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EP-4739394-A1 - NEW SOLID FORMS OF (3R)-N-[2-CYANO-4-FLUORO-3-(3-METHYL-4-OXO-QUINAZOLIN-6-YL)OXY-PHENYL]- 3-FLUORO-PYRROLIDINE-1-SULFONAMIDE

EP4739394A1EP 4739394 A1EP4739394 A1EP 4739394A1EP-4739394-A1

Abstract

The present invention provides solid forms of (3R)-N-[2-cyano-4- fluoro-3-(3-methyl-4-oxo-quinazolin -6-yl )oxy - phenyl]-3-fluoro- pyrrolidine-1-sulfonamide of formula (I) and solvates thereof, as well as therapeutic uses thereof and pharmaceutical composition comprising them.

Inventors

  • LARI, Giacomo Marco
  • SCHWARZ, SABINE
  • STADELMANN, Valentin Andreas

Assignees

  • F. Hoffmann-La Roche AG

Dates

Publication Date
20260513
Application Date
20240702

Claims (20)

  1. 1. A solid form of a compound of formula (I) wherein the solid form is crystalline polymorphic Form B characterized by a X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.88 degrees 2- theta and at least one additional peak expressed in values of degrees 2-theta at about 10.62, 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 or 26.90.
  2. 2. A solid form according to claim 1, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.88 degrees 2-theta and a peak at about 10.62 degrees 2-theta.
  3. 3. A solid form according to claim 1, characterized by an X-ray powder diffraction pattern comprising a peak at an angle of diffraction at about 12.88 degrees 2-theta and a peak at about 10.62 degrees 2-theta; wherein the pattern is further comprising at least one additional peak expressed in values of degrees 2-theta at about 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 or 26.90.
  4. 4. A solid form according to any one of claims 1 to 3, characterized by an X-ray powder diffraction pattern comprising at least three of the peaks at an angle of diffraction at about 10.62, 12.88, 16.82, 20.04 or 26.90 degrees 2-theta.
  5. 5. A solid form according to any one of claims 1 to 4, characterized by an X-ray powder diffraction pattern comprising peaks at an angle of diffraction at about 10.62, 12.88, 15.96, 16.82, 17.20, 20.04, 21.24, 23.78, 25.62, 25.88 and 26.90 degrees 2-theta.
  6. 6. A solid form according to any one of claims 1 to 5, which is further comprising a peak expressed in values of degrees 2-theta at about 8.38.
  7. 7. A solid form characterized by an X-Ray powder diffraction pattern according to any one of claims 1 to 6, which is further comprising at least one additional peak expressed in values of degrees 2-theta at about 9.76, 10.44, 12.74, 16.68, 17.54, 18.76, 19.00, 19.40, 19.52, 20.98, 23.02, 23.30, 24.02, 26.10, 26.48, 27.24, 27.46, 28.56, 28.72, 28.94, 29.08, 29.28, 29.80 or 30.22.
  8. 8. A solid form according to any one of claims 1 to 7, characterized by an X-ray powder diffraction pattern as shown in Figure 1.
  9. 9. A solid form according to any one of claims 1 to 8, characterized by having a melting point with a peak signal at about 214.2 °C to about 215.2 °C, in particular with a peak signal at about 214.7 °C, using differential scanning calorimetry with a heating rate of 10 K/min.
  10. 10. A solid form of a compound of formula (I) wherein the solid form is crystalline polymorphic Form B characterized by an IR spectrum comprising at least one peak at one of the positions 1685 cm’ 1 (±2) cm’ 1 , 1617 cm’ 1 (±2) cm’ 1 , 1425 cm’ 1 (±2) cm’ 1 , 852 cm’ 1 (±2) cm’ 1 or 762 cm’ 1 (±2) cm’ 1 , in particular comprising at least two peaks at positions 1685 cm’ 1 (±2) cm’ 1 , 1617 cm’ 1 (±2) cm’ 1 , 1425 cm’ 1 (±2) cm’ 1 , 852 cm’ 1 (±2) cm’ 1 or 762 cm’ 1 (±2) cm’ 1 , more particularly comprising the peaks at positions 1685 cm’ 1 (±2) cm’ 1 , 1617 cm’ 1 (±2) cm’ 1 , 1425 cm’ 1 (±2) cm’ 1 , 852 cm’ 1 (±2) cm’ 1 and 762 cm’ 1 (±2) cm’ 1 .
  11. 11. A solid form of a compound of formula (I) (I), wherein the solid form is crystalline polymorphic Form B characterized by a Raman spectrum comprising at least one peak at one of the positions 114 (±2) cm’ 1 , 132 (±2) cm’ 1 , 167 (±2) cm’ 1 , 349 (±2) cm’ 1 or 1620 (±2) cm’ 1 , in particular comprising at least two peaks at positions 114 (±2) cm’ 1 , 132 (±2) cm’ 1 , 167 (±2) cm’ 1 , 349 (±2) cm’ 1 or 1620 (±2) cm’ 1 , more particularly comprising the peaks at positions 114 (±2) cm’ 1 , 132 (±2) cm’ 1 , 167 (±2) cm’ 1 , 349 (±2) cm’ 1 and 1620 (±2) cm’ 1 .
  12. 12. A substantially pure solid form according to any one of claims 1 to 11.
  13. 13. A solid form according to any one of claims 1 to 12 for use as a medicament.
  14. 14. A solid form according to any one of claims 1 to 12 for the treatment or prophylaxis of cancer, in particular BRAF associated cancer.
  15. 15. A solid form according to any one of claims 1 to 12 for the treatment or prophylaxis of melanoma or colorectal cancer.
  16. 16. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 12 and one or more pharmaceutically acceptable auxiliary substances.
  17. 17. Use of a solid form according to any one of claims 1 to 12 for the treatment of cancer, in particular BRAF associated cancer.
  18. 18. Use of a solid form according to any one of claims 1 to 12 for the preparation of a medicament for the treatment of cancer, in particular BRAF associated cancer.
  19. 19. A method for treatment of cancer, in particular BRAF associated cancer, said method comprising administering an effective amount of a solid form according to any one of claims 1 to 12 to a patient in need thereof.
  20. 20. The invention as described herein.

