JP5934204B2 - C−met調節剤の薬学的組成物 - Google Patents
C−met調節剤の薬学的組成物 Download PDFInfo
- Publication number
- JP5934204B2 JP5934204B2 JP2013519870A JP2013519870A JP5934204B2 JP 5934204 B2 JP5934204 B2 JP 5934204B2 JP 2013519870 A JP2013519870 A JP 2013519870A JP 2013519870 A JP2013519870 A JP 2013519870A JP 5934204 B2 JP5934204 B2 JP 5934204B2
- Authority
- JP
- Japan
- Prior art keywords
- cancer
- compound
- tablet composition
- pharmaceutical tablet
- malate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000008194 pharmaceutical composition Substances 0.000 title description 30
- 150000001875 compounds Chemical class 0.000 claims description 168
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 90
- 239000000203 mixture Substances 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 48
- 239000007916 tablet composition Substances 0.000 claims description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 28
- 239000011230 binding agent Substances 0.000 claims description 23
- 239000000314 lubricant Substances 0.000 claims description 22
- 239000008187 granular material Substances 0.000 claims description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 201000011510 cancer Diseases 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 17
- 239000007884 disintegrant Substances 0.000 claims description 15
- 239000000945 filler Substances 0.000 claims description 15
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 14
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 14
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 14
- 239000007888 film coating Substances 0.000 claims description 13
- 238000009501 film coating Methods 0.000 claims description 13
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 11
- 206010006187 Breast cancer Diseases 0.000 claims description 11
- 208000026310 Breast neoplasm Diseases 0.000 claims description 11
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 11
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 11
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 11
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- 206010060862 Prostate cancer Diseases 0.000 claims description 8
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 229920002472 Starch Polymers 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 8
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 8
- 229960001375 lactose Drugs 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 8
- 102000005962 receptors Human genes 0.000 claims description 8
- 108020003175 receptors Proteins 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 7
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 7
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 239000000454 talc Substances 0.000 claims description 6
- 229910052623 talc Inorganic materials 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 208000009018 Medullary thyroid cancer Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 5
- 239000012530 fluid Substances 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 5
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 5
- 229940032147 starch Drugs 0.000 claims description 5
- 229940124597 therapeutic agent Drugs 0.000 claims description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000004375 Dextrin Substances 0.000 claims description 4
- 229920001353 Dextrin Polymers 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 206010038389 Renal cancer Diseases 0.000 claims description 4
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 150000004781 alginic acids Chemical class 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 235000019425 dextrin Nutrition 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 239000000665 guar gum Substances 0.000 claims description 4
- 235000010417 guar gum Nutrition 0.000 claims description 4
- 229960002154 guar gum Drugs 0.000 claims description 4
- 238000009478 high shear granulation Methods 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 201000010982 kidney cancer Diseases 0.000 claims description 4
- 201000005202 lung cancer Diseases 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229940005550 sodium alginate Drugs 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000002510 thyroid cancer Diseases 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 201000001342 Fallopian tube cancer Diseases 0.000 claims description 3
