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WO2015195863A1 - 2-((4s)-6-(4-chlorophényl)-1-méthyl-4h-benzo[c]isoxazolo[4,5-e]azépine-4-yl)acétamide hydraté - Google Patents

2-((4s)-6-(4-chlorophényl)-1-méthyl-4h-benzo[c]isoxazolo[4,5-e]azépine-4-yl)acétamide hydraté Download PDF

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Publication number
WO2015195863A1
WO2015195863A1 PCT/US2015/036348 US2015036348W WO2015195863A1 WO 2015195863 A1 WO2015195863 A1 WO 2015195863A1 US 2015036348 W US2015036348 W US 2015036348W WO 2015195863 A1 WO2015195863 A1 WO 2015195863A1
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Prior art keywords
azepin
chlorophenyl
benzo
acetamide
isoxazolo
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WO2015195863A8 (fr
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Michael L. Hall
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Constellation Pharmaceuticals Inc
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Constellation Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

Definitions

  • hydrated forms of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide processes for the preparing the hydrated forms, pharmaceutical compositions comprising the hydrated forms, and uses of the hydrated forms and compositions thereof in treating bromodomain-containing protein-mediated disorders.
  • 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide is an inhibitor of one or more bromodomain-containing proteins and is useful in treating bromodomain-containing protein-mediated disorders, such as, e.g., proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections.
  • the amorphous form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin- 4-yl)acetamide is exemplified in U.S.
  • novel hydrated forms e.g., a monohydrate
  • 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide which have improved properties and display advantageous characteristics over the prior disclosed amorphous form.
  • advantages include e.g., improved relative humidity stability, ease of isolation, favorable pharmacokinetic parameters, and process reproducibility of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5- e]azepin-4-yl)acetamide.
  • crystalline hydrated forms e.g., a crystalline
  • compositions comprising the hydrated and crystalline hydrated forms of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, methods for their manufacture, and uses thereof for treating bromodomain-containing protein-mediated disorders, such as, e.g., proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections.
  • bromodomain-containing protein-mediated disorders such as, e.g., proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections.
  • Figure 1 depicts a gravimetric moisture sorption curve for a monohydrate form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide.
  • Figure 2 depicts a gravimetric moisture sorption curve for amorphous 2-((4S)-6- (4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide.
  • Figure 3 depicts Individual Plasma Concentration vs. time in male Sprague Dawley rats after oral administration with a monohydrate form of 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide in 0.5% MC at 10 and 60 mg/kg.
  • Figure 4 depicts Individual Plasma Concentration vs. time in Male Beagle Dogs after Oral Administration with amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide in 0.5% MC at 2 mg/kg.
  • Figure 5 depicts Individual Plasma Concentration vs. time in Male Beagle Dogs after Oral Administration with a monohydrate form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-
  • Figure 6 depicts an optical micrograph for a crystalline monohydrate form of 2-
  • Anhydrous as used herein, means that the crystalline form comprises substantially no water in the crystal lattice e.g., less than 1% by weight as determined by Karl Fisher analysis.
  • amorphous means a solid that is present in a non-crystalline state or form.
  • Amorphous solids are disordered arrangements of molecules and therefore possess no distinguishable crystal lattice or unit cell and consequently have no definable long range ordering.
  • Solid state ordering of solids may be determined by standard techniques known in the art, e.g., by X-ray powder diffraction (XRPD) or differential scanning calorimetry (DSC).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • Amorphous solids can also be differentiated from crystalline solids e.g., by birefringence using polarized light microscopy.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not adversely affect the pharmacological activity of the compound with which it is formulated, and which is also safe for human use.
  • compositions of this 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, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances (e.g., microcrystalline cellulose, hydroxypropyl methylcellulose, lactose monohydrate, sodium lauryl sulfate, and crosscarmellose sodium), polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,
  • the present disclosure provides a hydrate of 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, or a
  • the present disclosure provides a monohydrate of 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, or a
  • the hydrate or monohydrate of 2-((4S)-6-(4-chlorophenyl)-l- methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, or pharmaceutically acceptable salt thereof as defined herein, is crystalline.
