WO2022220518A1 - 5-[(1,1-디옥시도-4-티오몰포리닐)메틸]-2-페닐-n-(테트라하이드로-2h-피란-4-일)-1h-인돌-7-아민 황산염 및 이의 신규 결정형 - Google Patents
5-[(1,1-디옥시도-4-티오몰포리닐)메틸]-2-페닐-n-(테트라하이드로-2h-피란-4-일)-1h-인돌-7-아민 황산염 및 이의 신규 결정형 Download PDFInfo
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- 230000002503 metabolic effect Effects 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- FWFGVMYFCODZRD-UHFFFAOYSA-N oxidanium;hydrogen sulfate Chemical compound O.OS(O)(=O)=O FWFGVMYFCODZRD-UHFFFAOYSA-N 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
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- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
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- CBXWGGFGZDVPNV-UHFFFAOYSA-N so4-so4 Chemical compound OS(O)(=O)=O.OS(O)(=O)=O CBXWGGFGZDVPNV-UHFFFAOYSA-N 0.000 description 1
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- 238000001694 spray drying Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
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- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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- 239000002341 toxic gas Substances 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
- C12N5/0657—Cardiomyocytes; Heart cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
Definitions
- the present invention relates to a compound of formula 1, 5-[(1,1-dioxido-4-thiomorpholinyl)methyl]-2-phenyl- N- (tetrahydro- 2H -pyran-4-yl) It relates to the sulfate salt of -1H -indole-7-amine and its crystalline form.
- Different salts or crystalline forms of the same drug may exhibit different solid state physical properties, such as hygroscopicity, behavior against compression, stability during storage, and flowability of milled solids. These properties in turn influence their suitability as active pharmaceutical substances for the commercial production of certain solid states. For example, flowability affects the ease of handling a substance during processing into a pharmaceutical product. If the particles of the powdered compound do not flow readily, the formulation specialist will have to take that fact into account in developing the formulation of tablets or capsules, which may contain lubricating agents such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate. may require use.
- lubricating agents such as colloidal silicon dioxide, talc, starch or tribasic calcium phosphate. may require use.
- dissolution rate is not only taken into account in formulating syrups, elixirs and other liquid medicaments, but may also vary the outcome of treatment.
- rate of dissolution of an active ingredient in a patient's gastric juice will vary the outcome of treatment as it places an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream.
- the compound of Formula 1 5-[(1,1-dioxido-4-thiomorpholinyl)methyl]-2-phenyl- N- (tetrahydro- 2H -pyran-4-yl)-1 H -indole-7-amine is a compound disclosed through International Patent Publication No. WO2009-025478, and is a substance known to exhibit preventive or therapeutic and ameliorating effects on cell necrosis and related diseases.
- the compound of Formula 1 has remarkably low solubility in water as well as in various other solvents.
- the present inventors have continuously conducted research on the salt form of the compound of Formula 1 in order to improve the solubility of the compound of Formula 1. As a result, the present inventors found the best physicochemical salt of the compound of Formula 1, and confirmed various crystalline forms of the salt and its properties.
- the present invention also provides various crystalline forms of the sulfate salts of the compounds of formula (1).
- the present invention also provides a process for preparing a sulfate of the compound of formula (1) and a process for preparing a crystalline form of the sulfate of the compound of formula (1).
- Another object of the present invention is to provide a pharmaceutical composition comprising the sulfate of the compound of Formula 1 or a crystalline form thereof as an active ingredient.
- the present invention also seeks to provide the use of a sulfate salt of a compound of formula 1 or a crystalline form thereof.
- the present invention provides a sulfate salt of the compound of formula (1) having excellent physicochemical properties among various salts of the compound of formula (1).
- the sulfate of the compound of Formula 1 may be represented by Formula 2 below.
- the compound of Formula 1 of the present invention may be referred to as “Compound 1” or “Compound 1”.
- the present invention also confirmed various crystalline forms of the sulfate salt of the compound of Formula 1, and 8 crystalline forms (crystalline forms I, II, III, IV, V, VI, VII, VIII) having different crystal structures were identified.
- the crystalline form I of the sulfate salt of the compound of Formula 1 is from 6.63 ⁇ 0.2, 17.34 ⁇ 0.2, 17.76 ⁇ 0.2, 18.70 ⁇ 0.2, 18.93 ⁇ 0.2, 20.24 ⁇ 0.2, 20.83 ⁇ 0.2, 21.56 ⁇ 0.2, 24.66 ⁇ 0.2 and 29.00 ⁇ 0.2 Characterized by an X-ray powder diffraction pattern having 4 or more, such as 4, 5, 6, 7, 8, 9, 10 or more diffraction peaks at a selected 2 [ ⁇ ] value. do.
- the X-ray powder diffraction pattern has a diffraction peak at a value of 2 [ ⁇ ] selected from 6.63 ⁇ 0.2, 17.34 ⁇ 0.2, 17.76 ⁇ 0.2, 18.93 ⁇ 0.2, 20.24 ⁇ 0.2, and 24.66 ⁇ 0.2 .
- the crystalline form II of the sulfate salt of the compound of Formula 1 was obtained from 6.57 ⁇ 0.2, 13.91 ⁇ 0.2, 16.05 ⁇ 0.2, 17.36 ⁇ 0.2, 18.41 ⁇ 0.2, 19.16 ⁇ 0.2, 19.36 ⁇ 0.2, 20.11 ⁇ 0.2, 20.77 ⁇ 0.2 and 24.31 ⁇ 0.2. Characterized by an X-ray powder diffraction pattern having 4 or more, such as 4, 5, 6, 7, 8, 9, 10 or more diffraction peaks at a selected 2 [ ⁇ ] value. do.
- the X-ray powder diffraction pattern has a diffraction peak at a value of 2 [ ⁇ ] selected from 6.57 ⁇ 0.2, 17.36 ⁇ 0.2, 19.16 ⁇ 0.2, 19.36 ⁇ 0.2, and 20.11 ⁇ 0.2.
- the crystalline form III of the sulfate salt of the compound of Formula 1 is 7.66 ⁇ 0.2, 16.32 ⁇ 0.2, 17.53 ⁇ 0.2, 18.05 ⁇ 0.2, 18.28 ⁇ 0.2, 18.95 ⁇ 0.2, 19.49 ⁇ 0.2, 19.91 ⁇ 0.2, 21.44 ⁇ 0.2, 22.24 ⁇ 0.2, 4 or more, such as 4, 5, 6, 7, at 2 [ ⁇ ] values selected from 23.52 ⁇ 0.2, 24.29 ⁇ 0.2, 25.10 ⁇ 0.2, 27.37 ⁇ 0.2, 29.07 ⁇ 0.2 and 31.90 ⁇ 0.2; Characterized by an X-ray powder diffraction pattern having 8, 9, 10 or more diffraction peaks.
- the X-ray powder diffraction pattern is characterized in that it has a diffraction peak at a value of 2 [ ⁇ ] selected from 7.66 ⁇ 0.2, 17.53 ⁇ 0.2, 18.28 ⁇ 0.2, and 19.91 ⁇ 0.2.
- the crystalline form IV of the sulfate salt of the compound of Formula 1 is 6.30 ⁇ 0.2, 6.87 ⁇ 0.2, 8.58 ⁇ 0.2, 9.02 ⁇ 0.2, 10.26 ⁇ 0.2, 12.46 ⁇ 0.2, 14.71 ⁇ 0.2, 15.50 ⁇ 0.2, 17.42 ⁇ 0.2, 18.27 ⁇ 0.2, 4 or more, such as 4, 5, 6, 7, 8, 9 at 2 [ ⁇ ] values selected from 19.56 ⁇ 0.2, 20.20 ⁇ 0.2, 21.55 ⁇ 0.2, 22.28 ⁇ 0.2 and 28.31 ⁇ 0.2 It is characterized in that it is characterized by an X-ray powder diffraction pattern having 10 or more diffraction peaks.
- the X-ray powder diffraction pattern is 2 [ ⁇ ] value, characterized in that it has a diffraction peak.
- the crystalline form V of the sulfate salt of the compound of Formula 1 is 6.88 ⁇ 0.2, 13.50 ⁇ 0.2, 16.17 ⁇ 0.2, 17.07 ⁇ 0.2, 17.10 ⁇ 0.2, 18.30 ⁇ 0.2, 18.54 ⁇ 0.2, 19.09 ⁇ 0.2, 19.71 ⁇ 0.2, 20.15 ⁇ 0.2, 4 or more, for example, 4, 5, 6, 7, 8, 9, 10 or more diffraction peaks at 2 [ ⁇ ] values selected from 20.52 ⁇ 0.2, 25.87 ⁇ 0.2 and 28.55 ⁇ 0.2 Branches are characterized by an X-ray powder diffraction pattern.
- the X-ray powder diffraction pattern is characterized in that it has a diffraction peak at a value of 2 [ ⁇ ] selected from 6.88 ⁇ 0.2, 18.54 ⁇ 0.2, 19.09 ⁇ 0.2, 19.71 ⁇ 0.2, and 20.15 ⁇ 0.2.
- the crystalline form VI of the sulfate salt of the compound of Formula 1 is 4 or more at 2 [ ⁇ ] values selected from 6.51 ⁇ 0.2, 15.73 ⁇ 0.2, 17.03 ⁇ 0.2, 19.01 ⁇ 0.2, 19.85 ⁇ 0.2, 20.45 ⁇ 0.2 and 24.20 ⁇ 0.2; For example, it is characterized by being characterized by an X-ray powder diffraction pattern having 4, 5, 6 or more diffraction peaks.
- the X-ray powder diffraction pattern is characterized in that it has a diffraction peak at a value of 2 [ ⁇ ] selected from 6.51 ⁇ 0.2, 17.03 ⁇ 0.2, 19.85 ⁇ 0.2, and 20.45 ⁇ 0.2.
- the crystalline form VII of the sulfate salt of the compound of Formula 1 is 3 or more, for example, 3, 4, 5, or more at a value of 2 [ ⁇ ] selected from 8.15 ⁇ 0.2, 16.30 ⁇ 0.2, 16.61 ⁇ 0.2 and 24.54 ⁇ 0.2 It is characterized by being characterized by an X-ray powder diffraction pattern having a diffraction peak.
