Crystalline salts of B-RAF kinase inhibitors

文档序号：1008703 发布日期：2020-10-23 浏览：17次中文

阅读说明：本技术 B-raf激酶抑制剂的结晶盐 (Crystalline salts of B-RAF kinase inhibitors ) 是由 U·韦特曼 G-M·迈尔 B·贝特泽梅尔 O·沙夫于 2018-10-26 设计创作，主要内容包括：本发明涉及RAF激酶抑制剂N-(3-(5-((1-乙基哌啶-4-基)(甲基)氨基)-3-(嘧啶-5-基)-1H-吡咯并[3,2-b]吡啶-1-基)-2,4-二氟苯基)丙烷-1-磺酰胺的结晶盐,其用于治疗癌症和其它疾病。(The present invention relates to crystalline salts of the RAF kinase inhibitor N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide for use in the treatment of cancer and other diseases.)

1. Crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

2. A crystalline salt according to claim 1 which is substantially anhydrous and non-solvated.

3. A crystalline salt according to claim 1 or 2 which is form a.

4. The crystalline salt of any one of claims 1 to 3 having an X-ray powder diffraction pattern comprising at least one of the following peaks, in terms of 2 θ: 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; and 21.8 ° ± 0.5 °.

5. A crystalline salt according to claim 4 wherein the crystalline form is crystalline at 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; the peak at 21.8 ° ± 0.5 ° is the peak of the highest relative intensity in the X-ray powder diffraction pattern.

6. The crystalline salt of any one of claims 1 to 5 having an X-ray powder diffraction pattern comprising at least one of the following peaks, in terms of 2 θ: 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; and 21.8 ° ± 0.2 °.

7. A crystalline salt according to claim 6 wherein the crystalline form is crystalline at 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; or 21.8 ° ± 0.2 ° is the peak of highest relative intensity in the X-ray powder diffraction pattern.

8. A crystalline salt according to any one of claims 1 to 7 having an X-ray powder diffraction pattern comprising at least one peak, in terms of 2 θ, at 15.4 ° ± 0.5 °.

9. A crystalline salt according to claim 8 wherein the peak at 15.4 ° ± 0.5 ° is the peak of highest relative intensity in the X-ray powder diffraction pattern.

10. A crystalline salt according to any one of claims 1 to 9 having an X-ray powder diffraction pattern comprising at least one peak, in terms of 2 Θ, at 15.4 ° ± 0.2 °.

11. A crystalline salt according to claim 10 wherein the peak at 15.4 ° ± 0.2 ° is the highest relative intensity peak in the X-ray powder diffraction pattern.

12. The crystalline salt of any one of claims 1 to 11 having an X-ray powder diffraction pattern comprising the following peaks, in terms of 2 Θ: 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; and 21.8 ° ± 0.5 °.

13. A crystalline salt according to claim 12 wherein the crystalline form is crystalline at 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; the peak at 21.8 ° ± 0.5 ° is the peak of the highest relative intensity in the X-ray powder diffraction pattern.

14. The crystalline salt of any one of claims 1 to 13 having an X-ray powder diffraction pattern comprising the following peaks, in terms of 2 Θ: 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; and 21.8 ° ± 0.2 °.

15. A crystalline salt according to claim 14 wherein the crystalline form is crystalline at 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; or 21.8 ° ± 0.2 ° is the peak of highest relative intensity in the X-ray powder diffraction pattern.

16. The crystalline salt of claim 1, having an X-ray powder diffraction pattern substantially as shown in figure 10, figure 26 or figure 38.

17. The crystalline salt of claim 1, having a Differential Scanning Calorimetry (DSC) spectrum substantially as shown in figure 11, figure 27 or figure 39.

18. The crystalline salt of claim 1, having a thermogravimetric analysis (TGA) substantially as shown in figure 12, figure 28, or figure 39.

19. The crystalline salt of any one of claims 1 to 18 which is substantially isolated.

20. A composition comprising the crystalline salt of any one of claims 1 to 19.

21. The composition of claim 20, wherein the composition comprises at least one pharmaceutically acceptable carrier.

22. A dosage form comprising a crystalline salt according to any one of claims 1 to 19 or a composition according to claim 20 or 21.

23. The dosage form of claim 22, wherein the dosage form is a tablet.

24. A process for preparing a crystalline salt according to any one of claims 1 to 19 comprising reacting N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide with one equivalent of succinic acid.

25. The method of claim 24, further comprising starting from C_1-4Alcohol or aqueous C_1-4Crystallizing the salt from alcohol or ethyl acetate.

26. The method of claim 24, further comprising crystallizing the salt from ethanol, isopropanol, aqueous ethanol or aqueous isopropanol or ethyl acetate.

27. A method of treating a disease in a patient, wherein the disease is associated with aberrant expression or activity of RAF kinase, the method comprising administering to the patient a therapeutically effective amount of a crystalline salt according to any one of claims 1 to 19.

28. The method of claim 27, wherein the disease is associated with aberrant expression or activity of B-RAF kinase.

29. The method of claim 28, wherein the B-RAF kinase is a mutant B-RAF kinase.

30. The method of claim 29, wherein the B-RAF kinase is a V600E mutant B-RAF kinase.

31. The method of any one of claims 27 to 30, wherein the disease is selected from the group consisting of cancer, infection, inflammation, and autoimmune disease.

32. A method of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a crystalline salt of any one of claims 1 to 19.

33. The method of claim 32, wherein the cancer is breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, renal cancer, gastric cancer, or hematologic cancer.

34. The method of claim 32, wherein the cancer is malignant melanoma, thyroid cancer, colorectal cancer, biliary tract cancer, prostate cancer, ovarian cancer, or non-small cell lung cancer.

35. The method of any one of claims 32 to 34, wherein the cancer is associated with expression or activity of RAF kinase.

36. The method of claim 35, wherein the cancer is associated with expression or activity of B-RAF kinase.

37. The method of claim 36, wherein the B-RAF kinase is a mutant B-RAF kinase.

38. The method of claim 37, wherein the B-RAF kinase is a V600E mutant B-RAF kinase.

39. The method of any one of claims 31-38, wherein the cancer is melanoma.

40. The method of any one of claims 31-38, wherein the cancer is colorectal cancer.

41. The method of any one of claims 31-38, wherein the cancer is colon cancer.

42. The method of any one of claims 31-38, wherein the cancer is thyroid cancer.

43. The method of any one of claims 31 to 39, wherein the cancer expresses a mutated B-RAF kinase.

44. The method according to any one of claims 31 to 40, wherein the cancer expresses a V600E mutant B-RAF kinase.

Technical Field

The present application is related salt forms, in particular N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide (BI 882370), crystalline salts of RAF kinase inhibitors, which are useful for the treatment of cancer and other diseases.

Background

The compound N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide (BI 882370), having the formula I:

are inhibitors of RAF kinase and are useful in the treatment of various diseases, including cancer. The compounds of formula I and their preparation and use have been described in WO/2012/104388, the entire content of which is incorporated herein by reference.

The RAS-RAF-MAPK (mitogen-activated protein kinase) signaling pathway plays a key role in transmitting proliferation signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. Constitutive activation of this pathway involves malignant transformation of several oncogenes. Activating mutations in RAS occur in about 15% of cancers, recent data indicate that B-RAF is mutated in about 7% of cancers (Wellbrock et al, "The RAF proteins target stage", nature rev. mol. cell biol.,2004,5,875- "identifying it as another important oncogene in this pathway. In mammals, the RAF family of serine/threonine kinases contains three members: A-RAF, B-RAF and C-RAF. However, to date, activating mutations have only been identified in B-RAF, highlighting the importance of this isoform. It is believed that B-RAF is the major isoform coupling RAS to MEK, whereas C-RAF and A-RAF signal ERK solely for the purpose of fine-tuning the cellular response (Wellbrock et al, Nature Rev. mol. cell biol.,2004,5, 875-885). The most common cancer mutations in B-RAF result in valine exchange for the glutamic acid at position 600 of the protein (V600E), thereby significantly enhancing B-RAF activity, probably because the negative charge mimics phosphorylation of the activation loop (Wan et al, "MechanThe asm of activation of the RAF-ERKsizing pathway by the environmental requirements of the B-RAF ", Cell,2004,116, 855-. The B-RAF V600 mutations occur most frequently in malignant melanoma (39%), thyroid Cancer (46%), colorectal Cancer (10%), biliary tract Cancer (10%), prostate Cancer (4%), ovarian Cancer (3%) and non-small cell lung Cancer (2%), but they also occur at a low frequency in a variety Of other cancers (the frequency Of mutations is reported in terms Of COSMIC (catalytic Of viral Mutationin Cancer; Wellcome Trust Sanger Institute), Vol.53, 5/2011;http:// www.sanger.ac.uk/genetics/CGP/cosmic/). The literature supports the hypothesis that B-RAF^V600EMutant tumor cells appear to be largely dependent on sustained activation of this pathway, a phenomenon known as "oncogene addiction", whereas normal B-RAF^wtCells use a wider range of signals. This provides Achilles' heel, which can be used to treat somatically mutated B-RAF by using orally available B-RAF inhibitors^V600EThe patient is treated.

B-RAF^V600EThe key role in aberrant ERK signaling and thus carcinogenesis has been demonstrated in several independent experimental approaches, such as overexpression of Oncogenic/mutated B-RAF in vitro and in vivo (Wan et al, Cell,2004,116, 855-867; Wellbrock et al, Cancer Res.2004,64:2338-2342), in vitro siRNA knockdown (Karasarides et al, Oncogene, "V599EB-RAF is an Oncogene in melanogenes", 2004,23,6292-6298), or in an inducible short hairpin RNA xenograft model, the discovery of functionally-acquired B-RAF signaling is closely related to Oncogenic in vivo, Cancer Res, 2006,66, 1006.

B-RAF^V600ETreatment of mutant melanoma or colon cancer cells induces a B-RAF inhibitory phenotype (e.g., decreased phosphorylated MEK and phosphorylated ERK levels, decreased cyclin D expression and induction of p27 expression). Thus, these cells are locked in the G1 phase of the cell cycle and do not proliferate.