  • the present disclosure provides a process for preparing hydrated forms of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin- 4-yl)acetamide.
  • the process includes, e.g., forming a hydrated form of 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide from a solution comprising amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5- e]azepin-4-yl)acetamide and water; or forming a hydrated form of 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide from a solution comprising amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5- e]azepin-4-yl
  • the hydrated form is precipitated from a solution comprising amorphous 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide and a
  • Acceptable solvent mixtures for the aforementioned processes include, e.g., ethanol/water, isopropanol/water, tetrahydrofuran/water, acetone/water, methanol/water, and acetonitrile/water.
  • the process described herein comprises formation of monohydrate 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide from amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide in a 60:40 mixture of ethanol/water.
  • Processes for preparing hydrated forms of 2-((4S)-6-(4-chlorophenyl)-l-methyl- 4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide also include seeding a solution comprising amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5- e]azepin-4-yl)acetamide and water with a hydrated form (e.g., a monohydrate form) of 2- ((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide; or seeding a solution comprising amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazol
  • the seeding is done with monohydrate 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin- 4-yl)acetamide to prepare the resulting monohydrate form.
  • Processes for preparing hydrated forms of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide can also be achieved upon suspending amorphous 2-((4S)-6-(4-chlorophenyl)-l- methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide in water, absent seeding.
  • Acceptable solvent mixtures for the process mention in the two preceding paragraphs also include, e.g., ethanol/water, isopropanol/water, tetrahydrofuran/water, acetone/water, methanol/water, and acetonitrile/water.
  • the process described herein comprises formation of monohydrate 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide from seeding amorphous 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide with monohydrate 2-((4S)-6-(4-chlorophenyl)- l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide in a 60:40 mixture of ethanol/water.
  • compositions are provided.
  • the present disclosure relates to a method of inhibiting a bromodomain-containing protein (such as a BET protein, e.g. , BRD2, BRD3, BRD4, and/or BRDT) using a composition comprising a hydrated form of 2-((4S)-6-(4-chlorophenyl)- l- methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide described herein and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • a bromodomain-containing protein such as a BET protein, e.g. , BRD2, BRD3, BRD4, and/or BRDT
  • the amount of hydrated form of 2- ((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide in a provided composition is such that is effective to measurably inhibit one or more
  • bromodomain-containing proteins such as a BET protein, e.g. , BRD2, BRD3, BRD4, and/or BRDT
  • the amount of the hydrated form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide in a provided composition is such that is effective to measurably inhibit one or more bromodomain-containing proteins (such as a BET protein, e.g.
  • a provided composition is formulated for administration to a patient in need of such composition. In some aspects, a provided composition is formulated for oral administration to a patient.
  • compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • compositions may be formulated such that a dosage of between 0.001 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.
  • the amount of a provided crystalline form in the composition will also depend upon the particular compound in the composition.
  • Hydrated forms of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide and compositions described herein are generally useful for the inhibition of activity of one or more proteins involved in epigenetic regulation e.g., as those described in U.S. Patent Publication No. 2012/0157428.
  • the present disclosure provides a method of inhibiting one or more proteins involved in epigenetic regulation, such as proteins containing acetyl-lysine recognition motifs, also known as bromodomains (e.g., BET proteins, such as BRD2, BRD3, BRD4, and/or BRDT), by administering a provided hydrated form (e.g., a monohydrate or crystalline monohydrate form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5- e]azepin-4-yl)acetamide) or composition described herein.
  • a provided hydrated form e.g., a monohydrate or crystalline monohydrate form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5- e]azepin-4-yl)acetamide
  • the present disclosure also relates to treating MYC-dependent cancers, inflammatory diseases, and viral diseases (e.g., as those described in U.S. Patent Publication No. 2012/0157428), comprising administering one or more of the hydrated forms described herein.
  • treatment refers to reversing, alleviating, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
