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CN-122003239-A - TYK2 inhibitors for the treatment of inflammatory bowel disease

CN122003239ACN 122003239 ACN122003239 ACN 122003239ACN-122003239-A

Abstract

Compounds, compositions thereof, and methods of using the same in dosing regimens for inhibiting TYK2 and treating inflammatory disorders including inflammatory bowel disease, including Crohn's disease or ulcerative colitis, are described.

Inventors

  • N. SINGER
  • C. E. Habison
  • C. Dulairaj
  • V.A.Ruan
  • G. A.R. Shipp
  • G.Xia

Assignees

  • 武田药品工业株式会社

Dates

Publication Date
20260508
Application Date
20240920
Priority Date
20240209

Claims (20)

  1. 1. A method of treating inflammatory bowel disease including crohn's disease or ulcerative colitis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of compound 1: 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  2. 2. The method of claim 1, wherein the administration is performed daily for a period of about 1 day to about 2 days, about 2 days to about 3 days, about 3 days to about 4 days, about 4 days to about 5 days, about 5 days to about 6 days, about 6 days to about 7 days, about 1 week to about 2 weeks, about 2 weeks to about 3 weeks, about 3 weeks to about 4 weeks, about 4 weeks to about 5 weeks, about 5 weeks to about 6 weeks, about 6 weeks to about 7 weeks, about 7 weeks to about 8 weeks, about 8 weeks to about 9 weeks, about 9 weeks to about 10 weeks, about 10 weeks to about 11 weeks, about 11 weeks to about 12 weeks, about 12 weeks to about 14 weeks, about 14 weeks to about 16 weeks, about 16 weeks to about 18 weeks, about 18 weeks to about 21 weeks, about 21 weeks to about 24 weeks, about 24 weeks to about 27 weeks, about 27 weeks to about 30 weeks, about 30 weeks to about 33 weeks, about 33 weeks to about 36 weeks, about 36 weeks to about 39 weeks, about 39 years to about 45 years, about 42 years to about 48 years, about 3 years to about 51, about 5 years to about 48 years, about 51, or about 51.
  3. 3. The method of claim 1, wherein the administration is performed daily for an indefinite period of time.
  4. 4. The method of any one of claims 1-3, wherein an average reduction of about 50% to 70% in crohn's disease simplified endoscopic score (SES-CD) is achieved for a patient with crohn's disease.
  5. 5. The method of any one of claims 1-3, wherein an average reduction of about 70% to 90% in crohn's disease simplified endoscopic score (SES-CD) is achieved for a patient with crohn's disease.
  6. 6. The method of claim 4 or 5, wherein an average reduction of about 90% to 100% in crohn's disease simplified endoscope score (SES-CD) is achieved for a patient suffering from crohn's disease.
  7. 7. The method of any one of claims 1-6, wherein a reduced endoscopic score for crohn's disease (SES-CD) of less than or equal to 4 or at least a2 score reduction from baseline is achieved for a patient with crohn's disease with isolated ileal disease, as read in a centralized fashion.
  8. 8. The method of any one of claims 1-6, wherein for patients with ulcerative colitis, a modified Mayo score (scoring system for assessing ulcerative colitis activity) of less than or equal to 2 is achieved, wherein the stool frequency sub-score is less than or equal to 1, the rectal bleeding sub-score is 0, and the center read internal mirror score is less than or equal to 1 (modified score 1 to exclude fragility).
  9. 9. The method of any one of claims 1-8, wherein the patient has inflammatory bowel disease.
  10. 10. The method of claim 9, wherein the inflammatory bowel disease is moderately to severely active.
  11. 11. The method of any one of claims 1-10, wherein the patient has crohn's disease.
  12. 12. The method of claim 11, wherein the crohn's disease is moderately to severely active.
  13. 13. The method of any one of claims 1-10, wherein the patient has ulcerative colitis.
  14. 14. The method of claim 13, wherein the ulcerative colitis is moderately to severely active.
  15. 15. The method of claim 11, wherein the method achieves a reduction in Crohn's simplified endoscopic score (SES-CD) of greater than or equal to 50% from baseline, or a reduction in SES-CD of about 50% to about 70%, about 70% to about 90%, or about 90% to about 100% for patients with Crohn's disease, including moderate to severe active Crohn's disease, in a centralized manner, or a reduction in SES-CD of less than or equal to 4 or at least 2 points from baseline for isolated ileal disease, in a centralized manner.
  16. 16. The method of claim 13, wherein for patients with ulcerative colitis, including moderate to severe active colitis, the method achieves a modified Mayo score (a scoring system for assessing ulcerative colitis activity) of less than or equal to 2, wherein the stool frequency sub-score is less than or equal to 1, the rectal bleeding sub-score is 0, and a center read internal mirror score is less than or equal to 1 (modified score 1 to exclude fragility).
  17. 17. A method of inhibiting interferon gamma (ifnγ) production in a patient, the method comprising administering to a patient suffering from inflammatory bowel disease a therapeutically effective amount of compound 1: 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
  18. 18. The method of claim 17, wherein the patient has crohn's disease.
  19. 19. The method of claim 17, wherein the patient has ulcerative colitis.
  20. 20. The method of claim 17, wherein the inflammatory bowel disease is moderately to severely active.

