Anhydrous crystalline form of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide

Abstract

An anhydrous crystalline form of perabresib and its use for treating diseases associated with BET proteins are provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 304,746, filed January 31, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002]

[0002] Pelablative, also known as CPI-0610, is a potent and selective small molecule designed to promote antitumor activity by selectively inhibiting the function of BET proteins to reduce the expression of aberrantly expressed genes in cancer. Pelablative has demonstrated a wide therapeutic window in lymphoma models, and its monohydrate form is currently being advanced in a Phase 3 clinical trial for patients with myelofibrosis (MF) and related diseases. See, for example, NCT04603495. Given the therapeutic potential of pelablative, the development of a stable crystalline form of the drug remains an attractive area of ​​research. Summary of the Invention

[0003]

[0003] Provided herein is an anhydrous form of perabresib. Also provided are pharma- ceutically acceptable compositions comprising the anhydrous form of perabresib, methods for its preparation, and uses for treating diseases associated with inhibition of BET proteins, such as myelofibrosis. [Brief description of the drawings]

[0004] [Figure 1]

[0004] Figure 1 shows the X-ray powder diffraction pattern (XRPD) for the anhydrous crystalline form B of Perabresiv. [Diagram 2]

[0005] 1 shows a differential scanning calorimetry (DSC) thermogram and thermogravimetric analysis (TGA) overlay for the anhydrous crystalline form B of Perabresive. [Diagram 3]

[0006] 1 shows the dynamic vapor sorption (DVS) profile for anhydrous crystalline form B of Perabresive. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0005]

[0007] Anhydrous crystalline form B of perabresiv is provided.

[0008] The chemical name of perabresib is 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide. Perabresib has a CAS number of 1380087-89-7, is disclosed in U.S. Pat. No. 8,796,261 as compound 144, and has the chemical structure shown below.

[0006] [ka]

[0007]

[0009] Monohydrate crystalline form A of perabresiv can be obtained according to the disclosures in U.S. Pat. No. 9,969,747 and WO 2015 / 195863.

[0008]

[0010] The term "anhydrous" means that the crystalline form referred to is substantially free of water in the crystal lattice, e.g., containing less than 1% by weight as determined by Karl Fischer analysis.

[0009]

[0011] "Anhydrous crystalline form B" and "Perabresive anhydrous crystalline form B" are used interchangeably.

[0012] As used herein, "crystalline" refers to a solid form of a compound in which there is long-range atomic order in the positions of the atoms. The crystalline nature of a solid can be confirmed, for example, by examination of the X-ray powder diffraction pattern.

[0010]

[0013] Unless otherwise specified, anhydrous crystalline form B is a single crystalline form. "Single crystalline form" means that the described compound, i.e., perabresive, exists as a single crystal or multiple crystals, each of which has the same crystalline form (e.g., anhydrous crystalline form B). The weight percentage of anhydrous crystalline form B is determined by dividing the weight of anhydrous crystalline form B by the total weight of anhydrous crystalline form B plus the weight of other crystalline forms present, multiplied by 100%.

[0011]

[0014] Chemical purity refers to the degree to which the disclosed forms are free of materials with different chemical structures. The chemical purity of perabresive in the disclosed anhydrous crystalline form B is the weight of perabresive divided by the sum of the weights of perabresive plus materials / impurities with different chemical structures multiplied by 100%, i.e., weight percent.

[0012]

[0015] In one embodiment, the anhydrous crystalline form B of Perabresive is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by at least five X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by at least six X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by at least seven X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by at least eight X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of perabresive is characterized by at least nine X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°.In another embodiment, the anhydrous crystalline form B of perabresiv is characterized by X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°.

[0013]

[0016] In one embodiment, the anhydrous crystalline form B of Perabresive is characterized by X-ray powder diffraction peaks at 2θ angles selected from 11.86°, 17.91°, and 21.01°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by X-ray powder diffraction peaks at 2θ angles selected from 11.86°, 17.91°, 21.01°, and 24.06°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by X-ray powder diffraction peaks at 2θ angles selected from 11.86°, 17.91°, 21.01°, 24.06°, and 24.16°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 11.86°, 17.91°, 21.01°, 24.06°, and 24.16°. In another embodiment, the anhydrous crystalline form B of perabresiv is characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 11.86°, 17.91°, 21.01°, 24.06°, and 24.16°.

