Patent Application
20240294521
The invention relates to crystalline forms, pharmaceutical compositions, and their use in the treatment of a disease or condition, e.g., cancer, and, in particular, those diseases or conditions (e.g., cancers) which are dependent on the activity of Ataxia-telangiectasia and RAD-3-related protein (ATR) kinase.
DNA damage occurs continually in cells as a result of environmental insults including ultraviolet radiation, X-rays and endogenous stress factors, such as reactive oxygen and hydrolysis of bases. Cancer cells are subject to a higher rate of DNA damage inherently induced by higher rates of DNA replication in these cells. Several DNA damage response (DDR) pathways have evolved in a highly coordinated manner to help repair DNA damage and to act as a cellular checkpoint to stop the replication of cells with damaged DNA, allowing for repair functions to occur before the damaged DNA is passed on to daughter cells. Each of the identified DNA repair pathways sense and repair distinct but overlapping types of DNA damage.
One major DDR protein that acts as a key cell cycle checkpoint is the ataxia telangiectasia mutated and rad3-related (ATR) kinase, related to the family of phosphoinositide 3-kinase-related protein kinases (PIKKs). ATR is activated by single stranded (ss) DNA lesions caused by stalled replication forks or during nucleotide excision repair but is also activated by double strand breaks following DNA end resection during homologous recombination.
ATR has been identified as an important cancer target since it is essential for dividing cells. Cancer cells that have high levels of replication stress due to oncogenic mutations, dysfunctional G1/S checkpoint control (e.g., loss of p53 function), defects in other DNA repair pathways (e.g., ATM) or that are subject to the effects of DNA damaging agents, e.g., radiation therapy or chemotherapeutic agents, are therefore more dependent on ATR for DNA repair and survival. Together, these results highlight a rationale for the selective sensitivity of proliferating tumor cells to ATR inhibition and the potential for a therapeutic window over healthy proliferating cells.
There is a need for new anti-cancer therapies and, in particular, for ATR inhibitor-based anti-cancer therapies.
The invention features crystalline forms, salts, pharmaceutical compositions, and their use in the treatment of a disease or condition (e.g., cancer) which is dependent on the activity of Ataxia-telangiectasia and RAD-3-related protein (ATR) kinase.
In one aspect, the invention provides a crystalline form of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 9.6°2θ±0.2°2θ and 15.8°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 8.9° 2θ±0.2°2θ and 20.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 19.8°2θ±0.2°2θ and 20.7°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 18.2°2θ±0.2°2θ and 19.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 17.8°2θ±0.2 °2θ, 22.2°2θ±0.2°2θ, and 23.9°2θ±0.2°2θ.
In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 243° C. to 247° C.
In another aspect, the invention provides a crystalline form of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 8.1°2θ±0.2°2θ and 20.3°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 9.1°2θ±0.2°2θ, 15.9°2θ±0.2°2θ, and 23.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 14.3°2θ±0.2°2θ, 16.8°2θ+0.2°2θ, and 19.3°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 16.1°2θ±0.2°2θ and 21.3°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 12.3°2θ±0.2°2θ.
In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 82° C. to 109° C. In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 245° C. to 248° C.
In another aspect, the invention provides a crystalline form of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 7.2°2θ±0.2°2θ, 20.4°2θ±0.2°2θ, and 29.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 10.2 °2θ±0.2°2θ, 14.4°2θ±0.2°2θ, and 17.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 17.6°20±0.2 °2θ and 27.0°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 12.5°2θ±0.2°2θ and 30.9°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 15.4°2θ±0.2°2θ and 18.3°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 19.7 °2θ±0.2°2θ.
In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 245° C. to 249° C. In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 111° C. to 154° C.
In another aspect, the invention provides a crystalline form of a hydrogen sulfate salt of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 13.0°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, and 25.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 14.8 °2θ±0.2°2θ and 16.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 20.1°2θ±0.2°2θ and 24.5 °2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 14.3°2θ±0.2°2θ, 17.9°2θ±0.2°2θ, and 18.2°2θ±0.2 °2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 19.3°2θ±0.2°2θ and 21.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 24.6°2θ±0.2°2θ and 25.6°2θ±0.2°2θ.