  • one aspect is a method of treating a subject having a disease, disorder, or symptom thereof the method including administration of a hydrated form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, (e.g., a monohydrate or crystalline monohydrate form), or composition herein to the subject.
  • a hydrated form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide e.g., a monohydrate or crystalline monohydrate form
  • a human patient is treated with a hydrated form of 2-((4S)-6-(4-chlorophenyl)- l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide described herein, (e.g., a monohydrate or crystalline monohydrate form), and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said hydrated form is present in an amount to measurably inhibit bromodomain-containing protein activity (such as BET protein, e.g. , BRD2, BRD3, BRD4, and/or BRDT) in the patient.
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle wherein said hydrated form is present in an amount to measurably inhibit bromodomain-containing protein activity (such as BET protein, e.g. , BRD2, BRD3, BRD4, and/or BRDT) in the patient.
  • bromodomain-containing protein activity such as BET protein, e.
  • the present disclosure further relates to a method for treating or ameliorating cancer or another proliferative disorder by administration of an effective amount of a hydrated form of 2-((4S)-6-(4-chlorophenyl)- l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide as described herein, (e.g., a monohydrate or crystalline monohydrate form), to a mammal, in particular a human in need of such treatment.
  • the disease to be treated is cancer.
  • cancers treated include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymph lymph
  • 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, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage 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 gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological mal
  • T-lymphoblastic lymphoma primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary' s disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma,
  • the present disclosure provides a method of treating a benign proliferative disorders, infectious and noninfectious inflammatory events and autoimmune and other inflammatory diseases, systemic inflammatory response syndromes, and viral infections, e.g., those as described in U.S. Patent Publication No. 2012/0157428.
  • the present disclosure further provides a method of treating a subject, such as a human, suffering from one of the abovementioned conditions, illnesses, disorders or diseases.
  • the method comprises administering a therapeutically effective amount of hydrated form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, (e.g., a monohydrate or crystalline monohydrate form), which functions by inhibiting a bromodomain and, in general, by modulating gene expression, to induce various cellular effects, in particular induction or repression of gene expression, arresting cell proliferation, inducing cell differentiation and/or inducing apoptosis, to a subject in need of such treatment.
  • the present disclosure further relates to the use of a hydrated form of 2-((4S)-6- (4-chlorophenyl)- l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, (e.g., a monohydrate or crystalline monohydrate form), for the production of pharmaceutical compositions which are employed for the treatment and/or amelioration of the diseases, disorders, illnesses and/or conditions as mentioned herein.
  • a hydrated form of 2-((4S)-6- (4-chlorophenyl)- l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide e.g., a monohydrate or crystalline monohydrate form
  • Another aspect of the present disclosure is the use of a hydrated form of 2-((4S)-6- (4-chlorophenyl)- l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide as described herein, (e.g., a monohydrate or crystalline monohydrate form), in the manufacture of a medicament for use in the treatment of a disorder or disease herein.
  • Another object of the present disclosure is the use the hydrated forms as described herein for use in the treatment of a disorder or disease herein.
  • additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of this disclosure or administered separately as a part of a dosage regimen.
  • additional therapeutic agents that are normally administered to treat a particular disease, or condition are known as "appropriate for the disease, or condition, being treated.”
  • a provided hydrated form may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • one aspect provides a single unit dosage form comprising a provided hydated form (e.g., a monohydrate or crystalline monohydrate form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide), an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use in the methods of the disclosure.
  • a provided hydated form e.g., a monohydrate or crystalline monohydrate form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle for use in the methods of the disclosure.
  • hydrated forms of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide) may be prepared according to the following general procedures.
  • Optical Micrographs were obtained using a Leica DMRB Polarized Microscope using a digital camera (1600 x 1200 resolution). Samples were dispersed on a glass slide with light mineral oil and viewed at lOOx magnification.