- the X-ray powder diffraction pattern is characterized in that it has a diffraction peak at a value of 2 [ ⁇ ] selected from 16.30 ⁇ 0.2 and 16.61 ⁇ 0.2.
- the crystalline form VIII of the sulfate of the compound of Formula 1 is 6.35 ⁇ 0.2, 6.78 ⁇ 0.2, 8.36 ⁇ 0.2, 9.40 ⁇ 0.2, 13.98 ⁇ 0.2, 15.98 ⁇ 0.2, 20.43 ⁇ 0.2, 21.15 ⁇ 0.2, 21.40 ⁇ 0.2, and Characterized by an X-ray powder diffraction pattern having 4 or more, such as 4, 5, 6, 7, 8, 9, 10 or more diffraction peaks at 2 [ ⁇ ] values selected from 21.61 ⁇ 0.2 characterized by being
- the X-ray powder diffraction pattern has a diffraction peak at a value of 2 [ ⁇ ] selected from 6.35 ⁇ 0.2, 6.78 ⁇ 0.2, 8.36 ⁇ 0.2, 21.15 ⁇ 0.2, 21.40 ⁇ 0.2, and 21.61 ⁇ 0.2.
- the present invention provides a method comprising: stirring a solution containing a compound of Formula 1 and a solvent selected from ethanol, methyl ethyl ketone (MEK), ethyl acetate, methanol, or acetone under heating; and
- a solvent selected from ethanol, methyl ethyl ketone (MEK), ethyl acetate, methanol, or acetone under heating; and
- a method for preparing a sulfate of the compound of Formula 1 comprising the step of cooling the solution after dropwise adding a solution containing the same solvent as the solvent and sulfuric acid to the solution.
- the present invention also comprises the steps of stirring a solution containing the compound of Formula 1 and methanol under heating; and
- the compound of Formula 1 used as a starting material may be in an amorphous form or in any crystalline form.
- the heating may be performed by increasing the temperature to a range of 30 to 120°C.
- the cooling can lower the temperature to a range of 0 to 25 °C.
- the stirring may be performed for 30 minutes to 3 hours.
- the dropwise addition may be performed for 1 to 8 hours, and the cooling may be performed for 5 to 30 hours.
- the solution containing methanol may further contain water, and the ratio of methanol to water may be 7:3 to 9.5:0.5, but is limited thereto not.
- a step of filtration or drying thereafter may be additionally performed in order to obtain a product with high purity by removing foreign substances, excess solvent, and the like.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the sulfate salt of the compound of Formula 1 or a crystalline form thereof, and a pharmaceutically acceptable carrier.
- the present invention also provides the use of the sulfate salt of the compound of Formula 1 or a crystalline form thereof in the prevention or treatment of the following diseases.
- the present invention also provides a method for preventing or treating the following diseases, comprising administering to a subject in need of a sulfate salt of the compound of Formula 1 or a crystalline form thereof in a pharmaceutically effective amount.
- the compound of Formula 1 is known to exhibit preventive or therapeutic and ameliorating effects on cell necrosis and related diseases.
- the cell necrosis and related diseases are acute/chronic liver diseases (eg hepatitis, liver fibrosis, cirrhosis), neurodegenerative diseases (eg dementia, Parkinson's disease, Huntington's disease), ischemic heart disease, Reperfusion injury (Korean Patent No.
- ischemic stroke or ischemic injury pancreatitis, bacterial/viral sepsis, diabetes or diabetic complications, diabetic vascular disease
- diabetes in particular, are caused by substances that destroy pancreatic cells and , virus, hyperglycemia, fatty acids, diet, toxins, streptozotocin, etc.] necrotizing procolitis, cystic fibrosis, rheumatoid arthritis, degenerative arthritis, nephropathy, bacterial infection, virus Infection (eg HIV), multiple sclerosis, leukemia, lymphoma, neonatal respiratory distress syndrome, asphyxiation, tuberculosis, endometriosis, angioplasty, psoriasis, frostbite, steroid treatment complications, necrosis, tenderness, hemoglobinuria, burns, hyperthermia, Crohn's disease, celiac disease, compartment syndrome, leprosy injury, glomerulonephritis, muscular dystrophy
- cell necrosis caused by drugs and toxic substances and related diseases include alcoholism, cocaine, drugs (eg paracetamol, antibiotics, anticancer drugs, adriamycin, puromycin, bleomycin) , NSAIDs, cyclosporine, chemical toxins (e.g. carbon tetrachloride, cyanide, methanol, ethylene glycol), toxic gases, pesticides, heavy metals (e.g. lead, mercury, cadmium) exposure and/or administration and/or or necrosis associated with self-administration, damage caused by radiation/UV exposure, and cell necrosis associated therewith.
- drugs eg paracetamol, antibiotics, anticancer drugs, adriamycin, puromycin, bleomycin
- NSAIDs e.g. cyclosporine
- chemical toxins e.g. carbon tetrachloride, cyanide, methanol, ethylene glycol
- toxic gases e.g. lead, mercury, cadmi
- the compound of Formula 1 is a cell necrosis and related diseases, additionally acute / chronic kidney disease, traumatic brain injury, neurodegenerative diseases such as Lou Gehrig's disease, necrotizing colitis, viral infection (eg SARS-CoV) , psoriasis and skin diseases including allergic dermatitis, organ preservation/organ transplantation (refer to Korean Patent Nos. 10-1098583, 10-1941004), etc., are expected to exhibit preventive or therapeutic and improvement effects.
- neurodegenerative diseases such as Lou Gehrig's disease, necrotizing colitis, viral infection (eg SARS-CoV) , psoriasis and skin diseases including allergic dermatitis, organ preservation/organ transplantation (refer to Korean Patent Nos. 10-1098583, 10-1941004), etc.
- the pharmaceutical composition comprising the compound of Formula 1 has a function of regulating intracellular calcium, and can improve ER stress and mitochondrial dysfunction caused by abnormal intracellular calcium levels. Accordingly, the pharmaceutical composition comprising the compound of Formula 1 is expected to exhibit preventive or therapeutic and ameliorating effects on related diseases.
- Related diseases include:
- Demyelination diseases including demyelination and amyotrophic lateral sclerosis (ALS), hypertension including pulmonary arterial hypertension, stroke, prion disease, epilepsy, ataxia, Neuronal and glial calcium signaling in Alzheimer's disease. Cell Calcium. Oct-Nov 2003;34(4-5):385-97. Mitochondrial disorders: challenges in diagnosis & treatment. See Indian J Med Res. 2015 Jan;141(1):13-26. )
- IBD inflammatory bowel disease
- metastasis reticulum stress and oxidative stress in cell fate decision and human disease
- retinitis pigmentosa retinitis pigmentosa, optic neuropathy, cataracts, glaucoma
- anemia cholestasis, hypoparathyroidism, pancytopenia, pancreatic disorders, lactic acidosis, lactacidaemia , Hearing loss, short stature, ileus, cardiac conduction defect, cardiomyopathy, endometriosis, infertility
- Mitochondrial diseases the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol.
- Duchenne muscular dystrophy is associated with the inhibition of calcium uniport in mitochondria and an increased sensitivity of the organelles to the calcium-induced permeability transition. See Biochim Biophys Acta Mol Basis Dis. 2020 May 1;1866(5):165674. )
- the pharmaceutical composition comprising the compound of Formula 1 exhibits liver protection and liver function improvement effects, as well as chronic liver diseases such as fatty liver, liver fibrosis and cirrhosis, hepatitis caused by viruses or drugs, etc. It shows the effect of preventing or treating chronic liver disease.
- the pharmaceutical composition according to the present invention can also be used for the treatment of liver diseases selected from liver transplantation, alcoholic or non-alcoholic fatty liver (refer to Korean Patent No.
- composition according to the present invention is effective for treating or preventing fatty liver-derived fatty liver or acute or chronic liver disease derived from fatty liver.
- the compound of Formula I can enhance the differentiation efficiency and maturity of stem cell-derived cardiomyocytes, including the step of culturing the stem cells.
- the compound of Formula 1 can be used for preventing and treating mucositis.
- treatment means stopping or delaying the progression of a disease when used in an object showing symptoms of onset
- prevention means stopping the symptom of an onset when used in a subject that does not show symptoms of onset but is at high risk. or delay.
- the "pharmaceutical composition” may include a pharmaceutically acceptable carrier along with the compound of the present invention, if necessary.
- the compound of Formula 1, the sulfate thereof, or the crystalline form of the sulfate thereof according to the present invention can be administered in various oral and parenteral dosage forms during clinical administration, and when formulated, commonly used fillers, extenders, binders, wetting agents, It is prepared using a diluent or excipient such as a disintegrant or a surfactant.
- Solid preparations for oral administration include tablets, pills, powders, granules, capsules, troches, and the like, and these solid preparations include one or more compounds of the present invention with at least one excipient, for example, starch, calcium carbonate, water It is prepared by mixing sucrose or lactose or gelatin.
- lubricants such as magnesium stearate talc are also used.
- Liquid formulations for oral administration include suspensions, oral solutions, emulsions, or syrups.
- various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can
- Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspension solutions, emulsions, lyophilized formulations, suppositories, and the like.
- Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
- injectable esters such as ethyl oleate.
- As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerol, gelatin, etc. may be used.
- the effective dose to the human body of the compound of Formula 1, the sulfate thereof, or the crystalline form of the sulfate of the present invention may vary depending on the patient's age, weight, sex, dosage form, health status and disease degree, and generally about 0.001-100 mg/kg/day, preferably 0.01-35 mg/kg/day. Based on an adult patient weighing 70 kg, it is generally 0.07-7000 mg/day, preferably 0.7-2500 mg/day, and once a day at regular time intervals according to the judgment of a doctor or pharmacist It may be administered in several divided doses.
- the sulfate of the compound of Formula 1 according to the present invention has much higher solubility than other salts, and exhibits excellent stability and absorption rate in the body.
- these sulfates can form various crystalline forms, and these crystalline forms are also stable even after long-term storage under various conditions and are useful for storage because their purity hardly decreases.