- 208000013452 Fallopian tube neoplasm Diseases 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 208000035327 Oestrogen receptor positive breast cancer Diseases 0.000 claims description 3
- 208000026149 Primary peritoneal carcinoma Diseases 0.000 claims description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229920002494 Zein Polymers 0.000 claims description 3
- 229940009868 aluminum magnesium silicate Drugs 0.000 claims description 3
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960004977 anhydrous lactose Drugs 0.000 claims description 3
- 210000003236 esophagogastric junction Anatomy 0.000 claims description 3
- 102000015694 estrogen receptors Human genes 0.000 claims description 3
- 108010038795 estrogen receptors Proteins 0.000 claims description 3
- 201000007281 estrogen-receptor positive breast cancer Diseases 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 229920000159 gelatin Polymers 0.000 claims description 3
- 239000008273 gelatin Substances 0.000 claims description 3
- 235000019322 gelatine Nutrition 0.000 claims description 3
- 235000011852 gelatine desserts Nutrition 0.000 claims description 3
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 208000014018 liver neoplasm Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 229920000193 polymethacrylate Polymers 0.000 claims description 3
- 108090000468 progesterone receptors Proteins 0.000 claims description 3
- 238000010298 pulverizing process Methods 0.000 claims description 3
- 229940080313 sodium starch Drugs 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 210000002784 stomach Anatomy 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 239000005019 zein Substances 0.000 claims description 3
- 229940093612 zein Drugs 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 206010062878 Gastrooesophageal cancer Diseases 0.000 claims description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims description 2
- 240000007472 Leucaena leucocephala Species 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- 229960001631 carbomer Drugs 0.000 claims description 2
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229960005168 croscarmellose Drugs 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 201000006974 gastroesophageal cancer Diseases 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 238000012216 screening Methods 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 210000004500 stellate cell Anatomy 0.000 claims description 2
- 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 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 102100025803 Progesterone receptor Human genes 0.000 claims 1
- 235000010216 calcium carbonate Nutrition 0.000 claims 1
- 235000011132 calcium sulphate Nutrition 0.000 claims 1
- 235000010980 cellulose Nutrition 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- 229960002900 methylcellulose Drugs 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 239000007787 solid Substances 0.000 description 31
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical group OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 238000009472 formulation Methods 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- -1 glidants Substances 0.000 description 10
- 229940049920 malate Drugs 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical group C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- 102000001253 Protein Kinase Human genes 0.000 description 8
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 8
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 8
- 108060006633 protein kinase Proteins 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 108091000080 Phosphotransferase Proteins 0.000 description 7
- 208000005017 glioblastoma Diseases 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- 238000000634 powder X-ray diffraction Methods 0.000 description 7
- 239000011877 solvent mixture Substances 0.000 description 7
- 238000002411 thermogravimetry Methods 0.000 description 7
- VXEQRXJATQUJSN-UHFFFAOYSA-N 4-(6,7-dimethoxyquinolin-4-yl)oxyaniline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC1=CC=C(N)C=C1 VXEQRXJATQUJSN-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 6
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 6
