IP Library › Granted Patent US 12,252,479
Granted Patent B2
US 12,252,479 · App. 17/858,713 · Granted Mar 18, 2025

Crystalline forms OF N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide

Inventors: Stephanie Kay Dodd (Ayer, MA); Arnaud Grandeury (Helfrantzkirch, FR); Emmanuel Suffert (Basel, CH); Evgenia Rousaki (Basel, CH)
Assignee: Novartis AG
C07D401/14A61K9/20C07B2200/13
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Quick Facts
Patent No.
US 12,252,479
App. No.
17/858,713
Granted
Mar 18, 2025
Kind
B2
Abstract

The present invention describes specific crystalline forms of N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide. The present invention further relates to methods for preparing said crystalline forms, pharmaceutical compositions comprising said crystalline forms, and methods of using said crystalline forms and pharmaceutical compositions to treat disease.

Claims (48)

1. A method for treating an ABL1/BCR-ABL1-mediated disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of a crystalline form A of asciminib hydrochloride, wherein the crystalline form A of asciminib hydrochloride is characterized by having an x-ray powder diffraction pattern comprising reflections at 2-Theta angles of 12.6±0.2°, 18.9±0.2° and 20.9±0.2°, when measured at a temperature in the range of from 20 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

2. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by having an x-ray powder diffraction pattern comprising reflections at 2-Theta angles of 12.6±0.2°, 17.0±0.2°, 18.9±0.2°, 20.9±0.2° and 32.5±0.2°, when measured at a temperature in the range of from 20 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

3. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by having an x-ray powder diffraction pattern comprising at least three 2 theta values selected from the group consisting of 8.5°±0.2° 9.5°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 12.6°±0.2°, 13.9°±0.2°, 14.8°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 17.0°±0.2°, 17.6°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.4°±0.2° 20.9°±0.2°, 21.2°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.3°±0.2°, 24.8°±0.2° 25.0°±0.2°, 25.9°±0.2°, 26.8°±0.2°, 27.0°±0.2°, 28.3°±0.2°, 28.6°±0.2°, 28.9°±0.2°, 29.8°±0.2°, 30.5°±0.2°, 31.3°±0.2°, 31.5°±0.2°, 31.8°±0.2°, 32.1°±0.2°, 32.5°±0.2° 32.9°±0.2°, 33.6°±0.2°, 34.0°±0.2°, 34.6°±0.2°, 35.0°±0.2°, 35.6°±0.2°, 36.3°±0.2° and 38.8°±0.2°, when measured at a temperature in the range of from 20 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

4. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by having an x-ray powder diffraction pattern comprising at least four 2 theta values selected from the group consisting of 8.5°±0.2° 9.5°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 12.6°±0.2°, 13.9°±0.2°, 14.8°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 17.0°±0.2°, 17.6°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.4°±0.2°, 20.9°±0.2°, 21.2°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.3°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 25.9°±0.2°, 26.8°±0.2°, 27.0°±0.2°, 28.3°±0.2°, 28.6°±0.2°, 28.9°±0.2°, 29.8°±0.2°, 30.5°±0.2°, 31.3°±0.2°, 31.5°±0.2°, 31.8°±0.2°, 32.1°±0.2°, 32.5°±0.2°, 32.9°±0.2°, 33.6°±0.2°, 34.0°±0.2°, 34.6°±0.2°, 35.0°±0.2°, 35.6°±0.2°, 36.3°±0.2° and 38.8°±0.2°, when measured at a temperature in the range of from 20 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

5. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by having an x-ray powder diffraction pattern comprising at least five 2 theta values selected from the group consisting of 8.5°±0.2°, 9.5°±0.2°, 11.8°±0.2°, 12.3°±0.2°, 12.6°±0.2°, 13.9°±0.2°, 14.8°±0.2°, 15.9°±0.2°, 16.5°±0.2°, 17.0°±0.2°, 17.6°±0.2°, 18.9°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.4°±0.2°, 20.9°±0.2°, 21.2°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 23.9°±0.2°, 24.3°±0.2°, 24.8°±0.2°, 25.0°±0.2°, 25.9°±0.2°, 26.8°±0.2°, 27.0°±0.2°, 28.3°±0.2°, 28.6°±0.2°, 28.9°±0.2°, 29.8°±0.2°, 30.5°±0.2°, 31.3°±0.2°, 31.5°±0.2°, 31.8°±0.2°, 32.1°±0.2°, 32.5°±0.2°, 32.9°±0.2°, 33.6°±0.2°, 34.0°±0.2°, 34.6°±0.2°, 35.0°±0.2°, 35.6°±0.2°, 36.3°±0.2° and 38.8°±0.2°, when measured at a temperature in the range of from 20 to 25° C. with Cu-Kalpha1,2 radiation having a wavelength of 0.1541 Å.

6. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by having a differential scanning calorimetry curve comprising an endothermic peak having an onset temperature of 90° C., when measured at a heating rate of 2° C./min.

7. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by having a thermogravimetric analysis curve showing a mass loss of not more than 3.3 weight % based on the weight of the crystalline form, when heated from 30 to 300° C. at a rate of 20° C./min.

8. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by having an x-ray powder diffraction pattern similar to FIG. 8 .

9. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by the following unit cell parameters from x-ray diffraction data measured at 100K:

Space symmetry

Triclinic

Space group

P1

Cell Volume (Å 3 )

1053.6(6)

Crystal Density (g/cm 3 )

1.533

a (Å)

 8.203(3)

b (Å)

11.116(3)

c (Å)

12.627(4)

beta (°)

 97.711(12)

Z

2 .

10. The method of claim 1 , wherein the crystalline form A of asciminib hydrochloride is characterized by the following unit cell parameters from x-ray diffraction data measured at 298K:

Space symmetry

Triclinic

Space group

P1

Cell Volume (Å 3 )

1082.9(6)

Crystal Density (g/cm 3 )

1.491

a (Å)

 8.245(3)

b (Å)

11.352(4)

c (Å)

12.697(4)

beta (°)

 97.289(18)

Z

2 .

11. The method of claim 1 , wherein the ABL1/BCR-ABL1-mediated disorder is a cancer selected from chronic myeloid leukemia and acute lymphoblastic leukemia.

