NZ713645B2 - 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof - Google Patents
2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof Download PDFInfo
- Publication number
- NZ713645B2 NZ713645B2 NZ720909A NZ72090914A NZ713645B2 NZ 713645 B2 NZ713645 B2 NZ 713645B2 NZ 720909 A NZ720909 A NZ 720909A NZ 72090914 A NZ72090914 A NZ 72090914A NZ 713645 B2 NZ713645 B2 NZ 713645B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- composition
- solid form
- ppm
- peaks
- Prior art date
Links
- 239000007787 solid Substances 0.000 title claims description 227
- 238000002360 preparation method Methods 0.000 title description 17
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 642
- 239000000203 mixture Substances 0.000 claims description 317
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 145
- -1 vidone Polymers 0.000 claims description 136
- 239000012453 solvate Substances 0.000 claims description 127
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 97
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 93
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 54
- 235000019441 ethanol Nutrition 0.000 claims description 52
- 239000000725 suspension Substances 0.000 claims description 50
- 238000010928 TGA analysis Methods 0.000 claims description 47
- 238000002411 thermogravimetry Methods 0.000 claims description 47
- 230000004580 weight loss Effects 0.000 claims description 47
- 239000011780 sodium chloride Substances 0.000 claims description 43
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 38
- 239000000843 powder Substances 0.000 claims description 37
- 239000000314 lubricant Substances 0.000 claims description 35
- 239000007884 disintegrant Substances 0.000 claims description 32
- 239000000945 filler Substances 0.000 claims description 30
- 229910017488 Cu K Inorganic materials 0.000 claims description 28
- 238000004519 manufacturing process Methods 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 239000003921 oil Substances 0.000 claims description 24
- 235000019198 oils Nutrition 0.000 claims description 24
- 238000001228 spectrum Methods 0.000 claims description 19
- 230000000875 corresponding Effects 0.000 claims description 17
- 229960001681 Croscarmellose Sodium Drugs 0.000 claims description 13
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 13
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims description 13
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 13
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 13
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 13
- 239000000194 fatty acid Substances 0.000 claims description 13
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 13
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 12
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 claims description 12
- 229960001375 Lactose Drugs 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 9
- 239000008101 lactose Substances 0.000 claims description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
- 150000004665 fatty acids Chemical class 0.000 claims description 8
- 239000000080 wetting agent Substances 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
- 239000000454 talc Substances 0.000 claims description 6
- 229910052623 talc Inorganic materials 0.000 claims description 6
- 235000012222 talc Nutrition 0.000 claims description 6
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 235000010443 alginic acid Nutrition 0.000 claims description 5
- 229920000615 alginic acid Polymers 0.000 claims description 5
- 235000010980 cellulose Nutrition 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 claims description 4
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- 229960001021 Lactose Monohydrate Drugs 0.000 claims description 4
- 239000000783 alginic acid Substances 0.000 claims description 4
- 229960001126 alginic acid Drugs 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 3
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L Calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- RYYKJJJTJZKILX-UHFFFAOYSA-M Sodium stearate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 3
- 229920001249 ethyl cellulose Polymers 0.000 claims description 3
- 235000019359 magnesium stearate Nutrition 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 235000010981 methylcellulose Nutrition 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 claims description 2
- 229940084030 CARBOXYMETHYLCELLULOSE CALCIUM Drugs 0.000 claims description 2
- 229960005069 Calcium Drugs 0.000 claims description 2
- 229960003563 Calcium Carbonate Drugs 0.000 claims description 2
- SXVBHNXTPNLOKR-FCLWLKJISA-L Calcium alginate Chemical compound [Ca+2].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O SXVBHNXTPNLOKR-FCLWLKJISA-L 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N Glyceryl behenate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 2
- 235000010469 Glycine max Nutrition 0.000 claims description 2
- 229920002907 Guar gum Polymers 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 2
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 0.000 claims description 2
- 229940005550 Sodium alginate Drugs 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 Xylitol Drugs 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 235000001465 calcium Nutrition 0.000 claims description 2
- 235000010410 calcium alginate Nutrition 0.000 claims description 2
- 239000000648 calcium alginate Substances 0.000 claims description 2
- 229960002681 calcium alginate Drugs 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims description 2
- 235000007983 food acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004676 glycans Polymers 0.000 claims description 2
- 229940049654 glyceryl behenate Drugs 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 235000010417 guar gum Nutrition 0.000 claims description 2
- 239000000665 guar gum Substances 0.000 claims description 2
- 229960002154 guar gum Drugs 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 239000003456 ion exchange resin Substances 0.000 claims description 2
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 2
- 235000005772 leucine Nutrition 0.000 claims description 2
- 229940035034 maltodextrin Drugs 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 150000004804 polysaccharides Polymers 0.000 claims description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 2
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims 1
- 210000004027 cells Anatomy 0.000 description 82
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 76
- 201000011510 cancer Diseases 0.000 description 75
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 47
- 239000000523 sample Substances 0.000 description 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical class CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 43
- 238000000113 differential scanning calorimetry Methods 0.000 description 42
- 235000002639 sodium chloride Nutrition 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- 238000006243 chemical reaction Methods 0.000 description 37
- 239000000047 product Substances 0.000 description 37
- 239000002904 solvent Substances 0.000 description 37
- 229910052757 nitrogen Inorganic materials 0.000 description 36
- 229910052805 deuterium Inorganic materials 0.000 description 33
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 33
- 239000003826 tablet Substances 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 239000003795 chemical substances by application Substances 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 229960004592 isopropanol Drugs 0.000 description 30
- 238000001914 filtration Methods 0.000 description 29
- 125000004429 atoms Chemical group 0.000 description 27
- 239000002253 acid Substances 0.000 description 26
- 230000002401 inhibitory effect Effects 0.000 description 26
- 150000002500 ions Chemical class 0.000 description 26
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 229910052739 hydrogen Inorganic materials 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
- JKEKMBGUVUKMQB-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JKEKMBGUVUKMQB-UHFFFAOYSA-N 0.000 description 24
- 239000001257 hydrogen Substances 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 23
- 238000007792 addition Methods 0.000 description 22
- 239000003814 drug Substances 0.000 description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 125000001931 aliphatic group Chemical group 0.000 description 21
- 150000001408 amides Chemical class 0.000 description 21
- 239000000010 aprotic solvent Substances 0.000 description 21
- 239000002585 base Substances 0.000 description 21
- 239000000543 intermediate Substances 0.000 description 20
- GBGVQFJZGHBZMC-UHFFFAOYSA-N [(6-chlorobenzotriazol-1-yl)oxy-(dimethylamino)methylidene]-dimethylazanium;tetrafluoroborate Chemical compound F[B-](F)(F)F.C1=C(Cl)C=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 GBGVQFJZGHBZMC-UHFFFAOYSA-N 0.000 description 19
- 238000002844 melting Methods 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 18
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 18
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000126 substance Substances 0.000 description 18
- LXZZYRPGZAFOLE-UHFFFAOYSA-L transplatin Chemical compound [H][N]([H])([H])[Pt](Cl)(Cl)[N]([H])([H])[H] LXZZYRPGZAFOLE-UHFFFAOYSA-L 0.000 description 18
- 238000004293 19F NMR spectroscopy Methods 0.000 description 17
- 238000004166 bioassay Methods 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 17
- 229960004316 cisplatin Drugs 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 229910052782 aluminium Inorganic materials 0.000 description 16
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 16
- 230000015556 catabolic process Effects 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 230000004059 degradation Effects 0.000 description 16
- 238000006731 degradation reaction Methods 0.000 description 16
- 150000001450 anions Chemical class 0.000 description 15
- 238000000806 fluorine-19 nuclear magnetic resonance spectrum Methods 0.000 description 15
- 238000005755 formation reaction Methods 0.000 description 15
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 15
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 15
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 15
- 102000004169 proteins and genes Human genes 0.000 description 15
- 108090000623 proteins and genes Proteins 0.000 description 15
- 238000001959 radiotherapy Methods 0.000 description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 15
- 229910052717 sulfur Chemical group 0.000 description 15
- 239000011593 sulfur Chemical group 0.000 description 15
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 125000005843 halogen group Chemical group 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
- 241000894007 species Species 0.000 description 14
- SDUQYLNIPVEERB-QPPQHZFASA-N Gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 13
- 102000001253 Protein Kinases Human genes 0.000 description 13
- 238000002512 chemotherapy Methods 0.000 description 13
- 238000009833 condensation Methods 0.000 description 13
- 230000005494 condensation Effects 0.000 description 13
- 125000004122 cyclic group Chemical group 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 239000002002 slurry Substances 0.000 description 13
- ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 12
- 108009000276 Base Excision Repair Proteins 0.000 description 12
- 108091000081 Phosphotransferases Proteins 0.000 description 12
- 239000008186 active pharmaceutical agent Substances 0.000 description 12
- 230000033590 base-excision repair Effects 0.000 description 12
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 12
- 125000005842 heteroatoms Chemical group 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- 108060006202 ATM Proteins 0.000 description 11
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 11
- 229910052796 boron Inorganic materials 0.000 description 11
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 11
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 11
- 201000002528 pancreatic cancer Diseases 0.000 description 11
- 238000009987 spinning Methods 0.000 description 11
- 238000002560 therapeutic procedure Methods 0.000 description 11
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 10
- AOJJSUZBOXZQNB-TZSSRYMLSA-N ADRIAMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 10
- 102100000648 ATM Human genes 0.000 description 10
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 description 10
- 108009000071 Non-small cell lung cancer Proteins 0.000 description 10
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 10
- 239000007822 coupling agent Substances 0.000 description 10
- 229960005277 gemcitabine Drugs 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 239000001301 oxygen Substances 0.000 description 10
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- VJJPUSNTGOMMGY-MRVIYFEKSA-N Etoposide Chemical group COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 9
- 102100013495 H2AX Human genes 0.000 description 9
- 101700085012 H2AX Proteins 0.000 description 9
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Nitrumon Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 9
- 238000010976 amide bond formation reaction Methods 0.000 description 9
- 125000003118 aryl group Chemical group 0.000 description 9
- DVQHYTBCTGYNNN-UHFFFAOYSA-N azane;cyclobutane-1,1-dicarboxylic acid;platinum Chemical compound N.N.[Pt].OC(=O)C1(C(O)=O)CCC1 DVQHYTBCTGYNNN-UHFFFAOYSA-N 0.000 description 9
- 239000007819 coupling partner Substances 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- 238000002076 thermal analysis method Methods 0.000 description 9
- 229960004562 Carboplatin Drugs 0.000 description 8
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 8
- 229960005420 Etoposide Drugs 0.000 description 8
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
- 125000002619 bicyclic group Chemical group 0.000 description 8
- 239000011230 binding agent Substances 0.000 description 8
- 201000009030 carcinoma Diseases 0.000 description 8
- 230000014509 gene expression Effects 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- 150000007530 organic bases Chemical class 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 8
- 229910052710 silicon Inorganic materials 0.000 description 8
- 239000010703 silicon Substances 0.000 description 8
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- 208000009956 Adenocarcinoma Diseases 0.000 description 7
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 7
- 231100000277 DNA damage Toxicity 0.000 description 7
- ZBCBWPMODOFKDW-UHFFFAOYSA-N Diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 7
- 229960004679 Doxorubicin Drugs 0.000 description 7
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- 206010039491 Sarcoma Diseases 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 125000006379 fluoropyridyl group Chemical group 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 201000005202 lung cancer Diseases 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 230000000051 modifying Effects 0.000 description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical class CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 7
- 230000028617 response to DNA damage stimulus Effects 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- UCSJYZPVAKXKNQ-HZYVHMACSA-N 1-[(1S,2R,3R,4S,5R,6R)-3-carbamimidamido-6-{[(2R,3R,4R,5S)-3-{[(2S,3S,4S,5R,6S)-4,5-dihydroxy-6-(hydroxymethyl)-3-(methylamino)oxan-2-yl]oxy}-4-formyl-4-hydroxy-5-methyloxolan-2-yl]oxy}-2,4,5-trihydroxycyclohexyl]guanidine Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 230000033616 DNA repair Effects 0.000 description 6
- RCINICONZNJXQF-MZXODVADSA-N Intaxel Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 6
- 206010025323 Lymphomas Diseases 0.000 description 6
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 6
- 206010025310 Other lymphomas Diseases 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 229940069328 Povidone Drugs 0.000 description 6
- TXRPHPUGYLSHCX-UHFFFAOYSA-N Selectfluor Chemical compound F[B-](F)(F)F.F[B-](F)(F)F.C1C[N+]2(CCl)CC[N+]1(F)CC2 TXRPHPUGYLSHCX-UHFFFAOYSA-N 0.000 description 6
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 6
- CXNIUSPIQKWYAI-UHFFFAOYSA-N Xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000007906 compression Methods 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- 229960001330 hydroxycarbamide Drugs 0.000 description 6
- VSNHCAURESNICA-UHFFFAOYSA-N hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 6
- 229940027318 hydroxyurea Drugs 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- DNUTZBZXLPWRJG-UHFFFAOYSA-N piperidine-1-carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000011534 wash buffer Substances 0.000 description 6
- 239000003643 water by type Substances 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 208000005623 Carcinogenesis Diseases 0.000 description 5
- 229960004397 Cyclophosphamide Drugs 0.000 description 5
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytosar Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 5
- 101700053624 PARP2 Proteins 0.000 description 5
- 229960001592 Paclitaxel Drugs 0.000 description 5
- PARWUHTVGZSQPD-UHFFFAOYSA-N Phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 5
- 229920001451 Polypropylene glycol Polymers 0.000 description 5
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 5
- 210000002966 Serum Anatomy 0.000 description 5
- GPDHNZNLPKYHCN-DZOOLQPHSA-N [[(Z)-(1-cyano-2-ethoxy-2-oxoethylidene)amino]oxy-morpholin-4-ylmethylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CCOC(=O)C(\C#N)=N/OC(=[N+](C)C)N1CCOCC1 GPDHNZNLPKYHCN-DZOOLQPHSA-N 0.000 description 5
- 201000005510 acute lymphocytic leukemia Diseases 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 5
- 235000012970 cakes Nutrition 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 229960005243 carmustine Drugs 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000006071 cream Substances 0.000 description 5
- 238000004807 desolvation Methods 0.000 description 5
- 239000012025 fluorinating agent Substances 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 238000005658 halogenation reaction Methods 0.000 description 5
- 238000011065 in-situ storage Methods 0.000 description 5
- 229910052759 nickel Inorganic materials 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 229920001983 poloxamer Polymers 0.000 description 5
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 239000007909 solid dosage form Substances 0.000 description 5
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 5
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N 289-95-2 Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- 239000012103 Alexa Fluor 488 Substances 0.000 description 4
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Belustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 4
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 4
- 229960000975 Daunorubicin Drugs 0.000 description 4
- 206010073071 Hepatocellular carcinoma Diseases 0.000 description 4
- 241000257303 Hymenoptera Species 0.000 description 4
- UWKQSNNFCGGAFS-XIFFEERXSA-N Irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 4
- 101700027219 LIG3 Proteins 0.000 description 4
- 102100003884 LRIG3 Human genes 0.000 description 4
- 101700041876 LRIG3 Proteins 0.000 description 4
- 206010024612 Lipoma Diseases 0.000 description 4
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N Melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 4
- 102100017733 PARP2 Human genes 0.000 description 4
- 101700061424 POLB Proteins 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M Potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 description 4
- 206010041067 Small cell lung cancer Diseases 0.000 description 4
- 206010041823 Squamous cell carcinoma Diseases 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 4
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temodal Chemical group O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 4
- UCFGDBYHRUNTLO-QHCPKHFHSA-N Topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 4
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 229960002938 bexarotene Drugs 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000004359 castor oil Substances 0.000 description 4
- 230000003034 chemosensitisation Effects 0.000 description 4
- 239000006114 chemosensitizer Substances 0.000 description 4
- 201000011231 colorectal cancer Diseases 0.000 description 4
- 238000005388 cross polarization Methods 0.000 description 4
- 230000002708 enhancing Effects 0.000 description 4
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 201000010536 head and neck cancer Diseases 0.000 description 4
- 230000003301 hydrolyzing Effects 0.000 description 4
- 229960004768 irinotecan Drugs 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 150000002829 nitrogen Chemical group 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 235000011056 potassium acetate Nutrition 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000001235 sensitizing Effects 0.000 description 4
- 239000008279 sol Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229930003347 taxol Natural products 0.000 description 4
- 229960000303 topotecan Drugs 0.000 description 4
- CFCUWKMKBJTWLW-BGLFSJPPSA-N (2S,3S)-2-[(2S,4R,5R,6R)-4-[(2S,4R,5R,6R)-4-[(2S,4S,5R,6R)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-5-hydroxy-6-methyloxan-2-yl]oxy-3-[(1S,3S,4R)-3,4-dihydroxy-1-methoxy-2-oxopentyl]-6-[(2S,4R,5S,6R)-4-[(2S,4R,5S,6R)-4,5-dih Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BGLFSJPPSA-N 0.000 description 3
- AOHJOMMDDJHIJH-UHFFFAOYSA-N 1,2-Diaminopropane Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 description 3
- DNJQFMOYVMLFHQ-UHFFFAOYSA-N 1-(oxetan-2-yl)piperazine Chemical compound O1CCC1N1CCNCC1 DNJQFMOYVMLFHQ-UHFFFAOYSA-N 0.000 description 3
- KGBBJPZIDRELDP-UHFFFAOYSA-N 1H-pyrazole-3,5-diamine Chemical compound NC=1C=C(N)NN=1 KGBBJPZIDRELDP-UHFFFAOYSA-N 0.000 description 3
- AVFCGLFLHBWEET-UHFFFAOYSA-N 1H-pyrazolo[4,3-d]pyrimidin-3-amine Chemical class N1=CN=C2C(N)=NNC2=C1 AVFCGLFLHBWEET-UHFFFAOYSA-N 0.000 description 3
- DJLQDAPCXQZGNZ-UHFFFAOYSA-N 3-(dimethoxymethyl)-4,4-dimethoxybutanenitrile Chemical compound COC(OC)C(CC#N)C(OC)OC DJLQDAPCXQZGNZ-UHFFFAOYSA-N 0.000 description 3
- 150000003929 3-aminopyridines Chemical class 0.000 description 3
- 241000283690 Bos taurus Species 0.000 description 3
- 210000000481 Breast Anatomy 0.000 description 3
- 108060006647 CHEK2 Proteins 0.000 description 3
- 102100019698 CHEK2 Human genes 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N Chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- HAWPXGHAZFHHAD-UHFFFAOYSA-N Chlormethine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 3
- HPXRVTGHNJAIIH-UHFFFAOYSA-N Cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 3
- 229960000684 Cytarabine Drugs 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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 3
- 108009000097 DNA Replication Proteins 0.000 description 3
- 230000004543 DNA replication Effects 0.000 description 3
- NOTIQUSPUUHHEH-UXOVVSIBSA-N Drostanolone propionate Chemical compound C([C@@H]1CC2)C(=O)[C@H](C)C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](OC(=O)CC)[C@@]2(C)CC1 NOTIQUSPUUHHEH-UXOVVSIBSA-N 0.000 description 3
- 229940088598 Enzyme Drugs 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 229960001031 Glucose Drugs 0.000 description 3
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 3
- 229960002913 Goserelin Drugs 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N Ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 102100005410 LINE-1 retrotransposable element ORF2 protein Human genes 0.000 description 3
- 229960004338 Leuprorelin Drugs 0.000 description 3
- 210000004072 Lung Anatomy 0.000 description 3
- 229960004961 Mechlorethamine Drugs 0.000 description 3
- 108020004999 Messenger RNA Proteins 0.000 description 3
- 208000003003 Muscular Dystrophy, Congenital, Lmna-Related Diseases 0.000 description 3
- 210000004940 Nucleus Anatomy 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 210000000496 Pancreas Anatomy 0.000 description 3
- 229940049954 Penicillin Drugs 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- 229960003171 Plicamycin Drugs 0.000 description 3
- 241000048284 Potato virus P Species 0.000 description 3
- CPTBDICYNRMXFX-UHFFFAOYSA-N Procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 3
- 102100016116 RAD50 Human genes 0.000 description 3
- 108060007644 RAD50 Proteins 0.000 description 3
- 229960005322 Streptomycin Drugs 0.000 description 3
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 3
- 102100019730 TP53 Human genes 0.000 description 3
- 101710026335 TP53 Proteins 0.000 description 3
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 3
- 229960004528 Vincristine Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 108090001123 antibodies Proteins 0.000 description 3
- 102000004965 antibodies Human genes 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229960000626 benzylpenicillin Drugs 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229960002092 busulfan Drugs 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- 230000001413 cellular Effects 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 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
- 229960002436 cladribine Drugs 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 230000001808 coupling Effects 0.000 description 3
- 230000002354 daily Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 201000011066 hemangioma Diseases 0.000 description 3
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 230000003463 hyperproliferative Effects 0.000 description 3
- 239000007943 implant Substances 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 230000001965 increased Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 238000002665 ion therapy Methods 0.000 description 3
- 229960001691 leucovorin Drugs 0.000 description 3
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 229960001924 melphalan Drugs 0.000 description 3
- 239000000155 melt Substances 0.000 description 3
- 229960001428 mercaptopurine Drugs 0.000 description 3
- 229920002106 messenger RNA Polymers 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 230000003000 nontoxic Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 230000000865 phosphorylative Effects 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000003752 polymerase chain reaction Methods 0.000 description 3
- 239000011698 potassium fluoride Substances 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- WXKCRCGKCOKJEF-UHFFFAOYSA-N prop-2-enyl 2-cyanoacetate Chemical compound C=CCOC(=O)CC#N WXKCRCGKCOKJEF-UHFFFAOYSA-N 0.000 description 3
- 230000002633 protecting Effects 0.000 description 3
- 230000001681 protective Effects 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 230000002829 reduced Effects 0.000 description 3
- 239000003352 sequestering agent Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 3
- 239000012258 stirred mixture Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 230000004083 survival Effects 0.000 description 3
- 229960004964 temozolomide Drugs 0.000 description 3
- 230000001225 therapeutic Effects 0.000 description 3
- 201000002510 thyroid cancer Diseases 0.000 description 3
- 229960005267 tositumomab Drugs 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- 229960002066 vinorelbine Drugs 0.000 description 3
- 239000001993 wax Substances 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- ZROHGHOFXNOHSO-BNTLRKBRSA-L (1R,2R)-cyclohexane-1,2-diamine;oxalate;platinum(2+) Chemical compound [H][N]([C@@H]1CCCC[C@H]1[N]1([H])[H])([H])[Pt]11OC(=O)C(=O)O1 ZROHGHOFXNOHSO-BNTLRKBRSA-L 0.000 description 2
- VWUXBMIQPBEWFH-WCCTWKNTSA-N (7R,8R,9S,13S,14S,17S)-13-methyl-7-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- 238000004482 13C cross polarization magic angle spinning Methods 0.000 description 2
- GLUUGHFHXGJENI-SVYQBANQSA-N 2,2,3,3,5,5,6,6-octadeuteriopiperazine Chemical compound [2H]C1([2H])NC([2H])([2H])C([2H])([2H])NC1([2H])[2H] GLUUGHFHXGJENI-SVYQBANQSA-N 0.000 description 2
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-Methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- SVNWFJQSJIUROM-UHFFFAOYSA-N 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylic acid Chemical compound C1=C(F)C=NC2=C(C(O)=O)C(N)=NN21 SVNWFJQSJIUROM-UHFFFAOYSA-N 0.000 description 2
- SBMKTKYEISQSLS-UHFFFAOYSA-M 3-(dimethoxymethyl)-4,4-dimethoxybutane-1-sulfonate Chemical compound COC(OC)C(C(OC)OC)CCS([O-])(=O)=O SBMKTKYEISQSLS-UHFFFAOYSA-M 0.000 description 2
- CUYKNJBYIJFRCU-UHFFFAOYSA-N 3-Aminopyridine Chemical compound NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 2
- ROADCYAOHVSOLQ-UHFFFAOYSA-N 3-Oxetanone Chemical compound O=C1COC1 ROADCYAOHVSOLQ-UHFFFAOYSA-N 0.000 description 2
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 2
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N 5-flurouricil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- IKWTVSLWAPBBKU-UHFFFAOYSA-N A1010_SIAL Chemical compound O=[As]O[As]=O IKWTVSLWAPBBKU-UHFFFAOYSA-N 0.000 description 2
- 101700004737 APTX Proteins 0.000 description 2
- 102100013042 APTX Human genes 0.000 description 2
- 229960003272 ASPARAGINASE Drugs 0.000 description 2
- 101710034857 ATIC Proteins 0.000 description 2
- 206010000880 Acute myeloid leukaemia Diseases 0.000 description 2
- 206010001019 Acute promyelocytic leukaemia Diseases 0.000 description 2
- 229940009456 Adriamycin Drugs 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N Anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 108010024976 Asparaginase Proteins 0.000 description 2
- 102000015790 Asparaginase Human genes 0.000 description 2
- 229960002756 Azacitidine Drugs 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 230000036912 Bioavailability Effects 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 229960001561 Bleomycin Drugs 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N Bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 102100018253 CLK2 Human genes 0.000 description 2
- 101700053639 CLK2 Proteins 0.000 description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N CN(C)\N=N\c1[nH]cnc1C(N)=O Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 2
- 102100006400 CSF2 Human genes 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
- IVFYLRMMHVYGJH-PVPPCFLZSA-N Calusterone Chemical compound C1C[C@]2(C)[C@](O)(C)CC[C@H]2[C@@H]2[C@@H](C)CC3=CC(=O)CC[C@]3(C)[C@H]21 IVFYLRMMHVYGJH-PVPPCFLZSA-N 0.000 description 2
- 229950009823 Calusterone Drugs 0.000 description 2
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 2
- 229960004117 Capecitabine Drugs 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229940105329 Carboxymethylcellulose Drugs 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 2
- 229960004630 Chlorambucil Drugs 0.000 description 2
- WDDPHFBMKLOVOX-AYQXTPAHSA-N Clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000012410 DNA Ligases Human genes 0.000 description 2
- 108010061982 DNA Ligases Proteins 0.000 description 2
- 102000020346 DNA glycosylase family Human genes 0.000 description 2
- 108020001738 DNA glycosylase family Proteins 0.000 description 2
- 229960000640 Dactinomycin Drugs 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M Dioctyl sodium sulfosuccinate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N Docetaxel Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- 102000008422 EC 2.7.1.78 Human genes 0.000 description 2
- 108010021757 EC 2.7.1.78 Proteins 0.000 description 2
- 102000010719 EC 4.2.99.18 Human genes 0.000 description 2
- 108010063362 EC 4.2.99.18 Proteins 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N EPIRUBICIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- 229960001904 EPIRUBICIN Drugs 0.000 description 2
- 108010042407 Endonucleases Proteins 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N Erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 229960001433 Erlotinib Drugs 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N Floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 229960002949 Fluorouracil Drugs 0.000 description 2
- 229960002258 Fulvestrant Drugs 0.000 description 2
- 206010017758 Gastric cancer Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000005017 Glioblastoma Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 208000002927 Hamartoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin hydrochloride Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- 229960001101 Ifosfamide Drugs 0.000 description 2
- MDOJTZQKHMAPBK-UHFFFAOYSA-N Iniparib Chemical compound NC(=O)C1=CC=C(I)C([N+]([O-])=O)=C1 MDOJTZQKHMAPBK-UHFFFAOYSA-N 0.000 description 2
- 229940119837 Isopropyl Alcohol Drugs 0.000 description 2
- 241000229754 Iva xanthiifolia Species 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 229940067606 Lecithin Drugs 0.000 description 2