- 230000011664 signaling Effects 0.000 description 6
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 5
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 5
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000000113 differential scanning calorimetry Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229960001433 erlotinib Drugs 0.000 description 5
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000002204 nitrogen-15 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- JQWTVIFNRAALHM-UHFFFAOYSA-N 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carbonyl chloride Chemical compound C1=CC(F)=CC=C1NC(=O)C1(C(Cl)=O)CC1 JQWTVIFNRAALHM-UHFFFAOYSA-N 0.000 description 4
- PFMAFXYUHZDKPY-UHFFFAOYSA-N 1-[(4-fluorophenyl)carbamoyl]cyclopropane-1-carboxylic acid Chemical compound C=1C=C(F)C=CC=1NC(=O)C1(C(=O)O)CC1 PFMAFXYUHZDKPY-UHFFFAOYSA-N 0.000 description 4
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 102000003745 Hepatocyte Growth Factor Human genes 0.000 description 4
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 4
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 108091008605 VEGF receptors Proteins 0.000 description 4
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 239000012296 anti-solvent Substances 0.000 description 4
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 229960002584 gefitinib Drugs 0.000 description 4
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229940116298 l- malic acid Drugs 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 150000003384 small molecules Chemical class 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- WRVHQEYBCDPZEU-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinoline Chemical compound C1=CC(Cl)=C2C=C(OC)C(OC)=CC2=N1 WRVHQEYBCDPZEU-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 3
- 206010003571 Astrocytoma Diseases 0.000 description 3
- 229920003084 Avicel® PH-102 Polymers 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- FDKLLWKMYAMLIF-UHFFFAOYSA-N cyclopropane-1,1-dicarboxylic acid Chemical compound OC(=O)C1(C(O)=O)CC1 FDKLLWKMYAMLIF-UHFFFAOYSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 235000011090 malic acid Nutrition 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 206010005949 Bone cancer Diseases 0.000 description 2
- 208000018084 Bone neoplasm Diseases 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 101100262697 Mus musculus Axl gene Proteins 0.000 description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000007891 compressed tablet Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 2
- 201000011610 giant cell glioblastoma Diseases 0.000 description 2
- 208000002409 gliosarcoma Diseases 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 208000030883 malignant astrocytoma Diseases 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 102000003998 progesterone receptors Human genes 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- CGRKYEALWSRNJS-UHFFFAOYSA-N sodium;2-methylbutan-2-olate Chemical compound [Na+].CCC(C)(C)[O-] CGRKYEALWSRNJS-UHFFFAOYSA-N 0.000 description 2
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- QOGPNCUTXVZQSL-UHFFFAOYSA-N 6,7-dimethoxy-1h-quinolin-4-one Chemical compound C1=CC(O)=C2C=C(OC)C(OC)=CC2=N1 QOGPNCUTXVZQSL-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000016844 Immunoglobulin-like domains Human genes 0.000 description 1
- 108050006430 Immunoglobulin-like domains Proteins 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- 102100020880 Kit ligand Human genes 0.000 description 1
- 101710177504 Kit ligand Proteins 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 208000035268 Mast Cell Activation disease Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- NGRZMRGYECEMTH-UHFFFAOYSA-N NC1=CC=C(F)C=C1.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC1=CC=C(N)C=C1 Chemical compound NC1=CC=C(F)C=C1.C=12C=C(OC)C(OC)=CC2=NC=CC=1OC1=CC=C(N)C=C1 NGRZMRGYECEMTH-UHFFFAOYSA-N 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000009905 Neurofibromatoses Diseases 0.000 description 1
- 208000003019 Neurofibromatosis 1 Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 201000010133 Oligodendroglioma Diseases 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 229940082483 carnauba wax Drugs 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 238000005388 cross polarization Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 230000000447 dimerizing effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000009837 dry grinding Methods 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 108060002566 ephrin Proteins 0.000 description 1
- 102000012803 ephrin Human genes 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000011066 hemangioma Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940059904 light mineral oil Drugs 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 201000008806 mesenchymal cell neoplasm Diseases 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 201000004931 neurofibromatosis Diseases 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 208000003154 papilloma Diseases 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- RCCYSVYHULFYHE-UHFFFAOYSA-N pentanediamide Chemical compound NC(=O)CCCC(N)=O RCCYSVYHULFYHE-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 238000012306 spectroscopic technique Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000001622 two pulse phase modulation pulse sequence Methods 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
-
- 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
-
- 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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本願は、2010年7月16日出願の米国出願第61/365,253号および2010年8月5日出願の米国出願第61/370,843号に対する優先権を主張し、これらのそれぞれの全体の内容が、参照によって本明細書に組み込まれる。
化合物Iの薬学的組成物
化合物I
(i)固体13C NMRスペクトルのピークが18.1、42.9、44.5、70.4、123.2、156.2、170.8、175.7、および182.1ppm、±0.2ppmにある。
(ii)粉末x線回折パターン(CuKα λ=1.5418Å)が、6.4、9.0、12.0、12.8、13.5、16.9、19.4、21.5、22.8、25.1、および27.6 °2θ±0.2 °2θから選択される4点以上のピークを含み、結晶質形態の測定は室温で行う。
(iii)固体15N NMRスペクトルのピークが118.6、119.6、120.7、134.8、167.1、176.0、および180ppm、±0.2ppmである、ならびに/または
(i)固体13C NMRスペクトルのピークが23.0、25.9、38.0、54.4、56.11、41.7、69.7、102.0、122.5、177.3、179.3、180.0、および180.3、±0.2ppmにある。
(ii)粉末x線回折パターン(CuKα λ=1.5418Å)が、6.4、9.1、12.0、12.8、13.7、17.1、20.9、21.9、22.6、および23.7 °2θ±0.2 °2θから選択される4点以上のピークを含み、結晶質形態の測定は室温で行う。
(iii)固体15N NMRスペクトルのピークが118.5、120.8、135.1、167.3、および180.1ppmである。
(i)固体13C NMRスペクトルが、20.8、26.2、44.8、55.7、70.7、100.4、101.0、114.7、115.2、116.0、119.7、120.4、121.6、124.4、136.9、138.9、141.1、145.7、150.3、156.5、157.6、159.6、165.2、167.4、171.2、176.3、182.1ppm、±0.2ppmから選択される4つ以上のピークを有する。
(ii)粉末x線回折パターン(CuKα λ=1.5418Å)が、12.8、13.5、16.9、19.4、21.5、22.8、25.1、および27.6、±0.2 °2θから選択される4つ以上の2θ値を含み、結晶質形態の測定は室温で行う、および/または
(iii)固体15N NMRスペクトルのピークが、119.6、134,7、および175.5ppm、±0.2ppmである。
格子の寸法:a=14.60Å
b=5.20Å
c=39.09Å
α=90.0°
β=90.4°
γ=90.0°
空間群:P21/n
化合物Iの分子/単位格子:4
体積=2969Å3
密度(計算値)=1.422g/cm3
回転式キャピラリーを用いる回折装置(CuKα)で収集したパターンに基づいた、室温での特徴的な回折ピークの位置(角度2θ±0.2)
充填剤
結合剤
崩壊剤
流動促進剤
潤滑剤
フィルムコーティング
本明細書に開示される形態のうちの少なくとも1つで、30〜32重量%の化合物I、
50〜70重量%の充填剤、
2〜4重量%の結合剤、
4〜8重量%の崩壊剤、
0.2〜0.6重量%の流動促進剤、および0.5〜1重量%の潤滑剤を含む。
本明細書に開示される形態のうちの少なくとも1つで、30〜32重量%の化合物I、
50〜70重量%の充填剤、
2〜4重量%の結合剤、
4〜8重量%の崩壊剤、
0.2〜0.6重量%の流動促進剤、および0.5〜1重量%の潤滑剤を含み、該組成物はコーティングされる。
プロセス
a)未粉砕の化合物Iを砕塊(delump)するステップと、
b)砕塊した化合物IをAvicel PH102、無水ラクトース 60M、およびクロスカルメロースナトリウムとともに予め混合して、結合剤を形成するステップと、
c)結合剤溶液の湿式高せん断造粒を行い、湿式顆粒を生成するステップと、
d)湿式顆粒を湿式スクリーニングし、湿式スクリーニング処理した顆粒を生成するステップと、
e)湿式スクリーニング処理した顆粒を流動床乾燥させて、乾燥顆粒を生成するステップと、
f)乾燥顆粒を乾式粉砕して、乾式粉砕した顆粒を生成するステップと、
g)乾式粉砕した顆粒をコロイド状ケイ素およびクロスカルメロースと混合して、粒外混合物を生成するステップと、
h)粒外混合物およびステアリン酸マグネシウムを潤滑剤と混合して、最終混合物を生成するステップと、
i)最終混合物を錠剤圧縮して、コーティングされていないコア錠剤を形成するステップと、
j)コーティングされていないコア錠剤をフィルムコーティングするステップと、を含む。
治療方法
実施例1
化合物Iならびに化合物Iおよび化合物IのL−リンゴ酸塩の調製
4−(6,7−ジメトキシ−キノリン−4−イルオキシ)−フェニルアミンの調製
4−(6,7−ジメトキシ−キノリン−4−イルオキシ)−フェニルアミンの代替的調製
1−(4−フルオロフェニルカルバモイル)−シクロプロパンカルボン酸の調製
1−(4−フルオロフェニルカルバモイル)−シクロプロパンカルボニルクロリドの調製
1−(4−フルオロフェニルカルバモイル)−シクロプロパンカルボニルクロリドの代替的調製
シクロプロパン−1,1−ジカルボン酸[4−(6,7−ジメトキシ−キノリン−4−イルオキシ)−フェニル]−アミド(4−フルオロフェニル)−アミドの調製
シクロプロパン−1,1−ジカルボン酸[4−(6,7−ジメトキシ− キノリン−4−イルオキシ)−フェニル]−アミド(4−フルオロフェニル)−アミドの代替的調製
シクロプロパン−1,1−ジカルボン酸[4−(6,7−ジメトキシ−キノリン−4−イルオキシ)−フェニル]−アミド(4−フルオロフェニル)−アミド、(L)リンゴ酸塩の調製
シクロプロパン−1,1−ジカルボン酸[4−(6,7−ジメトキシ−キノリン−4−イルオキシ)−フェニル]−アミド(4−フルオロフェニル)−アミド、(L)リンゴ酸塩の代替的調製
化合物Iおよび化合物I、リンゴ酸塩の結晶質形態の分析の一般的な方法
化合物Iの結晶質L−リンゴ酸塩の調製
固体核磁気共鳴(SSNMR)
化合物IのL−リンゴ酸塩
熱特性測定
熱重量分析(TGA)
示差走査熱量測定(DSC)分析
化合物IのL−リンゴ酸塩
水蒸気吸着等温線測定
Claims (26)
- 前記化合物IのL−リンゴ酸塩が、非晶質形態、実質的に非晶質形態、結晶形態、または実質的に結晶形態である、請求項4に記載の薬学的錠剤組成物。
- 前記化合物IのL−リンゴ酸塩が、結晶形態または非晶質形態である、請求項4に記載の薬学的錠剤組成物。
- 前記充填剤が、ナトリウムデンプングリコレート、コーンスターチ、タルク、スクロース、デキストロース、グルコース、ラクトース、キシリトール、フルクトース、ソルビトール、リン酸カルシウム、硫酸カルシウム、炭酸カルシウム、および微結晶性セルロース、またはそれらの混合物からなる群から選択される、請求項4に記載の薬学的錠剤組成物。
