TW202245746A - Compositions of essentially pure form iv of n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof - Google Patents
Compositions of essentially pure form iv of n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof Download PDFInfo
- Publication number
- TW202245746A TW202245746A TW111105793A TW111105793A TW202245746A TW 202245746 A TW202245746 A TW 202245746A TW 111105793 A TW111105793 A TW 111105793A TW 111105793 A TW111105793 A TW 111105793A TW 202245746 A TW202245746 A TW 202245746A
- Authority
- TW
- Taiwan
- Prior art keywords
- fluoro
- dihydroxypropoxy
- difluoro
- phenylamino
- benzamide
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 119
- SUDAHWBOROXANE-SECBINFHSA-N PD 0325901 Chemical compound OC[C@@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-SECBINFHSA-N 0.000 title claims abstract description 64
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 107
- 238000000034 method Methods 0.000 claims abstract description 102
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 87
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 46
- 201000011510 cancer Diseases 0.000 claims abstract description 23
- 239000003937 drug carrier Substances 0.000 claims abstract description 7
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 98
- -1 iodo-phenylamino Chemical group 0.000 claims description 80
- 239000002775 capsule Substances 0.000 claims description 58
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 51
- 239000012535 impurity Substances 0.000 claims description 47
- 229910052740 iodine Inorganic materials 0.000 claims description 36
- 239000011630 iodine Substances 0.000 claims description 36
- 239000003085 diluting agent Substances 0.000 claims description 31
- 201000004404 Neurofibroma Diseases 0.000 claims description 30
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 238000003860 storage Methods 0.000 claims description 28
- 201000010099 disease Diseases 0.000 claims description 27
- 239000007884 disintegrant Substances 0.000 claims description 27
- 239000000314 lubricant Substances 0.000 claims description 23
- 229940124647 MEK inhibitor Drugs 0.000 claims description 21
- 230000004075 alteration Effects 0.000 claims description 21
- 239000000539 dimer Substances 0.000 claims description 21
- 208000003019 Neurofibromatosis 1 Diseases 0.000 claims description 19
- 208000024834 Neurofibromatosis type 1 Diseases 0.000 claims description 19
- 230000035772 mutation Effects 0.000 claims description 19
- 102000016914 ras Proteins Human genes 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 17
- 108090000623 proteins and genes Proteins 0.000 claims description 16
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 14
- 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
- 239000007903 gelatin capsule Substances 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 13
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 13
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 13
- 201000005202 lung cancer Diseases 0.000 claims description 13
- 208000020816 lung neoplasm Diseases 0.000 claims description 13
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 claims description 12
- 206010025323 Lymphomas Diseases 0.000 claims description 12
- 208000032839 leukemia Diseases 0.000 claims description 12
- 208000002761 neurofibromatosis 2 Diseases 0.000 claims description 12
- 208000022032 neurofibromatosis type 2 Diseases 0.000 claims description 12
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 12
- 208000004748 plexiform neurofibroma Diseases 0.000 claims description 12
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 12
- 101710146526 Dual specificity mitogen-activated protein kinase kinase 1 Proteins 0.000 claims description 11
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 claims description 11
- 101710146529 Dual specificity mitogen-activated protein kinase kinase 2 Proteins 0.000 claims description 10
- 206010029748 Noonan syndrome Diseases 0.000 claims description 10
- 239000007937 lozenge Substances 0.000 claims description 10
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 230000005855 radiation Effects 0.000 claims description 8
- AHVXTFGWPOQIDO-SNVBAGLBSA-N (2R)-3-(2,3-difluoro-N-(2-fluoro-4-iodophenyl)anilino)oxypropane-1,2-diol Chemical compound O[C@@H](CON(C1=CC=CC(=C1F)F)C1=C(C=C(C=C1)I)F)CO AHVXTFGWPOQIDO-SNVBAGLBSA-N 0.000 claims description 7
- 206010009944 Colon cancer Diseases 0.000 claims description 7
- 206010067380 Costello Syndrome Diseases 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 6
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 6
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 claims description 6
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 6
- 206010003908 B-cell small lymphocytic lymphoma Diseases 0.000 claims description 6
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 6
- 206010005003 Bladder cancer Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 6
- 201000009030 Carcinoma Diseases 0.000 claims description 6
- 201000002927 Cardiofaciocutaneous syndrome Diseases 0.000 claims description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 6
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 6
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 claims description 6
- 206010014733 Endometrial cancer Diseases 0.000 claims description 6
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 6
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 6
- 102100029974 GTPase HRas Human genes 0.000 claims description 6
- 102100030708 GTPase KRas Human genes 0.000 claims description 6
- 102100039788 GTPase NRas Human genes 0.000 claims description 6
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 6
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 claims description 6
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 claims description 6
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 claims description 6
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 claims description 6
- 101000954986 Homo sapiens Merlin Proteins 0.000 claims description 6
- 101001130509 Homo sapiens Ras GTPase-activating protein 1 Proteins 0.000 claims description 6
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 6
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 6
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 6
- 102100037106 Merlin Human genes 0.000 claims description 6
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 6
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 6
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 6
- 102000007530 Neurofibromin 1 Human genes 0.000 claims description 6
- 108010085793 Neurofibromin 1 Proteins 0.000 claims description 6
- 108010085839 Neurofibromin 2 Proteins 0.000 claims description 6
- 102000007517 Neurofibromin 2 Human genes 0.000 claims description 6
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 208000031839 Peripheral nerve sheath tumour malignant Diseases 0.000 claims description 6
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 102100031426 Ras GTPase-activating protein 1 Human genes 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 6
- 206010039491 Sarcoma Diseases 0.000 claims description 6
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 claims description 6
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 6
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 6
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 6
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 6
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 6
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 6
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 claims description 6
- 208000002517 adenoid cystic carcinoma Diseases 0.000 claims description 6
- 201000009036 biliary tract cancer Diseases 0.000 claims description 6
- 208000020790 biliary tract neoplasm Diseases 0.000 claims description 6
- 208000035269 cancer or benign tumor Diseases 0.000 claims description 6
- 201000010881 cervical cancer Diseases 0.000 claims description 6
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 6
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 6
- 201000004101 esophageal cancer Diseases 0.000 claims description 6
- 201000003444 follicular lymphoma Diseases 0.000 claims description 6
- 201000010175 gallbladder cancer Diseases 0.000 claims description 6
- 206010017758 gastric cancer Diseases 0.000 claims description 6
- 201000010536 head and neck cancer Diseases 0.000 claims description 6
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 6
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 6
- 208000029824 high grade glioma Diseases 0.000 claims description 6
- 201000010982 kidney cancer Diseases 0.000 claims description 6
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 6
- 208000030173 low grade glioma Diseases 0.000 claims description 6
- 201000005249 lung adenocarcinoma Diseases 0.000 claims description 6
- 230000003211 malignant effect Effects 0.000 claims description 6
- 201000011614 malignant glioma Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000009020 malignant peripheral nerve sheath tumor Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 208000029974 neurofibrosarcoma Diseases 0.000 claims description 6
- 208000022982 optic pathway glioma Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 210000000578 peripheral nerve Anatomy 0.000 claims description 6
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 claims description 6
- 208000004548 serous cystadenocarcinoma Diseases 0.000 claims description 6
- 201000000849 skin cancer Diseases 0.000 claims description 6
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 6
- 239000008109 sodium starch glycolate Substances 0.000 claims description 6
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 6
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- 201000002510 thyroid cancer Diseases 0.000 claims description 6
- 206010044412 transitional cell carcinoma Diseases 0.000 claims description 6
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 6
- 208000023747 urothelial carcinoma Diseases 0.000 claims description 6
- 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 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 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 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 5
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 229940032147 starch Drugs 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 5
- 239000000454 talc Substances 0.000 claims description 5
- 229910052623 talc Inorganic materials 0.000 claims description 5
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- 150000004781 alginic acids Chemical class 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
- 229960001375 lactose Drugs 0.000 claims description 4
- 201000000564 macroglobulinemia Diseases 0.000 claims description 4
- 229960001855 mannitol Drugs 0.000 claims description 4
- 230000009826 neoplastic cell growth Effects 0.000 claims description 4
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 3
- 201000006037 primary mediastinal B-cell lymphoma Diseases 0.000 claims description 3
- 239000007909 solid dosage form Substances 0.000 claims description 3
- 208000005101 LEOPARD Syndrome Diseases 0.000 claims description 2
- 208000006286 Legius syndrome Diseases 0.000 claims description 2
- 208000010708 Noonan syndrome with multiple lentigines Diseases 0.000 claims description 2
- 208000016025 Waldenstroem macroglobulinemia Diseases 0.000 claims description 2
- 229930003231 vitamin Natural products 0.000 claims description 2
- 239000011782 vitamin Substances 0.000 claims description 2
- 235000013343 vitamin Nutrition 0.000 claims description 2
- 229940088594 vitamin Drugs 0.000 claims description 2
- WEENBLOBOHLAFE-UHFFFAOYSA-N docosanoic acid;propane-1,2,3-triol Chemical class OCC(O)CO.CCCCCCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCCCCCC(O)=O WEENBLOBOHLAFE-UHFFFAOYSA-N 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 150000001408 amides Chemical class 0.000 description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 47
- SUQGZILRDVFAIJ-LLVKDONJSA-N OC[C@H](CONCC(C=CC(F)=C1F)=C1NC(C=CC(I)=C1)=C1F)O Chemical class OC[C@H](CONCC(C=CC(F)=C1F)=C1NC(C=CC(I)=C1)=C1F)O SUQGZILRDVFAIJ-LLVKDONJSA-N 0.000 description 23
- SUDAHWBOROXANE-VIFPVBQESA-N PD 0325901-Cl Chemical compound OC[C@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-VIFPVBQESA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000007787 solid Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000007792 addition Methods 0.000 description 16
- 238000002844 melting Methods 0.000 description 15
- 230000008018 melting Effects 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 238000001953 recrystallisation Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 12
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 230000004083 survival effect Effects 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 150000001412 amines Chemical group 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 6
- CUMTUBVTKOYYOU-UHFFFAOYSA-N 2-fluoro-4-iodoaniline Chemical compound NC1=CC=C(I)C=C1F CUMTUBVTKOYYOU-UHFFFAOYSA-N 0.000 description 5
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 208000037821 progressive disease Diseases 0.000 description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 5
- 102000043136 MAP kinase family Human genes 0.000 description 4
- 108091054455 MAP kinase family Proteins 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000007660 Residual Neoplasm Diseases 0.000 description 4
- 238000005859 coupling reaction Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 230000009466 transformation Effects 0.000 description 4
- KWBXUOMYWXLJHA-UHFFFAOYSA-N 3-fluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical group FC=1C(=C(C(=O)N)C=CC=1)NC1=C(C=C(C=C1)I)F KWBXUOMYWXLJHA-UHFFFAOYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- FNAWJOBKLWLHTA-UHFFFAOYSA-N [4-(trifluoromethyl)benzoyl] 4-(trifluoromethyl)benzoate Chemical compound C1=CC(C(F)(F)F)=CC=C1C(=O)OC(=O)C1=CC=C(C(F)(F)F)C=C1 FNAWJOBKLWLHTA-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000001757 thermogravimetry curve Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 235000012431 wafers Nutrition 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- WEPXLRANFJEOFZ-UHFFFAOYSA-N 2,3,4-trifluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C(F)=C1F WEPXLRANFJEOFZ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000007894 caplet Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- BYNVYIUJKRRNNC-UHFFFAOYSA-N docosanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCCCCCCCC(O)=O BYNVYIUJKRRNNC-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000009533 lab test Methods 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 2
- 208000025421 tumor of uterus Diseases 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 1
- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102100038742 Cytochrome P450 2A13 Human genes 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 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 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- LFERELMXERXKKQ-KMXXXSRASA-N Fenugreekine Chemical compound NC(=O)C1=CC=CC([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=N1 LFERELMXERXKKQ-KMXXXSRASA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 101000957389 Homo sapiens Cytochrome P450 2A13 Proteins 0.000 description 1
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- 108010068342 MAP Kinase Kinase 1 Proteins 0.000 description 1
- 108010068353 MAP Kinase Kinase 2 Proteins 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 241001139947 Mida Species 0.000 description 1
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 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 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 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
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000001973 epigenetic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 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 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229940071539 mirdametinib Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000004208 shellac Substances 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
- 229940113147 shellac Drugs 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- HYEGLMPHWGFMSN-UHFFFAOYSA-N trifluoromethanesulfonic acid;trifluoromethylsulfonyl trifluoromethanesulfonate Chemical compound OS(=O)(=O)C(F)(F)F.FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F HYEGLMPHWGFMSN-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
Abstract
Description
本揭示案係關於:a)結晶組合物,其為N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV;b)醫藥組合物,其包含為N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV之該結晶組合物,及視情況醫藥學上可接受之載劑;及c)治療腫瘤、癌症或RAS病(Rasopathy disorder)之方法,其係藉由向有需要之個體投與為N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV之該結晶組合物來實施。This disclosure relates to: a) a crystalline composition which is N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- phenylamino)-benzamide in substantially pure form IV; b) a pharmaceutical composition comprising N-((R)-2,3-dihydroxypropoxy)-3,4-di The crystalline composition of fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in substantially pure Form IV, and optionally a pharmaceutically acceptable carrier; and c ) method for treating tumor, cancer or RAS disease (Rasopathy disorder) by administering N-((R)-2,3-dihydroxypropoxy)-3,4-di This crystalline composition of fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide in substantially pure Form IV was performed.
N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺(「米達替尼(mirdametinib)」或「PD-0325901」)係一種小分子藥物,其經設計以抑制促***原活化之蛋白激酶激酶1 (「MEK1」)及促***原活化之蛋白激酶激酶2 (「MEK2」)。MEK1及MEK2係在促***原活化之蛋白激酶(「MAPK」)信號傳導路徑中起關鍵作用之蛋白質。MAPK路徑對於細胞存活及增殖而言至關重要,且已顯示此路徑之過活化導致腫瘤發育及生長。米達替尼係MEK1及MEK2之高度強效及特異性別位非ATP競爭性抑制劑。由於其作用機制,米達替尼顯著抑制細胞外調控之MAP激酶ERK1及ERK2之磷酸化,藉此使得活體外及活體內之腫瘤細胞生長受損。另外,有證據指示,發炎性細胞介素誘導之MEK/ERK活性增加導致與類風濕性關節炎及其他發炎性疾病相關之發炎、疼痛及組織破壞。N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide ("Mida Mirdametinib" or "PD-0325901") is a small molecule drug designed to inhibit mitogen-activated protein kinase kinase 1 ("MEK1") and mitogen-activated protein kinase kinase 2 ("MEK1") MEK2"). MEK1 and MEK2 are proteins that play key roles in the mitogen-activated protein kinase ("MAPK") signaling pathway. The MAPK pathway is critical for cell survival and proliferation, and overactivation of this pathway has been shown to lead to tumor development and growth. Midatinib is a highly potent and specific allotopic non-ATP competitive inhibitor of MEK1 and MEK2. Due to its mechanism of action, midatinib significantly inhibits the phosphorylation of the extracellularly regulated MAP kinases ERK1 and ERK2, thereby impairing tumor cell growth in vitro and in vivo. In addition, evidence indicates that increased MEK/ERK activity induced by inflammatory cytokines contributes to the inflammation, pain and tissue destruction associated with rheumatoid arthritis and other inflammatory diseases.
先前已闡述N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之晶體形式。WO2002/006213闡述結晶形式I及II。美國專利第7,060,856號(「'856專利」)闡述產生形式IV之方法。'856專利指示,藉由此方法產生之材料為大於90%之形式IV (‘856專利,實例1)。'856專利亦陳述,所產生材料之示差掃描量熱法(「DSC」)顯示在110℃開始熔融以及在117℃開始之小峰,此與該材料為兩種形式之混合物一致。The effect of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide has been described previously. crystal form. WO2002/006213 describes crystalline forms I and II. US Patent No. 7,060,856 (the "'856 Patent") describes a method of producing Form IV. The '856 patent indicates that the material produced by this method is greater than 90% Form IV (the '856 patent, Example 1). The '856 patent also states that differential scanning calorimetry ("DSC") of the resulting material showed melting onset at 110°C and a small peak at 117°C, consistent with the material being a mixture of the two forms.
WO 2006/134469 (「'469 PCT公開案」)亦闡述合成N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之方法。'469 PCT公開案報導該方法所產生之產物與頒布為'856專利之美國專利申請案第10/969,681號中所揭示之多晶形式IV一致。WO 2006/134469 ("'469 PCT Publication") also describes the synthesis of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- Iodo-phenylamino)-benzamide method. The '469 PCT publication reports that this process produces a product consistent with polymorphic Form IV disclosed in US Patent Application Serial No. 10/969,681, which issued as the '856 patent.
含有一種以上多晶形式之組合物通常係不期望的,此乃因一種多晶形式有可能互變成另一種形式。由於溶解度或生物利用度之差異,多晶形互變可導致有效劑量或物理性質之差異,影響藥物加工性。因此,業內需要含有N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV之組合物,以用於治療腫瘤、癌症或RAS病。Compositions containing more than one polymorphic form are generally undesirable because of the potential for one polymorphic form to interconvert into another. Due to differences in solubility or bioavailability, polymorphic interconversion can lead to differences in effective dosage or physical properties, affecting drug processability. Therefore, there is a need in the industry to contain N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoyl Compositions of amines in substantially pure form IV for use in the treatment of tumors, cancer or RAS disease.
本揭示案係關於可用組合物及方法,其用以治療有需要之個體的涉及異常MEK1或MEK2活性之病症,該等病症為例如癌症、腫瘤或RAS病,諸如1型神經纖維瘤病。The present disclosure relates to compositions and methods useful for treating disorders involving aberrant MEK1 or MEK2 activity, such as cancer, tumors, or RAS disorders, such as neurofibromatosis type 1, in individuals in need thereof.
在一些態樣中,本揭示案係關於式(I)之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV之結晶組合物 。 In some aspects, the disclosure relates to N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- Substantially pure crystalline composition of form IV of iodo-phenylamino)-benzamide .
