FIELD

The present disclosure is related salt forms, and, in particular, crystalline salts 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 (BI 882370), a RAF kinase Inhibitor, useful in 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 Formula I:


is a RAF kinase inhibitor useful in the treatment of various diseases including cancer. The compound of Formula I, as well as its preparation and use, have been described in WO/2012/104388, which is incorporated herein by reference in its entirety.

The RAS-RAF-MAPK (mitogen-activated protein kinase) signaling pathway plays a critical role in transmitting proliferation signals generated by the cell surface receptors and cytoplasmic signaling elements to the nucleus. Constitutive activation of this pathway is involved in malignant transformation by several oncogenes. Activating mutations in RAS occur in approximately 15% of cancers, and recent data has shown that B-RAF is mutated in about 7% of cancers (Wellbrock et al., “The RAF proteins take centre stage”,Nature Rev. Mol. Cell Biol.,2004, 5, 875-885), identifying it as another important oncogene in this pathway. In mammals, the RAF family of serine/threonine kinases comprises three members: A-RAF, B-RAF and C-RAF. However, activating mutations have so far been only identified in B-RAF underlining the importance of this isoform. It is believed that B-RAF is the main isoform that couples RAS to MEK, and that C-RAF and A-RAF signal to ERK only to fine-tune cellular responses (Wellbrock et al.Nature Rev. Mol. Cell Biol.,2004, 5, 875-885). The most common cancer mutation in B-RAF results in a valine to glutamic acid exchange at position 600 of the protein (V600E), which dramatically enhances B-RAF activity, presumably because its negative charge mimics activation loop phosphorylation (Wan et al., “Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF”,Cell,2004, 116, 855-867). The highest incidence of B-RAF V600 mutations occurs in malignant melanoma (39%), thyroid cancer (46%), colorectal cancer (10%), biliary tract cancer (10%), prostate cancer (4%), ovary cancer (3%) and non-small cell lung cancer (2%), but they also occur at a low frequency in a wide variety of other cancers (frequencies of mutations according to COSMIC (Catalogue Of Somatic Mutations In Cancer; Wellcome Trust Sanger Institute) release v.53, 15 May 2011; http://www.sanger.ac.uk/genetics/CGP/cosmic/). Literature supported the hypothesis that B-RAFV600Emutated tumor cells seem to rely heavily on the continued activation of this pathway—a phenomenon termed “oncogene addiction”—whereas normal B-RAFwtcells use a broader range of signals. This provides an Achilles' heel that can be exploited therapeutically by treating patients with somatically mutated B-RAFV600Eusing orally available B-RAF inhibitors.

The key role of B-RAFV600Ein aberrant ERK signaling and consequently oncogenesis 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), siRNA knock-down in vitro (Karasarides et al., Oncogene, “V599EB-RAF is an oncogene in melanocytes”, 2004, 23, 6292-6298) or in inducible short-hairpin RNA xenograft models where gain-of-function B-RAF signaling was found to be strongly associated with in vivo tumorigenicity (Hoeflich et al., “Oncogenic BRAF is required for tumor growth and maintenance in melanoma models”,Cancer Res.,2006, 66, 999-1006).

Treatment of B-RAFv600Emutated melanoma or colon carcinoma cells induces a B-RAF inhibition phenotype (e.g. reduction of phospho-MEK and phospho-ERK levels, reduction of cyclin D expression and induction of p27 expression). Consequently, these cells are locked in the Gi-phase of the cell cycle and do not proliferate.