  • Carboxylic acid (1) was prepared from the procedures described in U.S. Patent Publication No. 2012/0157428. See e.g., Scheme 1, Step L of U.S. Patent Publication No. 2012/0157428. It should be noted that subsequent couplings following the procedures described in U.S. Patent Publication No. 2012/0157428 (e.g., the second step in Scheme 1, Step L) produced only amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide. This amorphous material did not result in any observable diffraction using XRPD and was further characterized e.g., by gravimetric moisture sorption ( Figure 2).
  • a reactor was charged with 700 g of carboxylic acid (1) with 65.8 wt% 1H NMR potency (460 g, 1.3 mol) in DCM (4.6 L).
  • the batch was charged with carbonyldiimidazole (CDI, 264 g, 1.6 mol, 1.3 equiv) in four portions with the solids addition system. Over the course of the addition, the batch temperature was 15-18 °C.
  • the batch was stirred for 1-2 hours at 20-25 °C when HPLC analysis indicated the starting material was ⁇ 2%.
  • the batch was cooled to 0-5 °C.
  • the batch was charged with 28% aqueous ammonium hydroxide solution (432 mL, 6.5 mol, 5 equiv) by an addition funnel over 20 minutes while maintaining the temperature at 0-5 °C.
  • the batch was stirred at 0-5 °C for 1 hour when HPLC analysis indicated the intermediate acyl-imidazole was ⁇ 2%.
  • the batch was warmed to 20-25 °C and DI water (2.3 L) was added.
  • the batch was stirred vigorously for 15 minutes. The stirring was stopped and the phases were separated.
  • the organic phase was washed with brine (2.3 L), dried (MgS0 4 ), treated with activated carbon (46 g, Darco G-60), filtered, and washed with DCM (1.5 L).
  • the combined filtrates and washes were concentrated to dryness by rotary evaporation.
  • the residue was redissolved in absolute alcohol (2.3 L) and heated to 50- 55 °C.
  • the batch was charged with DI water (2.3 L) by addition funnel over 1 hour while maintaining the temperature 50-55 °C.
  • the batch was cooled over a period of 2 hours and an oil, instead of solids, was observed to form.
  • the batch was reheated to 50-55 °C and gradually cooled to 15-25 °C over a period of 12-16 hours.
  • the batch was cooled to 0-5 °C and stirred for 1-2 hours.
  • the batch was filtered and washed with a 1 : 1 mixture of DI water to absolute ethanol (230 mL).
  • Microcrystalline Cellulose (Avicel Filler 95.00 267.2 PH-101)
  • HPMC capsule size 0, Swedish Capsule shell NA 1 each Orange (Quali Vcaps)
  • weight weight weight weight (mg) per (mg) per (mg) per unit unit weight dosage dosage dosage composition 25 mg (50 mg (100 mg
  • microcrystalline cellulose changes from 4 wt% at 20% relative humidity to approximately 18 wt% at 90% relative humidity.
  • a pharmaceutical formulation blend comprising an API with an excipient like, e.g., microcrystalline cellulose, or in a compressed tablet
  • the water content of the API and the excipients will equilibrate. Since the water content of the disclosed monohydrate remains very consistent from 5 to 95% RH, one achieves the unexpected advantage of not having to be concerned with the excipient(s) (e.g., microcrystalline cellulose) giving up water to the API or vice versa, which could lead to changes in API stability or to changes in friabitly or disintegration properties upon storage.
  • Figure 2 shows a gravimetric moisture sorption curve for amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide, where the water content of the amorphous form was found to increase from 0 to
  • amorphous 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide does not exhibit an effectively constant stoichiometric ratios of water over a broad relative humidity range and, as such, the aforementioned concerns and changes may be realized.
  • Table 3 Plasma concentration of amorphous 2-((4S)-6-(4-chlorophenyl)-l- methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide following single oral dose to male Sprague Dawley rats at 60 mg/Kg.
  • Table 4 Calculated pharmacokinetic parameters of amorphous 2-((4S)-6-(4- chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide following single oral dose to male Sprague Dawley rats at 60 mg/Kg.
  • Table 5 Plasma concentration of monohydrate 2-((4S)-6-(4-chlorophenyl)-l- methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide following single oral dose to male Sprague Dawley rats at 60 mg/Kg.
  • Table 7 Plasma concentration of monohydrate 2-((4S)-6-(4-chlorophenyl)-l- methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide following single oral dose to male Sprague Dawley rats at 10 mg/Kg.
  • Amorphous and monohydrate 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H- benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide were dosed orally in dogs at 2 mg/Kg. Both forms (amorphous and monohydrate) were suspended in Methylcellulose (0.4 mg/mL in 0.5 % MC). The objective was to compare the pharmacokinetic profiles of both forms in dogs using a crossover study design in which the same dogs were dosed sequentially with
  • Table 9 Plasma concentration and pharmacokinetic parameters of amorphous form of 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4- yl)acetamide following single oral dose to male beagle dog at 2mg/Kg.
  • Table 10 Plasma concentration and pharmacokinetic parameters of monohydrate 2-((4S)-6-(4-chlorophenyl)-l-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)acetamide following single oral dose to male beagle dog at 2mg/Kg.
  • Both the amorphous solid and the monohydrate show similar pharmacokinetic profiles and low inter- individual variability. These are favorable and unexpected properties of the monohydrate.