在一些態樣中,基本上純的N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物不含任何量之能藉由XRPD及/或DSC偵測到之形式I或形式II。In some aspects, substantially pure N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino The crystalline composition of )-benzamide did not contain any amount of Form I or Form II detectable by XRPD and/or DSC.
在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存3個月後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存6個月後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存1年後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存5年後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存68個月後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存≥140個月後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存≥14年後展現實質上不變之XRPD圖案及/或DSC曲線。In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage at standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 3 months. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage under standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 6 months. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage at standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 1 year. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage for 5 years under standard warehouse conditions (15°C-25°C and < 65% relative humidity). In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage under standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 68 months. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage for >140 months at standard warehouse conditions (15°C-25°C and <65% relative humidity). In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage >14 years under standard warehouse conditions (15°C-25°C and <65% relative humidity).
在一些態樣中,使用以下來生成XRPD圖案:PANALYTICAL® X'Pert Pro繞射儀,使用Ni濾波Cu Kα (45 kV/40 mA)輻射及0.03° 2θ之步長,利用X'CELERATOR®即時多帶偵測器,(a)入射光束側上之構形如下:可變發散狹縫(10 mm輻照長度)、0.04弧度索勒狹縫(Soller slit)、固定防散射狹縫(0.50°)及10 mm光束遮罩,及(b)繞射光束側上之構形如下:可變防散射狹縫(10 mm觀察長度)及0.04弧度索勒狹縫;或BRUKER® D8® ADVANCETM系統,使用Cu Kα (40 kV/40 mA)輻射及0.03° 2θ之步長,利用LYNXEYETM偵測器,(a)入射光束側上之構形如下:Göebel鏡、鏡出口狹縫(0.2 mm)、2.5°索勒狹縫、光束刀(beam knife),及(b)繞射光束側上之構形如下:防散射狹縫(8 mm)及2.5°索勒狹縫;其中樣品平坦地安裝在零背景Si晶圓上。在一些態樣中,使用TA Instruments Q100或Q2000示差掃描量熱計以約15℃/min之升溫速率生成DSC圖案。In some aspects, XRPD patterns were generated using: PANALYTICAL® X'Pert Pro diffractometer, using Ni filtered Cu Kα (45 kV/40 mA) radiation with a step size of 0.03° 2θ, using X'CELERATOR® in real time Multi-band detector, (a) The configuration on the incident beam side is as follows: variable divergence slit (10 mm irradiation length), 0.04 radian Soller slit (Soller slit), fixed anti-scatter slit (0.50° ) and 10 mm beam mask, and (b) configurations on the diffracted beam side as follows: variable anti-scatter slit (10 mm observation length) and 0.04 radian Soler slit; or BRUKER® D8® ADVANCETM system, Using Cu Kα (40 kV/40 mA) radiation and a step size of 0.03° 2θ, using a LYNXEYETM detector, (a) the configuration on the incident beam side is as follows: Göebel mirror, mirror exit slit (0.2 mm), 2.5 °Soller slit, beam knife (beam knife), and (b) configurations on the diffracted beam side are as follows: anti-scatter slit (8 mm) and 2.5° Soler slit; where the sample is mounted flat on zero background Si wafer. In some aspects, the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15°C/min.
在一些態樣中,結晶組合物含有≤ 0.2%之二聚體雜質PF-00191189。 In some aspects, the crystalline composition contains < 0.2% of the dimer impurity PF-00191189.
在一些態樣中,結晶組合物含有約0.05重量%至約0.19重量%之二聚體雜質PF-00191189。在一些態樣中,結晶組合物不含可偵測量之二聚體雜質PF-00191189。In some aspects, the crystalline composition contains from about 0.05% to about 0.19% by weight of the dimer impurity PF-00191189. In some aspects, the crystalline composition does not contain detectable amounts of the dimer impurity PF-00191189.
在一些態樣中,本揭示案提供醫藥組合物,其包含本文所闡述之結晶組合物以及醫藥學上可接受之載劑。在一些態樣中,醫藥組合物用於經口投與。在一些態樣中,醫藥組合物為固體劑型。在一些態樣中,醫藥組合物為錠劑或膠囊。在一些態樣中,醫藥組合物為錠劑。In some aspects, the disclosure provides pharmaceutical compositions comprising a crystalline composition described herein and a pharmaceutically acceptable carrier. In some aspects, pharmaceutical compositions are for oral administration. In some aspects, the pharmaceutical composition is a solid dosage form. In some aspects, the pharmaceutical composition is a tablet or capsule. In some aspects, the pharmaceutical composition is a lozenge.
在一些態樣中,醫藥組合物為膠囊。在一些態樣中,膠囊包含約1 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中膠囊之每一組分如下:(a)約0.25 wt/wt%至約1.5 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物;(b)約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;(c)約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;(d)約0.5 wt/wt%至約2 wt/wt%之一或多種潤滑劑;及囊封組分a至d之明膠膠囊。在一些態樣中,膠囊包含約2 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中膠囊之每一組分如下:(a)約0.25 wt/wt%至約1.5 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物;(b)約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;(c)約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;(d)約0.5 wt/wt%至約2 wt/wt%之一或多種潤滑劑;及(e)囊封組分a至d之明膠膠囊。在一些態樣中,膠囊包含約5 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中膠囊之每一組分如下:(a)約2.5 wt/wt%至約7.0 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物;(b)約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;(c)約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;及(d)囊封組分a至c之明膠膠囊。In some aspects, the pharmaceutical composition is a capsule. In some aspects, the capsules comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy crystalline composition of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/ wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and a gelatin capsule encapsulating components a to d. In some aspects, the capsules comprise about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy crystalline composition of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/ wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule encapsulating components a to d. In some aspects, the capsules comprise about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide, wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of N-((R)-2,3-dihydroxypropoxy crystalline composition of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/ wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and (d) a gelatin capsule encapsulating components a to c.
在一些態樣中,至少一種稀釋劑選自由以下組成之群:微晶纖維素、乳糖、甘露醇、澱粉及磷酸氫鈣。在一些態樣中,至少一種稀釋劑為微晶纖維素。In some aspects, the at least one diluent is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dicalcium phosphate. In some aspects, at least one diluent is microcrystalline cellulose.
在一些態樣中,至少一種崩解劑選自由以下組成之群:交聯羧甲基纖維素鈉、甘醇酸澱粉鈉、交聚維酮(crospovidone)及海藻酸。在一些態樣中,至少一種崩解劑為交聯羧甲基纖維素鈉。In some aspects, the at least one disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid. In some aspects, the at least one disintegrant is croscarmellose sodium.
在一些態樣中,至少一種潤滑劑選自由以下組成之群:硬脂酸鎂、硬脂醯富馬酸鈉、甘油二山崳酸酯及滑石。在一些態樣中,至少一種潤滑劑為硬脂酸鎂。In some aspects, the at least one lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, and talc. In some aspects, at least one lubricant is magnesium stearate.
在一些態樣中,本揭示案提供治療癌症、腫瘤或RAS病之方法,其包括向需要此治療之個體投與本文所闡述之醫藥組合物。In some aspects, the disclosure provides methods of treating cancer, tumors, or RAS disorders comprising administering to an individual in need of such treatment a pharmaceutical composition described herein.
在一些態樣中,腫瘤為神經纖維瘤。在一些態樣中,腫瘤為與1型神經纖維瘤病相關之神經纖維瘤。在一些態樣中,腫瘤選自由以下組成之群:皮膚神經纖維瘤、叢狀神經纖維瘤、視路神經膠質瘤、低級別神經膠質瘤、高級別神經膠質瘤或惡性外周神經鞘瘤。在一些態樣中,腫瘤為叢狀神經纖維瘤。In some aspects, the tumor is a neurofibroma. In some aspects, the tumor is a neurofibroma associated with neurofibromatosis type 1. In some aspects, the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor. In some aspects, the tumor is a plexiform neurofibroma.
在一些態樣中,個體經診斷患有選自由以下組成之群之RAS病:1型神經纖維瘤病、2型神經纖維瘤病、心面皮膚症候群、克斯提洛氏症候群(Costello syndrome)、雷吉士症候群(Legius syndrome)、努南氏症候群(Noonan syndrome)及多發雀斑樣痣型努南氏症候群(Noonan syndrome with multiple lentigines)。In some aspects, the individual is diagnosed with a RAS disease selected from the group consisting of: neurofibromatosis type 1,
在一些態樣中,癌症選自由以下組成之群:皮膚癌、惡性外周神經鞘癌、白血病、淋巴瘤、組織細胞性贅瘤、肺癌、乳癌、卵巢癌、腎癌、結腸直腸癌、甲狀腺癌、膽管癌、尿路上皮癌、子宮贅瘤、胃癌、肉瘤、膀胱癌、頭頸癌、子宮內膜癌、食管癌、腺樣囊性癌、膽囊癌、***癌、口腔癌、子宮頸癌、胰臟癌、黑色素瘤、肝細胞癌、膽道癌及腹膜漿液性癌。在一些態樣中,白血病選自由以下組成之群:急性淋巴球性白血病、急性骨髓性白血病、慢性淋巴球性白血病及慢性骨髓性白血病。在一些態樣中,淋巴瘤選自由以下組成之群:B細胞淋巴瘤、T細胞淋巴瘤、伯基特氏淋巴瘤(Burkitt's lymphoma)、濾泡性淋巴瘤、外套細胞淋巴瘤、原發性縱膈B細胞淋巴瘤、小淋巴球性淋巴瘤及瓦登斯特隆巨球蛋白血症(Waldenstrom macroglobulinemia)。在一些態樣中,肺癌選自由以下組成之群:肺腺癌、鱗狀非小細胞肺癌、非鱗狀非小細胞肺癌及小細胞肺癌。In some aspects, the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath carcinoma, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer , cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, Pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer and peritoneal serous carcinoma. In some aspects, the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. In some aspects, the lymphoma is selected from the group consisting of B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary Mediastinal B-cell lymphoma, small lymphocytic lymphoma, and Waldenstrom macroglobulinemia. In some aspects, the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
在一些態樣中,個體在一或多個基因中攜帶突變或其他畸變,該突變或其他畸變引起某些癌症之功能特徵增加或喪失,其中一或多個基因中之該突變或其他畸變為KRAS、NRAS、HRAS、BRAF、MEK1、MEK2、RASA1、MAP2K4、NF1或NF2中之一或多者中之突變或其他畸變。In some aspects, an individual carries a mutation or other aberration in one or more genes that causes an increase or loss of functional characteristics of certain cancers, wherein the mutation or other aberration in one or more genes is Mutations or other aberrations in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1 or NF2.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之個別劑量係以一個以上之膠囊或錠劑形式投與。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Individual doses of amide are administered as more than one capsule or lozenge.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過20 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過10 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過8 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過6 mg之總日劑量來投與。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 8 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 6 mg.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量為約0.1 mg至約20 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量為約2 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量為約4 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量為約6 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量為約8 mg。在一些態樣中,所投與之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量為約20 mg。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is from about 0.1 mg to about 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is about 2 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is about 4 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is about 6 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is about 8 mg. In some aspects, the administered N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino The total daily dose of )-benzamide is about 20 mg.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約0.1 mg至約10 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約1 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約2 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約3 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約4 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約10 mg。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose ranging from about 0.1 mg to about 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 1 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 2 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 3 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 4 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 10 mg.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a) 21天投與總日劑量;及(b) 7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)連續21天投與總日劑量;之後(b)連續7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The amide was administered in a 28-day dosing cycle consisting of: (a) 21 days of administration of the total daily dose; and (b) 7 days of non-administration of N-((R)-2,3-dihydroxypropane oxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The amide was administered in a 28-day dosing cycle consisting of: (a) 21 consecutive days of administration of the total daily dose; thereafter (b) 7 consecutive days of non-administration of N-((R)-2,3-di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)三個7天期,每期包含(i) 5天投與總日劑量及(ii) 2天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺;及(b) 7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)三個7天期,每期包含(i)連續5天投與總日劑量及(ii)連續2天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺;之後(b)連續7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides were administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each comprising (i) 5 days of administration of the total daily dose and (ii) 2 days of no administration of N-( (R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was not administered. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides were administered in a 28-day dosing cycle consisting of: (a) three 7-day periods, each consisting of (i) 5 consecutive days of administration of the total daily dose and (ii) 2 consecutive days of no administration of N -((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; after (b) No administration of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl for 7 consecutive days Amide.
在一些態樣中,重複28天投藥週期,直至總計24個連續28天投藥週期。In some aspects, the 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles.
在一些態樣中,本揭示案提供本文所闡述之醫藥組合物之用途,其用於製造用以治療腫瘤、癌症或RAS病之藥劑。 製造醫藥組合物之方法 In some aspects, the disclosure provides the use of the pharmaceutical compositions described herein for the manufacture of a medicament for the treatment of tumors, cancer or RAS disease. Method for manufacturing pharmaceutical composition
在一些態樣中,本揭示案提供製造醫藥組合物之方法,該方法包括形成本文所闡述之醫藥組合物。 定義 In some aspects, the disclosure provides methods of making pharmaceutical compositions, the methods comprising forming the pharmaceutical compositions described herein. definition
為有助於理解本文所陳述之揭示內容,下文定義許多術語。To facilitate understanding of the disclosure set forth herein, a number of terms are defined below.
一般而言,本文所用之命名法及本文所闡述之有機化學、藥物化學及藥理學中之實驗室程序為此項技術中熟知且常用之彼等程序。除非另外定義,否則本文所用之所有技術及科學術語一般均具有與熟習本揭示案所屬技術者通常所理解相同之含義。Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of skill in the art to which this disclosure belongs.
在本說明書及隨附申請專利範圍中,除非上下文另外明確指示,否則單數形式「一個/種(a、an)」及「該(the)」包括複數個/種指示物。術語「一個/種(a)」(或「一個/種(an)」)以及術語「一或多個/種」及「至少一個/種」在本文中可互換使用。在某些態樣中,術語「一個/種(a或an)」意指「單一的」。在其他態樣中,術語「一個/種(a或an)」包括「兩個/種或更多個/種」或「多個/種」。In this specification and the appended claims, unless the context clearly dictates otherwise, the singular forms "a, an" and "the" include plural referents. The term "a" (or "an") and the terms "one or more" and "at least one" are used interchangeably herein. In certain aspects, the term "a or an" means "single". In other aspects, the term "a or an" includes "two or more" or "a plurality".
此外,「及/或」當在本文中使用時,應視為特定揭示兩種指定特徵或組分中之每一者與另一者一起或不與另一者一起之情況。因此,在本文中諸如「A及/或B」之片語中所用之術語「及/或」意欲包括「A及B」、「A或B」、「A」(單獨)及「B」(單獨)。同樣,在諸如「A、B及/或C」之片語中所用之術語「及/或」意欲涵蓋以下態樣中之每一者:A、B及C;A、B或C;A或C;A或B;B或C;A及C;A及B;B及C;A (單獨);B (單獨);及C (單獨)。Furthermore, "and/or" when used herein shall be considered as specifically disclosing that each of the two specified features or components is with or without the other. Accordingly, the term "and/or" used herein in phrases such as "A and/or B" is intended to include "A and B", "A or B", "A" (alone) and "B" ( alone). Likewise, the term "and/or" used in phrases such as "A, B, and/or C" is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
術語「米達替尼」及「PD-0325901」係指單一鏡像異構物N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。The terms "midatinib" and "PD-0325901" refer to the single enantiomer N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- Fluoro-4-iodo-phenylamino)-benzamide.
術語「個體」係指動物,包括(但不限於)靈長類動物(例如人類)、牛、綿羊、山羊、馬、狗、貓、兔、大鼠或小鼠。術語「個體」及「患者」在本文中關於(例如)哺乳動物個體(諸如人類個體)使用時可互換使用。The term "subject" refers to an animal including, but not limited to, a primate (eg, human), cow, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "individual" and "patient" are used interchangeably herein when used with respect to, for example, a mammalian individual such as a human individual.
如本文所用,術語「治療(treat、treated及treating)」意指治療性治療及預防性或防禦性措施二者,其中目的為預防或減緩(減輕)不期望之生理疾患、病症或疾病,或獲得有益或期望之臨床結果。因此,需要治療者包括已診斷或疑似患有病症者。有益或期望之臨床結果包括(但不限於)症狀緩和;疾患、病症或疾病之程度減輕;疾患、病症或疾病之狀態穩定(亦即,不惡化);疾患、病症或疾病進程之發作延遲或減緩;疾患、病症或疾病狀態改善或消退(部分抑或完全),無論可偵測抑或不可偵測;至少一種可量測之身體參數改善,不一定可為患者所辨別;或疾患、病症或疾病好轉或改善。治療包括引發臨床上顯著之反應而無過度副作用。治療亦包括與未接受治療之預期存活期相比使存活期延長。術語「治療有效量」意欲包括在投與時足以防止所治療之病症、疾病或疾患之一或多種症狀發展或在一定程度上緩和該一或多種症狀的化合物之量。術語「治療有效量」亦指足以引發細胞、組織、系統、動物或人類之生物或醫學反應的化合物之量,此反應為研究人員、獸醫、醫師或臨床醫師所尋求的。As used herein, the terms "treat, treated and treating" mean both therapeutic treatment and prophylactic or preventive measures, wherein the purpose is to prevent or slow down (lessen) an undesired physiological disorder, disorder or disease, or Obtain beneficial or desired clinical results. Accordingly, those in need of treatment include those diagnosed or suspected of having the condition. Beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; lessening of the severity of the disorder, disorder or disease; stabilization (i.e., not worsening) of the state of the disorder, disorder or disease; delay in the onset or Alleviation; improvement or regression (partial or complete) of a disorder, disorder, or disease state, whether detectable or not; improvement in at least one measurable physical parameter, not necessarily identifiable by the patient; or disorder, disorder, or disease Get better or improve. Treatment includes eliciting a clinically significant response without undue side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. The term "therapeutically effective amount" is intended to include an amount of a compound which, when administered, is sufficient to prevent the development of, or to alleviate to some extent, one or more symptoms of the disorder, disease or disorder being treated. The term "therapeutically effective amount" also refers to the amount of a compound sufficient to elicit the biological or medical response in a cell, tissue, system, animal or human that is sought by the researcher, veterinarian, physician or clinician.