In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 183° C. to 218° C.
In another aspect, the invention provides a crystalline of form of a hydrate of a hydrogen sulfate salt of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 5.9°2θ±0.2°2θ and 11.8°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 14.9°2θ±0.2°2θ and 20.6 °2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 17.2°2θ±0.2°2θ and 21.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 13.3°2θ±0.2°2θ, 14.2°2θ±0.2°2θ, and 22.0°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 16.7°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 24.1°2θ±0.2°2θ and 29.5 °2θ±0.2°2θ.
In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 91° C. to 116° C.
In another aspect, the invention provides a crystalline form of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having a peak at 5.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 2.0°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 8.5°2θ±0.2 °2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 16.2°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 19.0°2θ±0.2°2θ and 21.1°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 12.0°2θ±0.2°2θ and 17.1°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 9.5°2θ±0.2°2θ and 14.7°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 18.7 °2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 18.4°2θ±0.2°2θ.
In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 252° C. to 253° C.
In another aspect, the invention provides a crystalline of form of a hemi-sulfate salt of a compound of formula (I):
wherein the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 8.3°2θ±0.2°2θ and 15.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 15.1°2θ±0.2°2θ and 23.4 °2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 17.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 17.9°2θ±0.2 °2θ.
In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 171° C. to 183° C.
In a further aspect, the invention provides a hydrogen sulfate salt of a compound of formula (I):
or a hydrate thereof.
In yet further aspect, the invention provides a hemi-sulfate salt of a compound of formula (I):
In still further aspect, the invention provides a sulfate salt of a compound of formula (I):
In yet another aspect, the invention provides a pharmaceutical composition including any one of the crystalline forms described herein or any one of the salts described herein.
In a further aspect, the invention provides a method of inhibiting ATR kinase in a cell expressing ATR kinase, the method including contacting the cell with an effective amount of any one of the crystalline forms described herein, the pharmaceutical composition described herein, or any one of the salts described herein. In some embodiments, the cell is in a subject.
In yet a further aspect, the invention provides a method of treating a subject in need thereof comprising administering to the subject an effective amount of any one of the crystalline forms described herein, the pharmaceutical composition described herein, or any one of the salts described herein. In some embodiments, the subject is suffering from, and is in need of a treatment for, a disease or condition having the symptom of cell hyperproliferation (e.g., a cancer (e.g., a carcinoma (e.g., medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum), sarcoma (e.g., chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, telang iectaltic sarcoma), adenocarcinoma, leukemia (e.g., nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia), or melanoma (e.g., acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, superficial spreading melanoma))).
In some embodiments, the cancer is prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, ampullary cancer, colorectal cancer, or pancreatic cancer.
In some embodiments, the cancer is Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
In some embodiments, the subject is suffering from, and is in need of a treatment for, a pre-malignant condition.
The term “adenocarcinoma,” as used herein, represents a malignancy of the arising from the glandular cells that line organs within an organism. Non-limiting examples of adenocarcinomas include non-small cell lung cancer, prostate cancer, pancreatic cancer, esophageal cancer, and colorectal cancer.
The term “ATR kinase,” as used herein, refers to Ataxia-telangiectasia and RAD-3-related protein kinase.
The term “cancer,” as used herein, refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, carcinomas and sarcomas. Non limiting examples of cancers that may be treated with a compound or method provided herein include prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, ampullary cancer, colorectal cancer, and pancreatic cancer.
Additional non-limiting examples may include, Hodgkin's disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, and prostate cancer.
The term “carcinoma,” as used herein, refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. Non limiting examples of carcinomas that may be treated with a compound or method provided herein include, e.g., medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.
The term “crystalline form B,” as used herein, refers to a crystalline form of a compound of formula (1):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 9.6°2θ±0.2°2θ and 15.8°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by a powder x-ray diffraction pattern having peaks at 8.9°2θ±0.2°2θ and 20.5°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by a powder x-ray diffraction pattern having peaks at 19.8°2θ±0.2°2θ and 20.7°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by a powder x-ray diffraction pattern having peaks at 18.2°2θ±0.2°2θ and 19.2°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by a powder x-ray diffraction pattern having peaks at 17.8°2θ±0.2°2θ, 22.2°2θ±0.2°2θ, and 23.9°2θ±0.2°2θ. In some embodiments, crystalline form B is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 243° C. to 247° C.
