PHARMACEUTICAL COMPOSITIONS OF THERAPEUTICALLY ACTIVE COMPOUNDS

• US 20170007661A1
• Filed: 03/13/2015
• Published: 01/12/2017
• Est. Priority Date: 03/14/2014
• Status: Abandoned Application

• Current Assignee: Servier Pharmaceuticals LLC (Servier Sas)
• Original Assignee: Agios Pharmaceuticals Inc.
• Inventors: Gu, Chong-Hui
• Application Number:
  US15/125,884
• Publication Number:
  US 20170007661A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: G01N 33/49 Blood chemical methods for determining blood cell populations G01N33/5094; chemical analysis of blood groups or blood types G01N33/80
• CPC Class Codes: G01N 33/493 urine

Abstract

Provided are compounds and pharmaceutical compositions useful for treating cancer and methods of treating cancer comprising administering to a subject in need thereof a compound or pharmaceutical composition described herein.

Claims

1. A method of treating advanced solid tumors in a subject, each characterized by the presence of a mutant allele of IDH1, the method comprising administering to the subject in need thereof a pharmaceutical composition comprising:

(a) a compound (S)—

N—

((S)-1-(2-chlorophenyl)-2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-1-(4-cyanopyridin-2-yl)-N-(5-fluoropyridin-3-yl)-5-oxopyrrolidine-2-carboxamide (Compound

     1), or a pharmaceutically acceptable salt thereof, as part of a solid dispersion;

Form 1 of the Compound 1;

or Form 2 of the Compound 1; and

optionally (b) one or more pharmaceutically acceptable carrier(s).

2. The method of claim 1, wherein the advanced solid tumors is selected from glioma, intrahepatic cholangiocarcinomas (IHCC), chondrosarcoma, prostate cancer, colon cancer, melanoma, and non-small cell lung cancer (NSCLC).

3. The method of claim 1, wherein at least a particular percentage by weight of Compound 1 is crystalline.

4. The method of claim 3, wherein the particular weight percentage of Compound 1 is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

5. The method of claim 3, wherein the particular weight percentage of Compound 1 is between 10% and 100%.

6. The method of claim 1, wherein a particular percentage by weight of Compound 1 is crystalline, and the remainder of Compound 1 is the amorphous form of Compound 1.

7. The method of claim 1, wherein Compound 1 comprises a single crystalline form of Compound 1 or a mixture of different single crystalline forms.

8. The method of claim 1, wherein Compound 1 is at least 90% by weight crystalline.

9. The method of claim 1, wherein Compound 1 is at least 95% by weight crystalline.

10. The method of claim 1, wherein Compound 1 is at least 99% by weight crystalline.

11. The method of claim 1, wherein Form 1 of Compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 1, and the data shown in Table 1.

12. The method of claim 11, wherein the single crystalline form is characterized by one or more of the peaks shown in FIG. 1, and as shown in Table 1.

13. The method of claim 11, wherein the single crystalline form is characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 1.

14. The method of claim 11, wherein Form 1 is characterized by the peaks identified at 20 angles of 8.6, 15.6, 18.5, 20.6, 21.6, and 26.4°

.

15. The method of claim 11, wherein Form 1 is characterized by the peaks identified at 20 angles of 8.6, 15.6, 18.5, and 21.6°

.

16. The method of claim 1, wherein Form 2 of the Compound 1 is characterized by the X-ray powder diffraction (XRPD) pattern shown in FIG. 4, and the data shown in Table 2.

17. The method of claim 16, wherein Form 2 is characterized by one or more of the peaks shown in FIG. 4, and as shown in Table 2.

18. The method of claim 16, wherein Form 2 is characterized by one or two or three or four or five or six or seven or eight or nine of the peaks shown in Table 2.

19. The method of claim 16, wherein Form 2 is characterized by the peaks identified at 20 angles of 9.8, 11.6, 19.6, 22.5, 23.0, and 31.4°

.

20. The method of claim 11, wherein Form 2 is characterized by the peaks identified at 20 angles of 9.8, 11.6, 19.6, and 23.0°

.

21. The method of claim 1, wherein the solid dispersion comprises a water-soluble polymer.

22. The method of claim 1, wherein the solid dispersion comprises one partially water-soluble polymer.

23. The method of claim 21, wherein the polymer is a cellulose polymer.

24. The method of claim 21, wherein the efficacy of treatment of advanced solid tumors is monitored by measuring the levels of 2HG in the subject.

25. The method of claim 1, wherein the subject is evaluated prior to and/or after treatment with the pharmaceutical composition comprising:

(a) Compound 1 or a pharmaceutically acceptable salt thereof, as part of a solid dispersion;

Form 1 of the Compound 1;

or Form 2 of the Compound 1; and

optionally (b) one or more pharmaceutically acceptable carrier(s), wherein the method comprises determining the 2HG level in the subject.

26. The method of claim 25, wherein the 2HG level is determined by spectroscopic analysis.

27. The method of claim 26, wherein the spectroscopic analysis comprises magnetic resonance-based analysis.

28. The method of claim 26, wherein the spectroscopic analysis comprises MRI and/or MRS measurement;

sample analysis of bodily fluid;

or by analysis of surgical material.

29. The method of claim 28, wherein the bodily fluid comprises blood, plasma, urine, or spinal cord fluid.

30. The method of claim 28, wherein the surgical material is analyzed by mass-spectroscopy.

31. The method of claim 30, wherein the mass-spectroscopy comprises LC-MS or GC-MS.

32. The method of claim 1, wherein the advanced solid tumors are characterized by a mutant allele of IDH1, wherein the IDH1 mutation results in a new ability of the enzyme to catalyze the NAPH-dependent reduction of α

-ketoglutarate to R(−

)-2-hydroxyglutarate (2HG) in a patient.

33. The method of claim 32, wherein the mutant IDH1 has an R132X mutation.

34. The method of claim 33, wherein the R132X mutation is selected from R132H, R132C, R132L, R132V, R132S and R132G.

35. The method of claim 33, wherein the R132X mutation is R132H or R132C.

36. The method of claim 1, wherein the method comprises administering to the subject in need thereof a pharmaceutical composition comprising Compound 1, or a pharmaceutically acceptable salt thereof, as part of a solid dispersion.

37. The method of claim 1, wherein the method comprises administering to the subject in need thereof Form 1 of the Compound 1.

38. The method of claim 1, wherein the method comprises administering to the subject in need thereof Form 2 of the Compound 1.