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Abstract

L'invention concerne des formes hydratées de 2-((4S)-6-(4-chlorophényl)-l-méthyl-4 H-benzo[c]isoxazolo [4,5-e] azépine-4-yl) acétamide, qui sont utiles en tant qu'inhibiteurs de protéines contenant des bromodomaines. L'invention concerne également des compositions pharmaceutiquement acceptables comprenant ces formes hydratées, ainsi que des procédés d'utilisation de ces compositions dans le traitement de divers troubles.
PCT/US2015/036348 2014-06-20 2015-06-18 2-((4s)-6-(4-chlorophényl)-1-méthyl-4h-benzo[c]isoxazolo[4,5-e]azépine-4-yl)acétamide hydraté Ceased WO2015195863A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019199816A1 (fr) 2018-04-13 2019-10-17 Arvinas Operations, Inc. Ligands de céréblon et composés bifonctionnels les contenant
US10730870B2 (en) 2015-03-18 2020-08-04 Arvinas Operations, Inc. Compounds and methods for the enhanced degradation of targeted proteins
US10772962B2 (en) 2015-08-19 2020-09-15 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of bromodomain-containing proteins
US11220515B2 (en) 2018-01-26 2022-01-11 Yale University Imide-based modulators of proteolysis and associated methods of use
WO2023147149A1 (fr) 2022-01-31 2023-08-03 Constellation Pharmaceuticals, Inc. Formes cristallines anhydres de 2-((4s)-6-(4-chlorophényl)-1-méthyl-4h-benzo[c]isoxazolo[4,5-e]azépin-4-yl)acétamide
US11883393B2 (en) 2019-12-19 2024-01-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor
US12239711B2 (en) 2014-04-14 2025-03-04 Arvinas Operations, Inc. Cereblon ligands and bifunctional compounds comprising the same
WO2025049555A1 (fr) 2023-08-31 2025-03-06 Oerth Bio Llc Compositions et procédés d'inhibition et de dégradation ciblées de protéines dans une cellule d'insecte
US12441708B2 (en) 2017-01-31 2025-10-14 Arvinas Operations, Inc. Cereblon ligands and bifunctional compounds comprising the same

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012075383A2 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals, Inc. Inhibiteurs de bromodomaines et leurs utilisations
WO2013184876A1 (fr) * 2012-06-06 2013-12-12 Constellation Pharmaceuticals, Inc. Inhibiteurs de bromo-domaine de benzo [c] isoxazoloazépines et applications associées

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012075383A2 (fr) * 2010-12-02 2012-06-07 Constellation Pharmaceuticals, Inc. Inhibiteurs de bromodomaines et leurs utilisations
US20120157428A1 (en) 2010-12-02 2012-06-21 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
WO2013184876A1 (fr) * 2012-06-06 2013-12-12 Constellation Pharmaceuticals, Inc. Inhibiteurs de bromo-domaine de benzo [c] isoxazoloazépines et applications associées

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12239711B2 (en) 2014-04-14 2025-03-04 Arvinas Operations, Inc. Cereblon ligands and bifunctional compounds comprising the same
US10730870B2 (en) 2015-03-18 2020-08-04 Arvinas Operations, Inc. Compounds and methods for the enhanced degradation of targeted proteins
US11512083B2 (en) 2015-03-18 2022-11-29 Arvinas Operations, Inc. Compounds and methods for the enhanced degradation of targeted proteins
US12264157B2 (en) 2015-03-18 2025-04-01 Arvinas Operations, Inc. Compounds and methods for the enhanced degradation of targeted proteins
US12171831B2 (en) 2015-08-19 2024-12-24 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of bromodomain- containing proteins
US10772962B2 (en) 2015-08-19 2020-09-15 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of bromodomain-containing proteins
US11554171B2 (en) 2015-08-19 2023-01-17 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of bromodomain-containing proteins
US12441708B2 (en) 2017-01-31 2025-10-14 Arvinas Operations, Inc. Cereblon ligands and bifunctional compounds comprising the same
US11220515B2 (en) 2018-01-26 2022-01-11 Yale University Imide-based modulators of proteolysis and associated methods of use
US11834460B2 (en) 2018-01-26 2023-12-05 Yale University Imide-based modulators of proteolysis and associated methods of use
WO2019199816A1 (fr) 2018-04-13 2019-10-17 Arvinas Operations, Inc. Ligands de céréblon et composés bifonctionnels les contenant
US11883393B2 (en) 2019-12-19 2024-01-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor
US12427144B2 (en) 2019-12-19 2025-09-30 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor
WO2023147149A1 (fr) 2022-01-31 2023-08-03 Constellation Pharmaceuticals, Inc. Formes cristallines anhydres de 2-((4s)-6-(4-chlorophényl)-1-méthyl-4h-benzo[c]isoxazolo[4,5-e]azépin-4-yl)acétamide
WO2025049555A1 (fr) 2023-08-31 2025-03-06 Oerth Bio Llc Compositions et procédés d'inhibition et de dégradation ciblées de protéines dans une cellule d'insecte

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