在某些態樣中,根據本文所闡述之方法,若患者顯示以下中之一或多者,則個體之腫瘤成功地「治療」:腫瘤大小減小;與具體腫瘤相關之一或多種症狀緩解;腫瘤體積減小;生活品質改善;無進展存活期(PFS)、無病存活期(DFS)、 總存活期(OS)、無轉移存活期(MFS)、完全反應(CR)、微量殘存疾病(MRD)、部分反應(PR)、穩定疾病(SD)增加、進行性疾病(PD)減少、疾病進展時間(TTP)增加,或其任何組合。在一些態樣中,可使用給定腫瘤之國家或國際公認之治療結果標準來確定有效量之米達替尼是否滿足該等特定終點中之任一者(例如CR、PFS、PR)。In certain aspects, according to the methods described herein, an individual's tumor is successfully "treated" if the patient exhibits one or more of the following: reduction in tumor size; remission of one or more symptoms associated with the specific tumor ; tumor volume decreased; quality of life improved; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease ( MRD), partial response (PR), increase in stable disease (SD), decrease in progressive disease (PD), increase in time to progressive disease (TTP), or any combination thereof. In some aspects, nationally or internationally accepted treatment outcome criteria for a given tumor can be used to determine whether an effective amount of midatinib meets any of these specific endpoints (eg, CR, PFS, PR).
在某些態樣中,根據本文所闡述之方法,若患者顯示以下中之一或多者,則個體之癌症(例如肺癌或卵巢癌)成功地「治療」:癌細胞之數量減少或完全不存在;與具體癌症相關之一或多種症狀緩解;發病率及死亡率降低;生活品質改善;無進展存活期(PFS)、無病存活期(DFS)、 總存活期(OS)、無轉移存活期(MFS)、完全反應(CR)、微量殘存疾病(MRD)、部分反應(PR)、穩定疾病(SD)增加、進行性疾病(PD)減少、疾病進展時間(TTP)增加,或其任何組合。在一些態樣中,可使用給定癌症之國家或國際公認之治療結果標準來確定有效量之米達替尼是否滿足該等特定終點中之任一者(例如CR、PFS、PR)。In certain aspects, according to the methods described herein, an individual's cancer (eg, lung or ovarian cancer) is successfully "treated" if the patient exhibits one or more of the following: a reduction in the number of cancer cells or none at all Relief of one or more symptoms associated with specific cancers; reduced morbidity and mortality; improved quality of life; progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), metastasis-free survival (MFS), complete response (CR), minimal residual disease (MRD), partial response (PR), increase in stable disease (SD), decrease in progressive disease (PD), increase in time to progression disease (TTP), or any combination thereof . In some aspects, nationally or internationally accepted treatment outcome criteria for a given cancer can be used to determine whether an effective amount of midatinib meets any of these specific endpoints (eg, CR, PFS, PR).
術語「醫藥學上可接受之載劑」、「醫藥學上可接受之賦形劑」、「生理學上可接受之載劑」或「生理學上可接受之賦形劑」係指醫藥學上可接受之材料、組合物或媒劑,諸如液體或固體賦形劑、溶劑或囊封材料。在一個態樣中,每一組分在以下意義上係「醫藥學上可接受的」:與醫藥調配物之其他成分相容,且適用於與人類及動物之組織或器官接觸而無過度毒性、刺激性、過敏反應、免疫原性或其他問題或併發症,與合理益處/風險比相稱。參見Remington: The Science and Practice of Pharmacy,第21版,Lippincott Williams & Wilkins: Philadelphia, PA, 2005;Handbook of Pharmaceutical Excipients,第5版,Rowe等人編輯,The Pharmaceutical Press and the American Pharmaceutical Association: 2005;及Handbook of Pharmaceutical Additives,第3版,Ash及Ash編輯,Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation,Gibson編輯,CRC Press LLC: Boca Raton, FL, 2004 (以引用方式併入本文中)。賦形劑可包括(例如):抗黏附劑、抗氧化劑、黏合劑、包衣、壓縮助劑、崩解劑、染料(色彩)、軟化劑、乳化劑、填充劑(稀釋劑)、成膜劑或包衣、調味劑、芳香劑、助流劑(流動增強劑)、潤滑劑、防腐劑、印刷墨水、吸附劑、懸浮劑或分散劑、甜味劑及水合水。例示性賦形劑包括(但不限於):二丁基羥基甲苯(BHT)、碳酸鈣、磷酸氫鈣、硬脂酸鈣、硫酸鈣、交聯羧甲基纖維素、交聯聚乙烯吡咯啶酮、檸檬酸、交聚維酮、半胱胺酸、乙基纖維素、明膠、羥丙基纖維素、羥丙基甲基纖維素、乳糖、硬脂酸鎂、麥芽糖醇、甘露醇、甲硫胺酸、甲基纖維素、對羥基苯甲酸甲酯、微晶纖維素、聚乙二醇、聚乙烯吡咯啶酮、聚維酮(povidone)、預膠凝澱粉、對羥基苯甲酸丙酯、棕櫚酸視黃酯、蟲膠、二氧化矽、羧甲基纖維素鈉、檸檬酸鈉、甘醇酸澱粉鈉、山梨醇、澱粉(玉米)、硬脂酸、蔗糖、滑石、二氧化鈦、維生素A、維生素E、維生素C及木糖醇。The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to pharmaceutical An acceptable material, composition or vehicle, such as a liquid or solid excipient, solvent or encapsulating material. In one aspect, each component is "pharmaceutically acceptable" in the sense that it is compatible with the other ingredients of the pharmaceutical formulation and suitable for use in contact with human and animal tissues or organs without undue toxicity , irritation, allergic reaction, immunogenicity or other problems or complications, commensurate with a reasonable benefit/risk ratio. See Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th ed., edited by Rowe et al., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and Ash eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson ed., CRC Press LLC: Boca Raton, FL, 2004 (incorporated herein by reference). Excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), softeners, emulsifiers, fillers (diluents), film-forming agents agents or coatings, flavoring agents, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, absorbents, suspending or dispersing agents, sweeteners, and water of hydration. Exemplary excipients include (but are not limited to): butylated hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, calcium sulfate, croscarmellose, crospovidone Ketone, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, lactose, magnesium stearate, maltitol, mannitol, formazan Thiamine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben , Retinyl Palmitate, Shellac, Silicon Dioxide, Sodium Carboxymethylcellulose, Sodium Citrate, Sodium Starch Glycolate, Sorbitol, Starch (Corn), Stearic Acid, Sucrose, Talc, Titanium Dioxide, Vitamins A, vitamin E, vitamin C and xylitol.
如本文所用,術語「醫藥組合物」代表含有與醫藥學上可接受之賦形劑一起調配的本文所闡述之化合物之組合物,且可在政府監管機構之批准下製造或銷售,作為治療哺乳動物疾病之治療方案之一部分。醫藥組合物可經調配(例如)以供以單位劑型經口投與(例如錠劑、膠囊、膠囊型錠劑、膠囊錠或糖漿)。As used herein, the term "pharmaceutical composition" refers to a composition containing a compound described herein formulated together with a pharmaceutically acceptable excipient, and which may be manufactured or sold under approval by a government regulatory agency as a treatment for lactation. Part of a treatment program for animal diseases. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (eg, tablets, capsules, caplets, caplets, or syrups).
術語「約」或「大約」意指在熟習此項技術者所測定之特定值之可接受誤差範圍內,其部分地取決於該值之量測或測定方式。在一些態樣中,術語「約」或「大約」意指在1、2、3或4個標準偏差內。在一些態樣中,術語「約」或「大約」意指數量、水準、值、數字、頻率、百分比、尺寸、大小、量、重量或長度相對於參考數量、水準、值、數字、頻率、百分比、尺寸、大小、量、重量或長度變化至多30%、25%、20%、15%、10%、9%、8%、7%、6%、5%、4%、3%、2%或1%。The term "about" or "approximately" means within an acceptable error range for a particular value as determined by one skilled in the art, which depends in part on the manner in which that value was measured or determined. In some aspects, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In some aspects, the term "about" or "approximately" means an amount, level, value, number, frequency, percentage, dimension, size, amount, weight, or length relative to a reference amount, level, value, number, frequency, Variation in percentage, dimension, size, volume, weight or length by up to 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% % or 1%.
如本文所用,術語「投與」係指向個體或系統投與組合物(例如化合物或包括如本文所闡述之化合物之製劑)。向動物個體(例如人類)投與可藉由任何適當途徑來實施,諸如本文所闡述之途徑。As used herein, the term "administration" refers to individual or systemic administration of a composition (eg, a compound or a formulation comprising a compound as described herein). Administration to an animal subject (eg, a human) can be effected by any suitable route, such as those described herein.
如本文所用,術語「結晶」係指由結構單元之有序排列組成之固態形式。相同化合物或其鹽、水合物或溶劑合物之不同結晶形式源於固態分子之不同堆積,此導致不同的晶體對稱性及/或單位晶胞參數。不同的結晶形式通常具有不同的X射線繞射圖案、紅外光譜、熔點、密度、硬度、晶形、光學及電學性質、穩定性及溶解性。例如,參見Remington's Pharmaceutical Sciences,第18版,Mack Publishing, Easton PA, 173 (1990);The United States Pharmacopeia,第23版,1843-1844 (1995) (以引用方式併入本文中)。As used herein, the term "crystalline" refers to a solid state form consisting of an ordered arrangement of structural units. Different crystalline forms of the same compound or a salt, hydrate or solvate thereof result from different packing of the molecules in the solid state, which results in different crystal symmetries and/or unit cell parameters. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shape, optical and electrical properties, stability and solubility. See, eg, Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing, Easton PA, 173 (1990); The United States Pharmacopeia, 23rd Ed., 1843-1844 (1995) (incorporated herein by reference).
結晶形式通常由X射線粉末繞射(XRPD)表徵。XRPD反射圖案(峰值,通常以度2-θ表示)通常視為特定結晶形式之指紋。XRPD峰之相對強度可廣泛地變化,尤其取決於樣品製備技術、晶體大小分佈、過濾器、樣品安裝程序及所採用之特定儀器。在一些情況下,可能觀察到新的峰或現有的峰可能消失,此取決於儀器類型或設置。在一些情況下,XRPD圖案中之任何特定峰均可能顯示為單峰、雙峰、三重峰、四重峰或多重峰,此取決於儀器類型或設置、儀器靈敏度、量測條件及/或結晶形式之純度。在一些情況下,XRPD中之任何特定峰均可能以對稱形狀或不對稱形狀出現,例如具有肩。此外,儀器變化及其他因素可影響2-θ值。理解該等變化之熟習此項技術者能夠使用XRPD以及使用其他已知物理化學技術來區分或確定特定結晶形式之定義特性或特徵。Crystalline forms are typically characterized by X-ray powder diffraction (XRPD). The XRPD reflection pattern (peak value, usually expressed in degrees 2-theta) is often considered a fingerprint of a particular crystalline form. The relative intensities of XRPD peaks can vary widely, depending, inter alia, on sample preparation techniques, crystal size distributions, filters, sample loading procedures, and the particular instrument employed. In some cases, new peaks may be observed or existing peaks may disappear, depending on the instrument type or settings. In some cases, any particular peak in an XRPD pattern may appear as a singlet, doublet, triplet, quartet, or multiplet, depending on instrument type or settings, instrument sensitivity, measurement conditions, and/or crystallization purity of form. In some cases, any particular peak in an XRPD may appear as a symmetrical shape or an asymmetrical shape, for example with a shoulder. In addition, instrument variations and other factors can affect 2-theta values. Those skilled in the art who understand these changes are able to use XRPD as well as use other known physicochemical techniques to distinguish or determine defined properties or characteristics of particular crystalline forms.
術語「無水物」在應用於化合物時係指該化合物在晶格內不含結構水之結晶形式。The term "anhydrate" when applied to a compound refers to a crystalline form of the compound that does not contain water of structure within the crystal lattice.
如本文所用,關於形式IV之術語「基本上純的」意指包含形式IV之組合物不含可偵測量之另一多晶形式(例如形式I或形式II),如藉由在單一形式IV晶體與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物之間的XRPD及/或DSC圖案中未觀察到可偵測到之差異所確定。然而,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之「基本上純的」形式IV可包括雜質,諸如(但不限於)在化學合成期間所生成之合成反應物或副產物。As used herein, the term "substantially pure" with respect to Form IV means that a composition comprising Form IV does not contain a detectable amount of another polymorphic form (e.g., Form I or Form II), as determined by the polymorphic form in a single form. IV crystals and N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide This was determined by the absence of detectable differences observed in the XRPD and/or DSC patterns between the crystalline compositions. However, the " Substantially pure "Form IV" may include impurities such as, but not limited to, synthesis reactants or by-products formed during chemical synthesis.
如本文所用,術語「畸變」在應用於基因時係指突變、染色體丟失或融合、表觀遺傳化學修飾或相對於與野生型基因相關之序列、表現水準或加工mRNA序列,改變與基因相關之序列、表現水準或加工mRNA序列之其他事件。As used herein, the term "aberration" when applied to a gene refers to a mutation, chromosomal loss or fusion, epigenetic chemical modification, or alteration of the sequence, expression level, or processed mRNA sequence associated with the gene relative to the sequence associated with the wild-type gene. Sequencing, expression levels, or other events that process mRNA sequences.
應理解,凡是本文利用言語「包含」來闡述態樣之處,均亦提供以「由......組成」及/或「基本上由......組成」闡述之其他類似態樣。It should be understood that where the word "comprising" is used herein to describe aspects, other similar terms described using "consisting of" and/or "consisting essentially of" are also provided. appearance.
一或多個態樣之細節在下文說明中予以陳述。其他特徵、目的及優點將自說明及自申請專利範圍顯而易見。The details of one or more aspects are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.
本文闡述基本上純的形式IV、為基本上純的形式IV之組合物以及治療需要治療劑之患者之方法,該等方法包括投與基本上純的形式IV。 結晶組合物 Described herein are substantially pure Form IV, compositions that are substantially pure Form IV, and methods of treating a patient in need of a therapeutic comprising administering substantially pure Form IV. Crystalline composition
本揭示案係關於N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的結晶組合物。與所有醫藥化合物及組合物一樣,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之化學及物理性質在其商業開發中係重要的。該等性質包括(但不限於):(1)填充性質,諸如莫耳體積、容積密度及吸濕性,(2)熱力學性質,諸如熔融溫度、蒸氣壓及溶解度,(3)動力學性質,諸如溶解速率及穩定性(包括在環境條件下之穩定性,尤其是針對潮濕及在儲存條件下之穩定性),(4)表面性質,諸如表面面積、可濕性、界面張力及形狀,(5)機械性質,諸如硬度、拉伸強度、可壓實性、處置性、流動及摻合;及(6)過濾性質。該等性質可影響(例如)化合物及包含化合物之醫藥組合物之處理及儲存。This disclosure is about N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoyl A substantially pure crystalline composition of amines. Like all pharmaceutical compounds and compositions, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) - The chemical and physical properties of benzamides are important in their commercial development. Such properties include, but are not limited to: (1) packing properties, such as molar volume, bulk density, and hygroscopicity, (2) thermodynamic properties, such as melting temperature, vapor pressure, and solubility, (3) kinetic properties, Such as dissolution rate and stability (including stability under environmental conditions, especially for humidity and stability under storage conditions), (4) surface properties, such as surface area, wettability, interfacial tension and shape, ( 5) mechanical properties such as hardness, tensile strength, compactability, handling, flow and blending; and (6) filtration properties. These properties can affect, for example, the handling and storage of the compounds and pharmaceutical compositions comprising the compounds.
N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之如下結晶形式係合意的:相對於該化合物之其他結晶形式,該等性質中之一或多者改良。分離可以商業規模製造並調配之該化合物之醫藥學上可接受之結晶形式可為一項挑戰。The following crystalline form of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Desirable: One or more of these properties are improved relative to other crystalline forms of the compound. It can be a challenge to isolate a pharmaceutically acceptable crystalline form of the compound that can be manufactured and formulated on a commercial scale.
在一些態樣中,本揭示案係關於式(I)之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV: (I)。 In some aspects, the disclosure relates to N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- Substantially pure Form IV of iodo-phenylamino)-benzamide: (I).
在一些態樣中,如藉由隨時間實質上不變之XRPD圖案及/或DSC曲線所證明,結晶組合物係穩定的。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存1個月、2個月、3個月、4個月、5個月、6個月、7個月、8個月、9個月、10個月、1年、2年、3年、4年、5年、68個月、6年、7年、8年、9年、10年、11年、140個月、12年、13年、14年或15年後,展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存3個月後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存6個月後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存1年後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存5年後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存68個月後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存≥140個月後展現實質上不變之XRPD圖案及/或DSC曲線。在一些態樣中,結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存≥14年後展現實質上不變之XRPD圖案及/或DSC曲線。In some aspects, the crystalline composition is stable as evidenced by an XRPD pattern and/or DSC curve that is substantially unchanged over time. In some aspects, the crystalline composition is stored under standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 1 month, 2 months, 3 months, 4 months, 5 months, 6 months month, 7 months, 8 months, 9 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years, 68 months, 6 years, 7 years, 8 years, 9 years, 10 After one year, 11 years, 140 months, 12 years, 13 years, 14 years or 15 years, exhibit a substantially unchanged XRPD pattern and/or DSC curve. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage at standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 3 months. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage under standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 6 months. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage at standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 1 year. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage for 5 years under standard warehouse conditions (15°C-25°C and < 65% relative humidity). In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage under standard warehouse conditions (15°C-25°C and < 65% relative humidity) for 68 months. In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage for >140 months at standard warehouse conditions (15°C-25°C and <65% relative humidity). In some aspects, the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage >14 years under standard warehouse conditions (15°C-25°C and <65% relative humidity).
在一些態樣中,使用以下來生成XRPD圖案:PANALYTICAL® X'Pert Pro繞射儀,使用Ni濾波Cu Kα (45 kV/40 mA)輻射及0.03° 2θ之步長,利用X'CELERATOR®即時多帶偵測器,(a)入射光束側上之構形如下:可變發散狹縫(10 mm輻照長度)、0.04弧度索勒狹縫、固定防散射狹縫(0.50°)及10 mm光束遮罩,及(b)繞射光束側上之構形如下:可變防散射狹縫(10 mm觀察長度)及0.04弧度索勒狹縫;或BRUKER® D8® ADVANCETM系統,使用Cu Kα (40 kV/40 mA)輻射及0.03° 2θ之步長,利用LYNXEYETM偵測器,(a)入射光束側上之構形如下:Göebel鏡、鏡出口狹縫(0.2 mm)、2.5°索勒狹縫、光束刀,及(b)繞射光束側上之構形如下:防散射狹縫(8 mm)及2.5°索勒狹縫;其中樣品平坦地安裝在零背景Si晶圓上。在一些態樣中,使用TA Instruments Q100或Q2000示差掃描量熱計以約15℃/min之升溫速率生成DSC圖案。In some aspects, XRPD patterns were generated using: PANALYTICAL® X'Pert Pro diffractometer, using Ni filtered Cu Kα (45 kV/40 mA) radiation with a step size of 0.03° 2θ, using X'CELERATOR® in real time Multi-band detector, (a) The configuration on the incident beam side is as follows: variable divergence slit (10 mm irradiation length), 0.04 radian Soler slit, fixed anti-scatter slit (0.50°) and 10 mm The beam mask, and (b) configuration on the diffracted beam side are as follows: variable anti-scatter slit (10 mm observation length) and 0.04 radian Soler slit; or BRUKER® D8® ADVANCETM system using Cu Kα ( 40 kV/40 mA) radiation and a step size of 0.03° 2θ, using LYNXEYETM detector, (a) The configuration on the incident beam side is as follows: Göebel mirror, mirror exit slit (0.2 mm), 2.5° Soler slit The configurations on the slit, beam knife, and (b) diffracted beam side are as follows: anti-scatter slit (8 mm) and 2.5° Soler slit; where the sample is mounted flat on a zero-background Si wafer. In some aspects, the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15°C/min.
在一些態樣中,結晶組合物含有≤ 0.2%之二聚體雜質PF-00191189。 In some aspects, the crystalline composition contains < 0.2% of the dimer impurity PF-00191189.
在一些態樣中,結晶組合物含有約0.05重量%至約0.19重量%之二聚體雜質PF-00191189。在一些態樣中,結晶組合物含有約0.05重量%至約0.15重量%之二聚體雜質PF-00191189。在一些態樣中,結晶組合物含有約0.05重量%至約0.10重量%之二聚體雜質PF-00191189。在一些態樣中,結晶組合物不含可偵測量之二聚體雜質PF-00191189。In some aspects, the crystalline composition contains from about 0.05% to about 0.19% by weight of the dimer impurity PF-00191189. In some aspects, the crystalline composition contains from about 0.05% to about 0.15% by weight of the dimer impurity PF-00191189. In some aspects, the crystalline composition contains from about 0.05% to about 0.10% by weight of the dimer impurity PF-00191189. In some aspects, the crystalline composition does not contain detectable amounts of the dimer impurity PF-00191189.
在一些態樣中,使用高效液相層析(「HPLC」)測定二聚體雜質PF-00191189之量。在一些態樣中,使用利用275 nm紫外偵測器之反相液相層析。In some aspects, the amount of dimeric impurity PF-00191189 is determined using high performance liquid chromatography ("HPLC"). In some aspects, reverse phase liquid chromatography with a 275 nm UV detector is used.
在一些態樣中,結晶組合物所展現之DSC曲線不具有在約117℃開始之吸熱事件。In some aspects, the DSC curve exhibited by the crystalline composition does not have an endothermic event onset at about 117°C.
N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之形式IV之特徵在於實質上如圖1A中所示之XRPD圖案、實質上如圖1B中所示之TGA曲線;及/或實質上如圖1B中所示之DSC曲線。 醫藥組合物 Form IV of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide Characterized by an XRPD pattern substantially as shown in FIG. 1A , a TGA curve substantially as shown in FIG. 1B ; and/or a DSC curve substantially as shown in FIG. 1B . pharmaceutical composition
在一些態樣中,本揭示案提供醫藥組合物,其包含本文所闡述之結晶組合物以及醫藥學上可接受之載劑。在一些態樣中,醫藥組合物用於經口投與。在一些態樣中,醫藥組合物為錠劑或膠囊。在一些態樣中,醫藥組合物為錠劑。在一些態樣中,醫藥組合物為膠囊。In some aspects, the disclosure provides pharmaceutical compositions comprising a crystalline composition described herein and a pharmaceutically acceptable carrier. In some aspects, pharmaceutical compositions are for oral administration. In some aspects, the pharmaceutical composition is a tablet or capsule. In some aspects, the pharmaceutical composition is a lozenge. In some aspects, the pharmaceutical composition is a capsule.
在一些態樣中,醫藥組合物包含約0.1 mg至約10 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。在一些態樣中,醫藥組合物包含約0.1 mg、約0.2 mg、約0.3 mg、約0.4 mg、約0.5 mg、約0.6 mg、約0.7 mg、約0.8 mg、約0.9 mg、約1 mg、約1.5 mg、約2 mg、約2.5 mg、約3 mg、約3.5 mg、約4 mg、約4.5 mg、約5 mg、約5.5 mg、約6 mg、約6.5 mg、約7 mg、約7.5 mg、約8 mg、約8.5 mg、約9 mg、約9.5 mg或約10 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。在一些態樣中,醫藥組合物包含約2 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。在一些態樣中,醫藥組合物包含約3 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。在一些態樣中,醫藥組合物包含約4 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。在一些態樣中,醫藥組合物包含約5 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。In some aspects, the pharmaceutical composition comprises from about 0.1 mg to about 10 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro- Crystalline composition of 4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, About 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg or about 10 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-( Crystalline composition of 2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- A crystalline composition of phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- A crystalline composition of phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- A crystalline composition of phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- A crystalline composition of phenylamino)-benzamide.
在一些態樣中,醫藥組合物包含約0.25 wt/wt%至約7 wt/wt%本文所闡述之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。在一些態樣中,醫藥組合物包含約0.25 wt/wt%、約0.3 wt/wt%、約0.4 wt/wt%、約0.5 wt/wt%、約0.6 wt/wt%、約0.7 wt/wt%、約0.8 wt/wt%、約0.9 wt/wt%、約1 wt/wt%、約1.1 wt/wt%、約1.2 wt/wt%、約1.3 wt/wt%、約1.4 wt/wt%、約1.5 wt/wt%、約1.6 wt/wt%、約1.7 wt/wt%、約1.8 wt/wt%、約1.9 wt/wt%、約2 wt/wt%、約2.1 wt/wt%、約2.2 wt/wt%、約2.3 wt/wt%、約2.4 wt/wt%、約2.5 wt/wt%、約2.6 wt/wt%、約2.7 wt/wt%、約2.8 wt/wt%、約2.9 wt/wt%、約3 wt/wt%、約3.1 wt/wt%、約3.2 wt/wt%、約3.3 wt/wt%、約3.4 wt/wt%、約3.5 wt/wt%、約3.6 wt/wt%、約3.7 wt/wt%、約3.8 wt/wt%、約3.9 wt/wt%、約4 wt/wt%、約4.1 wt/wt%、約4.2 wt/wt%、約4.3 wt/wt%、約4.4 wt/wt%、約4.5 wt/wt%、約4.6 wt/wt%、約4.7 wt/wt%、約4.8 wt/wt%、約4.9 wt/wt%、約5 wt/wt%、約5.1 wt/wt%、約5.2 wt/wt%、約5.3 wt/wt%、約5.4 wt/wt%、約5.5 wt/wt%、約5.6 wt/wt%、約5.7 wt/wt%、約5.8 wt/wt%、約5.9 wt/wt%、約6 wt/wt%、約6.1 wt/wt%、約6.2 wt/wt%、約6.3 wt/wt%、約6.4 wt/wt%、約6.5 wt/wt%、約6.6 wt/wt%、約6.7 wt/wt%、約6.8 wt/wt%、約6.9 wt/wt%或約7 wt/wt%本文所闡述之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。在一些態樣中,醫藥組合物包含約0.5 wt/wt%本文所闡述之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。在一些態樣中,醫藥組合物包含約0.8 wt/wt%本文所闡述之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物。In some aspects, the pharmaceutical composition comprises from about 0.25 wt/wt% to about 7 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-dihydroxypropoxy)-3,4-bis as described herein Crystalline compositions of fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 0.25 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt%, about 0.6 wt/wt%, about 0.7 wt/wt %, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, about 1.3 wt/wt%, about 1.4 wt/wt% , about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt%, about 2 wt/wt%, about 2.1 wt/wt%, About 2.2 wt/wt%, About 2.3 wt/wt%, About 2.4 wt/wt%, About 2.5 wt/wt%, About 2.6 wt/wt%, About 2.7 wt/wt%, About 2.8 wt/wt%, About 2.9 wt/wt%, about 3 wt/wt%, about 3.1 wt/wt%, about 3.2 wt/wt%, about 3.3 wt/wt%, about 3.4 wt/wt%, about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4 wt/wt%, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt% /wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt%, about 4.8 wt/wt%, about 4.9 wt/wt%, about 5 wt/ wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7 wt/wt %, about 5.8 wt/wt%, about 5.9 wt/wt%, about 6 wt/wt%, about 6.1 wt/wt%, about 6.2 wt/wt%, about 6.3 wt/wt%, about 6.4 wt/wt% , about 6.5 wt/wt%, about 6.6 wt/wt%, about 6.7 wt/wt%, about 6.8 wt/wt%, about 6.9 wt/wt%, or about 7 wt/wt% N-(( Crystalline compositions of R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 0.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- Crystalline composition of fluoro-4-iodo-phenylamino)-benzamide. In some aspects, the pharmaceutical composition comprises about 0.8 wt/wt% of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- Crystalline composition of fluoro-4-iodo-phenylamino)-benzamide.
在一些態樣中,醫藥組合物包含一或多種稀釋劑。在一些態樣中,醫藥組合物包含約70 wt/wt%至約95 wt/wt%之一或多種稀釋劑。在一些態樣中,醫藥組合物包含約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑。在一些態樣中,醫藥組合物包含約70 wt/wt%、約71 wt/wt%、約72 wt/wt%、約73 wt/wt%、約74 wt/wt%、約75 wt/wt%、約76 wt/wt%、約77 wt/wt%、約78 wt/wt%、約79 wt/wt%、約80 wt/wt%、約81 wt/wt%、約82 wt/wt%、約83 wt/wt%、約84 wt/wt%、約85 wt/wt%、約86 wt/wt%、約87 wt/wt%、約88 wt/wt%、約89 wt/wt%、約90 wt/wt%、約91 wt/wt%、約92 wt/wt%、約93 wt/wt%、約94 wt/wt%或約95 wt/wt%之一或多種稀釋劑。在一些態樣中,醫藥組合物包含約90 wt/wt%之一或多種稀釋劑。在一些態樣中,醫藥組合物包含約93 wt/wt%之一或多種稀釋劑。In some aspects, pharmaceutical compositions include one or more diluents. In some aspects, the pharmaceutical composition comprises from about 70 wt/wt% to about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises from about 85 wt/wt% to about 95 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 70 wt/wt%, about 71 wt/wt%, about 72 wt/wt%, about 73 wt/wt%, about 74 wt/wt%, about 75 wt/wt% %, about 76 wt/wt%, about 77 wt/wt%, about 78 wt/wt%, about 79 wt/wt%, about 80 wt/wt%, about 81 wt/wt%, about 82 wt/wt% , about 83 wt/wt%, about 84 wt/wt%, about 85 wt/wt%, about 86 wt/wt%, about 87 wt/wt%, about 88 wt/wt%, about 89 wt/wt%, One or more diluents of about 90 wt/wt%, about 91 wt/wt%, about 92 wt/wt%, about 93 wt/wt%, about 94 wt/wt%, or about 95 wt/wt%. In some aspects, the pharmaceutical composition comprises about 90 wt/wt% of one or more diluents. In some aspects, the pharmaceutical composition comprises about 93 wt/wt% of one or more diluents.
在一些態樣中,至少一種稀釋劑選自由以下組成之群:微晶纖維素、乳糖、甘露醇、澱粉及磷酸氫鈣。在一些態樣中,至少一種稀釋劑為微晶纖維素。在一些態樣中,稀釋劑為微晶纖維素。In some aspects, the at least one diluent is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and dicalcium phosphate. In some aspects, at least one diluent is microcrystalline cellulose. In some aspects, the diluent is microcrystalline cellulose.
在一些態樣中,醫藥組合物包含約70 wt/wt%至約95 wt/wt%之微晶纖維素。在一些態樣中,醫藥組合物包含約85 wt/wt%至約95 wt/wt%之微晶纖維素。在一些態樣中,醫藥組合物包含約70 wt/wt%、約71 wt/wt%、約72 wt/wt%、約73 wt/wt%、約74 wt/wt%、約75 wt/wt%、約76 wt/wt%、約77 wt/wt%、約78 wt/wt%、約79 wt/wt%、約80 wt/wt%、約81 wt/wt%、約82 wt/wt%、約83 wt/wt%、約84 wt/wt%、約85 wt/wt%、約86 wt/wt%、約87 wt/wt%、約88 wt/wt%、約89 wt/wt%、約90 wt/wt%、約91 wt/wt%、約92 wt/wt%、約93 wt/wt%、約94 wt/wt%或約95 wt/wt%之微晶纖維素。在一些態樣中,醫藥組合物包含約90 wt/wt%之微晶纖維素。在一些態樣中,醫藥組合物包含約93 wt/wt%之微晶纖維素。In some aspects, the pharmaceutical composition comprises about 70 wt/wt% to about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 85 wt/wt% to about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 70 wt/wt%, about 71 wt/wt%, about 72 wt/wt%, about 73 wt/wt%, about 74 wt/wt%, about 75 wt/wt% %, about 76 wt/wt%, about 77 wt/wt%, about 78 wt/wt%, about 79 wt/wt%, about 80 wt/wt%, about 81 wt/wt%, about 82 wt/wt% , about 83 wt/wt%, about 84 wt/wt%, about 85 wt/wt%, about 86 wt/wt%, about 87 wt/wt%, about 88 wt/wt%, about 89 wt/wt%, About 90 wt/wt%, about 91 wt/wt%, about 92 wt/wt%, about 93 wt/wt%, about 94 wt/wt%, or about 95 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 90 wt/wt% microcrystalline cellulose. In some aspects, the pharmaceutical composition comprises about 93 wt/wt% microcrystalline cellulose.
在一些態樣中,醫藥組合物包含約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑。在一些態樣中,醫藥組合物包含約3.5 wt/wt%、約3.6 wt/wt%、約3.7 wt/wt%、約3.8 wt/wt%、約3.9 wt/wt%、約4.0 wt/wt%、約4.1 wt/wt%、約4.2 wt/wt%、約4.3 wt/wt%、約4.4 wt/wt%、約4.5 wt/wt%、約4.6 wt/wt%、約4.7 wt/wt%、約4.8 wt/wt%、約4.9 wt/wt%、約5 wt/wt%、約5.1 wt/wt%、約5.2 wt/wt%、約5.3 wt/wt%、約5.4 wt/wt%、約5.5 wt/wt%、約5.6 wt/wt%、約5.7 wt/wt%、約5.8 wt/wt%、約5.9 wt/wt%或約6.0 wt/wt%之一或多種崩解劑。在一些態樣中,醫藥組合物包含約5 wt/wt%之一或多種崩解劑。In some aspects, the pharmaceutical composition comprises from about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt %, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt% , about 4.8 wt/wt%, about 4.9 wt/wt%, about 5 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, One or more disintegrants at about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7 wt/wt%, about 5.8 wt/wt%, about 5.9 wt/wt% or about 6.0 wt/wt%. In some aspects, the pharmaceutical composition comprises about 5 wt/wt% of one or more disintegrants.
在一些態樣中,至少一種崩解劑選自由以下組成之群:交聯羧甲基纖維素鈉、甘醇酸澱粉鈉、交聚維酮及海藻酸。在一些態樣中,至少一種崩解劑為交聯羧甲基纖維素鈉。在一些態樣中,崩解劑為交聯羧甲基纖維素鈉。在一些態樣中,醫藥組合物包含約3.5 wt/wt%至約6 wt/wt%之交聯羧甲基纖維素鈉。在一些態樣中,醫藥組合物包含約3.5 wt/wt%、約3.6 wt/wt%、約3.7 wt/wt%、約3.8 wt/wt%、約3.9 wt/wt%、約4.0 wt/wt%、約4.1 wt/wt%、約4.2 wt/wt%、約4.3 wt/wt%、約4.4 wt/wt%、約4.5 wt/wt%、約4.6 wt/wt%、約4.7 wt/wt%、約4.8 wt/wt%、約4.9 wt/wt%、約5 wt/wt%、約5.1 wt/wt%、約5.2 wt/wt%、約5.3 wt/wt%、約5.4 wt/wt%、約5.5 wt/wt%、約5.6 wt/wt%、約5.7 wt/wt%、約5.8 wt/wt%、約5.9 wt/wt%或約6.0 wt/wt%之交聯羧甲基纖維素鈉。在一些態樣中,醫藥組合物包含約5 wt/wt%之交聯羧甲基纖維素鈉。In some aspects, the at least one disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, crospovidone, and alginic acid. In some aspects, the at least one disintegrant is croscarmellose sodium. In some aspects, the disintegrant is croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt% to about 6 wt/wt% croscarmellose sodium. In some aspects, the pharmaceutical composition comprises about 3.5 wt/wt%, about 3.6 wt/wt%, about 3.7 wt/wt%, about 3.8 wt/wt%, about 3.9 wt/wt%, about 4.0 wt/wt %, about 4.1 wt/wt%, about 4.2 wt/wt%, about 4.3 wt/wt%, about 4.4 wt/wt%, about 4.5 wt/wt%, about 4.6 wt/wt%, about 4.7 wt/wt% , about 4.8 wt/wt%, about 4.9 wt/wt%, about 5 wt/wt%, about 5.1 wt/wt%, about 5.2 wt/wt%, about 5.3 wt/wt%, about 5.4 wt/wt%, Croscarmellose sodium at about 5.5 wt/wt%, about 5.6 wt/wt%, about 5.7 wt/wt%, about 5.8 wt/wt%, about 5.9 wt/wt% or about 6.0 wt/wt% . In some aspects, the pharmaceutical composition comprises about 5 wt/wt% croscarmellose sodium.