- 前記充填剤がラクトースおよび微結晶性セルロースを含む、請求項7に記載の薬学的錠剤組成物。
- 前記結合剤が、アカシア、アルギン酸、カルボマー、カルボキシメチルセルロースナトリウム、デキストリン、エチルセルロース、ゼラチン、グアーガム、硬化植物油(I型)、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、液体グルコース、ケイ酸アルミニウムマグネシウム、マルトデキストリン、メチルセルロース、ポリメタクリレート類、ポビドン、アルファデンプン、アルギン酸ナトリウム、デンプン、およびゼイン、またはそれらの混合物からなる群から選択される、請求項4に記載の薬学的錠剤組成物。
- 前記結合剤がヒドロキシプロピルセルロースである、請求項9に記載の薬学的錠剤組成物。
- 前記崩壊剤が、アルギン酸、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム、コロイド状二酸化ケイ素、クロスカルメロースナトリウム、クロスポビドン、グアーガム、ケイ酸アルミニウムマグネシウム、メチルセルロース、微結晶性セルロース、ポリアクリリン(polyacrilin)カリウム、粉末セルロース、アルファデンプン、アルギン酸ナトリウム、およびデンプン、またはそれらの混合物からなる群から選択される、請求項10に記載の薬学的錠剤組成物。
- 前記崩壊剤がクロスカルメロースナトリウムである、請求項11に記載の薬学的錠剤組成物。
- 前記流動促進剤がコロイド状二酸化ケイ素である、請求項4に記載の薬学的錠剤組成物。
- 前記潤滑剤が、ステアリン酸マグネシウム、Lubritab.RTM、ステアリン酸、およびタルク、またはそれらの混合物からなる群から選択される、請求項4に記載の薬学的錠剤組成物。
- 前記潤滑剤がステアリン酸マグネシウムである、請求項4に記載の薬学的錠剤組成物。
- フィルムコーティングをさらに含む、請求項4に記載の薬学的錠剤組成物。
- 前記フィルムコーティングがOpadry Yellowを含む、請求項16に記載の薬学的錠剤組成物。
- 錠剤製剤である、請求項1〜4に記載の薬学的錠剤組成物。
- フィルムコーティングをさらに含む、請求項18に記載の薬学的錠剤組成物。
- 前記フィルムコーティングがOpadry yellowを含む、請求項20に記載の薬学的錠剤組成物。
- 請求項1〜4または19に記載の薬学的錠剤組成物を含む癌を治療するための医薬であって、薬学的錠剤組成物が単独でまたは別の治療剤と組み合わせて投与される、医薬。
- 前記癌が、膵臓癌、腎臓癌、肝臓癌、前立腺癌、胃癌、胃食道癌、黒色腫、肺癌、乳癌、甲状腺癌、および星細胞系腫瘍からなる群から選択される、請求項22に記載の医薬。
- 前記癌が、膵臓癌、肝細胞癌(HCC)、腎細胞癌、去勢抵抗性前立腺癌(CRPC)、胃もしくは胃食道接合部癌、黒色腫、小細胞肺癌(SCLC)、卵巣癌、原発性腹膜癌もしくは卵管癌、エストロゲン受容体陽性乳癌、エストロゲン受容体/プロゲステロン受容体/HER2陰性(三重陰性)乳癌、炎症性(受容体の状態にかかわらず)乳癌、非小細胞肺癌(NSCLC)、または甲状腺髄様癌である、請求項23に記載の医薬。
- 化合物Iを含む薬学的錠剤組成物を製造するための方法であって、
a.未粉砕の化合物IのL−リンゴ酸塩を砕塊(delump)するステップと、
b.前記砕塊した化合物IのL−リンゴ酸塩を微結晶性セルロース、無水ラクトース、およびクロスカルメロースナトリウムとともに予め混合して、結合剤溶液を形成するステップと、
c.前記結合剤溶液の湿式高せん断造粒を行い、湿式顆粒を生成するステップと、
d.前記湿式顆粒を湿式スクリーニングし、湿式スクリーニング処理した顆粒を生成するステップと、
e.前記湿式スクリーニング処理した顆粒を流動床乾燥させて、乾燥顆粒を生成するステップと、
f.前記乾燥顆粒を乾式粉砕して、乾式粉砕した顆粒を生成するステップと、
g.前記乾式粉砕した顆粒をコロイド状ケイ素およびクロスカルメロースと混合して、粒外混合物を生成するステップと、
h.前記粒外混合物およびステアリン酸マグネシウムを潤滑剤混合して、最終混合物を生成するステップと、
i.前記最終混合物を錠剤圧縮して、コーティングされていないコア錠剤を形成するステップと、
を含み、化合物Iが
である、方法。 - 前記コーティングされていないコア錠剤のフィルムコーティングのステップをさらに含む、請求項25に記載の方法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US36525310P | 2010-07-16 | 2010-07-16 | |
US61/365,253 | 2010-07-16 | ||
US37084310P | 2010-08-05 | 2010-08-05 | |
US61/370,843 | 2010-08-05 | ||
PCT/US2011/044378 WO2012009722A1 (en) | 2010-07-16 | 2011-07-18 | C-met modulator pharmaceutical compositions |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016093433A Division JP6503317B2 (ja) | 2010-07-16 | 2016-05-06 | C−met調節剤の薬学的組成物 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2013531045A JP2013531045A (ja) | 2013-08-01 |
JP5934204B2 true JP5934204B2 (ja) | 2016-06-15 |
Family
ID=45469828
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013519870A Active JP5934204B2 (ja) | 2010-07-16 | 2011-07-18 | C−met調節剤の薬学的組成物 |
JP2016093433A Active JP6503317B2 (ja) | 2010-07-16 | 2016-05-06 | C−met調節剤の薬学的組成物 |
JP2019056131A Withdrawn JP2019142879A (ja) | 2010-07-16 | 2019-03-25 | C−met調節剤の薬学的組成物 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016093433A Active JP6503317B2 (ja) | 2010-07-16 | 2016-05-06 | C−met調節剤の薬学的組成物 |
JP2019056131A Withdrawn JP2019142879A (ja) | 2010-07-16 | 2019-03-25 | C−met調節剤の薬学的組成物 |
Country Status (23)
Country | Link |
---|---|
US (10) | US9724342B2 (ja) |
EP (2) | EP2593090B1 (ja) |
JP (3) | JP5934204B2 (ja) |
KR (6) | KR20200029633A (ja) |
CN (3) | CN106420743A (ja) |
AR (1) | AR082252A1 (ja) |
AU (4) | AU2011278950C1 (ja) |
BR (1) | BR112013000980B1 (ja) |
CA (1) | CA2805645C (ja) |
DK (1) | DK2593090T3 (ja) |
EA (1) | EA030435B1 (ja) |
ES (1) | ES2904646T3 (ja) |
HU (1) | HUE057184T2 (ja) |
IL (2) | IL224189A (ja) |
LT (1) | LT2593090T (ja) |
MX (1) | MX336741B (ja) |
NZ (1) | NZ607118A (ja) |
PL (1) | PL2593090T3 (ja) |
PT (1) | PT2593090T (ja) |
SG (2) | SG10201609324UA (ja) |
TW (3) | TWI619495B (ja) |
WO (1) | WO2012009722A1 (ja) |
ZA (1) | ZA201300458B (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016188215A (ja) * | 2010-07-16 | 2016-11-04 | エクセリクシス, インク. | C−met調節剤の薬学的組成物 |
Families Citing this family (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW202241853A (zh) | 2009-01-16 | 2022-11-01 | 美商艾克塞里克斯公司 | 包含n-(4-{[6,7-雙(甲氧基)喹啉-4-基]氧基}苯基)-n'-(4-氟苯基)環丙烷-1,1-二甲醯胺之蘋果酸鹽之醫藥組合物及其用途 |
UA108618C2 (uk) | 2009-08-07 | 2015-05-25 | Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку | |
WO2012044572A1 (en) | 2010-09-27 | 2012-04-05 | Exelixis, Inc. | Dual inhibitors of met and vegf for the treatment of castration- resistant prostate cancer and osteoblastic bone metastases |