- FIG. 14 is a DSC/TGA result of the hydrochloride of Compound 1
- FIG. 15 is a DSC/TGA result of sulfate
- FIG. 16 is a DSC/TGA result of methanesulfonate
- FIG. 17 is a DSC/TGA result of paratoluenesulfonate.
- Figure 18 shows the DSC/TGA results of maleate.
- Figure 19 is the HPLC spectrum of the free form of compound 1 in the physicochemical stability test
- Figure 20 is the HPLC spectrum of the hydrochloride of Compound 1
- Figure 21 is the HPLC spectrum of the sulfate
- Figure 22 is the HPLC spectrum of the methanesulfonate
- 23 shows the HPLC spectrum of paratoluenesulfonate
- FIG. 24 shows the HPLC spectrum of maleate.
- FIG. 25 is the XRPD result of the free form of Compound 1 in the physicochemical stability test
- FIG. 26 is the XRPD result of the hydrochloride of Compound 1
- FIG. 27 is the XRPD result of the sulfate
- FIG. 28 is the XRPD result of the methanesulfonate
- 29 shows the XRPD results of para-toluenesulfonate
- FIG. 30 shows the XRPD results of maleate.
- FIG. 33 is a DSC/TGA result of the sulfate of Compound 1 produced in an ethanol solvent
- FIG. 34 is a methylethylketone solvent
- FIG. 35 is an ethyl acetate solvent
- Figure 39 shows the XRPD results of the sulfate of Compound 1 produced through the slurry method (25 °C, 1 week) of Example 5-1
- Figure 40 is through the slurry method (50 °C, 1 week)
- 41 shows the XRPD results of the sulfate of Compound 1 produced through the slurry method (25°C, 4 weeks)
- FIG. 42 is the slurry method (50°C, 4 weeks).
- Figure 46 shows the DSC results of the sulfate of Compound 1 produced by the crystallization method 1 of Examples 5-6.
- FIG. 49 shows the DVS results of the sulfate salt of Compound 1 of Example 5-7
- FIG. 50 shows the XRPD results after the DVS test of the sulfate salt of Compound 1 of Example 5-7.
- Figure 54 shows the XRPD results of the sulfate crystalline Form I of Compound 1.
- Figure 55 shows the HPLC spectrum of the sulfate crystalline Form I of compound 1.
- FIG. 56 shows a TGA/DSC graph of Form I of Sulfate Sulfate of Compound 1
- FIG. 57 shows XRPD results before and after TGA of Form I.
- Figure 58 shows the XRPD results of the sulfate crystalline Form II of Compound 1.
- Figure 60 shows TGA/DSC of sulfate crystalline Form II of Compound 1
- Figure 61 shows XRPD results before and after TGA of sulfate crystalline Form II of Compound 1.
- Figure 62 shows the XRPD results of the sulfate crystalline form III of compound 1.
- Figure 63 shows the HPLC spectrum of the sulfate crystalline form III of compound 1.
- FIG. 64 shows TGA/DSC of sulfate crystalline Form III of Compound 1
- FIG. 65 shows 1 H-NMR of sulfate crystalline Form III of Compound 1
- FIG. 66 shows XRPD results before and after TGA of sulfate crystalline Form III.
- Figure 67 shows the XRPD results of the sulfate crystalline form IV of compound 1.
- Figure 68 shows the HPLC results of the sulfate crystalline Form IV of Compound 1.
- 69 shows the TGA/DSC of sulphate crystalline Form IV of compound 1.
- Figure 70 shows the XRPD results of the sulfate crystalline form V of compound 1.
- FIG. 71 shows the HPLC spectrum of the sulfate crystalline Form V of Compound 1
- FIG. 72 shows the TGA/DSC of the sulfate crystalline Form V of Compound 1
- FIG. 73 shows the XRPD results before and after TGA of the sulfate crystalline Form V of Compound 1.
- Figure 75 shows the HPLC spectrum of the sulfate crystalline Form VI of Compound 1
- Figure 76 shows the TGA/DSC of the sulfate crystalline Form VI of Compound 1
- Figure 77 shows the XRPD results after TGA of the sulfate crystalline Form VI of Compound 1.
- Figure 80 shows the XRPD results of the sulfate crystalline form VIII of Compound 1
- Figure 81 shows the XRPD results of the sulfate crystalline Form VIII of the compound 1.
- FIG. 82 shows the XRPD results of the sulfate crystalline Form II of Compound 1 scaled-up to 200 mg
- FIG. 83 shows the TGA/DSC results.
- Figure 84 shows the XRPD result of the sulfate crystalline form III of Compound 1 scaled up by 10 g
- Figure 85 shows the TGA/DSC result.
- Figure 86 shows the XRPD of the sulfate crystalline Form IV of Compound 1 scaled-up to 500 mg
- Figure 87 shows the HPLC
- Figure 88 shows the DSC/TGA.
- FIG. 89 shows the XRPD of the sulfate crystalline Form VI of compound 1 scaled up to 300 mg
- FIG. 90 shows the TGA/DSC.
- TA DSC Q2000 and Discovery DSC-2500 approximately 1 mg of sample was placed in a hermetic aluminum pan with pinhole and heated from 25 o C to 300 o C at a rate of 10 o C/min.
- TGA Q50 or TA Q5000 was used, and approximately 4 mg of a sample was placed in an open platinum pan and heated from 30 o C to 300 o C at a rate of 10 o C/min.
- PSD Particle size Distribution Analyzer
- Dispersing system using RODOS under a pressure of 0.5 bar was measured with Sympatec HELOS particles size analyzer.
- a 5 megapixel CCD Nikon LV100POL microscope equipped with a 20x physical lens was used.
- An SMS DVS Advantage 1 was used to place 10 mg of sample into a mesh stainless steel basket.
- the entire experimental cycle consisted of two scans (hygroscopic and dehumidified) at constant temperature (25° C. and 10% RH in the range of 40-90% (60-360 min for each humidity level) at intervals of 10% RH.
- a method for preparing the compound of Formula 1 known in WO2009-025478 is the same as in Scheme 1.
- P9 prepared according to Scheme 1 contains a large amount of impurities and foreign substances. Since the compound of Formula 1 has very low solubility, purification has become a very important process. In order to remove foreign substances and color of P9 obtained for research at the beginning, it was dissolved in DMSO, filtered, and EtOH was added as an anti-solvent to obtain the compound of Formula 1. In addition, the pure form without any modifications such as salt form to the compound of Formula 1 was described as "free form", and it was distinguished from the salt or crystalline form.
- the thus-prepared compound of Formula 1 has remarkably low solubility in water as well as various solvents, as shown in Table 1 below.
- the remarkably low solubility in various solvents adversely affects the development of pharmaceuticals, which must produce finished products in a completely dissolved state.
- the present invention deals with the invention of a salt of the compound of Formula 1 and a crystalline form thereof in a physicochemically stable form based on a study on the compound of Formula 1 in the form of a salt for enhancing solubility of the compound of Formula 1.
- Solvent Solubility (mg/mL) Solvent Solubility (mg/mL) 25°C 50°C 25°C 50°C Methanol (MeOH) 0.59 1.15 Tetrahydrofuran (THF) 17.40 16.26 Ethanol (EtOH) 1.41 1.08 2-Methyltetrahydrofuran (2-MeTHF) 2.78 3.41 Isopropanol (IPA) 0.32 0.54 N-Methyl pyrrolidone (NMP) 160.03 192.42 1-Butanol 0.65 1.00 Dimethyl sulfoxide (DMSO) 43.35 238.15 Acetonitrile (ACN) 3.09 4.04 Chloroform (CHCl 3 ) 4.70 4.62 Acetone 5.29 17.50 Toluene 0.02 0.02 Methyl ethyl ketone (MEK) 6.08 8.12 Heptane ⁇ LOQ ⁇ LOQ Methyl-isobutylketone (MIBK) 2.10
- Salt screening was performed by the following procedure, and a total of 52 (4X13) screening experiments were conducted simultaneously.
- Pattern A pattern of the compound of formula (1)
- the salt screening result hydrochloride (Pattern 1-I), sulfate (Pattern 2-I), methanesulfonate (Pattern 4-I), paratoluenesulfonate (Pattern 6-I) ), maleate salts (patterns 7-I, 7-II), with a total of six new crystalline forms, five potential salt compounds of the compound of formula 1 were found. 14 to 18 and Table 5 show the results of additional DSC and TGA experiments for the salt compounds of the five compounds of Formula 1 above.
- hydrochloride, sulfate, methanesulfonate, para-toluenesulfonate and maleate salts of the compounds of Formula 1 of Example 2 were confirmed by performing virtual gastrointestinal fluid solubility, physicochemical stability, and pharmacokinetic tests as follows.
- Example 3-1 Virtual Gastrointestinal Fluid Solubility Test
- the salts in SGF, FasSSIF, and FeSSIF showed higher solubility than the compound of Formula 1, among which sulfate was about 11 times higher in simulated gastric juice (SGF; pH 1.8) than in free form, in a fasting state.
- the solubility was about 10-fold in simulated intestinal fluid (FaSSIF; pH6.53) and 2-fold in simulated intestinal fluid in fed state (FeSSIF; pH 4.98).
- the sulfate salt showed the highest solubility among the salt compounds of the compound of Formula 1 in the simulated gastric juice (SGF) state related to the stomach, which is an organ that the oral dosage form is first decomposed in the body.
- the maleate of the compound of Formula 1 was sensitive to all conditions such as heat, humidity and light irradiation conditions, and the methanesulfonate of the compound of Formula 1 was sensitive to humidity and light conditions, especially A decrease in purity of about 3% or more was observed at 40 °C RH for 1 week.
- the hydrochloride salt of the compound of Formula 1 and the sulfate salt of the compound of Formula 1 were found to be sensitive to humidity conditions, and the paratoluenesulfonate salt of the compound of Formula 1 was found to be sensitive to light. All five salts showed color change after photostability test.