在一些態樣中,醫藥組合物包含0 wt/wt%至約2 wt/wt%之一或多種潤滑劑。在一些態樣中,醫藥組合物包含0 wt/wt%、約0.1 wt/wt%、約0.2 wt/wt%、約0.3 wt/wt%、約0.4 wt/wt%、約0.5 wt/wt%、約0.6 wt/wt%、約0.7 wt/wt%、約0.8 wt/wt%、約0.9 wt/wt%、約1 wt/wt%、約1.1 wt/wt%、約1.2 wt/wt%、約1.3 wt/wt%、約1.4 wt/wt%、約1.5 wt/wt%、約1.6 wt/wt%、約1.7 wt/wt%、約1.8 wt/wt%、約1.9 wt/wt%或約2 wt/wt%之一或多種潤滑劑。在一些態樣中,醫藥組合物包含約1 wt/wt%之一或多種潤滑劑。In some aspects, the pharmaceutical composition comprises 0 wt/wt% to about 2 wt/wt% of one or more lubricants. In some aspects, the pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt% , about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, About 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt% or about 2 wt/wt% one or more lubricants. In some aspects, the pharmaceutical composition comprises about 1 wt/wt% of one or more lubricants.
在一些態樣中,至少一種潤滑劑選自由以下組成之群:硬脂酸鎂、硬脂醯富馬酸鈉、甘油二山崳酸酯及滑石。在一些態樣中,至少一種潤滑劑為硬脂酸鎂。在一些態樣中,潤滑劑為硬脂酸鎂。在一些態樣中,醫藥組合物包含0 wt/wt%、約0.1 wt/wt%、約0.2 wt/wt%、約0.3 wt/wt%、約0.4 wt/wt%、約0.5 wt/wt%、約0.6 wt/wt%、約0.7 wt/wt%、約0.8 wt/wt%、約0.9 wt/wt%、約1 wt/wt%、約1.1 wt/wt%、約1.2 wt/wt%、約1.3 wt/wt%、約1.4 wt/wt%、約1.5 wt/wt%、約1.6 wt/wt%、約1.7 wt/wt%、約1.8 wt/wt%、約1.9 wt/wt%或約2 wt/wt%之硬脂酸鎂。在一些態樣中,醫藥組合物包含0 wt/wt%之硬脂酸鎂。在一些態樣中,醫藥組合物包含約1 wt/wt%之硬脂酸鎂。In some aspects, the at least one lubricant is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl dibehenate, and talc. In some aspects, at least one lubricant is magnesium stearate. In some aspects, the lubricant is magnesium stearate. In some aspects, the pharmaceutical composition comprises 0 wt/wt%, about 0.1 wt/wt%, about 0.2 wt/wt%, about 0.3 wt/wt%, about 0.4 wt/wt%, about 0.5 wt/wt% , about 0.6 wt/wt%, about 0.7 wt/wt%, about 0.8 wt/wt%, about 0.9 wt/wt%, about 1 wt/wt%, about 1.1 wt/wt%, about 1.2 wt/wt%, About 1.3 wt/wt%, about 1.4 wt/wt%, about 1.5 wt/wt%, about 1.6 wt/wt%, about 1.7 wt/wt%, about 1.8 wt/wt%, about 1.9 wt/wt% or about 2 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition comprises 0 wt/wt% magnesium stearate. In some aspects, the pharmaceutical composition comprises about 1 wt/wt% magnesium stearate.
在一些態樣中,醫藥組合物為膠囊。在一些態樣中,膠囊包含約1 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中膠囊之每一組分如下:(a)約0.25 wt/wt%至約1.5 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物;(b)約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;(c)約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;(d)約0.5 wt/wt%至約2 wt/wt%之一或多種潤滑劑;及(e)囊封組分(a)至(d)之明膠膠囊。In some aspects, the pharmaceutical composition is a capsule. In some aspects, the capsules comprise about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy crystalline composition of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/ wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule encapsulating components (a) to (d).
在一些態樣中,膠囊包含約2 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中膠囊之每一組分如下:(a)約0.25 wt/wt%至約1.5 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物;(b)約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;(c)約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;(d)約0.5 wt/wt%至約2 wt/wt%之一或多種潤滑劑;及(e)囊封組分(a)至(d)之明膠膠囊。In some aspects, the capsules comprise about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy crystalline composition of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/ wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule encapsulating components (a) to (d).
在一些態樣中,膠囊包含約3 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中膠囊之每一組分如下:(a)約0.25 wt/wt%至約1.5 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物;(b)約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;(c)約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;(d)約0.5 wt/wt%至約2 wt/wt%之一或多種潤滑劑;及(e)囊封組分(a)至(d)之明膠膠囊。In some aspects, the capsules comprise about 3 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy crystalline composition of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/ wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule encapsulating components (a) to (d).
在一些態樣中,膠囊包含約4 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中膠囊之每一組分如下:(a)約0.25 wt/wt%至約1.5 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物;(b)約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;(c)約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;(d)約0.5 wt/wt%至約2 wt/wt%之一或多種潤滑劑;及(e)囊封組分(a)至(d)之明膠膠囊。In some aspects, the capsules comprise about 4 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide, wherein each component of the capsule is as follows: (a) about 0.25 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3-dihydroxypropoxy crystalline composition of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/ wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; (d) about 0.5 wt/wt% to about 2 wt/wt% of one or more lubricants; and (e) a gelatin capsule encapsulating components (a) to (d).
在一些態樣中,膠囊包含約5 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中膠囊之每一組分如下:(a)約2.5 wt/wt%至約7.0 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物;(b)約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;(c)約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;及(d)囊封組分a至c之明膠膠囊。 治療方法 In some aspects, the capsules comprise about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenyl Amino)-benzamide, wherein each component of the capsule is as follows: (a) about 2.5 wt/wt% to about 7.0 wt/wt% of N-((R)-2,3-dihydroxypropoxy crystalline composition of -3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; (b) about 85 wt/wt% to about 95 wt/ wt% of one or more diluents; (c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and (d) a gelatin capsule encapsulating components a to c. treatment method
在一些態樣中,本揭示案提供治療腫瘤、癌症或RAS病之方法,其包括向需要此治療之個體投與本文所闡述之醫藥組合物。In some aspects, the disclosure provides methods of treating tumors, cancer, or RAS disease comprising administering to an individual in need of such treatment a pharmaceutical composition described herein.
在一些態樣中,腫瘤為神經纖維瘤。在一些態樣中,腫瘤為與1型神經纖維瘤病相關之神經纖維瘤。在一些態樣中,腫瘤選自由以下組成之群:皮膚神經纖維瘤、叢狀神經纖維瘤、視路神經膠質瘤、低級別神經膠質瘤、高級別神經膠質瘤或惡性外周神經鞘瘤。在一些態樣中,腫瘤為叢狀神經纖維瘤。In some aspects, the tumor is a neurofibroma. In some aspects, the tumor is a neurofibroma associated with neurofibromatosis type 1. In some aspects, the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low grade glioma, high grade glioma, or malignant peripheral nerve sheath tumor. In some aspects, the tumor is a plexiform neurofibroma.
在一些態樣中,個體經診斷患有選自由以下組成之群之RAS病:1型神經纖維瘤病、2型神經纖維瘤病、心面皮膚症候群、克斯提洛氏症候群、雷吉士症候群、努南氏症候群及多發雀斑樣痣型努南氏症候群。In some aspects, the individual is diagnosed with a RAS disorder selected from the group consisting of: neurofibromatosis type 1,
在一些態樣中,癌症選自由以下組成之群:皮膚癌、惡性外周神經鞘癌、白血病、淋巴瘤、組織細胞性贅瘤、肺癌、乳癌、卵巢癌、腎癌、結腸直腸癌、甲狀腺癌、膽管癌、尿路上皮癌、子宮贅瘤、胃癌、肉瘤、膀胱癌、頭頸癌、子宮內膜癌、食管癌、腺樣囊性癌、膽囊癌、***癌、口腔癌、子宮頸癌、胰臟癌、黑色素瘤、肝細胞癌、膽道癌及腹膜漿液性癌。在一些態樣中,白血病選自由以下組成之群:急性淋巴球性白血病、急性骨髓性白血病、慢性淋巴球性白血病及慢性骨髓性白血病。在一些態樣中,淋巴瘤選自由以下組成之群:B細胞淋巴瘤、T細胞淋巴瘤、伯基特氏淋巴瘤、濾泡性淋巴瘤、外套細胞淋巴瘤、原發性縱膈B細胞淋巴瘤、小淋巴球性淋巴瘤及瓦登斯特隆巨球蛋白血症。在一些態樣中,肺癌選自由以下組成之群:肺腺癌、鱗狀非小細胞肺癌、非鱗狀非小細胞肺癌及小細胞肺癌。In some aspects, the cancer is selected from the group consisting of: skin cancer, malignant peripheral nerve sheath carcinoma, leukemia, lymphoma, histiocytic neoplasm, lung cancer, breast cancer, ovarian cancer, renal cancer, colorectal cancer, thyroid cancer , cholangiocarcinoma, urothelial carcinoma, uterine neoplasm, gastric cancer, sarcoma, bladder cancer, head and neck cancer, endometrial cancer, esophageal cancer, adenoid cystic carcinoma, gallbladder cancer, prostate cancer, oral cancer, cervical cancer, Pancreatic cancer, melanoma, hepatocellular carcinoma, biliary tract cancer and peritoneal serous carcinoma. In some aspects, the leukemia is selected from the group consisting of acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and chronic myelogenous leukemia. In some aspects, the lymphoma is selected from the group consisting of: B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell Lymphoma, small lymphocytic lymphoma, and Wadenstrom's macroglobulinemia. In some aspects, the lung cancer is selected from the group consisting of lung adenocarcinoma, squamous non-small cell lung cancer, non-squamous non-small cell lung cancer, and small cell lung cancer.
在一些態樣中,個體在一或多個基因中攜帶突變或其他畸變,該突變或其他畸變引起某些癌症之功能特徵增加或喪失,其中一或多個基因中之該突變或其他畸變為KRAS、NRAS、HRAS、BRAF、MEK1、MEK2、RASA1、MAP2K4、NF1或NF2中之一或多者中之突變或其他畸變。In some aspects, an individual carries a mutation or other aberration in one or more genes that causes an increase or loss of functional characteristics of certain cancers, wherein the mutation or other aberration in one or more genes is Mutations or other aberrations in one or more of KRAS, NRAS, HRAS, BRAF, MEK1, MEK2, RASA1, MAP2K4, NF1 or NF2.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之個別劑量係以一個以上之膠囊或錠劑形式投與。舉例而言,3 mg劑量之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺可以兩個膠囊之形式投與(一個含有2 mg且另一個含有1 mg)或以三個膠囊之形式投與(各自含有1 mg)。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Individual doses of amide are administered as more than one capsule or lozenge. For example, a 3 mg dose of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)- Benzamide can be administered as two capsules (one containing 2 mg and the other 1 mg) or as three capsules (each containing 1 mg).
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以每劑本文所闡述之醫藥組合物約0.1 mg至約20 mg之量提供。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以每劑約0.1 mg、約0.2 mg、約0.3 mg、約0.4 mg、約0.5 mg、約0.6 mg、約0.7 mg、約0.8 mg、約0.9 mg、約1 mg、約2 mg、約3 mg、約4 mg、約5 mg、約6 mg、約7 mg、約8 mg、約9 mg、約10 mg、約11 mg、約12 mg、約13 mg、約14 mg、約15 mg、約16 mg、約17 mg、約18 mg、約19 mg或約20 mg之量提供。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以每劑約1 mg之量提供。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以每劑約2 mg之量提供。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以每劑約3 mg之量提供。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以每劑約4 mg之量提供。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以每劑約10 mg之量提供。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are provided in amounts of about 0.1 mg to about 20 mg per dose of the pharmaceutical compositions described herein. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The amide is in the form of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, About 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are provided in amounts of approximately 1 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are provided in amounts of approximately 2 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are provided in amounts of approximately 3 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are provided in amounts of approximately 4 mg per dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are provided in amounts of about 10 mg per dose.
在一些態樣中,包含N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之醫藥組合物每天投與一次、兩次、三次或四次。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzene The pharmaceutical composition of formamide is administered once, twice, three times or four times a day. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily.
在一些態樣中,若N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺在一天中欲投與一次以上,則可將N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量分開,使得患者在每次投與時接受相等的劑量。舉例而言,若N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量為4 mg,每天投與兩次,則患者可在早晨接受2 mg (例如兩個1 mg膠囊),且在晚上接受2 mg (例如一個2 mg膠囊)。In some aspects, if N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzene If formamide is to be administered more than once a day, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo The total daily dose of -phenylamino)-benzamide is divided such that the patient receives an equal dose at each administration. For example, if N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoyl With a total daily dose of amine of 4 mg administered twice daily, the patient may receive 2 mg in the morning (eg two 1 mg capsules) and 2 mg in the evening (eg one 2 mg capsule).
在一些態樣中,若N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺在一天中欲投與一次以上,則可將N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量分開,使得患者在每次投與時接受不同的劑量。舉例而言,若N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量為4 mg,每天投與兩次,則患者可在早晨接受1 mg (例如一個1 mg膠囊),且在晚上接受3 mg (例如一個1 mg膠囊及一個2 mg膠囊)。In some aspects, if N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzene If formamide is to be administered more than once a day, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo The total daily dose of -phenylamino)-benzamide is divided such that the patient receives a different dose with each administration. For example, if N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoyl The total daily dose of amine is 4 mg, administered twice daily, and the patient may receive 1 mg in the morning (eg, one 1 mg capsule) and 3 mg in the evening (eg, one 1 mg capsule and one 2 mg capsule).
在一些態樣中,本揭示案提供治療腫瘤、癌症或RAS病之方法,其包括向需要此治療之患者投與本文所闡述之醫藥組合物,其中N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次約0.1 mg至約10 mg。In some aspects, the disclosure provides methods of treating tumors, cancer, or RAS disease comprising administering to a patient in need of such treatment a pharmaceutical composition described herein, wherein N-((R)-2,3- The total daily dose of dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered twice a day, each time About 0.1 mg to about 10 mg.
在一些態樣中,經由本文所闡述之醫藥組合物投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之結晶組合物,其中N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過1 mg、2 mg、3 mg、4 mg、5 mg、6 mg、7 mg、8 mg、9 mg、10 mg、11 mg、12 mg、13 mg、14 mg、15 mg、16 mg、17 mg、18 mg、19 mg或20 mg之總日劑量提供。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過20 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過15 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過12 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過10 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過8 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過6 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過2 mg之總日劑量來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過1 mg之總日劑量來投與。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4- Iodo-phenylamino)-benzamide crystalline composition, wherein N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro- 4-iodo-phenylamino)-benzamide in doses not exceeding 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg , 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg total daily dose. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 15 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 12 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 8 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 6 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 2 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered at a total daily dose not to exceed 1 mg.
在一些態樣中,本揭示案提供治療腫瘤、癌症或RAS病之方法,其包括向需要此治療之患者投與本文所闡述之醫藥組合物,其中N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約0.1 mg至約20 mg。In some aspects, the disclosure provides methods of treating tumors, cancer, or RAS disease comprising administering to a patient in need of such treatment a pharmaceutical composition described herein, wherein N-((R)-2,3- The total daily dose of dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide is administered once daily at a dose of about 0.1 mg to about 20 mg.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約0.1 mg、約0.2 mg、約0.3 mg、約0.4 mg、約0.5 mg、約0.6 mg、約0.7 mg、約0.8 mg、約0.9 mg、約1 mg、約2 mg、約3 mg、約4 mg、約5 mg、約6 mg、約7 mg、約8 mg、約9 mg、約10 mg、約11 mg、約12 mg、約13 mg、約14 mg、約15 mg、約16 mg、約17 mg、約18 mg、約19 mg或約20 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約1 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約2 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約3 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約4 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約5 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約6 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約7 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約8 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約9 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約10 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約11 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約12 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約13 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約14 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約15 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約16 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約17 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約18 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約19 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天一次來投與,劑量為約20 mg。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once a day in doses of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, About 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, or about 20 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 1 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 2 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 3 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 4 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 5 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 6 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 7 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 8 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 9 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 11 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 12 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 13 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 14 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 15 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 16 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 17 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 18 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 19 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered once daily in a dose of about 20 mg.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約0.1 mg至約10 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約0.1 mg、約0.2 mg、約0.3 mg、約0.4 mg、約0.5 mg、約0.6 mg、約0.7 mg、約0.8 mg、約0.9 mg、約1 mg、約2 mg、約3 mg、約4 mg、約5 mg、約6 mg、約7 mg、約8 mg、約9 mg或約10 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約0.25 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約0.5 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約1 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約2 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約3 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約4 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約5 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約6 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約7 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約8 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約9 mg。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之總日劑量係以每天兩次來投與,每次劑量為約10 mg。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose ranging from about 0.1 mg to about 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice a day, each dose is about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg , about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 0.25 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 0.5 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 1 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 2 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 3 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 4 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 5 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 6 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 7 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 8 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 9 mg. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The total daily dose of amide is administered twice daily, with each dose being about 10 mg.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a) 21天投與總日劑量;及(b) 7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)連續21天投與總日劑量;之後(b)連續7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The amide was administered in a 28-day dosing cycle consisting of: (a) 21 days of administration of the total daily dose; and (b) 7 days of non-administration of N-((R)-2,3-dihydroxypropane oxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl The amide was administered in a 28-day dosing cycle consisting of: (a) 21 consecutive days of administration of the total daily dose; thereafter (b) 7 consecutive days of non-administration of N-((R)-2,3-di hydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)三個7天期,每期包含(i) 5天投與總日劑量及(ii) 2天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺;及(b) 7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)三個7天期,每期包含(i)連續5天投與總日劑量及(ii)連續2天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺;之後(b)連續7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides were administered in a 28-day dosing cycle comprising: (a) three 7-day periods, each comprising (i) 5 days of administration of the total daily dose and (ii) 2 days of no administration of N-( (R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; and (b) 7 days N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide was not administered. In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides were administered in a 28-day dosing cycle consisting of: (a) three 7-day periods, each consisting of (i) 5 consecutive days of administration of the total daily dose and (ii) 2 consecutive days of no administration of N -((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; after (b) No administration of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl for 7 consecutive days Amide.