JP2014505109A (ja) | 2011-02-10 | 2014-02-27 | エクセリクシス, インク. | キノリン化合物およびそのような化合物を含有する医薬組成物の調製方法 |
US20120252840A1 (en) | 2011-04-04 | 2012-10-04 | Exelixis, Inc. | Method of Treating Cancer |
GEP201706678B (en) | 2011-05-02 | 2017-06-12 | Exelixis Inc | Method of treating cancer and bone cancer |
MX351133B (es) | 2011-09-22 | 2017-10-03 | Exelixis Inc | Metodo para tratar osteoporosis. |
CA2852771C (en) | 2011-10-20 | 2019-11-26 | Exelixis, Inc. | Process for preparing quinoline derivatives |
JP2015515988A (ja) | 2012-05-02 | 2015-06-04 | エクセリクシス, インク. | 溶骨性骨転移を治療するためのmet−vegf二重調節剤 |
CN103664776B (zh) * | 2012-09-26 | 2016-05-04 | 正大天晴药业集团股份有限公司 | 一种酪氨酸激酶抑制剂及其中间体的制备方法 |
NZ712330A (en) | 2013-03-15 | 2020-04-24 | Exelixis Inc | Metabolites of n-(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl)-n’-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide |
US11564915B2 (en) | 2013-04-04 | 2023-01-31 | Exelixis, Inc. | Cabozantinib dosage form and use in the treatment of cancer |
CN104370811B (zh) * | 2013-08-15 | 2019-02-12 | 广东东阳光药业有限公司 | 一种喹啉化合物的新晶型及其制备方法 |
CN104649969B (zh) * | 2013-11-22 | 2019-02-12 | 广东东阳光药业有限公司 | 一种替尼类药物的盐及其制备方法 |
CN103751140A (zh) * | 2014-01-15 | 2014-04-30 | 青岛市肿瘤医院 | 一种Cabozantinib分散片及其制备方法 |
MX2021001583A (es) | 2014-02-14 | 2023-02-08 | Exelixis Inc | Formas sólidas cristalinas de n-{4-[(6,7-dimetoxiquinolin-4-il)oxi ] fenil}-n'-(4-fluorofenil)ciclopropan-1,1-dicarboxamida, procesos para elaboración y métodos de uso. |
EP3119476A1 (en) | 2014-03-17 | 2017-01-25 | Exelixis, Inc. | Dosing of cabozantinib formulations |
CN104788372B (zh) * | 2014-07-25 | 2018-01-30 | 上海圣考医药科技有限公司 | 一种氘代卡博替尼衍生物、其制备方法、应用及其中间体 |
WO2016019285A1 (en) | 2014-07-31 | 2016-02-04 | Exelixis, Inc. | Method of preparing fluorine-18 labeled cabozantinib and its analogs |
US11065240B2 (en) | 2014-08-05 | 2021-07-20 | Exelixis, Inc. | Drug combinations to treat multiple myeloma |
CN105503717A (zh) * | 2014-09-24 | 2016-04-20 | 江苏奥赛康药业股份有限公司 | 一种苹果酸卡博替尼化合物及其药物组合物 |
MA44672A (fr) * | 2016-04-15 | 2019-02-20 | Exelixis Inc | Procédé de traitement du cancer à cellules rénales à l'aide de n-(4-(6,7-diméthoxyquinolin-4-yloxy) phényl)-n'-(4-fluorophény)cyclopropane-1,1-dicarboxamide, (2s)-hydroxybutanedioate |
CN109475545A (zh) * | 2016-04-19 | 2019-03-15 | 埃克塞里艾克西斯公司 | 三阴性乳腺癌治疗方法 |
MA46355A (fr) | 2016-09-27 | 2019-08-07 | The Us Secretary Department Of Health And Human Services Office Of Technology Transfer | Procédé de traitement du carcinome urothélial et d'autres malignités génito-urinaires à l'aide de n-(4-(6,7-diméthoxyquinolin-4-yloxy)-phényl)-n'-(4-fluorophényl)cyclopropane -1,1-dicarboxamide |
EP3551612A4 (en) * | 2016-12-07 | 2020-08-12 | MSN Laboratories Private Limited, R&D Center | PROCESS FOR THE PREPARATION OF N- (4- (6,7-DIMETHOXYQUINOLIN-4-YLOXY) PHENYL) -N '- (4-FLUOROPHENYL) CYCLOPROPANE-1, 1-DICARBOXAMIDE, (2S) -HYDROXYBUTANYEDIOOR AND ITS POLYDROXYBUTANYMATE |
MA47310A (fr) | 2017-01-20 | 2019-11-27 | Exelixis Inc | Combinaisons de cabozantinib et d'atzolizumab pour traiter le cancer |
MA48776A (fr) | 2017-05-26 | 2020-04-08 | Exelixis Inc | Formes solides cristallines de sels de n-{4-[(6,7-diméthoxyquinolin-4-yl) oxy]phényl}-n'-(4-fluorphényl) cyclopropane-1,1-dicarboxamide, procédés de préparation et d'utilisation |
KR20200016969A (ko) * | 2017-06-16 | 2020-02-17 | 베타 파마, 인크. | N-(2-(2-(디메틸아미노)에톡시)-4-메톡시-5-((4-(1-메틸-1h-인돌-3-일)피리미딘-2-일)아미노)페닐)아크릴아미드 및 그의 염의 제약 제제 |
US20190262330A1 (en) * | 2017-12-21 | 2019-08-29 | Exelixis, Inc. | Method of Treating Hepatocellular Carcinoma Using N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate |
CN117820226A (zh) | 2018-01-26 | 2024-04-05 | 埃克塞里艾克西斯公司 | 用于治疗激酶依赖性病症的化合物 |
EP3806858A4 (en) | 2018-06-15 | 2022-03-09 | Handa Pharmaceuticals, Inc. | SALTS OF KINASE INHIBITORS AND ASSOCIATED COMPOSITIONS |
WO2020075196A1 (en) * | 2018-10-11 | 2020-04-16 | Cipla Limited | Polymorphs of n-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-n'-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide, (s)- malate, methods of production and pharmaceutical uses thereof |
PE20230110A1 (es) * | 2020-04-30 | 2023-01-25 | Exelixis Inc | Procesos para la preparacion de un inhibidor de cinasa |