- 206010024190 Leiomyosarcomas Diseases 0.000 description 2
- GOTYRUGSSMKFNF-UHFFFAOYSA-N Lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 2
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 description 2
- 208000007046 Leukemia, Myeloid, Acute Diseases 0.000 description 2
- 208000005749 Leukemia, Promyelocytic, Acute Diseases 0.000 description 2
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levotetramisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 2
- 102100008690 MBD4 Human genes 0.000 description 2
- 101700060039 MBD4 Proteins 0.000 description 2
- 102100003827 MUTYH Human genes 0.000 description 2
- 101700053678 MUTYH Proteins 0.000 description 2
- 206010025650 Malignant melanoma Diseases 0.000 description 2
- 206010027191 Meningioma Diseases 0.000 description 2
- GPKJTRJOBQGKQK-UHFFFAOYSA-N Mepacrine Chemical compound C1=C(OC)C=C2C(NC(C)CCCN(CC)CC)=C(C=CC(Cl)=C3)C3=NC2=C1 GPKJTRJOBQGKQK-UHFFFAOYSA-N 0.000 description 2
- 229960004635 Mesna Drugs 0.000 description 2
- 229940101533 Mesnex Drugs 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N Methyl iodide Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 229960004857 Mitomycin Drugs 0.000 description 2
- 229960000350 Mitotane Drugs 0.000 description 2
- 206010028576 Myeloproliferative disease Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 101700036395 NEIL2 Proteins 0.000 description 2
- 102100018379 NEIL2 Human genes 0.000 description 2
- 101700052800 NEIL3 Proteins 0.000 description 2
- 102100018378 NEIL3 Human genes 0.000 description 2
- 101710040088 NTG1 Proteins 0.000 description 2
- 101700063313 NTH2 Proteins 0.000 description 2
- 101710026674 NTHL1 Proteins 0.000 description 2
- 102100015692 NTHL1 Human genes 0.000 description 2
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N Nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N Octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- FAQDUNYVKQKNLD-UHFFFAOYSA-N Olaparib Chemical group FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 2
- 101700012117 POLG Proteins 0.000 description 2
- WRUUGTRCQOWXEG-UHFFFAOYSA-N Pamidronic acid Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 2
- NJBFOOCLYDNZJN-UHFFFAOYSA-N Pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 description 2
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N Retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- 241000231739 Rutilus rutilus Species 0.000 description 2
- 206010070834 Sensitisation Diseases 0.000 description 2
- JNYAEWCLZODPBN-CTQIIAAMSA-N Sorbitan Chemical class OCC(O)C1OCC(O)[C@@H]1O JNYAEWCLZODPBN-CTQIIAAMSA-N 0.000 description 2
- 229940032147 Starch Drugs 0.000 description 2
- 229960001052 Streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N Streptozotocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N Sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 108060008443 TPPP Proteins 0.000 description 2
- 101700053112 TREH Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 229960001603 Tamoxifen Drugs 0.000 description 2
- 229940099419 Targretin Drugs 0.000 description 2
- 206010043276 Teratoma Diseases 0.000 description 2
- 229960005353 Testolactone Drugs 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N ThioTEPA Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 229960005454 Thioguanine Drugs 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- AOBORMOPSGHCAX-UHFFFAOYSA-N Tocophersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-UHFFFAOYSA-N 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 108010001801 Tumor Necrosis Factor-alpha Proteins 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N U-18,496 Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- IDPUKCWIGUEADI-UHFFFAOYSA-N Uramustine Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 2
- 229960003048 Vinblastine Drugs 0.000 description 2
- HOFQVRTUGATRFI-XQKSVPLYSA-N Vinblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 HOFQVRTUGATRFI-XQKSVPLYSA-N 0.000 description 2
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 2
- WAEXFXRVDQXREF-UHFFFAOYSA-N Vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 2
- 208000008383 Wilms Tumor Diseases 0.000 description 2
- QXKHYNVANLEOEG-UHFFFAOYSA-N XANTHOTOXIN Chemical compound C1=CC(=O)OC2=C1C=C1C=COC1=C2OC QXKHYNVANLEOEG-UHFFFAOYSA-N 0.000 description 2
- 229940033942 Zoladex Drugs 0.000 description 2
- XRASPMIURGNCCH-UHFFFAOYSA-N Zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 2
- LIQODXNTTZAGID-OCBXBXKTSA-N [4-[(5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-methyl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-8-oxo-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-9-yl]-2,6-dimethoxyphenyl] dihydrogen phosphate Chemical compound COC1=C(OP(O)(O)=O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 2
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 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 description 2
- 230000003213 activating Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- 239000003945 anionic surfactant Substances 0.000 description 2
- 229940045719 antineoplastic alkylating agents Nitrosoureas Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 229960002594 arsenic trioxide Drugs 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 230000035514 bioavailability Effects 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- 201000005216 brain cancer Diseases 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 125000004432 carbon atoms Chemical group C* 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 230000003197 catalytic Effects 0.000 description 2
- 229960000590 celecoxib Drugs 0.000 description 2
- 230000012820 cell cycle checkpoint Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 201000006934 chronic myeloid leukemia Diseases 0.000 description 2
- 229960000928 clofarabine Drugs 0.000 description 2
- ZNEWHQLOPFWXOF-UHFFFAOYSA-N coenzyme M Chemical compound OS(=O)(=O)CCS ZNEWHQLOPFWXOF-UHFFFAOYSA-N 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 2
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- GVGUFUZHNYFZLC-UHFFFAOYSA-N dodecyl benzenesulfonate;sodium Chemical compound [Na].CCCCCCCCCCCCOS(=O)(=O)C1=CC=CC=C1 GVGUFUZHNYFZLC-UHFFFAOYSA-N 0.000 description 2
- 229940017743 dromostanolone propionate Drugs 0.000 description 2
- 229950004683 drostanolone propionate Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 229960000752 etoposide phosphate Drugs 0.000 description 2
- 201000008808 fibrosarcoma Diseases 0.000 description 2
- 229960000390 fludarabine Drugs 0.000 description 2
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 2
- 235000008191 folinic acid Nutrition 0.000 description 2
- 239000011672 folinic acid Substances 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000001738 genotoxic Effects 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 150000002334 glycols Chemical class 0.000 description 2
- 238000002744 homologous recombination Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000010965 in-process control Methods 0.000 description 2
- 230000003834 intracellular Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 229960004942 lenalidomide Drugs 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229960002247 lomustine Drugs 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 229960000901 mepacrine Drugs 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 235000013919 monopotassium glutamate Nutrition 0.000 description 2
- 201000009251 multiple myeloma Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- UBWXUGDQUBIEIZ-QNTYDACNSA-N nandrolone phenpropionate Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@H]4CCC(=O)C=C4CC3)CC[C@@]21C)C(=O)CCC1=CC=CC=C1 UBWXUGDQUBIEIZ-QNTYDACNSA-N 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 229960000801 nelarabine Drugs 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 229960000572 olaparib Drugs 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 108010027841 pegademase bovine Proteins 0.000 description 2
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-N pemetrexed Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-N 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 229940080469 phosphocellulose Drugs 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 2
- 229960000952 pipobroman Drugs 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 229960000624 procarbazine Drugs 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 229960002530 sargramostim Drugs 0.000 description 2
- 108010038379 sargramostim Proteins 0.000 description 2
- 238000003345 scintillation counting Methods 0.000 description 2
- 230000008313 sensitization Effects 0.000 description 2
- 231100000489 sensitizer Toxicity 0.000 description 2
- 231100000202 sensitizing Toxicity 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 231100000486 side effect Toxicity 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- 229910000077 silane Inorganic materials 0.000 description 2
- 239000001187 sodium carbonate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229940080264 sodium dodecylbenzenesulfonate Drugs 0.000 description 2
- XOGTZOOQQBDUSI-UHFFFAOYSA-M sodium;2-sulfanylethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCS XOGTZOOQQBDUSI-UHFFFAOYSA-M 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 201000011549 stomach cancer Diseases 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- 238000004808 supercritical fluid chromatography Methods 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002194 synthesizing Effects 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 2
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 2
- 125000004001 thioalkyl group Chemical group 0.000 description 2
- 229910052718 tin Inorganic materials 0.000 description 2
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 2
- 229960001055 uracil mustard Drugs 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 2
- GBABOYUKABKIAF-IELIFDKJSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IELIFDKJSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229960004276 zoledronic acid Drugs 0.000 description 2
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 1
- DFUSDJMZWQVQSF-XLGIIRLISA-N (2R)-2-methyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-ol Chemical class OC1=CC=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 DFUSDJMZWQVQSF-XLGIIRLISA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N (5S,5aR,8aR,9R)-5-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-2-thiophen-2-yl-4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy]-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-8-one Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- VVIAGPKUTFNRDU-STQMWFEESA-N (6S)-5-formyltetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1C=O)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-STQMWFEESA-N 0.000 description 1
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- LDPCXKXIOCOTLG-UHFFFAOYSA-N 1,2-dihydrobenzotriazol-4-one;1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.O=C1C=CC=C2NNN=C12 LDPCXKXIOCOTLG-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N 1,2-ethanediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- ITZHHMQIKLMWIN-UHFFFAOYSA-N 1,3$l^{2}-thiazolidine Chemical group C1CSC[N]1 ITZHHMQIKLMWIN-UHFFFAOYSA-N 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 description 1
- AICIYIDUYNFPRY-UHFFFAOYSA-N 1,3-dihydro-2H-imidazol-2-one Chemical compound O=C1NC=CN1 AICIYIDUYNFPRY-UHFFFAOYSA-N 0.000 description 1
- AOYSLJHKVBSXRU-UHFFFAOYSA-N 1-(oxetan-3-yl)piperazine Chemical compound C1OCC1N1CCNCC1 AOYSLJHKVBSXRU-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- HBXWUCXDUUJDRB-UHFFFAOYSA-N 1-octadecoxyoctadecane Chemical class CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC HBXWUCXDUUJDRB-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1H-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 description 1
- GLUUGHFHXGJENI-LNLMKGTHSA-N 2,2,3,3-tetradeuteriopiperazine Chemical compound [2H]C1([2H])NCCNC1([2H])[2H] GLUUGHFHXGJENI-LNLMKGTHSA-N 0.000 description 1
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical compound C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N 2-(2-Ethoxyethoxy)ethanol Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- JQMJMUYMMSPHMY-UHFFFAOYSA-N 2-(dimethoxymethyl)-3,3-dimethoxypropan-1-ol Chemical compound COC(OC)C(CO)C(OC)OC JQMJMUYMMSPHMY-UHFFFAOYSA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- GCSJOZFHZGHGTJ-UHFFFAOYSA-N 2-[2-[3,4-bis(2-hydroxyethoxy)oxolan-2-yl]-2-(2-hydroxyethoxy)ethoxy]ethyl formate Chemical compound O=COCCOCC(OCCO)C1OCC(OCCO)C1OCCO GCSJOZFHZGHGTJ-UHFFFAOYSA-N 0.000 description 1
- PCHKPVIQAHNQLW-CQSZACIVSA-N 2-[4-[(3S)-piperidin-3-yl]phenyl]indazole-7-carboxamide Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 description 1
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2S)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- HOVQIIGVBKXWRZ-UHFFFAOYSA-N 2-amino-4-methoxy-3-pentoxybenzaldehyde Chemical compound CCCCCOC1=C(N)C(C=O)=CC=C1OC HOVQIIGVBKXWRZ-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- MLIREBYILWEBDM-LBPDFUHNSA-N 2-cyanoacetic acid Chemical compound O[13C](=O)CC#N MLIREBYILWEBDM-LBPDFUHNSA-N 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JVKUCNQGESRUCL-UHFFFAOYSA-N 2-hydroxyethyl 12-hydroxyoctadecanoate Chemical compound CCCCCCC(O)CCCCCCCCCCC(=O)OCCO JVKUCNQGESRUCL-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N 2-stearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- LMWBCTADNYACQV-UHFFFAOYSA-N 2H-pyrrole Chemical group C1C=C=C=N1 LMWBCTADNYACQV-UHFFFAOYSA-N 0.000 description 1
- FSUYMKXZLQOFQY-UHFFFAOYSA-N 3,4-dihydro-1,2-benzodithiine Chemical compound C1=CC=C2SSCCC2=C1 FSUYMKXZLQOFQY-UHFFFAOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-PATWWPTKSA-N 3-[[2-[2-[2-[[(2R,3R)-2-[[(2R,3R,4S)-4-[[(2S)-2-[[6-amino-2-[(1S)-3-amino-1-[[(2R)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2S,3R,4R,5R,6R)-3-[(2R,3S,4S,5R,6R)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)oxan- Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@@H](C)[C@H](O)[C@@H](C)C(=O)N[C@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)C(O[C@@H]1[C@@H]([C@H](O)[C@@H](O)[C@@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-PATWWPTKSA-N 0.000 description 1
- DGAXTZFGBOIDAB-UHFFFAOYSA-N 3-bromo-4-chloro-5-fluoropyridine Chemical compound FC1=CN=CC(Br)=C1Cl DGAXTZFGBOIDAB-UHFFFAOYSA-N 0.000 description 1
- QNXOIVJNEKSECA-UHFFFAOYSA-N 3-bromo-4-chloro-5-fluoropyridine;hydrochloride Chemical compound Cl.FC1=CN=CC(Br)=C1Cl QNXOIVJNEKSECA-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- JVYNJRBSXBYXQB-UHFFFAOYSA-N 4-[3-(4-carboxyphenoxy)propoxy]benzoic acid;decanedioic acid Chemical compound OC(=O)CCCCCCCCC(O)=O.C1=CC(C(=O)O)=CC=C1OCCCOC1=CC=C(C(O)=O)C=C1 JVYNJRBSXBYXQB-UHFFFAOYSA-N 0.000 description 1
- HYNBNUYQTQIHJK-UHFFFAOYSA-N 4-[[4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one Chemical compound C1CC(OC)CCN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F HYNBNUYQTQIHJK-UHFFFAOYSA-N 0.000 description 1
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 1
- DRMMNFGYCLJZKD-UHFFFAOYSA-N 4-fluoro-1-hydroxy-1,4-diazoniabicyclo[2.2.2]octane;ditetrafluoroborate Chemical compound F[B-](F)(F)F.F[B-](F)(F)F.C1C[N+]2(F)CC[N+]1(O)CC2 DRMMNFGYCLJZKD-UHFFFAOYSA-N 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N AI2O3 Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229940100198 ALKYLATING AGENTS Drugs 0.000 description 1
- 101710043194 APLN Proteins 0.000 description 1
- 229940028652 Abraxane Drugs 0.000 description 1
- 229940060205 Adagen Drugs 0.000 description 1
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 229960001456 Adenosine Triphosphate Drugs 0.000 description 1
- 210000004100 Adrenal Glands Anatomy 0.000 description 1
- 229940064305 Adrucil Drugs 0.000 description 1
- 229940110282 Alimta Drugs 0.000 description 1
- 229940098174 Alkeran Drugs 0.000 description 1
- CBQYNPHHHJTCJS-UHFFFAOYSA-N Alline Chemical compound C1=CC=C2C3(O)CCN(C)C3NC2=C1 CBQYNPHHHJTCJS-UHFFFAOYSA-N 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N Allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N Altretamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K Aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229940063655 Aluminum stearate Drugs 0.000 description 1
- 229960001097 Amifostine Drugs 0.000 description 1
- JKOQGQFVAUAYPM-UHFFFAOYSA-N Amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N Anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 229940064005 Antibiotic throat preparations Drugs 0.000 description 1
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 description 1
- 229940042052 Antibiotics for systemic use Drugs 0.000 description 1
- 229940042786 Antitubercular Antibiotics Drugs 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 240000005781 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 229940115115 Aranesp Drugs 0.000 description 1
- 229940078010 Arimidex Drugs 0.000 description 1
- 229940087620 Aromasin Drugs 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 229940014583 Arranon Drugs 0.000 description 1
- 241000288575 Astomaea Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003594 Ataxia telangiectasia Diseases 0.000 description 1
- 229940120638 Avastin Drugs 0.000 description 1
- IUEWAGVJRJORLA-UHFFFAOYSA-N BMN673 Chemical compound CN1N=CN=C1C1C(NNC(=O)C2=CC(F)=C3)=C2C3=NC1C1=CC=C(F)C=C1 IUEWAGVJRJORLA-UHFFFAOYSA-N 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 229940108502 BiCNU Drugs 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 210000000988 Bone and Bones Anatomy 0.000 description 1
- 206010073106 Bone giant cell tumour malignant Diseases 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- 229940112133 Busulfex Drugs 0.000 description 1
- KVNRLNFWIYMESJ-UHFFFAOYSA-N Butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 1
- 102100003147 CCDC85B Human genes 0.000 description 1
- 101710009963 CCDC85B Proteins 0.000 description 1
- 102100003755 CCNO Human genes 0.000 description 1
- 101700047412 CCNO Proteins 0.000 description 1
- 102100019396 CDK2 Human genes 0.000 description 1
- 101700030325 CHKB Proteins 0.000 description 1
- 102100006435 CSF3 Human genes 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229940095672 Calcium Sulfate Drugs 0.000 description 1
- 229940112129 Campath Drugs 0.000 description 1
- 229940063834 Carboxymethylcellulose Sodium Drugs 0.000 description 1
- 208000002458 Carcinoid Tumor Diseases 0.000 description 1
- 208000009458 Carcinoma in Situ Diseases 0.000 description 1
- 229940047495 Celebrex Drugs 0.000 description 1
- 229920002301 Cellulose acetate Polymers 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- 210000003679 Cervix Uteri Anatomy 0.000 description 1
- 108010022830 Cetuximab Proteins 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N Cetyl alcohol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 208000006990 Cholangiocarcinoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 description 1
- 229940103380 Clolar Drugs 0.000 description 1
- 210000001072 Colon Anatomy 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229940088547 Cosmegen Drugs 0.000 description 1
- 229960000913 Crospovidone Drugs 0.000 description 1
- 229910002483 Cu Ka Inorganic materials 0.000 description 1
- MLIREBYILWEBDM-UHFFFAOYSA-N Cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 description 1
- 102000002554 Cyclin A Human genes 0.000 description 1
- 108010068192 Cyclin A Proteins 0.000 description 1
- 102000003909 Cyclin E Human genes 0.000 description 1
- 108090000257 Cyclin E Proteins 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N Cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N DCM Dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N DMSO dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 108010019673 Darbepoetin alfa Proteins 0.000 description 1
- 229940041983 Daunorubicin Liposomal Drugs 0.000 description 1
- 229940070968 DepoCyt Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 Dexamethasone Drugs 0.000 description 1
- 229960000605 Dexrazoxane Drugs 0.000 description 1
- BMKDZUISNHGIBY-ZETCQYMHSA-N Dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L Dipotassium phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229940018602 Docusate Drugs 0.000 description 1
- 229960000878 Docusate Sodium Drugs 0.000 description 1
- 229940115080 Doxil Drugs 0.000 description 1
- 208000007033 Dysgerminoma Diseases 0.000 description 1
- 108010092799 EC 2.7.7.49 Proteins 0.000 description 1
- 229940047652 Ear Drops Drugs 0.000 description 1
- 229940053594 Eligard Drugs 0.000 description 1
- 229940053603 Elitek Drugs 0.000 description 1
- 229940120655 Eloxatin Drugs 0.000 description 1
- 229940073038 Elspar Drugs 0.000 description 1
- 229940000733 Emcyt Drugs 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 108010074604 Epoetin Alfa Proteins 0.000 description 1
- 229960003388 Epoetin alfa Drugs 0.000 description 1
- 229940089118 Epogen Drugs 0.000 description 1
- 229940082789 Erbitux Drugs 0.000 description 1
- 210000003238 Esophagus Anatomy 0.000 description 1
- 229960001842 Estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N Estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N Ethyl iodide Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N Ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940047887 Etopophos Drugs 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 229920001272 Exogenous DNA Polymers 0.000 description 1
- 229940012356 Eye Drops Drugs 0.000 description 1
- 108060000495 FBXW7 Proteins 0.000 description 1
- 102100020077 FBXW7 Human genes 0.000 description 1
- 229940087861 Faslodex Drugs 0.000 description 1
- 206010016629 Fibroma Diseases 0.000 description 1
- 229960004177 Filgrastim Drugs 0.000 description 1
- 108010029961 Filgrastim Proteins 0.000 description 1
- 229960000961 Floxuridine Drugs 0.000 description 1
- 208000004463 Follicular Adenocarcinoma Diseases 0.000 description 1
- 102000020700 Formins Human genes 0.000 description 1
- 108091021778 Formins Proteins 0.000 description 1
- 230000020172 G2/M transition checkpoint Effects 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N Gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 229960003297 Gemtuzumab ozogamicin Drugs 0.000 description 1
- 229940020967 Gemzar Drugs 0.000 description 1
- 208000000527 Germinoma Diseases 0.000 description 1
- 208000007569 Giant Cell Tumors Diseases 0.000 description 1
- 229940084910 Gliadel Drugs 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- 108010069236 Goserelin Proteins 0.000 description 1
- 229960003690 Goserelin Acetate Drugs 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 229940093922 Gynecological Antibiotics Drugs 0.000 description 1
- 229910004039 HBF4 Inorganic materials 0.000 description 1
- 208000001258 Hemangiosarcoma Diseases 0.000 description 1
- 206010019629 Hepatic adenoma Diseases 0.000 description 1
- 208000006359 Hepatoblastoma Diseases 0.000 description 1
- 229940022353 Herceptin Drugs 0.000 description 1
- VHHHONWQHHHLTI-UHFFFAOYSA-N Hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 1
- 229960003911 Histrelin acetate Drugs 0.000 description 1
- 206010020243 Hodgkin's disease Diseases 0.000 description 1
- 238000010867 Hoechst staining Methods 0.000 description 1
- 229940088597 Hormone Drugs 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006822 Human Serum Albumin Proteins 0.000 description 1
- 229940088013 Hycamtin Drugs 0.000 description 1
- 206010020843 Hyperthermia Diseases 0.000 description 1
- 102100005044 IL11 Human genes 0.000 description 1
- 229940099279 Idamycin Drugs 0.000 description 1
- 229960000908 Idarubicin Drugs 0.000 description 1
- 229940090411 Ifex Drugs 0.000 description 1
- 206010022498 Insulinoma Diseases 0.000 description 1
- 229960003521 Interferon Alfa-2a Drugs 0.000 description 1
- 229960003507 Interferon Alfa-2b Drugs 0.000 description 1
- 229940047124 Interferons Drugs 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 229940047122 Interleukins Drugs 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 229940065638 Intron A Drugs 0.000 description 1
- 229940084651 Iressa Drugs 0.000 description 1
- 241000665848 Isca Species 0.000 description 1
- 101710033922 KRAS Proteins 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 210000001117 Keloid Anatomy 0.000 description 1
- 229940065223 Kepivance Drugs 0.000 description 1
- 206010023347 Keratoacanthoma Diseases 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 210000000867 Larynx Anatomy 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N Letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010024324 Leukaemias Diseases 0.000 description 1
- 208000000429 Leukemia, Lymphocytic, Chronic, B-Cell Diseases 0.000 description 1
- 208000002490 Leukemia, Myelomonocytic, Juvenile Diseases 0.000 description 1
- 229940063725 Leukeran Drugs 0.000 description 1
- 229940087875 Leukine Drugs 0.000 description 1
- 229940008250 Leuprolide Drugs 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- 229940089022 Leuprolide Acetate Drugs 0.000 description 1
- 210000000088 Lip Anatomy 0.000 description 1
- 206010024627 Liposarcoma Diseases 0.000 description 1
- 210000004185 Liver Anatomy 0.000 description 1
- 208000002404 Liver Cell Adenoma Diseases 0.000 description 1
- 229940100029 Lysodren Drugs 0.000 description 1
- HAVFFEMDLROBGI-UHFFFAOYSA-N M8926C7ILX Chemical compound C1CC(O)CCN1CC1=CC=C(OC=2C3=C(C(NN=C33)=O)C=CC=2)C3=C1 HAVFFEMDLROBGI-UHFFFAOYSA-N 0.000 description 1
- 102100017079 MPG Human genes 0.000 description 1
- 101710007617 MPG Proteins 0.000 description 1
- 102100013322 MTOR Human genes 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L Magnesium hydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 229940087732 Matulane Drugs 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 229940090004 Megace Drugs 0.000 description 1
- 229960004296 Megestrol Acetate Drugs 0.000 description 1
- 210000002418 Meninges Anatomy 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 229960004469 Methoxsalen Drugs 0.000 description 1
- 229960001156 Mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N Mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 210000000214 Mouth Anatomy 0.000 description 1
- 208000010492 Mucinous Cystadenocarcinoma Diseases 0.000 description 1
- 208000006876 Multiple Endocrine Neoplasia Type 2b Diseases 0.000 description 1
- 206010073148 Multiple endocrine neoplasia Type 2A Diseases 0.000 description 1
- 229940087004 Mustargen Drugs 0.000 description 1
- 206010028537 Myelofibrosis Diseases 0.000 description 1
- 229940090009 Myleran Drugs 0.000 description 1
- 208000009091 Myxoma Diseases 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N N-ethyl-N-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- CJYQZTZSYREQBD-UHFFFAOYSA-N N-fluorobenzenesulfonamide Chemical compound FNS(=O)(=O)C1=CC=CC=C1 CJYQZTZSYREQBD-UHFFFAOYSA-N 0.000 description 1
- VASDNRLXGWCWLJ-UHFFFAOYSA-N NC1=NN2C(N=CC(=C2)F)=C1 Chemical compound NC1=NN2C(N=CC(=C2)F)=C1 VASDNRLXGWCWLJ-UHFFFAOYSA-N 0.000 description 1
- 101700012596 NEIL1 Proteins 0.000 description 1
- 102100002714 NEIL1 Human genes 0.000 description 1
- VWBWQOUWDOULQN-UHFFFAOYSA-N NMP N-methylpyrrolidone Chemical compound CN1CCCC1=O.CN1CCCC1=O VWBWQOUWDOULQN-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101710033916 NRAS Proteins 0.000 description 1
- 102100001119 NRAS Human genes 0.000 description 1
- 229940097496 Nasal Spray Drugs 0.000 description 1
- 229940086322 Navelbine Drugs 0.000 description 1
- 229950007221 Nedaplatin Drugs 0.000 description 1
- 229940071846 Neulasta Drugs 0.000 description 1
- 229940082926 Neumega Drugs 0.000 description 1
- 229940029345 Neupogen Drugs 0.000 description 1
- 208000007538 Neurilemmoma Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- 229940080607 Nexavar Drugs 0.000 description 1
- 229940109551 Nipent Drugs 0.000 description 1
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 1
- 229940049964 Oleate Drugs 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N Oleyl alcohol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 description 1
- 229940099216 Oncaspar Drugs 0.000 description 1
- 229940100027 Ontak Drugs 0.000 description 1
- 229940041678 Oral Spray Drugs 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000000035 Osteochondroma Diseases 0.000 description 1
- 208000003388 Osteoid Osteoma Diseases 0.000 description 1
- 208000008798 Osteoma Diseases 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 210000003101 Oviducts Anatomy 0.000 description 1
- 229940098901 POLIFEPROSAN 20 Drugs 0.000 description 1
- 101710006355 PPP1R13L Proteins 0.000 description 1
- 229940026235 PROPYLENE GLYCOL MONOLAURATE Drugs 0.000 description 1
- 201000001146 Paget's disease of bone Diseases 0.000 description 1
- 229960002404 Palifermin Drugs 0.000 description 1
- 235000003177 Panax trifolius Nutrition 0.000 description 1
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 description 1
- 206010033701 Papillary thyroid cancer Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229960001373 Pegfilgrastim Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N Pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 210000003800 Pharynx Anatomy 0.000 description 1
- 102000003993 Phosphatidylinositol 3-Kinases Human genes 0.000 description 1
- 108090000430 Phosphatidylinositol 3-Kinases Proteins 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- 229940109328 Photofrin Drugs 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 229940063179 Platinol Drugs 0.000 description 1
- 231100000614 Poison Toxicity 0.000 description 1
- 229960000502 Poloxamer Drugs 0.000 description 1
- 229940044519 Poloxamer 188 Drugs 0.000 description 1
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 229960004293 Porfimer Sodium Drugs 0.000 description 1
- 208000003476 Primary Myelofibrosis Diseases 0.000 description 1
- 229940087463 Proleukin Drugs 0.000 description 1
- 210000002307 Prostate Anatomy 0.000 description 1
- 229950008679 Protamine sulfate Drugs 0.000 description 1
- 108060006633 Protein Kinases Proteins 0.000 description 1
- 229940117820 Purinethol Drugs 0.000 description 1
- 229940079923 Quinacrine Drugs 0.000 description 1
- 102100008299 RBBP8 Human genes 0.000 description 1
- 101710036782 RBBP8 Proteins 0.000 description 1
- 229960000424 Rasburicase Drugs 0.000 description 1
- 210000000664 Rectum Anatomy 0.000 description 1
- 229940120975 Revlimid Drugs 0.000 description 1
- 208000005678 Rhabdomyoma Diseases 0.000 description 1
- 229940003641 Rituxan Drugs 0.000 description 1
- 108010001645 Rituximab Proteins 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N Rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 Rubitecan Drugs 0.000 description 1
- 229940080350 SODIUM STEARATE Drugs 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010039667 Schwannoma Diseases 0.000 description 1
- 229940053186 Sclerosol Drugs 0.000 description 1
- 208000004548 Serous Cystadenocarcinoma Diseases 0.000 description 1
- 208000000097 Sertoli-Leydig Cell Tumor Diseases 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- 210000003625 Skull Anatomy 0.000 description 1
- 229940045870 Sodium Palmitate Drugs 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N Sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M Sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 240000001016 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 229920001304 Solutol HS 15 Polymers 0.000 description 1
- IJCWFDPJFXGQBN-BIFNRIDTSA-N Sorbitan tristearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)[C@H]1OC[C@@H](O)[C@@H]1OC(=O)CCCCCCCCCCCCCCCCC IJCWFDPJFXGQBN-BIFNRIDTSA-N 0.000 description 1
- 210000000278 Spinal Cord Anatomy 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 206010042135 Stomatitis necrotising Diseases 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N Sulfuryl chloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 229940034785 Sutent Drugs 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
- 102100009576 TOPBP1 Human genes 0.000 description 1
- 101710037544 TOPBP1 Proteins 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N Talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 229940120982 Tarceva Drugs 0.000 description 1
- 229940061353 Temodar Drugs 0.000 description 1
- 229960001278 Teniposide Drugs 0.000 description 1
- 208000001608 Teratocarcinoma Diseases 0.000 description 1
- 210000001550 Testis Anatomy 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N Tetrahydro-2-furanmethanol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 229960001196 Thiotepa Drugs 0.000 description 1
- 208000005485 Thrombocytosis Diseases 0.000 description 1
- 210000001685 Thyroid Gland Anatomy 0.000 description 1
- 229940035295 Ting Drugs 0.000 description 1
- 210000002105 Tongue Anatomy 0.000 description 1
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N Toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 206010044412 Transitional cell carcinoma Diseases 0.000 description 1
