Crystalline form of nitrogen-containing tricyclic compound and use thereof
A crystalline form A of a nitrogen-containing tricyclic compound shown in formula (I), a pharmaceutical composition containing the crystalline form A, and the use of the crystalline form A or the pharmaceutical composition in the preparation of a medication for preventing, treating or relieving an FXR-mediated disease of a patient.
1 . A crystal form of a compound having Formula (I), wherein the crystal form is crystal form A,
wherein the crystal form A exhibits the following characteristic X-ray powder diffraction pattern comprising peaks expressed as 2θ at 11.11°±0.2°, 14.07°±0.2°, 20.37°±0.2°, 21.00°±0.2°, 22.59°±0.2°, 22.86°±0.2°, 23.32°±0.2°, 24.85°±0.2°, 25.57°±0.2°, 26.11°±0.2°, 26.30°±0.2°, 28.92°±0.2°, 38.74°±0.2°.
2 . The crystal form according to claim 1 , wherein the crystal form A exhibits the following characteristic X-ray powder diffraction pattern comprising peaks expressed as 2θ at 7.22°±0.2°, 8.65°±0.2°, 11.11°±0.2°, 12.61°±0.2°, 12.92°±0.2°, 13.86°±0.2°, 14.07°±0.2°, 14.37°±0.2°, 15.94°±0.2°, 16.68°±0.2°, 17.29°±0.2°, 18.95°±0.2°, 19.90°±0.2°, 20.37°±0.2°, 20.89°±0.2°, 21.00°±0.2°, 21.60°±0.2°, 22.24°±0.2°, 22.59°±0.2°, 22.86°±0.2°, 23.32°±0.2°, 24.28°±0.2°, 24.85°±0.2°, 25.29°±0.2°, 25.57°±0.2°, 26.11°±0.2°, 26.30°±0.2°, 26.77°±0.2°, 27.62°±0.2°, 27.94°±0.2°, 28.15°±0.2°, 28.92°±0.2°, 30.61°±0.2°, 31.13°±0.2°, 31.41°±0.2°, 32.14°±0.2°, 33.65°±0.2°, 34.39°±0.2°, 34.73°±0.2°, 35.54°±0.2°, 36.38°±0.2°, 36.80°±0.2°, 37.76°±0.2°, 38.24°±0.2°, 38.74°±0.2°, 39.48°±0.2°, 40.08°±0.2°, 40.59°±0.2°, 42.34°±0.2°, 43.30°±0.2°, 43.99°±0.2°, 44.53°±0.2°, 45.29°±0.2°, 46.10°±0.2°, 47.83°+0.2°, 48.64°±0.2°, 49.91°±0.2°, 51.75°+0.2°, 54.43°+0.2°, 58.46°±0.2°.
3 . The crystal form according to claim 1 , wherein the crystal form A has an X-ray powder diffraction pattern comprising peaks substantially as shown in FIG. 1 .
4 . A crystal form of a compound having Formula (I), wherein the crystal form is crystal form A,
wherein the crystal form A has a differential scanning calorimetry thermogram comprising an endothermic peak at 196.35° C.±3° C.
5 . The crystal form according to claim 4 , wherein the crystal form A has a differential scanning calorimetry thermogram substantially as shown in FIG. 2 .
6 . A pharmaceutical composition comprising the crystal form of claim 1 , and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
7 . A method for treating or lessening a disease mediated by FXR in a patient, comprising administering a pharmaceutically acceptable effective dose of the crystal form of claim 1 , wherein
the disease mediated by FXR is cardiovascular and cerebrovascular disease, a disease related to dyslipidemia, metabolic syndrome, hyperproliferative disease, fibrosis, inflammatory disease or a disease related to liver and gallbladder and wherein cardiovascular and cerebrovascular disease is atherosclerosis, acute myocardial infarction, venous occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral arterial occlusive disease, sexual dysfunction, stroke or thrombosis;
in the metabolic syndrome is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acid or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, or comorbidities of diabetes and abnormally high body mass index;
the hyperproliferative disease is hepatocellular carcinoma, colonic adenocarcinoma, polyposis, colonic adenocarcinoma, breast cancer, membrane adenocarcinoma, Barrett's esophagus cancer, or other forms of gastrointestinal or liver neoplastic diseases; and,
the fibrosis, inflammatory disease or disease related to liver and gallbladder is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, cystic fibrosis, drug-induced bile duct damage, gallstones, liver cirrhosis, hepatitis B, sebaceous gland disease, alcohol-induced liver cirrhosis, bile duct obstruction, gallstone disease, colitis, neonatal Jaundice, nuclear jaundice, or overgrowth of intestinal bacteria.