Clinical proof of mechanism and proof of concept has been established for treating in cancer in B-RAFv600Emutated melanoma patients treated with Zelboraf®, B-RAF inhibitor (PLX-4032, vemurafenib, from Plexxikon/Daiichi Sankyo/Roche. Bollag et al., “Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma”,Nature,2010, 467(7315), 596-9; Flaherty et al.,New Engl. J. Med., “Inhibition of Mutated, Activated BRAF in Metastatic Melanoma”,2010, 363, 809-819; Chapman et al. “Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation”,New Engl. J. Med,2011, 364:2507-2516. Favorable response rates were observed in both Phase I and Phase III clinical trials. It was reported, that melanoma patients carrying a B-RAFv600Kmutation also do respond to therapy (Rubinstein et al., “Incidence of the V600K mutation among 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 mutation is the exchange at amino acid position 600 from valine to glutamate with more than 90% frequency of all B-RAF mutations (Wellbrock et al.Nature Rev. Mol. Cell Biol.,2004, 5, 875-885), the second most frequent mutation is an alteration from valine to lysine, other mutations were found with lower frequency at that position (Wellbrock et al.Nature Rev. Mol. Cell Biol.,2004, 5, 875-885 and frequencies of mutations according to COSMIC (Catalogue Of Somatic Mutations In Cancer; Wellcome Trust Sanger Institute) release v53, 15 May 2011; http://www.sanger.ac.uk/genetics/CGP/cosmic/). Additional mutations were found at e.g. the glycine rich loop (Wellbrock et al.Nature Rev. Mol. Cell Biol.,2004, 5, 875-885). Not all of these rather rare mutations seem to lead to direct activation of B-RAF (Wan et al., “Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF”,Cell,2004, 116, 855-867).

The compound of Formula I is a highly potent and selective RAF inhibitor that binds to the DFG-out (inactive) conformation of the B-RAF kinase. The compound inhibited proliferation of human B-RAF-mutant melanoma cells with 100 times higher potency (1-10 nmol/L) than vemurafenib, whereas wild-type cells were not affected at 1,000 nmol/L. A solution of the compound administered orally was efficacious in mouse models of B-RAF-mutant melanomas and colorectal carcinomas, and at 25 mg/kg twice daily showed superior efficacy compared with vemurafenib, dabrafenib, or trametinib. The compound was also active in A375 melanoma-bearing mice that were resistant to vemurafenib, particularly when dosed in combination with trametinib. Mice treated with the compound did not show any body weight loss or clinical signs of intolerability, and no pathologic changes were observed in several major organs investigated, including skin. Furthermore, in a pilot study in rats (up to 60 mg/kg daily for 2 weeks), the compound lacked toxicity in terms of clinical chemistry, hematology, pathology, and toxicogenomics. These results are described in Waizenegger et al.,Mol. Cancer Ther.,2016, 15(3); 354-65, which is incorporated herein by reference in its entirety.

For the manufacture, purification, and formulation of a drug, it may be advantageous to employ a form of the drug having superior stability or other desirable formulation property exhibited by, for example, one or more salt or crystalline forms of the drug. Formation of salts of basic or acidic drugs can sometimes provide forms of the drug that have advantageous properties such as solubility, non-hygroscopicity, crystallinity, and other physical properties that advantageous for formulating the drug. On the other hand, discovering a suitable salt or other crystalline form that is suitable for formulation is difficult, since there are numerous variables in the formation of a salt or crystalline form. These include the existence of numerous possible acids and bases that might be used as a counter-ion, various stoichiometric ratios that may be possible for combining a given basic or acid drug with an acid or base counter-ion, a wide variety of solvents and solvent systems (including combinations of solvents) that potentially can be used to attempt to form salts or crystalline forms, and a variety of conditions (such as temperature or heating or cooling conditions) under which salts or crystalline forms may be generated. All of these variables of which may affect the properties of the salts or crystalline forms that might be obtained. Salts or solid forms may also have a variety of properties that render them unsuitable for drug development and formulation such as lack of crystallinity (amorphous forms), the presence or formation of multiple crystalline forms, which may interconvert and/or have different properties (polymorphism), lack of aqueous solubility, hygroscopicity, or stickiness of the solid. Furthermore, the formation of salts and crystalline forms and their properties are generally very unpredictable.

Accordingly, the crystalline salt forms of the compound of Formula I provided herein help satisfy the ongoing need for the development of a RAF kinase inhibitor for the treatment of serious diseases.