在一些態樣中,N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含28天投與總日劑量。In some aspects, N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzyl Amides are administered in a 28-day dosing cycle consisting of 28-day administration of the total daily dose.
在一些態樣中,重複28天投藥週期,直至總計24個連續28天投藥週期。In some aspects, the 28-day dosing cycle is repeated for a total of 24 consecutive 28-day dosing cycles.
在一些態樣中,本揭示案提供本文所闡述之醫藥組合物之用途,其用於製造用以治療癌症、腫瘤或RAS病之藥劑。
實例
使用下文之匯聚式合成方案,自市售2,3,4-三氟苯甲酸(TFBA)、2-氟-4-碘苯胺(FIA)及手性S-甘油縮丙酮(SGA)起始已製備出2 kg PD-0325901。 步驟1:PD-0337792「側鏈」之製備 Starting from commercially available 2,3,4-trifluorobenzoic acid (TFBA), 2-fluoro-4-iodoaniline (FIA) and chiral S-glycerolacetal (SGA) using the convergent synthetic scheme below, 2 kg of PD-0325901 was prepared. Step 1: Preparation of PD-0337792 "side chain"
除非另有說明,否則所有反應均在甲苯中實施。三氟甲磺酸酐得到最佳產率。
表1:用於步驟1之偶合劑
認識到三氟甲磺酸酯得到最高產率,故對取消低溫條件之可能性進行研究,此有可能係出於對「甲磺酸酯」中間體穩定性之考慮。以下實驗表明,在-20℃下運行之實驗無顯著之產率損失。
表2:偶合反應之產率
*在-20℃下利用三氟甲磺酸酐三氟甲磺酸(TFMSA) (4.2 g, 1.002當量)處理於16 ml甲苯中之2 g (1當量) SGA,且接著攪拌規定時間,之後添加固體N-羥基酞醯亞胺(NHP)或轉移至含有固體NHP之燒瓶中。*2 g (1 eq) of SGA in 16 ml of toluene were treated with trifluoromethanesulfonic anhydride trifluoromethanesulfonic acid (TFMSA) (4.2 g, 1.002 eq) at -20°C and then stirred for the specified time before adding The solid N-hydroxyphthalimide (NHP) or transferred to the flask containing the solid NHP.
上文呈現之數據表明,在添加N-羥基酞醯亞胺之前長時間攪拌「三氟甲磺酸酯」中間體後未觀察到有害效應。將中間體混合物反向添加至固體NHP中似乎得到最高產率。The data presented above indicate that no deleterious effects were observed after prolonged stirring of the "triflate" intermediate prior to the addition of N-hydroxyphthalimide. Reverse addition of the intermediate mixture to solid NHP appeared to give the highest yield.
使用三氟甲磺酸酯之另一優點在於,藉由水洗即可輕鬆去除Et 3N三氟甲磺酸鹽副產物。此在甲苯中產生高純度的N-羥基酞醯亞胺保護醇IPGAP (PD-0333760),其可以晶體形式分離或進行最終之去保護反應。 Another advantage of using triflate is that the Et3N triflate by-product can be easily removed by washing with water. This yields highly pure N-hydroxyphthalimide-protected alcohol IPGAP (PD-0333760) in toluene, which can be isolated in crystal form or subjected to a final deprotection reaction.
氨水鹼及無水氨鹼二者均作為去保護劑進行了檢查。二者結果均為成功的。當使用無水氨時,酞醯亞胺副產物自產物(PD-0337792)於甲苯中之溶液中簡單地過濾出。類似地,當使用氨水(28%溶液)時,在自甲苯中實施共沸除水後自溶液中過濾出該副產物。然而,無水氨需要反應在高壓安全殼中實施。藉由吹掃氨氣進行的實驗得到可接受之產率;然而,該等實驗需要較大體積及使用低溫冷凝器(以避免氣體自反應器頂部空間中逸出)。
表3:鹼去保護之產率
在自動化反應器中對反應之檢查揭示,反應在起始期後基本上為劑量控制的。增加胺化鋰之量且增加攪動速率似乎縮短誘導時間。已顯示添加水延長誘導時間。然而,尚不清楚此是否係由於形成氫氧化鋰所致。Examination of the reactions in the automated reactor revealed that the reactions were essentially dose-controlled after the initiation period. Increasing the amount of lithium amide and increasing the agitation rate appeared to shorten the induction time. Addition of water has been shown to extend the induction time. However, it is unclear whether this is due to the formation of lithium hydroxide.
當添加0.1當量H 2O時,誘導時間增加。然而當添加0.1當量氫氧化鋰時,該趨勢逆轉。在增加胺化鋰當量並攪動時,誘導時間減少。 步驟3:醯胺偶合及去保護 The induction time increased when 0.1 equiv of H 2 O was added. However, this trend was reversed when 0.1 equivalent of lithium hydroxide was added. The induction time decreased with increasing lithium amide equivalents and agitation. Step 3: Amide Coupling and Deprotection
CDI輔助之PD-0315209酸與側鏈試劑之偶合、之後進行酸(HCl水溶液)水解在實驗室中始終產生良好結果。此步驟之開發關注點在於確保雜質水準在規格限度內。最終分離之二醇產物中之已知雜質為過量之PD-0315209酸、二聚體雜質及手性雜質。藉由限制起始s-甘油縮丙酮中之R-鏡像異構物來控制手性雜質。已知二聚體雜質(d)水準升高在多晶型物轉變步驟中造成困難。二聚體雜質最初係藉由咪唑(CDI活化酸)在過量酸PD-0315209存在下反應形成,形成二聚體(a)及可能(b),其接著在隨後的IPGA偶合及酸水解步驟中繼續進行反應,分別形成二聚體(c)及(d)。雜質d稱為PF-00191189。 CDI-assisted coupling of PD-0315209 acid to side chain reagents followed by acid (aqueous HCl) hydrolysis has consistently yielded good results in the laboratory. The development focus at this step is to ensure that impurity levels are within specification limits. Known impurities in the final isolated diol product are excess PD-0315209 acid, dimer impurities and chiral impurities. Chiral impurities were controlled by limiting the R-enantiomer in the starting s-glycerolacetal. Elevated levels of dimer impurity (d) are known to cause difficulties in the polymorph conversion step. The dimer impurity is initially formed by the reaction of imidazole (CDI activating acid) in the presence of excess acid PD-0315209, forming dimers (a) and possibly (b), which are then followed in the subsequent IPGA coupling and acid hydrolysis steps The reaction continues to form dimers (c) and (d), respectively. Impurity d is called PF-00191189.
該反應可藉由加入兩種固體FIPFA及CDI、之後加入溶劑(乙腈)或將固體CDI加入至FIPFA於乙腈中之漿液中而在實驗室中容易地進行。該等固體最初均不溶於乙腈中。酸活化反應快速(幾乎為瞬時的),形成高度可溶之咪唑化物產物,其將漿液轉化成澄清均質之溶液,同時發生CO 2氣體逸出。 The reaction can be easily performed in the laboratory by adding two solid FIPFA and CDI followed by solvent (acetonitrile) or by adding solid CDI to a slurry of FIPFA in acetonitrile. None of these solids were initially soluble in acetonitrile. The acid activation reaction is rapid (nearly instantaneous), forming a highly soluble imidazolide product, which converts the slurry into a clear homogeneous solution with simultaneous CO2 gas evolution.
實驗室實驗通常產生水準低於3%之雜質,其可藉由隨後自3%-5%乙醇-甲苯系統中重結晶而完全去除。在雜質水準高於0.3%之少數情況下,實施額外重結晶。表4顯示在實驗室實驗中觀察到高雜質水準之選定結果及如何在隨後重結晶中將該等雜質去除。使用乙腈/甲苯系統獲得粗製PD-0325901,且使經純化之產物自5%乙醇/甲苯系統中重結晶。條目號4及5使用額外溶劑以確保雜質去除,其中條目5需要兩次重結晶以在多晶型物轉變中達成「ND」水準。在維持可濾過性漿液並確保去除雜質的同時,選擇8-10 ml/g粗結晶體積以限制產物損失。
表4:PD-0325901之純化
考慮到固體CDI添加速率,開發出一種按比例放大之程序,該程序將在多晶型物轉變前產生可容忍水準之雜質(<0.3%),而在重結晶中不損失過多產物。為使雜質形成最小化,快速添加較佳;然而,添加速率需要確保所逸出之CO 2安全排出。 Considering the solid CDI addition rate, a scale-up procedure was developed that would yield tolerable levels of impurities (<0.3%) prior to polymorph conversion without excessive product loss in recrystallization. To minimize impurity formation, rapid addition is preferred; however, the rate of addition is needed to ensure the escaped CO2 is safely vented.
首先將半份固體CDI添加至PD-0325901酸中,之後添加溶劑。接著在不到30分鐘內經由加料漏斗添加剩餘CDI,以確保雜質水準低於3%。 多晶型物轉變 Half of the solid CDI was added to the PD-0325901 acid first, followed by the addition of solvent. The remaining CDI was then added via the addition funnel in less than 30 minutes to ensure the impurity level was below 3%. polymorphic transformation
下文表徵PD-0325901之三種多晶形式。形式I具有最高熔點(約117℃),且對映性地與形式IV (熔點112℃)相關,該形式IV在低於73℃估計轉變溫度下為更穩定之形式。形式II為低熔點形式(熔點約85℃)。
表5:晶體形式熔點及熔化熱
大多數多晶型物轉變實驗係使用含有各種形式之高純度PD-0325901實施的,且通常展現出低於80℃之低熔點,此為在直接自反應混合物中分離出粗晶體後進行有效EtOH/甲苯重結晶之結果。將該等各種多晶型物完全溶解於EtOH中,且隨後藉由在20℃-25℃下以15至60分鐘時期添加水(20體積)進行沈澱。對在攪拌不到2小時時取樣之固體之分析顯示,多晶型物完全轉變成形式IV。唯一的失敗發生在當將水幾乎立即一次性添加至PD-0325901於EtOH (4體積)中之溶液中時。在此情形下,僅獲得不期望之多晶型物形式I。Most polymorph conversion experiments were carried out with highly pure PD-0325901 containing various forms, and generally exhibited low melting points below 80 °C, which is the result of efficient EtOH after isolation of crude crystals directly from the reaction mixture. /The result of toluene recrystallization. The various polymorphs were completely dissolved in EtOH and then precipitated by addition of water (20 vol) at 20°C-25°C over a period of 15 to 60 minutes. Analysis of the solid sampled when stirred for less than 2 hours showed complete conversion of the polymorph to Form IV. The only failure occurred when water was added almost immediately to a solution of PD-0325901 in EtOH (4 vol) in one go. In this case, only the undesired polymorph form I was obtained.
在標準程序中觀察到一處異常。一個批次產生混合多晶型物,但在重結晶後不具有可偵測水準之雜質。此情形之校正程序包括在接近或高於73℃之溫度下將低熔點形式(形式II)轉變成所有形式I,之後緩慢(約4 h時期)冷卻至20℃。An anomaly was observed in standard procedures. One batch produced mixed polymorphs but had no detectable levels of impurities after recrystallization. The corrective procedure for this case included conversion of the low melting form (Form II) to all of Form I at temperatures near or above 73°C, followed by slow (approximately 4 h period) cooling to 20°C.
EtOH/水系統產生有效多晶型物轉變。重結晶(經純化)之PD-0325901最初由對映性多晶型物形式I (熔點約117℃)及形式IV (熔點約112℃)組成,其完全轉變成形式IV。 基本上純的形式IV之領試工廠製備 步驟1:PD-0337792「側鏈」之製備 The EtOH/water system produced efficient polymorph conversion. Recrystallized (purified) PD-0325901 initially consisted of the enantiopolymorphs Form I (melting point about 117°C) and Form IV (melting point about 112°C), which completely converted to Form IV. Pilot Plant Preparation of Substantially Pure Form IV Step 1: Preparation of PD-0337792 "side chain"
將14.4 kg醇(化學純度99.4%,光學純度99.6%鏡像異構物過量)轉化成97.5 kg 9.7% w/w PD-0337792 (IPGA)於甲苯中之溶液(總產率約60%)。在三氟甲磺酸酐添加期間藉由維持溫度低於-20℃在200 L反應器中實施三氟甲磺酸酯活化。接著將所產生之活化醇轉移至含有固體N-羥基酞醯亞胺(NHP)之400 L反應器中,且使反應在環境溫度下進行至完成。藉由添加氨水(約28%溶液,5當量,34 kg)實施最終的鹼去保護。在反應完成後,藉由蒸餾自甲苯中去除水,且過濾出所得固體副產物以產生產物溶液。 步驟2:PD-0315209之製備 14.4 kg of alcohol (chemical purity 99.4%, optical purity 99.6% enantiomer excess) was converted into 97.5 kg of a 9.7% w/w solution of PD-0337792 (IPGA) in toluene (total yield about 60%). Triflate activation was performed in a 200 L reactor by maintaining the temperature below -20 °C during the triflic anhydride addition. The resulting activated alcohol was then transferred to a 400 L reactor containing solid N-hydroxyphthalimide (NHP), and the reaction was allowed to proceed to completion at ambient temperature. Final base deprotection was performed by addition of aqueous ammonia (approximately 28% solution, 5 equiv, 34 kg). After the reaction was complete, water was removed from the toluene by distillation, and the resulting solid by-product was filtered off to yield a product solution. Step 2: Preparation of PD-0315209
該製程產生21.4 kg (99.4% w/w分析),其為自起始材料2,3,4-三氟苯甲酸(12 kg, 1當量)及2-氟-4-碘苯胺(16.4 kg, 1.02當量)與胺化鋰鹼(5 kg, 3.2當量)之理論值之80%。藉由在50℃下將5%之TFBA及FIA總溶液添加至胺化鋰漿液中起始反應。此反應展示最短起始期為約10分鐘,其可藉由色彩變化及輕微放熱觀察到。經由壓力罐在一小時內緩慢添加剩餘的TFBA/FIA於THF中之溶液,同時將反應溫度維持在45℃-55℃內。在整個操作期間,未觀察到明顯的壓力上升(由於氨氣釋放)。
步驟3:PD-0325901之製備
The process yielded 21.4 kg (99.4% w/w analysis) from the starting
對CDI裝料進行改進,以減少潛在氣體生成。在溶劑添加之前及之後,將兩等份CDI添加至固體FIPFA中(經由注入式裝載器(shot loader))。兩次固體CDI添加(每次4.6 kg)之間的時間不應超過30分鐘。接著用乙醇溶解兩個中間濾餅。在PD-0325901重結晶前,蒸餾過量乙醇且用甲苯替換至大約5% v/v乙醇。實驗室研究表明,自甲苯及乙腈結晶以及自甲苯中之乙醇重結晶無法減少雜質,此為多晶型物轉變所必需。已知二聚體雜質(PF-00191189)之存在水準大於0.2%會導致形成不期望之多晶型物。 Modifications to CDI charging to reduce potential gas generation. Two aliquots of CDI were added to solid FIPFA (via shot loader) before and after solvent addition. The time between two additions of solid CDI (4.6 kg each) should not exceed 30 minutes. The two intermediate filter cakes are then dissolved with ethanol. Before recrystallization of PD-0325901, excess ethanol was distilled and replaced with toluene to approximately 5% v/v ethanol. Laboratory studies showed that crystallization from toluene and acetonitrile and recrystallization from ethanol in toluene failed to reduce the impurity necessary for the polymorphic transformation. The dimer impurity (PF-00191189) is known to be present at levels greater than 0.2% leading to the formation of undesired polymorphs.
