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EP-4054541-B1 - SALT FORMS OF A COMPLEMENT COMPONENT C5A RECEPTOR

EP4054541B1EP 4054541 B1EP4054541 B1EP 4054541B1EP-4054541-B1

Inventors

  • SINGH, RAJINDER
  • YAU, Kwok
  • ZENG, YIBIN
  • ZHANG, PENGLIE
  • LUI, Rebecca M.
  • YANG, JU
  • ROTH, Howard S.

Dates

Publication Date
20260506
Application Date
20201106

Claims (20)

  1. A crystalline salt of Compound 1 which is: (a) a crystalline besylate salt of Compound 1; or (b) a crystalline tosylate salt of Compound 1; or (c) a crystalline napadisylate salt of Compound 1; or (d) a crystalline napsylate salt of Compound 1; or (e) a crystalline camsylate salt of Compound 1; or (f) a crystalline edisylate salt of Compound 1; wherein, the crystalline besylate salt of Compound 1 is a besylate salt Form I or a besylate salt Form II, wherein the besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9, 13.3, 16.2, 17.6 and 21.8 degrees 2θ (± 0.2 degrees 2θ); wherein the besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.6, 7.1, 12.3, 12.8, and 16.7 degrees 2θ (± 0.2 degrees 2θ); wherein the crystalline tosylate salt of Compound I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 7.6, 10.8, 13.1, 16.5, 19.7, 21.6 degrees 2θ (± 0.2 degrees 2θ); wherein the crystalline napadisylate salt of Compound I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 7.0, 12.4, 14.7, 15.2, and 18.0 degrees 2θ (± 0.2 degrees 2θ); wherein the crystalline napsylate salt of Compound I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.5, 7.7, 10.4, 12.9, and 16.1 degrees 2θ (± 0.2 degrees 2θ); wherein the crystalline camsylate salt of Compound I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.3, 7.9, 10.8, 12.2, and 16.1 degrees 2θ (± 0.2 degrees 2θ); and wherein the edisylate salt of Compound I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.4, 5.6, 12.9, 15.3, 18.1, and 20.8 degrees 2θ (± 0.2 degrees 2θ).
  2. The crystalline salt of claim 1, wherein the crystalline salt is the besylate salt of Compound 1 in a crystalline form which is free of other crystalline or amorphous forms.
  3. The crystalline salt of claim 1, wherein the crystalline salt is the besylate salt Form I, wherein the besylate salt Form I is further characterized by XRPD peaks at 6.6, 7.6, 14.5, 16.2, and 28.2 degrees 2θ (± 0.2 degrees 2θ),
  4. The crystalline salt of claim 1, wherein the crystalline salt is the besylate salt Form I, wherein the besylate salt Form I is further characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at 207.2 °C, or further characterized by a melting point onset of 200.6 °C as determined by differential scanning calorimetry thermogram (DSC).
  5. The crystalline salt of claim 1, wherein the crystalline salt is the besylate salt Form I, wherein the besylate salt Form I is further characterized by a weight loss of 0.14% upon heating to 202.9 °C, as measured by thermal gravimetric analysis (TGA).
  6. The crystalline salt of claim 1, wherein the crystalline salt is the besylate salt Form I, wherein the besylate salt Form I is further characterized by a weight gain of 0.5 % after undergoing a dynamic vapor sorption cycle from 0% relative humidity (RH) to 75% RH at 25 °C, or further characterized by a weight gain of 0.73 % after undergoing a dynamic vapor sorption cycle from 5% relative humidity (RH) to 95% RH at 25 °C.
  7. The salt of claim 1, wherein the crystalline salt is the besylate salt Form I, wherein the besylate salt Form I is further characterized by a scanning electron microscopy (SEM) image having predominantly prismatic or anhedral particles wherein particle sizes are 1 µm to 73 µm as determined by scanning electron microscopy (SEM).