Has already established useB-RAF inhibitor (PLX-4032, Verofinib, from Plexikon/Daiichi Sankyo/Roche) treatment^V600EClinical evidence and proof of concept of the cancer treatment mechanism of patients with Mutated Melanoma (Bollag et al, "Clinical efficacy of a RAF inhibitor New branched target Block in BRAF-Mutated Melanoma", Nature,2010,467(7315), 596-9.; Flaherty et al, New Engl. J. Med., "Inhibition of Mutation, Activated BRAF involved Metastatic Melanoma",2010,363, 809-819; Chamman et al, "Improved viral with Vemurafenib in Melanoma with BRAF V600E Mutation", New Engl. J. 2011,364: 2507-2516. favorable B-RAF-carrying rates were observed in both phase I and phase III Clinical trials^V600KPatients with mutant melanoma also respond to treatment (Rubinstein et al, "science of the V600 mutation across melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032", J.Transl.Med.,2010,8, 67).

The most frequent B-RAF Mutations are 600 amino acid exchanges from valine to glutamate, all Of which occur at a frequency Of more than 90% (Wellbrock et al, Nature Rev. mol. cell biol.,2004,5, 875-;http://www.sanger.ac.uk/genetics/CGP/cosmic/). Additional mutations were found, for example, in glycine-rich loops (Wellbrock et al, Nature Rev. mol. cell biol.,2004,5,875- "885). It appears that not all of these rather rare mutations result in direct activation of B-RAF (Wan et al, "Mechanism of activation of the RAF-ERK signaling pathway by oncogenesis of B-RAF", Cell,2004,116, 855-.

The compounds of formula I are highly potent and selective RAF inhibitors which bind to B-RAF kinase in the DFG-out (inactive) conformation. The compound has 100 times of effect (1-10 nmol/L) of inhibiting the proliferation of human B-RAF mutant melanoma cells compared with that of vemurafenib, and wild type cells are not influenced at 1,000 nmol/L. The oral compound solution was effective in mouse models of B-RAF mutated melanoma and colorectal cancer and showed higher efficacy compared to vemurafenib, dabrafenib or trametinib given twice daily at a dose of 25 mg/kg. The compounds are also active in vemurafenib resistant a375 melanoma tumor bearing mice, particularly when dosed in combination with trametinib. Mice treated with the compounds did not show any clinical signs of weight loss or intolerance, and no pathological changes were observed in several major organs including the skin under study. Furthermore, in a rat experimental study (up to 60mg/kg per day for 2 weeks), the compound was devoid of toxicity in all clinical chemistry, hematology, pathology and toxicology genomics. These results are described in Waizenegger et al, mol. 354-65, the entire contents of which are incorporated herein by reference.

For the manufacture, purification and formulation of a drug, it may be advantageous to employ a drug form that has excellent stability or other desired formulation properties, for example, exhibited by one or more salts or crystalline forms of the drug. The formation of salts of basic or acidic drugs can sometimes provide a drug form with advantageous properties such as solubility, non-hygroscopicity, crystallinity, and other physical properties that are advantageous for formulating drugs. On the other hand, finding a suitable salt or other crystalline form suitable for formulation is difficult due to the numerous variables that form the salt or crystalline form. These include the presence of numerous possible acids and bases that may be used as counterions, various stoichiometric ratios that may be used to combine a given basic or acidic drug with the acid or base counterions, various solvents and solvent systems (including combinations of solvents) that may be used to attempt to form salts or crystalline forms, and various conditions (e.g., temperature, heating or cooling conditions) under which salts or crystalline forms may be produced. All of these variables may affect the properties of the salt or crystalline form that may be obtained. The salt or solid form may also have various properties that make it unsuitable for pharmaceutical development and formulation, such as lack of crystallinity (amorphous form), presence or formation of multiple crystalline forms that may interconvert and/or have different properties (polymorphic form), lack of water solubility, hygroscopicity or viscosity of the solid. Furthermore, the formation of salts and crystalline forms and their properties are often very difficult to predict.

Thus, the crystalline salt forms of the compounds of formula I provided herein help meet the continuing need to develop RAF kinase inhibitors for the treatment of severe diseases.

Disclosure of Invention

In some embodiments, the crystalline salt is substantially anhydrous.

In some embodiments, the crystalline salt is substantially unsolvated.

In some embodiments, the crystalline salt is form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least one of the following peaks, in terms of 2 Θ: 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; and 21.8 ° ± 0.5 °. In some embodiments, at 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; the peak at 21.8 ° ± 0.5 ° is the peak of the highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least one of the following peaks, in terms of 2 Θ: 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; and 21.8 ° ± 0.2 °. In some embodiments, at 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; or 21.8 ° ± 0.2 ° is the peak of highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least one peak, in terms of 2 Θ, at 15.4 ° ± 0.5 °. In some embodiments, the peak at 15.4 ° ± 0.5 ° is the highest relative intensity peak in an X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least one peak, in terms of 2 Θ, at 15.4 ° ± 0.2 °. In some embodiments, the peak at 15.4 ° ± 0.2 ° is the highest relative intensity peak in an X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising the following peaks, in terms of 2 Θ: 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; and 21.8 ° ± 0.5 °. In some embodiments, at 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; the peak at 21.8 ° ± 0.5 ° is the peak of the highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising the following peaks, in terms of 2 Θ: 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; and 21.8 ° ± 0.2 °. In some embodiments, at 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; or 21.8 ° ± 0.2 ° is the peak of highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern substantially as shown in figure 10, figure 26, or figure 38.

In some embodiments, the crystalline salt has a Differential Scanning Calorimetry (DSC) spectrum substantially as shown in figure 11, figure 27, or figure 39.

In some embodiments, the crystalline salt has a thermogravimetric analysis (TGA) substantially as shown in figure 12, figure 28, or figure 39.

In some embodiments, the crystalline salt is substantially isolated.

The present application provides a composition (e.g., a pharmaceutical composition) comprising crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, or any of its embodiments. The composition may include at least one pharmaceutically acceptable carrier.

The present application provides a dosage form comprising the crystalline salt N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinic acid salt, or any of its embodiments, or a composition comprising the crystalline salt, or any of its embodiments. The dosage form may be in the form of a tablet.

The present application provides N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b) for the preparation of crystals]A method for preparing pyridine-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate. The method comprises reacting N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide was reacted with one equivalent of succinic acid. The method may comprise reacting a salt from C_1-4Alcohol, aqueous C_1-4Crystallizing or recrystallizing in alcohol or ethyl acetate. The process may comprise crystallizing or recrystallizing the salt from ethanol, isopropanol, aqueous ethanol or aqueous isopropanol or ethyl acetate.

The present application provides a method of treating a disease in a patient, wherein the disease is associated with aberrant expression or activity of a RAF kinase, comprising administering to the patient a therapeutically effective amount of crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, or any of its embodiments, or comprising crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate. The present application also provides crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, or any of its embodiments, for use in treating a disease associated with aberrant expression or activity of RAF kinase. Also provided is the use of crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, or any of its embodiments, for the treatment of a disease associated with aberrant expression or activity of RAF kinase. Also provided is the use of crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, or any of its embodiments, in the manufacture of a medicament for the treatment of a disease associated with aberrant expression or activity of RAF kinase.

In some embodiments, the disease is associated with aberrant expression or activity of B-RAF kinase. In some embodiments, the B-RAF kinase is a mutant B-RAF kinase. In some embodiments, the B-RAF kinase is a V600E mutant B-RAF kinase. In some embodiments, the disease is selected from the group consisting of cancer, infection, inflammation, and autoimmune disease.

The application further provides a method of treating cancer comprising administering to the patient a therapeutically effective amount of crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, or any of its embodiments, or a composition comprising crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate. The present application also provides crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, or any of its embodiments, for use in the treatment of cancer. Also provided is the use of crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinic acid salt, or any of its embodiments, in the treatment of cancer. Also provided is the use of crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinic acid salt, or any of its embodiments, in the manufacture of a medicament for the treatment of cancer.

In some embodiments, the cancer is associated with expression or activity of RAF kinase. In some embodiments, the cancer is associated with expression or activity of B-RAF kinase. In some embodiments, the B-RAF kinase is a mutant B-RAF kinase. In some embodiments, the B-RAF kinase is a V600E mutant B-RAF kinase. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is thyroid cancer. In some embodiments, the cancer expresses a mutant B-RAF kinase. In some embodiments, the cancer expresses a V600E mutant B-RAF kinase.

Drawings

Figure 1 is an XRPD of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide free base.

Figure 2A is an image of a main plate showing a salt of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide prepared with various acids and solvents and by crystallization in a slurry experiment.

Fig. 2B is a collection of images of XRPD scans performed on each main plate well of fig. 2A showing the crystallinity of a salt of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-B ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide prepared by slurrying with various acids and solvents.

Figure 3A is an image of an evaporation plate showing a salt of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide prepared with various acids and solvents and by crystallization in an evaporation experiment.

Fig. 3B is a collection of images of XRPD scans performed on each main plate well of fig. 3A showing the crystallinity of the salt of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-B ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide prepared by evaporation with various acids and solvents.

Figure 4 is a collection of images of XRPD scans performed on various crystalline salt samples of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide.

Figure 5 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride from a sample of well E2 (lower panel) compared to a sample from a scaled-up synthesis (upper panel).

FIG. 6 is a DSC of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride.

FIG. 7 is a TGA diagram of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride.

Figure 8 is an adsorption-desorption curve for N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride showing an increase and decrease in weight when the relative humidity was varied between 0-100%.

Figure 9 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride before (lower panel) and after (upper panel) adsorption-desorption experiments.

Figure 10 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate from the sample of well F10 (lower panel) compared to the sample from the scaled-up synthesis (upper panel).

FIG. 11 is a DSC of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

FIG. 12 is a TGA diagram of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

Figure 13 is an adsorption-desorption curve for N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate showing weight increase and decrease when relative humidity is varied between 0-100%.

Figure 14 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride before (lower panel) and after (upper panel) adsorption-desorption experiments, indicating that no significant change in structure occurred.

FIG. 15 is an XRPD pattern for N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride.

FIG. 16 is a DSC of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride. The sample showed an onset of endotherm at about 313 ℃. Typically, the sample begins to absorb heat in the range of 312-322 ℃ corresponding to the melting point. The melting point was therefore measured at about 317. + -. 5 ℃. Some samples show an additional endothermic event at about 250 ℃, which corresponds to solvent loss.

Figure 17 is a TGA diagram of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride. The samples exhibited a loss of drying of about 1.7-2.5% at temperatures up to about 250 ℃, which corresponds to the release of water and solvent. The water content was measured to be about 0.9% (karl fischer method).

Figure 18 is a graph of isothermal adsorption-desorption of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride showing weight gain and loss when relative humidity was varied between 0-90%.

Figure 19 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride before (lower panel) and after (upper panel) adsorption-desorption experiments, indicating that no significant change in structure occurred.

Figure 20 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride after milling at 30rps for 10min in a rocking mill.

Figure 21 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride after compression to a tablet (diameter-5 mm) at 2000N for 1 second.

FIG. 22 is N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride¹H NMR spectrum (400MHz, DMSO-d 6).

FIG. 23 is N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride¹Insert of H NMR spectra (400MHz, DMSO-d6) over the aliphatic region (-0.5-6.0).

FIG. 24 is N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride¹Insert of H NMR spectrum (400MHz, DMSO-d6) over aromatic region (6.0-11.5).

FIG. 25 is a graph showing the dissolution rate of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride in aqueous media at pH 1.0 to 7.4 over 0-60 min.

FIG. 26 is an XRPD pattern for N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate).

FIG. 27 is a DSC of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

FIG. 28 is a TGA diagram of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

Figure 29 is a graph of isothermal adsorption-desorption of N- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate showing weight gain and loss when relative humidity was varied between 0-90%.

Figure 30 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate before (lower panel) and after (upper panel) adsorption-desorption experiments, indicating that no significant change in structure occurred.

Figure 31 is an XRPD pattern of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate after 10min grinding at 30rps in a rocking mill.

FIG. 32 is an XRPD pattern for N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate after 1 second compression at 2000N into a tablet (diameter-5 mm).

FIG. 33 is N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate¹H NMR Spectroscopy (400MHz, D)MSO-d6)。

FIG. 34 is N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate¹Insert of H NMR spectra (400MHz, DMSO-d6) over the aliphatic region (-0.5-6.0).

FIG. 35 is N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate¹Insert of H NMR spectrum (400MHz, DMSO-d6) over aromatic region (6.0-10.0).

FIG. 36 is a graph showing the dissolution rate of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride in aqueous media at pH 1.0 to 7.4 over 0-60 min.

FIG. 37 is a graph of plasma concentration values versus time for rats orally administered with: (A) at 40mg/kg of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride; (B) n- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monohydrochloride at 80 mg/kg; (C) n- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate at 40 mg/kg; (D) n- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate at 80 mg/kg.

Figure 38 is an XRPD pattern of two batches of form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

Figure 39 is a pair of graphs of TGA and DSC analyses of form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

FIG. 40 is form A of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate¹H NMR spectrum (DMSO-d 6).

FIG. 41 is form A of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate¹H NMR spectrum (deuterated methanol).

Figure 42 is a pair of graphs of the XRPD of form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate before and after heating to 170 ℃ and cooling to room temperature.

Figure 43 is a pair of graphs of the TGA of form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate before and after heating to 170 ℃ and cooling to room temperature.

Figure 44 is a pair of plots of DSC of form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate before and after heating to 170 ℃ and cooling to room temperature.

FIG. 45 is form A of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b) before and after heating to 170 ℃ and cooling to room temperature]Process for preparing pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate¹A pair of spectra by H NMR (DMSO-d 6).

Figure 46 is a set of XPRD patterns showing that N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, form a, does not change in an equilibrium solubility test.

Figure 47 is a set of XPRD plots showing the stability of form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate after storage under various conditions.

Figure 48 is a set of DVS isotherm plots showing the low hygroscopicity of form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

Figure 49 is a pair of XPRD patterns showing that form a of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate does not change form after DVS testing.

FIG. 50 is a pair of polarized light microscope images of form A N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate.

Detailed Description

I. Definition of

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

The terms "for example" and "such as," as well as grammatically equivalent words thereof, should be construed as being followed by "and not limited to," unless expressly specified otherwise.

As used in this application, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

The term "about" as used herein means "about" (e.g., about 10% of the indicated value).

In various places throughout this specification, certain features may be disclosed in groups or in ranges. It is specifically intended that such disclosure include each individual subcombination of the group and range members. For example, the term "C_1-4Alkyl "specifically means the independent disclosure (but not limited to) methyl, ethyl, C₃Alkyl and C₄An alkyl group.

The terms "individual", "subject" or "patient" are used interchangeably to refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, most preferably humans.

The term "treating" or "treatment" refers to one or more of the following: (1) preventing diseases; for example, preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but does not yet experience or exhibit the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition, or disorder (i.e., arresting or slowing the further development of the pathology and/or symptom) in an individual experiencing or exhibiting the pathology or symptom of the disease, condition, or disorder; and (3) ameliorating the disease; for example, ameliorating a disease, condition, or disorder (i.e., reversing the pathology and/or symptomatology) in an individual experiencing or exhibiting the pathology or symptomatology of the disease, condition, or disorder, e.g., reducing the severity of the disease.

The phrase "therapeutically effective amount" means the amount of active salt or crystalline form or pharmaceutical agent that elicits the biological or medicinal response sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human.

Certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Abbreviations

The following abbreviations and symbols may be used throughout this application: ac (acetyl); aq. (aqueous); boc (tert-butoxycarbonyl); bu (butyl); deg.C (degrees Celsius); c (concentration); con. (concentration); d (days); DCM (dichloromethane); DEA (diethylamine); DIPEA (N-ethyl-N, N-diisopropylamine (schnischig base)); DMF (N, N-dimethylformamide); DMSO (dimethyl sulfoxide); DSC (differential scanning calorimetry); DVS (dynamic vapor sorption); EDTA (ethylenediaminetetraacetic acid); EGTA (ethylene glycol tetraacetic acid); eq. (eq); ESI (electric)Spray ionization); et (ethyl); et (Et)₂O (diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); g (grams); h (hours); HPLC (high performance liquid chromatography); HCl (hydrochloric acid); i (iso); iPrOH (isopropanol); l (liter); LC (liquid chromatography); m (molar concentration); mg (milligrams); me (methyl); MeCN (acetonitrile); MeOH (methanol); min (minutes); mL (milliliters); mM (millimolar concentration); MPLC (medium pressure liquid chromatography); MS (mass spectrometry); NP (normal phase); ph (phenyl); pr (propyl); py (pyridine); rac (racemic); rf (retention factor); RH (relative humidity); RP (reverse phase); rps (revolutions per second); rt (ambient temperature); tBu (tert-butyl); TEA (triethylamine); temp. (temperature); tert (tertiary); tf (triflate); TFA (trifluoroacetic acid); TGA (thermogravimetric analysis); THF (tetrahydrofuran); TLC (thin layer chromatography); tRet. (retention time (HPLC)); UV (ultraviolet), XRPD (X-ray powder diffraction). Other common abbreviations may also be used in this application.

Crystalline salts

The present application relates in particular to (N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide (BI 882370) in salt form, in particular in crystalline salt form, having the formula I:

which can be used, for example, to prepare solid dosage forms of the above compounds for the treatment of various diseases, including cancer.

Different salts and crystalline forms of the same substance may have different bulk properties with respect to, for example, hygroscopicity, solubility, stability, and the like. The form with a high melting point may have a good thermodynamic stability, which may be advantageous in terms of extended shelf life pharmaceutical formulations comprising a specific salt or crystalline form. Forms with lower melting points may be thermodynamically less stable, but have the advantage that they have increased water solubility, which translates into increased drug bioavailability. Poorly hygroscopic forms may be desirable because they are stable to heat and moisture and resistant to degradation over long periods of storage. Anhydrous forms may be desirable because they can be prepared consistently without fear of weight or composition changes due to changes in solvent or water content. On the other hand, it may be advantageous if the hydrated or solvated form is less hygroscopic and exhibits improved stability to humidity under storage conditions.

As used herein, "crystalline form" refers to a certain lattice structure of a crystalline material (which may include a salt as described herein). Different crystalline forms of the same substance may have different crystalline lattices (e.g., unit cells) that may be attributed to the different physical properties that characterize each crystalline form. In some cases, different lattice structures have different water or solvent contents. The different crystalline lattices can be identified by solid state characterization methods, such as X-ray powder diffraction (XRPD). Other characterization methods such as Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), Dynamic Vapor Sorption (DVS), solid state NMR, etc., further aid in identifying the crystalline form and help in determining stability and solvent/water content.

Crystalline forms of a substance may include solvated (e.g., hydrated) forms and unsolvated (e.g., anhydrous) forms. The hydrated form is a crystalline form that includes water in the crystalline lattice. The hydrated form may be a stoichiometric hydrate, wherein water is present in the crystal lattice at a certain water/molecule ratio, such as hemihydrate, monohydrate, dihydrate, and the like. The hydrated form may also be a non-stoichiometric form in which the water content is variable and dependent on external conditions such as humidity.

The crystalline form may be characterized by X-ray powder diffraction (XRPD). The XRD pattern of reflections (peaks) is generally considered to be a fingerprint of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary widely, depending on, among other things, the sample preparation technique, the crystal size distribution, the filter, the sample installation procedure, and the particular instrument used. In some cases, new peaks may be observed or existing peaks may disappear, depending on the instrument type or setup (e.g., whether a Ni filter is used). The term "peak" as used herein refers to a reflection having a relative height/intensity of at least about 4% of the maximum peak height/intensity. In addition, instrument variations and other factors may affect the 2 θ value. Thus, peak assignments such as those reported herein may vary between ± 0.2 ° (2 θ), and the term "substantially" as used in the context of XRPD herein is intended to encompass such variations.

Likewise, temperature readings associated with Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), or other thermal experiments can vary at about ± 4 ℃, depending on the instrument, particular setup, sample preparation, and the like. For example, with respect to DSC, it is known that the observed temperature will depend on the rate of temperature change as well as the sample preparation technique and the particular instrument used. Thus, as indicated above, the values reported herein relating to DSC thermograms may differ by ± 4 ℃. Thus, crystalline forms having a DSC thermogram "substantially" as shown in any of the figures reported herein are understood to accommodate such a change.

The salts described herein may be isolated in various crystalline forms, which may include anhydrous, hydrated, unsolvated, or solvated crystalline forms. Examples of hydrates include hemihydrate, monohydrate, dihydrate, and the like. In some embodiments, the crystalline form is anhydrous and unsolvated. By "anhydrous" is meant that the crystalline form of the compound of formula I contains substantially no bound water in the lattice structure, i.e., the compound does not form a crystalline hydrate.

In some embodiments, the salts and crystalline forms of the present invention may be substantially isolated. By "substantially isolated" is meant that a particular salt or crystalline form of a compound is at least partially separated from impurities. For example, in some embodiments, a salt or crystalline form of the invention includes less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% impurities. Impurities generally include any material that is not a substantially isolated salt or crystalline form, including other salts or other crystalline forms and other materials.

In some embodiments, the salt or crystalline form is substantially free of other crystalline forms. The phrase "substantially free of other crystalline forms" means that the particular crystalline form constitutes greater than about 80%, greater than about 90%, greater than about 95%, greater than about 98%, greater than about 99%, or greater than about 99.5% by weight of the particular crystalline form.

The term "monosuccinate" means that the succinic acid and N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide base moieties present in the salt have an acid to base ratio of about 1:1, e.g., a ratio in the range of about 0.8:1 to about 1.2:1, about 0.9:1 to about 1.1:1, about 1:1.2 to about 1:0.8 or about 1:1.1 to about 1:0.9, e.g., a ratio of about 0.8:1, about 0.9:1, about 1:1 or about 1.1:1 or about 1:0.8, about 1:0.9, about 1:1, about 1:1.1 or about 1: 1.2.

As described in further detail below, crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate has unexpected properties compared to the free base and other salt forms of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide, such as improved solubility, improved intrinsic dissolution rate and improved pharmacokinetic properties.

In some embodiments, the crystalline salt is substantially anhydrous. By "substantially anhydrous" is meant that the crystalline salt contains less than a stoichiometric equivalent of water and does not contain water as part of the crystal structure of the salt. In some embodiments, water, if present, is present in an amount of about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.5% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less of the crystalline salt. The use of the term "substantially anhydrous" does not exclude the presence of trace amounts of water.

In some embodiments, the crystalline salt is substantially unsolvated. By "substantially unsolvated" is meant that a crystalline salt contains less than a stoichiometric equivalent of solvent and does not contain solvent molecules that are part of the crystal structure of the salt. In some embodiments, the solvent, if present, is present in an amount of about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.5% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less of the crystalline salt. The use of the term "substantially non-solvated" does not exclude the presence of trace amounts of solvent.

In some embodiments, the crystalline salt is substantially free of solvents other than water. By "substantially free" it is meant that the crystalline salt contains less than a stoichiometric equivalent of solvent other than water, and does not contain solvent molecules other than water as part of the salt's crystal structure. In some embodiments, the solvent other than water, if present, is present in an amount of about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.5% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less of the crystalline salt. The use of the term "substantially free of solvents other than water" does not exclude the presence of trace amounts of such solvents.

The crystalline forms of the salts are identified by unique characteristics with respect to, for example, X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA) and Dynamic Vapor Sorption (DVS).

In some embodiments, form a N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate is characterized by an XRPD pattern substantially as shown in figure 10, figure 26, or figure 38.

In some embodiments, form a of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate is characterized by having an XRPD pattern substantially as shown in table 9.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising the following peaks, in terms of 2 Θ: 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; and 21.8 ° ± 0.5 °. In some embodiments, at 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; or 21.8 ° ± 0.5 ° is the peak of highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or all of the following peaks, in 2 Θ: 15.4 ° ± 0.5 °; 16.1 ° ± 0.5 °; 17.2 ° ± 0.5 °; 19.1 ° ± 0.5 °; 19.8 ° ± 0.5 °; 20.0 ° ± 0.5 °; 20.2 ° ± 0.5 °; 20.5 ° ± 0.5 °; 21.5 ° ± 0.5 °; and 21.8 ° ± 0.5 °. In some embodiments, the X-ray powder diffraction pattern comprises at 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; or 21.8 ° ± 0.5 ° as the peak of the highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the X-ray powder diffraction pattern comprises a peak at 15.4 ° ± 0.5 ° as the peak of highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or all of the following peaks, in 2 Θ: 15.4 ° ± 0.2 °; 16.1 ° ± 0.2 °; 17.2 ° ± 0.2 °; 19.1 ° ± 0.2 °; 19.8 ° ± 0.2 °; 20.0 ° ± 0.2 °; 20.2 ° ± 0.2 °; 20.5 ° ± 0.2 °; 21.5 ° ± 0.2 °; and 21.8 ° ± 0.2 °. In some embodiments, the X-ray powder diffraction pattern comprises at 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; or 21.8 ° ± 0.2 ° as the peak of the highest relative intensity in the X-ray powder diffraction pattern. In some embodiments, the X-ray powder diffraction pattern comprises a peak at 15.4 ° ± 0.2 ° as the peak of highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the X-ray powder diffraction pattern comprises at 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; or at least two of the peaks at 21.8 ° ± 0.5 ° as the highest relative intensity peaks in the X-ray powder diffraction pattern.

In some embodiments, the X-ray powder diffraction pattern comprises at 15.4 ° ± 0.5 °; 20.0 ° ± 0.5 °; or at least three of the peaks at 21.8 ° ± 0.5 ° as the highest relative intensity peaks in the X-ray powder diffraction pattern.

In some embodiments, the X-ray powder diffraction pattern comprises at 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; or at least two of the peaks at 21.8 ° ± 0.2 ° as the two peaks of the highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the X-ray powder diffraction pattern comprises at 15.4 ° ± 0.2 °; 20.0 ° ± 0.2 °; or 21.8 ° ± 0.2 ° as the three peaks of the highest relative intensity in the X-ray powder diffraction pattern.

In some embodiments, the crystalline salt has a Differential Scanning Calorimetry (DSC) spectrum substantially as shown in figure 11, figure 27, or figure 39.

In some embodiments, the crystalline salt has a thermogravimetric analysis (TGA) substantially as shown in figure 12, figure 28, or figure 39.

In some embodiments, the crystalline salt is substantially isolated. In some embodiments, the crystalline salt is at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate form a.

N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate can be prepared by: n- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide is reacted with an appropriate amount, typically about one equivalent, of succinic acid.

The reaction may be carried out in a suitable solvent. The reaction can be carried out by: dissolving N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide, adding succinic acid, and optionally dissolving in an acid. If desired, a solution of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide and/or succinic acid may be heated to dissolve the compounds. It may be heated to a temperature above: room temperature, e.g., about 30 ℃, about 40 ℃, about 50 ℃, about 60 ℃, about 70 ℃, about 80 ℃, about 90 ℃ or about 100 ℃. The reaction may be carried out for a period of time, for example, about 5min, about 10min, about 20min, about 30min, about 40min, about 50min, about 1h, about 2h, about 3h, or about 4 h. After heating, the solution can be cooled, e.g., to room temperature or lower, e.g., about 25 ℃, about 20 ℃, about 15 ℃, about 10 ℃, about 5 ℃, or about 0 ℃. After such cooling, the reaction mixture may be held at the lower temperature for an additional period of time, for example, about 5min, about 10min, about 20min, about 30min, about 40min, about 50min, about 1h, about 2h, about 3h, about 4h, about 8h, about 16h, or about 24 h.

In carrying out the step of forming a salt or crystalline form thereof, the solution or suspension subjected to the reaction may be agitated, e.g., stirred.

For the formation of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3, 2-b)]Suitable solvents for pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, including salts of form A, include C_1-4Alcohol, aqueous C_1-4Alcohol or ethyl acetate. The solvent may include methanol, ethanol, isopropanol, aqueous methanol, aqueous ethanol, aqueous isopropanol, or ethyl acetate.

Crystalline N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide monosuccinate, particularly form a, can be obtained directly from: reaction of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide with succinic acid under appropriate conditions. Alternatively, the crystalline salt or form a thereof may be prepared by crystallizing the salt in a suitable solvent and/or recrystallizing the salt.

Suitable methods of crystallizing or recrystallizing the salt include solutions or suspensions of the salt in a suitable solvent. It may be heated to a temperature above: room temperature, e.g., about 30 ℃, about 40 ℃, about 50 ℃, about 60 ℃, about 70 ℃, about 80 ℃, about 90 ℃ or about 100 ℃. The heating may be performed for a period of time, for example, about 5min, about 10min, about 20min, about 30min, about 40min, about 50min, about 1h, about 2h, about 3h, or about 4 h. After heating, the solution can be cooled, e.g., to room temperature or lower, e.g., about 25 ℃, about 20 ℃, about 15 ℃, about 10 ℃, about 5 ℃, or about 0 ℃. After such cooling, the reaction mixture may be held at the lower temperature for an additional period of time, for example, about 5min, about 10min, about 20min, about 30min, about 40min, about 50min, about 1h, about 2h, about 3h, about 4h, about 8h, about 16h, or about 24 h. In carrying out the step of crystallizing or recrystallizing the salt or the crystalline form thereof, the solution or suspension subjected to the reaction may be agitated, for example, stirred.

Method of use

The salts and crystalline forms described herein are B-RAF kinase inhibitors and are therefore useful in the treatment of pathological conditions (diseases) that activate the RAS-RAF-MAPK signaling pathway, particularly cell proliferative conditions such as cancer. The salt and crystalline forms can inhibit cell proliferation, particularly by inhibiting entry into the DNA synthesis phase. The treated cells stagnated in the G1 phase of the cell cycle. Thus, the salts and crystalline forms are useful in the treatment of diseases characterized by excessive or abnormal cell proliferation.

Pathological conditions that can be treated with the salts and crystalline forms described herein include diseases associated with aberrant expression or activity of RAF kinase. Diseases may be treated by administering to a patient in need of such treatment a therapeutically effective amount of any of the crystalline salts described herein or embodiments thereof. In some embodiments, the disease is associated with aberrant expression or activity of B-RAF kinase. In some embodiments, the disease is associated with aberrant expression or activity of a mutant B-RAF kinase. In some embodiments, the disease is associated with aberrant expression or activity of the V600E mutant B-RAF kinase. In other embodiments, the disease may be associated with expression or activity of a mutant B-RAF kinase selected from the group consisting of: R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K and a 727V.

Pathological conditions that may be treated with the salts and crystalline forms described herein include cancer, infection, inflammation, and autoimmune diseases.

Pathological conditions that may be treated with the salts and crystalline forms described herein include cancer. The cancer may include a tumor, and may also include a cancer that does not form a tumor, such as a hematologic cancer.

In some embodiments, the cancer is breast cancer, prostate cancer, colon cancer, endometrial cancer, brain cancer, bladder cancer, skin cancer, uterine cancer, ovarian cancer, lung cancer, pancreatic cancer, renal cancer, gastric cancer, or hematologic cancer. In some embodiments, the hematologic cancer is acute myeloid leukemia, chronic myeloid leukemia, B-cell lymphoma, Chronic Lymphocytic Leukemia (CLL), non-hodgkin's lymphoma, hairy cell leukemia, mantle cell lymphoma, burkitt's lymphoma, small lymphocytic lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, extranodal marginal zone lymphoma, activated B-cell-like (ABC) diffuse large B-cell lymphoma, or germinal center B-cell (GCB) diffuse large B-cell lymphoma. In some embodiments, the non-hodgkin's lymphoma (NHL) is selected from relapsed NHL, refractory NHL, and relapsed follicular NHL.

In some embodiments, the cancer is malignant melanoma, thyroid cancer, colorectal cancer, biliary tract cancer, prostate cancer, ovarian cancer, or non-small cell lung cancer.

In some embodiments, the cancer is associated with expression or activity of RAF kinase.

In some embodiments, the cancer is associated with expression or activity of B-RAF kinase.

In some embodiments, the cancer is associated with expression or activity of a mutant B-RAF kinase.

In some embodiments, the cancer is associated with expression or activity of a V600E mutant B-RAF kinase.

In some embodiments, the cancer is associated with expression or activity of a mutant B-RAF kinase selected from the group consisting of: R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, and a 727V.

In some embodiments, the cancer is melanoma.

In some embodiments, the cancer is colorectal cancer.

In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer expresses a mutant B-RAF kinase. In some embodiments, the cancer expresses a V600E mutant B-RAF kinase. In some embodiments, the cancer expresses one or more of the following B-RAF kinase mutants: R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, and a 727V.

The following cancers may be treated with compounds according to the present invention, but are not limited thereto: brain tumors such as acoustic neuroma, astrocytoma such as hairy cell astrocytoma, fibrous astrocytoma, plasmogenic astrocytoma, adipocyte astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphoma, brain metastasis, pituitary tumors such as prolactin tumor, HGH (human growth hormone) producing tumor and ACTH (adrenocorticotropic hormone) producing tumor, craniopharyngioma, medulloblastoma, meningioma and oligodendroglioma; neural tumors (tumors), such as vegetative nervous system tumors, for example, sympathetic neuroblastoma, ganglioneuroma, paraganglioma (pheochromocytoma), pheochromocytoma (chromaffinoma), and carotid body (glomus-caroticum) tumors, tumors of the peripheral nervous system, for example, amputation neuroma, neurofibroma, Schwannoma (neurinoma) (neurilemoma), Schwannoma (Schwannoma), and malignant Schwannoma, and tumors of the central nervous system, for example, brain tumors and myeloma tumors; intestinal cancers such as rectal cancer, colon cancer, colorectal cancer, anal cancer, large intestine cancer, small intestine and duodenal tumor; eyelid tumors such as basal cell tumors or basal cell carcinomas; pancreatic cancer (pancreatic cancer) or pancreatic cancer (cancer of the pancreas); bladder cancer (bladder cancer) or bladder cancer (cartinosoma of the bladder); lung cancer (bronchial cancer) such as small-cell bronchial cancer (oat cell cancer), and non-small-cell bronchial cancer (NSCLC) such as squamous cell carcinoma, adenocarcinoma, and large-cell bronchial cancer; breast cancer (breast cancer), e.g., breast cancer (mammary carcinosoma), such as invasive ductal carcinoma, jelly-like carcinoma, lobular invasive carcinoma, ductal adenocarcinoma of the gland (tubular carcinosoma), adenocystic carcinoma, and papillary carcinoma; non-hodgkin's lymphoma (NHL) such as burkitt's lymphoma, low malignancy non-hodgkin's lymphoma (NHL), and mycosis fungoides; uterine cancer or endometrial cancer or uterine body cancer; CUP syndrome (cancer with unknown primary focus); ovarian cancer (ovarian cancer) or ovarian cancer (ovarian carcinoma), such as a mucous, endometrial, or serous cancer; gallbladder cancer; bile duct cancers such as kratz's lymphoma; testicular cancers such as seminoma and non-seminoma; lymphomas (lymphosarcomas) such as malignant lymphoma, hodgkin's disease, non-hodgkin's lymphoma (NHL) such as chronic lymphocytic leukemia, leukemic reticuloendotheliosis, immune cell tumors, plasmacytoma (multiple myeloma), immunoblastoma, burkitt's lymphoma, T-zone mycosis fungoides, large cell anaplastic lymphoblastoma, and lymphoblastoma; laryngeal cancers such as vocal cord tumors, supraglottic, glottic, and subglottic laryngeal tumors; bone cancers such as osteochondroma, chondroma, chondroblastoma, chondroromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumor, chondrosarcoma, osteosarcoma, ewing's sarcoma, reticulocytoma, plasmacytoma, fibrodysplasia, juvenile bone cyst, and aneurysm-like bone cyst; head and neck tumors such as tumors of the lips, tongue, floor of mouth, gums, palate, salivary glands, larynx, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as hepatocellular carcinoma (liver cell carcinoma) or hepatocellular carcinoma (HCC); leukemias, e.g., acute leukemias such as acute lympho/lymphoblastic leukemia (ALL), Acute Myeloid Leukemia (AML); chronic leukemias such as Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML); gastric (stomach cancer) or gastric (gastric carcinoma) cancers such as papillary, tubular and mucinous adenocarcinomas, signet ring cell carcinomas, adenosquamous carcinomas, small cell carcinomas and undifferentiated carcinomas; melanomas such as superficial spreading type, nodular type, malignant lentigo and acromatic malignant melanoma; kidney cancers such as renal cell carcinoma or suprarenal adenoid or glauyveri; esophageal cancer (oesophageal cancer) or esophageal cancer (carcinoma of the oesophagus); penile cancer; prostate cancer; laryngeal or pharyngeal cancer such as nasopharyngeal, oropharyngeal, and hypopharyngeal cancers; retinoblastoma, vaginal cancer (vacuum cancer) or vaginal cancer (vacuum carcinoma); squamous carcinoma, adenocarcinoma, carcinoma in situ, malignant melanoma and sarcoma; thyroid cancer such as papillary, follicular and medullary thyroid cancer and anaplastic carcinoma; acanthocellular carcinoma (spinolioma), epidermoid carcinoma, and squamous cell carcinoma of the skin; thymoma, cancer of the urethra and cancer of the vulva.

The novel salts and crystalline forms are useful for the prevention, short-term or long-term treatment of the above-mentioned diseases, which optionally can also be combined with radiotherapy or other "advanced" compounds, such as cytostatic or cytotoxic substances, cytostatic agents, antiangiogenic substances, steroids or antibodies.

The salts and crystalline forms described herein are also useful for treating non-cancerous proliferative disorders. Examples of proliferative diseases that can be treated include, but are not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine tumors, nasal polyps, pituitary tumors, prolactinoma, pseudotumor brain, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic tumors, hemangiomas, vocal cord nodules, polyps and cysts, castleman's disease, chronic villosis, cutaneous fibromas, hair cysts, pyogenic granulomas, and juvenile polyposis syndrome.

Other diseases that may be treated include viral infections (e.g., epstein-barr virus, hepatitis b virus, hepatitis c virus, herpes virus, human immunodeficiency virus, human papilloma virus, kaposi's sarcoma, adenovirus, poxvirus, and other episomal based DNA viruses). Thus, the salts and crystalline forms are useful in the treatment of diseases and conditions such as herpes simplex infection and reactivation, herpes labialis, herpes zoster infection and reactivation, varicella, shingles, human papilloma virus, cervical tumors, adenovirus infections, including acute respiratory diseases as well as poxvirus infections such as vaccinia and smallpox and african swine fever virus. In a particular embodiment, the salt and crystalline forms are intended for use in the treatment of human papillomavirus infected skin or cervical epithelium.

Other diseases that may be treated include inflammatory and autoimmune diseases. Examples of autoimmune and inflammatory conditions that may be treated include acute, hyperacute or chronic rejection of transplanted organs, acute gout, acute inflammatory reactions (e.g., acute respiratory distress syndrome and ischemia/reperfusion injury), addison's disease, agammaglobulinemia, allergic rhinitis, allergy, alopecia, alzheimer's disease, appendicitis, atherosclerosis, asthma, osteoarthritis, juvenile arthritis, psoriatic arthritis, rheumatoid arthritis, atopic dermatitis, autoimmune alopecia, autoimmune hemolysis and thrombocytopenia, autoimmune hypopituitarism, autoimmune polyadenylic disease, behcet's disease, bullous skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, Chronic Obstructive Pulmonary Disease (COPD), cirrhosis, degenerative joint disease, depression, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, gastritis, glomerulonephritis, giant cell arteritis, goodpasture's syndrome, guillain barre syndrome, gingivitis, graves' disease, hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease (crohn's disease and ulcerative colitis), pelvic inflammatory disease, irritable bowel syndrome, kawasaki disease, LPS-induced endotoxic shock, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungoides, myositis, nephritis, osteomyelitis, pancreatitis, parkinson's disease, pericarditis, pernicious anemia, pneumonia, primary biliary sclerosing cholangitis, polyarteritis nodosa, psoriasis, retinitis, scleritis (scleroma), scleroderma, sinusitis, sjogren's disease, sepsis, septic shock, sunburn, systemic lupus erythematosus, tissue transplant rejection, thyroiditis, type I diabetes, takayasu arteritis, urethritis, uveitis, vasculitis including giant cell arteritis, vasculitis with organ involvement such as glomerulonephritis, vitiligo, waldenstrom's macroglobulinemia, and wegener's granulomatosis.

Other diseases include bacterial, fungal and/or parasitic infections; skin diseases (e.g., psoriasis); hyperplasia-based diseases characterized by an increased number of cells (e.g., endometrial hyperplasia) (e.g., fibroblasts, hepatocytes, skeletal and myeloid cells, cartilage or smooth muscle cells, or epithelial cells); bone diseases and cardiovascular diseases (e.g., restenosis and hypertrophy).

The salts and crystalline forms described herein are also suitable for protecting proliferating cells (e.g., hair, gut, blood, and progenitor cells) from DNA damage caused by radiation, UV treatment, and/or cytostatic therapy.

Combination therapy

The salts and crystalline forms described herein can be used alone or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances, for example other chemotherapeutic agents.

For the treatment of cancer and other proliferative diseases, the compounds of the invention may be used in combination with chemotherapeutic or other antiproliferative agents. Chemotherapeutic agents that may be administered in combination with the salts and crystalline forms described herein for the treatment of cancer or other proliferative diseases include, but are not limited to, hormones, hormone analogs and anti-hormonal agents (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluometrenol, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., anastrozole, letrozole, liazole, vorozole, exemestane, atantane), LHRH agonists and antagonists (e.g., goserelin acetate, leuprolide)), growth factor inhibitors (growth factors, e.g., "platelet-derived growth factor (PDGF)", "Fibroblast Growth Factor (FGF)", and antagonists (e.g., goserelin acetate, leuprolide), growth factor inhibitors (FGF) ", "Vascular Endothelial Growth Factor (VEGF)", "Epidermal Growth Factor (EGF)", "insulin-like growth factor (IGF)", "human epidermal growth factor (HER, e.g., HER2, HER3, HER 4)" and "Hepatocyte Growth Factor (HGF)"), inhibitors are, for example, "growth factor" antibodies, "growth factor receptor" antibodies and tyrosine kinase inhibitors, e.g., cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g., antifolates such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil, capecitabine, and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine, and pentostatin, cytarabine, fludarabine); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, actinomycin, plicamycin, streptozocin); platinum derivatives (e.g., cisplatin, oxaliplatin, carboplatin); alkylating agents (e.g., estramustine, meclorethamine, melphalan, chlorambucil, busulfan, dacarbazine, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as carmustine and lomustine, thiotepa); antimitotic agents (e.g., vinca alkaloids such as vinblastine, vindesine, vinorelbine, and vincristine; taxanes such as paclitaxel, docetaxel); a tubulin inhibitor; PARP inhibitors, topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and valpiride, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone), serine/threonine kinase inhibitors (e.g., PDK 1 inhibitors, B-Raf inhibitors, mTOR inhibitors, mTORC1 inhibitors, PI3K inhibitors, mTOR/PI3K dual inhibitors, STK 33 inhibitors, AKT inhibitors, PLK 1 inhibitors, CDK inhibitors, Aurora kinase inhibitors), tyrosine kinase inhibitors (e.g., PTK2/FAK inhibitors), protein-protein interaction inhibitors (e.g., IAP, Mcl-1, MDM2/MDMX), MEK inhibitors, ERK inhibitors, IGF-1R inhibitors, ErbB receptor inhibitors, rapamycin analogs (e.g., everolimus, temsirolimus) and various chemotherapeutic agents, such as amifostine, anagrelide, clodronate, filgrastim, interferon, alpha-interferon, calcium folinate, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate, and porfimer sodium.

Other agents that may be administered in combination with the salts and crystalline forms described herein include 2-chlorodeoxyadenosine, 2-fluorodeoxycytidine, 2-methoxyestradiol, 2C4, 3-alanine, 131-I-TM-601, 3CPA, 7-ethyl-10-hydroxycamptothecin, 16-aza-epothilone B, A105972, A204197, abarelix, abiraterone, aldesleukin, alemtuzumab, alitretinol, allopurinol, alloviten-7, hexamethylmelamine, fraxidil (alvocidib), amonafide, anastrozole, anthrapyrazole, AG-2037, AP-5280, apaziquqone, apone, aranosine, arganose, argatrobin, diarsene trioxide, azoxifene, aspartamide, atamestane, atrasentan, auristape, AVLB, avitin 92, ABX-479, EGF-47gamumab (AMG-K) (AMT-K), aTM-K-A-K, ARRY 162, ARRY 438162, ARRY-300, ARRY-142886/AZD-6244 (Semetinib), ARRY-704/AZD-8330, AR-12, AR-42, AS-703988, AXL-1717, AZD-8055, AZD-5363, AZD-6244, ARQ-736, ARQ 680, AS-703026 (primasertib), avastin, AZD-2014, azacytidine, azaepothilone B, azonafide, BAY-43-9006, BAY 80-6946, BBR-3464, BBR-3576, bevacizumab, bexarotene, BEZ-235, bicitrate bicifrada, BCX-1777, BKM-120, bleomycin, BLP-25, BMS-184476, BMS-2450, BMS-24797, BMS-277991, BMS-275236, BMS-36 754807, BMS-365396, BNP-3643, BNP-43, and BBR-3576, BNP-7787, BIBW 2992 (afatinib, afatinib (tomtak)), BIBF 1120 (nintedanib (vargatef)), BI836845, BI 2536, BI 6727, BI836845, BI 847325, BI 853520, BIIB-022, bleomycin acid, bleomycin A, bleomycin B, brimonib, bryostatin-1, bortezomib, bromtalicin, busulfan, BYL-719, CA-4 prodrug, CA-4, Capcell, calcitriol, Carlutosterone, canertinib, Canoflurane (canfosfamide), Capecitabine, carboplatin phthalate, carmustine, CCI-779, CC-115, -223. CEP-701, CEP-751, CBT-1 cefixime, homoharringtonine, ceftriaxone, celecoxib, simon-leukin, cimadotin, cetuximab, chlorambucil, CH4987655/RO-4987655, clenbuterol, cilengitide, cisplatin, CDA-II, CDC-394, CKD-602, CKI-27, cladribine, clofarabine, colchicine, combretastatin A4, COT inhibitors, CHS-828, CH-5132799, CLL-Thera, CMT-3 Nostoc 52, CTP-37, CTLA-4 monoclonal antibody, CP-461, CV-247, cyanomorpholino doxorubicin, cyclophosphamide, cyclosporine, cytarabine, D24851, dacarbazine, actinomycin D, dalbavancin sodium, dasatinib, daunorubicin, decitabine, dithiin-1, interleukin, Dinil-diphtheria toxin linker, doxorubicin, deoxyrubicin, deoxycoformycin, depsipeptide, deoxyepothilone B, dexamethasone, dexrazimine, dexrazoxane, diethylstilbestrol, diflutecan, 3, 4-dihydroxy benzohydroxamic acid (didox), DMDC, dolastatin 10, docetaxel, doladazole, doxorubicin, drotaandrosterone propionate, DS-7423, E7010, E-6201, eculizumab, edatrexate, idotricin, ethacrylox, eflornithine, EGFR inhibitor, EKB-569, EKB-509, enzastatin, elsamitrucin, epirubicin, epothilone B, epratuzumab, ER-86526, erlotinib, estramustine, ET-18-0CH3, ethynylcytidine, ethinyl estradiol, etoposide phosphate, etoposide, 3, 4-dihydroxy benzohydroxamic acid (didox), DMDC, DMC, DMT, MDA, Irinotecan mesylate, exemestane, fentanyl citrate, fenretinide, figitumumab, filgrastim, floxuridine, fludarabine, folic acid, fluorouracil, FOLFOX4, FOLFIRI, formestan, fotemustine, fulvestrant, garrubicin, maltol gallium, gefitinib, gemcitabine, gemumab, gemuzumab ozotacin, gemmace, glufosfamide, GCS-100, GDC-0623, GDC-0941 (pictelisib), GDC-0980, GDC-0032, GDC-0068, GDC-0349, GDC-0879, G17DT immunogen, GMK, GPX-100, gs100-peptide vaccine, GSK-5126766, GSK-690693, GSK-1120212 (trimetinib), GSK-2118457, GSK-36648454, GSK-36366436 2110183, GSK-366454, GSK-36363654, GSK-36643654, GSK-2132231A, GSK, and GSK-36643654, GSK-2141795, GW2016. Goserelin acetate, granisetron, herceptin, altretamine, histamine, histrelin acetate, homoharringtonine, hyaluronic acid, hydroxyurea, hydroxyprogesterone caproate, ibandronate, ibritumomab (ibritumomab), ibritumomab tiuxetan (ibritumomab tiuxetan), idarubicin, idatrexate, dienestenol (ideestrol), IDN-5109, ifosfamide, IGF-1R inhibitors, IMC-1C11, IMC-A12 (cetuximab), imatinib mesylate, immunol, indoismam, interferon alpha-2 a, interferon alpha-2B, pegylated interferon alpha-2B, interleukin-2, INK-1117, INK-128, M INS-18, lonafarnib, ipinacatinib, iproplatin, irinotecan, irvesin, isofusin B, isofusin A, isofusidic acid, isofusidic, Ixabepilone, JRX-2, JSF-154, J-107088, gestrel, kahalid F, ketoconazole, KW-2170, KW-2450, lapatinib ditosylate, leflunomide, lenalidomide, lenetin, letrozole, aldehydoic acid, leuprolide, leuprorelin acetate, leuprolide (leuprorelin), levamisole, leprospan, LGD-1550, linezolid, lobaplatin, dachiavalinate lutetium (lutetium texaphyrin), lometrexol, lomustine, losoxantrone, LU 223651, lurtotecan, LY-S6AKT1, testosterone-2780301, malafosfamide, marimastat, bis (chloroethyl) methylamine (mechlorethamine), megestrol acetate, MEK inhibitor, MEK-162, melphalan, mercaptopurine, methothreonin, methoprim, MEK-10755, MDX-210, MEK-M, MDX-447, MDX-1379, MGV, midostaurin, minodronic acid, mitomycin C, mitotane, mitoxantrone, mitobutraline, MK-2206, MK-0646 (dalotuzumab), MLN518, motoxafen gadolinium, MS-209, MS-275, MX6, nandrolone phenylpropionate, nelarabine, neridronate, neratinib, sorafenib (Nexavar), neovastat, nilotinib, nimesulide, nitroglycerin, Noflumumab, Nolatrexed, norrelin, N-acetyl cysteine, 06-benzyl guanine, Olimerson, omeprazole, cancer phage, oncophage oncoveX, oncoveX^GM-CSFOxirastin (ormiplatin), ortataxel (ortataxel), oxaliplatin, OX44 antibody, OSI-027, OSI-906(linsitinib), 4-1BB anti-antibodyA monomer, pyrrolidoner anthraquinone, estrogen, paclitaxel, pamidronate, panitumumab, paclitaxel, filgrastim, PCK-3145, pemetrexed, pefilgrastim, PBI-1402, PBI-05204, PDO325901, PD-1 antibody, PEG-paclitaxel, albumin stabilized paclitaxel, PEP-005, PF-05197281, PF-05212384, PF-04691502, PHT-427, P-04, PKC412, P54, PI-88, pelitinib, pemetrexed disodium, pentostatin, pentrix, perifosine, perillyl alcohol, pertuzumab, PI3K inhibitor, PI3K/mTOR inhibitor, PG-TXL, PG2, PLX-2/RO-5185426 (vemurafenib), PLX-3603/RO-5212054, PT-100, PWT-338667, PX-59866, PX-597, platinum, Pipobroman, pivaloyloxymethylbutyrate, pixantrone, dehydroequol O, PKI166, pralletricin, plicamycin, perbromic acid, podofibrycin, prednisone, prednisolone, procarbazine, quinacrilin, qui name d, quinupristin, R115777, RAF-265, ramosetron, ranpirnase, labyrine, RDEA-119/BAY 869766, RDEA-436, a butterfly mycin analog, a Receptor Tyrosine Kinase (RTK) inhibitor, revimid, RG-7167, RG-7304, RG-7421, RG-7321, RG 7440, rhizomycin, rhu-MAb, linfenpezil, risedronate, rituximab, rofecoxib, RO-31-7453, RO-5126766, RO-6850760, RPR 109881A, benzoylhydrazone, rubicin, R-0201, flurbiprofen, S-9788, sabaubicin, SAHA, samostin, satraplatin, SB 408075, Se-015/Ve-015, SU5416, SU6668, SDX-101, semustine, seocalcitol, SM-11355, SN-38, SN-4071, SR-27897, SR-31747, SR-13668, SRL-172, sorafenib, spiroplatinum, squalamine, streptozocin, cycloheptane hydroxamic acid (suberanilohydroxamic acid), sunitinib maleate, sutinib, sotitan, T900607, T138067, TAK-733, TAS-103, tacroline, talaporfin, tamoxifen, tertioxib, tariquar, tasolan, taxotere, tataxifolin, tebuconazole, testosterone, temoportisone, temocidin, temocinolactone, temozoloside, texolone, texol, tetrahydropyrane doxorubicin, thioguanine, thiotepa and thymus therapyNew, thymofectin, thifluthrin, tipifarnib, tirapazamine, tolazamide, raltitrexed, topotecan, toremifene, toremifin, tositumomab, trabetinid, TransMID-107, trans retinoic acid, traszutumab, tiximumab, tretinoin, triacetyluridine, tripaine, triciribine, tritrexate, K-286TXD258, tylpoecib/lapatinib (tyverb), urocidin, uracil mustard, valrubicin, varanib, vinblastine, vincristine, vinflunine, vinorelbine, viloliqin, WX-UK1, WX-554, victoribi, vorexast, Hiloda, XELXL-147, XL-511, XL-228-281, XL-518/R-7420/GDC-7473, TLYM-4190-XL-5954, ZD-418-5954, ZD-594, ZD-5954, ZD-598, ZD-413, ZD-5954, ZD-598, ZD-S-598, ZD-0473, ZD-6126, ZD-9331, ZD1839, ZSTK-474, zoledronate and zosuquidar.

The compounds of the present invention may also be used in combination with medical treatments such as surgery or radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes).

For the treatment of autoimmune or inflammatory conditions, the compounds of the invention may be used in combination with a corticosteroid such as triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone or fluorometholone.

For the treatment of autoimmune or inflammatory conditions, the compounds of the invention may be combined with immunosuppressive agents such as fluocinolone acetonideRimexolone (AL-2178, Vexol, Alcon) or cyclosporinAnd (4) combined administration.

For the treatment of autoimmune or inflammatory conditions, the compounds of the invention may be administered in combination with one or more other agents selected from the group consisting of: dehydrex^TM(Holles Labs), dacarbazine (Opko), sodium hyaluronate (Vismed, lantibiio/TRB Chemicals), cyclosporin (ST-603, Sirion therapeutics), ARG101(T) (Testosterone, Argentis), AGR1012(P) (Argentis), ecabet sodium (Senju-Ista), gefarnate (Santen), 15- (S) -hydroxycicosanoic acid (15(S) -HETE), cevimeline, doxycycline (ALTY-0501, Alacrit), minocycline, iDesrin^TM(NP50301, Nascent Pharmaceuticals), cyclosporin A (Nova22007, Novagali), oxytetracycline (MOLI 1901, Lantibio), CF101(2S,3S,4R,5R) -3, 4-dihydroxy-5- [6- [ (3-iodophenyl) methylamino ] methyl]Purin-9-yl]N-methyl-oxacyclopentane-2-carbamoyl, Can-Fine Biopharma), voclosporin (LX212 or LX214, Lux Biosciences), ARG103(Agentis), RX-10045 (synthetic resolvin analogs, Resolvyx), DYN15 (Dynamis Therapeutics), linaglitazone (DE011, Daiichi Sanko), 4(RegeneRx), OPH-01 (Ophtalmis), PCS101(Pericor Science), REV1-31 (Rev 1-31 (Lacritec), Lacritin (Senju), rebamipide (Ouka-Novartis), OT-551(Othera), PAI-2(University of Pesylvania and Tenn University), Pharma, Pimpire (Kivaclis), Piraco-1, Epsilolimus-981, Epsilodosis-sodium), Epsilodosina (Acetobacter asiatic-A), Epsilodosis-7 (Acetobacter asiatic-1, Acetoricipin-1, Acetoricipine (Edisoniacol-A), Acetoricipine, Acidovorax-D-1, Acidovorax-D-E (Acetoricipin-D-S-E-A), Acidophilips-A, Acidomycin-D-E (Acidomycin-S-E, Ac

Hydroxychloroquine, NGX267(TorreyPines Therapeutics), or thalidomide.

In some embodiments, the compounds of the present invention may be administered in combination with one or more agents selected from the group consisting of: antibiotics, antivirals, antifungals, anesthetics, anti-inflammatory agents (including steroidal and non-steroidal anti-inflammatory agents), and antiallergic agents. Examples of suitable drugs include aminoglycosides such as amikacin, gentamicin, tobramycin, streptomycin, netilmicin, and kanamycin; fluoroquinolones, such as ciprofloxacin, norfloxacin, ofloxacin, trovafloxacin, lomefloxacin, levofloxacin and enoxacin; naphthyridine; a sulfonamide; polymyxin; chloramphenicol; neomycin; paromomycin; colistin methanesulfonic acid; bacitracin; vancomycin; a tetracycline; rifampin and its derivatives ("rifamycins"); a cyclic serine; beta-lactams; a cephalosporin; amphotericin; fluconazole; fluorocytosine; natamycin; miconazole; ketoconazole; a corticosteroid; diclofenac acid; flurbiprofen; ketorolac; suprofen; cromolyn; lodoxylamine; levocabastine; naphazoline; an antazoline; (ii) pheniramine; or an azalide antibiotic.

One or more additional agents may be administered to the patient simultaneously or sequentially.

Formulations, dosage forms and administrations

When used as a medicament, the salts and crystalline forms described herein may be administered in the form of a pharmaceutical composition. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered by a variety of routes depending on whether local or systemic treatment is desired and the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and mucosal, including intranasal, vaginal and rectal), pulmonary (e.g. by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal administration), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular injection or infusion; or intracranial administration, such as intrathecal or intracerebroventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be administered, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. The pharmaceutically active compound should be present in an amount of 0.1% to 90%, preferably 0.5% to 50% by weight of the total composition, i.e. an amount sufficient to achieve the dosage ranges specified below.