[0014]

[0017] In one embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at an angle of 11.86° 2θ and at least one additional X-ray powder diffraction peak at a 2θ angle selected from 11.56°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at an angle of 11.86° 2θ and at least two additional X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at an angle of 11.86° 2θ and at least three additional X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at an angle of 11.86° 2θ and at least four additional X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at an angle of 11.86° 2θ and at least five additional X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at an angle of 11.86° 2θ and at least six additional X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°.In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at an angle of 11.86° 2θ and at least seven additional X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at an angle of 11.86° 2θ and at least eight additional X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°.

[0015]

[0018] In one embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at a 2θ angle of 11.86° and at least one X-ray powder diffraction peak at a 2θ angle selected from 17.91°, 21.01°, 24.06°, and 24.16°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at a 2θ angle of 11.86° and at least two X-ray powder diffraction peaks at a 2θ angle selected from 17.91°, 21.01°, 24.06°, and 24.16°. In another embodiment, the anhydrous crystalline form B of Perabresive is characterized by an X-ray powder diffraction peak at a 2θ angle of 11.86° and at least three X-ray powder diffraction peaks at a 2θ angle selected from 17.91°, 21.01°, 24.06°, and 24.16°.

[0016]

[0019] In one embodiment, the anhydrous crystalline form B of Perabresiv is characterized by one or more X-ray powder diffraction peaks at 2θ angles in Table 2.

[0020] In one embodiment, the anhydrous crystalline form B of Perabresive is characterized by an XRPD substantially similar to that shown in FIG.

[0017]

[0021] In one embodiment, the anhydrous crystalline form B is at least 60% single crystalline form, at least 70% single crystalline form, at least 80% single crystalline form, at least 90% single crystalline form, at least 95% single crystalline form, or at least 99% single crystalline form, by weight.

[0018]

[0022] In one embodiment, the anhydrous crystalline form B has a chemical purity of at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% by weight.

[0019]

[0023] As used, "substantially the same XRPD pattern as shown in Figure 1" means, for purposes of comparison, that the XRPD has at least 90%, at least 95%, or at least 99% of the peaks shown in Figure 1. Alternatively, "substantially the same XRPD pattern as shown in Figure 1" means, for purposes of comparison, that the XRPD is identical to Figure 1 except for normal experimental variations in, e.g., temperature, processing conditions, instrumentation, etc.

[0020]

[0024] The term "amorphous" refers to a solid that exists in a non-crystalline state or form. Amorphous solids are disordered arrangements of molecules and therefore have no distinguishable crystal lattice or unit cell, and thus no definable long-range order. The solid-state order of a solid can be determined by standard techniques known in the art, such as X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC). Amorphous solids can also be distinguished from crystalline solids by birefringence, for example, using polarized light microscopy.

[0021]

[0025] The 2θ values ​​of the X-ray powder diffraction pattern for Form B described herein may vary slightly between one instrument and another, and also depending on sample preparation variations and batch-to-batch variations due to factors such as temperature changes, sample displacement, and the presence or absence of internal standards. Thus, unless otherwise specified, the XRPD patterns / assignments described herein should not be taken as absolute and may vary by ±0.2°. In one embodiment, the variation for the angle 11.86° varies by ±0.15° or less. It is well known in the art that this variability accounts for the above factors without preventing unambiguous identification of the crystalline form. Unless otherwise specified, the 2θ values ​​provided herein were obtained using Cu Kα1 radiation.

[0022]

[0026] For example, the temperature values ​​for DSC peaks herein may vary slightly from one instrument to another, and also depending on sample preparation variations, batch-to-batch variations, and environmental factors. Thus, unless otherwise defined, the temperature values ​​described herein should not be taken as absolute and may vary, for example, by ±5°C or ±2°C.

[0023]

[0027] According to another aspect, the present disclosure relates to a pharmaceutical composition comprising anhydrous crystalline form B and a pharma- ceutically acceptable carrier.