  8. The crystalline salt of claim 1, wherein the crystalline salt is the besylate salt Form I, wherein the besylate salt Form I is further characterized by particles ranging in size from 2.5 to 83 µm as determined by polarized light microscope (PLM).
  9. The crystalline salt of claim 1, wherein the crystalline salt is the besylate salt Form II, wherein besylate salt Form II is further characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at 187.2 °C, or further characterized by a melting point onset of 80.5 °C as determined by differential scanning calorimetry thermogram (DSC).
  10. The crystalline salt of claim 1, wherein the crystalline sakt is the besylate salt Form II, wherein the besylate salt Form II is further characterized by a weight loss of 0.095% upon heating to 189.5 °C, as measured by thermal gravimetric analysis (TGA).
  11. The crystalline salt of claim 1, wherein the crystalline salt is the tosylate salt of Compound 1, wherein the tosylate salt is free of other crystalline or amorphous forms.
  12. The crystalline salt of claim 1, wherein the crystalline salt is the tosylate salt of Compound 1,iswherein the tosylate salt isfurther characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 6.6, 15.3, 16.0, and 27.8 degrees 2θ (± 0.2 degrees 2θ).
  13. The crystalline salt of claim 1, wherein the crystalline salt is the tosylate salt of Compound 1, wherein the tosylate salt is further characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at 209.8 °C, or further characterized by a melting point onset of 206.2 °C as determined by differential scanning calorimetry thermogram (DSC).
  14. The crystalline salt of claim 1, wherein the crystalline salt is the tosylate salt of Compound 1, wherein the tosylate salt is further characterized by a weight loss of 0.19% upon heating to 204.2 °C, as measured by thermal gravimetric analysis (TGA).
  15. The crystalline salt of claim 1, wherein the crystalline salt is the tosylate salt of Compound 1, wherein the tosylate salt is further characterized by a weight gain of 0.58 % after undergoing a dynamic vapor sorption cycle from 0% relative humidity (RH) to 75% RH at 25 °C, or further characterized by a weight gain of 0.83 % after undergoing a dynamic vapor sorption cycle from 5% relative humidity (RH) to 95% RH at 25 °C.
  16. The crystalline salt of claim 1, wherein the crystalline salt is the tosylate salt of Compound 1, wherein the tosylate salt is further characterized by a scanning electron microscopy (SEM) image having predominantly blade, rod, or equant particles, wherein particle sizes are 1 µm to 500 µm as determined by scanning electron microscopy (SEM), or further characterized by particles ranging in size from 2.5 to 440 µm as determined by polarized light microscope (PLM).
  17. The crystalline salt of claim 1, wherein the crystalline salt is the napadisylate salt of Compound 1 in a crystalline form which is free of other crystalline or amorphous forms.
  18. The crystalline salt of claim 1, wherein the crystalline salt is the napadisylate salt of Compound 1, wherein the napadisylate salt is further characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks 9.6, 11.2, 18.6, and 20.4 degrees 2θ (± 0.2 degrees 2θ).
  19. The crystalline salt of claim 1, wherein the crystalline salt is the napadisylate salt of Compound 1, wherein the napadisylate salt is further characterized by a differential scanning calorimetry thermogram (DSC) comprising an endothermic peak at 232.8 °C, or further characterized by a melting point onset of 222.7 °C as determined by differential scanning calorimetry thermogram (DSC).
  20. The crystalline salt of claim 1, wherein the crystalline salt is the napadisylate salt of Compound 1, wherein the napadisylate salt is further characterized by a weight loss of 2.0% upon heating to 233.1 °C, as measured by thermal gravimetric analysis (TGA).

Description

BACKGROUND OF THE INVENTION The complement system plays a central role in the clearance of immune complexes and in immune responses to infectious agents, foreign antigens, virus infected cells and tumor cells. Inappropriate or excessive activation of the complement system can lead to harmful, and even potentially life-threatening consequences due to severe inflammation and resulting tissue destruction. These consequences are clinically manifested in various disorders including septic shock; myocardial, as well as, intestinal ischemia/reperfusion injury; graft rejection; organ failure; nephritis; pathological inflammation; and autoimmune diseases. The complement system is composed of a group of proteins that are normally present in the serum in an inactive state. Activation of the complement system encompasses mainly three distinct pathways, i.e., the classical, the alternative, and the lectin pathway (V. M. Holers, In Clinical Immunology: Principles and Practice, ed. R. R. Rich, Mosby Press; 1996, 363-391): 1) The classical pathway is a calcium/magnesium-dependent cascade, which is normally activated by the formation of antigen-antibody complexes. It can also be activated in an antibody-independent manner by the binding of C-reactive protein, complexed with ligand, and by many pathogens including gram-negative bacteria. 2) The alternative pathway is a magnesium-dependent cascade which is activated by deposition and activation of C3 on certain susceptible surfaces (e.g. cell wall polysaccharides of yeast and bacteria, and certain biopolymer materials). 3) The lectin pathway involves the initial binding of mannose-binding lectin and the subsequent activation of C2 and C4, which are common to the classical pathway (Matsushita, M. et al., J. Exp. Med. 176: 1497-1502 (1992); Suankratay, C. et al., J. Immunol. 160: 3006-3013 (1998)). The activation of the complement pathway generates biologically active fragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxins and C5b-9 membrane attack complexes (MAC), all which mediate inflammatory responses by affecting leukocyte chemotaxis; activating macrophages, neutrophils, platelets, mast cells and endothelial cells; and increasing vascular permeability, cytolysis and tissue injury. Complement C5a is one of the most potent proinflammatory mediators of the complement system. (The anaphylactic C5a peptide is 100 times more potent, on a molar basis, in eliciting inflammatory responses than C3a.) C5a is the activated form of C5 (190 kD, molecular weight). C5a is present in human serum at approximately 80 µg/ml (Kohler, P. F. et al., J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptide chains, α and β, with approximate molecular weights of 115 kD and 75 kD, respectively (Tack, B. F. et al., Biochemistry 18: 1490-1497 (1979)). Biosynthesized as a single-chain promolecule, C5 is enzymatically cleaved into a two-chain structure during processing and secretion. After cleavage, the two chains are held together by at least one disulphide bond as well as noncovalent interactions (Ooi, Y. M. et al., J. Immunol. 124: 2494-2498(1980)). Recent work has identified (2R,3S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide, Compound 1 as useful for treating C5a mediated diseases. Despite the disclosure of this compound, the efficient delivery of biologically relevant amounts of Compound 1 remains challenging. Moreover, no salt forms of this compound have been reported. Salt forms may improve important biological characteristics such as solubility, dissolution rate, and bioavailability, thereby improving the therapeutic efficacy of this compound. As such, there exists a need to provide salt forms of Compound 1 that may offer advantageous pharmacokinetic properties. The present disclosure addresses these needs and provides related advantages as well. BRIEF SUMMARY OF THE INVENTION The present disclosure provides salt forms of Compound 1, (2R,3 S)-2-(4-(cyclopentylamino)phenyl)-1-(2-fluoro-6-methylbenzoyl)-N-(4-methyl-3-(trifluoromethyl)phenyl)piperidine-3-carboxamide, which is: (a) a crystalline besylate salt of Compound 1; or(b) a crystalline tosylate salt of Compound 1; or(c) a crystalline napadisylate salt of Compound 1; or(d) a crystalline napsylate salt of Compound 1; or(e) a crystalline camsylate salt of Compound 1; or(f) a crystalline edisylate salt of Compound 1; wherein, the crystalline besylate salt of Compound 1 is a besylate salt Form I or a besylate salt Form II,wherein the besylate salt Form I is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 10.9, 13.3, 16.2, 17.6 and 21.8 degrees 2θ (± 0.2 degrees 2θ);wherein the besylate salt Form II is characterized by an X-ray powder diffraction (XRPD) pattern comprising peaks at 3.6, 7.1, 12.3, 12.8, and 16.7 degrees 2θ (± 0.2 degrees 2θ);wherein the crystalline tosylate salt of Compound I is characterized