Description

New solid forms of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy- phenyl]-3-fluoro-pyrrolidine-l-sulfonamide Field of the invention The present invention provides new solid forms of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4- oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-l-sulfonamide, as well as therapeutic uses thereof and pharmaceutical compositions comprising said forms. Background Art The Rapidly Accelerated Fibrosarcoma (RAF) class of serine-threonine kinases comprise three members (ARAF, BRAF, RAFI) that compose the first node of the MAP kinase signalling pathway. Despite the apparent redundancy of the three RAF isoforms in signalling propagation through phosphorylation of MEK1 and 2, frequent oncogenic activating mutations are commonly found only for BRAF. In particular, substitution of V600 with glutamic acid or lysine renders the kinase highly activated with consequent hyper-stimulation of the MAPK pathway, independently from external stimulations (Cell. 2015 Jun 18; 161(7): 1681-1696). Mutant BRAF is a targetable oncogenic driver and three BRAF inhibitors (vemurafenib, dabrafenib and encorafenib) reached the market up to now showing efficacy in BRAFV600E- positive melanoma. However rapid acquisition of drug resistance is almost universally observed and the duration of the therapeutic benefits for the targeted therapy remains limited. Moreover, the developed BRAF inhibitors revealed an unexpected and “paradoxical” ability to repress MAPK signalling in BRAFV600E-driven tumours while the same inhibitors presented MAPK stimulatory activities in BRAF wild type (WT) models (N Engl J Med 2012; 366:271-273; and British Journal of Cancer volume 111, pages640-645(2014)). Mechanistic studies on the RAF paradox then clarified that oncogenic BRAFV600E phosphorylates MEK 1/2 in its monomeric cytosolic form while WT BRAF and RAFI activation requires a complex step of events including cell membrane translocation and homo and/or heterodimerization promoted by activated RAS (KRAS, NRAS, HRAS) (Nature Reviews Cancer volume 14, pages455-467(2014)). The binding of inhibitors like vemurafenib, dabrafenib or encorafenib to a WT BRAF or RAFI protomer, quickly induces RAF homo and/or hetero dimerization and membrane association of the newly formed RAF dimer. In the dimeric conformation, one RAF protomer allosterically induces conformational changes of the second resulting in a kinase active status and, importantly, in a conformation unfavourable for the binding of the inhibitor. The dimer induced by drug treatment, as a result, promotes MEK phosphorylation by the catalysis operated by the unbound protomer with hyperactivation of the pathway. The RAF paradox results in two clinically relevant consequences: 1) accelerated growth of secondary tumours upon BRAFi monotherapy (mainly keratochantoma and squamous-cell carcinomas) (N Engl J Med 2012; 366:271-273) and 2) the acquisition of drug resistance in the setting of BRAFi monotherapy as well as in combinations of BRAFi+MEKi presents activation of dimer-mediated RAF signalling by genetically driven events including RAS mutations, BRAF amplifications, expression of dimeric-acting BRAF splice variants (Nature Reviews Cancer volume 14, pages 455-467(2014)). There is thus the need for RAF inhibitors capable of breaking that paradox. Furthermore, the currently approved classical BRAF inhibitors Vemurafenib (Mol. Pharmaceutics 2012, 9, 11, 3236-3245), Dabrafenib (J Pharmacol Ex Ther 2013, 344 (3) 655- 664) and Encorafenib (Pharmacol Res. 2018;129:414-423) all have very poor brain permerability. This is major limitation for the use of those classical BRAF inhibitors for the treatment of brain cancer or brain metastases. There is thus the need for BRAF inhibitors having improved brain permeability. There is accordingly a need for compounds that are efficient BRAF inhibitors showing considerably less paradoxial activation of the MAPK signaling pathway while retaining high potency. Such compounds can be referred to as a paradox breaker or RAF paradox breaker, in contrast to compounds inducing the RAF paradox (and which could be referred to as paradox inducers or RAF paradox inducers). (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6- yl)oxy-phenyl] -3 -fluoro-pyrrolidine-1 -sulfonamide satisfies these needs, and is a paradox breaking BRAF inhibitor with favourable brain penetration properties. Polymorphs are different crystalline forms of the same compound. Polymorphs typically have a different crystal structure due to a different packing of the molecules in the lattice. Polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not held constant during clinical studies, the exact dosage form used or studie may not be comparable form one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphi