death.” Circulation, 1986, 73(3):418-427. [cited by applicant]
Felfernig-Boehm et al., “Early Detection of Preeclampsia by Determination of Platelet Aggregability,” Thrombosis Research, 2000, 98:139-146. [cited by applicant]
Feokistov et al., “Adenosine A [cited by applicant]
Fox et al., “Benefits and Risks of the Combination of Clopidogrel and Aspirin in Patients Undergoing Surgical Revascularization for Non-ST-Elevation Acute Coronary Syndrome,” Circulation, 2004, 110:1202-1208. [cited by applicant]
Halushka et al., “Protective Effects of Aspirin in Endotoxic Shock,” The Journal of Pharmacology and Experimental Therapeutics, 1981, 218(2):464-469. [cited by applicant]
Hilfiker et al., “Polymorphism in the Pharmaceutical Industry, Chapter 8: U.J. Griesser: The Importance of Solvates.” 2006, 19 pages. [cited by applicant]
Hovens et al., “Aspirin in the prevention and treatment of venous thromboembolism,” Journal of Thrombosis and Haemostasis, 2006, 4:1470-1475. [cited by applicant]
International Search Report for International Application No. PCT/EP2017/073858, prepared by the International Searching Authority, Date Mailed: Oct. 18, 2017, 4 pages. [cited by applicant]
Jagroop, I.A., et al., “The effect of clopidogrel, aspirin and both antiplatelet drugs on platelet function in patients with peripheral arterial disease,” Platelets, 2004, 15:117-125. [cited by applicant]
Jneid, H., et al., “2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and Replacing the 2011 Focused Up… [cited by applicant]
Kharbanda et al., “Prevention of Inflammation-Induced Endothelial Dysfunction—A Novel Vasculo-Protective Action of Aspirin,” Circulation, 2002, 105:2600-2604. [cited by applicant]
Liu et al., “P2Y [cited by applicant]
Matsagas, M., et al., “The Effect of a Loading Dose (300 mg) of Clopidogrel on Platelet Function in Patients with Peripheral Arterial Disease,” Clin Appl Thromb Hemost., 2003, 9:115-120. [cited by applicant]
Megalopoulos, A., et al., “Recurrent arterial thromboses in a woman with heparin induced thrombocytopenia, successfully managed with iloprost followed by clopidogrel. An alternative therapeutic option for heparin induce… [cited by applicant]
Mehta et al., “Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study,” The Lancet, 2001, 358:527-533. [cited by applicant]
Norgard, N., “Cangrelor: a novel P2Y12 receptor antagonist,” Expert Opinion on Investigational Drugs, 2009, 18(8):1219-1230. [cited by applicant]
Notice of Allowance dated Jun. 27, 2011, for U.S. Appl. No. 12/936,661. [cited by applicant]
Office Action dated Aug. 31, 2012, for U.S. Appl. No. 12/936,664. [cited by applicant]
Office Action dated Jan. 21, 2011, for U.S. Appl. No. 12/936,661. [cited by applicant]
Office Action dated Jan. 19, 2011, for U.S. Appl. No. 12/445,352. [cited by applicant]
Office Action dated Oct. 28, 2010, for U.S. Appl. No. 11/912,545. [cited by applicant]
O'Gara, P.T., “2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction,” Circulation, 2013, 127:e362-425. [cited by applicant]
Parlow, J.J., et al., “Piperazinyl Glutamate Pyridines as Potent Orally Bioavailable P2Y [cited by applicant]
Parlow, J.J., et al., “Piperazinyl-glutamate-pyridines as Potent Orally Bioavailable P2Y [cited by applicant]
Parlow, J.J., et al., “Piperazinyl-glutamate-pyridines as Potent Orally Bioavailable P2Y [cited by applicant]
Payne et al., “Beneficial Effects of Clopidogrel Combined with Aspirin in Reducing Cerebral Emboli in Patients Undergoing Carotid Endarterectomy,” Circulation 2004, 109:1476-1481. [cited by applicant]
Remington, The Science and Practice of Pharmacy, 21 [cited by applicant]
Rey, M., et al., “The reversible P2Y [cited by applicant]
Shao et al., “Phenoxyphenyl Pyridines as Novel State-Dependent, High-Potency Sodium Channel Inhibitors,” J. Med. Chem., 2004, 47:4277-4285. [cited by applicant]
Sheppard et al., Discovery and Optimization of Anthranilic Acid Sulfonamides as Inhibitors of Methionine Aminopeptidase-2: A Structural Basis for the Reduction of Albumin Binding, 2006, 49:3832-3849. [cited by applicant]
Stahl, H., C.G. Wermuth Handboook of Pharmaceutical Salts. Properties, Selection and Use, 2008, 22 pages. [cited by applicant]
Stathakis et al., “Platelet Dysfunction in Essential Thrombocythaemia,” Annals of Clinical Research, 1974, 6:198-202. [cited by applicant]
Thomas, M.R., et al., “The future of P2Y [cited by applicant]
Thorsen, C.A., et al., “The Treatment of the Hemolytic-Uremic Syndrome with Inhibitors of Platelet Function,” The American Journal of Medicine, 1979, 66:711-716. [cited by applicant]
Triadou et al., “Platelet function in sickle cell disease during steady state,” Nouvelle Revue Francaise Hematologie, 1990, 32:137-142. [cited by applicant]
Wallentin, L., et al., “P2Y [cited by applicant]
Wiviott, S.D., et al., “Novel antithrombotic agents 2—Clinical evidence for oral antiplatelet therapy in acute coronary syndromes,” Lancet, 2015, 386:292-302. [cited by applicant]
Johan Wouters and Luc Quéré, “Pharmaceutical Salts and Co-crystals,” RSC Drug Discovery, 2012, Series No. 16, pp. vii-xiv. [cited by applicant]
Yao et al., “Clopidogrel is more effective than aspirin as adjuvant treatment to prevent reocclusion after thrombolysis,” Am. J. Physiol., 1994, 267:H488-H493. [cited by applicant]
U.S. Appl. No. 18/016,299, Jan. 13, 2023 (371(c) Date), Buchmann et al. [cited by applicant]