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EP-4739695-A1 - CRYSTALLINE FORM

EP4739695A1EP 4739695 A1EP4739695 A1EP 4739695A1EP-4739695-A1

Abstract

Provided herein is a crystalline form of a compound of Formula (I): i.e. (7R,14R)-11-[2-(1-aminocyclobutyl)pyrimidin-5-yl]-1-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one. A pharmaceutical composition comprising the crystalline form, and medical uses of the crystalline form and pharmaceutical composition are also described.

Inventors

  • Greciet, Hélène
  • MONNIER, OLIVIER
  • ZIRI, ISABELLE
  • FLASZ, Jakub Tadeusz
  • GRAFFEO, Sabrina Raymonde Sophie
  • ROUGEOT, Céline

Assignees

  • Sanofi
  • UCB Biopharma SRL

Dates

Publication Date
20260513
Application Date
20240703

Claims (18)

  1. 1. A crystalline form of a compound of Formula (I): wherein the crystalline form is of Form A, having an X-ray powder diffraction pattern comprising characteristic peaks at 4.0° ± 0.2° 29, 10.5° ± 0.2° 29, and 12.9° ± 9.2° 29.
  2. 2. The crystalline form according to claim 1, wherein the X-ray powder diffraction pattern further comprises a peak at 12.6° ± 9.2° 29.
  3. 3. The crystalline form according to claim 1 or claim 2, wherein the X-ray powder diffraction pattern further comprises a peak at 16.1° ± 9.2° 29.
  4. 4. The crystalline form according to any one of claims 1 to 3, wherein the X-ray powder diffraction pattern further comprises a peak at 18.9° ± 9.2° 29.
  5. 5. The crystalline form according to any one of claims 1 to 4, wherein the X-ray powder diffraction pattern comprises peaks at 4.9, 19.5, 12.9, 12.6, 15.5, 16.1, and 18.9°, with each peak measured to ± 9.2° 29.
  6. 6. The crystalline form according to any one of claims 1 to 5, wherein the X-ray powder diffraction pattern is substantially as illustrated in Fig. 2.
  7. 7. The crystalline form according to any one of claims 1 to 6, wherein the DSC thermogram of crystalline Form A has a single endothermic peak at about 222 °C ± 2 °C.
  8. 8. The crystalline form according to any one of claims 1 to 7, wherein the crystalline form is an anhydrate.
  9. 9. A pharmaceutical composition comprising: a) crystalline Form A as defined in any one of claims 1 to 8; and b) one or more pharmaceutically acceptable excipients, carriers, or diluents.
  10. 10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition comprises at least about 50 wt% of crystalline Form A as defined in any one of claims 1 to 8.
  11. 11. The pharmaceutical composition according to claim 9 or claim 10, wherein at least about 80 mol% of the compound of Formula (I) in the composition is crystalline Form A as defined in any one of claims 1 to 8.
  12. 12. A crystalline form as defined in any one of claims 1 to 8, or a pharmaceutical composition as defined in any one of claims 9 to 11, for use in therapy.
  13. 13. A crystalline form as defined in any one of claims 1 to 8, or a pharmaceutical composition as defined in any one of claims 9 to 11, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.
  14. 14. A process of manufacturing a crystalline form as defined in any one of claims 1 to 8, wherein the process comprises: a) combining compound of Formula (I): with a solvent to form a mixture; b) heating the mixture to a temperature of about 50 °C or greater; c) cooling the mixture to ambient temperature or lower.
  15. 15. The process of claim 14, wherein the solvent is selected from acetonitrile, ethyl acetate and propyl acetate, and is optionally acetonitrile.
  16. 16. The process according to claim 14 or 15, wherein in step b) the mixture is cooled for greater than about 4 h.
  17. 17. The process according to any one of claims 14 to 16, wherein in step b) the mixture is heated to a temperature of about 50 °C or greater, optionally from about 60 °C to about 90 °C.
  18. 18. The process according to any one of claims 14 to 17, wherein the process further comprises adding a seed crystal to the mixture, wherein the seed crystal is a crystal of Form A as defined in any one of claims 1 to 8.