EP4240333A1 (en) * | 2020-11-05 | 2023-09-13 | Exelixis, Inc. | Pharmaceutical compositions of a kinase inhibitor |
US11613630B2 (en) | 2020-12-03 | 2023-03-28 | Iowa State University Research Foundation | Solid dry-type lubricant |
WO2023122723A1 (en) | 2021-12-23 | 2023-06-29 | The Broad Institute, Inc. | Panels and methods for diagnosing and treating lung cancer |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003225668A1 (en) | 2002-03-01 | 2003-09-16 | Pintex Pharmaceutical, Inc. | Pin1-modulating compounds and methods of use thereof |
ES2371383T3 (es) | 2003-09-26 | 2011-12-30 | Exelixis, Inc. | N-[3-fluoro-4-({6-(metiloxi)-7-[(3-morfolin-4-ilpropil)oxi]quinolin-4-il}oxi)fenil]-n'-(4-fluorofenil)ciclopropan-1,1-dicarboxamida para el tratamiento del cáncer. |
CA2543820C (en) * | 2003-11-07 | 2012-07-10 | Chiron Corporation | Methods for synthesizing quinolinone compounds |
JP4648835B2 (ja) * | 2003-12-25 | 2011-03-09 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 4−(3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ)−7−メトキシ−6−キノリンカルボキサミドの塩またはその溶媒和物の結晶およびそれらの製造方法 |
US7977345B2 (en) | 2004-07-02 | 2011-07-12 | Exelixis, Inc. | c-MET modulators and method of use |
WO2006108059A1 (en) | 2005-04-06 | 2006-10-12 | Exelixis, Inc. | C-met modulators and methods of use |
WO2008076415A1 (en) | 2006-12-14 | 2008-06-26 | Exelixis, Inc. | Methods of using mek inhibitors |
WO2008083319A1 (en) | 2006-12-29 | 2008-07-10 | Il Yang Pharmaceutical Company, Ltd. | Solid state forms of enantiopure ilaprazole |
UY31800A (es) | 2008-05-05 | 2009-11-10 | Smithkline Beckman Corp | Metodo de tratamiento de cancer usando un inhibidor de cmet y axl y un inhibidor de erbb |
AR075084A1 (es) | 2008-09-26 | 2011-03-09 | Smithkline Beecham Corp | Metodo de preparacion de quinolinil -oxidifenil - ciclopropanodicarboxamidas e intermediarios correspondientes |
MX2011005038A (es) | 2008-11-13 | 2011-06-16 | Exelisis Inc | Metodo de preparacion de derivados de quinolina. |
TW201028383A (en) | 2008-12-04 | 2010-08-01 | Exelixis Inc | Methods of preparing quinoline derivatives |
TW202241853A (zh) | 2009-01-16 | 2022-11-01 | 美商艾克塞里克斯公司 | 包含n-(4-{[6,7-雙(甲氧基)喹啉-4-基]氧基}苯基)-n'-(4-氟苯基)環丙烷-1,1-二甲醯胺之蘋果酸鹽之醫藥組合物及其用途 |
WO2011009095A1 (en) | 2009-07-17 | 2011-01-20 | Exelixis, Inc. | Crystalline forms of n-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quin0lin-4-yl}oxy)phenyl]-n'-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide |
UA108618C2 (uk) | 2009-08-07 | 2015-05-25 | Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку | |
WO2011031840A1 (en) * | 2009-09-09 | 2011-03-17 | Quintiles Transnational Corp. | Methods and compositions for the treatment of receptor tyrosine kinase mediated diseases or disorders |
US20130143881A1 (en) | 2010-03-12 | 2013-06-06 | Exelixis, Inc. | Hydrated Crystalline Forms of N-[3-fluoro-4-(oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide |
US20120070368A1 (en) | 2010-04-16 | 2012-03-22 | Exelixis, Inc. | Methods of Using C-Met Modulators |
WO2012009723A1 (en) | 2010-07-16 | 2012-01-19 | Exelixis, Inc. | C-met modulator pharmaceutical compositions |
MX336741B (es) | 2010-07-16 | 2016-01-29 | Exelixis Inc | Composiciones farmaceuticas de moduladores de c-met. |
WO2012044572A1 (en) | 2010-09-27 | 2012-04-05 | Exelixis, Inc. | Dual inhibitors of met and vegf for the treatment of castration- resistant prostate cancer and osteoblastic bone metastases |
US20140057908A1 (en) | 2010-09-27 | 2014-02-27 | Exelixis, Inc. | Method of Treating Cancer |
JP2013540759A (ja) | 2010-09-27 | 2013-11-07 | エクセリクシス, インク. | 去勢抵抗性前立腺癌および造骨性転移の治療のためのmetおよびvegfの二元阻害薬 |
US20130252956A1 (en) | 2010-11-22 | 2013-09-26 | Howard Kallender | Methods of treating cancer |
JP2014505109A (ja) | 2011-02-10 | 2014-02-27 | エクセリクシス, インク. | キノリン化合物およびそのような化合物を含有する医薬組成物の調製方法 |
US20120252840A1 (en) | 2011-04-04 | 2012-10-04 | Exelixis, Inc. | Method of Treating Cancer |
GEP201706678B (en) | 2011-05-02 | 2017-06-12 | Exelixis Inc | Method of treating cancer and bone cancer |
TW201306842A (zh) | 2011-06-15 | 2013-02-16 | Exelixis Inc | 使用pi3k/mtor吡啶並嘧啶酮抑制劑及苯達莫司汀及/或利妥昔單抗治療惡性血液疾病之組合療法 |
CA2852771C (en) | 2011-10-20 | 2019-11-26 | Exelixis, Inc. | Process for preparing quinoline derivatives |
-
2011
- 2011-07-18 MX MX2013000567A patent/MX336741B/es unknown
- 2011-07-18 JP JP2013519870A patent/JP5934204B2/ja active Active