Description

TYK2 inhibitors for the treatment of inflammatory bowel disease Technical Field The present invention relates to methods of administering a non-receptor tyrosine kinase 2 (TYK 2) inhibitor, such as N- ((1 r,2 r) -2-methoxycyclobutyl) -7- (methylamino) -5- ((2-oxo-2H- [1,2 '-bipyridyl ] -3-yl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxamide (compound 1), and to the use thereof for the treatment of inflammatory disorders, such as inflammatory bowel disease, including Crohn's disease or ulcerative colitis. Background Protein kinases constitute a large family of structurally related enzymes responsible for controlling a variety of signal transduction processes within cells. Protein kinases are thought to evolve from a common ancestral gene due to conservation of their structure and catalytic function. Almost all kinases contain similar catalytic domains of 250-300 amino acids. Substrates phosphorylated by kinases (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.) can be classified into families. In general, protein kinases mediate intracellular signaling by effecting phosphoryl transfer from nucleoside triphosphates to protein receptors involved in the signaling pathway. These phosphorylation events act as molecular on/off switches that can regulate or modulate the biological function of the target protein. These phosphorylation events ultimately trigger in response to a variety of extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxins, and H 2O2), cytokines (e.g., interleukin-1 (IL-1), interleukin-8 (IL-8), interleukin-12 (IL-12), interleukin-23 (IL-23), and tumor necrosis factor alpha (TNF-alpha)), and growth factors (e.g., granulocyte macrophage colony-stimulating factor (GM-CSF) and Fibroblast Growth Factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell growth, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, control of protein synthesis, and regulation of the cell cycle. Many diseases are associated with abnormal cellular responses triggered by kinase-mediated events. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, skeletal diseases, metabolic diseases, neurological and neurodegenerative diseases, some cancers, cardiovascular diseases, allergies and asthma, alzheimer's disease and hormone-related diseases. Tyrosine kinase 2 (TYK 2) catalyzes the phosphorylation of STAT proteins downstream of a variety of cytokine receptors, including the type I interferon receptor as well as the IL-12 and IL-23 receptors. Activation of TYK 2-dependent receptors by their cytokine ligands leads to activation of STAT-dependent transcription and cellular functional responses specific for the receptor and the cell type expressing the receptor. Cytokine signaling pathways regulated by TYK2 play a key role in several immune-mediated disorders. Cytokine IL-12 is essential for the development of T helper cell type 1 (Th 1), which produces interferon-gamma, the main effector molecule for systemic autoimmune disorders such as systemic lupus erythematosus. The cytokine IL-23 is critical for the expansion and survival of Th17 cells and congenital lymphoid cells, both of which have been shown to play a critical pathogenic role in autoimmunity. IL-23 stimulates production of key pro-inflammatory cytokines, including IL-17A, IL-17F and IL-22, by Th17 cells, all of which are effector molecules important for the pathogenesis of conditions such as inflammatory bowel disease, including Crohn's disease or ulcerative colitis. Since TYK2 has effects on the IL-23/Th17/Th22 axis, IL-12 mediated Th1 function, and type I interferon-driven modulation of different immune pathways and cell types, inhibition of TYK2 is expected to affect a variety of immune-mediated disorders. Thus, there remains a need to find TYK2 inhibitors that can be used as therapeutic agents. The present disclosure meets this need and provides other related advantages. Disclosure of Invention It has been found that certain TYK2 inhibitors are suitable for oral administration to a patient for the treatment of inflammatory disorders, such as Inflammatory Bowel Disease (IBD), including Crohn's Disease (CD) or Ulcerative Colitis (UC). Thus, in one aspect, a method of treating IBD (including CD or UC) in a patient in need thereof may comprise administering to the patient a therapeutically effective amount of a TYK2 inhibitor (e.g., compound 1), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Compound 1 has the following structure: 1 Compound 1 has the IUPAC name N- ((1 r,2 r) -2-methoxycyclobutyl) -7- (methylamino) -5- ((2-oxo-2H- [1,2' -bipyridyl ] -3-yl) amino) pyrazolo [1,5-a ] pyrimidine-3-carboxamide. In some embodiments, the patient may have