自最終反應混合物粗結晶使二聚體雜質PF-00191189減少至大約1.9%,且後續重結晶使其進一步減少至大約0.4%。結果,產生不期望之多晶型物。DSC圖案指示兩種不同的熔點約80℃ (低熔點形式II)及約117℃ (形式I)。此外在處理期間,固體在較預期顯著更低之溫度下結晶(實際約10℃,預期約40℃)。懷疑重結晶不成功係由於粗製物乾燥不完全所致之溶劑組成的變化。在約36小時後,當粗產物為約28 kg (理論值為26 kg)時,停止乙醇溶解前之粗製濕濾餅乾燥。 多晶型物轉變 Crude crystallization from the final reaction mixture reduced the dimer impurity PF-00191189 to about 1.9%, and subsequent recrystallization further reduced it to about 0.4%. As a result, undesired polymorphs are produced. The DSC pattern indicated two distinct melting points of about 80°C (low melting Form II) and about 117°C (Form I). Also during processing, the solids crystallized at significantly lower temperatures than expected (actually about 10°C, expected about 40°C). The unsuccessful recrystallization was suspected to be due to a change in solvent composition due to incomplete drying of the crude. After about 36 hours, when the crude product was about 28 kg (theoretical value is 26 kg), the crude wet cake was dried before stopping ethanol dissolution. polymorphic transformation
將來自最終EtOH/水結晶之大約7.4 kg PD-0325901 (混合多晶型物)及來自早期EtOH/甲苯濾液之沈澱材料進行多晶型物轉變。將兩個批次在過濾器中單獨乾燥至恆重,且將每一者溶解於EtOH中。藉由HPLC分析合併的EtOH溶液且得到16.4 kg估計量之PD-0325901。在經由真空蒸餾去除EtOH且在65℃下將溶劑組成調整為於甲苯中之約5% EtOH (亦即在65℃下逐滴添加EtOH直至固體完全溶解)後,開始重結晶。Approximately 7.4 kg of PD-0325901 (mixed polymorphs) from the final EtOH/water crystallization and precipitated material from the earlier EtOH/toluene filtrate were subjected to polymorph conversion. Both batches were dried separately on filter to constant weight and each was dissolved in EtOH. The combined EtOH solution was analyzed by HPLC and an estimated 16.4 kg of PD-0325901 was obtained. After removing EtOH via vacuum distillation and adjusting the solvent composition to about 5% EtOH in toluene at 65°C (ie, adding EtOH dropwise at 65°C until the solids were completely dissolved), recrystallization started.
實施緩慢4小時冷卻斜坡至5℃,之後攪拌12 h以確保結果滿意。過濾所得漿液,且在過濾器中再次將其完全乾燥至恆重(大約3天)。經純化之固體顯示99.8%純的PD-0325901,不含偵測水準之二聚體雜質PF-00191189。A slow 4 hour cooling ramp to 5 °C was implemented followed by 12 h stirring to ensure satisfactory results. The resulting slurry was filtered and completely dried again on the filter to constant weight (approximately 3 days). The purified solid showed 99.8% pure PD-0325901 with no detectable levels of dimeric impurity PF-00191189.
將經乾燥之固體(15.4 kg)重新溶解於恰好4體積之EtOH (62 L)中,自過濾器轉移至反應器中,且藉由在30℃-35℃下緩慢(約3 h)添加水(308 L)進行沈澱,冷卻至20℃並攪拌12 h。在2 h採集之漿液樣品之DSC分析顯示,固體完全為形式IV (期望之多晶型物)。The dried solid (15.4 kg) was redissolved in exactly 4 volumes of EtOH (62 L), transferred from the filter to the reactor, and added by slow (about 3 h) addition of water at 30°C-35°C (308 L) for precipitation, cooled to 20 °C and stirred for 12 h. DSC analysis of a sample of the slurry taken at 2 h showed that the solid was entirely Form IV (desired polymorph).
使用21.4 kg PD-0315209、9.7 kg CDI (1.05當量)、91 kg於甲苯中之9.7% PD-0337792溶液(1.1當量),且產生12.74 kg PD-0325901 (分析99.4%,100%形式IV,產率為約48%)。 實例2:PD-0325901之分析/雜質及鑑別 Using 21.4 kg PD-0315209, 9.7 kg CDI (1.05 equiv), 91 kg 9.7% solution of PD-0337792 in toluene (1.1 equiv), and yielded 12.74 kg PD-0325901 (99.4% assay, 100% Form IV, yield The rate is about 48%). Example 2: Analysis/impurity and identification of PD-0325901
藉由反相液相層析(275 nm UV偵測)將PD-0325901與製程雜質及降解物分離。除HPLC滯留時間以外,亦藉由獲得紅外或質子NMR光譜來鑑別PD-0325901。對於純度評估,藉由特徵性相對滯留時間來鑑別製程雜質及降解物且藉由面積正規化來定量。PD-0325901 was separated from process impurities and degradation products by reversed-phase liquid chromatography (275 nm UV detection). In addition to HPLC retention times, PD-0325901 was also identified by obtaining infrared or proton NMR spectra. For purity assessment, process impurities and degradants were identified by characteristic relative residence times and quantified by area normalization.
層析條件:Agilent Zorbax SB C18, 5 µm, 4.6 x 250 mm (或等效物);流量為1.0 mL/min;管柱溫度為30℃;偵測器波長為275 nm;稀釋劑為50/50乙腈/水;移動相A為0.1%三氟乙酸(TFA)水溶液;移動相B為甲醇;及下文梯度條件。針對參考標準測定分析且在無水、無溶劑之基礎上進行報告。按面積百分比報告指定及未指定雜質之量化。總雜質為高於報告臨限值(0.05%)存在之所有雜質之總和。 實例3:形式IV之單晶X射線繞射分析 Chromatographic conditions: Agilent Zorbax SB C18, 5 µm, 4.6 x 250 mm (or equivalent); flow rate is 1.0 mL/min; column temperature is 30°C; detector wavelength is 275 nm; diluent is 50/ 50 acetonitrile/water; mobile phase A is 0.1% trifluoroacetic acid (TFA) aqueous solution; mobile phase B is methanol; and gradient conditions below. Analyzes are determined against a reference standard and reported on an anhydrous, solvent-free basis. Quantification of specified and unspecified impurities is reported as area percent. Total impurities are the sum of all impurities present above the reporting threshold (0.05%). Example 3: Single Crystal X-ray Diffraction Analysis of Form IV
藉由所涉及之偶合劑與實例1中所揭示方法中所用的偶合劑不同之方法製備適宜之形式IV單晶。然而,該晶體所產生之形式IV具有與藉由實例1之方法所製備之形式IV相同的XRPD特徵,且因此具有適於形式IV分析之純度。A suitable single crystal of Form IV was prepared by a method involving a different coupler than that used in the method disclosed in Example 1 . However, the resulting Form IV of the crystals has the same XRPD characteristics as Form IV prepared by the method of Example 1 and is therefore of a purity suitable for Form IV analysis.
使用配備有CuKα INCOATEC Imus微焦點源(λ = 1.54178 Å)之Bruker D8 Venture Photon II CPAD繞射儀對單一形式IV晶體進行分析。模擬PXRD圖案係自下文所示之低溫(100 K)結構及室溫(298 K, 25℃)單位晶胞參數計算而來。首先基於自151個1°繞射圖框收穫之235次反射,藉由差異向量法測定室溫下之單位晶胞。隨後在由Saint (Bruker (2020). SAINT. Data Reduction Software)進行數據整合期間精修單位晶胞參數,且係基於在19.1 Å與1.1 Å解析度之間記錄的903次反射。模擬圖案與如圖1A中所示之實驗形式IV圖案一致。
表6:室溫下最初測定之單位晶胞參數
藉由將批料之XRPD光譜與參考標準XRPD光譜進行比較來確定形式IV材料之穩定性。此分析係在批料釋放時實施,且所獲得之XRPD光譜對應於形式IV之參考標準之XRPD光譜(圖2)。接著將形式IV批料儲存在25℃及65%相對濕度下。在68個月(圖3A)及再次在140個月(圖3B)對所儲存之形式IV實施XRPD分析。隨時間推移,XRPD光譜中未偵測到變化指示形式IV在25℃及≤65%相對濕度下穩定。The stability of the Form IV material was determined by comparing the XRPD spectrum of the batch to the XRPD spectrum of a reference standard. This analysis was carried out when the batch was released and the XRPD spectrum obtained corresponded to that of the reference standard of Form IV (Figure 2). The Form IV batch was then stored at 25°C and 65% relative humidity. XRPD analysis was performed on stored Form IV at 68 months (Figure 3A) and again at 140 months (Figure 3B). Over time, no changes were detected in the XRPD spectrum indicating that Form IV was stable at 25°C and < 65% relative humidity.
本說明書中所提及之所有公開案、專利及專利申請案均係以全文引用的方式併入本文中,其併入程度如同每一個別公開案、專利或專利申請案明確地且個別地指示以全文引用的方式併入一般。倘若發現本申請案中之術語在以引用方式併入本文中之文獻中定義不同,則將本文所提供之定義用作該術語之定義。All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Incorporated generally by reference in its entirety. If a term in this application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is used as the definition of that term.
儘管本發明已結合其具體態樣予以描述,但應理解,本發明能夠進行進一步修改且本申請案意欲涵蓋任何變更、用途或改動,該等變更、用途或改動一般遵循本揭示案之原則且包括本揭示案之偏離情況,此類偏離情況處於本發明所屬技術內之已知或常規慣例範圍內,且可應用於前文所陳述及以下所主張之範疇內的基本特徵。While the invention has been described in conjunction with specific aspects thereof, it is to be understood that the invention is capable of further modifications and this application is intended to cover any alteration, use or adaptation which generally follows the principles of the disclosure and The disclosure includes such departures as come within known or customary practice in the art to which the invention pertains and which are applicable to essential features in the scope of the foregoing statement and the following claim.
除本文所闡述之各個實施例以外,本揭示案亦包括以E1至E94編號之以下實施例。此實施例清單以例示性清單呈現,且本申請案不限於該等實施例。
E1. 一種結晶組合物,其為式(I)之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV:
(I)。
E2. 如E1之結晶組合物,其中該結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存3個月後展現實質上不變之XRPD圖案及/或DSC曲線。
E3. 如E1或E2之結晶組合物,其中該結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存6個月後展現實質上不變之XRPD圖案及/或DSC曲線。
E4. 如E1至E3中任一項之結晶組合物,其中該結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存1年後展現實質上不變之XRPD圖案及/或DSC曲線。
E5. 如E1至E4中任一項之結晶組合物,其中該結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存68個月後展現實質上不變之XRPD圖案及/或DSC曲線。
E6. 如E1至E5中任一項之結晶組合物,其中該結晶組合物在標準倉庫條件(15℃-25℃及≤65%相對濕度)下儲存≥140個月後展現實質上不變之XRPD圖案及/或DSC曲線。
E7. 如E2至E6中任一項之結晶組合物,其中該XRPD圖案使用以下來生成:
PANALYTICAL
®X'Pert Pro繞射儀,使用Ni濾波Cu Kα (45 kV/40 mA)輻射及0.03° 2θ之步長,利用X'CELERATOR
®即時多帶偵測器,
(a) 入射光束側上之構形如下:可變發散狹縫(10 mm輻照長度)、0.04弧度索勒狹縫、固定防散射狹縫(0.50°)及10 mm光束遮罩,及
(b) 繞射光束側上之構形如下:可變防散射狹縫(10 mm觀察長度)及0.04弧度索勒狹縫;或
BRUKER
®D8
®ADVANCE
TM系統,使用Cu Kα (40 kV/40 mA)輻射及0.03° 2θ之步長,利用LYNXEYE
TM偵測器,
(a) 入射光束側上之構形如下:Göebel鏡、鏡出口狹縫(0.2 mm)、2.5°索勒狹縫、光束刀,及
(b) 繞射光束側上之構形如下:防散射狹縫(8 mm)及2.5°索勒狹縫;且
其中樣品平坦地安裝在零背景Si晶圓上。
E8. 如E1至E7中任一項之結晶組合物,其中DSC圖案係使用TA Instruments Q100或Q2000示差掃描量熱計以約15℃/min之升溫速率生成。
E9. 如E1至E8中任一項之結晶組合物,其中該結晶組合物含有≤ 0.2%之二聚體雜質PF-00191189。
E10. 如E1至E9中任一項之結晶組合物,其中該結晶組合物含有約0.05重量%至約0.19重量%之二聚體雜質PF-00191189。
E11. 如E1至E9中任一項之結晶組合物,其中該結晶組合物不含可偵測量之二聚體雜質PF-00191189。
E12. 一種醫藥組合物,其包含如E1至E11中任一項之結晶組合物以及醫藥學上可接受之載劑。
E13. 如E12之醫藥組合物,其中該醫藥組合物用於經口投與。
E14. 如E13之醫藥組合物,其中該醫藥組合物為固體劑型。
E15. 如E12至E14中任一項之醫藥組合物,其中該醫藥組合物為錠劑或膠囊。
E16. 如E15之醫藥組合物,其中該醫藥組合物為錠劑。
E17. 如E15之醫藥組合物,其中該醫藥組合物為膠囊。
E18. 如E17之醫藥組合物,其中該膠囊包含約1 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中該膠囊之每一組分如下:
a) 約0.25 wt/wt%至約1.5 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該結晶組合物;
b) 約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;
c) 約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;
d) 約0.5 wt/wt%至約2 wt/wt%之一或多種潤滑劑;及
e) 囊封組分a至d之明膠膠囊。
E19. 如E17之醫藥組合物,其中該膠囊包含約2 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中該膠囊之每一組分如下:
a) 約0.25 wt/wt%至約1.5 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該結晶組合物;
b) 約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;
c) 約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;
d) 約0.5 wt/wt%至約2 wt/wt%之一或多種潤滑劑;及
e) 囊封組分a至d之明膠膠囊。
E20. 如E17之醫藥組合物,其中該膠囊包含約5 mg之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺,其中該膠囊之每一組分如下:
a) 約2.5 wt/wt%至約7.0 wt/wt%之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該結晶組合物;
b) 約85 wt/wt%至約95 wt/wt%之一或多種稀釋劑;
c) 約3.5 wt/wt%至約6 wt/wt%之一或多種崩解劑;及
d) 囊封組分a至c之明膠膠囊。
E21. 如E18至E20中任一項之醫藥組合物,其中該等稀釋劑中之至少一者選自由以下組成之群:微晶纖維素、乳糖、甘露醇、澱粉及磷酸氫鈣。
E22. 如E21之醫藥組合物,其中該等稀釋劑中之至少一者為微晶纖維素。
E23. 如E18至E22中任一項之醫藥組合物,其中該等崩解劑中之至少一者選自由以下組成之群:交聯羧甲基纖維素鈉、甘醇酸澱粉鈉、交聚維酮及海藻酸。
E24. 如E23之醫藥組合物,其中該等崩解劑中之至少一者為交聯羧甲基纖維素鈉。
E25. 如E18至E24中任一項之醫藥組合物,其中該等潤滑劑中之至少一者選自由以下組成之群:硬脂酸鎂、硬脂醯富馬酸鈉、甘油二山崳酸酯及滑石。
E26. 如E25之醫藥組合物,其中該等潤滑劑中之至少一者為硬脂酸鎂。
E27. 一種治療腫瘤、癌症或RAS病之方法,其包括向需要此治療之個體投與如E12至E26中任一項之醫藥組合物。
E28. 如E27之方法,其中該腫瘤為神經纖維瘤。
E29. 如E28之方法,其中該腫瘤為與1型神經纖維瘤病相關之神經纖維瘤。
E30. 如E27至E29中任一項之方法,其中該腫瘤選自由以下組成之群:皮膚神經纖維瘤、叢狀神經纖維瘤、視路神經膠質瘤、低級別神經膠質瘤、高級別神經膠質瘤或惡性外周神經鞘瘤。
E31. 如E30之方法,其中該腫瘤為叢狀神經纖維瘤。
E32. 如E27之方法,其中該個體經診斷患有選自由以下組成之群之RAS病:1型神經纖維瘤病、2型神經纖維瘤病、心面皮膚症候群、克斯提洛氏症候群、雷吉士症候群、努南氏症候群及多發雀斑樣痣型努南氏症候群。
E33. 如E27之方法,其中該癌症選自由以下組成之群:皮膚癌、惡性外周神經鞘癌、白血病、淋巴瘤、組織細胞性贅瘤、肺癌、乳癌、卵巢癌、腎癌、結腸直腸癌、甲狀腺癌、膽管癌、尿路上皮癌、子宮贅瘤、胃癌、肉瘤、膀胱癌、頭頸癌、子宮內膜癌、食管癌、腺樣囊性癌、膽囊癌、***癌、口腔癌、子宮頸癌、胰臟癌、黑色素瘤、肝細胞癌、膽道癌及腹膜漿液性癌。
E34. 如E33之方法,其中該白血病選自由以下組成之群:急性淋巴球性白血病、急性骨髓性白血病、慢性淋巴球性白血病及慢性骨髓性白血病。
E35. 如E33之方法,其中該淋巴瘤選自由以下組成之群:B細胞淋巴瘤、T細胞淋巴瘤、伯基特氏淋巴瘤、濾泡性淋巴瘤、外套細胞淋巴瘤、原發性縱膈B細胞淋巴瘤、小淋巴球性淋巴瘤及瓦登斯特隆巨球蛋白血症。
E36. 如E33之方法,其中該肺癌選自由以下組成之群:肺腺癌、鱗狀非小細胞肺癌、非鱗狀非小細胞肺癌及小細胞肺癌。
E37. 如E27至E36中任一項之方法,其中該個體在一或多個基因中攜帶突變或其他畸變,該突變或其他畸變引起某些癌症之功能特徵增加或喪失,其中一或多個基因中之該突變或其他畸變為KRAS、NRAS、HRAS、BRAF、MEK1、MEK2、RASA1、MAP2K4、NF1或NF2中之一或多者中之突變或其他畸變。
E38. 如E27至E37中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過20 mg之總日劑量投與。
E39. 如E27至E37中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過10 mg之總日劑量投與。
E40. 如E27至E37中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過8 mg之總日劑量投與。
E41. 如E27至E37中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過6 mg之總日劑量投與。
E42. 如E27至E41中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與。
E43. 如E42之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約0.1 mg至約20 mg。
E44. 如E42之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約2 mg。
E45. 如E42之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約4 mg。
E46. 如E42之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約6 mg。
E47. 如E42之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約8 mg。
E48. 如E42之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約20 mg。
E49. 如E27至E42中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與。
E50. 如E49之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約0.1 mg至約10 mg。
E51. 如E49之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約1 mg。
E52. 如E49之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約2 mg。
E53. 如E49之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約3 mg。
E54. 如E49之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約4 mg。
E55. 如E49之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約10 mg。
E56. 如E27至E55中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之個別劑量係以一個以上之膠囊或錠劑形式投與。
E57. 如E27至E56中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a) 21天投與總日劑量;及(b) 7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。
E58. 如E27至E56中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)連續21天投與總日劑量;之後(b)連續7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。
E59. 如E27至E56中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)三個7天期,每期包含(i) 5天投與總日劑量及(ii) 2天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺;及(b) 7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。
E60. 如E27至E56中任一項之方法,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)三個7天期,每期包含(i)連續5天投與總日劑量及(ii)連續2天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺;之後(b)連續7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。
E61. 如E57至E60中任一項之方法,其中重複該28天投藥週期,直至總計24個連續28天投藥週期。
E62. 一種如E12至E26中任一項之醫藥組合物之用途,其用於製造用以治療腫瘤、癌症或RAS病之藥劑。
E63. 如E62之用途,其中該腫瘤為神經纖維瘤。
E64. 如E63之用途,其中該腫瘤為與1型神經纖維瘤病相關之神經纖維瘤。
E65. 如E62至E64中任一項之用途,其中該腫瘤選自由以下組成之群:皮膚神經纖維瘤、叢狀神經纖維瘤、視路神經膠質瘤、低級別神經膠質瘤、高級別神經膠質瘤或惡性外周神經鞘瘤。
E66. 如E65之用途,其中該腫瘤為叢狀神經纖維瘤。
E67. 如E62之用途,其中該個體經診斷患有選自由以下組成之群之RAS病:1型神經纖維瘤病、2型神經纖維瘤病、心面皮膚症候群、克斯提洛氏症候群、雷吉士症候群、努南氏症候群及多發雀斑樣痣型努南氏症候群。
E68. 如E62之用途,其中該癌症選自由以下組成之群:皮膚癌、惡性外周神經鞘癌、白血病、淋巴瘤、組織細胞性贅瘤、肺癌、乳癌、卵巢癌、腎癌、結腸直腸癌、甲狀腺癌、膽管癌、尿路上皮癌、子宮贅瘤、胃癌、肉瘤、膀胱癌、頭頸癌、子宮內膜癌、食管癌、腺樣囊性癌、膽囊癌、***癌、口腔癌、子宮頸癌、胰臟癌、黑色素瘤、肝細胞癌、膽道癌及腹膜漿液性癌。
E69. 如E68之用途,其中該白血病選自由以下組成之群:急性淋巴球性白血病、急性骨髓性白血病、慢性淋巴球性白血病及慢性骨髓性白血病。
E70. 如E68之用途,其中該淋巴瘤選自由以下組成之群:B細胞淋巴瘤、T細胞淋巴瘤、伯基特氏淋巴瘤、濾泡性淋巴瘤、外套細胞淋巴瘤、原發性縱膈B細胞淋巴瘤、小淋巴球性淋巴瘤及瓦登斯特隆巨球蛋白血症。
E71. 如E68之用途,其中該肺癌選自由以下組成之群:肺腺癌、鱗狀非小細胞肺癌、非鱗狀非小細胞肺癌及小細胞肺癌。
E72. 如E62至E71中任一項之用途,其中該個體在一或多個基因中攜帶突變或其他畸變,該突變或其他畸變引起某些癌症之功能特徵增加或喪失,其中一或多個基因中之該突變或其他畸變為KRAS、NRAS、HRAS、BRAF、MEK1、MEK2、RASA1、MAP2K4、NF1或NF2中之一或多者中之突變或其他畸變。
E73. 如E62至E72中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過20 mg之總日劑量投與。
E74. 如E62至E72中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過10 mg之總日劑量投與。
E75. 如E62至E72中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過8 mg之總日劑量投與。
E76. 如E62至E72中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以不超過6 mg之總日劑量投與。
E77. 如E62至E75中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與。
E78. 如E76之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約0.1 mg至約20 mg。
E79. 如E77之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約2 mg。
E80. 如E77之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約4 mg。
E81. 如E77之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約6 mg。
E82. 如E77之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約8 mg。
E83. 如E77之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天一次來投與,劑量為約20 mg。
E84. 如E62至E76中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與。
E85. 如E84之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約0.1 mg至約10 mg。
E86. 如E84之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約1 mg。