Description

CRYSTALLINE FORM Disclosed herein is a crystalline form of a compound of Formula (I): i.e. (7R,14R)-1 l-[2-(l-aminocyclobutyl)pyrimidin-5-yl]-l-(difhroromethoxy)-6-methyl-6,7- dihydro-7, 14-methanobenzimidazo[l,2-b][2,5]benzodiazocin-5(14H)-one. A pharmaceutical composition comprising this crystalline form, and medical uses of the crystalline form and pharmaceutical composition are also described. Background (7R,14R)-1 l-[2-(l-aminocyclobutyl)pyrimidin-5-yl]-l-(difluoromethoxy)-6-methyl- 6,7-dihydro-7,14-methanobenzimidazo[l,2-b][2,5]benzodiazocin-5(14H)-one (the compound of Formula (I)) is a pharmacologically active substituted fused pentacyclic benzimidazole derivative which shows pharmacological activity on TNFa signalling. TNFa is the prototypical member of the Tumour Necrosis Factor (TNF) superfamily of proteins that share a primary function of regulating cell survival and cell death. One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to, and activate, specific TNF superfamily receptors. By way of example, TNFa exists in soluble and transmembrane forms and signals through two receptors, known as TNFR1 and TNFR2, with distinct functional endpoints. Various products capable of modulating TNFa activity are already commercially available. All are approved for the treatment of inflammatory and autoimmune disorders such as rheumatoid arthritis and Crohn’s disease. All currently approved products are macromolecular and act by inhibiting the binding of human TNFa to its receptor. Typical macromolecular TNFa inhibitors include anti-TNFa antibodies and soluble TNFa receptor fusion proteins. Examples of commercially available anti-TNFa antibodies include fully human antibodies such as adalimumab (Humira®) and golimumab (Simponi®), chimeric antibodies such as infliximab (Remicade®), and pegylated Fab' fragments such as certolizumab pegol (Cimzia®). An example of a commercially available soluble TNFa receptor fusion protein is etanercept (Enbrel®). The compound of Formula (I) is a potent modulator of human TNFa activity and is therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders, cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders. The compound of Formula (I) is known in the art in its amorphous form (see Example 6 of WO 2018/197503). However, no crystalline or polymorphic forms of the compound of Formula (I) are known in the art. In general, there is a desire to produce solid forms of pharmacologically active substances with advantageous physical properties, for example in terms of optimal chemical and physical stability, acceptable solubility, better handling properties, etc. From a chemistry point of view, generating a crystalline form of an active ingredient allows access to purification processes, which permits easier control of the final impurity profile of the compound. Typically, amorphous forms (such as known in the art for Formula (I)) are not desirable, for example due to having sub-optimal stability profiles and/or handling properties. Amorphous compounds often exhibit a high propension to absorb water. Thus, there is a need to develop solid forms of the compound of Formula (I) with advantageous properties. Polymorphism refers to the existence of multiple crystalline forms of the same substance. Particular polymorphic or crystalline forms of a drug may have advantageous characteristics versus other polymorphic, crystalline, or amorphous forms, including, for example, increased stability, increased solubility, better handling properties, lack of associated toxic solvents, and increased purity. Thus, the polymorphic behaviour of drugs can be of crucial importance in pharmacy and pharmacology. However, the existence of polymorphic or different crystalline forms, and the properties associated with each particular form, is highly unpredictable. Summary The present disclosure is based on the unexpected finding that: a) several crystalline forms of (7R,14R)-1 l-[2-(l-aminocyclobutyl)pyrimidin-5-yl]-l-(difluoromethoxy)-6-methyl- 6,7-dihydro-7,14-methanobenzimidazo[l,2-b][2,5]benzodiazocin-5(14H)-one (the compound of Formula (I)) exist; and b) that one particular crystalline form (referred to herein as Form A) has significantly improved properties compared to the other crystalline forms that have been identified. Herein is therefore provided a specific crystalline form of a compound of Formula (I): wherein the crystalline form is Form A, having an X-ray powder diffraction pattern comprising characteristic peaks at 4.0° ± 0.2° 29, 10.5° ± 0.2° 29, and 12.9° ± 9.2° 29. Herein is also provided a pharmaceutical composition comprising crystalline Form A as described above. Herein is also provided crystalline Form A as defined above, or a ph