12. The method of claim 11 , wherein the ABL1/BCR-ABL1-mediated disorder is chronic myeloid leukemia.

Assignments (9)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 29, 2025
From: NOVARTIS AG
To: NOVARTIS PHARMACEUTICALS CORPORATION
Reel/Frame 072711/0382 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2023
From: DODD, STEPHANIE KAY
To: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
Reel/Frame 062986/0688 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2023
From: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
To: NOVARTIS AG
Reel/Frame 062986/0783 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2023
From: GRANDEURY, ARNAUD; ROUSAKI, EVGENIA; SUFFERT, EMMANUEL
To: NOVARTIS PHARMA AG
Reel/Frame 062986/0925 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2023
From: NOVARTIS PHARMA AG
To: NOVARTIS AG
Reel/Frame 062986/0990 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2023
From: DODD, STEPHANIE KAY
To: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
Reel/Frame 062987/0124 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2023
From: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
To: NOVARTIS AG
Reel/Frame 062987/0292 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2023
From: GRANDEURY, ARNAUD; ROUSAKI, EVGENIA; SUFFERT, EMMANUEL
To: NOVARTIS PHARMA AG
Reel/Frame 062987/0380 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 15, 2023
From: NOVARTIS PHARMA AG
To: NOVARTIS AG
Reel/Frame 062987/0470 →
Continuity (4)
Division 16874622 · May 14, 2020
Provisional Application 62949599 · Dec 18, 2019
Provisional Application 62848857 · May 16, 2019
Related Publication 20230074064A1 · Mar 9, 2023
References Cited (52)
US 11407735B2 · Dodd · 2022 [cited by examiner]
US 20170216289A1 · Pendergast · 2017 [cited by applicant]
US 20190374618A1 · Krause et al. · 2019 [cited by applicant]
US 20200361904A1 · Dodd et al. · 2020 [cited by applicant]
EP 3120851A1 · 2017 [cited by applicant]
EP 3292870A1 · 2018 [cited by applicant]
EP 3509626A1 · 2019 [cited by applicant]
WO 9835681A1 · 1998 [cited by applicant]
WO 0151919A2 · 2001 [cited by applicant]
WO 2004005281A1 · 2004 [cited by applicant]
WO 2013171639A1 · 2013 [cited by applicant]
WO 2013171642A1 · 2013 [cited by applicant]
WO WO2013171639 · 2013 [cited by examiner]
WO 2014101986A1 · 2014 [cited by applicant]
WO 2016012963A1 · 2016 [cited by applicant]
WO 2016100882A1 · 2016 [cited by applicant]
WO 2017013160A1 · 2017 [cited by applicant]
WO 2018046666A1 · 2018 [cited by applicant]
WO 2018060843A1 · 2018 [cited by applicant]
WO 2019084499A1 · 2019 [cited by applicant]
WO 2019232244A2 · 2019 [cited by applicant]
Tran, et al. “Disposition of asciminib, a potent BCR-ABL1 Tyrosine kinase inhibitor, in healthy male subjects”, Novartis Pharmaceuticals Corporation, Xenobiotica (2020) 50(2), 160-179. [cited by applicant]
Menssen et al., “Relative Bioavailability and Food Effect Evaluation for 2 Tablet Formulations of Asciminib in a 2-Arm Crossover, Randomized, Open-Label; Study in Healthy Volunteers”, Novartis Pharma AG, Clinical Pharma… [cited by applicant]
Elrashedy et al., “The Perplexity of Synergistic Duality: Inter-molecular Mechanisms of Communication in BCR-ABL1”, Anti-Cancer Agents in Medicinal Chemistry (2019), 19(13), 1642-1650. [cited by applicant]
Hughes et al., “Asciminib in chronic myeloid leukemia after ABL kinase inhibitors failure”, New England Journal of Medicine (2019), 381(24), 2315-2326. [cited by applicant]
Manley et al., “Progress in the discovery of BCR-ABL kinase inhibitors for the treatment of leukemia”, Topics in Medicinal Chemistry (2018), 28(Cancer II), 1-37. [cited by applicant]
Zanforlin et al., “A Chemical Approach to Overcome Tyrosine Kinase Inhibitors Resistance:Learning from Chronic Myeloid Leukemia”, Current Medicinal Chemistry (2019), 26(33), 6033-6052. [cited by applicant]
Singh et al., “Ponatinib-induced cardiotoxicity: delineating the signalling mechanisms and potential rescue strategies”, Cardiovascular Research (2019), 115(5), 966-977. [cited by applicant]
Eide et al., “Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants”, Cancer Cell (2019), 36(4), 431-443.e5. [cited by applicant]
El Rashedy et al., “A Synergistic Combination Against Chronic Myeloid Leukemia: An Intra-molecular Mechanism of Communication in BCR-ABL 1 Resistance”, Molecular Bio-computation and Drug Design Lab, School of Health Sci… [cited by applicant]
Zhan et al., “Molecular Dynamics Investigation on the Asciminib Resistance Mechanism of I502L and V468F Mutations in BCR-ABL”, Journal of Molecular Graphics & Modelling (2019), 89, 242-249. [cited by applicant]
Madhi et al., “c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis”, Journal of Leukocyte Biology (2019), 106(2), 455-466. [cited by applicant]
Inoue et al., “Chronic myeloid leukemia stem cells and molecular target therapies for overcoming resistance and disease persistence”, International Journal of Hematology (2018), 108(4), 365-370. [cited by applicant]
Massaro et al., “Novel tyrosine-kinase inhibitors for the treatment of chronic myeloid leukemia: safety and efficacy”, Expert Review of Hematology (2018), 11(4), 301-306. [cited by applicant]
Qiang et al., “Mechanisims of resistance to the BCR-ABL1 allosteric inhibitor asciminib”, Leukemia (2017), 31(12), 2844-2847. [cited by applicant]
European Medicines Agency, ICH Topic Q6A Specifications, May 2000. [cited by applicant]
Kawaguchi, et al., Drug and crystal polymorphism, Life Engineering Research, 2002, 310-317, 4(2). [cited by applicant]
Takada, API form screening and selection in drug discovery stage, Pharm Stage, 2007, 20-25, 6(10). [cited by applicant]
Yamano, Approach to Crystal Polymorph in Process Research of New Drug, Journal of Synthetic Organic Chemistry, 2007, 907-913, 65. [cited by applicant]
Bastin, et al., Salt Selection and Optimisation Procedures for Pharmaceutical New Chemical Entities, Organic Process Research & Development, 4(5), 427-435, 2000. [cited by applicant]
Caira, Crystalline Polymorphism of Organic Compounds, Topics in Current Chemistry, 198, 163-208, 1998. [cited by applicant]
Kummerer, Pharmaceuticals in the environment, Annual Review of Environment and Resources, 35, 57-75, Aug. 18, 2010. [cited by applicant]
Kuznetsova, High-resolution X-Ray Analysis, Irkutsk State University, 2005. [cited by applicant]
Reichardt, Solvents and environmental effects in organic chemistry, 611-614, 1991. [cited by applicant]
Sarma, et al., Solid forms of pharmaceuticals: Polymorphs, salts and cocrystals, Korean J. Chem. Eng., 28(2), 315-322, Feb. 2011. [cited by applicant]
Variankaval, et al., From form to function: Crystallization of active pharmaceutical ingredients, AIChE Journal, 54 (7), 1682-1688, Jul. 2008. [cited by applicant]
Aaltonen, et al., Solid form screening—A review, European Journal of Pharmaceutics and Biopharmaceutics, 71(1), 23-37, 2009. [cited by applicant]
Augsburger, et al., Approaches for Improving Bioavailability of Poorly Soluble Drugs—Salt formation, Pharmaceutical Dosage Forms: Tablets, 3rd Edition, vol. 2, 62-66, 2008. [cited by applicant]
Brittain, et al., Polymorphism in pharmaceutical solids, chapter 1 and 5, 1-10, 183-226, 1999. [cited by applicant]
Byrn, et al., Pharmaceutical Solids: A Strategic Approach to Regulatory Considerations, Pharmaceutical Research, 12(7), 945-954, 1995. [cited by applicant]
Schoepfer et al., Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1, Journal of Medicinal Chemistry, 61(18), 8120-8135, Aug. 23, 2018. [cited by applicant]
Eck, et al., The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl, Current Opinion in Cell Biology, 21, 288-295, Feb. 11, 2009. [cited by applicant]