E87. 如E84之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約2 mg。
E88. 如E84之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約3 mg。
E89. 如E84之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約4 mg。
E90. 如E76之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之該總日劑量係以每天兩次來投與,每次劑量為約10 mg。
E91. 如E61至E90中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之個別劑量係以一個以上之膠囊或錠劑形式投與。
E92. 如E62至E91中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a) 21天投與總日劑量;及(b) 7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。
E93. 如E62至E91中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)連續21天投與總日劑量;之後(b)連續7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。
E94. 如E62至E91中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)三個7天期,每期包含(i) 5天投與總日劑量及(ii) 2天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺;及(b) 7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。
E95. 如E62至E91中任一項之用途,其中該N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺係以28天投藥週期投與,該投藥週期包含:(a)三個7天期,每期包含(i)連續5天投與總日劑量及(ii)連續2天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺;之後(b)連續7天不投與N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺。
E96. 如E92至E95中任一項之用途,其中重複該28天投藥週期,直至總計24個連續28天投藥週期。
In addition to the various embodiments set forth herein, the disclosure also includes the following embodiments numbered El through E94. This list of examples is presented as an exemplary list, and the application is not limited to these examples. E1. A crystalline composition, which is N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo- Substantially pure Form IV of phenylamino)-benzamide: (I). E2. The crystalline composition of E1, wherein the crystalline composition exhibits a substantially unchanged XRPD pattern and/or DSC curve after storage for 3 months under standard warehouse conditions (15°C-25°C and ≦65% relative humidity) . E3. The crystalline composition of E1 or E2, wherein the crystalline composition exhibits a substantially unchanged XRPD pattern and/or after storage for 6 months under standard warehouse conditions (15°C-25°C and ≦65% relative humidity) DSC curve. E4. The crystalline composition according to any one of E1 to E3, wherein the crystalline composition exhibits a substantially unchanged XRPD pattern after storage for 1 year under standard warehouse conditions (15°C-25°C and ≦65% relative humidity) and/or DSC curves. E5. The crystalline composition of any one of E1 to E4, wherein the crystalline composition exhibits a substantially unchanged XRPD after storage for 68 months under standard warehouse conditions (15°C-25°C and ≦65% relative humidity) pattern and/or DSC curve. E6. The crystalline composition according to any one of E1 to E5, wherein the crystalline composition exhibits substantially no change after storage for ≥140 months under standard warehouse conditions (15°C-25°C and ≤65% relative humidity) XRPD pattern and/or DSC curve. E7. The crystalline composition of any one of E2 to E6, wherein the XRPD pattern is generated using: a PANALYTICAL ® X'Pert Pro diffractometer using Ni filtered Cu Kα (45 kV/40 mA) radiation and 0.03° The step size of 2θ, using X'CELERATOR ® real-time multi-band detector, (a) The configuration on the incident beam side is as follows: variable divergence slit (10 mm irradiation length), 0.04 radian Soler slit, fixed An anti-scatter slit (0.50°) and a 10 mm beam mask, and (b) configurations on the diffracted beam side as follows: a variable anti-scatter slit (10 mm observation length) and a 0.04 radian Soler slit; or BRUKER ® D8 ® ADVANCE TM system, using Cu Kα (40 kV/40 mA) radiation and a step size of 0.03° 2θ, using a LYNXEYE TM detector, (a) The configuration on the incident beam side is as follows: Göebel mirror, mirror Exit slit (0.2 mm), 2.5° Soler slit, beam knife, and (b) configurations on the diffracted beam side are as follows: anti-scattering slit (8 mm) and 2.5° Soler slit; and where The samples were mounted flat on zero-background Si wafers. E8. The crystalline composition of any one of E1 to E7, wherein the DSC pattern is generated using a TA Instruments Q100 or Q2000 differential scanning calorimeter at a ramp rate of about 15°C/min. E9. The crystalline composition according to any one of E1 to E8, wherein the crystalline composition contains ≤ 0.2% of dimer impurity PF-00191189. E10. The crystalline composition of any one of E1 to E9, wherein the crystalline composition contains about 0.05% to about 0.19% by weight of dimer impurity PF-00191189. E11. The crystalline composition according to any one of E1 to E9, wherein the crystalline composition does not contain a detectable amount of dimer impurity PF-00191189. E12. A pharmaceutical composition comprising the crystalline composition according to any one of E1 to E11 and a pharmaceutically acceptable carrier. E13. The pharmaceutical composition according to E12, wherein the pharmaceutical composition is for oral administration. E14. The pharmaceutical composition according to E13, wherein the pharmaceutical composition is a solid dosage form. E15. The pharmaceutical composition according to any one of E12 to E14, wherein the pharmaceutical composition is a tablet or a capsule. E16. The pharmaceutical composition according to E15, wherein the pharmaceutical composition is a lozenge. E17. The pharmaceutical composition according to E15, wherein the pharmaceutical composition is a capsule. E18. The pharmaceutical composition as in E17, wherein the capsule comprises about 1 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 - iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: a) about 0.25 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3 The crystalline composition of -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; d) about 0.5 wt/wt% to about 2 wt/ wt% of one or more lubricants; and e) a gelatin capsule encapsulating components a to d. E19. The pharmaceutical composition as in E17, wherein the capsule comprises about 2 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 - iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: a) about 0.25 wt/wt% to about 1.5 wt/wt% of N-((R)-2,3 The crystalline composition of -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; d) about 0.5 wt/wt% to about 2 wt/ wt% of one or more lubricants; and e) a gelatin capsule encapsulating components a to d. E20. The pharmaceutical composition as in E17, wherein the capsule comprises about 5 mg of N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4 - iodo-phenylamino)-benzamide, wherein each component of the capsule is as follows: a) about 2.5 wt/wt% to about 7.0 wt/wt% of N-((R)-2,3 The crystalline composition of -dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide; b) about 85 wt/wt% to about 95 wt/wt% of one or more diluents; c) about 3.5 wt/wt% to about 6 wt/wt% of one or more disintegrants; and d) gelatin capsules encapsulating components a to c . E21. The pharmaceutical composition according to any one of E18 to E20, wherein at least one of the diluents is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, starch, and calcium hydrogen phosphate. E22. The pharmaceutical composition according to E21, wherein at least one of the diluents is microcrystalline cellulose. E23. The pharmaceutical composition according to any one of E18 to E22, wherein at least one of the disintegrants is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, cross-polymerized Vitamin ketone and alginic acid. E24. The pharmaceutical composition according to E23, wherein at least one of the disintegrants is croscarmellose sodium. E25. The pharmaceutical composition according to any one of E18 to E24, wherein at least one of the lubricants is selected from the group consisting of magnesium stearate, sodium stearyl fumarate, glyceryl dibehenic acid esters and talc. E26. The pharmaceutical composition according to E25, wherein at least one of the lubricants is magnesium stearate. E27. A method of treating tumor, cancer or RAS disease, comprising administering the pharmaceutical composition according to any one of E12 to E26 to an individual in need of the treatment. E28. The method of E27, wherein the tumor is neurofibroma. E29. The method of E28, wherein the tumor is a neurofibroma associated with neurofibromatosis type 1. E30. The method according to any one of E27 to E29, wherein the tumor is selected from the group consisting of cutaneous neurofibroma, plexiform neurofibroma, optic pathway glioma, low-grade glioma, high-grade glioma tumor or malignant peripheral nerve sheath tumor. E31. The method of E30, wherein the tumor is plexiform neurofibroma. E32. The method of E27, wherein the individual is diagnosed with a RAS disease selected from the group consisting of: neurofibromatosis type 1,
圖1A係對應於N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的結晶形式IV之X射線粉末繞射圖案(「XRPD」)。 圖1B係對應於N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的結晶形式IV之熱重分析溫度記錄圖(「TGA」)及示差掃描量熱法溫度記錄圖(「DSC」)。 圖2係對應於如最初製備之N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV批料之XRPD以及形式IV之已知參考標準之XRPD。 圖3A係對應於N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV在產生後在25℃及65%相對濕度下儲存68個月後之XRPD。 圖3B係對應於N-((R)-2,3-二羥基丙氧基)-3,4-二氟-2-(2-氟-4-碘-苯基胺基)-苯甲醯胺之基本上純的形式IV在產生後在25℃及65%相對濕度下儲存140個月後之XRPD。 Figure 1A corresponds to N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoyl X-ray powder diffraction pattern ("XRPD") of substantially pure crystalline Form IV of the amine. Figure 1B corresponds to N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoyl Thermogravimetric analysis thermogram ("TGA") and differential scanning calorimetry thermogram ("DSC") of substantially pure crystalline Form IV of the amine. Figure 2 corresponds to N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino) as originally prepared - XRPD of a substantially pure Form IV batch of benzamide and a known reference standard of Form IV. Figure 3A corresponds to N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoyl XRPD of substantially pure Form IV of the amine after storage at 25°C and 65% relative humidity for 68 months after production. Figure 3B corresponds to N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoyl XRPD of substantially pure Form IV of the amine after storage at 25°C and 65% relative humidity for 140 months after production.
Claims (96)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2021/018378 WO2022177556A1 (en) | 2021-02-17 | 2021-02-17 | Compositions of essentially pure form iv of n-((r)-2,3- dihydroxypropoxy)-3,4-difluoro-2- (2-fluoro-4-iodophenylamino)- benzamide and uses thereof |
WOPCT/US21/18378 | 2021-02-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
TW202245746A true TW202245746A (en) | 2022-12-01 |
Family
ID=74860567
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW111105793A TW202245746A (en) | 2021-02-17 | 2022-02-17 | Compositions of essentially pure form iv of n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP4294789A1 (en) |
JP (1) | JP2024507822A (en) |
KR (1) | KR20230148177A (en) |
CN (1) | CN117500781A (en) |
AR (1) | AR124907A1 (en) |
AU (1) | AU2021428932A1 (en) |
CA (1) | CA3211395A1 (en) |
IL (1) | IL304974A (en) |
TW (1) | TW202245746A (en) |
WO (1) | WO2022177556A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023223205A1 (en) | 2022-05-17 | 2023-11-23 | Teva Pharmaceuticals International Gmbh | Solid state forms of mirdametinib and process for preparation thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2001273498B2 (en) | 2000-07-19 | 2006-08-24 | Warner-Lambert Company | Oxygenated esters of 4-iodo phenylamino benzhydroxamic acids |
EP1682495A1 (en) | 2003-10-21 | 2006-07-26 | Warner-Lambert Company LLC | Polymorphic form of n- (r)-2,3-dihydroxy-propoxy -3,4-d ifluoro-2-(2-fluoro-4-iodophenylamino)-benzamide |
WO2006134469A1 (en) | 2005-06-14 | 2006-12-21 | Warner-Lambert Company Llc | Methods of preparing mek inhibitor |
-
2021
- 2021-02-17 IL IL304974A patent/IL304974A/en unknown
- 2021-02-17 EP EP21710827.3A patent/EP4294789A1/en active Pending
- 2021-02-17 JP JP2023549999A patent/JP2024507822A/en active Pending
- 2021-02-17 KR KR1020237030268A patent/KR20230148177A/en unknown
- 2021-02-17 AU AU2021428932A patent/AU2021428932A1/en active Pending
- 2021-02-17 CA CA3211395A patent/CA3211395A1/en active Pending
- 2021-02-17 WO PCT/US2021/018378 patent/WO2022177556A1/en active Application Filing
- 2021-02-17 CN CN202180095226.2A patent/CN117500781A/en active Pending
-
2022
- 2022-02-17 AR ARP220100332A patent/AR124907A1/en unknown
- 2022-02-17 TW TW111105793A patent/TW202245746A/en unknown
Also Published As
Publication number | Publication date |
---|---|
EP4294789A1 (en) | 2023-12-27 |
JP2024507822A (en) | 2024-02-21 |
KR20230148177A (en) | 2023-10-24 |
IL304974A (en) | 2023-10-01 |
AR124907A1 (en) | 2023-05-17 |
AU2021428932A1 (en) | 2023-09-21 |
CN117500781A (en) | 2024-02-02 |
WO2022177556A1 (en) | 2022-08-25 |
CA3211395A1 (en) | 2022-08-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11453641B2 (en) | Methods of treating neurofibromatosis with N-((R)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-benzamide | |
AU2014239995B2 (en) | Salt of omecamtiv mecarbil and process for preparing salt | |
KR101612642B1 (en) | Tenofovir alafenamide hemifumarate | |
RU2376294C2 (en) | POLYMORPHOUS MODIFICATION OF COMPOUND {6,7-BIS (2-METHOXYETHOXY)CHINAZOLINE-4-YL}-(3e) | |
JP2005516009A (en) | Deuterated substituted pyrazolyl-benzenesulfonamide and pharmaceutical containing the same | |
EP2603503A1 (en) | Dabigatran etexilate bismesylate salt, solid state forms and process for preparation thereof | |
US20230330047A1 (en) | Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2- fluoro-4-iodo-phenylamino)-benazmide and uses thereof | |
JP2024517431A (en) | Solid state forms of (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and its salts | |
TW202245746A (en) | Compositions of essentially pure form iv of n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof | |
TWI815820B (en) | Solid forms of 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-n-benzylacetamide | |
TWI374136B (en) | Water adduct of acetamide moohydrochloride and its crystal | |
US20110269838A1 (en) | Novel processes and pure polymorphs | |
TW202200594A (en) | Crystalline form a of GLP-1 receptor agonist and preparation method therefor | |
JPH02306962A (en) | New n-substituted-1-deoxynojirimycin derivative and metastasis-inhibitor for cancerous cell | |
JP2018515566A (en) | Pharmaceutical composition | |
US8754129B2 (en) | Crystalline vorinostat form VI | |
TW202245745A (en) | Dispersible formulations of n-((r)-2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide and uses thereof | |
US20220089550A1 (en) | Crystalline forms of (s)-2-(7-cyano-1h-benzimidazol-1 yl)-n-{1-[4-(1-cyano-1-methylethyl)phenyl]ethyl}acetamide | |
WO2023196900A1 (en) | Solid forms, pharmaceutical compositions and preparation of heteroaromatic macrocyclic ether compounds | |
CA3218813A1 (en) | Indene compounds, pharmaceutical compositions thereof, and their therapeutic applications | |
JP2003048882A (en) | Method for producing 1-substituted-1,2,3-triazole derivative |