- mice for the free form of the compound of Formula 1 and five salt compounds of the compound of Formula 1 of the present invention were conducted using mice for the free form of the compound of Formula 1 and five salt compounds of the compound of Formula 1 of the present invention, and the results are shown in Table 8 and FIG. 31 .
- the median Tmax of the free form was found to have a half-life of 1.2 hours after being rapidly absorbed in 0.5 hours.
- the Tmax of the methanesulfonate, sulfate, para-toluenesulfonate, and maleate salts of the compound of Formula 1 was 0.5 hours, which was equivalent to that of Compound 1 free form, whereas it was found to have a longer half-life than 2.3-3.0 hours.
- the Tmax of hydrochloride was found to be absorbed relatively slowly in 2 hours.
- the sulfate salt was compared with the free form and other salts, and excellent pharmacological properties It was found to be the best salt that can increase the absorption rate in the body by improving the solubility while maintaining the salt.
- the sulfate of the compound of Formula 1 was about 11 times higher in simulated gastric juice (SGF; pH 1.8) compared to the free form of the compound of Formula 1, and simulated intestinal fluid in a fasting state (FaSSIF; pH6.53) It showed about 10-fold solubility in the fed simulated intestinal fluid (FeSSIF; pH 4.98) and 2-fold solubility.
- the sulfate of the compound of Formula 1 showed comparable results to the free form of the compound of Formula 1 under high temperature and photostability conditions except for humidity conditions.
- the sulfate of the compound of Formula 1 was finally selected as the final salt compound.
- the crystalline form of the sulfate salt of the compound of Formula 1 prepared by the salt screening of Example 2 was designated as crystalline Form 2-I or Form I.
- the crystalline form (or pattern, pattern) newly discovered in further processing and polycrystalline form studies for the sulfate of the compound of Formula 1 is 2-II, 2-III, 2-IV, 2-V, 2-VI, 2-VII and 2-VIII, respectively, meaning crystalline forms II, III, IV, V, VI, VII and VIII.
- 500 mg of the compound of Formula 1 was dissolved in 7.5 mL of ethanol by stirring at 51 o at 500 rpm, and maintained at 50 °C for 1 hour.
- 1.1 equivalents of ethanolic sulfuric acid solution (2.502 mL, 0.5 mol/L) was added dropwise over 4 hours, and maintained at 50°C for 22 hours. After that, after cooling to 5°C for 9 hours, it was maintained at 5°C for 24 hours.
- the suspension was filtered to collect solids, washed with ethanol, and then dried under vacuum at 40°C for 16 hours, drying 612.0 mg. A white solid was obtained.
- Example 4-1 the same procedure was followed except that MEK was used instead of ethanol and MEK sulfuric acid solution was used instead of ethanolic sulfuric acid solution. As a result, 518.7 mg dry powder (yellow solid) was obtained.
- Example 4-1 the same procedure was followed except that ethyl acetate was used instead of ethanol and ethyl acetate sulfuric acid solution was used instead of ethanol sulfuric acid solution. As a result, 557.3 mg of dry white powder (white solid) was obtained.
- Example 4-1 the same procedure was followed except that methanol/water (9/1) was used instead of ethanol and methanol/water (9/1) sulfuric acid solution was used instead of ethanolic sulfuric acid solution. As a result, 587.3 mg of dry white powder (white solid) was obtained.
- Example 4-1 the same procedure was followed except that acetone/water (9/1) was used instead of ethanol, and acetone/water (9/1) sulfuric acid solution was used instead of ethanolic sulfuric acid solution. As a result, 563.3 mg of dry white powder (white solid) was obtained.
- Table 10 summarizes the XRPD, DSC, and TGA of the sulfate salt of the compound of Formula 1 prepared using various solvents of Examples 4-1 to 4-5.
- 32 shows the XRPD results of the sulfate of the compound of Formula 1 produced in the above five solvents
- FIGS. 33 to 38 show the DSC/TGA results of the sulfate of the compound of Formula 1 for each solvent.
- Table 12 and FIGS. 39 to 42 show the XRPD results of the sulfate salt of the compound of Formula 1 produced through the slurry method.
- the precipitated solid was subjected to XRPD test after centrifugation. As a result of the XRPD test, it was confirmed that crystalline Form II was generated in the DMF-ethanol anti-solvent condition.
- Table 13 and FIG. 45 show the XRPD results of the sulfate salt of the compound of Formula 1 according to the anti-solvent method.
- Example 5-5 vapor diffusion method
- Example 5-6 Crystallization method by melting-cooling method
- Crystallization method 1 3 mg of the sulfate salt of the compound of formula 1 having crystalline form III is placed in an airtight aluminum pan and heated from room temperature to 230 °C at a rate of 10 °C/min, from 230 °C to 30 °C at 10 °C After cooling at a rate of C/min, it was again heated from 30 °C to 275 °C at a rate of 10 °C/min. 46 shows the DSC results of the sulfate salt of the compound of Formula 1 produced by crystallization method 1.
- Crystallization method 2 3 mg of the sulfate salt of the compound of formula 1 having crystalline form III is placed in an airtight aluminum pan and heated from room temperature to 240 °C at a rate of 10 °C/min, from 240 °C to 30 °C at 10 °C After cooling at a rate of C/min, it was again heated from 30 °C to 275 °C at a rate of 10 °C/min. According to the XRPD results, no new crystalline form was formed. 47 shows the DSC results of the sulfate salt of the compound of Formula 1 produced by crystallization method 2. 48 shows the XRPD results of the sulfate salt of the compound of Formula 1 produced by the crystallization methods 1 and 2 above.
- Example 5-7 Water absorption and desorption method (Dynamic Vapor Sorption (DVS) cycle)
- FIG. 49 shows the DVS results of the sulfate salt of the compound of Formula 1
- FIG. 50 shows the XRPD results after the DVS test of the sulfate salt of the compound of Formula 1.
- Example 5 In addition to the crystalline forms I to III found in Examples 3 and 4, a total of four new crystalline forms were discovered through the polycrystalline form study of Example 5.
- Form V was the crystalline form also found in systems with water activity >0.501 in the water activity method.
- new XRPD patterns are not found in slow evaporation, anti-solvent method, vapor diffusion method, crystallization method by melting-cooling method, water absorption and desorption method, compression method, and grinding method, etc. didn't
- Example 6 According to the salt screening of Example 3, the process study of Example 4, and the polycrystalline study of Example 5, a total of seven sulfate crystalline forms of the compound of Formula 1 were identified, and as mentioned in the summary of Example 3, the crystalline forms in turn (or pattern, pattern) was named in the order of 2-I, 2-II, 2-III, 2-IV, 2-V, 2-VI and 2-VII, which are crystalline forms I, II, III, IV, V, VI and VII. This analysis was performed in Example 6 below.
- Example 6 Identification of the crystalline form of the sulfate salt of the compound of Formula 1
- Figure 54 and Table 15 show the XRPD results of sulfate crystalline Form I.
- Form I of Form I is 2[ ⁇ ] selected from 6.63 ⁇ 0.2, 17.34 ⁇ 0.2, 17.76 ⁇ 0.2, 18.70 ⁇ 0.2, 18.93 ⁇ 0.2, 20.24 ⁇ 0.2, 20.83 ⁇ 0.2, 21.56 ⁇ 0.2, 24.66 ⁇ 0.2 and 29.00 ⁇ 0.2 ], characterized in that it is specified as a powder X-ray diffraction pattern having 4 or more diffraction peaks.
- Figure 56 shows the TGA/DSC graph of Form I
- Figure 57 shows the XRPD results before and after TGA of Form I.
- Form II was produced in a process study using the slurry method of ethanol of Example 5-1, the antisolvent method of DMF-EtOH of Example 5-4 and the ethanol solvent of Example 4-1.
- Form II of Form II is 2[ ⁇ ] selected from 6.57 ⁇ 0.2, 13.91 ⁇ 0.2, 16.05 ⁇ 0.2, 17.36 ⁇ 0.2, 18.41 ⁇ 0.2, 19.16 ⁇ 0.2, 19.36 ⁇ 0.2, 20.11 ⁇ 0.2, 20.77 ⁇ 0.2 and 24.31 ⁇ 0.2 ], characterized in that it is specified as a powder X-ray diffraction pattern having 4 or more diffraction peaks.
- the DSC of FIG. 60 showed a TGA loss of 6.5% at 100-220 °C.
- crystalline Form 2-II was changed to an amorphous state, which was a phenomenon representing a solvate.
- Forms of Form III are 7.66 ⁇ 0.2, 16.32 ⁇ 0.2, 17.53 ⁇ 0.2, 18.05 ⁇ 0.2, 18.28 ⁇ 0.2, 18.95 ⁇ 0.2, 19.49 ⁇ 0.2, 19.91 ⁇ 0.2, 21.44 ⁇ 0.2, 22.24 ⁇ 0.2, 23.52 ⁇ 0.2, 24.29 It is characterized as specified by a powder X-ray diffraction pattern having four or more diffraction peaks at a value of 2[ ⁇ ] selected from ⁇ 0.2, 25.10 ⁇ 0.2, 27.37 ⁇ 0.2, 29.07 ⁇ 0.2 and 31.90 ⁇ 0.2.
- Figure 67 and Table 18 show the XRPD results of sulfate crystalline Form IV.
- the forms of Form IV are 6.30 ⁇ 0.2, 6.87 ⁇ 0.2, 8.58 ⁇ 0.2, 9.02 ⁇ 0.2, 10.26 ⁇ 0.2, 12.46 ⁇ 0.2, 14.71 ⁇ 0.2, 15.50 ⁇ 0.2, 17.42 ⁇ 0.2, 18.27 ⁇ 0.2, 19.56 ⁇ 0.2, 20.20 It is characterized by being specified as a powder X-ray diffraction pattern having four or more diffraction peaks at 2[ ⁇ ] values selected from ⁇ 0.2, 21.55 ⁇ 0.2, 22.28 ⁇ 0.2 and 28.31 ⁇ 0.2.
- the DSC of FIG. 69 showed a TGA loss of 4.38% and 1.80% at about 90 °C and 200 °C, respectively.