The term “crystalline form C,” as used herein, refers to a crystalline form of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 8.1°20±0.2°20 and 20.3°20±0.2 026. In some embodiments, crystalline form C is characterized by a powder x-ray diffraction pattern having peaks at 9.1°2θ±0.2°2θ, 15.9°2θ±0.2°2θ, and 23.6°2θ±0.2°2θ. In some embodiments, crystalline form C is characterized by a powder x-ray diffraction pattern having peaks at 14.3°2θ±0.2°2θ, 16.8°2θ±0.2°2θ, and 19.3 °2θ±0.2°2θ. In some embodiments, crystalline form C is characterized by a powder x-ray diffraction pattern having peaks at 16.1°2θ±0.2°2θ and 21.3°2θ±0.2°2θ. In some embodiments, crystalline form C is characterized by a powder x-ray diffraction pattern having a peak at 12.3°2θ±0.2°2θ. In some embodiments, crystalline form C is characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 82° C. to 109° C. In some embodiments, crystalline form C is characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 245° C. to 248° C.
The term “crystalline form F,” as used herein, refers to a crystalline form of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 7.2°2θ±0.2°2θ, 20.4°2θ±0.2°2θ, and 29.4°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by a powder x-ray diffraction pattern having peaks at 10.2°2θ±0.2 °2θ, 14.4°2θ±0.2°2θ, and 17.2°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by a powder x-ray diffraction pattern having peaks at 17.6°20±0.2°20 and 27.0 °2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by a powder x-ray diffraction pattern having peaks at 12.5°2θ±0.2°2θ and 30.9°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by a powder x-ray diffraction pattern having peaks at 15.4°2θ±0.2°2θ and 18.3°2θ±0.2°2θ. In some embodiments, crystalline form F is further characterized by a powder x-ray diffraction pattern having a peak at 19.7°2θ±0.2°2θ.
In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 245° C. to 249° C. In some embodiments, crystalline form F is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 111° C. to 154° C.
The term “crystalline form M,” as used herein, refers to a crystalline form of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having a peak at 5.5°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 2.0°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by a powder x-ray diffraction pattern having a peak at 8.5°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by a powder x-ray diffraction pattern having a peak at 16.2°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by a powder x-ray diffraction pattern having peaks at 19.0°2θ±0.2°2θ and 21.1 °2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by a powder x-ray diffraction pattern having peaks at 12.0°2θ±0.2°2θ and 17.1°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by a powder x-ray diffraction pattern having peaks at 9.5°2θ±0.2°2θ and 14.7°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by a powder x-ray diffraction pattern having a peak at 18.7°2θ±0.2 °2θ. In some embodiments, crystalline form M is further characterized by a powder x-ray diffraction pattern having a peak at 18.4°2θ±0.2°2θ. In some embodiments, crystalline form M is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 252° C. to 253° C.
The term “crystalline hydrogen sulfate form A,” as used herein, refers to a crystalline form of a hydrogen sulfate salt of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 13.0°2θ±0.2°2θ, 19.7°2θ±0.2°2θ, and 25.6°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form A is further characterized by a powder x-ray diffraction pattern having peaks at 14.8°2θ±0.2°2θ and 16.5°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form A is further characterized by a powder x-ray diffraction pattern having peaks at 20.1°2θ±0.2 °2θ and 24.5°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form A is further characterized by a powder x-ray diffraction pattern having peaks at 14.3°2θ±0.2°2θ, 17.9°2θ±0.2°2θ, and 18.2°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form A is further characterized by a powder x-ray diffraction pattern having peaks at 19.3°2θ±0.2°2θ and 21.4°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form A is further characterized by a powder x-ray diffraction pattern having peaks at 24.6°2θ±0.2 026 and 25.6 °2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form A is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 183° C. to 218° C.