- 108010010691 Trastuzumab Proteins 0.000 description 1
- 229960001727 Tretinoin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 229940086984 Trisenox Drugs 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- HWKQNAWCHQMZHK-UHFFFAOYSA-N Trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 1
- 210000003708 Urethra Anatomy 0.000 description 1
- 210000003932 Urinary Bladder Anatomy 0.000 description 1
- 241001459538 Ute Species 0.000 description 1
- 210000004291 Uterus Anatomy 0.000 description 1
- 229940001814 Uvadex Drugs 0.000 description 1
- 210000001215 Vagina Anatomy 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N Valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229940099039 Velcade Drugs 0.000 description 1
- 229950011257 Veliparib Drugs 0.000 description 1
- 229940065658 Vidaza Drugs 0.000 description 1
- 208000009540 Villous Adenoma Diseases 0.000 description 1
- 208000009311 Vipoma Diseases 0.000 description 1
- 229940046009 Vitamin E Drugs 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 229940053446 Vitamin E D-Alpha Drugs 0.000 description 1
- 229960000237 Vorinostat Drugs 0.000 description 1
- 210000003905 Vulva Anatomy 0.000 description 1
- 210000002268 Wool Anatomy 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 229940053867 Xeloda Drugs 0.000 description 1
- 229940053890 Zanosar Drugs 0.000 description 1
- 241000209149 Zea Species 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229940061261 Zolinza Drugs 0.000 description 1
- 229940002005 Zometa Drugs 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N [(8R,9S,10R,13S,14S,17R)-17-acetyl-6,10,13-trimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- CWUYOSYHUNLLRT-UHFFFAOYSA-N [2H-benzotriazol-4-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound CN(C)C(=[N+](C)C)OC1=CC=CC2=C1N=NN2 CWUYOSYHUNLLRT-UHFFFAOYSA-N 0.000 description 1
- SRJOCJYGOFTFLH-UHUJFCCWSA-N [2H]C1(NC(C(C(C1([2H])[2H])(C(=O)O)[2H])([2H])[2H])([2H])[2H])[2H] Chemical compound [2H]C1(NC(C(C(C1([2H])[2H])(C(=O)O)[2H])([2H])[2H])([2H])[2H])[2H] SRJOCJYGOFTFLH-UHUJFCCWSA-N 0.000 description 1
- GLUUGHFHXGJENI-RUKOHJPDSA-N [2H]C1(NCC(NC1)([2H])[2H])[2H] Chemical compound [2H]C1(NCC(NC1)([2H])[2H])[2H] GLUUGHFHXGJENI-RUKOHJPDSA-N 0.000 description 1
- CTCBPRXHVPZNHB-VQFZJOCSSA-N [[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate;(2R,3R,4S,5R)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O.C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O CTCBPRXHVPZNHB-VQFZJOCSSA-N 0.000 description 1
- UQYZFNUUOSSNKT-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 UQYZFNUUOSSNKT-UHFFFAOYSA-N 0.000 description 1
- 229960002184 abarelix Drugs 0.000 description 1
- 108010023617 abarelix Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- IKDXDQDKCZPQSZ-JHYYTBFNSA-N acetic acid;(2S)-N-[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopro Chemical compound CC(O)=O.C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 IKDXDQDKCZPQSZ-JHYYTBFNSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 231100000494 adverse effect Toxicity 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000000172 allergic Effects 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 201000003076 angiosarcoma Diseases 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003474 anti-emetic Effects 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940027983 antiseptics and disinfectants Quaternary ammonium compounds Drugs 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 235000020127 ayran Nutrition 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- VJDWVTGQLRWGKY-UHFFFAOYSA-N benzyl 4-(oxetan-3-yl)piperazine-1-carboxylate Chemical compound C1CN(C2COC2)CCN1C(=O)OCC1=CC=CC=C1 VJDWVTGQLRWGKY-UHFFFAOYSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CTOUWUYDDUSBQE-UHFFFAOYSA-N benzyl piperazine-1-carboxylate Chemical compound C1CNCCN1C(=O)OCC1=CC=CC=C1 CTOUWUYDDUSBQE-UHFFFAOYSA-N 0.000 description 1
- 201000009036 biliary tract cancer Diseases 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 230000004611 cancer cell death Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000004452 carbocyclyl group Chemical group 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 201000005217 chondroblastoma Diseases 0.000 description 1
- 201000009047 chordoma Diseases 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229910052570 clay Inorganic materials 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005824 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000005356 cycloalkylalkenyl group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960005029 darbepoetin alfa Drugs 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 229960002923 denileukin diftitox Drugs 0.000 description 1
- 108010017271 denileukin diftitox Proteins 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide DMF Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- LLRANSBEYQZKFY-UHFFFAOYSA-N dodecanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCCCCCC(O)=O LLRANSBEYQZKFY-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940017825 dromostanolone Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 201000009051 embryonal carcinoma Diseases 0.000 description 1
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229960004750 estramustine phosphate Drugs 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- BFZXXCSKNHQBEF-UHFFFAOYSA-N ethane-1,2-diamine;propane-1,3-diamine Chemical compound NCCN.NCCCN BFZXXCSKNHQBEF-UHFFFAOYSA-N 0.000 description 1
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 229960005304 fludarabine phosphate Drugs 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 1
- 201000005160 follicular thyroid carcinoma Diseases 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000002496 gastric Effects 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 201000003115 germ cell cancer Diseases 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002314 glycerols Chemical class 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000002140 halogenating Effects 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000002489 hematologic Effects 0.000 description 1
- 201000002138 hematopoietic system disease Diseases 0.000 description 1
- 201000002735 hepatocellular adenoma Diseases 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 1
- 229960002193 histrelin Drugs 0.000 description 1
- BKEMVGVBBDMHKL-VYFXDUNUSA-N histrelin acetate Chemical compound CC(O)=O.CC(O)=O.CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 BKEMVGVBBDMHKL-VYFXDUNUSA-N 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229940072106 hydroxystearate Drugs 0.000 description 1
- 230000036031 hyperthermia Effects 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 108010061572 ibritumomab tiuxetan Proteins 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- ZIPLUEXSCPLCEI-UHFFFAOYSA-N iminomethylideneazanide Chemical compound [NH-]C#N ZIPLUEXSCPLCEI-UHFFFAOYSA-N 0.000 description 1
- 238000010820 immunofluorescence microscopy Methods 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910001410 inorganic ion Inorganic materials 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000002570 interstitial cell Anatomy 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 229940079866 intestinal antibiotics Drugs 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 230000000155 isotopic Effects 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000003902 lesions Effects 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 201000004593 malignant giant cell tumor Diseases 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- 208000009018 medullary Thyroid cancer Diseases 0.000 description 1
- 229960001786 megestrol Drugs 0.000 description 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 1
- URXWVWVPMJSAJD-KOORYGTMSA-N megestrol acetate Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 URXWVWVPMJSAJD-KOORYGTMSA-N 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- IKXILDNPCZPPRV-RFMGOVQKSA-N metholone Chemical compound C1C[C@@H]2[C@@]3(C)C[C@@H](C)C(=O)C[C@@H]3CC[C@H]2[C@@H]2CC[C@H](O)[C@]21C IKXILDNPCZPPRV-RFMGOVQKSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 230000000869 mutational Effects 0.000 description 1
- 201000003793 myelodysplastic syndrome Diseases 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960001133 nandrolone phenpropionate Drugs 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 238000004172 nitrogen cycle Methods 0.000 description 1
- 201000008585 noma Diseases 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- FSVSNKCOMJVGLM-UHFFFAOYSA-N octanoic acid;propane-1,2-diol Chemical compound CC(O)CO.CCCCCCCC(O)=O FSVSNKCOMJVGLM-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 description 1
- 201000010133 oligodendroglioma Diseases 0.000 description 1
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 description 1
- 229960001840 oprelvekin Drugs 0.000 description 1
- 108010046821 oprelvekin Proteins 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002188 osteogenic Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 201000001539 ovarian carcinoma Diseases 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 229960002502 paclitaxel protein-bound Drugs 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N palmityl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 201000005170 papillary thyroid carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960001218 pegademase Drugs 0.000 description 1
- 229940048111 pegademase bovine Drugs 0.000 description 1
- 229960001744 pegaspargase Drugs 0.000 description 1
- 108010001564 pegaspargase Proteins 0.000 description 1
- 108010044644 pegfilgrastim Proteins 0.000 description 1
- NYDXNILOWQXUOF-GXKRWWSZSA-L pemetrexed disodium Chemical compound [Na+].[Na+].C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 NYDXNILOWQXUOF-GXKRWWSZSA-L 0.000 description 1
- 229960003349 pemetrexed disodium Drugs 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 230000000737 periodic Effects 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 201000004123 pineal gland cancer Diseases 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229930001140 podophyllotoxin Natural products 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229920005589 poly(ferrocenylsilane) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- PSBAZVJEUNOIDU-UHFFFAOYSA-L potassium;sodium;diacetate Chemical compound [Na+].[K+].CC([O-])=O.CC([O-])=O PSBAZVJEUNOIDU-UHFFFAOYSA-L 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 230000002062 proliferating Effects 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- BNXGMSOVZHRHKF-UHFFFAOYSA-N prop-2-enyl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate Chemical compound C1=C(F)C=NC2=C(C(=O)OCC=C)C(N)=NN21 BNXGMSOVZHRHKF-UHFFFAOYSA-N 0.000 description 1
- QPTWDVFFLRWIAM-UHFFFAOYSA-N prop-2-enyl 3,5-diamino-1H-pyrazole-4-carboxylate Chemical compound NC1=NNC(N)=C1C(=O)OCC=C QPTWDVFFLRWIAM-UHFFFAOYSA-N 0.000 description 1
- YBHQMNOSBMVHMU-UHFFFAOYSA-N prop-2-enyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate Chemical compound ClC(Cl)(Cl)C(N)=C(C#N)C(=O)OCC=C YBHQMNOSBMVHMU-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000002661 proton therapy Methods 0.000 description 1
- 201000004681 psoriasis Diseases 0.000 description 1
- 239000000649 purine antagonist Substances 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- XMRIUEGHBZTNND-UHFFFAOYSA-N pyrazolo[1,5-a]pyrimidine-3-carboxamide Chemical compound C1=CC=NC2=C(C(=O)N)C=NN21 XMRIUEGHBZTNND-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 239000003790 pyrimidine antagonist Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 108010084837 rasburicase Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 210000004176 reticulum cell Anatomy 0.000 description 1
- 201000000582 retinoblastoma Diseases 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- CKNPWBAXEKSCRG-UHFFFAOYSA-J satraplatin Chemical compound CC(=O)O[Pt-2]([NH3+])(Cl)(Cl)(OC(C)=O)[NH2+]C1CCCCC1 CKNPWBAXEKSCRG-UHFFFAOYSA-J 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000646 scanning calorimetry Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 201000010208 seminoma Diseases 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003385 sodium Chemical group 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 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
- 229940045845 sodium myristate Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 description 1
- JUQGWKYSEXPRGL-UHFFFAOYSA-M sodium;tetradecanoate Chemical compound [Na+].CCCCCCCCCCCCCC([O-])=O JUQGWKYSEXPRGL-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000279 solid-state nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 201000008736 systemic mastocytosis Diseases 0.000 description 1
- PCZOZSATUTWXIC-UHFFFAOYSA-N tetraethylazanium;cyanide Chemical compound N#[C-].CC[N+](CC)(CC)CC PCZOZSATUTWXIC-UHFFFAOYSA-N 0.000 description 1
- ODGCEQLVLXJUCC-UHFFFAOYSA-O tetrafluoroboric acid Chemical compound [H+].F[B-](F)(F)F ODGCEQLVLXJUCC-UHFFFAOYSA-O 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 201000005204 thyroid medullary carcinoma Diseases 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- KDQAABAKXDWYSZ-JKDPCDLQSA-N vincaleukoblastine sulfate Chemical compound OS(O)(=O)=O.C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 KDQAABAKXDWYSZ-JKDPCDLQSA-N 0.000 description 1
- CILBMBUYJCWATM-IJDPFCGHSA-N vinorelbine L-tartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-IJDPFCGHSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 150000003712 vitamin E derivatives Chemical class 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N β-Propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07B2200/05—Isotopically modified compounds, e.g. labelled
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Description
-AMINOFLUORO-N-[5-FLUORO-PYRIDINYL]PYRAZOLO[1,5-A]PYRIMIDINCARBOXAMIDE
COMPOUND USEFUL AS ATR KINASE INHIBITOR, ITS PREPARATION, DIFFERENT SOLID FORMS
AND RADIOLABELLED TIVES THEREOF
OUND OF THE INVENTION
ATR (“ATM and Rad3 related”) kinase is a protein kinase involved in cellular responses to
DNA damage. ATR kinase acts with ATM (“ataxia telangiectasia mutated”) kinase and many other
proteins to regulate a cell’s response to DNA , commonly referred to as the DNA Damage
Response ). The DDR ates DNA , promotes survival and stalls cell cycle
progression by activating cell cycle checkpoints, which provide time for repair. Without the DDR,
cells are much more sensitive to DNA damage and readily die from DNA lesions induced by
endogenous cellular processes such as DNA replication or exogenous DNA damaging agents
commonly used in cancer therapy.
Healthy cells can rely on a host of different proteins for DNA repair ing the DDR
kinase ATR. In some cases these ns can compensate for one another by activating onally
redundant DNA repair processes. On the contrary, many cancer cells harbour defects in some of their
DNA repair processes, such as ATM signaling, and therefore display a greater reliance on their
remaining intact DNA repair proteins which include ATR.
In addition, many cancer cells express activated oncogenes or lack key tumour suppressors,
and this can make these cancer cells prone to dysregulated phases of DNA replication which in turn
cause DNA damage. ATR has been implicated as a critical component of the DDR in response to
disrupted DNA replication. As a result, these cancer cells are more dependent on ATR activity for
survival than healthy cells. Accordingly, ATR inhibitors may be useful for cancer treatment, either
used alone or in combination with DNA damaging agents, because they shut down a DNA repair
ism that is more important for cellular survival in many cancer cells than in y normal
cells.
In fact, disruption of ATR function (e.g. by gene deletion) has been shown to e
cancer cell death both in the absence and presence of DNA damaging . This suggests that ATR
inhibitors may be effective both as single agents and as potent sensitizers to radiotherapy or
genotoxic herapy.
For all of these reasons, there is a need for the development of potent and selective ATR
inhibitors for the treatment of cancer, either as single agents or as combination therapies with
radiotherapy or genotoxic chemotherapy. Furthermore, it would be desirable to have a synthetic
route to ATR inhibitors that is amenable to large-scale synthesis and improves upon currently known
methods.
ATR peptide can be expressed and isolated using a variety of methods known in the
literature (@ e.g., Unsal—Kacmaz et al, PNAS 99: 10, pp6673—6678, May 14, 2002; see also
Kumagai et al. Cill 124, 955, March 10, 2006; Unsal-Kacmaz et al. Molecular and Cellular
m,Feb 2004, p1292-1300; and Hall—Jackson et al. Oncogene 1999, 18, 6707—6713).
BRIEF DESCRIPTION OF THE FIGURES
FIGURE 1a: XRPD Compound I-I ethanol solvate
FIGURE 2a: TGA Compound I-1° ethanol e
FIGURE 3a: DSC Compound I ethanol solvate
FIGURE 4a: solid state 13C NMR spectrum (12.5 kHz spinning) of Compound I-1° ethanol solvate
FIGURE 5a: solid state 19F NMR spectrum (12.5 kHz spinning) of Compound I-1° ethanol solvate
FIGURE 1b: XRPD Compound I-1° hydrate I
FIGURE 2b: TGA nd I-1° hydrate I
FIGURE 3b: DSC Compound I hydrate I
FIGURE 4b: XRPD Compound I-1° hydrate II
FIGURE 5b: solid state 13C NMR um (11 kHz spinning) of Compound I-1° hydrate II
FIGURE 6b: solid state 19F NMR spectrum (11 kHz spinning) of Compound I-1° hydrate II
FIGURE 1c: XRPD Compound I-I anhydrous form A
FIGURE 2c: TGA Compound I-I anhydrous form A
FIGURE 3c: DSC Compound I-I anhydrous form A
FIGURE 4c: is a conformational plot of Compound I-1° anhydrous form A based on single crystal
X—ray analysis.
FIGURE 5c: is a conformational plot showing the stacking order of Compound I-1° anhydrous form
FIGURE 6c: solid state 13C NMR spectrum (12.5 kHz ng) of Compound I-1° anhydrous form
FIGURE 7c: solid state 19F NMR spectrum (12.5 kHz ng) of Compound I-1° anhydrous form
FIGURE 1d: XRPD nd I-1° anhydrous form B
FIGURE 2d: TGA Compound I-1° anhydrous form B
FIGURE 3d: DSC nd I anhydrous form B
FIGURE 4d: solid state 13 C NMR um (12.5 kHz spinning) of Compound I-1° anhydrous form
FIGURE 5d: solid state 19F NMR spectrum (12.5 kHz spinning) of Compound I-1° anhydrous form
FIGURE 1e: XRPD Compound I-1° anhydrous form C
FIGURE 2e: TGA Compound I-1° anhydrous form C
FIGURE 3e: DSC nd I-1° anhydrous form C
FIGURE 4e: solid state 13C NMR spectrum (12.5 kHz spinning) of Compound I-1° ous form
FIGURE 5e: solid state 19F NMR spectrum (12.5 kHz spinning) of Compound I-1° anhydrous form
FIGURE 1f: XRPD Compound I-1° amorphous form
FIGURE 2f: DSC Compound I-1° amorphous form
FIGURE 3f: solid state 13C NMR spectrum (12.5 kHz spinning) of Compound I-1° amorphous
FIGURE 4f: solid state 19F NMR spectrum (12.5 kHz spinning) of Compound I-1° amorphous
FIGURE lg: XRPD Compound I-1° DMSO solvate
FIGURE 2g: TGA nd I-1° DMSO solvate
FIGURE 3g: DSC Compound I-1° DMSO solvate
FIGURE lh: XRPD Compound I-1° DMAC solvate
FIGURE 2h: TGA Compound I-1° DMAC solvate
FIGURE 3h: DSC Compound I-1° DMAC solvate
FIGURE 1i: XRPD Compound I-1° acetone solvate
FIGURE 2i: TGA Compound I-1° acetone solvate
FIGURE 3i: DSC nd I-1° e solvate
FIGURE lj: XRPD Compound I-1° isopropanol solvate
FIGURE 2j: TGA Compound I-1° isopropanol solvate
FIGURE 3j: DSC Compound I-1° isopropanol solvate
SUMMARY OF THE INVENTION
The present ion relates to solid forms ofATR inhibitors, compositions including ATR
inhibitors, as well as deuterated ATR inhibitors. The present invention also s to ses and
intermediates for preparing compounds useful as tors of ATR kinase, such as amino-
pyrazolopyrimidine derivatives and related molecules. Amino-pyrazolopyrimidine derivatives are
useful as ATR inhibitors and are also useful for preparing ATR inhibitors.
One aspect of the invention provides a process for preparing a compound of formula I-A:
Another aspect comprises a process for preparing a compound of formula 1-1:
0 {FM
Another aspect of the present invention comprises a nd of formula I-B:
or a ceutically acceptable salt or derivative thereof, wherein:
each Y1 Y2 Y3 Y4 Y5 Y6 Y7 Y8 Y9 Y10 Y“ Y12 YB Y14 Y15 Yrs Y17 Y18 and Y19 is
independently hydrogen or deuterium; provided at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9,
Y10,Y11,Y12, Y”, Y14,Y15,Y16,Y17,Y18, and Y” is deuterium
each X1, X2, X4, X5, X6, X7, X8, and X9 is independently ed from 12C or 13C; and
X3 is independently selected from -12C(O)- or -13C(O)-.
Yet another aspect of the invention provides solid forms of a compound of formula I-1:
I-1.
[0011A] In a particular aspect, the present invention provides a compound of formula I-1
wherein the form is selected from the group consisting of Compound I-1 hydrate I, Compound I-1
anhydrous form A, Compound I-1 anhydrous form B, Compound I-1 anhydrous form C, Compound
I-1 DMSO solvate, Compound I-1 DMAC solvate, Compound I-1 acetone solvate, or Compound I-1
isopropanol solvate,
n Compound I-1 hydrate I is crystalline Compound I-1 hydrate I characterized by one or more
peaks expressed in 2-theta ± 0.2 at 6.5, 12.5, 13.7, 18.8, and 26.0 degrees in an X-Ray powder
ction pattern obtained using Cu K alpha radiation,
Compound I-1 anhydrous form A is crystalline Compound I-1 ous form A characterized by
one or more peaks expressed in 2-theta ± 0.2 at 6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X-Ray
powder diffraction pattern obtained using Cu K alpha radiation,
Compound I-1 anhydrous form B is crystalline Compound I-1 anhydrous form B characterized by
two or more peaks expressed in 2-theta ± 0.2 at 7.2, 8.3, 12.9, 19.5, and 26.6 degrees in an X-Ray
powder diffraction pattern obtained using Cu K alpha radiation,
Compound I-1 anhydrous form C is crystalline Compound I-1 ous form C characterized by
two or more peaks expressed in a ± 0.2 at 6.8, 13.4, 15.9, 30.9, and 32.9 degrees in an X-Ray
powder diffraction pattern obtained using Cu K alpha radiation.
Some embodiments disclosed herein generally relate to a composition that can include an
effective amount of Compound I-1 or polymorphic anhydrous form A of nd I-1. (hereinafter
“Form A”), or a ceutically acceptable salt of the entioned compounds.
[0012A] In a particular aspect, the present ion provides a composition comprising:
(followed by page 5a)
a) Compound I-1, or a pharmaceutically acceptable salt thereof, wherein nd I-1 is
ented by the following structural formula:
; and
b) one or more excipients, n at least 90% by weight of Compound I-1 is crystalline Compound
I-1•anhydrous form A characterized by one or more peaks expressed in 2-theta ± 0.2 at 6.1, 12.2,
14.5, 22.3, and 31.8 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha
radiation.
[0012B] In another particular aspect, the present invention provides a crystal form of
Compound I-1 having a monoclinic crystal system, a P21/c centrosymmetric space group, and the
following unit cell parameters:
a = 15.29(3)Å α = 90°
b = 12.17(2)Å β = 107.22(3)°
c = 14.48(3)Å γ = 90°,
wherein nd I-1 is represented by the following structural formula:
[0012C] In yet another particular aspect, the present invention provides a process for preparing
Compound I-1•anhydrous form A comprising stirring a suspension containing Compound I-
1•ethanol solvate and ydrofuran, wherein Compound I-1•anhydrous form A is crystalline
Compound I-1•anhydrous form A characterized by one or more peaks expressed in a ± 0.2 at
6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X-Ray powder diffraction pattern obtained using Cu K
alpha ion, wherein Compound I-1 is represented by the following structural formula:
5a (followed by page 5b)
[0012D] In a further ular aspect, the present invention provides a process for preparing
Compound hydrous form A comprising stirring a suspension containing Compound I-
phous, isopropanol, and water, wherein Compound I-1•anhydrous form A is crystalline
Compound I-1•anhydrous form A characterized by one or more peaks expressed in 2-theta ± 0.2 at
6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X-Ray powder diffraction pattern obtained using Cu K
alpha radiation, wherein Compound I-1 is represented by the following ural formula:
Other embodiments disclosed herein generally relate to a method of preparing such
compositions described herein (for example, a composition that can include an effective amount of
Compound I-1 or Form A, or a pharmaceutically acceptable salt of the aforementioned compounds).
Still other embodiments disclosed herein generally relate to a method of ng cancer using a
composition described herein.
Some embodiments disclosed herein generally relate to the use of a composition described
herein (for example, a composition that includes an ive amount of Compound I-1 or Form A, or
a pharmaceutically acceptable salt of the aforementioned compounds) in the manufacture of a
medicament for treating .
Other aspects of the invention are set forth .
5b (followed by page 5c)
DETAILED DESCRIPTION OF THE INVENTION
For purposes of this application, it will be understood that the terms embodiment,example,
and aspect are used hangeably.
Processes
Another aspect of the present invention comprises a process for preparing a compound of
formula I-A:
[FOLLOWED BY PAGE 6]
under suitable conditions to form an amide bond, wherein:
R1 is independently selected from fluoro, chloro, or —C(J1)2CN;
J1 is independently selected from H or C1_2alkyl; or
two occurrences of J1 ,together with the carbon atom to which they are attached, form a 3—4
membered optionally substituted carbocyclic ring;
R2 is independently selected from H; halo; -CN; NHz; a C1_2alkyl optionally substituted with
0—3 occurrences of fluoro; or a iphatic chain n up to two methylene units of
the aliphatic chain are optionally replaced with —O—, —NR—, —C(O)—, or —S(O)n;
R3 is ndently ed from H; halo; C1_4alkyl optionally substituted with 1-3
occurrences of halo; C3_4cycloalkyl; -CN; or a C1_3aliphatic chain wherein up to two
methylene units of the aliphatic chain are optionally replaced with —O-, -NR—, —C(O)—, or —
S(O)n;
R4 is independently selected from Q1 or a liphatic chain n up to four methylene
units of the aliphatic chain are optionally ed with —O—, —NR—, —C(O)—, or —S(O)n—;
each R4 is optionally substituted with 0—5 occurrences of JQ; or
R3 and R4, taken er with the atoms to which they are bound, form a 5—6 membered
aromatic or non-aromatic ring haVing 0-2 heteroatoms selected from oxygen, nitrogen or
sulfur; the ring formed by R3 and R4 is optionally substituted with 0—3 occurrences of JZ;
Q1 is independently selected from a 3—7 membered fully saturated, partially unsaturated, or
aromatic monocyclic ring, the 3-7 membered ring having 0—3 heteroatoms selected from
oxygen, nitrogen or sulfur; or an 7-12 membered fully saturated, partially unsaturated, or
ic bicyclic ring having 0-5 heteroatoms selected from , nitrogen, or sulfur;
JZ is independently selected from C1_6aliphatic, :0, halo, or ->O;
JQ is independently selected from —CN; halo; =0; Q2; or a C1_galiphatic chain wherein up to
three methylene units of the aliphatic chain are optionally replaced with —O-, -NR-, -C(O)-
or —S(O)n—; each occurrence of JQ is optionally tuted by 0—3 occurrences of JR; or
two occurrences of J on the same atom, taken together with the atom to which they are
joined, form a 3-6 membered ring haVing 0-2 heteroatoms selected from oxygen, nitrogen,
Q is optionally tuted with
or sulfur; wherein the ring formed by two occurrences of J
0—3 occurrences of JX; or
two occurrences of JQ, together with Q, form a 6—10 membered saturated or partially
unsaturated bridged ring system;
Q2 is independently selected from a 3—7 membered fully saturated, partially unsaturated, or
aromatic monocyclic ring haVing 0-3 atoms selected from , nitrogen, or
sulfur; or an 7-12 membered fully saturated, partially unsaturated, or aromatic bicyclic
ring haVing 0-5 heteroatoms selected from oxygen, nitrogen, or sulfur;
JR is independently selected from —CN; halo; =0; ->O; Q3; or a C1_6aliphatic chain wherein
up to three methylene units of the aliphatic chain are optionally ed with —O-, -NR-, -
C(O)—, or —S(O)n—; each JR is optionally substituted with 0—3 occurrences of JT; or
two occurrences of J on the same atom, er with the atom to which they are ,
form a 3-6 membered ring haVing 0-2 heteroatoms selected from oxygen, nitrogen, or
sulfur; wherein the ring formed by two occurrences of JR is optionally substituted with 0—3
occurrences of JX; or
two occurrences of JR, together with Q2, form a 6—10 membered saturated or partially
unsaturated bridged ring system;
Q3 is a 3-7 membered fully saturated, partially unsaturated, or aromatic monocyclic ring
haVing 0-3 heteroatoms selected from oxygen, en, or sulfur; or an 7-12 membered
fully saturated, partially unsaturated, or aromatic bicyclic ring haVing 0-5 atoms
selected from oxygen, nitrogen, or sulfur;
JX is independently selected N; :0; halo; or a iphatic chain wherein up to two
methylene units of the aliphatic chain are optionally replaced with —O-, -NR—, —C(O)—, or —
JT is independently selected from halo, -CN; ->O; =0; —OH; a iphatic chain wherein up
to two methylene units of the aliphatic chain are optionally replaced with —O-, -NR-, -
C(O)—, or —S(O)n—; or a 3—6 ed non—aromatic ring having 0—2 heteroatoms selected
from , nitrogen, or sulfur; each occurrence of IT is optionally tuted with 0—3
occurrences of JM; or
two occurrences of IT on the same atom, together with the atom to which they are joined,
form a 3-6 membered ring having 0-2 heteroatoms selected from , nitrogen, or
sulfur; or
two occurrences of IT, together with Q3, form a 6—10 membered saturated or lly
unsaturated d ring system;
JM is independently selected from halo or C1_6aliphatic;
J is H or Cl;
n is 0, l or 2; and
R is independently selected from H or C1_4aliphatic.
For purposes of this application, it will be understood that when two occurrences of IQ,
together with Q, form a bridged ring system, the two occurrences of IQ are attached to separate
atoms of Q1. Additionally, when two occurrences of JR, together with Q2, form a bridged ring
system, the two occurrences of JR are attached to separate atoms of Q2. Moreover, when two
occurrences of IT, together with Q3, form a d ring system, the two occurrence of IT are attached
to separate atoms of Q3.
It will be understood by those d in the art that the arrow in ->O represents a dative
bond.
Reaction Conditions
In some examples, the suitable conditions for forming the amide bond comprises reacting
the compound of formula 6 with a substituted 3-amino pyridine in an aprotic solvent under heat. In
other examples, the aprotic solvent is ed from NMP, optionally substituted pyridine, or DMF.
In another embodiment, the aprotic solvent is optionally substituted pyridine. In still other
embodiments, the on temperature is at least 80°C. In another ment, the reaction
temperature is at least 100°C.
In another embodiment, the process, described above, further comprises preparing a
compound of formula 6:
WO 85132
by reacting a compound of formula 5:
\MOH
under suitable conditions to form an activated ester, wherein R1 and J are as defined herein.
In some embodiments, suitable ions for forming the activated ester comprises
reacting the compound of formula 5 with an amide coupling agent in the presence of an organic base.
In other embodiments, the organic base is an tic amine. In still other embodiments, the organic
base is independently selected from triethylamine or DIPEA. In one or more embodiments, the
amide coupling agent is independently selected from TBTU, TCTU, HATU, T3P, or COMU. In yet
another embodiment, the amide coupling agent is independently selected from TBTU or TCTU. In
another embodiment, the amide ng agent is TCTU.
Another aspect of the invention comprises a process for preparing a nd of formula
I-A:
NH2 0 N
/ R2
"i / / N \ l
N H R3
g\ //N R4
comprising reacting a compound of formula 5:
NH2 0
\MOH
under suitable conditions to form an amide bond, wherein R1, R2, R3, and R4 are as defined
herein.
Yet another apect of the present invention comprises a process for ing a compound
of formula 5:
by reacting a compound of a 4:
NH2 0
"l / / O,AII
under suitable hydrolytic conditions, wherein R1 is as defined herein.
In some embodiments, suitable hydrolytic conditions comprise reacting the compound of
formula 4 with a silane in the presence of a metal catalyst. In other embodiments, the silane is a
phenylsilane. In another embodiment, the metal catalyst is a palladium catalyst. In yet another
embodiment, the palladium st is Pd(PPh3)4. In another ment suitable hydrolytic
conditions comprise reacting the compound of formula 4 with 4-methylbenzenesulf1nate in the
presence of a metal catalyst.
In still other embodiments, suitable ytic conditions comprise reacting the compound
of formula 4 with an aqueous alkali. In some embodiments, the aqueous alkali is selected from
LiOH, NaOH or KOH.
Another aspect of the present ion comprises a process for preparing a compound of
formula 4:
by reacting a compound of formula 3:
NH2 0
N\/ / O,AII
under suitable condensation conditions to form a pyrimidine ring.