SUMMARY

The present disclosure provides a 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 salt and particular crystalline 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 monosuccinate salt.

In some embodiments, the crystalline salt is substantially anhydrous.

In some embodiments, the crystalline salt is substantially non-solvated.

In some embodiments, the crystalline salt is 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 salt.

In some embodiments, the crystalline salt has an X-ray powder diffraction pattern comprising at least one of the following peaks, in terms of 2θ: 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5°. In some embodiments, the peak at 15.4°±0.5°; 20.0°±0.5°; 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 2θ: 15.4°±0.2°; 20.0°±0.2°; and 21.8°±0.2°. In some embodiments, the peak at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° 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 peak, in terms of 20, at 15.4°±0.5°. In some embodiments, the peak at 15.4°±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 peak, in terms of 20, at 15.4°±0.2°. In some embodiments, the peak at 15.4°±0.2° 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 2θ: 15.4°±0.5°; 20.0°±0.5°; and 21.8°±0.5°. In some embodiments, the peak at 15.4°±0.5°; 20.0°±0.5°; 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 2θ: 15.4°±0.2°; 20.0°±0.2°; and 21.8°±0.2°. In some embodiments, the peak at 15.4°±0.2°; 20.0°±0.2°; or 21.8°±0.2° 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 substantially as shown inFIG. 10,FIG. 26, orFIG. 38.

In some embodiments, the crystalline salt has a differential scanning calorimetry thermogram (DSC) substantially as shown inFIG. 11,FIG. 27, orFIG. 39.

In some embodiments, the crystalline salt has a thermogravimetric analysis (TGA) substantially as shown inFIG. 12,FIG. 28orFIG. 39.

In some embodiments, the crystalline salt is substantially isolated.

The present disclosure provides a composition (e.g., a pharmaceutical composition) comprising the 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 salt, or any of the embodiments thereof. The composition may include at least one pharmaceutically acceptable carrier.

The present disclosure 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 monosuccinate salt, or any of the embodiments thereof, or the composition comprising the crystalline salt, or any of the embodiments thereof. The dosage form may be in the form of a tablet.

The present disclosure provides a method for preparing 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 salt. The method includes 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. The method can include crystallizing or recrystallizing the salt from a C1-4alcohol, aqueous C1-4alcohol or ethyl acetate. The method can include crystallizing or recrystallizing the salt from ethanol, isopropanol, aqueous ethanol or aqueous isopropanol, or ethyl acetate.

The present disclosure provides a method of treating a disease in a patient, wherein the disease is associated with abnormal 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 salt, or any of the embodiments thereof, or a composition comprising the 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 salt. The present disclosure 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 salt, or any of the embodiments thereof, for use in treating a disease associated with abnormal expression or activity of a 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 salt, or any of the embodiments thereof, for treating a disease associated with abnormal expression or activity of a 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 salt, or any of the embodiments thereof, in the manufacture of a medicament for treating a disease associated with abnormal expression or activity of a RAF kinase.

In some embodiments, the disease is associated with abnormal expression or activity of a B-RAF kinase. In some embodiments, the B-RAF-kinase is a mutated B-RAF kinase. In some embodiments, the B-RAF-kinase is a V600E mutated B-RAF kinase. In some embodiments, the disease is selected from cancer, infections, inflammation and autoimmune diseases.

The present disclosure further provides a method of treating a 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 salt, or any of the embodiments thereof, or a composition comprising the 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 salt. The present disclosure 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 salt, or any of the embodiments thereof, for use in treating 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 monosuccinate salt, or any of the embodiments thereof, for treating 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 monosuccinate salt, or any of the embodiments thereof, in the manufacture of a medicament for treating cancer.

In some embodiments, the cancer is breast, prostate, colon, endometrial, brain, bladder, skin, uterus, ovary, lung, pancreatic, renal, gastric, or a hematological cancer. In some embodiments, the cancer is malignant melanoma, thyroid cancer, colorectal cancer, biliary tract cancer, prostate cancer, ovary cancer or non-small cell lung cancer

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