8 . A method for treating or lessening a disease mediated by FXR in a patient, comprising administering a pharmaceutically acceptable effective dose of the pharmaceutical composition of claim 6 , wherein
the disease mediated by FXR is cardiovascular and cerebrovascular disease, a disease related to dyslipidemia, metabolic syndrome, hyperproliferative disease, fibrosis, inflammatory disease or a disease related to liver and gallbladder,
the cardiovascular and cerebrovascular disease is atherosclerosis, acute myocardial infarction, venous occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral arterial occlusive disease, sexual dysfunction, stroke or thrombosis;
the metabolic syndrome is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acid or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, or comorbidities of diabetes and abnormally high body mass index;
the hyperproliferative disease is hepatocellular carcinoma, colonic adenocarcinoma, polyposis, colonic adenocarcinoma, breast cancer, membrane adenocarcinoma, Barrett's esophagus cancer, or other forms of gastrointestinal or liver neoplastic diseases; and
the fibrosis, inflammatory disease or disease related to liver and gallbladder is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, cystic fibrosis, drug-induced bile duct damage, gallstones, liver cirrhosis, hepatitis B, sebaceous gland disease, alcohol-induced liver cirrhosis, bile duct obstruction, gallstone disease, colitis, neonatal Jaundice, nuclear jaundice, or overgrowth of intestinal bacteria.
9 . A pharmaceutical composition comprising the crystal form of claim 4 , and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
10 . A method for treating or lessening a disease mediated by FXR in a patient, comprising administering a pharmaceutically acceptable effective dose of the crystal form of claim 4 , wherein
the disease mediated by FXR is cardiovascular and cerebrovascular disease, a disease related to dyslipidemia, metabolic syndrome, hyperproliferative disease, fibrosis, inflammatory disease or a disease related to liver and gallbladder;
the cardiovascular and cerebrovascular disease is atherosclerosis, acute myocardial infarction, venous occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral arterial occlusive disease, sexual dysfunction, stroke or thrombosis;
the metabolic syndrome is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acid or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, or comorbidities of diabetes and abnormally high body mass index;
the hyperproliferative disease is hepatocellular carcinoma, colonic adenocarcinoma, polyposis, colonic adenocarcinoma, breast cancer, membrane adenocarcinoma, Barrett's esophagus cancer, or other forms of gastrointestinal or liver neoplastic diseases; and
the fibrosis, inflammatory disease or disease related to liver and gallbladder is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, cystic fibrosis, drug-induced bile duct damage, gallstones, liver cirrhosis, hepatitis B, sebaceous gland disease, alcohol-induced liver cirrhosis, bile duct obstruction, gallstone disease, colitis, neonatal Jaundice, nuclear jaundice, or overgrowth of intestinal bacteria.
11 . A method for treating or lessening a disease mediated by FXR in a patient, comprising administering a pharmaceutically acceptable effective dose of the pharmaceutical composition of claim 9 , wherein
the disease mediated by FXR is cardiovascular and cerebrovascular disease, a disease related to dyslipidemia, metabolic syndrome, hyperproliferative disease, fibrosis, inflammatory disease or a disease related to liver and gallbladder;
the cardiovascular and cerebrovascular disease is atherosclerosis, acute myocardial infarction, venous occlusive disease, portal hypertension, pulmonary hypertension, heart failure, peripheral arterial occlusive disease, sexual dysfunction, stroke or thrombosis;
the metabolic syndrome is insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acid or glycerol in the blood, hyperlipidemia, obesity, hypertriglyceridemia, hypercholesterolemia, syndrome X, diabetic complications, atherosclerosis, hypertension, acute anemia, neutropenia, dyslipidemia, type II diabetes, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, dyslipidemia, or comorbidities of diabetes and abnormally high body mass index; and
the hyperproliferative disease is hepatocellular carcinoma, colonic adenocarcinoma, polyposis, colonic adenocarcinoma, breast cancer, membrane adenocarcinoma, Barrett's esophagus cancer, or other forms of gastrointestinal or liver neoplastic diseases; wherein the fibrosis, inflammatory disease or disease related to liver and gallbladder is non-alcoholic fatty liver, non-alcoholic steatohepatitis, cholestasis, liver fibrosis, primary biliary cirrhosis, primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, cystic fibrosis, drug-induced bile duct damage, gallstones, liver cirrhosis, hepatitis B, sebaceous gland disease, alcohol-induced liver cirrhosis, bile duct obstruction, gallstone disease, colitis, neonatal Jaundice, nuclear jaundice, or overgrowth of intestinal bacteria.