The invention also includes pharmaceutical compositions containing, as active ingredients, a combination of a salt and a crystalline form as described herein, together with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that serves as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing the formulations, the active compounds described herein in the form of salts or crystalline forms may be milled to provide the appropriate particle size and then combined with the other ingredients. If the salt or crystalline form is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the salt or crystalline form is substantially water soluble, the particle size may be adjusted by milling to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

The salts and crystalline forms described herein can be milled using known milling procedures, such as wet milling, to obtain a particle size suitable for tablet formation and other formulation types. Finely divided (e.g., nanoparticulate) formulations of the salts and crystalline forms described herein can be prepared by methods known in the art, see, for example, international application No. WO 2002/000196.

Examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulation may additionally include: lubricants such as talc, magnesium stearate and mineral oil; a wetting agent; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoate; a sweetener; and a flavoring agent. The salts and crystalline forms described herein can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient by using methods known in the art.

Suitable tablets may be obtained, for example, by mixing the active substance or substances with known excipients, for example, inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrating agents, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc, and/or agents delaying release, such as carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablet may also comprise several layers.

The compositions may be formulated in unit dosage forms, each dose containing from about 5 to about 1,000mg (1g), more typically from about 100mg to about 500mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

In some embodiments, the compositions of the present invention comprise from about 5mg to about 50mg of the active ingredient. One skilled in the art will appreciate that this is embodied as a compound or composition comprising from about 5mg to about 10mg, from about 10mg to about 15mg, from about 15mg to about 20mg, from about 20mg to about 25mg, from about 25mg to about 30mg, from about 30mg to about 35mg, from about 35mg to about 40mg, from about 40mg to about 45mg, or from about 45mg to about 50mg of the active ingredient. The dosage described may be that amount specified for a particular salt or crystalline form, or an amount that provides a specified dosage of the free base compound, i.e., the particular salt or crystalline form of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide.

In some embodiments, the compositions of the present invention comprise from about 50mg to about 500mg of the active ingredient. One skilled in the art will appreciate that this is embodied as a compound or composition comprising from about 50mg to about 100mg, from about 100mg to about 150mg, from about 150mg to about 200mg, from about 200mg to about 250mg, from about 250mg to about 300mg, from about 350mg to about 400mg, or from about 450mg to about 500mg of the active ingredient. The dosage described may be that amount specified for a particular salt or crystalline form, or an amount that provides a specified dosage of the free base compound, i.e., the particular salt or crystalline form of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide.

In some embodiments, the compositions of the present invention comprise from about 500mg to about 1,000mg of active ingredient. One skilled in the art will appreciate that this is embodied as a compound or composition comprising from about 500mg to about 550mg, from about 550mg to about 600mg, from about 600mg to about 650mg, from about 650mg to about 700mg, from about 700mg to about 750mg, from about 750mg to about 800mg, from about 800mg to about 850mg, from about 850mg to about 900mg, from about 900mg to about 950mg, or from about 950mg to about 1,000mg of the active ingredient. The dosage described may be that amount specified for a particular salt or crystalline form, or an amount that provides a specified dosage of the free base compound, i.e., the particular salt or crystalline form of N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide.

The specified dose may be administered once a day, or if desired, several times a day, e.g., two, three or four times a day.

The active compounds can be effective over a wide dosage range and are generally administered in a pharmaceutically effective amount. It will be understood, however, that the dose actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

To prepare a solid composition, such as a tablet, the primary active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition comprising a homogeneous mixture of the salts or crystalline forms described herein. When these preformulation compositions are referred to as homogeneous, the active ingredient is generally dispersed uniformly throughout the composition so that the composition may be readily subdivided into equivalent unit dosage forms such as tablets, pills and capsules. The solid pre-formulations are then subdivided into unit dosage forms of the type described above containing, for example, from about 0.1 to about 1000mg of the active ingredient.

Tablets or pills comprising the salt or crystalline forms described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. Coated tablets may be prepared by: cores of similarly prepared tablets are coated with substances which are customarily used for tablet coatings, for example collidone (collidone) or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of a number of layers in order to achieve delayed release or to prevent incompatibilities. Similarly, the tablet coating may be composed of a number of layers to achieve delayed release, possibly using the excipients of the tablets described above.

For example, a tablet or pill may contain an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms that may incorporate the salts, crystalline forms and compositions of the present invention for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, as well as flavored emulsions with edible oils (e.g., cottonseed oil, sesame oil, coconut oil or peanut oil), as well as elixirs and similar pharmaceutical vehicles. Although liquid formulations in which the salt is dissolved will generally not comprise the salt in crystalline form, the salts and crystalline forms described herein may still be used to prepare liquid formulations, for example by dissolving the salt or crystalline form in a suitable medium.

Solutions for injection and infusion can be prepared in a customary manner, for example by adding isotonic agents, preservatives (e.g. parabens) or stabilizers (e.g. alkali metal salts of ethylenediamine tetraacetic acid), optionally using emulsifiers and/or dispersants, while if water is used as diluent, for example organic solvents can optionally be used as dissolving agents or dissolving aids and transferred into injection bottles or ampoules or infusion bottles.

Capsules containing one or more active substances or combinations of active substances can be prepared, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and packaging them in gelatin capsules.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid composition may comprise suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route to produce a local or systemic effect. The composition therein may be atomized by using an inert gas. The nebulized solution may be breathed directly from the nebulizing device, or the nebulizing device may be attached to a mask, tent, or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered orally or nasally from a device that delivers the formulation in a suitable manner.

The topical formulations may contain one or more conventional carriers. In some embodiments, the ointment may comprise water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier composition of the cream may be based on a combination of water with glycerin and one or more other components such as glyceryl monostearate, PEG-glyceryl monostearate and cetyl stearyl alcohol. Gels can be formulated using isopropanol and water, suitably in combination with other components such as glycerol, hydroxyethyl cellulose and the like. In some embodiments, the topical formulation comprises at least about 0.1 wt%, at least about 0.25 wt%, at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, or at least about 5 wt% of a compound of the present invention. The topical formulation may be suitably packaged in, for example, a 100g tube, optionally in combination with instructions for the treatment of a selected indication, such as psoriasis or other skin condition.

The amount of the salt or crystalline form or composition administered to a patient will vary depending on the content of administration, the purpose of administration (e.g., prophylaxis or treatment), the condition of the patient, the mode of administration, and the like. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the condition being treated and the judgment of the attending physician based on such factors as the severity of the condition, the age, weight and general condition of the patient.

The therapeutic dosage of the compounds of the invention may vary depending, for example, on the particular use being treated, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical properties (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present invention may be administered parenterally in a physiologically buffered aqueous solution containing from about 0.1% to about 10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight per day. In some embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg body weight per day. The dosage may depend on variables such as: the type and extent of progression of the disease or condition, the overall health status of the particular patient, the relative biological efficacy of the selected compounds, the adjuvant formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

Suitable dosage ranges for administration to humans are contemplated to be from about 50mg to about 2000mg, such as from about 100mg to about 2000mg, from about 200mg to about 2000mg, from about 400mg to about 2000mg, from about 600mg to about 2000mg, from about 800mg to about 2000mg, from about 1000mg to about 2000mg, from about 1200mg to about 2000mg, from about 1400mg to about 2000mg, from about 1500mg to about 2000mg, from about 1600mg to about 2000mg, from about 1800mg to about 2000mg, from about 50mg to about 1500mg, from about 100mg to about 1500mg, from about 200mg to about 1500mg, from about 400mg to about 1500mg, from about 600mg to about 1500mg, from about 800mg to about 1500mg, from about 1000mg to about 1500mg, from about 1200mg to about 1500mg, from about 1500mg to about 1500mg, from about 50mg to about 1000mg, from about 100mg to about 1000mg, from about 200mg to about 1000mg, from about 400mg to about 1000mg, from about 600mg to about 1000mg, from about 500mg to about 500mg, from about 500mg, About 400mg to about 500mg, or the dose is about 50mg, about 100mg, about 150mg, about 200mg, about 250mg, about 300mg, about 350mg, about 400mg, about 450mg, about 500mg, about 600mg, about 700mg, about 750mg, about 800mg, about 900mg, about 1000mg, about 1200mg, about 1400mg, about 1500mg, about 1600mg, about 1800mg, or about 2000 mg. The appropriate dosage specified may be that of the salt itself, or that which provides the specified amount of the salt of the free base compound, i.e., N- (3- (5- ((1-ethylpiperidin-4-yl) (methyl) amino) -3- (pyrimidin-5-yl) -1H-pyrrolo [3,2-b ] pyridin-1-yl) -2, 4-difluorophenyl) propane-1-sulfonamide.

The compositions of the invention may further comprise one or more additional agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressive agents, examples of which are listed above.

The following formulation examples illustrate the invention without limiting its scope:

examples of pharmaceutical preparations

The finely divided active substance, lactose and some corn starch are mixed together. The mixture is sieved, then moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, wet-granulated and dried. The granules, the remaining corn starch and magnesium stearate are sieved and mixed together. The mixture is compressed into tablets of suitable shape and size.

The finely ground active substance, some corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and then processed with the remaining corn starch and water to granules, which are dried and sieved. Sodium fluoromethyl starch and magnesium stearate are added and mixed, and the mixture is then compressed into tablets of appropriate size.

V. kit

The invention also includes a pharmaceutical kit for, e.g., treating or preventing a disease or disorder associated with B-RAF, e.g., cancer, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a salt or crystalline form described herein. Such kits may further include, if desired, one or more of a variety of conventional pharmaceutical kit components, such as a container with one or more pharmaceutically acceptable carriers, additional containers, and the like, as will be apparent to those skilled in the art. Instructions (as an insert or label) may also be included in the kit indicating the amount of the ingredients to be administered, the guidelines for administration, and/or the guidelines for mixing the ingredients.

The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of non-critical parameters that may be varied or modified to achieve substantially the same results.

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Crystalline salts of B-RAF kinase inhibitors

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