Crystalline form of (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate

Patent metadata

Field	Value
Publication number	US-2016137654-A1
Application number	US-201514943014-A
Country	US
Kind code	A1
Filing date	Nov 16, 2015
Priority date	Nov 16, 2014
Publication date	May 19, 2016
Grant date	—

Abstract

A novel crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, pharmaceutical compositions containing said crystalline form and the use of said crystalline form in the treatment of pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection are disclosed. In some embodiments, the novel crystalline form comprises a stable polymorph of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate. The present invention is further directed to a process for the preparation of the novel crystalline form.

First claim

What is claimed:

1 . A crystalline form (I-HS) having the formula:

2 . The crystalline form according to claim 1 , characterized by having XRPD diffraction peaks (2θ degrees) at 18.4±0.2, 20.7±0.2, 23.1±0.2, and 24.0±0.2.

3 . The crystalline form according to claim 1 , characterized by having XRPD diffraction peaks (2θ degrees) at 10.7±0.2, 18.4±0.2, 20.7±0.2, 23.1±0.2, and 24.0±0.2.

4 . The crystalline form according to claim 1 , characterized by having XRPD diffraction peaks (2θ degrees) at 10.7±0.2, 18.4±0.2, 19.2±0.2, 20.2±0.2, 20.7±0.2, 21.5±0.2, 23.1±0.2, and 24.0±0.2.

5 . The crystalline form according to claim 1 , characterized by having XRPD diffraction peaks (2θ degrees) at 10.7±0.2, 15.3±0.2, 16.5±0.2, 18.4±0.2, 19.2±0.2, 19.9±0.2, 20.2±0.2, 20.7±0.2, 21.5±0.2, 22.1±0.2, 23.1±0.2, 24.0±0.2. 24.4±0.2, 25.6±0.2, 26.5±0.2, 27.6±0.2, 28.2±0.2, 28.7±0.2, 30.8±0.2, and 38.5±0.2.

6 . The crystalline form according to claim 1 , wherein the crystalline form has XRPD pattern substantially as shown in FIG. 29 .

7 . The crystalline form according to claim 1 , wherein the crystalline form exhibits an onset to maximum of about 193 to about 205° Celsius, as measured by differential scanning calorimetry.

8 . The crystalline form according to claim 1 , wherein the crystalline form exhibits a heat of melting of about 2.415 mW, as measured by differential scanning calorimetry.

9 . The crystalline form according to claim 1 , wherein the crystalline form has a DSC thermogram substantially as shown in FIG. 26 .

10 . The crystalline form according to claim 1 , wherein the crystalline form is non-hygroscopic.

11 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a crystalline form according to claim 1 .

12 . A pharmaceutical composition made by mixing a crystalline form according to claim 1 and a pharmaceutically acceptable carrier.

13 . A process for making a pharmaceutical composition comprising mixing a crystalline form according to claim 1 and a pharmaceutically acceptable carrier.

14 . A method of treating a disorder selected from the group consisting of cancer, pain, inflammation, neurodegenerative disease or Trypanosoma cruzi infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline form according to claim 1 .

15 . A method of treating a cancer mediated by a Trk kinase in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a crystalline form according to claim 1 .

16 . The method of claim 15 , wherein the cancer is mediated by TrkA.

17 . The method of claim 15 , wherein the cancer is mediated by TrkB.

18 . The method of claim 15 , wherein the cancer is mediated by TrkA and TrkB.

19 . A method of treating a patient diagnosed or identified as having a Trk-associated cancer, the method comprising administering to the subject a therapeutically effective amount of a crystalline form according to claim 1 .

20 . A method for treating cancer in a subject in need thereof, the method comprising:
(a) determining if the cancer is associated with one or more of overexpression, activation, amplification, and mutation of a Trk kinase; and (b) if the cancer is determined to be associated with one or more of overexpression, activation, amplification, and mutation of a Trk kinase, administering to the subject a therapeutically effective amount of a crystalline form according to claim 1 .

21 . A method for treating cancer in a subject in need thereof, the method comprising:
(a) determining if the cancer is mediated by a Trk kinase; and (b) if the cancer is determined to be mediated by a Trk kinase, administering to the subject a therapeutically effective amount of a crystalline form according to claim 1 .

22 . A method of treating a subject comprising:
(a) performing an assay on a sample obtained from the subject to determine whether the subject has dysregulation of a NTRK gene, a Trk protein, or expression or level of the same; and (b) administering to a subject determined to have dysregulation of a NTRK gene, a Trk protein, or expression or activity, or level of the same a therapeutically effective amount of a crystalline form according to claim 1 .

23 . The method of claim 19 or 22 , wherein the dysregulation of a NTRK gene, a Trk protein, or expression or level of the same is a chromosome translation that results in the translation of a Trk fusion protein.

24 . The method of claim 23 , wherein the Trk fusion protein is selected from the group consisting of: TP53-TrkA, LMNA-TrkA, CD74-TrkA, TFG-TrkA, TPM3-TrkA, NFASC-TrkA, BCAN-TrkA, MPRIP-TrkA, TPR-TrkA, RFWD2-TrkA, IRF2BP2-TrkA, SQSTM1-TrkA, SSBP2-TrkA, RABGAP1L-TrkA, C18ORF8-TrkA, RNF213-TrkA, TBC1D22A-TrkA, C20ORF112-TrkA, DNER-TrkA, ARHGEF2-TrkA, CHTOP-TrkA, PPL-TrkA, PLEKHA6-TrkA, PEAR1-TrkA, MRPL24-TrkA, MDM4-TrkA, LRRC71-TrkA, GRIPAP1-TrkA, EPS15-TrkA, DYNC2H1-TrkA, CEL-TrkA, EPHB2-TrkA, TGF-TrkA, NACC2-TrkB, QKI-TrkB, AFAP1-TrkB, PAN3-TrkB, SQSTM1-TrkB, TRIM24-TrkB, VCL-TrkB, AGBL4-TrkB, DAB2IP-TrkB, ETV6-TrkC, BTBD1-TrkC, LYN-TrkC, RBPMS-TrkC, EML4-TrkC, HOMER2-TrkC, TFG-TrkC, FAT1-TrkC, and TEL-TrkC.

25 . The method of claim 19 or 23 , wherein the dyregulation of a NTRK gene, a Trk protein, or expression or activity of the same is one or more point mutation in the gene.

26 . The method of claim 25 , wherein the NTRK gene is a NTRK1 gene, and the one or more point mutations in the NTRK1 gene results in the translation of a TrkA protein having substitutions are one or more of the following amino acid positions: 33, 336, 337, 324, 420, 444, 517, 538, 649, 682, 683, 702, and 1879.

27 . The method of claim 26 , wherein the one or more point mutations in the NTRK1 gene results in the translation of a TrkA protein having one or more of the following amino acid substitutions: R33W, A336E, A337T, R324Q, R324W, V420M, R444Q, R444W, G517R, G517V, K538A, R649W, R649L, R682S, V683G, R702C, and C1879T.

28 . A process for the preparation of crystalline form (I-HS) according to claim 1 , comprising:
(a) adding concentrated sulfuric acid to a solution of (S)—N-(5-((R)-2-(2,5-difuorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide in EtOH to form the hydrogen sulfate salt of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide; (b) adding heptane to the solution in Step (a) to form a slurry; (c) filtering the slurry to isolate (S)—N-(5((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate; (d) mixing said (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate with a 5:95 w/w solution of water/2-butanone; (e) heating the mixture from step (d) at about 65-70° C. with stirring until the weight percent of ethanol is about 0.5% to form a slurry of the crystalline form of (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate; and (f) isolating the crystalline form of (S)—

Assignees

• Array Biopharma Inc

Inventors

• Arrigo Alisha B
• Juengst Derrick
• Shah Khalid

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P31/04

  Antibacterial agents · CPC title