NZ749956B2 - Crystalline solid forms of a bet inhibitor - Google Patents
Crystalline solid forms of a bet inhibitorInfo
- Publication number
- NZ749956B2 NZ749956B2 NZ749956A NZ74995617A NZ749956B2 NZ 749956 B2 NZ749956 B2 NZ 749956B2 NZ 749956 A NZ749956 A NZ 749956A NZ 74995617 A NZ74995617 A NZ 74995617A NZ 749956 B2 NZ749956 B2 NZ 749956B2
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- Prior art keywords
- compound
- cancer
- solution
- solid form
- temperature
- Prior art date
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P31/12—Antivirals
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- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The present application relates to crystalline solid forms of an inhibitor of BET proteins such as BRD2, BRD3, BRD4, and BRD-t, including methods of preparation thereof, and intermediates in the preparation thereof, where the compound is useful in the treatment of diseases such as cancer.
Claims (41)
1. A solid form of a nd having the formula: Compound 1 n the solid form is crystalline; and wherein the solid form is: a) Form I, having three or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.7, 9.8, 11.6, 12.7, 14.7, 15.7, 20.0, 21.4, 23.3 and 27.1 degrees; or b) Form II, having three or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 6.7, 9.5, 10.5, 14.8, 16.2, 17.0, 18.8, and 19.3 degrees.
2. The solid form of claim 1 which is an anhydrate.
3. The solid form of claim 1, having three or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.7, 9.8, 11.6, 12.7, 14.7, 15.7, 20.0, 21.4, 23.3 and 27.1 degrees.
4. The solid form of claim 3 having an XRPD pattern substantially as shown in
5. The solid form of claim 3 having a DSC thermogram characterized by an endothermic peak at a temperature of 266 ºC ± 3°C.
6. The solid form of claim 3 having a DSC thermogram substantially as shown in The solid form of claim 3 having a TGA thermogram substantially as shown in The solid form of claim 1, wherein the solid form is Form II having three or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 6.
7. 7, 9.5, 10.5, 14.8, 16.2, 17.0, 18.
8. 8, and 19.3 degrees.
9. The solid form of claim 8 having an XRPD pattern substantially as shown in
10. The solid form of claim 8 having a DSC thermogram characterized by an endothermic peak at a temperature of 268 ºC ± 3°C.
11. The solid form of claim 8 having a DSC thermogram ntially as shown in .
12. The solid form of claim 8 having a TGA gram ntially as shown in .
13. A ceutical composition comprising a solid form of any one of claims 1-12 and at least one pharmaceutically acceptable carrier.
14. A method of inhibiting a BET protein comprising contacting in vitro a solid form of any one of claims 1-12 or a pharmaceutical composition of claim 13 with said BET protein.
15. Use of a solid form of any one of claims 1-12 or a pharmaceutical composition of claim 13, in the manufacture of a medicament for treatment of a disease or condition that is associated with a BET protein.
16. Use of a solid form of any one of claims 1-12 or a pharmaceutical composition of claim 13, in the manufacture of a medicament for treatment of a proliferative disorder that is ated with a BET protein.
17. The use of claim 16, wherein the proliferative disorder is cancer.
18. The use of claim 17, wherein the cancer is a logical cancer.
19. The use of claim 17, wherein the cancer is adenocarcinoma, bladder cancer, blastoma, bone cancer, breast cancer, brain cancer, carcinoma, d sarcoma, al cancer, colorectal cancer, esophageal cancer, gastrointestinal cancer, glioblastoma multiforme, glioma, gallbladder cancer, gastric cancer, head and neck cancer, Hodgkin's lymphoma, non- Hodgkin's lymphoma, intestinal cancer, kidney cancer, laryngeal cancer, leukemia, lung cancer, lymphoma, liver cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, le myeloma, AML (acute myeloid leukemia), DLBCL (diffuse large B- cell lymphoma), ocular cancer, optic nerve tumor, oral cancer, n cancer, pituitary tumor, primary central nervous system lymphoma, prostate cancer, pancreatic cancer, pharyngeal cancer, renal cell carcinoma, rectal , a, skin cancer, spinal tumor, small intestine cancer, stomach cancer, T-cell leukemia, T-cell lymphoma, testicular cancer, d , throat cancer, urogenital cancer, urothelial carcinoma, uterine cancer, l , or Wilms' tumor.
20. The use of claim 17, wherein the cancer is multiple myeloma, AML (acute myeloid leukemia), or DLBCL (diffuse large B-cell lymphoma).
21. The use of claim 16, wherein the proliferative disorder is a non-cancerous proliferative disorder.
22. Use of a solid form of any one of claims 1-12 or a pharmaceutical composition of claim 13, in the cture of a medicament for treatment of an autoimmune or inflammatory disease that is associated with a BET protein.
23. The use of claim 22, wherein the autoimmune or inflammatory disease is selected from allergy, allergic rhinitis, arthritis, asthma, chronic obstructive pulmonary e, degenerative joint disease, dermatitis, organ rejection, eczema, hepatitis, inflammatory bowel disease, multiple sclerosis, myasthenia gravis, psoriasis, sepsis, sepsis syndrome, septic shock, systemic lupus erythematosus, tissue graft rejection, and type I diabetes.
24. Use of a solid form of any one of claims 1-12 or a pharmaceutical composition of claim 13, in the manufacture of a medicament for treatment of a viral ion that is associated with a BET protein.
25. The use of claim 24, n the viral infection is infection with adenovirus, Epstein- Barr virus, tis B virus, hepatitis C virus, a herpes virus, human immunodeficiency virus, human papilloma virus or a pox virus.
26. A process of preparing Form I of Compound 1: Compound 1 sing itating Form I from a solution sing Compound 1 and a solvent, wherein Form I has three or more teristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 8.7, 9.8, 11.6, 12.7, 14.7, 15.7, 20.0, 21.4, 23.3 and 27.1 degrees.
27. The process of claim 26, wherein the solvent comprises methanol, acetone, nheptane , or a e thereof.
28. The process of claim 26, wherein the precipitating is carried out by (1) reducing the temperature of the solution of Compound 1, (2) trating the solution of Compound 1, (3) adding an anti-solvent to the solution of Compound 1, or (4) any ation thereof.
29. The process of claim 26, wherein the preparation of Form I comprises: (ia) heating the solution of Compound 1 to a temperature of 50 ºC to 60 ºC ± 3°C; (iia) reducing the volume of the solution of Compound 1 at the temperature of 50 ºC to 60 ºC ± 3°C to form a reduced-volume solution of Compound 1; (iiia) adding an anti-solvent to the reduced-volume solution of Compound 1 while maintaining the temperature at 55 ºC to 65 ºC ± 3°C to form a warm solution of Compound 1; (iva) cooling the warm solution of Compound 1 to a temperature of 15 ºC to 30 ºC ± 3°C to precipitate Form I.
30. The process of any one of claims 26-29, wherein the preparation of Form I ses: (ib) heating the solution of Compound 1, wherein the solution comprises methanol and acetone as solvent, to a temperature of 50 ºC to 60 ºC ± 3°C; (iib) reducing the volume of the solution of Compound 1 at the temperature of 50 ºC to 60 ºC ± 3°C to form a reduced-volume solution of Compound 1; (iiib) adding n-heptane to the reduced-volume solution of Compound 1 while maintaining the temperature at 55 ºC to 65 ºC ± 3°C to form a warm solution of Compound 1; (ivb) cooling the warm on of Compound 1 to a ature of 15 ºC to 30 ºC ± 3°C to precipitate Form I.
31. A process of preparing Form II of Compound 1: Compound 1 sing precipitating Form II from a solution sing Compound I and a solvent, wherein Form II has three or more characteristic XRPD peaks, in terms of 2-theta (± 0.2°), selected from 6.7, 9.5, 10.5, 14.8, 16.2, 17.0, 18.8, and 19.3 degrees.
32. The s of claim 31, wherein the solvent comprises tetrahydrofuran (THF), e, n-heptane, or a mixture thereof.
33. The process of claim 31, wherein the precipitating is carried out by (1) reducing the temperature of the solution of Compound 1, (2) concentrating the solution of Compound 1, (3) adding an olvent to the solution of Compound 1, or (4) any combination thereof.
34. The process of any claim 31, wherein the preparation of Form II comprises: (ic) heating the solution of Compound 1 to a temperature of 50 ºC to 60 ºC ± 3°C; (iic) reducing the volume of the solution of Compound 1 at the temperature of 50 ºC to 60 ºC ± 3°C to form a reduced-volume solution of Compound 1; (iiic) adding an anti-solvent to the reduced-volume solution of Compound 1 while maintaining the temperature at 55 ºC to 65 ºC ± 3°C to form a warm solution of Compound 1; (ivc) cooling the warm solution of Compound 1 to a temperature of 15 ºC to 30 ºC ± 3°C to precipitate Form II.
35. The process of any one of claims 26-34 further comprising ing Compound 1, or a salt thereof, by a process comprising reacting Compound 8: Compound 8 with B1, wherein B1 is a base.
36. The process of claim 35, wherein B1 is an alkali metal hydroxide base.
37. The process of any one of claims 35-36, wherein the reacting of Compound 8 with B1 is carried out in a first solvent, and wherein the first solvent is an ether t.
38. The process of any one of claims 35-37 further comprising preparing Compound 8 by a process sing reacting Compound 7: Compound 7 with Compound 9: Compound 9 in the presence of P2 and B2, wherein P2 is a transition metal catalyst and B2 is a base.
39. The process of any one of claims 35-37 further sing preparing Compound 8 by a process comprising reacting Compound 6: Compound 6 with Compound 15: Compound 15 in the presence of P4 and B4, wherein P4 is transition metal st and B4 is a base.
40. The process of claim 48, wherein P4 is a palladium catalyst.
41. The process of any one of claims 39-40, wherein the reacting of Compound 6 with nd 15 is carried out in a fourth solvent, and wherein the fourth solvent is a protic solvent, an ether solvent, or a mixture thereof. {xtgxxxas?nnnnnx v).x. ?\\n”mumm \0.1K” a 3 x a.“A» 264.67°C 102 8J/g \\~~\\\“,‘....___ __ssss 266.é9°c -7.071W/g 70
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NZ787662A NZ787662B2 (en) | 2017-06-19 | Crystalline solid forms of a bet inhibitor |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662352220P | 2016-06-20 | 2016-06-20 | |
| US201662397575P | 2016-09-21 | 2016-09-21 | |
| PCT/US2017/038121 WO2017222977A1 (en) | 2016-06-20 | 2017-06-19 | Crystalline solid forms of a bet inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ749956A NZ749956A (en) | 2025-06-27 |
| NZ749956B2 true NZ749956B2 (en) | 2025-12-10 |
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