- the results of DSC heating at 105 °C for 30 min showed that the water evaporated, indicating that Form IV was a hydroxide, but the same pattern when compared to XRPD overlaid with a DSC/TGA overlay without water removal. This indicated that sulfate crystalline Form IV could reversibly revert back to hydroxide after drying.
- the results were consistent when comparing XRPD overlaid with DSC/TGA overlay without water removal after vacuum drying at 50°C for 5 days.
- Form V was produced in the slurry method of Examples 5-1 and the water activity 0.501 of Examples 5-8.
- Figure 70 and Table 19 show the XRPD results of sulfate crystalline Form V.
- the forms of Form V are 6.88 ⁇ 0.2, 13.50 ⁇ 0.2, 16.17 ⁇ 0.2, 17.07 ⁇ 0.2, 17.10 ⁇ 0.2, 18.30 ⁇ 0.2, 18.54 ⁇ 0.2, 19.09 ⁇ 0.2, 19.71 ⁇ 0.2, 20.15 ⁇ 0.2, 20.52 ⁇ 0.2, 25.87 It is characterized in that it is specified as a powder X-ray diffraction pattern having four or more diffraction peaks at a value of 2 [ ⁇ ] selected from ⁇ 0.2 and 28.55 ⁇ 0.2.
- the DSC of FIG. 72 showed one peak of TGA peak loss at 80-100 °C.
- the XRPD of Form V reverted to pattern 2-III after heating to 105 °C, indicating that Form V is a hydrate and not a new pattern.
- Form VI was prepared in DMF by a one-week slurry method at 25 °C and 50 °C.
- Form VI is powder X having 4 or more diffraction peaks at a value of 2 [ ⁇ ] selected from 6.51 ⁇ 0.2, 15.73 ⁇ 0.2, 17.03 ⁇ 0.2, 19.01 ⁇ 0.2, 19.85 ⁇ 0.2, 20.45 ⁇ 0.2 and 24.20 ⁇ 0.2 - Characterized by being characterized by a line diffraction pattern.
- the XRPD of Form VI was different from Form III, which means that Pattern VI may be a new pattern.
- the DSC of FIG. 76 showed a peak of 12.87% of TGA loss up to 210°C.
- the XRPD of Form VI changed to amorphous after heating to 210 °C by TGA (Fig. 77). It is likely a DMF solvate.
- Form VII is characterized by being characterized by a powder X-ray diffraction pattern having three or more diffraction peaks at a value of 2 [ ⁇ ] selected from 8.15 ⁇ 0.2, 16.30 ⁇ 0.2, 16.61 ⁇ 0.2 and 24.54 ⁇ 0.2.
- Form IV was heated to remove water and maintained for 10 minutes, and then a new crystalline form was discovered, which was designated as Form VIII.
- Figure 80 and Table 22 show the XRPD results of sulfate crystalline Form VIII.
- the form of Form VIII has 2 [ ⁇ ] value, characterized in that it is specified as a powder X-ray diffraction pattern having four or more diffraction peaks.
- Form VIII was different from Form IV, and it was found to be retained under nitrogen charge protection after cooling to 25°C. However, when crystalline Form VIII disappeared after 1 hour when exposed to air, metastable Form VIII was a new pattern, indicating that it was a new crystalline form that was easy to absorb water and change to IV (FIG. 81).
- Scale-up was carried out for four crystalline forms of the crystalline form II, III, IV and VI of the compound of formula 1. As a result, the scaled-up crystalline form could be prepared in the same way as the existing crystalline form.
- Example 7-1 200 mg scale-up of crystalline form II of the sulfate of the compound of formula 1
- Example 7-2 10 g scale-up of sulfate crystalline Form III of the compound of formula 1
- Example 7-3 Sulfate crystalline Form IV of the compound of formula 1 500 mg scale-up
- Example 7-4 300 mg Scale-up of Sulfate Crystalline Form VI of the Compound of Formula 1
- FIG. 89 shows the XRPD results of the prepared sulfate crystalline Form VI of the compound of Formula 1, and FIG. 90 shows the TGA/DSC results.
- crystalline Form III was stable under light and shading conditions, and was stable at 60°C for 1 month, and the purity decreased by only 0.67% at 40°C for 1 month.
Abstract
Description
Solvent | Solubility (mg/mL) | Solvent | Solubility (mg/mL) | ||
25°C | 50°C | 25°C | 50°C | ||
Methanol (MeOH) | 0.59 | 1.15 | Tetrahydrofuran (THF) | 17.40 | 16.26 |
Ethanol (EtOH) | 1.41 | 1.08 | 2-Methyltetrahydrofuran (2-MeTHF) | 2.78 | 3.41 |
Isopropanol (IPA) | 0.32 | 0.54 | N-Methyl pyrrolidone (NMP) | 160.03 | 192.42 |
1-Butanol | 0.65 | 1.00 | Dimethyl sulfoxide (DMSO) | 43.35 | 238.15 |
Acetonitrile (ACN) | 3.09 | 4.04 | Chloroform (CHCl3) | 4.70 | 4.62 |
Acetone | 5.29 | 17.50 | Toluene | 0.02 | 0.02 |
Methyl ethyl ketone (MEK) | 6.08 | 8.12 | Heptane | <LOQ | <LOQ |
Methyl-isobutylketone (MIBK) | 2.10 | 2.82 | Water | 0.001 | 0.046 |
Ethyl acetate (EtOAc) | 1.36 | 1.86 | MeOH/water=1:1(v/v) | 0.03 | 0.08 |
Isopropyl acetate (iPrOAc) |
0.71 | 0.91 | Acetone-water (1:2) | 0.08 | 0.16 |
Methyl tert-butyl ether (MTBE) | 0.06 | 0.07 | Acetic acid-water (1:1) | 52.77 | 75.61 |
N,N-Dimethylformamide (DMF) | 206.03 | 332.99 | - |
Counter-ions | Acetone | THF | DMSO | IPA/H2O (95/5, v/v) |
Control | 0A | 0B | 0C* | 0D |
Hydrochloric acid | 1A | 1B* | 1C* | 1D* |
Sulfuric acid | 2A | 2B | 2C* | 2D |
Phosphoric acid | 3A | 3B* | 3C* | 3D |
Methane sulfonic acid | 4A | 4B | 4C* | 4D |
Acetic acid | 5A | 5B | 5C* | 5D |
Para-Toluenesulfonic acid monohydrate | 6A | 6B | 6C* | 6D* |
Maleic acid | 7A | 7B | 7C* | 7D |
L(+)-Tartaric acid | 8A | 8B | 8C* | 8D |
Fumaric acid | 9A | 9B | 9C* | 9D |
Citric acid | 10A | 10B | 10C* | 10D |
L-Malic acid | 11A | 11B | 11C* | 11D |
Succinic acid | 12A | 12B | 12C* | 12D |
No. | Counter-ions | Acetone | THF | DMSO | IPA/H2O (95/5, v/v) |
Con. | None | S-S*, Pattern A | S-S, Pattern A | H-C, Pattern A | S-S, Pattern A |
1 | Hydrochloric acid | H-S, Pattern 1-I | C with wax-C with wax, Amorphouseva | H-C, LCeva | H-H, Amorphouseva |
2 | Sulfuric acid | S-S, LC | S-S, Amorphous | H-C, Amorphouseva | S-S, Pattern 2-I |
3 | Phosphoric acid | S-S, Pattern A | C with wax-C, Pattern Aeva | H-C, Pattern Aeva | S-S, Pattern A |
4 | Methane sulfonic acid | S-S, Pattern (4-I)+A | S-S, LC | H-C, LC eva | S-S, Pattern 4-I |
5 | Acetic acid | S-S, Pattern A | S-S, Pattern A | H-C, Pattern Aeva | S-S, Pattern A |
6 | Para-Toluene sulfonic acid | H-S, Pattern 6-I | C-S, Amorphous | H-C, LC eva | H-C with wax, LCeva |
7 | Maleic acid | S-S, Pattern 7-I | C-S, Pattern 7-II | H-C, LC eva | S-S, Pattern 7-I |
8 | L(+)-Tartaric acid | S-S, Pattern A | S-S, Pattern A | H-C, Pattern Aeva | S-S, Pattern A |
9 | Fumaric acid | S-S, Pattern A | S-S, Pattern A | H-C, Pattern Aeva | S-S, Pattern A |
10 | Citric acid | S-S, Pattern A | S-S, Pattern A | H-C, Pattern Aeva | S-S, Pattern A |
11 | L-Malic acid | S-S, Pattern A | S-S, Pattern A | H-C, Pattern Aeva | S-S, Pattern A |
12 | Succinic acid | S-S, Pattern A | S-S, Pattern A | H-C, Pattern Aeva | S-S, Pattern A |
solvent counter-ion |
Acetone | THF | DMSO | IPA / H2O (95/5, v/v) |
None | A | A | A | A |
Hydrochloric acid | 1-I | * | LC | * |
Sulfuric acid | LC | * | * | 2-I |
Phosphoric acid | A | A | A | A |
Methane sulfonic acid | (4-I)+A | LC | LC | 4-I |
Acetic acid | A | A | A | A |
Para-Toluenesulfonic acid | 6-I | * | LC | LC |
Maleic acid | 7-I | 7-II | LC | 7-I |
L(+)-Tartaric acid | A | A | A | A |
Fumaric acid | A | A | A | A |
Citric acid | A | A | A | A |
L-Malic acid | A | A | A | A |
Succinic acid | A | A | A | A |
Compound 1 |
Hydrochloride | Sulfate | Mesylate | Tosylate | Maleate | |
Batch No. | - | 1A | 2D | 4D | 6A | 7A |
XRPD | A | 1-I | 2-I | 4-I | 6-I | 7-I |
Crystallinity(XRD) | High | High | High | High | High | High |
Melting Point(DSC, ºC) | 274 | 167, 272 | multiple peaks+ 193, 271 |
217 | 215 | 200 |
Enthalpy (DSC, J/g) | 120.73 | 6.85, 45.42 | 16.07, 30.74 | 44.49 | 40.14 | 91.34 |
Weight loss (TGA, %) | 0.038% <105ºC |
0.494% <167ºC |
0.485% <105ºC |
0.081% <105ºC |
0.306% <105ºC |
0.164% <105ºC |
화학식 1의 화합물의 염 |
용해도 (mg/mL) / pH | |||||
SGF (pH=1.80) |
FaSSIF (pH=6.53) |
FeSSIF (pH=4.98) |
||||
용해도 | pH | 용해도 | pH | 용해도 | pH | |
화학식 1의 화합물 free form | 0.75 | 1.89 | 0.01 | 6.47 | 0.07 | 5.02 |
화학식 1의 화합물의 염산염 | 2.19 | 2.06 | 0.02 | 3.64 | 0.14 | 4.95 |
화학식 1의 화합물의 황산염 | 8.60 | 1.83 | 0.10 | 2.86 | 0.13 | 4.91 |
화학식 1의 화합물의 메탄설폰산염 | 2.12 | 1.73 | 0.01 | 5.20 | 0.06 | 5.00 |
화학식 1의 화합물의 파라톨루엔설폰산염 | 0.81 | 1.97 | 0.06 | 5.67 | 0.03 | 4.86 |
화학식 1의 화합물의 말레산염 | 1.10 | 2.02 | 0.01 | 4.70 | 0.19 | 4.97 |
Starting materials | Conditions | Appearance | XRPD patterns | Final purity (%) | Purity change (%) | Assay (%) |
Compound 1 free form (99.76%) |
60°C, 1 w | White powder | Pattern A | 99.94 | +0.18 | 105.89 |
40°C/75%RH, 1w | White powder | Pattern A | 99.95 | +0.19 | 110.59 | |
1.2 million lux-hrs | White powder | Pattern A | 99.89 | +0.13 | 107.41 | |
Dark control | White powder | Pattern A | 99.94 | +0.18 | 109.40 | |
Hydrochloride (Purity: 99.95%) |
60°C, 1 w | White powder | Pattern 1-I | 100.0 | +0.05 | 110.29 |
40°C/75%RH, 1w | White powder | Pattern 1-I | 99.40 | -0.55 | 109.18 | |
1.2 million lux-hrs | Light yellow-brown powder | Pattern 1-I | 99.95 | 0 | 108.65 | |
Dark control | White powder | Pattern 1-I | 100.0 | +0.05 | 108.99 | |
Sulfate (Purity: 99.73%) |
60°C, 1 w | White powder | Pattern 2-I | 99.83 | +0.1 | 110.59 |
40°C/75%RH, 1w | White powder | Pattern 2-I | 99.30 | -0.43 | 109.86 | |
1.2 million lux-hrs | Light yellow-brown powder | Pattern 2-I | 99.87 | +0.14 | 104.98 | |
Dark control | White powder | Pattern 2-I | 99.75 | +0.02 | 105.93 | |
Mesylate (Purity: 100%) |
60°C, 1 w | White powder | Pattern 4-I | 100.0 | 0 | 107.36 |
40°C/75%RH, 1w | White powder | Pattern 4-I | 96.71 | -3.29 | 101.35 | |
1.2 million lux-hrs | Yellow-brown powder | Pattern 4-I | 99.18 | -0.82 | 102.69 | |
Dark control | White powder | Pattern 4-I | 100.0 | 0 | 103.03 | |
Tosylate (Purity: 99.01%) |
60°C, 1 w | White powder | Pattern 6-I | 98.96 | -0.05 | 108.33 |
40°C/75%RH, 1w | White powder | Pattern 6-I | 99.00 | -0.01 | 107.73 | |
1.2 million lux-hrs | Yellow-brown powder | Pattern 6-I | 98.77 | -0.24 | 105.78 | |
Dark control | White powder | Pattern 6-I | 98.98 | -0.03 | 108.98 | |
Maleate (Purity: 97.03%) |
60°C, 1 w | Yellow powder | Pattern 7-I | 96.59 | -0.44 | 110.00 |
40°C/75%RH, 1w | Yellow powder | Pattern 7-I | 96.26 | -0.77 | 108.85 | |
1.2 million lux-hrs | Yellow-brown powder | Pattern 7-I | 96.86 | -0.17 | 109.56 | |
Dark control | Yellow powder | Pattern 7-I | 97.04 | +0.01 | 109.66 |
Test article / Dose | Compound 1 / 10 mg/kg | |||||
Form | Free | Mesylate | Sulfate | Hydrochloride | Tosylate | Maleate |
Cmax (ng/mL) | 1015.2 | 2595.2 | 3154.8 | 2381.1 | 3151.3 | 3115.9 |
Tmax (hr) | 0.5 | 0.5 | 0.5 | 2 | 0.5 | 0.5 |
AUClast(ng·hr/mL) | 3603.9 | 10119.7 | 11499.35 | 12261.43 | 18850.98 | 15780.45 |
t1/2 (hr) | 1.2 | 2.3 | 4.0 | 3.0 | 2.8 | 2.8 |
Cmax ratio | 1.0 | 2.6 | 3.1 | 2.3 | 3.1 | 3.1 |
AUClast ratio | 1.0 | 2.8 | 3.2 | 3.4 | 5.2 | 4.4 |
가상 위장관 액 용해도 (mg/mL) | 화학적 안정성 (순도 변화 %/ 1주) |
약물동태 시험 | ||||||
SGS | FaSSIF | FeSSIF | 60°C | 40°C /75%RH | 광안정성 | AUC (ng·hr/mL) | t1/2 (hr) | |
화학식 1의 화합물의 free form | 0.75 | 0.01 | 0.07 | 0.18 | 0.19 | 0.13 | 3603.90 | 1 |
염산염 | 2.19 | 0.02 | 0.14 | 0.18 | - 0.05 | 0 | 12261.43 | 3 |
황산염 | 8.6 | 0.1 | 0.13 | 0.1 | -0.43 | 0.14 | 11499.35 | 4 |
메탄설폰산염 | 2.12 | 0.01 | 0.06 | 0 | -3.29 | -0.82 | 10119.70 | 2 |
파라톨루엔설폰산염 | 0.81 | 0.06 | 0.03 | -0.05 | -0.01 | -0.24 | 18850.98 | 3 |
말레산염 | 1.1 | 0.01 | 0.19 | -0.44 | -0.77 | -0.17 | 15780.45 | 3 |
용매 분석 |
EtOH | MEK | EtOAc | MeOH/H2O 9/1 | Acetone/H2O 9/1 |
XRPD | 결정형 II | Low crystallization |
Low crystallization |
결정형 III | Low crystallization |
DSC | multiple peaks+ 165°C / 44.06J/g ; 231°C/ 20.61J/g | multiple peaks+ 75°C / 127.21J/g ; 173°C/ 17.27J/g | multiple peaks+ 78°C / 75.14J/g ; 144°C/ 18.60J/g | 231°C/ 38.95J/g | multiple peaks+ 69°C / 12.25J/g ; 206°C/ 11.80J/g |
TGA | 1.461%<105°C | 5.759%<105°C | 5.077%<105°C | 2.404%<105°C | 6.523%<105°C |
Solvents | Solubility (mg/mL) | Solvents | Solubility (mg/mL) | ||
25°C | 50°C | 25°C | 50°C | ||
MeOH | S<2 | 2<S<3 | THF | S<2 | S<2 |
EtOH | S<2 | S<2 | 2-MeTHF | S<2 | S<2 |
IPA | S<2 | S<2 | NMP | 156<S<208 | 202<S<304 |
1-Butanol | S<2 | S<2 | DMSO | 158<S<210 | 301<S<602 |
ACN | S<2 | S<2 | CHCl3 | S<2 | S<2 |
Acetone | S<2 | S<2 | Toluene | S<2 | S<2 |
MEK | S<2 | S<2 | Heptane | S<2 | S<2 |
MIBK | S<2 | S<2 | Water | S<2 | S<2 |
EtOAc | S<2 | S<2 | MeOH/H2O=1:1(v/v) | 2<S<3 | 9<S<19 |
iPrOAc | S<2 | S<2 | Acetone-H2O (1:2) | 9<S<19 | 37<S<75 |
MTBE | S<2 | S<2 | Acetic acid-H2O (1:1) | 196<S<295 | 300<S<599 |
DMF | 202<S<302 | 304<S<608 | - | - | - |
Solvents | Temp. | XRPD Results | Temp. | XRPD Results | ||
1 week | 4 weeks | 1 week | 4 weeks | |||
EtOH | 25°C | Pattern 2-III | Pattern 2-II | 50°C | Pattern 2-II | Pattern 2-II |
Acetone | Pattern 2-III | Pattern 2-III | Pattern 2-III | Pattern 2-III | ||
MEK | Pattern 2-III | Pattern 2-III | Pattern 2-III | Pattern 2-III | ||
EtOAc | Pattern 2-III | Pattern 2-III | Pattern 2-III | Pattern 2-III | ||
MTBE | Pattern 2-III | Pattern 2-III | Pattern 2-III | Pattern 2-III | ||
DMSO | Amorphous | Amorphous | Amorphous | Amorphous | ||
DMF | Pattern 2-VI | Amorphous | Pattern 2-VI | Amorphous | ||
NMP | Amorphous | Amorphous | Amorphous | Amorphous | ||
MeOH/water (1:1) | Pattern 2-V | Pattern 2-V | Amorphous | Amorphous | ||
Acetone/water (1:2) | Pattern 2-V | Pattern 2-V | Pattern 2-V | Pattern 2-VII | ||
IPA/water (95:5) | Pattern 2-I | Pattern 2-I | Pattern 2-I | Pattern 2-I |
Solvent Name | Anti-solvents | Observation | XRPD results |
NMP | EtOH | Suspension | Amorphous |
EtOAc | Suspension | Amorphous | |
DMSO | EtOH | Suspension | Amorphous |
MTBE | Clear | N/A | |
DMF | EtOH | Suspension | Pattern 2-II |
Acetone | Suspension | Amorphous |
No. | Water activity | water/acetone (%, v/v) |
Observation | XRPD results |
1 | 0 | 0 | suspension | Pattern 2-III |
2 | 0.103 | 0.6% | suspension | Pattern 2-III |
3 | 0.206 | 1.5% | suspension | Pattern 2-III |
4 | 0.301 | 2.8% | suspension | Pattern 2-III |
5 | 0.400 | 5.0% | suspension | Pattern 2-III |
6 | 0.501 | 8.6% | suspension | Pattern 2-V |
7 | 0.603 | 14.5% | suspension | Pattern 2-V |
8 | 0.703 | 24.0% | suspension | Pattern 2-V |
9 | 0.803 | 40.0% | suspension | Pattern 2-V |
10 | 0.901 | 65.0% | suspension | Pattern 2-V |
Angle | d value | Intensity | Intensity % |
2-Theta ° | Angstrom | Count | % |
6.625 | 13.331 | 2527 | 100.0 |
9.497 | 9.305 | 178 | 4.8 |
12.293 | 7.194 | 164 | 3.6 |
12.758 | 6.933 | 163 | 3.3 |
13.205 | 6.699 | 251 | 6.8 |
13.435 | 6.585 | 284 | 8.1 |
14.816 | 5.974 | 179 | 4.0 |
15.734 | 5.628 | 175 | 3.5 |
16.026 | 5.526 | 237 | 5.8 |
17.342 | 5.109 | 1198 | 43.7 |
17.757 | 4.991 | 811 | 27.8 |
18.698 | 4.742 | 542 | 16.5 |
18.933 | 4.683 | 2517 | 96.3 |
19.837 | 4.472 | 310 | 7.1 |
20.242 | 4.384 | 1794 | 67.3 |
20.827 | 4.262 | 485 | 14.7 |
21.564 | 4.118 | 395 | 11.5 |
22.416 | 3.963 | 167 | 2.7 |
24.663 | 3.607 | 817 | 28.7 |
25.891 | 3.438 | 228 | 5.1 |
26.565 | 3.353 | 232 | 5.2 |
27.181 | 3.278 | 190 | 3.4 |
28.044 | 3.179 | 229 | 4.9 |
29.004 | 3.076 | 405 | 12.0 |
33.130 | 2.702 | 198 | 3.9 |
36.068 | 2.488 | 221 | 4.7 |
2-Theta | d(A) | Counts | Intensity% |
6.569 | 13.445 | 608 | 100.0 |
13.908 | 6.363 | 133 | 16.2 |
16.054 | 5.516 | 113 | 12.3 |
17.362 | 5.104 | 415 | 62.1 |
18.405 | 4.817 | 194 | 22.6 |
19.156 | 4.630 | 243 | 30.7 |
19.358 | 4.582 | 347 | 48.8 |
20.109 | 4.412 | 347 | 49.0 |
20.769 | 4.273 | 157 | 16.9 |
24.311 | 3.658 | 169 | 20.7 |
2-Theta | d(A) | Counts | Intensity% |
6.844 | 12.905 | 289 | 7.7 |
7.657 | 11.536 | 1491 | 49.7 |
12.255 | 7.217 | 168 | 2.5 |
13.913 | 6.360 | 234 | 4.6 |
15.275 | 5.796 | 185 | 2.7 |
15.786 | 5.609 | 328 | 7.1 |
16.318 | 5.428 | 568 | 14.8 |
17.532 | 5.055 | 1971 | 62.8 |
18.048 | 4.911 | 711 | 18.5 |
18.277 | 4.850 | 3044 | 100.0 |
18.946 | 4.680 | 521 | 11.6 |
19.492 | 4.550 | 877 | 24.1 |
19.912 | 4.455 | 2784 | 90.9 |
21.435 | 4.142 | 500 | 11.2 |
22.236 | 3.995 | 535 | 12.1 |
22.603 | 3.931 | 334 | 5.1 |
23.522 | 3.779 | 515 | 11.2 |
24.288 | 3.662 | 1011 | 28.5 |
25.102 | 3.545 | 581 | 13.6 |
27.374 | 3.255 | 477 | 10.5 |
28.054 | 3.178 | 370 | 6.6 |
29.070 | 3.069 | 730 | 19.4 |
29.990 | 2.977 | 317 | 5.4 |
31.904 | 2.803 | 529 | 12.8 |
39.624 | 2.273 | 302 | 4.0 |
2-Theta | d(A) | Counts | Intensity% |
6.296 | 14.028 | 154 | 40.3 |
6.870 | 12.857 | 107 | 20.1 |
8.576 | 10.302 | 155 | 39.9 |
9.020 | 9.796 | 193 | 55.4 |
10.262 | 8.613 | 109 | 16.8 |
12.457 | 7.100 | 140 | 27.1 |
14.711 | 6.017 | 141 | 18.9 |
15.504 | 5.711 | 167 | 29.1 |
17.416 | 5.088 | 182 | 28.7 |
18.269 | 4.852 | 163 | 18.0 |
19.558 | 4.535 | 302 | 75.7 |
20.200 | 4.393 | 167 | 17.0 |
21.554 | 4.120 | 361 | 100.0 |
22.284 | 3.986 | 309 | 78.6 |
28.309 | 3.150 | 130 | 17.3 |
2-Theta | d(A) | Counts | Intensity% |
6.876 | 12.845 | 2180 | 100.0 |
7.995 | 11.050 | 156 | 4.4 |
11.453 | 7.720 | 164 | 4.2 |
13.495 | 6.556 | 357 | 12.7 |
16.173 | 5.476 | 422 | 14.8 |
17.066 | 5.191 | 406 | 12.9 |
17.102 | 5.181 | 386 | 11.9 |
18.303 | 4.843 | 529 | 17.8 |
18.535 | 4.783 | 699 | 25.7 |
19.086 | 4.646 | 2260 | 99.4 |
19.707 | 4.501 | 758 | 28.4 |
20.151 | 4.403 | 1030 | 41.3 |
20.523 | 4.324 | 491 | 16.0 |
22.429 | 3.961 | 260 | 6.1 |
22.801 | 3.897 | 307 | 8.3 |
23.125 | 3.843 | 337 | 9.7 |
24.183 | 3.677 | 222 | 4.2 |
24.882 | 3.576 | 237 | 4.1 |
25.868 | 3.442 | 649 | 22.7 |
27.734 | 3.214 | 294 | 5.7 |
28.548 | 3.124 | 479 | 14.8 |
29.204 | 3.055 | 329 | 8.2 |
32.206 | 2.777 | 325 | 8.7 |
2-Theta | d(A) | Counts | Intensity% |
6.514 | 13.558 | 1578 | 26.7 |
8.502 | 10.391 | 418 | 5.1 |
9.162 | 9.645 | 203 | 1.1 |
12.043 | 7.343 | 231 | 0.9 |
12.534 | 7.057 | 422 | 4.3 |
15.728 | 5.630 | 1241 | 17.1 |
16.474 | 5.377 | 643 | 4.9 |
17.030 | 5.202 | 5711 | 97.9 |
17.407 | 5.090 | 916 | 8.8 |
18.013 | 4.921 | 623 | 2.7 |
18.299 | 4.844 | 823 | 6.1 |
19.006 | 4.666 | 1548 | 19.0 |
19.851 | 4.469 | 5959 | 100.0 |
20.453 | 4.339 | 2000 | 26.6 |
20.817 | 4.264 | 950 | 7.1 |
21.530 | 4.124 | 1013 | 8.2 |
22.654 | 3.922 | 745 | 3.4 |
24.200 | 3.675 | 1816 | 24.1 |
24.650 | 3.609 | 725 | 4.3 |
25.398 | 3.504 | 864 | 7.6 |
26.107 | 3.410 | 795 | 6.9 |
28.473 | 3.132 | 713 | 6.1 |
28.703 | 3.108 | 551 | 3.2 |
29.151 | 3.061 | 586 | 4.1 |
29.427 | 3.033 | 510 | 2.8 |
31.987 | 2.796 | 488 | 3.1 |
34.070 | 2.629 | 358 | 1.1 |
35.520 | 2.525 | 408 | 2.3 |
37.002 | 2.428 | 320 | 0.8 |
39.492 | 2.280 | 306 | 0.8 |
2-Theta | d(A) | Counts | Intensity% |
8.153 | 10.835 | 460 | 12.6 |
16.304 | 5.432 | 3224 | 100.0 |
16.611 | 5.333 | 1241 | 36.0 |
24.541 | 3.624 | 385 | 9.0 |
24.993 | 3.560 | 150 | 1.6 |
32.895 | 2.721 | 317 | 7.9 |
33.566 | 2.668 | 164 | 2.9 |
2-Theta | d(A) | Counts | Intensity% |
6.350 | 13.909 | 2002 | 100.0 |
6.775 | 13.036 | 993 | 40.7 |
8.012 | 11.027 | 422 | 7.6 |
8.356 | 10.573 | 801 | 30.0 |
9.396 | 9.405 | 579 | 16.4 |
10.427 | 8.477 | 477 | 8.3 |
12.274 | 7.205 | 532 | 6.8 |
12.498 | 7.077 | 578 | 9.0 |
13.983 | 6.328 | 736 | 15.5 |
15.975 | 5.544 | 844 | 16.0 |
17.846 | 4.966 | 764 | 6.7 |
19.033 | 4.659 | 834 | 9.0 |
19.660 | 4.512 | 845 | 8.9 |
20.427 | 4.344 | 911 | 12.4 |
21.149 | 4.197 | 1189 | 28.7 |
21.401 | 4.149 | 1315 | 36.2 |
21.614 | 4.108 | 1425 | 42.7 |
Starting materials | Conditions | Appearance | XRPD patterns | Final purity | Purity change | Assay | |
Pattern III (Anhydrate, non-solvate) |
Initial | White powder | Pattern III | 99.38% | - | - | |
Light | Taupe powder | Pattern III | 99.38% | -0.00% | 101.77% | ||
Dark | White powder | Pattern III | 99.33% | -0.05% | 103.17% | ||
60°C | 2w | White powder | Pattern III | 99.24% | -0.14% | 101.08% | |
1M | White powder | Pattern III | 99.25% | -0.13% | 106.79% | ||
2M | pending | pending | pending | pending | pending | ||
3M | pending | pending | pending | pending | pending | ||
40°C /75%RH |
2w | White powder | Pattern III | 98.77% | -0.61% | 99.42% | |
1M | White powder | Pattern III | 98.71% | -0.67% | 102.84% | ||
2M | pending | pending | pending | pending | pending | ||
3M | pending | pending | pending | pending | pending |
Peak # | RT (min) | RRT | Area of Sulfate (%) | ||||||
Initial | 1.2 million lux-hrs | Dark control | 60°C | 40°C/75%RH | |||||
2w | 1M | 2w | 1M | ||||||
1 | 1.512 | 0.50 | - | - | - | - | - | 0.069 | - |
2 | 1.888 | 0.63 | - | - | - | - | 0.168 | - | 0.183 |
3 | 2.022 | 0.67 | 0.204 | 0.226 | 0.209 | 0.231 | - | 0.226 | - |
4 | 2.036 | 0.68 | - | - | - | - | 0.056 | - | 0.061 |
5 | 2.481 | 0.82 | - | - | - | 0.052 | - | - | - |
6 | 2.704 | 0.91 | - | - | - | - | - | - | 0.102 |
7 | 3.021 | 1.00 | 99.319 | 99.382 | 99.326 | 99.237 | 99.247 | 98.769 | 98.711 |
8 | 3.362 | 1.11 | 0.069 | - | 0.069 | 0.114 | - | 0.206 | - |
9 | 3.355 | 1.12 | - | - | - | - | 0.325 | - | 0.518 |
10 | 3.75 | 1.24 | 0.215 | 0.221 | 0.219 | 0.211 | - | 0.321 | - |
11 | 3.938 | 1.32 | - | - | - | - | 0.088 | - | 0.149 |
12 | 4.299 | 1.42 | 0.08 | 0.073 | 0.078 | 0.054 | - | 0.084 | - |
Claims (14)
- 제1항에 따른 화학식 1의 화합물의 황산염의 결정형 I로서,상기 결정형이 6.63±0.2, 17.34±0.2, 17.76±0.2, 18.70±0.2, 18.93±0.2, 20.24±0.2, 20.83±0.2, 21.56±0.2, 24.66±0.2 및 29.00±0.2로부터 선택되는 2[θ]값에서 4개 이상의 회절 피크를 가지는 X선 분말 회절패턴으로 특정되는 것을 특징으로 하는 결정형.