The term “crystalline hydrogen sulfate form B,” as used herein, refers to a crystalline form of a hydrate of a hydrogen sulfate salt of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 5.9°2θ±0.2°20 and 11.8°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form B is further characterized by a powder x-ray diffraction pattern having peaks at 14.9°2θ±0.2°2θ and 20.6°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form B is further characterized by a powder x-ray diffraction pattern having peaks at 17.2°2θ±0.2°2θ and 21.2 °2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form B is further characterized by a powder x-ray diffraction pattern having peaks at 13.3°2θ±0.2°2θ, 14.2°2θ±0.2°2θ, and 22.0°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form B is further characterized by a powder x-ray diffraction pattern having a peak at 16.7°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form B is further characterized by a powder x-ray diffraction pattern having peaks at 24.1°2θ±0.2°2θ and 29.5°2θ±0.2°2θ. In some embodiments, crystalline hydrogen sulfate form B is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 91° C. to 116° C.
The term “crystalline sulfate form A,” as used herein, refers to a crystalline form of a hemi-sulfate salt of a compound of formula (I):
where the crystalline form is characterized by a powder x-ray diffraction pattern having peaks at 8.3°2θ±0.2°20 and 15.6°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having peaks at 15.1°2θ±0.2°2θ and 23.4 °2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 17.4°2θ±0.2°2θ. In some embodiments, the crystalline form is further characterized by a powder x-ray diffraction pattern having a peak at 17.9°2θ±0.2 °2θ. In some embodiments, the crystalline form is further characterized by a differential scanning calorimetry thermogram having an endothermic event onset at 171° C. to 183° C.
“Disease” or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
The term “leukemia,” as used herein, refers broadly to progressive, malignant diseases of the blood-forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood-leukemic or aleukemic (subleukemic). Exemplary leukemias that may be treated with a compound or method provided herein include, e.g., acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.
The term “lymphoma,” as used herein, refers to a cancer arising from cells of immune origin. Non-limiting examples of T and B cell lymphomas include non-Hodgkin lymphoma and Hodgkin disease, diffuse large B-cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue (MALT) lymphoma, small cell lymphocytic lymphoma-chronic lymphocytic leukemia, Mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma-Waldenstrom macroglobulinemia, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL)/follicular T-cell lymphoma (FTCL), anaplastic large cell lymphoma (ALCL), enteropathy-associated T-cell lymphoma (EATL), adult T-cell leukemia/lymphoma (ATLL), or extranodal NK/T-cell lymphoma, nasal type.
The term “melanoma,” as used herein, is taken to mean a tumor arising from the melanocytic system of the skin and other organs. Melanomas that may be treated with a compound or method provided herein include, e.g., acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.
The term “pharmaceutical composition,” as used herein, represents a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein.
The term “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier,” as used interchangeably herein, refers to any ingredient other than the compounds described herein (e.g., a vehicle capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.
The term “pre-malignant” or “pre-cancerous,” as used herein, refers to a condition that is not malignant but is poised to become malignant. Non-limiting examples of pre-malignant conditions include myelodysplastic syndrome, polyps in the colon, actinic keratosis of the skin, dysplasia of the cervix, metaplasia of the lung, and leukoplakia.
The term “sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance. Non-limiting examples of sarcomas that may be treated with a compound or method provided herein include, e.g., a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.
The term “subject,” as used herein, represents a human or non-human animal (e.g., a mammal) that is suffering from, or is at risk of, disease or condition, as determined by a qualified professional (e.g., a doctor or a nurse practitioner) with or without known in the art laboratory test(s) of sample(s) from the subject. Preferably, the subject is a human. Non-limiting examples of diseases and conditions include diseases having the symptom of cell hyperproliferation, e.g., a cancer.
“Treatment” and “treating,” as used herein, refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent, or cure a disease or condition. This term includes active treatment (treatment directed to improve the disease or condition); causal treatment (treatment directed to the cause of the associated disease or condition); palliative treatment (treatment designed for the relief of symptoms of the disease or condition); preventative treatment (treatment directed to minimizing or partially or completely inhibiting the development of the associated disease or condition); and supportive treatment (treatment employed to supplement another therapy).
In general, the invention provides crystalline forms of a compound of formula (I) as well as its hydrogen sulfate, hemi-sulfate, and sulfate salts. The compound of formula (I) is of the following structure:
The crystalline form of the compound of formula (I) may be, e.g., crystalline form B, crystalline form C, crystalline form F, crystalline form M. The crystalline form of the hydrogen sulfate salt of the compound of formula (I) may be, e.g., crystalline hydrogen sulfate form A. The crystalline form of the hydrate of the hydrogen sulfate salt of the compound of formula (I) may be, e.g., crystalline hydrogen sulfate form B. The crystalline form of the hemi-sulfate salt of the compound of formula (I) may be, e.g., crystalline sulfate form A.
As described in the examples, crystalline form B was found to be crystalline with block-like crystals (see
Crystalline form C was crystalline with needle/plate-like morphology (
Crystalline form F was found to be crystalline with cube-like morphology (see
Crystalline form M was found to be crystalline (by XRPD,
Crystalline hydrogen sulfate form A was found to be crystalline with square-like morphology (
Crystalline hydrogen sulfate form B was found to be crystalline with needle/thin plate-like morphology (
Crystalline sulfate form A was found to be crystalline with elongated particles (
The invention also provides a hydrogen sulfate salt of a compound of formula (I) or a hydrate thereof. The invention further provides a hemi-sulfate salt of a compound of formula (I). The invention further provides a sulfate salt of a compound of formula (I). Advantageously, the salts described herein (e.g., the hydrogen sulfate salt) may possess superior physicochemical properties for the purpose of pharmaceutical development.
Methods of treating a disease or condition having the symptom of cell hyperproliferation (e.g., a cancer) and methods for ATR kinase have been described in WO 2020/087170, the disclosure of which is incorporated by reference herein in its entirety.
A method of inhibiting ATR kinase in a cell (e.g., a cell in a subject) expressing ATR kinase may include contacting the cell with an effective amount of a crystalline form or a pharmaceutical composition containing the crystalline form disclosed herein.
A method of treating a subject in need thereof (e.g., a subject suffering from, and is in need of a treatment for, a disease or condition having the symptom of cell hyperproliferation (e.g., a cancer (e.g., a carcinoma, sarcoma, adenocarcinoma, leukemia, or melanoma) and/or a pre-malignant condition)) may include administering to the subject an effective amount of a crystalline form or a pharmaceutical composition containing the crystalline form disclosed herein.
Non-limiting examples of carcinomas include medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epidermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, and carcinoma villosum.
In some embodiments, the crystalline form used in the methods described herein is a crystalline form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline form C. In some embodiments, the crystalline form used in the methods described herein is a crystalline form F. In some embodiments, the crystalline form used in the methods described herein is a crystalline form M. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline sulfate form A.
Non-limiting examples of leukemias include nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia. In some embodiments, the crystalline form used in the methods described herein is a crystalline form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline form C. In some embodiments, the crystalline form used in the methods described herein is a crystalline form F. In some embodiments, the crystalline form used in the methods described herein is a crystalline form M. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline sulfate form A.
Non-limiting examples of melanomas include acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma. In some embodiments, the crystalline form used in the methods described herein is a crystalline form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline form C. In some embodiments, the crystalline form used in the methods described herein is a crystalline form F. In some embodiments, the crystalline form used in the methods described herein is a crystalline form M. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline sulfate form A.
Non-limiting examples of cancer include prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, ampullary cancer, colorectal cancer, or pancreatic cancer. In some embodiments, the crystalline form used in the methods described herein is a crystalline form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline form C. In some embodiments, the crystalline form used in the methods described herein is a crystalline form F. In some embodiments, the crystalline form used in the methods described herein is a crystalline form M. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline sulfate form A.
Other non-limiting examples of cancer include Hodgkin's Disease, Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, cancer, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, or papillary thyroid cancer. In some embodiments, the crystalline form used in the methods described herein is a crystalline form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline form C. In some embodiments, the crystalline form used in the methods described herein is a crystalline form F. In some embodiments, the crystalline form used in the methods described herein is a crystalline form M. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form A. In some embodiments, the crystalline form used in the methods described herein is a crystalline hydrogen sulfate form B. In some embodiments, the crystalline form used in the methods described herein is a crystalline sulfate form A.