- 2011-07-18 KR KR1020207007177A patent/KR20200029633A/ko active Application Filing
- 2011-07-18 PL PL11740764T patent/PL2593090T3/pl unknown
- 2011-07-18 KR KR1020227000133A patent/KR20220005631A/ko not_active Application Discontinuation
- 2011-07-18 KR KR1020137003043A patent/KR101862324B1/ko active IP Right Review Request
- 2011-07-18 HU HUE11740764A patent/HUE057184T2/hu unknown
- 2011-07-18 TW TW105119659A patent/TWI619495B/zh active
- 2011-07-18 LT LTEPPCT/US2011/044378T patent/LT2593090T/lt unknown
- 2011-07-18 KR KR1020197010923A patent/KR20190042768A/ko active Application Filing
- 2011-07-18 CN CN201610157218.7A patent/CN106420743A/zh active Pending
- 2011-07-18 CA CA2805645A patent/CA2805645C/en active Active
- 2011-07-18 SG SG10201609324UA patent/SG10201609324UA/en unknown
- 2011-07-18 AR ARP110102584A patent/AR082252A1/es not_active Application Discontinuation
- 2011-07-18 CN CN202111624430.7A patent/CN114209699A/zh active Pending
- 2011-07-18 EP EP11740764.3A patent/EP2593090B1/en active Active
- 2011-07-18 PT PT117407643T patent/PT2593090T/pt unknown
- 2011-07-18 KR KR1020187014254A patent/KR20180056807A/ko active Application Filing
- 2011-07-18 US US13/810,537 patent/US9724342B2/en active Active
- 2011-07-18 NZ NZ607118A patent/NZ607118A/en unknown
- 2011-07-18 AU AU2011278950A patent/AU2011278950C1/en active Active
- 2011-07-18 WO PCT/US2011/044378 patent/WO2012009722A1/en active Application Filing
- 2011-07-18 BR BR112013000980-2A patent/BR112013000980B1/pt active IP Right Grant
- 2011-07-18 TW TW100125336A patent/TWI516477B/zh active
- 2011-07-18 DK DK11740764.3T patent/DK2593090T3/da active
- 2011-07-18 CN CN2011800446021A patent/CN103221035A/zh active Pending
- 2011-07-18 TW TW104132637A patent/TW201602083A/zh unknown
- 2011-07-18 EA EA201300146A patent/EA030435B1/ru active Protection Beyond IP Right Term
- 2011-07-18 EP EP21202135.6A patent/EP4014971A1/en active Pending
- 2011-07-18 KR KR1020217003243A patent/KR20210014770A/ko not_active Application Discontinuation
- 2011-07-18 ES ES11740764T patent/ES2904646T3/es active Active
- 2011-07-18 SG SG2013002704A patent/SG187060A1/en unknown
-
2013
- 2013-01-13 IL IL224189A patent/IL224189A/en active IP Right Grant
- 2013-01-17 ZA ZA2013/00458A patent/ZA201300458B/en unknown
-
2016
- 2016-05-06 JP JP2016093433A patent/JP6503317B2/ja active Active
- 2016-10-18 AU AU2016247044A patent/AU2016247044A1/en not_active Abandoned
-
2017
- 2017-02-07 US US15/426,804 patent/US10039757B2/en active Active
- 2017-06-02 US US15/612,703 patent/US10034873B2/en active Active
- 2017-07-05 IL IL253333A patent/IL253333A0/en unknown
-
2018
- 2018-07-03 US US16/026,708 patent/US10548888B2/en active Active
- 2018-08-22 AU AU2018220045A patent/AU2018220045B2/en active Active
-
2019
- 2019-03-25 JP JP2019056131A patent/JP2019142879A/ja not_active Withdrawn
- 2019-12-20 US US16/722,563 patent/US11123338B2/en active Active
-
2020
- 2020-06-03 AU AU2020203645A patent/AU2020203645A1/en not_active Abandoned
-
2021
- 2021-08-23 US US17/409,098 patent/US20210379050A1/en not_active Abandoned
- 2021-10-19 US US17/505,307 patent/US20220031688A1/en not_active Abandoned
- 2021-11-30 US US17/538,310 patent/US20220087999A1/en not_active Abandoned
-
2022
- 2022-07-20 US US17/869,427 patent/US20220370436A1/en not_active Abandoned
-
2023
- 2023-10-20 US US18/491,407 patent/US20240156804A1/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2016188215A (ja) * | 2010-07-16 | 2016-11-04 | エクセリクシス, インク. | C−met調節剤の薬学的組成物 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5934204B2 (ja) | C−met調節剤の薬学的組成物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20140714 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20150623 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20150924 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20151022 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20151120 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20151224 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20160405 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20160506 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5934204 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R153 | Grant of patent term extension |
Free format text: JAPANESE INTERMEDIATE CODE: R153 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |