IP Library › Granted Patent US 12,570,628
Granted Patent B2
US 12,570,628 · App. 19/178,837 · Granted Mar 10, 2026

Salts of obicetrapib and processes for their manufacture and intermediates thereof

Inventors: Sheng Cui (Lexington, MA); Andreas René Rötheli (Wellesley, MA); Christopher J. Borths (Sherborn, MA); Muneki Kishida (Osaka, JP)
Assignee: NewAmsterdam Pharma B.V.
C07D401/12A61K31/33A61P9/00C07B2200/13
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,570,628
App. No.
19/178,837
Granted
Mar 10, 2026
Kind
B2
Abstract

Provided herein is a method for the manufacture of a compound of obicetrapib and salts thereof, such as calcium salts thereof. Also provided herein is amorphous obicetrapib hemicalcium. New intermediates for use in the synthesis of obicetrapib, and salts thereof, are also provided, including obicetrapib HCl and a mesylate salt for the use in the synthesis of obicetrapib and amorphous obicetrapib hemicalcium.

Claims (28)

1 . A pharmaceutical composition comprising:

amorphous obicetrapib hemicalcium and one or more pharmaceutically acceptable carriers.

2 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium has an x-ray powder diffraction pattern comprising one or more peaks at about 3.4°2θ, about 7.0°2θ, and about 9.2°2θ.

3 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium has a glass transition temperature at a value between about 109° C. and about 112° C., when measured by modulated differential scanning calorimetry in a sample pan with an opening.

4 . The pharmaceutical composition of claim 2 , wherein the amorphous obicetrapib hemicalcium has a glass transition temperature at a value between about 109° C. and about 112° C., when measured by modulated differential scanning calorimetry in a sample pan with an opening.

5 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium has a solid-state 13 C-NMR spectrum substantially the same as that of FIG. 17 .

6 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium has a solid-state 13 C-NMR spectrum where no peak is present at either about 22.1 ppm or about 29.5 ppm.

7 . The pharmaceutical composition of claim 2 , wherein the amorphous obicetrapib hemicalcium has a solid-state 13 C-NMR spectrum substantially the same as that of FIG. 17 .

8 . The pharmaceutical composition of claim 2 , wherein the amorphous obicetrapib hemicalcium has a solid-state 13 C-NMR spectrum where no peak is present at either about 22.1 ppm or about 29.5 ppm.

9 . The pharmaceutical composition of claim 3 , wherein the amorphous obicetrapib hemicalcium has a solid-state 13 C-NMR spectrum substantially the same as that of FIG. 17 .

10 . The pharmaceutical composition of claim 3 , wherein the amorphous obicetrapib hemicalcium has a solid-state 13 C-NMR spectrum where no peak is present at either about 22.1 ppm or about 29.5 ppm.

11 . The pharmaceutical composition of claim 4 , wherein the amorphous obicetrapib hemicalcium has a solid-state 13 C-NMR spectrum substantially the same as that of FIG. 17 .

12 . The pharmaceutical composition of claim 4 , wherein the amorphous obicetrapib hemicalcium has a solid-state 13 C-NMR spectrum where no peak is present at either about 22.1 ppm or about 29.5 ppm.

13 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium has a d90 particle size distribution of between 6 and 15 microns.

14 . The pharmaceutical composition of claim 2 , wherein the amorphous obicetrapib hemicalcium has a d90 particle size distribution of between 6 and 15 microns.

15 . The pharmaceutical composition of claim 3 , wherein the amorphous obicetrapib hemicalcium has a d90 particle size distribution of between 6 and 15 microns.

16 . The pharmaceutical composition of claim 4 , wherein the amorphous obicetrapib hemicalcium has a d90 particle size distribution of between 6 and 15 microns.

17 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium has a chemical purity of at least 99.0%.

18 . The pharmaceutical composition of claim 2 , wherein the amorphous obicetrapib hemicalcium has a chemical purity of at least 99.0%.

19 . The pharmaceutical composition of claim 17 , wherein the amorphous obicetrapib hemicalcium has a chemical purity of at least 99.9%.

20 . The pharmaceutical composition of claim 18 , wherein the amorphous obicetrapib hemicalcium has a chemical purity of at least 99.9%.

21 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium has an x-ray powder diffraction pattern substantially the same as that of FIG. 3 .

22 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium does not birefringe.

23 . The pharmaceutical composition of claim 2 , wherein the amorphous obicetrapib hemicalcium does not birefringe.

24 . The pharmaceutical composition of claim 3 , wherein the amorphous obicetrapib hemicalcium does not birefringe.

25 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium is milled.

26 . The pharmaceutical composition of claim 1 , wherein the amorphous obicetrapib hemicalcium has a water content of less than about 4% by weight.

27 . The pharmaceutical composition of claim 26 , wherein the amorphous obicetrapib hemicalcium has a water content of between about 0.5% and about 1.5% by weight.

Assignments (5)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2025
From: CUI, SHENG
To: NEWAMSTERDAM PHARMA B.V.
Reel/Frame 071234/0134 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2025
From: KISHIDA, MUNEKI
To: MITSUBISHI TANABE PHARMA CORPORATION
Reel/Frame 071234/0160 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2025
From: RÖTHELI, ANDREAS RENÉ; BORTHS, CHRISTOPHER J.
To: AMGEN INC.
Reel/Frame 071234/0192 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2025
From: MITSUBISHI TANABE PHARMA CORPORATION
To: NEWAMSTERDAM PHARMA B.V.
Reel/Frame 071234/0213 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 28, 2025
From: AMGEN INC.
To: NEWAMSTERDAM PHARMA B.V.
Reel/Frame 071429/0412 →
Continuity (4)
Division 18637425 · Apr 16, 2024
Division 18346342 · Jul 3, 2023
Provisional Application 63358363 · Jul 5, 2022
Related Publication 20250296921A1 · Sep 25, 2025
References Cited (70)
US 6313142B1 · Damon et al. · 2001 [cited by applicant]
US 7872126B2 · Kubota · 2011 [cited by examiner]
US 8084611B2 · Okamoto et al. · 2011 [cited by applicant]
US 8158640B2 · Kubota et al. · 2012 [cited by applicant]
US 10112904B2 · Ford et al. · 2018 [cited by applicant]
US 10300059B2 · Ford et al. · 2019 [cited by applicant]
US 10653692B2 · Ford et al. · 2020 [cited by applicant]
US 11013742B2 · Ford et al. · 2021 [cited by applicant]
US 11642344B2 · Ford et al. · 2023 [cited by applicant]
US 20070082896A1 · Kubota et al. · 2007 [cited by applicant]
EP 0412848A2 · 1991 [cited by applicant]
EP 0456442A1 · 1991 [cited by applicant]
EP 1125929A1 · 2001 [cited by applicant]
JP 2007119450A · 2007 [cited by applicant]
WO WO2005095409A2 · 2005 [cited by applicant]
WO WO2007116922A1 · 2007 [cited by applicant]
WO WO2014178040A1 · 2014 [cited by applicant]
WO WO2015119495A1 · 2015 [cited by applicant]
WO WO2016024858A1 · 2016 [cited by applicant]
WO WO2016032324A1 · 2016 [cited by applicant]
WO WO2017023165A1 · 2017 [cited by applicant]
WO WO2017023166A1 · 2017 [cited by applicant]
WO WO2020030814A1 · 2020 [cited by applicant]
WO WO2022177428A1 · 2022 [cited by applicant]
WO WO2022185120A1 · 2022 [cited by applicant]
WO WO2023006657A1 · 2023 [cited by applicant]
WO WO2023129595A1 · 2023 [cited by applicant]
WO WO2024226537A1 · 2024 [cited by examiner]
Clinicaltrials.gov, “Evaluation of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TA-8995 With Single, Escalating Doses in Healthy Subjects,” ClinicalTrials.gov Identifier: NCT01878474, Jun. 17, 2013, fi… [cited by applicant]
Clinicaltrials.gov, “Evaluation of Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TA-8995 After Multiple Doses in Healthy Subjects,” ClinicalTrials.gov Identifier: NCT01879020, Jun. 17, 2013, five pages,… [cited by applicant]
Clinicaltrials.gov, “TA-8995: Its Use in Patients With Mild Dyslipidemia (TULIP) (TULIP),” ClinicalTrials.gov Identifier: NCT01970215, Aug. 21, 2014, six pages, [Online] [Retrieved on Sep. 12, 2020] Retrieved from the I… [cited by applicant]
Clinicaltrials.gov, “A Phase I, Open Label Study to Assess the Effects of TA-8995 on the Pharmacokinetics of Midazolam and Digoxin in Healthy Male Subjects,” ClinicalTrials.gov Identifier: NCT02124954, Oct. 3, 2016, fou… [cited by applicant]
Clinicaltrials.gov, “Study of the Electrocardiographic Effects of TA-8995,” ClinicalTrials.gov Identifier: NCT02241759, Feb. 16, 2015, four pages, [Online] [Retrieved on Sep. 12, 2020] Retrieved from the Internet <URL: … [cited by applicant]
Clinicaltrials.gov, “A Study on the Effects of TA-8995 on Lp(a) in Subjects With Elevated Lp(a),” ClinicalTrials.gov Identifier: NCT02241772, Feb. 16, 2015, three pages, [Online] [Retrieved on Sep. 12, 2020] Retrieved f… [cited by applicant]
Clinicaltrials.gov, “ADME Study in Healthy Male Subjects With TA-8995,” ClinicalTrials.gov Identifier: NCT02408055, Oct. 3, 2016, three pages, [Online] [Retrieved on Sep. 12, 2020] Retrieved from the Internet <URL: http… [cited by applicant]
Clinicaltrials.gov, “A Phase I, Randomised, Open-label Cross-over Bioequivalence Study of Capsule and Tablet Formulations of TA-8995 in Healthy Male Subjects,” ClinicalTrials.gov Identifier: NCT02523391, Aug. 14, 2015, … [cited by applicant]
Clinicaltrials.gov, “A Placebo-Controlled, Double-Blind, Randomized, Phase 2 Dose-Finding Study to Evaluate the Effect of Obicetrapib as an Adjunct to High-Intensity Statin Therapy,” ClinicalTrials.gov Identifier NCT047… [cited by applicant]
Clinicaltrials.gov, “A Placebo-Controlled, Double-Blind, Randomized Phase 2 Study to Evaluate the Effect of Obicetrapib in Combination With Ezetimibe in Participants With Mild Dyslipidemia,” ClinicalTrials.gov Identifie… [cited by applicant]
Clinicaltrials.gov, “A Placebo-Controlled, Double-Blind, Randomized Phase 3 Study to Evaluate the Effect of 10mg Obicetrapib in Participants With HeFH and/or ASCVD and LDL-C ≥70 and <100 mg/dL Who Are Not Adequately Con… [cited by applicant]
Clinicaltrials.gov, “A Phase 2a, Proof-of-Concept, Open-Label Study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Obicetrapib in Patients With Early Alzheimer's Disease (Hetero/Homozygote APOE4 Carri… [cited by applicant]
Clinicaltrials.gov, “Placebo Controlled, Double Blind, Randomized Cardiovascular Outcome Study to Evaluate the Effect of 10 mg Obicetrapib in Participants With ASCVD Not Adequately Controlled Despite Maximally Tolerated… [cited by applicant]
Clinicaltrials.gov, “A Placebo-Controlled, Double-Blind, Randomized, Phase 2 Study to Evaluate the Effect of Obicetrapib 10 mg Daily in Combination With Ezetimibe 10 mg Daily as an Adjunct to High-Intensity Statin Thera… [cited by applicant]
Clinicaltrials.gov, “A Placebo-Controlled, Double-Blind, Randomized, Phase 2 Dose-Finding Study to Evaluate the Effect of Obicetrapib as an Adjunct to Stable Statin Therapy in Japanese Subjects,” ClinicalTrials.gov Iden… [cited by applicant]
Clinicaltrials.gov, “A Placebo-Controlled, Double-Blind, Randomized, Phase 3 Study to Evaluate the Effect of 10 mg Obicetrapib in Participants With a History of HeFH Who Are Not Adequately Controlled by Their Lipid Modi… [cited by applicant]
EU Clinical Trials Register, “A Multi-Centre, Randomised, Double Blind, Placebo Controlled, Parallel Group Study of TA 8995 in Patients with Mild Dyslipidemia, Alone and In Combination with Statin Therapy,” EudraCT No. … [cited by applicant]
EU Clinical Trials Register, “A Placebo-Controlled, Double-Blind, Randomized Phase 2Study to Evaluate the Effect of Obicetrapib in Combination with Ezetimibe in Participants with Mild Dyslipidemia,” EudraCT No. 2019-004… [cited by applicant]
EU Clinical Trials Register, “A Phase 2a, Proof-of-Concept, Open-Label Study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Obicetrapib in Patients with Early Alzheimer's Disease (Hetero/Homozygote AP… [cited by applicant]
EU Clinical Trials Register, “A Placebo-Controlled Phase 3 Study to Evaluate the Effect of 10 mg Obicetrapib in Participants With Atherosclerotic Cardiovascular Disease (ASCVD) Whose Current Treatment with Lipid-Modifyi… [cited by applicant]
EU Clinical Trials Register, “Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies (Brooklyn): A Placebo-Controlled, Double-Blind, Randomized, Phase 3 Study to Evaluate the Effect of 10 mg Obicetrapib in Pa… [cited by applicant]
EU Clinical Trials Register, “Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies (Broadway): A Placebo-Controlled, Double-Blind, Randomized Phase 3 Study to Evaluate the Effect of 10 mg Obicetrapib in Par… [cited by applicant]
Ballantyne C.M. et al., “Obicetrapib plus ezetimibe as an adjunct to high-intensity statin therapy: A randomized phase 2 trial,” Journal of Clinical Lipidology, May 29, 2023, 000, pp. 1-13. [cited by applicant]
Ford, J. et al., “Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects,” British Journal of Clinical Pharmacology, vol. 78,… [cited by applicant]
Hovingh, G.K. et al., “Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial,” The Lancet, vol. 386, Iss. 9992… [cited by applicant]
Khomtchouk B.B. et al., “CETP and SGLT2 inhibitor combination therapy improves glycemic control,” medRxiv preprint, Jun. 16, 2023, pp. 1-28, [Online] [Retrieved on Oct. 2, 2023] Retrieved from the Internet <URL: https:/… [cited by applicant]
Nicholls, S.J. et al., “Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial,” Nature Medicine 28, Aug. 11, 2022, pp. 1672-1678. [cited by applicant]
Van Capelleveen, J.C. et al., “Effects of the cholesteryl ester transfer protein inhibitor, TA-8995, on cholesterol efflux capacity and high-density lipoprotein particle subclasses,” Journal of Clinical Lipidology, vol.… [cited by applicant]
Kanaujia P et al: “Amorphous formulations for dissolution and bioavailability enhancement of poorly soluble APIs”, Powder Technology, vol. 285, May 15, 2015, pp. 2-15. [cited by applicant]
Lee, S. et al., “Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8 (Large-Scale Aspects of Salt Formation: Processing of Intermediates and Final Products), Chapter 12 (Monographs on Acids and B… [cited by applicant]
PCT Invitation to Pay Additional Fees, PCT Application No. PCT/IB2023/000392, Oct. 4, 2023, 12 pages. [cited by applicant]
Hancock, B.C. et al., “What is the True Solubility Advantage for Amorphous Pharmaceuticals?,” Pharm. Res., vol. 17, 2000, pp. 397-404. [cited by applicant]
Khadka, P. et al., “Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability,” Asian Journal of Pharmaceutical Sci., vol. 9, Jun. 13, 2014, pp. 304-316. [cited by applicant]
Vranić, E. “Amorphous pharmaceutical solids,” Bosn J Basic Med Sci., 4(3), Jul. 2004, pp. 35-39. [cited by applicant]
Ohtake, S. et al., “Effect of Water on the Chemical Stability of Amorphous Pharmaceuticals: I. Small Molecules,” Journal of Pharmaceutical Sciences, 102(4), Apr. 2013, pp. 1139-1154. [cited by applicant]
Escribano, A. et al., “Design and synthesis of new tetrahydroquinolines derivatives as CETP inhibitors,” Bioorganic & Medicinal Chemistry Letters, vol. 22, Apr. 13, 2012, pp. 3671-3675. [cited by applicant]
Katritzky, A.R. et al., “Synthesis of Pyrido[4,3,2-de]quinazolines via Nitro-Substituted Tetrahydroquinolines,” J. Heterocyclic Chem., vol. 36, May 1999, pp. 755-759. [cited by applicant]
Mearns, B.M. et al., “Dyslipidaemia: Promising results for TA-8995 in TULIP,” Nature Reviews, Cardiology, vol. 12, Jun. 23, 2015, pp. 443. [cited by applicant]
Rano, T.A. et al., “Design and synthesis of potent inhibitors of cholesteryl ester transfer protein (CETP) exploiting a 1,2,3,4-tetrahydroquinoline platform,” Bioorganic & Medicinal Chemistry Letters, vol. 19, Mar. 18, … [cited by applicant]
PCT International Search Report and Written Opinion, PCT Application No. PCT/IB2023/000392, Nov. 27, 2023, 18 pages. [cited by applicant]
Minton, P.E., “Chapter 2: Evaporation,” In: Handbook of Evaporation Technology, 1986, pp. 2. [cited by applicant]
Subrahmanyam, C.V.S. et al., “Chapter 12: Evaporation,” In: Pharmaceutical Engineering: Principles and Practices, Aug. 2005, pp. 337-339. [cited by applicant]