- 제1항에 따른 화학식 1의 화합물의 황산염의 결정형 II로서,상기 결정형이 6.57±0.2, 13.91±0.2, 16.05±0.2, 17.36±0.2, 18.41±0.2, 19.16±0.2, 19.36±0.2, 20.11±0.2, 20.77±0.2 및 24.31±0.2로부터 선택되는 2[θ]값에서 4개 이상의 회절 피크를 가지는 X선 분말 회절패턴으로 특정되는 것을 특징으로 하는 결정형.
- 제1항에 따른 화학식 1의 화합물의 황산염의 결정형 III로서,상기 결정형이 7.66±0.2, 16.32±0.2, 17.53±0.2, 18.05±0.2, 18.28±0.2, 18.95±0.2, 19.49±0.2, 19.91±0.2, 21.44±0.2, 22.24±0.2, 23.52±0.2, 24.29±0.2, 25.10±0.2, 27.37±0.2, 29.07±0.2 및 31.90±0.2로부터 선택되는 2[θ]값에서 4개 이상의 회절 피크를 가지는 X선 분말 회절 패턴으로 특정되는 것을 특징으로 하는 결정형.
- 제1항에 따른 화학식 1의 화합물의 황산염의 결정형 IV로서,상기 결정형이 6.30±0.2, 6.87±0.2, 8.58±0.2, 9.02±0.2, 10.26±0.2, 12.46±0.2, 14.71±0.2, 15.50±0.2, 17.42±0.2, 18.27±0.2, 19.56±0.2, 20.20±0.2, 21.55±0.2, 22.28±0.2 및 28.31±0.2로부터 선택되는 2[θ]값에서 4개 이상의 회절 피크를 가지는 X선 분말 회절 패턴으로 특정되는 것을 특징으로 하는 결정형.
- 제1항에 따른 화학식 1의 화합물의 황산염의 결정형 V로서,상기 결정형이 6.88±0.2, 13.50±0.2, 16.17±0.2, 17.07±0.2, 17.10±0.2, 18.30±0.2, 18.54±0.2, 19.09±0.2, 19.71±0.2, 20.15±0.2, 20.52±0.2, 25.87±0.2 및 28.55±0.2로부터 선택되는 2[θ]값에서 4개 이상의 회절 피크를 가지는 X선 분말 회절 패턴으로 특정되는 것을 특징으로 하는 결정형.
- 제1항에 따른 화학식 1의 화합물의 황산염의 결정형 VI로서,상기 결정형이 6.51±0.2, 15.73±0.2, 17.03±0.2, 19.01±0.2, 19.85±0.2, 20.45±0.2 및 24.20±0.2로부터 선택되는 2[θ]값에서 4개 이상의 회절 피크를 가지는 X선 분말 회절 패턴으로 특정되는 것을 특징으로 하는 결정형.
- 제1항에 따른 화학식 1의 화합물의 황산염의 결정형 VII로서,상기 결정형이 8.15±0.2, 16.30±0.2, 16.61±0.2 및 24.54±0.2로부터 선택되는 2[θ]값에서 3개 이상의 회절 피크를 가지는 X선 분말 회절 패턴으로 특정되는 것을 특징으로 하는 결정형.
- 제1항에 따른 화학식 1의 화합물의 황산염의 결정형 VIII로서,상기 결정형이 6.35±0.2, 6.78±0.2, 8.36±0.2, 9.40±0.2, 13.98±0.2, 15.98±0.2, 20.43±0.2, 21.15±0.2, 21.40±0.2, 및 21.61±0.2로부터 선택되는 2[θ]값에서 4개 이상의 회절 피크를 가지는 X선 분말 회절 패턴으로 특정되는 것을 특징으로 하는 결정형.
- 제1항에 따른 화학식 1의 화합물의 황산염 또는 제2항 내지 제9항 중 어느 한 항에 따른 화학식 1의 화합물의 황산염의 결정형, 및 약제학적으로 허용가능한 담체를 포함하는 약제학적 조성물.
- 제1항에 따른 화학식 1의 화합물의 황산염 또는 제2항 내지 제9항 중 어느 한 항에 따른 화학식 1의 화합물의 황산염의 결정형, 및 약제학적으로 허용가능한 담체를 포함하는 하기 그룹에서 선택되는 세포 괴사 및 관련 질환에 대한 예방 또는 치료용 약제학적 조성물: 급성 또는 만성 간 질환, 치매, 파킨슨병, 헌팅톤병, 허혈성 질환, 당뇨병, 췌장염, 박테리아성 또는 바이러스성 패혈증, 괴사성 프로콜리티스(necrotizing procolitis), 낭포성 섬유증, 류마티스성 관절염, 퇴행성 관절염, 신증, 박테리아 감염, 바이러스 감염, 다발성 경화증, 백혈병, 림프종, 신생아 호흡곤란증후군, 질식, 결핵, 자궁내막증, 혈관무력증, 건선, 동상, 스테로이드처리 합병증, 회저병, 압통, 혈색소뇨증, 화상, 고열증, 크론씨병, 셀리악병, 구획증후군, 나상맥 손상, 사구체신염, 근이양증, 마이코플라즈마 질환, 탄저병, 앤더슨병, 선천성 마이토콘드리아병, 페닐케톤뇨증, 태반경색, 매독 및 무균성 괴사; 및 알코올 중독 및 코카인, 항생제, 항암제, 비스테로이드성 항염증 약물(NSAID), 사이클로스포린 (cyclosporine), 화학독소, 독가스, 농약, 중금속에의 노출 또는 이들의 투여 또는 자가투여와 관련된 괴사, 방사능 또는 UV에의 노출에 의한 손상 및 이와 관련된 세포괴사, 급성/만성 신장질환, 외상성뇌손상, 루게릭병, 괴사성 대장염 (necrotizing colitis), 바이러스 감염, 건선 및 알러지성 피부염을 포함하는 피부질환, 장기보존/장기이식, 급성폐장애신드롬/급성 폐질환, 폐렴, 결핵, 천식, 폐동맥 고혈압, 만성폐쇄성 폐질환 (chronic obstruction pulmonary disease), 특발성 폐섬유화증 (idiopathic pulmonary fibrosis) 및 낭포성 폐섬유화증 (cystic fibrosis)을 포함하는 염증성 폐질환 (chronic Inflammatory pulmonary disease), 탈수초화 (demyelination)와 근위축측삭경화증 (ALS; amyotrophic lateral sclerosis)를 포함하는 탈수초질환, 폐동맥고혈압을 포함하는 고혈압, 뇌졸중, 프라이온 질병 (prion disease), 뇌전증, 운동실조 (ataxia), 편두통, 인지력 감퇴, 발작, 떨림, 정신질환, 인슐린저항성, 고지혈증, 죽상동맥경화증 (atherosclerosis), 크론병과 궤양성결장염을 포함하는 염증성 장질환 (IBD; inflammatory bowel disease), 암 및 암의 전이, 색소 망막염, 시신경병, 백내장 및 녹내장을 포함하는 시각장애 관련 질병, 빈혈, 담즙울혈 (cholestasis), 부갑상선 기능저하증, 범혈구 감소증, 췌장 장애, 젖산 산증 (lactic acidosis), 젖산혈증 (lactacidaemia), 청력손실, 저신장, 장폐색증, 심장 전도 결함 (cardiac conduction defect), 심장근육병증 (cardiomyopathy), 자궁내막증, 불임, 조기 갱년기, 림바그리드/베커 근위측증 (GGMD/BMD; limbar gride/Becker muscular dystrophy)와 뒤센 근위축증 (DMD; Duchenne muscular dystrophy)을 포함하는 근위측증 질환, 노화 및 노화관련 질환, 및 점막염.
- 제1항에 따른 화학식 1의 화합물의 황산염 또는 제2항 내지 제9항 중 어느 한 항에 따른 화학식 1의 화합물의 황산염의 결정형을 포함하는 줄기세포로부터 심근세포로의 분화 유도용 조성물.
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