A crystalline form described herein (e.g., a crystalline form of a compound of formula (I)) may be formulated into a pharmaceutical composition for administration to human subjects in a biologically compatible form suitable for administration in vivo. A pharmaceutical composition typically includes an active agent as described herein and a physiologically acceptable excipient (e.g., a pharmaceutically acceptable excipient). Formulation principles for the compound of formula (I) have been described in WO 2020/087170, the disclosure of which is incorporated by reference herein in its entirety. The crystalline forms described herein are especially beneficial for solid pharmaceutical compositions, e.g., solid dosage forms (e.g., tablets, powders, lozenges, sachets, cachets, and soft and hard gelatin capsules).
The compound of formula (I) may be administered, for example, by oral, parenteral, buccal, sublingual, nasal, or rectal administration, and the pharmaceutical compositions formulated accordingly. Preferably, a crystalline form of the compound of formula (I) is administered orally.
Suitable pharmaceutical carriers, as well as pharmaceutical necessities for use in pharmaceutical formulations, are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), a well-known reference text in this field, and in the USP/NF (United States Pharmacopeia and the National Formulary).
The following examples are meant to illustrate the invention. They are not meant to limit the invention in anyway.
Abbreviations Explanations
Methods. During the preparations described in the examples, the methods described herein below have been used to monitor the experimental setups and products obtained.
Malvern Panalytical
Preparation of the compound of formula (I) is described in WO 2020/087170, the disclosure of which is incorporated by reference herein in its entirety.
Preparation of the compound of formula (I) as crystalline form B. Crystalline form B of the compound of formula (I) was obtained by suspending the compound of formula (I) (50 mg, crystalline form A) in EtOAc, then adding methanol to dissolve. The solvent was evaporated to obtain crystals of crystalline form B. Table 1 summarizes the physical and chemical characteristics for crystalline form B.
The compound of formula (I) (crystalline form A) was suspended in acetone-water, and after evaporation, crystalline form C was obtained after vacuum drying at room temperature overnight. Crystalline form C was also isolated from aqueous ethanol. The physical and chemical characteristics of crystalline form C are summarized in Table 2.
The compound of formula (I) (crystalline form A) was suspended in aqueous ethanol at room temperature, which afforded large, long rod/prism crystals of crystalline form C which later converted to cube-like crystals of crystalline form F shown in
Furthermore, to better understand behaviors of crystalline form F upon heating, samples were generated by heating crystalline form F to 170° C., 190° C., and 195° C., using a TG instrument, and were analyzed by XRPD. Prior to selection of these temperature points, an open-pan DSC was run (
Table 4 summarizes the crystalline free base forms.
Table 5 summarizes other solvents from which various crystalline forms were isolated.
Crystalline form K was obtained after suspending 50 mg of the compound of formula (I) (crystalline form A) in DCM for 3 days. The sample was oven dried overnight and XRPD was collected on the solid. The material was a DCM solvate of the free-base compound before oven drying, and confirmed by SCXRD. The XRPD changed after oven drying at 48° C. (
Crystalline form D was obtained after suspending 50 mg of the compound of formula (I) (crystalline form A) in THF for 3 days. The sample was dried overnight and XRPD was collected on the solid (
Crystalline form E was obtained after suspending 50 mg of the compound of formula (I) (crystalline form A) in 2-MeTHF for 3 days. The sample was dried overnight and XRPD was collected on the solid (
Crystalline form M was obtained after heating crystalline form H (which was isolated from isopropyl acetate) to 248° C.
Preparation of crystalline hydrogen sulfate form A. Crystalline hydrogen sulfate form A (neat) was prepared using crystalline form H (82 mg) in EtOH. Sulfuric acid was added to the suspension at 1:1.5 (compound of formula (1):H2SO4) molar ratio, and precipitate was observed. After 18 hours of stirring, the solids were isolated and oven vacuum dried at room temperature. Table 6 summarizes the physical and chemical characteristics for crystalline hydrogen sulfate form A.
Preparation of crystalline hydrogen sulfate form B. Approximately 1.0 g of the compound of formula (I) (97.3% pure by quantitative NMR; 99.9% pure by HPLC (A); 0.9% water (w/w, as determined by Karl Fisher titration); 1.9% residual EtOAc (w/w)) was added to a 20 mL vial followed by the addition of 2 mL of THF:water (9:1 v/v). A white slurry formed and was left to stir at 45° C. for 1 h. A solution of concentrated sulfuric acid (95-98%) was then prepared in THF:water (9:1 v/v) with concentration of 98.0 mg/mL. A total of 3.1 equiv of sulfuric acid (total volume of 8.0 mL from prepared solution) was then added in eight equal portions, dropwise, over 2 h to the slurry of compound of formula (I). After each addition, the sample was left to stir for 5 min then the pH of the slurry was measured. The pH value became above saturation level of the pH probe after the first addition. The sample was seeded with crystalline hydrogen sulfate form B (spatula tip) after the addition of the 6th portion. When all the required volume of sulfuric acid was added, the sample was left to stir at 45° C. for 1 h then at RT overnight. The observations from the scale-up experiment are included in Table 15. After overnight stirring, the sample was filtered for 3 min and washed with 2×1 vol. of THF:water (9:1 v/v). An aliquot was collected from the wet cake and XRPD analysis confirmed the solid state to be crystalline hydrogen sulfate form B. The filtered solids were then transferred to a vacuum oven and left to dry at 50° C. for 5 h under active vacuum (−29.5 inHg). The sample was then transferred to an oven at RT and left to dry under active vacuum for 5 h, then under static vacuum for 3 days. XRPD analysis confirmed that crystalline hydrogen sulfate form B was stable after drying. The yield after drying was 79.6%, w/w (with respect to the mono-sulfate mono-hydrate salt). The sulfate content determined for the sample was 19.5 wt %, which is slightly higher than the value of 18.6 wt % expected from a mono-sulfate mono-hydrate salt. The stoichiometry of crystalline hydrogen sulfate form B determined from the sulfate content was 1:1.05 API: mono-sulfate mono-hydrate. Table 7 summarizes the physical and chemical characteristics for crystalline hydrogen sulfate form B.
Preparation of crystalline sulfate form A. Crystalline sulfate form A was prepared from the compound of formula (I) stirred in ethanol with 0.55, 0.75, 1.0, and 1.5 equiv of sulfuric acid (see
Crystalline sulfate form A showed slightly reduced crystallinity after drying under active vacuum (−29.5 inHg) for 3 h at 50° C. TG thermogram of crystalline sulfate form A showed two mass losses of 2.2 wt. % between 50 and 160° C., and 3.9 wt. % between 160 and 210° C. (
Example 3. Analysis of the Crystalline Forms of the Compound of Formula (I)
The XRPD peak list for crystalline form B is provided in Table 8, the XRPD peak list for crystalline form C is provided in Table 9, the XRPD peak list for crystalline form F is provided in Table 10, the XRPD peak list for crystalline form M is provided in Table 10A, the XRPD peak list for crystalline hydrogen sulfate form A is provided in Table 11, the XRPD peak list for crystalline hydrogen sulfate form B is provided in Table 12, and the XRPD peak list for crystalline sulfate form A is provided in Table 12A. The XRPD diffractogram for crystalline form B is provided in
The PLM image for crystalline form B isolated from ethyl acetate is shown in
An appropriate amount of crystalline form B and crystalline form F were each weighed into 4 mL vials, and water was added to the solids with increments of 0.1 mL until 0.7 mL was added to each vial. The samples were shaken at 25° C., 200 rpm. XRPD (taken after the crystalline forms were mixed with water, and after 1 day suspended in water) and PLM (after 5 days) were recorded. Crystalline form B converted to crystalline form C in water as confirmed by PLM (
During preparation of crystalline hydrogen sulfate form A in EtOH, the suspension was monitored by PLM (
Crystalline form F (56 mg) was weighed in a 20 mL vial and 0.5% methylcellulose (v/v) (400 cps)/0.02% sodium lauryl sulfate (v/v) (14 mL) was added to the solid and stirred at room temperature (500 rpm). Another vial was prepared with the same experimental conditions but with ground crystalline form F instead. The samples were evaluated at designated time points and PLM images were recorded up to 7 days. No form change was obtained after 7 days, as also confirmed by XRPD (
Crystalline hydrogen sulfate form A was used for form stability studies in 0.5% methylcellulose (v/v) (400 cps)/0.02% sodium lauryl sulfate (v/v) with citrate buffer (pH 4.5) with a concentration of 0.1 mg/mL, 0.2 mg/mL, 0.5 mg/mL and 1 mg/mL with and without stirring. HPLC purity was obtained for the solutions at 3 and 7 days. The purity of the solutions remained in the range 99.8-99.9% (Table 14).
An additional sample of crystalline hydrogen sulfate form A in the same buffered formulation was prepared with a concentration of 1 mg/ml and stirred at 500 rpm at room temperature. The sample was monitored every hour for form assessment. The solution was nearly clear at the first 3 hours. Precipitation of the free form, crystalline form C was observed after 3 hours. XRPD analysis of the precipitate confirmed crystalline form C had formed (
Crystalline Form F and Crystalline Hydrogen Sulfate Form A. 7-day, 14-day, and 4-week stability assessments of crystalline form F and crystalline hydrogen sulfate form A were performed as follows: samples of each form were weighed (about 40 mg) into separate vials and placed under 25° C./60% RH and 400C/75% RH. The forms were evaluated with a closed vial and an open vial. The XRPD of the samples after 1, 2 and 4 weeks of exposure matched with the starting materials (t=0) patterns (
Crystalline Hydrogen Sulfate Form B. The solid-form stability of crystalline hydrogen sulfate form B was tested after one-week exposure to 75% RH at 40° C. Approximately 30 mg of crystalline hydrogen sulfate form B was weighed into a 4 mL vial and covered with a KIMWIPE. The vial was placed inside a 20 mL scintillation vial containing a saturated sodium chloride (NaCl) solution producing 75% RH at 40° C. The vial was sealed with PARAFILM and placed on a hotplate and left undisturbed for one week. After one week, no significant changes were observed (confirmed through XRPD analysis) and the sample remained a flowable, white powder.
Crystalline Sulfate Form A. The solid-form stability of crystalline sulfate form A was tested after one-week exposure to 75% RH at 40° C. Approximately 30 mg of crystalline sulfate form A was weighed into a 4 mL vial and covered with a KIMWIPE. The vial was placed inside a 20 mL scintillation vial containing a saturated sodium chloride (NaCl) solution producing 75% RH at 40° C. The vial was sealed with PARAFILM and placed on a hotplate and left undisturbed for one week. After one week, no significant changes were observed and the sample remained a flowable, white powder. XRPD analysis showed that crystalline sulfate form A changed to a mixture of crystalline sulfate form A+another crystalline form of a sulfate salt of the compound of formula (I) after one week at 75% RH (
Solid state screening of the compound of formula (I) was conducted by slurry crystallization. The solubility of crystalline form A in 25 single solvents was measured at room temperature (Table 17). About 20 mg of the starting material was weighed into 2 mL vials, and solvents were added in increments of 0.2 mL. Crystalline form A had a low solubility in the solvents tested except for DMF, DMSO, NMP and DMAc (>100 mg/mL). XRPD data were collected on the resulting solids after 7 days.
Salt screening of the compound of formula (I) was conducted with multiple solvents (Table 18). The compound of formula (I) (about 41 mg in each experiment) was mixed with corresponding amounts of each acid to make 1:1 molar ratio. The samples were stirred overnight at room temperature, and XRPD was recorded on the resulting solids after oven drying.
Thirteen salt hits of the compound of formula (1) obtained in the salt screen were scaled up using 82 mg of starting material (crystalline form A) in the appropriate solvents. 8 salts were repeated compared to previous data. HCl-2, SA-4, BSA-3, MSA-1 and MSA-2 were not reproduced. Screening conditions with H2SO4 were repeated and 4 salt hits were obtained. 5 salts (bold in Table 19) were selected based on crystallinity, repeatability, physical stability (drying, thermal (by DSC and TG), ambient moisture-uptake), and MSA and BSA excluded (see Table 19). An overlay of XRPD diffractograms of the selected salts are shown
Various modifications and variations of the described invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.
Other embodiments are in the claims.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CA2022/050892 | 6/3/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63197131 | Jun 2021 | US |