[0028] The term "pharmaceutical acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is combined and is safe for human use. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, magnesium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, dicalcium phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, glyceryl phosphate, sorbitol ... Examples of suitable additives include polyvinylpyrrolidone-vinyl acetate, cellulosic substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate), starch, lactose monohydrate, mannitol, sodium lauryl sulfate, and croscarmellose sodium, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, polymethacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0024]

[0029] Diseases and conditions treatable according to the methods described herein include, but are not limited to, cancer and other proliferative diseases, inflammatory diseases, sepsis, autoimmune diseases, and viral infections. Thus, one embodiment is a method of treating a subject having a disease, disorder, or symptoms thereof, comprising administering to the subject anhydrous crystalline Form B or a composition herein.

[0025]

[0030] The present disclosure further relates to a method for treating cancer or another proliferative disease by administration of an effective amount of anhydrous crystalline Form B described herein to a mammal, particularly a human in need of such treatment. In certain embodiments, the disease to be treated is cancer. Examples of cancers to be treated include, but are not limited to, adrenal gland carcinoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrohidrosis, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoid odontogenic tumor, adenosquamous carcinoma, adipose tissue tumor, adrenocortical carcinoma, adult T-cell leukemia / lymphoma, aggressive NK cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastoma, undifferentiated leukemia, and leukemia. large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, osteosarcoma, Brenner tumor, brown tumor, Burkitt lymphoma, breast cancer, brain tumor, carcinoma, carcinoma in situ, carcinosarcoma, chondrogenic tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell Lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine tumor, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, inclusion fetal malformation, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa Cell tumors, hemispheric positive ovarian tumors, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, malignant hematological diseases, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma,Malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant Triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, mixed Müllerian tumor, mucinous tumor, multiple myeloma, muscle tissue tumor, myotis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal Head cancer, neurilemmoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, eye cancer, oligoastrocytoma, oligodendroglioma, eosinophilic adenoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pineoblastoma, pineocytoma, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma, polyblastoma, precursor T-lymphoblastic lymphoma, primary central nervous Lymphoma of the system, primary effusion lymphoma, primary peritoneal carcinoma, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, medullary renal carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, schwannoma, seminoma, Sertoli cell tumor, sex cord / gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small round blue cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty wart, spinal tumor , splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sézary's disease, small intestine cancer, squamous cell carcinoma, gastric cancer, T-cell lymphoma, testicular cancer, theca cell tumor, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, genitourinary cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, optic pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.

[0026]

[0031] In one embodiment, the present disclosure further relates to a method for treating myelofibrosis, comprising administering an effective amount of anhydrous crystalline Form B to a subject in need thereof.

[0027]

[0032] In one embodiment, the present disclosure further relates to a method for treating essential thrombocythemia (ET), comprising administering an effective amount of anhydrous crystalline Form B to a subject in need thereof.

[0028]

[0033] In certain aspects, the disclosure provides methods of treating benign proliferative diseases, infectious and non-infectious inflammatory events and autoimmune and other inflammatory diseases, systemic inflammatory response syndrome, and viral infections.

[0029]

[0034] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, body weight, general health, sex, dietary habits, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of crystalline form provided in the composition will also depend on the specific compound in the composition.

[0030]

[0035] The terms "treatment," "treat," and "treating," as described herein, refer to ameliorating, alleviating, reducing the likelihood of occurrence, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof. In certain embodiments, treatment may be administered after one or more symptoms have occurred (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the condition and / or taking into account genetic or other susceptibility factors) (i.e., prophylactic treatment). Treatment may also be continued after the symptoms have resolved, e.g., to prevent or delay their recurrence.

[0031]

[0036] The term "effective amount" or "therapeutically effective amount" includes an amount of a compound described herein that elicits a biological or medical response in a subject, e.g., a dosage of 0.001 to 100 mg / kg body weight / day of anhydrous Form B. EXAMPLES

[0032]

[0037] Anhydrous crystalline Form B may be prepared according to the following procedure outlined below in Table 1. The starting material, amorphous perabresive, was prepared according to the procedure outlined for compound 144 in U.S. Pat. No. 8,796,261.

[0033] [Table 1]

[0034]

[0038] The XRPD spectrum for Form B is shown in Figure 1. Representative data points are shown in Table 2.

[0035] [Table 2]

[0036]

[0039] Temperature data indicates that Form B is anhydrous and non-solvated with a single sharp endothermic onset at about 188° C. See Figure 2. DVS data indicates that Form B is non-hygroscopic with a weight gain of about 0.5% at 95% RH. See Figure 3.

[0037] Competitive slurry experiments

[0041] The following competitive slurry experiment was conducted using anhydrous Form B according to the present invention and monohydrate Form A as disclosed in US Pat. No. 9,969,747.

[0038]

[0042] Aqueous mixtures were made and tested in duplicate at water activity at ambient temperature. Saturated solutions in each solvent were made with amorphous perforated. The supernatants were added to monohydrate form A and anhydrous form B solids and allowed to stir at the respective temperatures for approximately 5-7 days. In all samples except the butanol:water mixture, a small amount of form C was also added to the competitive slurry. Form C can be prepared by slurrying amorphous perforated in water:ethanol (90:10) for approximately 5 days. The competitive slurry results are shown below in Table 3.

[0039] [Table 3]

[0040]

[0043] Competitive slurry results show that Form B is thermodynamically stable at water activities below 72% and Form A is thermodynamically stable at water activities above 97%.

[0041] Pharmacokinetics of anhydrous form B in beagle dogs

[0044] Single-dose PK parameters in plasma were determined following oral gavage of 5 mg / kg micronized anhydrous Form B in 0.5% (w / v) aqueous Methocel (4000 cps) to male beagle dogs (n=6 / group). The dose volume for the PO group was 2 mL / kg. For intravenous (0.5 mg / kg) and oral gavage (5 mg / kg), plasma samples were collected and analyzed at the following time points: 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose. Following oral dosing (5 mg / kg, 2.5 mg / mL, suspension), Tmax was 1.17 ± 0.41 hours, Cmax was 1747 ± 225 ng / mL, and AUC0-24hr was 12133 ± 1452 hours. * ng / mL (5 mg / kg, 2.5 mg / mL, suspension).

[0042]

[0045] Although several embodiments of this have been described, it is clear that our basic examples can be varied to provide other embodiments that employ the compounds and methods of the present disclosure. It will therefore be understood that the scope of the present disclosure should be defined by the appended claims rather than the specific embodiments that have been represented by way of example.

[0043]

[0046] The contents of all references cited throughout this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art.

Claims

1. Anhydrous crystalline form B of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide.

2. 2. The anhydrous crystalline form B of claim 1, characterized by at least three X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°.

3. 3. The anhydrous crystalline form B of claim 1 or 2, characterized by at least four X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°.

4. 4. The anhydrous crystalline form B of any one of claims 1 to 3, characterized by at least five X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°.

5. 5. The anhydrous crystalline form B of any one of claims 1 to 4, characterized by at least six X-ray powder diffraction peaks at 2θ angles selected from 11.56°, 11.86°, 14.61°, 17.91°, 20.46°, 21.01°, 24.06°, 24.16°, 24.76°, and 26.86°.

6. The anhydrous crystalline form B according to any one of claims 1 to 5, wherein the crystalline form 1 is at least 90% by weight of a single crystalline form.

7. The anhydrous crystalline form B according to any one of claims 1 to 6, wherein the crystalline form 1 is at least 95% by weight of a single crystalline form.

8. The anhydrous crystalline form B of any one of claims 1 to 7, wherein the compound has a chemical purity of at least 90% by weight.

9. The anhydrous crystalline form B of any one of claims 1 to 8, wherein the compound has a chemical purity of at least 95% by weight.

10. The anhydrous crystalline form B of any one of claims 1 to 9, wherein the compound has a chemical purity of at least 99% by weight.

11. A pharmaceutical composition comprising the anhydrous crystalline form B of any one of claims 1 to 10 and a pharma- ceutically acceptable carrier.

12. 11. A method of treating a disease or disorder associated with inhibition of BET in a subject in need of such treatment, comprising administering to said subject an effective amount of anhydrous crystalline form B according to any one of claims 1 to 10.

13. 13. The method of claim 12, wherein the disease or disorder is myelofibrosis.

Images