In some embodiments, suitable condensation conditions to form a pyrimidine ring
comprise reacting the compound of formula 3 with a electrophilic species in the presence of a
t. In another ment, the 1,3—dielectrophilic species is selected from 1,3—dialdehyde or
3-(dialkylamino)-propenal. In still other embodiments, the solvent is selected from DMF or
DMSO. In other embodiments, the electrophilic species is generated in situ from a protected
1,3-dielectrophilic species. In another embodiment, the 1,3-dielectrophilic species is generated from
a ketal in the presence of a sulfonic acid. In yet another embodiment, the ic acid is PTSA.
Another aspect of the present invention ses a process for preparing the compound
offormula3:
NH2 0
"l / / O,AII
by reacting a compound of formula 2:
NCI?“All
H2N col3
under suitable sation conditions to form a pyrazole ring.
In some embodiments, suitable condensation conditions to form a pyrazole ring comprise
WO 85132 2014/068713
reacting the nd of formula 2 with a hydrazine or hydrazine hydrate in the presence of an
c solvent under basic conditions. In another embodiment, the aprotic solvent is DMF. In yet
another embodiment, the basic conditions comprise reacting the compound of formula 2 in the
presence of potassium acetate or sodium acetate.
Yet another aspect of the present invention comprises a process for preparing a compound
of formula 2:
NCfiO’AII
H2N CCI3
by reacting a compound of formula 1:
NC\)J\OAII
under suitable anion sation conditions.
In some ments, suitable anion condensation conditions comprise l) reacting the
compound of formula 1 with a base, in the presence of a solvent, to generate the anion of the
compound of formula 1; and 2) reacting the anion of the compound of formula 1 with
trichloroacetonitrile. In still other ments, the base is potassium acetate. In yet another
embodiment, the solvent is an alcohol. In other embodiments, the solvent is isopropylalcohol.
One embodiment of the present invention comprises a s for preparing a compound
of formula I-A:
NH2 0 /N R2
"l / / N \ /
N H R3
g\ R4 //N
comprising reacting a compound of formula 9:
NH2 0 /N R2
N\ / / N \ /
HN H R3
NH2 R4
WO 85132
under suitable condensation conditions to form a pyrimidine ring, wherein R1, R2, R3 and R4
are as defined herein.
In some embodiments, suitable condensation conditions to form a dine ring
comprise reacting the compound of a 9 with a electrophilic species in the presence of a
solvent. In another embodiment, the 1,3—dielectrophilic species is selected from 1,3—dialdehyde or
3-(dialkylamino)-prop-2—enal. In still other embodiments, the solvent is selected from DMF or
DMSO in water. In other embodiments, the 1,3-dielectrophilic species is generated in situ from a
protected 1,3—dielectrophilic species. In another embodiment, the 1,3—dielectrophilic s is
generated from a ketal in the ce of a sulfonic acid. In yet another embodiment, the sulfonic
acid is PTSA.
r embodiment of the present invention comprises a s for preparing a
compound of formula 9:
by reacting a compound of formula 8:
NMH R3
under suitable condensation conditions to form a pyrazole ring.
In some embodiments, suitable condensation conditions to form a pyrazole ring comprise
l) reacting the compound of formula 8 with a base, in the presence of a solvent, to generate the anion
of the compound of formula 8; 2) reacting the anion with trichloroacetonitrile; and 3) reacting the
product from 2) with a hydrazine or hydrazine hydrate in the presence of an aprotic solvent. In
another ment, the aprotic solvent is NMP or DMF. In some embodiments, the base is
selected from sodium acetate or potassium acetate.
Yet another embodiment comprises a process for preparing a compound of formula 8:
O N 2
/ R
g/l/
by reacting a compound of formula 7:
NC\/[(
under suitable conditions to form an amide bond.
In some examples, the suitable ions for forming the amide bond ses ng
the compound of formula 7 with a substituted 3-amino pyridine with an amide coupling agent in the
presence of an aprotic solvent and an organic base. In other examples, the aprotic solvent is selected
from NMP or DMF. In another embodiment, the organic base is an aliphatic amine. In still other
embodiments, the organic base is independently selected from triethylamine or DIPEA. In yet
another embodiment, the amide coupling agent is independently selected from TBTU or TCTU.
Synthesis of Compound 1-1
Another aspect of the present invention provides a s of preparing a compound of
formula 1-1:
comprising the step of reacting the compound of formula 30
NH2 0 /N
N N
<\ /N .HCl
O OH
with a compound of formula 25:
WO 85132
under suitable conditions to form an amide bond.
Still other embodiments of the t invention comprise provides a process for preparing
the compound of formula 30:
%QNH2 0 /
209IN
by reacting the compound of formula 28:
under suitable deprotection conditions to form the carboxylic acid.
Another embodiment provides a process for preparing a compound of formula 28:
NHZO /|
N\// N\ F
N N
[>\//N
o o
by reacting the compound of formula 621*:
NH2 0 N:N
N / 0’
MN CI
with a compound of formula 27:
H2N F
under le conditions to form an amide bond.
In some embodiments, suitable conditions for forming the amide bond comprise reacting
the compound of formula 30 with the compound of formula 25 in the ce of an amide coupling
partner, an aprotic solvent, and a base. In other embodiments, the aprotic solvent is independently
selected from NMP, DMF, or tetrahydrofuran. In still other embodiments, the aprotic solvent is
ydrofuran. In another embodiment, the base is an aliphatic amine. In yet another embodiment,
the base is DIPEA. In some embodiments, the amide coupling partner is independently selected
from CDI, TBTU or TCTU. In one or more embodiments, the amide coupling partner is TCTU. In
yet r embodiment, the amide coupling partner is CD1.
In other embodiments, suitable deprotection conditions comprise reacting the compound of
WO 85132
a 28 with an acid in the presence of a solvent. In some embodiments, the acid is HCl. In
another ment, the solvent is l,4-dioxane.
In yet another embodiment, suitable conditions for forming the amide bond comprise
ng the compound of formula 621* with the compound of formula 27 in an aprotic solvent under
heat. In still other embodiments, the aprotic solvent is independently selected from NMP, pyridine,
or DMF. In another embodiment, the aprotic solvent is pyridine. In some embodiments, the reaction
is carried out at a temperature of at least 80°C.
Another aspect of the present invention provides a process of preparing a compound of
formula 27:
F/NH2
comprising the step of reacting a compound of formula 26:
F /Br
09.x
under le conditions to form an amine.
In some embodiments, suitable conditions to form an amine comprise reacting the
compound of formula 27 under Buchwald-Hartwig amination conditions, known to those skilled in
the art.
Yet another ment provides a process for ing a compound of formula 26:
WO 85132
F Br
0 0k
by 1) reacting a compound of formula 18:
F Br
under suitable halogen ge conditions to generate the compound of formula 32
F Br
32 and
2) ng the compound of formula 32:
F Br
with a compound of formula 22:
0 OX
under suitable displacement conditions.
In some embodiments, suitable halogen exchange ions comprise reacting the
compound of formula 18 with potassium fluoride in the presence of an aprotic solvent and a phase
er catalyst. In other embodiments, the aprotic solvent is independently selected from DMSO,
DMF, or sulfolane. In still other embodiments, the phase transfer catalyst is Me4NCl. In still other
embodiments, suitable displacement conditions comprise reacting the compound of formula 32 with
2014/068713
a compound of formula 22 in the presence of a base. In another embodiment, the base is an aliphatic
amine. In some embodiments, the aliphatic amine is DIPEA.
Other embodiments of the present invention provides a process for preparing a compound
of formula 18:
by reacting the compound of formula 31:
under suitable halogenation conditions.
In some embodiments, suitable halogenation conditions comprise l) reacting the
compound of formula 31 with a base to generate an anion; and 2) reacting the anion with a
chlorinating agent. In yet another embodiment, the base is LDA. In r embodiment, the
chlorinating agent is l, l , l,2,2,2-hexachloroethane.
Some embodiments of the present ion provides a process for preparing a nd
of a I-1:
3%;NH2 0 /
ONTO
comprising the step of reacting the compound of formula 33:
with a compound of formula 25:
under le conditions to form an amide bond.
In some embodiments, suitable conditions for forming the amide bond comprise ng
the nd of formula 33 with the compound of formula 25 in the presence of an amide coupling
partner, an aprotic solvent, and a base. In other embodiments, the aprotic solvent is independently
selected from NMP, DMF, or tetrahydrofuran. In still other embodiments, the aprotic t is
tetrahydrofuran. In another embodiment, the base is an aliphatic amine. In yet another ment,
the base is DIPEA. In some embodiments, the amide coupling partner is independently selected
from TBTU or TCTU. In one or more embodiments, the amide coupling partner is TCTU.
Yet another embodiment provides a process for preparing a compound of formula 33:
comprising the step of reacting the compound of formula 28:
NHZO /|
M V F
N N
[>\ //N
O O
under suitable deprotecting conditions.
In some embodiments, suitable deprotecting ions for cleaving the tert-butyl ester
comprise ng the compound of formula 28 with an acid in the presence of a solvent. In one
embodment, the acid is selected from, but not limited to, esulphonic acid (preferred), PTSA,
TFA, or HCl. In still other embodiments, the solvent is selected from, but is not limited to, 1,4-
dioxane or acetonitrile. In another embodiment, the solvent is acetonitrile.
Another embodiment provides a process for ing a compound of formula 43:
comprising the steps of:
a) reacting a compound of formula 35:
RMOWCLR"
,O O\
R° R°
wherein R0 is C1_6aliphatic,
under acidic conditions to form a compound of formula 36:
HOVH
b) reacting a compound of formula 36 with an electrophilic fluorinating agent to
form a compound of formula 38:
HOVH
c) reacting a compound of a 38 with a compound of formula 3:
o—\:
under suitable sation conditions to form the compound of formula 43.
In some embodiments, R0 is independently selected from methyl, ethyl, propyl, isopropyl,
butyl, and pentyl. In still other embodiments, RO is independently selected from methyl or ethyl.
In another ment, the ophilic fluorinating agent is l-(Chloromethyl)fluoro-
l,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate. In other embodiments, the electrophilic
fluorinating agent is fluorine gas.
In yet r embodiment, the suitable condensation conditions comprise reacting the
compound of formula 38 With the compound of formula 3 in the presence of a solvent and heat. In
some ments, the solvent is selected from DMF or DMSO.
Yet another embodiment provides a process for preparing a compound of formula I-1:
gig?
ONTO
comprising the steps of:
a) reacting the compound of formula 63*:
NHZO NZN
W/ O
<> /,N CI
with a compound of formula 27:
O 0%
under suitable amide bond formation conditions to form a compound of formula 28:
NHZO /|
NH V F
N N
S\ //N
b) ing the compound of formula 28 using a suitable palladium sequestering agent;
c) reacting the nd of formula 28 under suitable deprotection conditions to form a
compound of formula 30
NHZQ /NI
”3/ n F
N N
<\ /N .HCl
O OH
; and
d) reacting the compound of formula 30 with a compound of formula 25:
under le amide bond ion conditions to form the compound of formula 1-1.
In some embodiments, the suitable palladium sequestering agent is independently selected
from propane-1,2-diamine; ethane-1,2-diamine; ethane-1,2-diamine; propane-1,3-diamine;
tetramethylethelenediamine; ethylene glycol; l,3-bis(diphenylphosphanyl)propane; 1,4-
bis(diphenylphosphanyl)butane; and s(diphenylphosphanyl)ethane/Pr-1,2-diamine. In still
other embodiments, the suitable palladium sequestering agent is propane-1,2-diamine.
Another embodiment provides a process for ing a compound of formula 28:
NHZQ /N|
N’/ V F
N N
[>\ //N
o o
comprising the steps of:
a) reacting the compound of formula Sa
NH2 0
N OH
under suitable halogenation conditions to form a compound of formula 34:
NH2 0
N/ X
wherein X is halogen;
b) reacting the compound of a 34 with a compound of formula 27:
under suitable amide bond ion conditions to form a compound of formula 28.
In some embodiments X is independently ed from fluoro or chloro. In another
embodiment, X is chloro. In some embodiments, the suitable halogenation conditions comprise
reacting the compound of formula 521 with a halogenating agent and a base in the presence of a
solvent. In yet another embodiment the nating agent is SOClz. In some embodiments, the
base is triethylamine. In still other embodiments, the solvent is DCM.
Yet another aspect of the present invention provides a process for ing a compound of
formula I-l:
gig?
ONTO
comprising the steps of:
a) reacting the compound of formula Sa
NH2 0
N OH
under suitable halogenation conditions to form a compound of a 34:
NH2 0
N/ x
wherein X is halogen;
b) reacting the compound of formula 34 with a compound of formula 27:
O OJ<
under suitable amide bond formation conditions to form a nd of formula 28:
NHZO /|
NH V F
N N
S\ //N
c) reacting the compound of formula 28 under suitable deprotection conditions to form a
compound of formula 30
NHZQ /N|
N/ N F
\ / H
N N
<\ /N .HCl
0 OH
d) reacting the compound of formula 30 with a compound of formula 25:
under le amide bond formation conditions to form the compound of formula I-1.
Deuterated Compounds
In another embodiment, Isotopes can be introduced into compound 1-1 by selecting
building blocks that contain the ic atoms (either commercially available or that can be prepared
according to processes known to those skilled in the art) and engaging them into a sequence similar
to the one reported for the unlabelled material.
Another aspect of the present invention provides a compound of Formula I-B:
or a ceutically able salt thereof, wherein:
each Y1 Y2 Y3 Y4 Y5 Y6 Y7 Y8 Y9 Y10 Y“ Y12 YB Y14 Y15 Yrs Y17 Y18 and Y19 is
independently hydrogen or deuterium; provided at least one of Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9,
Y10,Y11,Y12, Y”, Y14,Y15,Y16,Y17,Y18, and Y” is deuterium
each X1, X2, X4, X5, X6, X7, X8, and X9 is independently selected from 12C or 13C; and
X3 is independently selected from —12C(O)— or —13C(O)—.
The following labeled building blocks, which can be used in the tic route for
preparing the compound of formula I-B, are all commercially available:
0 2,2,3,3,5,5,6,6—octadeuteropiperazine;
0 2,3,5,6-tetra-13C-piperazine;
0 2,2,3,3,4,5,5,6,6—nonadeuteropiperidine—4—carboxylic acid;
0 l, 2—Di13Ccyanoacetic acid;
o 2-cyano(13C)acetic acid ethyl ester; and
o 2—13C—2—cyano(13C)acetic acid ethyl ester.
Other labeled building , which may be utilized in the synthetic route for preparing a
compound of formula I-B, are known to those skilled in the art. These may include, but are not
limited to, the following labeled building blocks:
0 2—13C-oxetan—3—one;
0 3—13C—oxetan—3—one;
0 2,2,3 ,3 -tetradeuteropiperazine;
0 2,2,5,5-tetradeuteropiperazine;
0 4—deuteropiperidinecarboxylic acid ethyl ester;
0 2—cyano(13C)acetic acid;
0 1—13C—2—cyanoacetic acid;
0 2-13Ccyanoacetic acid; and
0 l-deutero-3 -(diethylamino)-2—fluoroacrylaldehyde;
In one or more embodiments, Y”, Y13 and Y19 are deuterium, and
, Y”, Y”, Y16, Y”, Y”,
Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, and Y11 are independently selected from en or
deuterium. In another embodiment, Y”, Y”, Y”, Y”, Y16, Y”, Y”, and Y19 are ium, and Y1,
Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y“), and Y“ are hydrogen.
In yet r embodiment, X1, X2, X4, X5, X6, X7, X8, and Xgare 12C; and
X3 is -12C(O)-. In still other embodiments, X1, X4, X5, X6, X7, X8, and X9 are 12C; X3 is -13C(O)-;
and X2 is 13 C.
In some embodiments, Y“, Y”, Y”, Y”, Y”, Y16, Y”, Y”, and Y19 are deuterium, and
Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, and Y10 are independently selected from hydrogen or deuterium.
In other embodiments, Y“, Y”, Y”, Y”, Y”, Y16, Y17, Y18, and Y19 are deuterium, and Y1, Y2, Y3,
Y4, Y5, Y6, Y7, Y8, Y9, and Y10 are hydrogen.
In yet another embodiment, Y2, Y”, Y”, Y”, Y”, Y16, Y17, Y18, and Y19 are deuterium,
and Y1, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, and Y11 are independently selected from hydrogen or
deuterium. In another aspect of the invention, Y2, Y”, Y13 and Y19 are
, Y”, Y”, Y16, Y”, Y”,
deuterium, and Y1, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, and Y11 are hydrogen.
In some embodiments, Y”, Y13 and Y19 are deuterium, and Y1, Y2, Y3, Y4, Y5, Y6,
, Y18,
Y7, Y8, Y9, Ylo, Y“, Y”, Y”, Y16, and Y17 are en or deuterium. In still other embodiments,
Y”, Y”, Y”, and Y” are deuterium, and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y”, Y“, Y”, Y”, Y”,
and Y17 are hydrogen.
In one or more embodiments, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, and Y11 are deuterium, and
Y1, Y2, Y”, Y13 , Y”, Y”, Y”, Y”, Y”, and Y19 are independently selected from deuterium or
hydrogen. In another embodiment, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, and Y11 are deuterium, and Y1,
Y2, Y”, Y”, Y”, Y”, Y”, Y”, Y”, and Y” are hydrogen.
In yet another ment, Y2 and Y11 are deuterium, and Y1, Y3, Y4, Y5, Y6, Y7, Y8, Y9,
Ylo, Y”, Y”, Y”, Y”, Y16, Y”, Y18, and Y19 are deuterium or hydrogen. In other embodiments, Y2
and Y11 are deuterium, and Y1, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y”, Y”, Y”, Y”, Y”, Y”, Y”, Y”, and
Y19 are hydrogen.
In some embodiments, Y2 is deuterium, and Y1, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y“), Y“, Y”,
Y13 and Y19 are deuterium or hydrogen. In another embodiment, Y2 is
, Y”, Y”, Y16, Y”, Y”,
deuterium, and Y1, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y”, Y“, Y”, Y”, Y”, Y”, Y”, Y”, Y”, and Y” are
hydrogen.
In still other embodiments, X1, X2, X4, X5, X6, X7, and X8 are 12C; X3 is -12C(O)-; and X9
is 13C. In another ment, X1, X2, X8, and Xgare 12C; X3 is -12C(O)-; and X4, X5, X6, and X7 are
13C. In yet another embodiment, X2, X4, X5, X6, X7, X8, and X9 are 12C; X3 is )-; and X1 is
13C. In other embodiments, X2, X4, X5, X6, X7, and X9 are 12C; X3 is -13C(O)-; and X1 and X8 are
13C.
In some embodiments, Y11 is deuterium, and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y“), Y”,
Y13 and Y19 are ndently ed from hydrogen or deuterium. In
, Y”, Y”, Y”, Y”, Y”,
another embodiment, Y11 is deuterium, and Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Ylo, Y”, Y13
, Y”,
Y”, Y16, Y”, Y”, and Y19 are hydrogen.
In yet another embodiment, X1, X4, X5, X6, X7, X8, and X9 are 12C; X3 is -12C(O)-; and X2
is ”C.
In another example, the compounds of formula I-B of this ion are represented in
Table 1. It will be appreciated by those skilled in the art that the compounds of the present invention
2014/068713
may be represented in varying tautomeric forms.
Table 1
1-2 1-3 1-4
1-5 1-6 1-7
1-8 1-9 1-10
NH2 NH NH
13I O 2
/N A II0 2
/N O
4C 1.3C /l /N
N / N /13C / /13 A
x N C
N/ N \ N \ N \ /
H N—/( H H
F F N—/< F
<\ N N < N N < N N
/ \ / \ /
F D F F
DD D
o o o
K/N“W WD
Dig/N D K/N”V
b Do b
o o b0
I-11 I-12 I-13
136; :9 /N
N” 130‘
x / N \ /
N H
1-14
Solid Forms
Another aspect of the present invention provides a solid form of a compound of formula I-
3thNH2 0 /
n the form is selected from the group consisting of Compound I-1° ethanol solvate,
Compound I-1° hydrate 1, Compound I-1° hydrate 11, Compound I-1° ous form A, Compound
2014/068713
I-1° anhydrous form B, Compound I-1° ous form C, Compound I-1° DMSO solvate,
Compound I-1° DMAC solvate, Compound I-1° acetone solvate, and Compound I isopropanol
solvate.
Compound I-I° ethanol e
In some aspects of the present inventions, the solid form is Compound I ethanol
solvate. In another aspect of the t ion, the solid form is crystalline Compound I-1°
ethanol solvate. In still other embodiments, crystalline nd I-1° ethanol solvate has a
Compound I-1 to ethanol ratio of about 1:0.72. In another aspect of the present invention, the
crystalline nd I-1° ethanol solvate is characterized by a weight loss of from about 5.76% in a
temperature range of from about 166°C to about 219°C. In yet r aspect of the present
invention, the crystalline Compound I-1° ethanol solvate is characterized by one or more peaks
expressed in 2—theta :: 0.2 at about 17.2, 19.7, 23.8, 24.4, and 29.0 degrees in an X—Ray powder
ction pattern obtained using Cu K alpha radiation. In other embodiments, the crystalline
Compound I-1° ethanol solvate is characterized as having an X-ray powder diffraction pattern
substantially the same as that shown in Figure 1a. In still other embodiments, the crystalline
Compound I-1°ethanol solvate is characterized as having one or more peaks corresponding to 175.4
:: 0.3 ppm, 138.0 :: 0.3 ppm, 123.1 :: 0.3 ppm, 57.8 :: 0.3 ppm, 44.0 :: 0.3 ppm, and 19.5 :: 0.3 ppm
in a C13 ssNMR spectrum. In yet another ment, the crystalline Compound I-1°ethanol solvate
is characterized as having one or more peaks corresponding to —136.0 :: 0.3 ppm and —151.6 :: 0.3
ppm in an F19 ssNMR spectrum.
Compound I-I° hydrate I
In some aspects of the present invention, the solid form is Compound I hydrate I. In
another aspect of the present ion, the solid form is crystalline Compound I-1° hydrate I. In still
other embodiments, the crystalline Compound I-1° hydrate I has a compound I-1 to H20 ratio of
about 1:45. In yet another embodiment, crystalline Compound I-1° hydrate I is characterized by a
weight loss of from about 14.56% in a temperature range of from about 25°C to about 100°C. In
other embodiments, crystalline Compound I-1° e I is characterized by one or more peaks
expressed in 2—theta :: 0.2 at about 6.5, 12.5, 13.7, 18.8, and 26.0 degrees in an X—Ray powder
diffraction pattern obtained using Cu K alpha radiation. In another embodiment, crystalline
Compound I-1° hydrate I is characterized as having an X-ray powder diffraction pattern substantially
the same as that shown in Figure 1b.
Compound I-I °hydrate II
In some s of the present ion, the solid form is nd I e II. In
another aspect of the present invention, the solid form is crystalline Compound I-1° e II. In
other embodiments, crystalline Compound I-1° hydrate II is characterized by one or more peaks
expressed in 2-theta :: 0.2 at about 10.1, 11.3, 11.9, 20.2, and 25.1 degrees in an X-Ray powder
diffraction pattern obtained using Cu K alpha radiation. In still other embodiments, the crystalline
Compound Ihydrate II is characterized as having one or more peaks corresponding to 177.0 :: 0.3
ppm, 158.2 0.3 ppm, 142.9 0.3 ppm, 85.1: 0.3 ppm, 58.9 0.3 ppm, and 31.9 0.3 ppm in a C13
ssNMR spectrum. In yet another embodiment, the lline Compound I-1°hydrate II is
characterized as having one or more peaks corresponding to —138.0 :: 0.3 ppm and —152.7 :: 0.3 ppm
in an F19 ssNMR spectrum.
Compound I-I° anhydrousform A
In one embodiment, the solid form is Compound I-1° anhydrous form A. In another
embodiment, the solid form is crystalline Compound I-1° anhydrous form A. In still other
embodiments, crystalline Compound I-1° anhydrous form A is characterized by a weight loss of
from about 0.96 % in a temperature range of from about 25°C to about 265°C. In other
embodiments, crystalline Compound I-1° anhydrous form A is characterized by one or more peaks
expressed in 2—theta :: 0.2 at about 6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X—Ray powder
diffraction pattern obtained using Cu K alpha radiation. In yet another embodiment, the crystalline
Compound I-1° anhydrous form A is characterized as having an X-ray powder ction pattern
substantially the same as that shown in Figure 1c. In still other embodiments, the crystalline
Compound Ianhydrous form A is characterized as having one or more peaks corresponding to
175.9 0.3 ppm, 138.9 0.3 ppm, 74.1 0.3 ppm, 42.8 0.3 ppm, and 31.5: 0.3 ppm in a c13
ssNMR spectrum. In yet another embodiment, the crystalline Compound I-1°anhydrous form A is
characterized as having one or more peaks corresponding to —136.8 :: 0.3 ppm and —155.7 :: 0.3 ppm
in an F19 ssNMR spectrum. One embodiment describes a process for preparing Compound I-
1°anhydrous form A sing ng a suspension ning Compound I-1°ethanol solvate and
a suitable organic solvent. In another ment, the suitable organic solvent is tetrahydrofuran.
Another aspect of the invention describes a process for preparing Compound I-1°anhydrous form A
comprising stirring a suspension containing Compound orphous, isopropanol, and water. In
some embodiments, the suspension is heated to between about 65°C and about 80°C. In yet another
ment, the suspension is heated to between about 70°C and about 75°C. In other
embodiments, nd I-1°anhydrous form A is characterized as a crystal form of Compound I-1
having a monoclinic crystal system, a P21/c symmetric space group, and the following unit cell
parameters:
a = 15.29(3)A 0t = 900
b = 2)A [3: (3)O
c = 14.48(3)A y = 90°.
Compound I-I° anhydrousform B
As used herein, “anhydrous form B” refers to the THF solvate form of Compound I-1. In
some embodiments, the solid form is Compound I anhydrous form B. In another ment,
the solid form is crystalline Compound I-1° anhydrous form B. In yet another embodiment
crystalline Compound I-1° anhydrous form B is characterized by a weight loss of from about 2.5 %
in a temperature range of from about 25°C to about 175°C. In other embodiments, Compound I-1°
anhydrous form B is terized by one or more peaks sed in 2-theta :: 0.2 at about 7.2, 8.3,
12.9, 19.5, and 26.6 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha
radiation. In still other embodiments, crystalline Compound I-1° anhydrous form B is characterized
as haVing an X-ray powder diffraction pattern substantially the same as that shown in Figure Id. In
still other embodiments, the crystalline Compound I-1°anhydrous form B is characterized as haVing
one or more peaks corresponding to 173.4 :: 0.3 ppm, 164.5 :: 0.3 ppm, 133.5 :: 0.3 ppm, 130.8 :: 0.3
ppm, 67.7 :: 0.3 ppm, 45.3 :: 0.3 ppm, and 25.9 :: 0.3 ppm in a C13 ssNMR spectrum. In yet another
embodiment, the crystalline Compound I-1°anhydrous form B is characterized as haVing one or more
peaks ponding to —138.0 :: 0.3 ppm and —153.5 :: 0.3 ppm in an F19 ssNMR um.
Compound I-I° anhydrousform C
In some embodiments, the solid form is Compound I anhydrous form C.
In another embodiment, the solid form is crystalline Compound I-1° anhydrous form C. In other
embodiments, crystalline Compound I-1° anhydrous form C is characterized by one or more peaks
expressed in a :: 0.2 at about 6.8, 13.4, 15.9, 30.9, and 32.9 degrees in an X—Ray powder
diffraction pattern obtained using Cu K alpha radiation. In still other embodiments, lline
Compound I-1° anhydrous form C is characterized as haVing an X-ray powder diffraction pattern
substantially the same as that shown in Figure 1e. In still other embodiments, the crystalline
Compound I-1°anhydrous form C is characterized as haVing one or more peaks corresponding to
175.2 :: 0.3 ppm, 142.5 :: 0.3 ppm, 129.6 :: 0.3 ppm, 73.5: 0.3 ppm, 54.0 :: 0.3 ppm, and 46.7 :: 0.3
ppm in a C13 ssNMR spectrum. In yet another embodiment, the crystalline Compound I-
2014/068713
1-anhydrous form C is terized as having one or more peaks corresponding to —131.2 :: 0.3 ppm
and —150.7 :: 0.3 ppm in an F19 ssNMR spectrum.
Compound I-I hous
In some embodiments, the solid form is Compound I amorphous. In another
embodiment, the solid form is crystalline Compound I-1° amorphous. In still other embodiments,
the crystalline Compound I-1°amorphous is characterized as having one or more peaks
corresponding to 173.8 :: 0.3 ppm, 144.2 :: 0.3 ppm, 87.5 :: 0.3 ppm, 45.6 :: 0.3 ppm, and 29.5 :: 0.3
ppm in a C13 ssNMR spectrum. In yet another embodiment, the crystalline Compound I-
1-amorphous is characterized as having one or more peaks corresponding to —137.7 :: 0.3 ppm and —
153.1 :: 0.3 ppm in an F19 ssNMR spectrum.
nd I-I° DMSO solvate
In one embodiment, the solid form is Compound I DMSO e. In another
embodiment, the solid form is crystalline Compound I-1° DMSO solvate. In still other
embodiments, the crystalline Compound I-1° DMSO solvate has a nd I-1° to DMSO ratio of
about 1:1. In yet another embodiment, crystalline Compound I-1° DMSO solvate is characterized by
a weight loss of from about 12.44% in a temperature range of from about 146°C to about 156°C. In
some embodiments, crystalline Compound I-1° DMSO solvate characterized by one or more peaks
expressed in 2-theta :: 0.2 at about 8.9, 14.8, 16.5, 18.6, 20.9, 22.2, and 23.4 degrees in an X-Ray
powder diffraction pattern obtained using Cu K alpha radiation. In other embodiments, compound I-
DMSO solvate is characterized as having an X-ray powder diffraction pattern substantially the
same as that shown in Figure 1g.
Compound I-I° DMAC solvate
In some embodiments, the solid form is Compound I DMAC e. In another
embodiment, the solid form is crystalline Compound I-1° DMAC solvate. In other embodiments, the
crystalline Compound I-1° DMAC solvate has a compound I-1 to DMAC ratio of about 1:13. In yet
another embodiment, crystalline compound I-1° DMAC solvate is characterized by a weight loss of
from about 17.76% in a temperature range of from about 85°C to about 100°C. In still other
embodiments, compound I-1° DMAC solvate is characterized by one or more peaks sed in 2—
theta :: 0.2 at about 6.0, 15.5, 17.7, 18.1, 20.4, and 26.6 degrees in an X-Ray powder diffraction
pattern obtained using Cu K alpha radiation. In some embodiments, compound I-1° DMAC solvate
is terized as having an X-ray powder diffraction n substantially the same as that shown
in Figure 1h.
Compound I-I° acetone solvate
In one or more ents, the solid form is Compound I acetone solvate. In another
embodiment, the solid form is crystalline Compound I-1° acetone solvate. In yet r
embodiment, the crystalline Compound I-1° acetone solvate has a compound I-1 to acetone ratio of
about 1:0.44. In still other embodiment, Compound I-1° acetone solvate is characterized by a weight
loss of from about 4.55% in a temperature range of from about 124°C to about 151°C. In some
embodiments, Compound I-1° acetone e is characterized by one or more peaks expressed in 2—
theta :: 0.2 at about 8.9, 15.5, 15.8, 16.7, 22.3, 25.7, and 29.0 s in an X-Ray powder diffraction
pattern obtained using Cu K alpha radiation. In other embodiments, Compound I-1° acetone solvate
is characterized as haVing an X-ray powder ction pattern substantially the same as that shown
in Figure 1i.
Compound I-I° isopropanol solvate
In one ment, the solid form is Compound I isopropanol solvate. In another
embodiment, the solid form is crystalline Compound I-1° panol solvate. In still other
embodiments, crystalline nd I-1° isopropanol solvate has a Compound I-1 to isopropanol
ratio of about . In yet another embodiment, Compound I-1° isopropanol solvate is
characterized by a weight loss of from about 3.76% in a temperature range of from about 136°C to
about 180°C. In some embodiments, Compound I-1° isopropanol solvate is characterized by one or
more peaks expressed in 2—theta :: 0.2 at about 6.9, 17.1, 17.2, 19.1, 19.6, 23.7, 24.4, and 28.9
degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation. In another
embodiment, Compound I-1° isopropanol solvate is characterized as haVing an X-ray powder
diffraction pattern substantially the same as that shown in Figure 1j.
Formulation
Some embodiments disclosed herein lly relate to a composition that can e an
effective amount of Compound I-1, or a pharmaceutically acceptable salt thereof; and one or more
excipients. Compound I-1 is believed to be an ATR inhibitor, and described in ,
which is hereby incorporated by reference in its entirety.
Compound I-1 and Form A can exist in free form or as a salt. Those salts that are
pharmaceutically acceptable can be useful in administering Compound I-1 or Form A for medical
purposes. Salts that are not pharmaceutically acceptable can be useful for manufacturing, isolating,
ing and/or separating stereoisomeric forms of Compound I-1, Form A and/or one or more
intermediates thereof
As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound,
which are, within the scope of sound medical judgment, suitable for use in humans and lower
animals without undue side effects, such as, toxicity, tion, allergic response and the like, and are
commensurate with a reasonable t/risk ratio. Various ceutically acceptable salts can be
used. For example, those salts disclosed in S. M. Berge et al., J. Pharmaceutical Sciences, 1977, 66,
l-l9, which is hereby incorporated by reference. Pharmaceutically acceptable salts of the
compounds described herein include those derived from suitable inorganic and organic acids and
bases. A salt of a compound described herein (for example, Compound I-l) can be ed in situ
during the final isolation and purification of the compound.
As described above, Compound I-1 can exist in ent rphic forms (i.e., “solid
forms”). Polymorphism is the ability of a compound to exist as more than one distinct lline or
"polymorphic" s, wherein each species has a ent arrangement of its molecules in the
crystal lattice. Each distinct crystalline species is a “polymorph.” Each polymorph has the same
chemical formula, however, can be display ent physical property(ies) as a result of its different
arrangement in the crystal lattice. Polymorphs can be characterized by analytical methods such as X—
ray powder diffraction (XRPD) pattern, thermogravimetric analysis (TGA), differential scanning
calorimetry (DSC), melting point, and/or other techniques known in the art.
Form A, described herein, can be in pure form or in a mixture with other materials.
Examples of other materials e, for e, other forms of Compound I-1 (such as amorphous
forms, other polymorphic forms, solvates and hydrates); other diastereomers of Compound I-l;
and/or other materials besides Compound LL
Thus, in some embodiments, a composition can include an effective amount of pure Form
A. As used herein, “pure” Form A is over 95% (w/w) (wherein w/w is weight of Form A/weight of
Compound I-1 (wherein weight of Compound I-1 is weight of Form A + weight of all other forms of
Compound I-1)), for example, over 98% (w/w), over 99% (w/w %), over 99.5% (w/w %), or over
99.9% (w/w %). In some embodiments, a composition can include an effective amount of Form A in
an amount at least 95% (w/w %), at least 97% (w/w %) or at least 99% (w/w %) free of any other
diastereomers of Compound I-1. In some embodiments, a composition can include an effective
amount of Form A in an amount at least 95% (w/w %), at least 97% (w/w %) or at least 99% (w/w
%) free of any other polymorphs and amorphous forms of Compound LL
In some embodiments, a ition can include Form A with one or more other forms of
Compound I-1. Other forms of Compound I-1 include, for example, hydrates, solvates, amorphous
forms, other rphic forms, or combinations thereof.
In some embodiments, a composition can include an amount of Compound I-1 or Form A
(or a pharmaceutically acceptable salt of the aforementioned compounds) in the range of a trace
amount (0.1%) up to 100% (w/w %) relative to the total weight of the composition. In some
embodiments, a composition can include less than about 50% of Compound I-1 or Form A relative
to the total weight of the composition (wherein the total weight includes the weight of Compound I-1
or Form A). For example, a composition can e an amount of Compound I-1 or Form A in a
range selected from 0.1% — 0.5%, 0.1% — 1%, 0.1% — 2%, 0.1% — 5%, 0.1% — 10%, 0.1% — 20%, 0.1%
— 30%, 0.1% — 40%, and 0.1% — <50% (w/w %) ve to the total weight of the composition
(wherein the total weight includes the weight of Compound I-1 or Form A). In other embodiments, a
composition can include equal to or r than about 50% of Compound I-1 or Form A relative to
the total weight of the composition in the total weight includes the weight of Compound I-1 or
Form A). For example, a composition can include at least 50%, 60%, 70%, 80%, 90%, 95%, 97%,
98%, 99%, 99.5% or 99.9% (w/w) of Compound I-1 or Form A relative to the total weight of the
composition (wherein the total weight includes the weight of Compound I-1 or Form A). In some
embodiments, a composition can include an amount of Compound I-1 or Form A in the range of
about 1 wt% to about 50 wt%; about 5 wt% to about 40 wt%, about 5 wt% to about 25 wt% or about
wt% to about 15 wt% of Compound I-1 or Form A relative to the total weight of the composition
(wherein the total weight includes the weight of Compound I-1 or Form A).
As used herein, an “excipient” is used herein in its ordinary sense as understood by those
skilled in the art, and includes one or more inert substances that are ed in a composition to
provide, t limitation, bulk, consistency, stability, binding ability, lubrication, egrating
ability etc., to the composition. Examples of excipients include , binders, disintegrants, wetting
agents, ants, ts, ants and absorbants.
] In some embodiments, a composition can include Compound I-1 or Form A and one or
more other components selected from one or more fillers, one or more binders, one or more
disintegrants, one or more wetting agents and one or more lubricants. In some embodiments, a
composition can include an amount of one or more fillers in the range of about 10 wt% to about 95
wt%; about 25 wt% to about 90 wt%; about 50 wt% to about 90 wt%; or about 70 wt% to about 90
wt% of the filler(s) by total weight of the composition (wherein the total weight includes the weight
of one or more fillers). In some embodiments, a composition can include an amount of one or more
lubricants in the range of about 0.1 wt% to about 10 wt%, about 0.5 wt% to about 7 wt%, or about 1
wt% to about 5 wt% of the lubricant(s) by total weight of the composition (wherein the total weight
includes the weight of one or more lubricants). In some embodiments, a composition can include an
amount of one or more disintegrants in the range of about 1 wt% to about 15 wt%, about 1 wt% to
2014/068713
about 10 wt%, or about 1 wt% to about 7 wt% of the disintegrant(s) by total weight of the
composition (wherein the total weight includes the weight of one or more disintegrants).
The g , binders, disintegrants, lubricants and fillers suitable for inclusion can
be ible with the ingredients of the compositions, for e, they do not substantially reduce
the chemical stability of the active pharmaceutical ingredient(s).
The term “wetting agent” is used herein in its ordinary sense as understood by those
skilled in the art, and includes surfactants, such as non-ionic surfactants and anionic surfactants.
Wetting agents can enhance the solubility of the composition. Exemplary surfactants include sodium
lauryl sulfate (SLS), polyoxyethylene sorbitan fatty acids (e. g., TWEENTM), sorbitan fatty acid esters
(e.g., Spans®), sodium dodecylbenzene sulfonate (SDBS), dioctyl sodium sulfosuccinate (Docusate),
dioxycholic acid sodium salt (DOSS), an monostearate, an tristearate, sodium N-
lauroylsarcosine, sodium oleate, sodium myristate, sodium stearate, sodium palmitate, Gelucire
44/ 14, ethylenediamine tetraacetic acid (EDTA), Vitamin E d-alpha tocopheryl polyethylene glycol
1000 succinate (TPGS), Lecithin, MW 677—692, Glutanic acid dium monohydrate, Labrasol,
PEG 8 caprylic/capric glycerides, utol, diethylene glycol monoethyl ether, Solutol HS-15,
polyethylene glycol/hydroxystearate, Taurocholic Acid, copolymers of polyoxypropylene and
polyoxyethylene (e. g., poloxamers also known and commercially available under Pluronics®, such
as, Pluronic® L61, ic® F68, ic® F108, and Pluronic® F127), ted polyglycolized
glycerides (Gelucirs®), docusate sodium, polyoxyethylene an fatty acid esters,
polyoxyethylene 20 stearyl ethers, polyoxyethylene alkyl ethers, yethylene castor oil
derivatives, pegylated hydrogenated castor oils, sorbitan esters of fatty acids, Vitamin E or tocol
derivatives, vitamin E TPGS, tocopheryl esters, in, phospholipids and their tives, stearic
acid, oleic acid, oleic alcohol, cetyl alcohol, mono and diglycerides, propylene glycol esters of fatty
acids, glycerol esters of fatty acids, ethylene glycol palmitostearate, polyoxylglycerides, propylene
glycol monocaprylate, propylene glycol monolaurate, polyglyceryl oleate and any combinations
thereof. Sodium lauryl sulfate is an anionic surfactant; and copolymers of polyoxypropylene and
polyoxyethylene are non-ionic tants. Specific examples of copolymers of polyoxypropylene
and polyoxyethylene include poloxamers, such as a poloxamer with a polyoxypropylene molecular
mass of 1,800 g/mol and a 80% polyoxyethylene content (e. g., poloxamer 188).
The term “binder” is used herein in its ordinary sense as understood by those skilled in the
art, and includes agents used while making granules of the active ingredient (for example,
Compound I-1 or Form A), wherein a binder holds the active ingredient together with one or more
inactive agents. Exemplary binders include polyvinyl pyrrolidones (PVPs), pregelatinized starch,
starch, microcrystalline cellulose, modifled cellulose (e. g., hydroxyl propyl methyl cellulose
(HPMC), hydroxypropyl cellulose (HPC) and hydroxy ethyl ose (HEC)), and any combination
thereof. PVP’s are commonly characterized by the “K-value,” which is a ement of the
polymeric composition's viscosity. PVPs can be commercially sed (e. g., Tokyo Chemical
Industry Co., Ltd.) under the trade name of Povidone® K12, Povidone® K17, Povidone® K25,
Povidone® K30, Povidone® K60, and ne® K90. Specific examples of PVPs e soluble
spray dried PVP. PVPs can have an average molecular weight of 3,000 daltons to 4,000 daltons,
such as Povidone® K12 having an average molecular weight of 4,000 daltons. PVP can be used in
either a wet or a dry state.
The term “filler” (or “diluent”) is used herein in its ry sense as understood by those
skilled in the art, and includes microcrystalline celluloses (e.g., ® PH 101), lactoses, sorbitols,
celluoses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like), dextrose,
maltodextrin, sorbitol, xylitol, powdered cellulose, fled microcrystalline cellulose,
methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, pregelatinized
starch, dibasic calcium phosphate, calcium sulfate, calcium carbonate and any combination thereof.
Specific es of fillers include microcrystalline celluloses and lactoses. Specific examples of
microcrystalline celluloses include cially available Avicel® series, such as microcrystalline
celluloses having a particle size of 200 mesh over 70% and a particle size of 65 mesh less than 10%
(e.g., Avicel® PH 101). A specific example of a lactose is lactose drate.
The term “disintegrant” is used herein in its ordinary sense as understood by those skilled
in the art, and can e the dispersal of a composition. Examples of disintegrants e
croscarmellose sodium, starch (e.g., corn starch, potato starch), sodium starch glycolate,
crospovidone, microcrystalline cellulose, sodium alginate, calcium alginate, alginic acid,
pregelatinized starch, cellulose and its tives, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, soy polysaccharide, guar gum, ion exchange resins, an effervescent
system based on food acids and an alkaline carbonate component, sodium bicarbonate and any
combinations thereof. Specific examples of disintegrants include croscarmellose sodium (e. g., Ac—
®) and sodium starch glycolate.
The term “lubricant” is used herein in its ordinary sense as understood by those skilled in
the art, and can improve the compression and ejection of a ition, e. g., through a die press.
Exemplary lubricants include magnesium te, stearic acid in), hydrogenated oils, sodium
stearyl fumarate, sodium lauryl sulfate, talc, fatty acid, calcium stearate, sodium stearate, glyceryl
monostearate, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, leucine,
sodium benzoate and any combination thereof. A specific example of a lubricant is sodium l
fumarate.
Those skilled in the art tand that a specific compound described as a wetting agent,
binder, filler, disintegrant and lubricant can serve one or more purpose. For example,
microcrystalline cellulose can be used as a disintegrant and filler.
In some ments, a composition can include an amount of Compound 1-1 or Form A
in the range of about 5 wt% to about 50 wt% by the total weight of the composition; and an amount
of one or more fillers in the range of about 10 wt% to about 90 wt% by the total weight of the
composition. In other embodiments, a composition can include an amount of Compound 1-1 or
Form A in the range of about 5 wt% to about 50 wt% by the total weight of the composition; an
amount of one or more fillers in the range of about 10 wt% to about 90 wt% by the total weight of
the composition; and an amount of one or more disintegrants in the range of about 1 wt% to about 15
wt% by the total weight of the composition. In still other ments, a composition can include
an amount of Compound 1-1 or Form A in the range of about 5 wt% to about 50 wt% by the total
weight of the composition; an amount of one or more fillers in the range of about 10 wt% to about 90
wt% by the total weight of the composition; an amount of one or more disintegrants in the range of
about 1 wt% to about 15 wt% by the total weight of the composition; and an amount of one or more
lubricants in the range of about 0.1 wt% to about 10 wt% by the total weight of the composition.
In some embodiments, a composition can include an amount of Compound 1-1 or Form A
in the range of about 5 wt% to about 20 wt% by the total weight of the composition; an amount of
one or more lubricants in the range of about 1 wt% to about 5 wt% by the total weight of the
ition; an amount of one or more disintegrants in the range of about 1 wt% to about 10 wt%
by the total weight of the composition; and an amount of one or more fillers in the range of about 70
wt% to about 90 wt% by the total weight of the composition. In other embodiments, a composition
can include an amount of Compound 1-1 or Form A in the range of about 5 wt% to about 15 wt% by
the total weight of the composition; an amount of one or more lubricants in the range of about 1 wt%
to about 5 wt% by the total weight of the composition; an amount of one or more disintegrants in the
range of about 1 wt% to about 5 wt% by the total weight of the composition; and an amount of one
or more fillers in the range of about 70 wt% to about 90 wt% by the total weight of the composition.
In some embodiments, a ition can include an amount of nd 1-1 or Form A
of about 10 wt% by the total weight of the composition, an amount of lactose monohydrate of about
28 wt% by the total weight of the ition, an amount of AVicel PH-101 crystalline
cellulose) of about 55 wt% by the total weight of the composition, an amount of Ac—Di—Sol
(croscarmellose sodium) of about 5 wt% by the total weight of the composition, and an amount of
sodium stearyl fumarate of about 3 wt% by the total weight of the composition.
In some embodiments, a composition can further include one or more glidants (or “flow
aids”). A glidant enhances the flow properties of a ition by reducing article friction and
cohesion. Exemplary glidants include colloidal silicon dioxide, talc, and any combination thereof. A
c example of glidant is amorphous, colloidal n dioxide having an average particle size in
0.2 — 0.3 microns, such as Cab—O—Sil® MSP. The amount of a glidant can vary. For example, the
amount of glidant(s) can be in the range of about 0.1 wt% to about 3 wt%, or about 0.1 wt% to about
1 wt% by total weight of the composition (wherein the total weight includes the weight of one or
more glidants).
In some embodiments, a ition described herein can further include a coating.
In some embodiments, a composition described herein can be in a solid dosage form, for
example, a tablet.
] Some embodiments described herein relate to a method of preparing a composition
described herein. In some embodiments, a method can include providing a mixture that includes
nd 1-1 or Form A and one or more fillers to form a composition. In other embodiments, a
method can include providing a mixture that includes Compound 1-1 or Form A, a lubricant, a
disintegrant, and a filler to form a ition. Examples, including c examples, of
lubricants, disintegrants, and fillers are each and independently described herein.
In some embodiments, a method can include ing Compound 1-1 or Form A and one
or more first ents to form a mixture; and combining the mixture (that includes Compound 1-1
or Form A and one or more first excipients) with one or more second excipients. In some
embodiments, the first ents can include one or more of the following: one or more fillers, one
or more disintegrants, and one or more lubricants. In some ments, the second excipients can
include one or more of the following: one or more disintegrants and one or more lubricants.
In other embodiments, a method of preparing a composition described herein can include:
i) combining Compound 1-1 or Form A with one or more first excipients that can include one or
more fillers, one or more disintegrants and one or more lubricants, and ii) combining the mixture
from i) with one or more second excipients that can include one more disintegrants and one or more
lubricants to form a composition. In some embodiments, the one or more first excipients can include
an amount of one or more fillers in the range of about 70 wt% to about 90 wt%, an amount of one or
more egrants in the range of about 1 wt% to about 15 wt%, and an amount of one or more
lubricants in the range of about 1 wt% to about 5 wt% each by the total weight of the composition,
and the second excipients can include an amount of one or more lubricants in the range of about 0.5
wt% to about 5 wt% and an amount of one or more disintegrants in the range of about 0.5 wt% to
about 5 wt% each by the total weight of the composition.
In some embodiments, a method of preparing a composition described herein can include:
i) providing granules of Compound 1-1 or Form A by combining Compound 1-1 or Form A with first
excipients that may include one or more fillers, one or more disintegrants, and one or more
ants; and ii) mixing the granules of Compound 1-1 or Form A obtained from i) with second
excipients that may include one or more disintegrants and one or more lubricants and optionally one
or more flllers to form a composition. In some embodiments, the first ents can include an
amount of one or more fillers in the range of about 70 wt% to about 90 wt%, an amount of one or
more disintegrants in the range of about 0.5 wt% to about 5 wt%, and an amount of a first lubricant
in the range of about 1% to about 5% each by the total weight of the composition; and the second
excipients can e an amount of one or more second lubricants in the range of about 0.5 wt% to
about 5 wt% and an amount of one or more egrants in the range of about 0.5 wt% to about 5
wt% each by the total weight of the composition. Examples, including specific examples, of suitable
lubricants, egrants, and fillers are described herein.
In some embodiments, a method of preparing a composition described herein can include
passing Compound 1-1 or Form A through a sieve; mixing granules of nd 1-1 or Form A
with one or more flllers, one or more disintegrants, and one or more lubricants; and blending the
resulting granules with one or more disintegrants and one or more lubricants.
In some embodiments, a method of preparing a composition described herein can include
compressing granules that e Compound 1-1 or Form A through a tablet compression machine
to form a tablet that es Compound 1-1 or Form A.
In some embodiments, a tablet that can include Compound 1-1 or Form A (for example,
the tablets obtained after tablet compression) can be film coated.
The compositions described herein may further include one or more pharmaceutically
acceptable carriers other than those described usly. As used herein, aceutically
acceptable” means being inert without unduly inhibiting the biological activity of the compounds.
The pharmaceutically acceptable carriers should be biocompatible, e.g., non—toxic, non—
inflammatory, non—immunogenic or devoid of other red reactions or side—effects upon the
administration to a subject. Further, standard pharmaceutical formulation ques can be
employed for ating the aforementioned one or more pharmaceutically acceptable carriers.
] Some examples of materials which can serve as pharmaceutically able carriers
include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins
(such as human serum albumin); buffer substances (such as phosphates or glycine); partial glyceride
mixtures of saturated vegetable fatty acids; water; salts or olytes (such as protamine sulfate,
disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts);
2014/068713
colloidal silica; magnesium trisilicate; polyacrylates; waxes; polyethylene-polyoxypropylene—block
rs; methylcellulose; hydroxypropyl methylcellulose; wool fat; sugars such as glucose;
cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and itory
waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and
soybean oil; glycols; such a propylene glycol or hylene ; esters such as ethyl oleate and
ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic
acid; n-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions;
other non-toxic compatible lubricants; coloring agents; ing agents; sweetening; flavoring
agents; perfuming agents; preservatives; sorbents and antioxidants can also be present in the
composition, according to the judgment of the formulator.
Some embodiments described herein relate to a method of inhibiting or reducing the
activity ofATR in a subject that can include administering to the subject a composition described
herein that contains an effective amount of Compound 1-1 or Form A, or a pharmaceutically
acceptable salt the aforementioned compounds.
Other embodiments described herein relate to a method of treating cancer in a subject that
can include administering to the subject a composition described herein that contains an effective
amount of Compound 1-1 or Form A, or a pharmaceutically acceptable salt the aforementioned
compounds.
Yet still other embodiments described herein relate to an use of a composition described
herein that contains an effective amount of Compound 1 or Form A, or a pharmaceutically
able salt the entioned compounds, in the cture of a medicament for treating
In some embodiments, substantially all by weight of Compound 1-1 in a composition
described herein can be Form A.
In some embodiments, at least 90% by weight of Compound 1-1 in a composition
described herein can be Form A.
In some embodiments, at least 95% by weight of Compound 1-1 in a composition
described herein can be Form A.
In some embodiments, at least 98% by weight of nd 1-1 in a composition
described herein can be Form A.
In some embodiments, at least 99% by weight of Compound 1-1 in a composition
bed herein can be Form A.
] The compositions described herein can be administered to humans and other animals
orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by
powders, ointments, or drops), bucally, as an oral or nasal spray, or the like. The term "parenteral"
as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra—
articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection
or infusion techniques. In some ments, a composition described herein can be administered
orally, intraperitoneally and/or intravenously.
Any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous
suspensions or solutions. In the case of tablets, suitable carriers used include, but are not limited to,
lactose and corn starch. Lubricating agents, such as magnesium stearate, and/or g agents can
be added. When aqueous suspensions are used, the active ient can be combined with
emulsifying and/or suspending agents. If desired, sweetening, flavoring, coloring agents and/or
perfuming agents can be included.
Liquid dosage forms for oral stration include, but are not limited to,
ceutically acceptable emulsions, microemulsions, ons, suspensions, syrups and elixirs.
In on to the active compound, the liquid dosage forms may contain inert excipients, for
e, water or other ts, solubilizing agents and emulsifiers such as ethyl alcohol, pyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3—
butylene , dimethylformamide, oils (such as, cottonseed, groundnut, corn, germ, olive, castor,
and sesame oils), glycerol, tetrahydrofurfuryl alcohol, hylene glycols and fatty acid esters of
sorbitan, and mixtures thereof.
Solid dosage forms for oral administration include es (for example, soft and hard-
filled gelatin capsules), tablets, pills, powders, and es. In such solid dosage forms, the active
nd can be mixed with at least one inert, pharmaceutically acceptable excipient or carrier such
as sodium citrate or dicalcium phosphate and/or a) fillers such as starches, lactose, milk sugar,
sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose,
alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d)
disintegrating agents such as agar, calcium ate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption
accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants
such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,
and mixtures f. In the case of es, tablets and pills, the dosage form can also include a
buffering agent.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared
WO 85132
with coatings and shells such as enteric gs and other coatings known in the pharmaceutical
formulating art. They may optionally contain ying agents and can also be of a composition
that can release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract,
ally, in a delayed manner. Examples of embedding compositions that can be used include
polymeric nces and waxes. The active compound(s) can be in a microencapsulated form with
one or more excipients.
Sterile injectable forms may be aqueous or oleaginous suspension. Injectable preparations
may be formulated according to the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may be a sterile able solution, suspension
or emulsion in a nontoxic parenterally acceptable diluent or t, for e, as a solution in
propylene glycol. Among the acceptable vehicles and solvents that may be employed are water,
Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils can be
employed as a solvent or ding medium. For this purpose any bland f1xed oil can be employed
including synthetic mono— or diglycerides. Fatty acids, such as oleic acid and its glyceride
derivatives are useful in the preparation of inj ectables, as are natural pharmaceutically-acceptable
oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl
cellulose or similar sing agents which are commonly used in the formulation of
pharmaceutically acceptable dosage forms including emulsions and suspensions.
] Inj ectable formulations can be sterilized, for example, by filtration through a bacterial-
retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which
can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
Dosage forms for topical or transdermal administration include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants and patches. The active component can be
admixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives
and/or buffers may be included. Ophthalmic formulation, eardrops, and eye drops can be
formulated. Such dosage forms can be made by dissolving or dispensing the compound in the proper
medium. Absorption ers can also be used to increase the flux of the compound across the
skin. The rate can be lled by either providing a rate controlling membrane or by dispersing the
compound in a r matrix or gel.
Alternatively, the active nds and pharmaceutically acceptable compositions
thereof may also be administered by nasal aerosol or inhalation. Such compositions are prepared
ing to techniques well-known in the art of ceutical formulation and may be prepared as
solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to
enhance bioavailability, fluorocarbons, and/or other tional solubilizing or dispersing agents.
Surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability
enhancers can be ed in a solid, liquid and other dosage forms described herein.
The compositions described herein can be ated in an unit dosage form. The term
“unit dosage form” refers to physically discrete units suitable as unitary dosage for subjects
undergoing treatment, with each unit containing a predetermined quantity of active material
calculated to produce the d therapeutic effect, optionally in association with a suitable
pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily
doses (e. g., about 1 to 4 or more times per day). When le daily doses are used, the unit dosage
form can be the same or different for each dose. The amount of the active compound in a unit
dosage form will vary depending upon, for example, the host treated, and the particular mode of
administration, for example, from 0.01 mg/kg body weight/dose to 100 mg/kg body weight/dose.
In some embodiments, a compositions described herein can be in the form of a solid
dosage form. In some embodiments, a composition described herein can be in the form of a tablet.
In still other embodiments, the composition may be in the form of a 100 mg tablet, or a 500 mg
tablet.
It will be appreciated that the amount of the active nd (for example, Compound I-
1 or Form A) required for use in treatment will vary not only with the ular compound selected
but also with the route of stration, the nature of the condition for which treatment is required
and the age and condition of the subject and will be ultimately at the discretion of the attendant
ian or veterinarian. In general, however, a suitable dose will be in the range of from about 0.1
to about 100 mg/kg of body weight per dose, for example, in the range of 0.5 to 50 mg/kg/dose, or,
for e, in the range of l to 10 mg/kg/dose.
In some ments, a composition described herein can be administered in an amount
in the range of about 5 mg to about 100 mg of Compound 1-1 or Form A, or a pharmaceutically
able salt the aforementioned compounds, per dose.
In some embodiments, a composition described herein can be administered:
a) in an amount of about 5 mg Compound 1-1 or Form A, or a pharmaceutically
acceptable salt the aforementioned compounds, per dose;
b) in an amount of about 10 mg Compound 1-1 or Form A, or a pharmaceutically
acceptable salt the aforementioned compounds, per dose;
c) in an amount of about 20 mg Compound 1-1 or Form A, or a pharmaceutically
acceptable salt the aforementioned compounds, per dose;
d) in an amount of about 30 mg Compound 1-1 or Form A, or a pharmaceutically
WO 85132
acceptable salt the aforementioned compounds, per dose;
e) in an amount of about 50 mg Compound 1-1 or Form A, or a pharmaceutically
acceptable salt the aforementioned compounds, per dose;
f) in an amount of about 60 mg Compound 1-1 or Form A, or a pharmaceutically
acceptable salt the aforementioned compounds, per dose;
g) in an amount of about 80 mg Compound 1-1 or Form A, or a ceutically
acceptable salt the aforementioned compounds, per dose; or
h) in an amount of about 100 mg Compound 1-1 or Form A, or a pharmaceutically
acceptable salt the aforementioned compounds, per dose.
In some embodiments, a composition described herein can be stered in a fasted
state (for example, the subject has not eaten food or s, except for water, for at least 8 hours). In
other ments, a composition described herein can be administered in a fed state (for example,
with food or within 1 hour of eating food).
Comp_ound Uses
One aspect of this invention provides compounds or compositions that are inhibitors of
ATR kinase, and thus are useful for treating or lessening the severity of a disease, condition, or
disorder in a subject or patient where ATR is implicated in the disease, condition, or disorder.
Another aspect of this invention provides compounds or compositions that are useful for
the treatment of diseases, disorders, and conditions characterized by excessive or abnormal cell
proliferation. Such es include a erative or hyperproliferative disease. es of
erative and hyperproliferative diseases include, without limitation, cancer and
roliferative disorders.
In some embodiments, said compounds are selected from compound 1-1 or Form A. In
other embodiments, said compositions include compound 1-1 or Form A. The term “cancer”
includes, but is not limited to the following cancers. Oral: buccal cavity, lip, tongue, mouth,
pharynx; Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma),
myxoma, rhabdomyoma, fibroma, lipoma and teratoma; mg: non-small cell, ogenic
carcinoma (squamous cell or moid, undifferentiated small cell, undifferentiated large cell,
adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,
chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell oma,
larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach noma, lymphoma,
leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma,
carcinoid tumors, vipoma), small bowel or small intestines (adenocarcinoma, ma, oid
tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurof1broma, f1broma), large bowel
or large intestines carcinoma, r adenoma, villous adenoma, hamartoma, leiomyoma),
colon, colon—rectum, colorectal; rectum, Genitourinam tract: kidney (adenocarcinoma, Wilm's tumor
[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional
cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, a), testis (seminoma, teratoma,
embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma,
f1broma, f1broadenoma, adenomatoid , lipoma); Liver: hepatoma (hepatocellular carcinoma),
cholangiocarcinoma, hepatoblastoma, arcoma, hepatocellular adenoma, hemangioma, biliary
passages; Bone: osteogenic a (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,
osarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple
myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses),
benign oma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
Nervous system: skull (osteoma, hemangioma, granuloma, ma, osteitis deformans), meninges
(meningioma, meningiosarcoma, gliomatosis), brain cytoma, medulloblastoma, glioma,
ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma,
retinoblastoma, congenital tumors), spinal cord neurof1broma, meningioma, glioma, sarcoma);
Gynecological/Female: uterus (endometrial carcinoma), cervix cal carcinoma, pre-tumor
cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous
cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell
tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial
carcinoma, adenocarcinoma, f1brosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell
carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;
Hematologic: blood (myeloid ia [acute and c], acute lymphoblastic leukemia, chronic
lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome),
Hodgkin's e, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell; id disorders;
&: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma,
keratoacanthoma, moles stic nevi, lipoma, a, dermatof1broma, keloids, psoriasis,
Thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma, undifferentiated thyroid
cancer, medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine
neoplasia type 2B, familial ary thyroid cancer, romocytoma, nglioma; and
Adrenal glands: neuroblastoma.
In some embodiments, the cancer is selected from a cancer of the lung or the pancreas. In
other embodiments, the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer,
gastric cancer, or brain cancer. In yet other ments, the cancer is selected from non-small cell
lung cancer, small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer,
bladder cancer, ctal cancer, glioblastoma, esophageal cancer, breast , hepatocellular
carcinoma, or ovarian cancer.
In some embodiments, the cancer is lung cancer. In other embodiments, the lung cancer is
non-small cell lung cancer or small cell lung cancer. In another embodiment, the cancer is non-small
cell lung cancer. In yet another embodiment, the non-small cell lung cancer is squamous non-small
cell lung cancer.
Thus, the term "cancerous cell" as provided herein, includes a cell afflicted by any one of
the above—identified conditions. In some embodiments, the cancer is selected from colorectal,
thyroid, or breast cancer. In other embodiments, the cancer is triple negative breast cancer.
The term “myeloproliferative disorders”, includes ers such as themia vera,
thrombocythemia, d metaplasia with myelofibrosis, hypereosinophilic me, juvenile
myelomonocytic leukemia, systemic mast cell disease, and hematopoietic disorders, in particular,
acute—myelogenous leukemia (AML), chronic—myelogenous leukemia (CML), acute—promyelocytic
leukemia (APL), and acute lymphocytic leukemia (ALL).
Combination Therapies
Another aspect of this invention is directed towards a method of treating cancer in a
t in need thereof, comprising administration of a compound or ition of this invention or
a pharmaceutically acceptable salt thereof, and an additional therapeutic agent. In some
embodiments, said method comprises the sequential or inistration of the compound or
composition (or a pharmaceutically able salt thereof), and the additional therapeutic agent.
As used herein, the term “in combination” or “co-administration” can be used
interchangeably to refer to the use of more than one therapy (e. g., one or more therapeutic agents).
The use of the term does not restrict the order in which ies (e. g., therapeutic ) are
administered to a subject or the dosing schedule of each therapeutic agent.
In some embodiments, said additional therapeutic agent is an anti-cancer agent. In other
embodiments, said additional therapeutic agent is a DNA-damaging agent. In yet other
embodiments, said additional therapeutic agent is selected from ion therapy, chemotherapy, or
other agents lly used in combination with radiation therapy or chemotherapy, such as
radiosensitizers and chemosensitizers. In yet other embodiments, said additional therapeutic agent is
ionizing radiation.
As would be known by one of skill in the art, radiosensitizers are agents that can be used
in combination with radiation therapy. Radiosensitizers work in s different ways, including,
but not limited to, making cancer cells more sensitive to radiation therapy, working in synergy with
ion therapy to provide an improved synergistic effect, acting additively with radiation therapy,
or protecting surrounding healthy cells from damage caused by radiation therapy. Likewise
chemosensitizers are agents that can be used in combination with chemotherapy. Similarly,
chemosensitizers work in various different ways, including, but not limited to, making cancer cells
more ive to chemotherapy, working in synergy with chemotherapy to provide an ed
istic effect, acting additively to chemotherapy, or protecting surrounding healthy cells from
damage caused by chemotherapy.
Examples of DNA-damaging agents that may be used in combination with compounds or
compositions of this invention e, but are not limited to Platinating agents, such as Cisplatin,
Carboplatin, Nedaplatin, Satraplatin and other derivatives; Topo I inhibitors, such as Topotecan,
ecan/SN3 8, rubitecan and other derivatives; tabolites, such as Folic family
(Methotrexate, Pemetrexed and relatives); Purine antagonists and Pyrimidine antagonists
(Thioguanine, Fludarabine, Cladribine, Cytarabine, Gemcitabine, 6-Mercaptopurine, rouracil
(SFU) and relatives); Alkylating agents, such as Nitrogen mustards (Cyclophosphamide, Melphalan,
Chlorambucil, mechlorethamine, Ifosfamide and relatives); nitrosoureas (eg Carmustine); Triazenes
(Dacarbazine, lomide); Alkyl sulphonates (eg Busulfan); Procarbazine and Aziridines;
Antibiotics, such as Hydroxyurea, Anthracyclines (doxorubicin, daunorubicin, epirubicin and other
derivatives); cenediones (Mitoxantrone and relatives); Streptomyces family (Bleomycin,
Mitomycin C, actinomycin); and Ultraviolet light.
In some ments, the additional therapeutic agent is ionizing radiation. In other
embodiments, the additional eutic agent is Cisplatin or Carboplatin. In yet other embodiments,
the additional therapeutic agent is Etoposide. In yet other embodiments, the additional therapeutic
agent is Temozolomide. In still other embodiments, the additional therapeutic agent is
irinotecan/SN3 8.
] In certain embodiments, the additional therapeutic agent is selected from one or more of
the following: Cisplatin, Carboplatin, irinotecan/SN3 8, abine, ide, Temozolomide, or
ionizing radiation.
] Other therapies or anticancer agents that may be used in combination with the inventive
compounds and compositions of the present ion include surgery, radiotherapy (in but a few
examples, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy,
brachytherapy, and systemic radioactive isotopes, to name a few), ine therapy, biologic
response modifiers (interferons, interleukins, and tumor necrosis factor (TNF) to name a few),
hyperthermia and erapy, agents to attenuate any adverse effects (e.g., antiemetics), and other
ed chemotherapeutic drugs, including, but not limited to, the DNA damaging agents listed
herein, e poisons (Vinblastine, Vincristine, Vinorelbine, Paclitaxel), podophyllotoxins
(Etoposide, Irinotecan, Topotecan), nitrosoureas (Carmustine, Lomustine), inorganic ions (Cisplatin,
Carboplatin), s (Asparaginase), and hormones (Tamoxifen, Leuprolide, ide, and
Megestrol), cTM, adriamycin, dexamethasone, and cyclophosphamide.
A compound or composition of the instant invention may also be useful for treating cancer
in combination with any of the following therapeutic : abarelix (Plenaxis depot®); aldesleukin
(Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin tin®);
allopurinol rim®); altretamine en®); amifostine l®); anastrozole (Arimidex®);
arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab
(Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin
(Blenoxane®); bortezomib (Velcade®); an intravenous (Busulfex®); busulfan oral
(Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®);
carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant
(Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®);
tin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide
(Cytoxan®, ®); cyclophosphamide (Cytoxan Inj ®); cyclophosphamide (Cytoxan
Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC—
; dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin
liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin
(Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane ard®); docetaxel (Taxotere®);
doxorubicin mycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin
PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (dromostanolone®);
dromostanolone propionate (masterone injection®); Elliott's B Solution (Elliott's B Solution®);
epirubicin ce®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);
etoposide phosphate (Etopophos®); etoposide, VP—l6 (Vepesid®); tane (Aromasin®);
Filgrastim (Neupogen®); floxuridine arterial) (FUDR®); fludarabine (Fludara®); fluorouracil,
—FU (Adrucil®); fulvestrant (Faslodex®); gef1tinib (Iressa®); gemcitabine (Gemzar®);
gemtuzumab ozogamicin (Mylotarg®); goserelin e (Zoladex Implant®); goserelin acetate
(Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea a®); Ibritumomab Tiuxetan
(Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); ib mesylate ec®); interferon
alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan osar®); lenalidomide
(Revlimid®); letrozole a®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate
(Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen
mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®);
mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); rexate
(Methotrexate®); methoxsalen (Uvadex®); mitomycin C ycin®); mitotane (Lysodren®);
ntrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®);
Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®);
paclitaxel (Taxol®); paclitaxel protein-bound les (Abraxane®); palifermin (Kepivance®);
pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®);
Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); tatin (Nipent®); pipobroman
(Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine
(Matulane®); quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim
(Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib
maleate (Sutent®); talc (Sclerosol®); tamoxifen dex®); temozolomide (Temodar®);
teniposide, VM—26 ®); testolactone (Teslac®); anine, 6-TG (Thioguanine®); thiotepa
(Thioplex®); topotecan (Hycamtin®); toremifene ton®); Tositumomab (Bexxar®);
Tositumomab/I-l3l tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA
(Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin ar®); vinblastine
(Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); zoledronate (Zometa®) and
vorinostat (Zolinza®).
For a comprehensive discussion of d cancer therapies see, http://www.nci.nih.gov/,
a list of the FDA approved oncology drugs at http://wwwfda.gov/cder/cancer/druglistframe.htm, and
The Merck Manual, Seventeenth Ed. 1999, the entire contents of which are hereby incorporated by
reference.
r embodiment provides administering a compound or ition of this invention
with an additional therapeutic agent that inhibits or modulates a base excision repair protein. In some
embodiments, the base on repair protein is selected from UNG, SMUGl, MBD4, TDG, OGGl,
MYH,NTH1, MPG, NEILl, NEIL2, NEIL3 (DNA glycosylases); APEl, APEXZ (AP
endonucleases); LIGl, LIG3 (DNA ligases I and III); XRCCl (LIG3 ory); PNK, PNKP
(polynucleotide kinase and phosphatase); PARPl, PARP2 (Poly(ADP-Ribose) Polymerases); PolB,
PolG erases); FENl (endonuclease) or Aprataxin. In other embodiments, the base excision
repair protein is selected from PARP l, PARPZ, or PolB. In yet other embodiments, the base excision
repair protein is selected from PARPl or PARPZ. In some embodiments, the agent is selected from
Olaparib (also known as AZD2281 or KU-0059436), ib (also known as BSI-201 or
SAR240550), Veliparib (also known as ABT-888), rib (also known as PF—01367338), CEP—
9722, INO—lOOl, MK—4827, E7016, BMN673, or AZD2461.
Methods of Treatment
One aspect of the invention relates to a method of inhibiting ATR kinase activity in a
patient, which method comprises administering to the patient a compound described herein, or a
composition comprising said compound. In some embodiments, said method is used to treat or
prevent a condition selected from proliferative and hyperproliferative diseases, such as cancer.
In some ments, the cancer is selected from the s described herein. In some
ments, said cancer is lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, or
brain cancer. In other embodiments, the cancer is selected from a cancer of the lung or the pancreas.
In yet other embodiments, the cancer is selected from all cell lung cancer, small
cell lung , atic cancer, y tract cancer, head and neck cancer, bladder cancer,
colorectal cancer, astoma, esophageal cancer, breast , hepatocellular carcinoma, or
ovarian .
In some embodiments, the lung cancer is small cell lung cancer and the additional
therapeutic agents are cisplatin and etoposide. In other examples, the lung cancer is non-small cell
lung cancer and the additional therapeutic agents are gemcitabine and cisplatin. In yet other
embodiments, the non-small cell lung cancer is squamous non-small cell lung cancer. In another
embodiment, the cancer is breast cancer and the additional therapeutic agent is cisplatin. In other
embodiments, the cancer is triple negative breast cancer.
In certain ments, an "effective amount" of the compound or pharmaceutically
acceptable composition is that amount effective in order to treat said disease. The compounds and
compositions, according to the method of the present invention, may be administered using any
amount and any route of administration effective for treating or lessening the severity of said disease.
] One aspect provides a method for inhibiting ATR in a patient comprising administering a
compound or composition as described herein. Another embodiment provides a method of treating
cancer comprising stering to a patient a compound or composition described herein, wherein
the variables are as d herein.
Another embodiment provides methods for treating pancreatic cancer by administering a
compound or composition described herein in combination with another known pancreatic cancer
treatment. One aspect of the invention includes administering a compound or composition described
herein in combination with gemcitabine. In some embodiments, the pancreatic cancer comprises one
of the following cell lines: PSN—l, MiaPaCa-2 or Panc-l. According to another aspect, the cancer
comprises one of the following primary tumor lines: Panc-M or MRCS.
r aspect of the invention includes administering a compound or composition
bed herein in combination with radiation therapy. Yet another aspect provides a method of
abolishing radiation-induced G2/M checkpoint by administering a compound or composition
described herein in combination with radiation treatment.
Another aspect provides a method of treating pancreatic cancer by administering to
pancreatic cancer cells a nd or composition described herein in ation with one or
more cancer therapies. In some embodiments, the compound or composition is combined with
chemoradiation, chemotherapy, and/or radiation y. As would be understood by one of skill in
the art, “chemoradiation” refers to a treatment regime that includes both chemotherapy (such as
gemcitabine) and radiation. In some embodiments, the chemotherapy is gemcitabine.
Yet r aspect provides a method of increasing the ivity of atic cancer
cells to a cancer therapy selected from gemcitabine or radiation therapy by administering a
nd or composition described herein in combination with the cancer therapy.
] In some embodiments, the cancer therapy is abine. In other embodiments, the
cancer therapy is radiation therapy. In yet another embodiment the cancer therapy is chemoradiation.
Another aspect provides a method of inhibiting phosphorylation of Chkl (Ser 345) in a
pancreatic cancer cell comprising administering a compound or composition described herein after
treatment with gemcitabine (100 nM) and/or radiation (6 Gy) to a pancreatic cancer cell.
Another aspect provides a method of ting damage—induced cell cycle checkpoints by
administering a compound or composition bed herein in combination with radiation therapy to
a cancer cell.
r aspect provides a method of inhibiting repair of DNA damage by homologous
recombination in a cancer cell by administering a compound or composition described herein in
combination with one or more of the following treatments: chemoradiation, chemotherapy, and
ion therapy.
In some embodiments, the chemotherapy is gemcitabine.
WO 85132
Another aspect provides a method of inhibiting repair of DNA damage by homologous
recombination in a cancer cell by stering a compound or ition described herein in
combination with gemcitabine and radiation therapy.
Another aspect of the invention provides a method of treating non-small cell lung cancer
comprising administering to a patient a compound or composition described herein in combination
with one or more of the following additional therapeutic agents: Cisplatin or Carboplatin, Etoposide,
and ionizing radiation. Some embodiments comprise administering to a patient a compound
described herein in combination with Cisplatin or Carboplatin, Etoposide, and ionizing radiation. In
some embodiments the ation is Cisplatin, Etoposide, and ionizing radiation. In other
embodiments the combination is Carboplatin, Etoposide, and ionizing radiation.
Another embodiment es a method of promoting cell death in cancer cells
comprising stering to a patient a compound described herein, a composition comprising
, or
said nd.
Yet another embodiment provides a method of preventing cell repair of DNA damage in
cancer cells comprising administering to a patient a compound described herein, or a composition
comprising said compound. Yet another embodiment provides a method of preventing cell repair
caused by of DNA damage in cancer cells comprising administering to a patient a compound of the
present invention, or composition comprising said compound.
Another embodiment es a method of sensitizing cells to DNA damaging agents
sing administering to a patient a compound described herein, or a composition comprising
said compound.
In some embodiments, the method is used on a cancer cell having defects in the ATM
signaling cascade. In some embodiments, said defect is altered expression or activity of one or more
ofthe following: ATM, p53, CHK2, MREl l, RAD50, NBSl, 53BP1, MDCl, H2AX,
MCPHl/BRITl, CTIP, or SMCl. In other ments, said defect is altered expression or activity
of one or more ofthe following: ATM, p53, CHK2, MREl l, RAD50, NBSl, 53BP1, MDCl or
H2AX. According to r embodiment, the method is used on a cancer, cancer cell, or cell
expressing DNA damaging oncogenes.
] In another embodiment, the cell is a cancer cell expressing DNA ng oncogenes. In
some embodiments, said cancer cell has altered sion or activity of one or more of the
following: K-Ras, N-Ras, H-Ras, Raf, Myc, Mos, E2F, Cdc25A, CDC4, CDK2, Cyclin E, Cyclin A
and Rb.
According to another embodiment, the method is used on a cancer, cancer cell, or cell has
a defect in a protein ed in base excision repair (“base excision repair protein”). There are many
methods known in the art for determining whether a tumor has a defect in base on . For
example, cing of either the genomic DNA or mRNA products of each base excision repair
gene (e.g., UNG, PARPl, or LIGl) can be performed on a sample of the tumor to establish whether
mutations expected to modulate the function or expression of the gene product are present (Wang et
al., Cancer Research 52:4824 ). In addition to the mutational inactivation, tumor cells can
modulate a DNA repair gene by hypermethylating its promoter region, leading to d gene
expression. This is most commonly assessed using ation-specific polymerase chain reaction
(PCR) to quantify methylation levels on the promoters of base excision repair genes of interest.
Analysis of base excision repair gene promoter ation is available commercially
(http://www.sabiosciences.com/dna_methylation_product/HTML/MEAH—421A.html).
Finally, the expression levels of base excision repair genes can be assessed by directly
quantifying levels of the mRNA and protein ts of each gene using standard techniques such as
quantitative reverse transcriptase-coupled polymerase chain reaction (RT-PCR) and
immunhohistochemistry (IHC), tively (Shinmura et al., Carcinogenesis 25: 2311 (2004);
Shinmura et al., Journal of Pathology 225:414 (2011)).
In some embodiments, the base excision repair protein is UNG, SMUGl, MBD4, TDG,
OGGl, MYH, NTH1, MPG, NEIL1, NEIL2, NEIL3 (DNA glycosylases); APE1, APEX2 (AP
endonucleases); LIGl, LIG3 (DNA ligases I and III); XRCCl (LIG3 ory); PNK, PNKP
(polynucleotide kinase and phosphatase); PARPl, PARP2 (Poly(ADP-Ribose) Polymerases); PolB,
PolG (polymerases); FENl (endonuclease) or Aprataxin.
In sorme embodiments, the base excision repair protein is PARPl, PARP2, or PolB. In
other embodiments, the base excision repair protein is PARPl or PARP2.
The methods described above (gene sequence, promoter methylation and mRNA
expression) may also be used to characterize the status (e. g., expression or mutation) of other genes
or proteins of interesting, such DNA—damaging oncogenes expressed bv a tumor or defects in the
ATM signaling cascade of a cell.
Yet another embodiment provides use of a compound or composition described herein as a
sensitizer or a chemo-sensitizer.
] Yet other embodiment provides use of a compound or composition described herein as a
single agent (monotherapy) for treating cancer. In some embodiments, the compounds or
compositions described herein are used for treating patients having cancer with a DNA-damage
response (DDR) defect. In other embodiments, said defect is a mutation or loss of ATM, p53,
CHK2, MREl l, RAD50, NBSl, 53BP1, MDCl, or H2AX.
Terminology
The terms "subject," “host,” or “patient” includes an animal and a human (e. g., male or
female, for example, a child, an adolescent, or an adult). Preferably, the "subj ect," “host,” or
“patient” is a human.
nds of this invention include those described generally herein, and are further
illustrated by the s, subclasses, and species disclosed herein. As used herein, the ing
definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical
elements are identified in accordance with the Periodic Table of the ts, CAS version,
Handbook of Chemistry and Physics, 75th Ed. Additionally, general ples of organic chemistry
are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999,
and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, MB. and March, J., John Wiley
& Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
As described herein, a specified number range of atoms includes any integer therein. For
e, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.
As described herein, nds of the invention may optionally be substituted with one
or more substituents, such as are illustrated generally herein, or as exemplified by ular classes,
subclasses, and species of the invention. It will be appreciated that the phrase “optionally
substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the
term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of
hydrogen radicals in a given structure with the radical of a specified tuent. Unless otherwise
ted, an optionally substituted group may have a substituent at each substitutable position of the
group, and when more than one position in any given structure may be substituted with more than
one substituent selected from a specified group, the substituent may be either the same or ent at
every position. Combinations of substituents envisioned by this invention are preferably those that
result in the formation of stable or chemically feasible compounds.
Unless otherwise indicated, a substituent connected by a bond drawn from the center of a
ring means that the substituent can be bonded to any position in the ring. In example i below, for
instance, JW can be bonded to any position on the l ring. For bicyclic rings, a bond drawn
h both rings indicates that the substituent can be bonded from any position of the bicyclic ring.
In example ii below, for instance, JW can be bonded to the 5-membered ring (on the nitrogen atom,
for instance), and to the ered ring.
/ §_<,Z\n/\\ —|—<JW)o.5 ' (JW)0-5
N H
1 11
The term “stable”, as used herein, refers to compounds that are not substantially altered
when subjected to conditions to allow for their production, detection, recovery, purification, and use
for one or more of the purposes disclosed herein. In some embodiments, a stable compound or
chemically feasible nd is one that is not substantially altered when kept at a temperature of
40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
] The term “dative bond”, as used , is defined as the coordination bond formed upon
interaction between molecular s, one of which serves as a donor and the other as an acceptor of
the electron pair to be shared in the complex formed.
The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.,
unbranched), ed, or cyclic, substituted or unsubstituted hydrocarbon chain that is completely
saturated or that contains one or more units of unsaturation that has a single point of attachment to
the rest of the molecule.
Unless ise specified, tic groups contain 1-20 aliphatic carbon atoms. In some
embodiments, aliphatic groups contain l-lO aliphatic carbon atoms. In other embodiments, aliphatic
groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6
aliphatic carbon atoms, and in yet other ments, aliphatic groups contain 1-4 aliphatic carbon
atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or
alkynyl groups. Specific examples include, but are not d to, methyl, ethyl, isopropyl, n-propyl,
sec-butyl, vinyl, n-butenyl, ethynyl, and utyl. Aliphatic groups may also be cyclic, or have a
combination of linear or branched and cyclic groups. Examples of such types of aliphatic groups
include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, —CH2—
cyclopropyl, CHzCHzCH(CH3)—cyclohexyl.
The term “cycloaliphatic” (or “carbocycle” or “carbocyclyl”) refers to a monocyclic C3—C8
hydrocarbon or ic C8-C12 hydrocarbon that is completely saturated or that contains one or more
units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the
molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Examples of
cycloaliphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl . Specific
es include, but are not limited to, cyclohexyl, cyclopropyl, and cyclobutyl.
The term “heterocycle”, “heterocyclyl”, or “heterocyclic” as used herein means non—
aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring s are an
independently selected heteroatom. In some embodiments, the “heterocycle”, “heterocyclyl”, or
“heterocyclic” group has three to fourteen ring members in which one or more ring members is a
heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the
system contains 3 to 7 ring s.
Examples of heterocycles e, but are not limited to, 3—lH-benzimidazol-2—one, 3-(1-
alkyl)-benzimidazolone, 2-tetrahydrofuranyl, ahydrofuranyl, 2-tetrahydrothiophenyl, 3-
tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3-
thiomorpholino, 4-thiomorpholino, l-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, l-
tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, l-piperidinyl, 2-piperidinyl,
3-piperidinyl, l-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, l-piperidinyl, 2-piperidinyl,
3—piperidinyl, ridinyl, 2—thiazolidinyl, 3—thiazolidinyl, 4—thiazolidinyl, l—imidazolidinyl, 2—
imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro-imidazolone.
Cyclic groups, (e. g. cycloaliphatic and heterocycles), can be linearly fused, bridged, or
spirocyclic.
The term oatom” means one or more of oxygen, , nitrogen, orus, or
silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form
of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-
dihydro-2H—pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N—substituted pyrrolidinyl)).
The term “unsaturated”, as used herein, means that a moiety has one or more units of
unsaturation. As would be known by one of skill in the art, unsaturated groups can be partially
unsaturated or fully unsaturated. Examples of partially unsaturated groups include, but are not
limited to, butene, cyclohexene, and tetrahydropyridine. Fully unsaturated groups can be aromatic,
romatic, or non-aromatic. Examples of fully unsaturated groups include, but are not limited to,
phenyl, ctatetraene, pyridyl, thienyl, and l-methylpyridin-2(lH)-one.
The term “alkoxy”, or “thioalkyl”, as used , refers to an alkyl group, as previously
defined, attached h an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.
The terms “haloalkyl”, “haloalkenyl”, “haloaliphatic”, and “haloalkoxy” mean alkyl,
alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. This term
includes perfluorinated alkyl groups, such as —CF3 and 3.
The terms en”, “halo”, and “hal” mean F, Cl, Br, or I.
The term “aryl” used alone or as part of a larger moiety as in “arylalkyl”, “arylalkoxy”, or
“aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems haVing a total of five to
fourteen ring members, wherein at least one ring in the system is ic and wherein each ring in
the system contains 3 to 7 ring s. The term “aryl” may be used interchangeably with the
term “aryl ring”.
The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroarylalkyl” or
“heteroarylalkoxy”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to
fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the
system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring
s. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the
term “heteroaromatic”. Examples of heteroaryl rings include, but are not limited to, 2-furanyl, 3-
furanyl, N—imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, benzimidazolyl, 3-isoxazolyl, 4-
isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N—pyrrolyl, 2-pyrrolyl, olyl, 2-
pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, midinyl, 5-pyrimidinyl, pyridazinyl (e. g., 3-
zinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e. g., 5-tetrazolyl), triazolyl (e.g., 2-
triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, benzofuryl, benzothiophenyl, indolyl (e. g., 2-indolyl),
pyrazolyl (e.g., 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl,
1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, pyrazinyl, 1,3,5-
triazinyl, quinolinyl (e. g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and nolinyl (e.g., l-
isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
It shall be tood that the term “heteroaryl” includes certain types of heteroaryl rings
that exist in equilibrium n two different forms. More ically, for example, species such
hydropyridine and pyridinone (and likewise hydroxypyrimidine and pyrimidinone) are meant to be
encompassed within the definition of “heteroaryl.”
|\ |\
/N‘_ NH
OH 0
The term cting group” and “protective group” as used herein, are interchangeable
and refer to an agent used to arily block one or more desired functional groups in a compound
with multiple ve sites. In n embodiments, a protecting group has one or more, or
preferably all, of the following characteristics: a) is added selectively to a functional group in good
yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other
reactive sites; and c) is selectively removable in good yield by reagents that do not attack the
regenerated, deprotected onal group. As would be understood by one skilled in the art, in some
cases, the reagents do not attack other reactive groups in the compound. In other cases, the ts
may also react with other reactive groups in the compound. Examples of protecting groups are
detailed in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition,
John Wiley & Sons, New York: 1999 (and other editions of the book), the entire contents of which
are hereby incorporated by reference. The term “nitrogen protecting group”, as used herein, refers to
an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional
compound. Preferred en protecting groups also possess the teristics exemplified for a
protecting group above, and certain exemplary nitrogen protecting groups are also detailed in
Chapter 7 in Greene, T.W., Wuts, P. G in “Protective Groups in Organic Synthesis”, Third Edition,
John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by
reference.
In some embodiments, a methylene unit of an alkyl or aliphatic chain is optionally
replaced with another atom or group. Examples of such atoms or groups include, but are not limited
to, nitrogen, , sulfur, —C(O)—, —C(=N—CN)—, —C(=NR)—, —C(=NOR)—, —SO—, and —SOz—. These
atoms or groups can be combined to form larger groups. Examples of such larger groups include,
but are not limited to, —OC(O)—, —C(O)CO—, -COz-, —C(O)NR—, —C(=N—CN), —NRCO—, —NRC(O)O—
, —SOzNR—, —NRSOz—, —NRC(O)NR—, —OC(O)NR—, and —NRSOzNR-, wherein R is, for example, H
or C1_6aliphatic. It should be understood that these groups can be bonded to the methylene units of
the aliphatic chain via single, double, or triple bonds. An example of an optional replacement
(nitrogen atom in this case) that is bonded to the tic chain via a double bond would be —
N—CH3. In some cases, especially on the terminal end, an al replacement can be
bonded to the aliphatic group via a triple bond. One example of this would be CHZCHZCHZCEN. It
should be tood that in this ion, the terminal nitrogen is not bonded to r atom.
It should also be understood that, the term “methylene unit” can also refer to branched or
tuted methylene units. For example, in an isopropyl moiety H3)2], a nitrogen atom (e. g.
NR) replacing the first recited “methylene unit” would result in dimethylamine [-N(CH3)2]. In
ces such as these, one of skill in the art would understand that the nitrogen atom will not have
any additional atoms bonded to it, and the “R” from “NR” would be absent in this case.
Unless ise indicated, the optional replacements form a chemically stable compound.
Optional replacements can occur both within the chain and/or at either end of the chain; i.e. both at
the point of attachment and/or also at the terminal end. Two optional replacements can also be
adjacent to each other within a chain so long as it results in a chemically stable compound. For
example, a C3 aliphatic can be optionally replaced by 2 nitrogen atoms to form —C—NEN. The
optional replacements can also completely replace all of the carbon atoms in a chain. For e, a
C3 aliphatic can be optionally replaced by —NR-, -C(O)—, and —NR— to form )NR— (a urea).
Unless otherwise indicated, if the replacement occurs at the terminal end, the replacement
atom is bound to a hydrogen atom on the terminal end. For e, if a methylene unit of —
CH2CH2CH3 were optionally replaced with —O—, the resulting compound could be —
2014/068713
OCH2CH3, —CHZOCH3, or —CH2CHZOH. It should be understood that if the terminal atom does not
contain any free valence electrons, then a hydrogen atom is not required at the al end
(e.g., —CH2CH2CH=O or —CH2CH2CEN).
Unless otherwise indicated, structures depicted herein are also meant to e all
isomeric (e. g., enantiomeric, diastereomeric, geometric, conformational, and rotational) forms of the
structure. For e, the R and S configurations for each tric center, (Z) and (E) double
bond isomers, and (Z) and (E) conformational isomers are ed in this invention. As would be
understood to one skilled in the art, a substituent can freely rotate around any rotatable bonds. For
\I N/l
example, a substituent drawn as also represents \
Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric,
geometric, conformational, and rotational mixtures of the present compounds are within the scope of
the invention.
Unless otherwise ted, all tautomeric forms of the compounds of the invention are
within the scope of the invention.
In the compounds of this invention any atom not specifically designated as a particular
isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a
on is designated specifically as “H” or “hydrogen”, the position is tood to have hydrogen
at its natural abundance isotopic composition. Also unless otherwise stated, when a position is
designated specifically as “D” or “deuterium”, the position is understood to have deuterium at an
abundance that is at least 3340 times greater than the natural abundance of deuterium, which is
0.015% (i.e., at least 50.1% incorporation of deuterium).
“D” and “d” both refer to deuterium.
Additionally, unless otherwise indicated, structures depicted herein are also meant to
include nds that differ only in the presence of one or more isotopically enriched atoms. For
example, compounds having the present structures except for the replacement of hydrogen by
deuterium or tritium, or the replacement of a carbon by a 13C- or 14C—enriched carbon are within the
scope of this invention. Such nds are useful, for example, as analytical tools or probes in
biological assays.
As used herein alline” refers to a solid that has a specific arrangement and/or
conformation of the les in the l lattice.
As used herein the term “amorphous” refers to solid forms that consist of disordered
arrangements of molecules and do not possess a distinguishable l lattice.
As used herein, the term “solvate” refers to a crystalline solid adduct containing either
stoichiometric or ichiometric amounts of a t incorporated within the crystal ure. If
the incorporated solvent is water, such adduct is refered to as a “hydrate”.
iations
The following abbreviations are used:
DMSO dimethyl sulfoxide
DCM dichloromethane
ATP adenosine triphosphate
TFA trifluoroacetic acid
1HNMR proton nuclear magnetic resonance
HPLC high performance liquid chromatography
LCMS liquid chromatography-mass ometry
Rt retention time
MTBE Methyl utyl ether
XRPD X-Ray Powder Diffraction
DSC Differential scanning calorimetry
TGA Thermogravimetric analysis
RT room temperature
NMP N—methylpyrrolidone
Bp boiling point
DMF dimethylformamide
PTSA p—Toluenesulfonic acid
DIPEA N,N—diisopropylethylamine
HOBT hydroxybenzotriazole
HATU l -[Bis(dimethylamino)methylene]- lH- 1,2,3 -triazolo [4,5-b]pyridinium 3 -oxid
hexafluorophosphate
TBTU 2-(1 H-benzotriazole- l -yl)- l , 1,3 ,3 -tetramethyluronium tetrafluoroborate
T3P Propylphosphonic anhydride
COMU l— [( l -(Cyanoethoxyoxoethylideneaminooxy)-dimethylamino-
morpholino)]uroniumhexafluorophosphate
TCTU [(6-chlorobenzotriazol- l -yl)oxy-(dimethylamino)methylene]-dimethyl-ammonium
tetrafluoroborate
HBTU O-Benzotriazole-N,N,N’ ,N’ -tetramethyl-uronium-hexafluoro-phosphate
ECDI l-Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide
LDA Lithium diisopropylamide
CD1 1, l'-Carbonyldiimidazole
Processes
ses and compounds described herein are useful for producing ATR tors that
contain an aminopyrazolopyrimidine core. The general synthetic procedures shown in s
herein are useful for generating a wide array of chemical species Which can be used in the
manufacture of pharmaceutical compounds.
SCHEMEA
NH2 0
O NH2 0 /
o anion NC ,AII pyrazole dine N\ / O’All
NCQL condensation 0 formation N// O,AII formation N
OAII —’ —>HN _’
\ N
H2N CCI3 /
1 R1
2 3
4a-c
amide bond
formation
NH2 NH
0 2 o
N=N NH2 0
. /N R2
/ activated ester /
N N ,NI amide-bond /
O /
deprotection / OH formation N / / formation Ni / \
—> —>N —> \ N M R3
<> \
//N g\ //N \J <\ /N R4
5a-c 6a-c l-A
Compounds of this ion can be synthesised according to methods similar to the one
depicted in Scheme A.
The anion of commercially available allyl cyanoacetate 1 can react with, e.g.,
trichloroacetonitrile to provide intermediate 2. In the anion condensation step, the anion of
commercially available allyl cyanoacetate 1 can be generated with a base such as ium e
in an appropriate solvent such as an alcohol (e.g., isopropylalcohol). The anion then reacts with
trichloroacetonitrile at room temperature.
Step 2
Intermediate 2 then reacts with hydrazine to form the diaminopyrazole 3. In the pyrazole
formation step, intermediate 2 is reacted with hydrazine (or its hydrate) in an aprotic solvent, such as
DMF, to provide the diaminopyrazole 3. The reaction occurs under basic conditions (e.g., in the
presence of potassium e or AcONa) with heating (e. g.,2 110°C) to ensure complete cyclisation.
Step 3
] Intermediate 3 can further be condensed with a dielectrophilic ng partner to form the
pyrimidine 4a-c. In the pyrimidine formation step, intermediate 3 is reacted with a 1,3-
dielectrophilic species (e. g., a l,3—dialdehyde or a 3-(dialkylamino)—prop—2—enal) in various types of
solvents (e. g., DMF or ater) to furnish the bicyclic cores 4a-c. When one or two of the
electrophilic centers is protected/masked (e.g., aldehyde masked as a ketal), introduction of a
ic acid (e. g., PTSA) is required to liberate the reactive functional group.
Step 4
Deprotection, e. g, via hydrolysis, of the allyl ester leads to the carboxylic acids Sa-c. In
the deprotection step, compound 4a-c is subjected to hydrolytic conditions that are known to those
skilled in the art. For example, ent of 4a-c with phenylsilane or 4-methylbenzenesulf1nate in
the presence of a catalytic amount of palladium (e. g., Pd(PPh3)4) leads to the formation of the
corresponding ylic acid 5a-c. Alternatively, compounds 4a-c could be d with aqueous
alkali (e.g., NaOH, LiOH, or KOH) to produce acids 5a-c.
Step 5
In the activated ester formation step, the carboxylic acids Sa-c are d with amide
coupling agents known to those skilled in the art. Suitable amide coupling partners include, but are
not limited to TBTU, TCTU, HATU, T3P, and COMU. When the coupling agent is chosen
appropriately, the reactions can proceed rapidly (~lhr.) at room temperature in the presence of an
organic base such as an aliphatic amine (e.g., triethylamine, DIPEA) to provide the activated esters
6a-c. For example, when the amide coupling agents TBTU [J=H] or TCTU[J=Cl] are used,
compounds 6a-c are obtained readily by filtration of the reaction mixture.
Formation of the activated esters 6a-c prior to the amide bond formation to prepare LA is
generally preferred, gh a direct conversion of Sa-c into the compounds of formula I-A of this
invention is also possible. Alternative activated esters can also be ed (isolated or formed in situ)
and will be known to those skilled in the art (e. g., using CDI, TBTU, TCTU, HATU, T3P, COMU
coupling agents).
Step_ 6
] In the amide bond formation step, activated esters 6a-c can react with a substituted or
tituted 3—aminopyridine to e compounds of formula I-A of this invention. The reaction
conditions for the amide coupling are generally in an aprotic solvent (e. g., NMP, pyridine, DMF, etc
...) with heating (e. g., 2 90°C). The 3-aminopyridine may be further nalized following amide
bond formation.
Alternatively, the two steps described above can be combined: carboxylic acids 5a-c can
be used as starting points for the amide bond formation, the activated esters being generated in situ,
using the same amide couplings agents as those described above. Compounds I-A of this invention
are isolated in a similar manner to the one described above.
Selle—meB
pyrazole NH 'dine O
amide bond 0 2 N
N 2 o N /
/ pyrImII R2
0 R ’ R2
formation formation formation
”OJ—’ NC\/[LN\/ —>N/N\// N / I
—>\/N\
OH N H
H R3 HN H R3
R4 R4 €\ //N R4
Alternatively, compounds of the present disclosure can be prepared according to methods
similar to the one depicted in Scheme B.
Step 1
The amide 8 can readily be prepared from commercially available cyanoacetic acid 7. In
the amide bond formation step, cetic acid 7 can react with a substituted 3-aminopyridine to
provide compounds 8 of this ion. The reaction conditions for the amide coupling are generally
in an c solvent (e.g., DCM, NMP, DMF, etc), in the ce of an organic base, such as an
aliphatic amine, (e. g., triethylamine or DIPEA) and an amide coupling agent known to those skilled
in the art: for example EDCI, TBTU, COMU, T3P, etc....
Step 2
In the pyrazole formation step, the anion of cyanoamide 8 can be generated with a base
(such as potassium or sodium acetate) in an appropriate solvent such as an alcohol (e.g., l).
The anion then reacts with trichloroacetonitrile at room temperature. The resulting solid, which can
be ted by filtration, is then reacted with hydrazine (or its hydrate) in an aprotic solvent, such as
DMF or NMP, to provide the diaminopyrazole 9, the latter being further condensed with a
dielectrophilic coupling partner to form the pyrimidine portion of the nds of formula I-A of
this invention.
Step 3
In the pyrimidine ion step, intermediate 9 is reacted with a l,3-dielectrophilic
species (e. g., a aldehyde or a 3—(dialkylamino)—prop—2—enal) in various types of solvents (e.g.,
iPrOH/water, DMF, or DMSO/water) to h the desired products I-A. When one or two of the
electrophilic s is protected/masked (e.g., aldehyde masked as a ketal), introduction of a
sulfonic acid (e. g., PTSA) is required to liberate the reactive functional group.
PREPARATIONS AND EXAMPLES
All cially available ts and reagents were used as received. Microwave
reactions were carried out using a CEM Discovery microwave. Flash Chromatography, e.g., was
carried out on an ISCO© CombiflashR CompanionTM system eluting with a 0 to 100%
petroleum ether gradient. Other methods known in the art were also utilized to perform Flash
Chromotography. Samples were applied pre—absorbed on silica. Where stated, supercritical fluid
chromatography (SFC) was performed on a Berger Minigram SFC machine. All 1H NMR spectra
were recorded using a Bruker Avance III 500 instrument at 500 MHz. MS samples were analyzed on
a Waters SQD mass ometer with electrospray ionization operating in positive and negative ion
mode. Samples were introduced into the mass spectrometer using chromatography. All final
products had a purity 295%, unless specified otherwise in the experimental details. HPLC purity
was measured on a Waters Acquity UPLC system with a Waters SQD MS instrument ed with
a Waters UPLC BEH C8 1.7 um, 2.1 x 50 mm column and a rd BEH C8 1.7 um, 2.1 x 5 mm
guard column.
As used herein, the term “Rt(min)” refers to the HPLC retention time, in minutes,
associated with the compound. Unless otherwise indicated, the HPLC methods utilized to obtain the
reported retention times are as described below:
HPLC Method
Instrument: Waters Acquity UPLC—MS;
Column: Waters UPLC BEH C8 1.7 um, 2.1 x 50 mm with Vanguard BEH C8 1.7 um, 2.1 x 5 mm
guard column;
Column temperature: 45°C;
Mobile Phase A: lOmM um formate in water:acetonitrile 95:5, pH 9;
Mobile Phase B: acetonitrile;
Detection: 210—400 nm;
Gradient: 0-0.40 min: 2% B, 0.40-4.85 min: 2% B to 98% B, 4.85-4.90 min: 98% B to 2% B, 4.90-
.00 min: hold at 2% B;
Flow rate: 0.6 ute.
Preparation 1: Allyl 3,5-diamino-lH-pyrazolecarboxylate
NH2 0
O”N ’ /
Step I: allyl 3-amin0-4, 4, 4-trichl0r0cyan0but—2-en0ate 2
To a solution of KOAc (589.4 g, 6.006 mol) in isopropanol (3 L) was added allyl
cyanoacetate (429.4 g, 403.2 mL, 3.432 mol) and the reaction mixture was cooled to 5°C.
Trichloroacetonitrile (495.5 g, 3.432 mol) was added in 50 mL portions, maintaining temperature
below 15°C. The reaction mixture was then allowed to warm to 20°C and stirred for 3 hr. Water (~4
L) was added to dissolve the inorganic materials and precipitate out the desired product. The
e was stirred for 20 s and the solid was isolated by filtration under vacuum. This solid
was filtered, washed with water (2 x 0.5 L) and dried in a vacuum oven overnight at 40°C to afford
allyl 3—amino—4,4,4—trichloro—2—cyanobut—2—enoate 2 as an off—white powder (787 g, 85%).
Step 2: Allyl 3, in0-IH-pyrazolecarb0xylate 3
To a suspension of allyl 3-amino-4,4,4-trichlorocyano-butenoate 2 (619 g, 2.297
mol) and KOAc (676.3 g, 6.891 mol) in DMF (2.476 L) at 0°C was slowly added hydrazine hydrate
(172.5 g, 167.6 mL, 3.446 mol) over 15 min. The reaction mixture was then stirred at ambient
temperature for 2 hr., at which stage 1H NMR shows complete consumption of the starting material.
Reaction mixture was then heated overnight at 110°C before being allowed to cool to ambient and
stirred for another 48hr. The mixture was filtered through a sintered glass funnel to remove the
precipitated solid and the filtrate was evaporated under reduced pressure to give a thick liquid. DCM
(approx. 2 L) was added, and the mixture filtered again to remove additional solids that have
precipitated. The te was purified through a 1 kg silica gel plug (gradient of DCM/MeOH as an
eluent), and the solvent was removed to afford an orange solid which was suspended in acetonitrile
and heated at about 70°C until all the solid went into solution, at which point the on was
allowed to cool to ambient temperature, then to 2°C. The precipitate that formed was isolated by
filtration under vacuum, washed with chilled MeCN (~50 mL) and dried to constant mass in a
vacuum oven to furnish the title compound as an off-white powder (171.2 g, 41%).
Preparation 2a: 1H-benzo[d] [1,2,3]triazol—1-yl 2-aminofluoropyrazolo[1,5—a]pyrimidine—3-
carboxylate
Step I: allyl 2-amin0fluor0-pyrazolo[1,5-a]pyrimidine-S-carboxylate 421
To a suspension of allyl 3,5-diamino-1H-pyrazolecarboxylate 3 (42.72 g, 234.5 mmol)
in DMSO (270.8 mL) / Water (270.8 mL), was added p—TsOH hydrate (46.72 g, 245.6 mmol) and 3—
propylamino)—2—fluoro—prop—2—enal (described in Tetrahedron s, 33(3), ; 1992)
(38.69 g, 223.3 mmol). The reaction mixture was heated to 100°C for 3hr. during which time a solid
slowly precipitated out of solution. The orange suspension was allowed to cool down to RT
overnight. The solid was filtered, washed with water and dried under vacuum to give allyl 2-amino-
6—fluoro—pyrazolo[1,5—a]pyrimidine—3 —carboxylate 421 as a sand solid (45.05 g, 85% yield).
] In an alternative method, allyl 2-aminofluoro-pyrazolo[1,5-a]pyrimidinecarboxylate
421 may be synthesized via generic Scheme C—1, below.
Scheme C-1
-- NH
O electrophlllc 2
RO/OWQRO 0 _,
acid fluorinating agent 3 N O
—> HO \ H —> HO \
O O H
Pyrimidine fi/
F Formation O—\__
36 38 4a
Reaction 1
Bisacetal ted ldehyde (Intermediate 35) may be deprotected under acidic
conditions to form intermediate 36. In some embodiments, the acidic conditions may be generated by
utilizing an acid independently selected from HCl, H2804, MeSOzH, TFA, HBF4, or pTSA in a
suitable solvent, e. g., water. Preferably, the acid used in the reaction is selected from pTSA or
. RO is preferably a C1_6aliphatic group. In some embodiments, RO is selected from methyl,
ethyl, propyl, isopropyl, butyl or pentyl. In still other embodiments, RO is selected from methyl or
ethyl.
Reaction 2
] Intermediate 36 may be reacted with an electrophilic ating agent to form
intermediate 38. In some embodiments, the electrophilic fluorinating agent is ndently selected
from l-(Chloromethyl)—4-fluoro-l,4-diazoniabicyclo[2.2.2]octane afluoroborate (Selectfluor®),
Accufluor®, N—fluorobenzenesulfonamide, substituted l—fluoropyridinium salts, or fluorine gas.
Reaction 3
Intermediate 38 may be reacted with intermediate 3 under suitable condensation conditions
to form intermediate 43. In some embodiments, the suitable condensation conditions may include
reacting intermediate 38 with intermediate 3 in the presence of a solvent and heat to furnish the
bicyclic core of 4a. The reaction may take place in in various types of solvents, e. g., water,
DMSO/water, or DMF.
In one example, intermediate 4a is formed using the methodology described in Scheme C—
Scheme C-2
+/—C| HI}! \
£1 N\
' O
,N ZBF4
NH _\: NH2
pTSA O F 2
0 o o N, o
/ \
water V 37 3 [\j /
HO H
/0 0\ “O \ H Aq.DMSO o
H |
F 80°C /N \_—
35a 36 38 43
l,l,3,3-tetramethoxypropane 35a (20 g, 121.8 mmol) was dissolved in water (200ml). p—
Toluenesulphonic acid monohydrate (23. 17g, 121.8mmol) was added and the mixture stirred at 19-
°C for 90 minutes. 1-(Chloromethyl)fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate
37 (Selectfluor, 1.4 eqv, 60.4g, 170.5 mmol) was added portionwise. The addition was endothermic
(201°C to 194°C) however the temperature began to rise slowly once the addition was complete
(temp sed to 254°C over 45 minutes). The selectfluor dissolved over 1hr. The e was
allowed to stir at ambient temperature for 18hrs. The mixture was homogeneous after this time.
DMSO (150ml) was added slowly over 5 minutes. The on was exothermic- the temperature
increased from 204°C to 342°C during the addition. The mixture then began to cool. The resulting
mixture was d for 45 minutes. Compound 3 (21.4g, 115.7 mmol) was then added portionwise.
The addition was not exothermic. The mixture was heated to 85°C for 4hrs (LC/Ms profile was
identical at 2hr and 4hr time points). The stirred mixture was then allowed to cool to ambient
temperature overnight. The resulting reaction mixture was a slurry. Water (150ml) was added
slowly to the resulting slurry. The temperature increased from 204°C to 215°C. The slurry was
stirred for 2 hrs, and then the product was isolated by filtration. The cake was washed with water and
dried on the sinter to a beige solid (15.5 g). The product was further dried in a vac oven at 40°C for
20hrs. This gave compound 421 as a beige solid (13.5 g, 50% yield). HPLC purity 97.7 % area; 1H
NMR (500 MHz, 6) 5 4.83 (2H, d),5.29(1H, d), 5.49(1H, d), 6.04—6.14(1H, m), 6.57
(2H, brs), 8.80 (1H, m), 9.40 (1H, m); 19F NMR (500 MHz, DMSO—d6) 5 —153.1.
Step 2: 0fluor0-pyrazolofl,5-a]pyrimidine-S-carboxylic acid 521
To a suspension of allyl 2-aminofluoro-pyrazolo[1,5-a]pyrimidinecarboxylate 4a (45
g, 190.5 mmol) in DCM (1.35 L) was added phenylsilane (41.23 g, 46.96 mL, 381.0 mmol),
followed by Pd(PPh3)4 (8.805 g, 7.620 mmol). The reaction was stirred at room temperature for 2hr.
30min. The reaction mixture was filtered and the solid was washed with DCM to give a light yellow
solid (43.2g). This solid was triturated further in DCM (225 mL) at RT for 45 min, then filtered and
dried overnight under vacuum to provide 2—amino—6—fluoro—pyrazolo[1,5—a]pyrimidine—3—carboxylic
acid 521 as a light yellow solid (3 7.77g, 100% .
In an alternative method, sodiummethylbenzenesulfinate (anhydrous, 1.2 eqv, 22.6g,
127mmol) was ded in dry DMSO (20 vol, 500ml). The stirred mixture was warmed to 30°C
under a nitrogen atmosphere. Upon complete dissolution Pd(PPh3)4 (2 mol%, 2.4g, 2.1 mmol) was
added. The mixture was stirred for 10 min at 25-30°C after which time a turbid yellow solution was
present. Allyl 2-aminofluoro-pyrazolo[1,5-a]pyrimidine-3 -carboxylate 421 (25g, 105.8mmol) was
added portionwise, ining the temperature at 25—30°C. Once on was complete the cloudy
solution was d until the reaction was te by HPLC (2-3 hrs). A heavy precipitate formed
after 15 minutes post addition of the substrate. The mixture became thicker as the reaction
proceeded. The on mixture was diluted with water (125 ml) and 2M HCl (66 ml) was added
slowly, maintaining the temperature at 25-30°C. The slurry was stirred for 30 minutes, then filtered.
The filtration was slow (2hrs). The resulting solid was washed with water, then dried on the sinter.
The solid was slurried in DCM (8 vol) for 1hr. The solid was filtered (rapid filtration) and washed
with DCM. The solid was re-slurried in chloroform (8 vol) for 1 hr. The acid was filtered and dried
on the sinter. It was further dried in a vacuum oven at 50°C for 24 hrs. The product 521 was obtained
as an off—white solid , 85%); 1H NMR (500 MHz, DMSO—d6) 5 12.14 (1H, brs), 9.31 (1H, dd),
8.69 (1H, m), 6.47 (2H, brS); 19F NMR (500 MHz, DMSO—d6) 5 —153.65; MS (ES+) 197.1.
Step 3 .‘ IH-benzo[d][1, 2, 3]triazol—I-yl 2-amin0-6—flu0r0pyrazolo[I, 5-a]pyrimidine-S-carboxylate
To a suspension of 2—aminofluoro-pyrazolo[1,5-a]pyrimidinecarboxylic acid 521 (20
g, 102.0 mmol) in chloroform (300 mL) was added Et3N (11.35 g, 15.63 mL, 112.2 mmol). The
suspension was stirred for ~ 5mins and then (benzotriazol-l-yloxy-dimethylamino-methylene)-
yl-ammonium Boron Tetrafluoride was added (32.75 g, 102.0 mmol). The suspension was
heated to 60°C for 1hr. before the thick suspension was allowed to cool down to RT. The resulting
suspension was filtered, washed with chloroform (200 mL) and dried under vacuum overnight to
afford the title compound 63 as a light yellow powder (32.5g, 88%).
Preparation 2b: (6-chlor0benzotriazol—1-yl)aminofluoro-pyrazolo[1,5-a]pyrimidine
carboxylate
621*
In a 2.5 L necked flask equipped with stirrer bar, condenser, nitrogen line and Hanna
temperature probe was d 2-aminofluoro-pyrazolo[1,5-a]pyrimidinecarboxylic acid 521
(60 g, 305.9 mmol), chloroform (900.0 mL) and triethylamine (32.44 g, 44.68 mL, 320.6 mmol). [(6—
chlorobenzotriazolyl)oxy-(dimethylamino)methylene]-dimethyl-ammonium (Boron Tetrafluoride
Ion (1)) (87.00 g, 244.7 mmol) was added portionwise over 5 mins (internal dropped from 22.7 to
21.5°C on complete on). Mixture heated at 60°C nal temp) for 2hr., still a cream
suspension. Mixture cooled to room temperature then solid collected by filtration, washed well with
chloroform (until filtrate runs essentially colourless) and dried by suction to leave product 621* as a
cream solid (82.2g, 77% yield). 1H NMR (500 MHz, DMSO-d6) 5 9.55 (dd, 1H), 8.91 (d, 1H), 8.22
(dd, 1H), 8.09 (dd, 1H), 7.57 (dd, 1H) and 6.87 (s, 2H). MS (ES+) 348.1.
In an ative method, 2-Aminofluoropyrazolo[1,5-a]pyrimidine—3-carboxylic acid
521 (30g, 153 mmol) was slurried in acetonitrile (540ml). Triethylamine (22.5ml, 153mmol) was
added, followed by [(6—chlorobenzotriazol-1yl)oxy-(dimethylamino)methylene]-dimethylammonium
tetrafluoroborate (TCTU, 54.4g, 153mmol). The mixture was stirred at room temperature for 2 hrs.
The t was isolated by filtration- the filter cake was washed with acetonitrile (2x60ml). The
product was obtained as a brown solid (49.3 g, 93%); 1H NMR (500 MHz, DMSO—dg) 5 9.55 (dd,
1H), 8.91 (d, 1H), 8.22 (dd, 1H), 8.09 (dd, 1H), 7.57 (dd, 1H) and 6.87 (s, 2H); 19F NMR (500 MHz,
DMSO—d6) 5 —150.1; MS (ES+) 348.1.
Preparation 3: 1H-benzo[d] [1,2,3]triazol—1-yl 2-amin0-6—chloropyrazolo[1,5-a]pyrimidine—3-
carboxylate
NH2 0
,N=N
Ntil/(0 0,N
g\ //N
Step I: 2-amin0-6—chlor0-pyrazolo[1,5-a]pyrimidine-S-carboxylate 4b
To a suspension of allyl amino-1H-pyrazole—4-carboxylate 3 (1 g, 5.489 mmol) in
DMF (5 mL) was added (Z)—2-chlorodimethylamino-propenylidene]-dimethyl-ammonium
hexafluorophosphate (1.683 g, 5.489 mmol), followed by triethylamine (722.1 mg, 994.6 uL, 7.136
mmol). The reaction mixture was heated to 60°C for 4hr. during which time a solid slowly
precipitated out of solution. The brown suspension was d to cool down to RT. The solid was
filtered, washed with water and dried under vacuum to give allyl 2-aminochloro-pyrazolo[1,5-
midinecarboxylate 4b as a brown solid (1.092 g, 72% yield).
Step 2: 2-amin0-6—chlor0-pyrazolo[1,5-a]pyrimidine-S-carboxylic acid 5b
To a suspension of allyl 2-aminochloro-pyrazolo[1,5-a]pyrimidine-3 -carboxylate 4b (1
g, 3.96 mmol) in DCM (15 mL) was added phenylsilane (856.6 mg, 0.9756 mL, 7.916 mmol),
followed by Pd(PPh3)4 (182.9 mg, 0.1583 mmol). The reaction was stirred at room temperature for
7hr. The reaction mixture was filtered and the solid was washed with DCM to give a light yellow
solid (43.2g). This solid was triturated further in DCM (225 mL) at RT for 45 min, then filtered and
dried overnight under vacuum to provide 2-aminochloro-pyrazolo[1,5-a]pyrimidine-3 -carboxylic
acid 5b as a yellow solid (791m, 94% .
Step 3 .‘ IH-benzo[d][1,2, 3]triazol—I-yl 2-amin0chlor0pyrazolo[1,5-a]pyrimidinecarb0xylate
To a solution of 2-aminochloro-pyrazolo[1,5-a]pyrimidinecarboxylic acid 5b (1.51
g, 7.103 mmol) in chloroform (15.1 mL) was added TBTU boron uoride (2.737 g, 8.524 mmol)
and TEA (862.5 mg, 1.188 mL, 8.524 mmol). The reaction mixture was stirred at 50°C for one hour.
The resulting sion was filtered, and the solid triturated in ethyl acetate to afford the title
nd 6b as a yellow solid (2.05 g, 88%).
ation 4: 1H-benzo[d] [1,2,3]triazol—1-yl 2-amino(cyanomethyl)pyrazolo[1,5-
a]pyrimidinecarboxylate
NH2 0
IN:N
N‘Nj/MO 0,N
E\ //N
Step I: allyl 2-amin0(cyan0methyl)-pyrazolo[1,5-a]pyrimidine-S-carboxylate 4c
To a suspension of allyl 3,5-diamino-1H-pyrazole—4-carboxylate 3 (63.49 g, 348.5 mmol)
in a mixture of DMSO (340 mL) and water (340 mL), was added 3-(dimethoxymethyl)-4,4-
dimethoxy-butanenitrile (prepared according to Preparation 5, below) (85 g, 418.2 mmol), followed
by para—toluene Sulfonic acid hydrate (1) (11.27 g, 59.24 mmol). The reaction mixture was heated
to 85°C and stirred overnight. The reaction e was cooled with an ice bath. The mixture was
diluted with EtOAc (680 mL) and a saturated aqueous solution O3 (1.36 L). The precipitate
was filtered and rinsed with water, then with a mixture of water and EtOAc. The brown solid was
dried under vacuum to give allyl 2-amino(cyanomethyl)-pyrazolo[1,5-a]pyrimidinecarboxylate
4c as a brown solid (55.94 g, 62% yield).
Step 2: 2-amin0-6—(cyanomethyD-pyrazolofl,5-a]pyrimidine-S-carboxylic acid SC
To a sion of allyl 2-amino(cyanomethyl)-pyrazolo[1,5-a]pyrimidine
carboxylate 4c (10.2 g, 39.65 mmol) in DCM (350 mL) was added phenylsilane (8.581g, 9.773 mL,
79.3 mmol), followed by Pd(PPh3)4 (1.5 g, 1.298 mmol). The reaction was stirred at room
temperature for 2hr. The reaction mixture was filtered and the solid was washed with DCM and
dried under vacuum to provide 2-amino(cyanomethyl)-pyrazolo[1,5-a]pyrimidinecarboxylic
acid 5c as a yellow solid (8.61g, 100% yield).
Step 3 .‘ IH-benzo[d][1,2, 3]triazol—I-yl 0(cyanomethybpyrazolofl,5-a]pyrimidine
ylate 6c
To a solution of 2-amino(cyanomethyl)-pyrazolo[1,5-a]pyrimidinecarboxylic acid 5c
(5.11 g, 23.53 mmol) in DCM (51 mL) was added TBTU boron tetrafluoride (9.067 g, 28.24 mmol)
and TEA (2.858 g, 3.937 mL, 28.24 mmol). The reaction mixture was d at room temperature
for one hour. The resulting suspension was filtered, and the solid triturated in hot chloroform to
afford the title compound 6c as a beige solid (6.59 g, 84%).
\ N N
NH2 I ’ /
|)TFA/DCM (1/3). O .
N=N / N\// N \ / triethylsilane
’ H N N// N \ /
N 2 F 90°C,12h
/ o—N N H
F RT, 12h N H
N N
+ —, \ ,N \ /N N
s\ N
// 56% 96%
F F
F CI .TFA
o OtBu 0 0
0,3” OH
27 28 29
i)TCTU.1.1eq
DIPEA3eq
RT, 30mins “Hz 0 N
n) /
NH2 NH N/
O /N 2 O /N HNflN-CO /
1,4 eq \ / N \
4M HCI 1.2 sq \_z N H
N , F
\ / N \ / NMP N / N \ / 25 N N
N \ /
H RT, 20mins N
F H
\ ,N N
\ /N N RT,30 F
0 mins
100%)
F F —> O
-TFA I»
O .HCI 647
0 °
OH OH LN
1-1
Step I: tert—butyl I-[3-[(2-amin0-6—fluor0-pyrazolofl,5-a]pyrimidine-S-carbonybamin0]flu0r0-
4-pyridyl]pmeridine-él-carboxylate 28
A e of (6-chlorobenzotriazolyl) 2-aminofluoro-pyrazolo[1,5-a]pyrimidine
carboxylate 621* (44.02 g, 126.6 mmol) and tert—butyl 1-(3-aminofluoropyridyl)piperidine
carboxylate 27 (prepared according to Preparation 7b) (34 g, 115.1 mmol) in pyridine (510.0 mL)
was heated at 95°C internally overnight (18hr.). Mixture was cooled to room temperature (product
precipitated) then added ethanol (340.0 mL) and stirred at room temperature for 10 mins. Collected
yellow solid by filtration, washed well with ethanol, dried by suction, then on high vac line for 1hr.
to leave t 28 as a yellow solid, (32.5g 56% yield). 1H NMR (500 MHz, 6) 5 10.45 (s,
1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15 — 2.93 (m, 4H), 2.55
— 2.47 (masked signal, 1H), 2.02 — 1.91 (m, 4H), 1.47 (s, 9H). MS (ES+) 474.2.
Step 2: I-[3-[(2-amin0flu0r0-pyrazolofl,5-a]pyrimidine-S-carbonyl)amin0]flu0r0
pyridyUpiperidinecarb0xylic acid trifluorocetate 29
To a suspension of tert—butyl 1—[3—[(2—aminofluoro-pyrazolo[1,5—a]pyrimidine—3—
carbonyl)amino]fluoropyridyl]piperidinecarboxylate 28 (69.7 g, 147.2 mmol) in DCM
(348.5 mL) and triethylsilane (18.83 g, 25.87 mL, 161.9 mmol) was added TFA (151.1 g, 102.1 mL,
1.325 mol) (mixture sets solid on initial addition of TFA then goes into solution after complete
on). Resulting orange solution was stirred at room temperature overnight. Additional TFA
(16.78 g, 11.34 mL, 147.2 mmol) was added and the mixture stirred at room temperature for 2hr.
Mixture then heated at 40°C for 20 mins to force on to completion. Mixture was concentrated
in vacuo, chloroform (300 mL) was added and mixture again concentrated in vacuo to leave an
orange solid suspension. Mixture triturated in DCM (approx. 200 mL), stirred for 20 mins then solid
collected by filtration, washed with minimal DCM and dried by suction to leave a yellow solid.
Filtrate was trated in vacuo, residue re-slurried in DCM (approx. 50 mL), stirred for 20 mins
then solid collected by tion, washed with minimal DCM and dried by suction to leave a yellow
solid which was combined with first crop of solid. Solid dried under vacuum overnight to leave
desired product 29 as a yellow solid (82.8g, 96%). 1H NMR (500 MHz, 6) 5 10.44 (s, 1H),
9.59 (s, 1H), 9.50 (dd, 1H), 8.84 (dd, 1H), 8.33 (d, 1H), 3.13 — 3.10 (m, 4H), 2.57 — 2.47 (masked
signal, 1H) and 2.08 — 1.93 (m, 4H). MS (ES+) 418.1.
Step 3: I—[3-[(2-amin0-6—flu0r0-pyrazolofl,5-a]pyrimidinecarb0nyl)amin0]flu0r0
pyridyUpzperidinecarb0xylic acid hydrochloride 30
To a solution of 1-[3-[(2-aminofluoro-pyrazolo[1,5-a]pyrimidine-3 -carbonyl)amino]
fluoropyridyl]piperidinecarboxylic acid (Trifluoroacetic Acid) 29 (73 g, 124.7 mmol) in NMP
(662.7 mL) was added hydrogen chloride (4M in 1,4—dioxane) (37.40 mL of 4 M, 149.6 mmol). After
a few seconds a yellow itate formed. Mixture stirred at room temperature for 20 mins, then
solid collected by filtration, washed with minimal NMP then MTBE, and dried by suction to leave
pure product 30 as a light yellow solid, (59.7g, quantitative yield). MS (ES+) 418.1.
Step 4: 2-amin0-6—flu0r0-N-[5-flu0r0-4—[4-[4—(oxetan-S-priperazine-I—carbonyU—I—piperidyU-S-
pyridyUpyrazolofl,5-a]pyrimidine—S-carboxamide (Compound I-1)
To a yellow suspension of 1—[3—[(2—amino—6—fluoro—pyrazolo[1,5—a]pyrimidine—3—
carbonyl)amino]fluoropyridyl]piperidinecarboxylic acid (Hydrochloric Acid) 30 (59.7 g,
131.5 mmol) in NMP (477.6 mL) was added DIPEA (50.99 g, 68.72 mL, 394.5 mmol) then [(6—
chlorobenzotriazolyl)oxy-(dimethylamino)methylene]-dimethyl-ammonium (Boron Tetrafluoride
Ion (1)) (51.44 g, 144.7 mmol). A yellow suspension forms after a few minutes. The mixture was
sirred for 30 mins at room temperature then 1-(oxetanyl)piperazine 25 (prepared according to
Preparation 8, below) (26.18 g, 184.1 mmol) was added. The tan sion turns to an
orange on (exotherms from 23.9 to 294°C). The flask was placed on ice/water bath until
internal temperature was at 24°C, then ice bath was removed and internal ature steady at 24°C
thereafter.
WO 85132
The solution was stirred for 30 mins at room temperature then cooled on an ice/salt/water
bath to 10°C before the slow addition of water (1.015 L) in 100 mL portions. Prior to adding the
next 100mL of water, waited for rm to between 17°C and 20°C (internal) then allow to cool to
between 10 and 15°C. Repeated until all water added. Once exotherm had ceased, ice/salt/water bath
removed and mixture stirred at ambient temperature for 20 mins (thick yellow/cream suspension
forms). Solid collected by filtration through a sinter funnel, washed well with water then dried by
n for 10 mins. Vacuum removed and solid slurried in water on sinter funnel, then vacuum
ied and solid dried by suction overnight then dried in vacuum oven for 24 h at 40°C <10 mBar.
Solid (54.5 g) suspended in ethanol (545 mL, 10 vol eq.) and heated under reflux for 2hr.
then cooled to room temperature over 2h. Solid collected by filtration, washed with minimum
ethanol and dried by suction for 1h to leave product as a pale yellow solid. Solid placed in vacuum
oven at 23.5°C and <10mBar overnight to leave the ethanol e solid form of LI as a pale yellow
solid, (51g, 64% yield). 1H NMR (500 MHz, DMSO—d6) 5 10.64 (s, 1H), 9.67 (s, 1H), 9.48 (dd,
1H), 9.26 (dd, 1H), 8.26 (d, 1H), 6.79 (s, 2H), 4.55 (t, 2H), 4.47 (t, 2H), 4.34 (t, 0.7H), 3.61 (dt, 4H),
3.48 — 3.41 (m, 25H), 3.22 — 3.17 (m, 2H), 3.05 — 3.03 (m, 2H), 3.99 — 2.93 (m, 1H), 2.28 (dt, 4H),
2.17 — 2.10 (m, 2H), 1.74 (d, 2H), 1.07 (t, 2H). MS (ES+) 542.3.
S} E 1
NH2 0 / N d N
NH / NH
NH2 0 N=N 2 O 2 O /
O O/i< N/ NQF HCI I O I
/ \
N/ \
,N 27 \
/ H dioxane/ N F N’
/ N F
N O N N water \ H 25 \ / H
N / —» —>N N —> N N N
° \ /
>—’ />\ N TCTU
Pyndme,9oc
\ IN CI // -HC'
DlPEA \ /N
F THF
F O O
4\ 0 OH 0 N/fi
6a* \C\O
28 30 [.1
Step I: tert—butyl I-(3-(Z-amino-6—fluor0pyrazolofl,5-a]pyrimidine-S-carboxamido)
fluoropyridin-4—yl)pzperidinecarb0xylate 28
6-chloro-1H—benzo[d][1,2,3]triazolyl 2-aminofluoropyrazolo[1,5-a]pyrimidine-3 -
carboxylate 621* (45g, mol) and tert—butyl 1-(3-aminofluoropyridinyl)piperidine
carboxylate 27 (prepared according to ation 7b, described below) (40.1g, 135.9mmol) were
slurried in pyridine (675ml). The mixture was heated at 95°C under nitrogen until the reaction was
complete (determined by HPLC analysis). The mixture was cooled and ethanol ) was added
dropwise. The mixture was d and the filter cake washed with ethanol (2x70ml). The damp cake
was dried to give the product 28 as a yellow lline solid (47.7g, 78%); 1H NMR (500 MHz,
DMSO—d6) 5 10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15
— 2.93 (m, 4H), 2.55 — 2.47 (masked signal, 1H), 2.02 — 1.91 (m, 4H), 1.47 (s, 9H); 19F NMR (500
MHz, DMSO—d6) 5 — 153.5, —136.3; MS (ES+) 474.2.
In an alternative embodiment, intermediate 28 may be purified prior to performing step 2
by using a procedure similar to the following:
Step Ia: ation oftert-butyl I-[3-[(2-amino-6—fluoro-pyrazolo[1,5-a]pyrimidine
yl)amino]fluoropyridyl]pzperidinecarboxylate 28
tert—Butyl 1—[3-[(2-aminofiuoro-pyrazolo[1,5-a]pyrimidinecarbonyl)amino]
fiuoropyridyl]piperidinecarboxylate 28 (530g; 1.12moles) was added to a mixture ofNMP
(5.3L) and 1,2-diaminopropane (249g; 3.3 6moles) and the resulting thin suspension was stirred at
—25°C for 15 hours. l (10.4L) was added to the suspension and the suspension was stirred
for 4 hours at 20-25°C. The crystalline golden solid was collected by filtration, washed with ethanol
(2 x 2.6L), dried by suction then dried in a vacuum oven for 24 hours at 35—40°C to give 28 as a
crystalline golden solid (479g; 90%). 1H NMR (500 MHz, DMSO—d6) 5 10.45 (s, 1H), 9.57 (s, 1H),
9.49 (dd, 1H), 8.71 (d, 1H), 8.24 (d, 1H), 6.79 (s, 2H), 3.44 — 3.33 (m, 1H), 3.34 — 3.20 (m, 4H), 3.07
(dt, 4H), 2.01 — 1.89 (m, 4H), 1.46 (s, 9H). 191: NMR (500 MHz, DMSO—d6) 5 -136.3, —153.4.
Step 2: I-(3-(2-amino-6—fluoropyrazolo[1,5-a]pyrimidinecarboxamido)fluoropyridin
yl)pzperidinecarboxylic acid hydrochloride 30
Tert—butyl 2-aminofiuoropyrazolo[1,5-a]pyrimidinecarboxamido)
fiuoropyridinyl)piperidinecarboxylate 28 (36g, 76mmol) was suspended in a on of HCl in
1,4—dioxane (4M, 670ml). Water (36ml) was added dropwise to the rapidly stirred slurry. The
mixture was stirred under nitrogen until the reaction was complete (determined by HPLC analysis).
The mixture was diluted with 1,4-dioxane (180ml) and filtered. The filter cake was washed with
TBME (2x72ml). The damp cake was dried to give a pale brown solid (hydrochloride salt, 32.7g,
95%); 1H NMR (500 MHz, DMSO—d6) 5 10.34 (s, 1H), 9.53—9.49 (m, 2H), 8.82 (m, 1H), 8.50 (m,
1H), 3.13 — 3.22 (m, 4H), 2.57 — 2.47 (masked signal, 1H) and 2.08 — 1.93 (m, 4H); 19F NMR (500
MHz, 6) 5 — 152.9, —133.8; MS (ES+) 418.1.
Step 3 .‘ 0-6—flu0r0-N-[5-flu0r0-4—[4-[4—(oxetan-S-priperazine-I—carbonyU—I—piperidyU-S-
ljpyrazolofl,5-a]pyrimidine-S-carboxamide (Compound Iamorphous)
To a solution of 1-(oxetanyl)piperazine 25 (525mg, 3.69mmol) in THF (12ml) was
added DIPEA (1.72ml, 9.91mmol), followed by 1-(3-(2-aminofluoropyrazolo[1,5-a]pyrimidine
carboxamido)fluoropyridinyl)piperidinecarboxylic acid (hydrochloride salt, 1.5g, 3.3mmol).
[(6-chlorobenzotriazolyl)oxy-(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate
(TCTU, 1.29g, 3.64mmol) was added and the mixture stirred under nitrogen until reaction
tion (determined by HPLC analysis). The mixture was cooled and water (24ml) was added
dropwise. The mixture was allowed to warm to ambient and stirred for 3 hrs, then filtered. The filter
cake was washed with (3x3 ml). The damp cake was dried under vacuum (with a nitrogen bleed) at
40°C. An amorphous form of compound I-1 was ed. (1.54g, 86%); 1H NMR (500 MHz,
DMSO—d6) 5 10.64 (s, 1H), 9.67 (s, 1H), 9.48 (dd, 1H), 9.26 (dd, 1H), 8.26 (d, 1H), 6.79 (s, 2H),
4.55 (t, 2H), 4.47 (t, 2H), 4.34 (t, 0.7H), 3.61 (dt, 4H), 3.48 — 3.41 (m, 2.5H), 3.22 — 3.17 (m, 2H),
3.05 — 3.03 (m, 2H), 3.99 — 2.93 (m, 1H), 2.28 (dt, 4H), 2.17 — 2.10 (m, 2H), 1.74 (d, 2H), 1.07 (t,
2H); 19F NMR (500 MHz, DMSO—d6) 5 — 152.8, —136.1; MS (ES+) 542.3.
Compound I-1°amorphous may be prepared using an alternative method from Example
2, Step 3, above.
In another example, Compound orphous was prepared by adding N,N—
Diisopropylethylamine (461uL; 342mg; 2.64mmol) to a suspension of 1-[3-[(2-amino—6—fluoro—
pyrazolo[1,5 -a]pyrimidine-3 -carbonyl)amino] -5 -fluoropyridinyl]piperidinecarboxylic acid
hydrochloride 30 (1.00g; 2.20mmol; LR) in THF (20mL). 1,1'-Carbonyldiimidazole (CD1) ;
2.65mmol) was added and the mixture was heated at C. Additional charges of 1,1'—
Carbonyldiimidazole (CD1) (213mg total; 1.31mmol) were made and the mixture heated until
reaction completion (determined by HPLC analysis). 1-(oxetan-3 -yl)piperazine 25 (375mg;
2.64mmol) was added and the mixture was heated at 55-60°C until on completion (determined
by HPLC analysis). The on was cooled to 20-25°C. Water (40mL) and 2M NaOH(aq) (551uL)
were added and the suspension was stirred for 5—10 minutes. The solids were collected by filtration,
washed with water (2 x 5mL), dried by suction then dried in a vacuum oven at 45—50°C for 16 hours
to give 1—1 as a yellow solid (869mg; 73%).
Pre aration 5: Alternative a roach to s nthesis of tert-but l 1- 3- 2-amino
fluoro razolo 1 5—a rimidine—3-carboxamido fluoro ridin l i e—4-
ylate (Compound 281
WO 85132
/ m
N OH SOCIZ, Et3N / 27
N CI N
‘N ’ —.' ‘N /
f” \ x”
CHZCIZ, 40 C
\ /N \ /N Pyrldlne, 90°C
F F
53 34 28
Step I: 2-amin0-6—fluor0-pyrazolofl,5-a]pyrimidine-S-carbonyl chloride 34
To a suspension of 2—amino-6—fluoro—pyrazolo[1,5—a]pyrimidine—3—carboxylic acid 521
(500mg, 2.55mmol) in dichloromethane (7.5mL) was added triethylamine , 297mg,
2.93mmol). Thionyl chloride (205uL, 334mg, 2.80mmol) was added and the mixture heated at 35-
40°C for 2 hours. The mixture was cooled to t ature and d at ambient temperature
until reaction tion (monitored by HPLC). The solid was collected by filtration, washed with
dichloromethane (2 x 1mL) and dried by suction to give the product 34 as a beige solid (465mg,
85%); 1H NMR (500 MHz, DMSO—d6) 5 9.30 (dd, J= 4.9, 2.7 Hz, 1H), 8.68 (d, J= 2.7 Hz, 1H);
19F NMR (500 MHz, DMSO—d6) 5 —154. 1.
Step 2: tert—bulyl I-(3-(2-amin0-6—fluor0pyrazolofl,5-a]pyrimidinecarb0xamid0)flu0r0pyridin-
4-yl)pzperidine—4-carb0xylate 28
2-aminofluoro-pyrazolo[1,5-a]pyrimidinecarbonyl chloride 34 (100mg, 0.466mmol)
and tert—butyl 1-(3-aminofluoropyridinyl)piperidinecarboxylate 27 (138mg, 0.466mmol)
were slurried in pyridine (1.5mL). The mixture was heated to 90-100°C for 16 hours. The mixture
was cooled and l (3mL) was added. The mixture was stirred for 1—2 hours, filtered and the
filter cake washed with ethanol (0.5mL). The solids were dried by suction to give the product 28
(162mg, 73%). 1H NMR (400 MHz, DMSO—d6) 5 10.45 (s, 1H), 9.57 (s, 1H), 9.50 (dd, J= 4.8, 2.5
Hz, 1H), 8.71 (d, J=2.5 Hz, 1H), 8.24 (d, J= 2.5 Hz, 1H), 6.80 (s, 2H), 3.07 (dd, J= 6.5, 3.3 Hz,
4H), 2.11 — 1.80 (m, 4H), 1.46 (s, 9H); 19F NMR (500 MHz, DMSO—d6) 5 —136.8, —153.9; MS
(ES+) 474.2.
1C0mpound I-lz
HZN F H
N E J
” N
5N OHOJ<NOHF/NI o 6 NH
2/ NH2 O /
NH2 0 N \
MsOH I
MeCN
N O,N N F
/ N H
N —> N‘fi/k N
\>_//N
—>$—/NHPyndine 90°C FSN:N 339::
THF $_//N
F .MSOHO O N/fi
6a* \C\O
28 33 1.1
Step I: tert—bulyl I-(3-(2-amin0-6—fluor0pyrazolofl,5-a]pyrimidinecarb0xamid0)flu0r0pyridin-
4-yl)pzperidine—4-carb0xylate 28
6-chloro-1H—benzo[d][1,2,3]triazolyl 2-aminofluoropyrazolo[1,5-a]pyrimidine-3 -
carboxylate 621* (45g, 129.4mmol) and tert—butyl 1-(3-aminofluoropyridinyl)piperidine
carboxylate 27 red accoding to Preparation 7b, described below) (40.1g, 135.9mmol) were
slurried in pyridine (675ml). The mixture was heated at 95°C under nitrogen until the reaction was
complete (determined by HPLC analysis). The mixture was cooled and ethanol (450ml) was added
dropwise. The mixture was filtered and the filter cake washed with ethanol (2x70ml). The damp cake
was dried to give the product 28 as a yellow lline solid (47.7g, 78%); 1H NMR (500 MHz,
DMSO—dg) 5 10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15
- 2.93 (m, 4H), 2.55 — 2.47 (masked signal, 1H), 2.02 — 1.91 (m, 4H), 1.47 (s, 9H); 19F NMR (500
MHz, DMSO—d6) 5 — 153.5, ; MS (ES+) 474.2.
Step 2: I-[3-[(2-amin0flu0r0-pyrazolofl,5-a]pyrimidine-S-carbonyl)amin0]flu0r0
l]piperidinecarb0xylic acid mesylate 33
esulphonic acid (274uL; 406mg; ol) was added to a suspension of tert—
butyl 1-[3-[(2-aminofluoro-pyrazolo[1,5-a]pyrimidine-3 -carbonyl)amino]fluoro
pyridyl]piperidinecarboxylate 28 (1.00g; 2.11mmol) in acetonitrile (15mL) and the mixture was
heated to 75—80°C for 16 hours. The solids were collected by filtration, washed with acetonitrile (2 x
2mL) and dried under vacuum to give 1-[3-[(2-aminofluoro-pyrazolo[1,5-a]pyrimidine
carbonyl)amino]fluoropyridyl]piperidine—4—carboxylic acid mesylate 33 (0.94g; 87%). 1H
NMR (500 MHz, DMSO—d6) 5 10.43 (s, 1H), 9.58 (s, 1H), 9.49 (dd, 1H), 8.83 (d, 1H), 8.32 (d, 1H),
6.85 (bs, 2H), 3.11 (dt, 4H), 2.31 (s, 3H), 1.99 (m, 4H); 19F NMR (500 MHz, DMSO—d6) 5 —135.5, —
153.1; MS (ES+) 418.1.
Step 3 .‘ 2-amin0-6—fla0r0-N-[5-fla0r0[4-[4-(oxetan-S-priperazine-I-carbonyU—I-piperidyl]
pyridyljpyrazolofl,5-a]pyrimidine—S-carboxamide (Compound I-1 amorphous)
MN—Diisopropylethylamine (51uL; 38mg; 0.29mmol) was added to a suspension of 1—[3—
[(2-aminofluoro-pyrazolo[1,5-a]pyrimidinecarbonyl)amino]fluoropyridyl]piperidine
carboxylic acid mesylate (50mg; mol) and 1-(oxetanyl)piperazine (15mg; 0.11mmol) in
THF (1.00mL). lorobenzotriazolyl)oxy-(dimethylamino)methylene]-dimethyl-ammonium
uoroborate (TCTU, 36.3mg; 0.10mmol) was added and the mixture stirred under nitrogen until
reaction completion (determined by HPLC analysis). Water (2mL) was added to the suspension and
stirred for 5 hours. The solids were collected by filtration, washed with water (2 x 200uL), dried by
suction then dried in a vacuum oven for 24 hours at 45—50°C to give I-1 as a pale yellow solid
(3 1mg; 59%).
Pre aration 6: Pre aration of butanenitrile intermediates
OMe OMe OMe OMe
functional
MeO OMe MeO OMe M90 O'V'e M60 OMe
group alkylation
’ +
transformation
OMe OMe R8 OMe R88 OMe
OH ON ON CN
11 12a (R8=Me) 13a (R8=Me)
12b (R8=Et) 13b (R8=Et)
Step I: eth0xymethyD-4,4-dimeth0xybatanenitrile 11
2—(dimethoxymethyl)—3,3—dimethoxy—propan—1—ol 10 (Journal 0fthe American Chemical
Society (1973), 95(26), 8741) (92 g, 473.7 mmol) was dissolved in dry THF (920 mL) and the
mixture was cooled down with an ice bath. Triethylamine (143.8g, 198.1 mL, 1.421 mol) was added
at once, ed by dropwise addition of e sulfonyl chloride (59.69g, L, 521.1
mmol), over 1hr. and keeping the internal temperature below 5°C. The reaction mixture was stirred
for 1 hr. and then allowed to warm to room temperature. The mixture was diluted with ethyl acetate
WO 85132
(920mL) and water (920mL). The layers were separated and the organic layer was isolated, washed
with a saturated solution ofNaHCO3, then brine. The organics were dried over MgSO4, filtered and
evaporated to give [2-(dimethoxymethyl)-3,3-dimethoxypropyl]methanesulfonate as an orange oil
(125.31g, 97%) which was used ly without further cation.
Tetraethylammonium cyanide (142.3g, 910.8mmol) was added portionwise over 10
minutes to a solution of [2-(dimethoxymethyl)-3,3-dimethoxypropyl]methanesulfonate (124g,
mol) in MeCN (1.24L). The reaction mixture was stirred at room temperature for 72hr., then
portioned between ethyl acetate (1 .24L) and water (1 .24L). The layers were separated and the
organic layer was isolated, washed with brine. The organics were dried over MgSO4, filtered and
evaporated to give 3-(dimethoxymethyl)-4,4-dimethoxybutanenitrile 11 as a dark brown oil (86. lg).
Step 2: 3-(dimeth0xymethyD-4,4-dimeth0xymethylbutanenitrile 12a and 3-(dimeth0xymethyD-4,4-
dimethoxy-Z,2-dimethylbutanenitrile 13a
To a on of 3-(dimethoxymethyl)-4,4-dimethoxy-butanenitrile 11 (250 mg, 1.205
mmol) in THF (3 mL) at —75°C was added a solution of iodomethane (513.1 mg, 225.0 uL, 3.615
mmol) in THF (1 ml). A THF solution of (bis(trimethylsilyl)amino)sodium (1.808 mL of 2M, 3.615
mmol) was then added, keeping the ature below -60°C. After addition, the reaction mixture
was stirred at —75°C for 2hrs and then slowly quenched with aqueous saturated NH4C1 solution (5ml).
The mixture diluted with water and ether and layers separated. The c layer was washed with
brine, dried 4) and concentrated in vacuo to afford a yellow oil which was purified by
chromatography on silica gel, eluting with a petroleum ether:EtOAc gradient of 100:0 to 80:20.
Solvents were concentrated in vacuo to afford a clear oil (194mg). NMR proved this oil to be a
mixture of 80% mono methyl compound 12a with and 20% bis methyl compound 13a. This mixture
was used directly in subsequent steps.
Step 3: 3-(dimethoxymethyl)ethyl—4,4-dimeth0xybutanenitrile 12b and 3-(dimeth0xymethyD
diethyl—4, 4-dimeth0xybutanenitrile 13b
When ethyl iodide was used instead of methyl iodide in a similar procedure to
Preparation 6, step 2, above, a mixture of monosubsituted compound 12b and disubstituted
compound 13b was isolated and used directly in subsequent steps.
Pre aration 7a: S nthesis of tert—but 11- 3-amino-5—fluoro rid l i eridinecarbox late
i) PhZC=NH
o OtBu N\ Pd2(dba)3, xantphos N\
NaZC03 ) | C32003, dioxane I
N\ / /
cyclohexanol 8.5 vol eq Br F 95°C 12h H2N F
| 120°C, 24h
/ N ii) 2M HCI/THF, rt N
Br F
0' 49% 83%
.HCI
o OtBu o OtBu
26 27
Step I: tert—butyl I-(3-br0m0fluor0pyridyl)piperidinecarb0xylate 26
A 3L flange flask equipped with a thermometer, condensor, nitrogen line and overhead
stirrer was heated at 40°C (external) then charged with cyclohexanol (750 mL), disodium carbonate
(129.8 g, 1.225 mol), 3-bromo-4—chloro—5—fluoro—pyridine (Hydrochloric Acid 18) (137.5 g, 556.8
mmol) and tert—butyl piperidinecarboxylate (123.8 g, 668.2 mmol) rinsed in with cyclohexanol
(350 mL). Mixture was heated to 120°C internal temperature overnight (18hr.). Reaction mixture
was removed from hotplate and allowed to cool to room temperature. Water (687.5 mL) and EtOAc
(687.5 mL) were added, stirred for 10 mins then transferred to separating funnel. Additional EtOAc
(1.238 L) was added, mixed and aqueous phase was removed. Organic phase was r washed
with water (687 mL), aqueous phase removed, organic layer ted. Aqueous phases were
combined and back extracted with EtOAc (687.5 mL), aqueous layer removed and c phase
combined with other organics. Organics concentrated in vacuo (water bath temp = 60°C, vacuum
down to 2 mBar) leaving a viscous brown oil.
Oil was dissolved in 25% EtOAc/petrol then passed through a short silica pad, g with
% EtOAc/petrol until no more product came off. Filtrate was concentrated in vacuo to leave a
brown oil, 127.1g. Product re—purified by ISCO companion (1.5Kg Silica, loaded in DCM, eluting 0
to 20% EtOAc/petrol), product ons combined and concentrated in vacuo to leave desired
product 26 as a pale yellow to cream solid, (98g, 49% yield). 1H NMR (500 MHz, DMSO—d6) 5 8.47
(s, 1H), 8.41 (d, 1H), 3.39 — 3.36 (m, 2H), 3.12 (tt, 2H), 2.49 —2.43 (m, 1H), 1.91 — 1.87 (m, 2H),
1.71 — 1.64 (m, 2H) and 1.43 (s, 9H). MS (ES+) 361.0.
Step 2: tert—butyl minofluor0pyridyl)piperidinecarb0xylate 27
To a solution of utyl romofluoropyridyl)piperidinecarboxylate 26 (98
g, 272.8 mmol), diphenylmethanimine (59.34 g, 54.94 mL, 327.4 mmol) and CszCO3 (177.8 g, 545.6
mmol) in 1,4-dioxane (1.274 L) was added Xantphos (15.78 g, 27.28 mmol) and Pd2(dba)3 (12.49 g,
13.64 mmol). The mixture was stirred under nitrogen at 95°C overnight. The mixture was cooled to
room temperature then partitioned between EtOAc (1000 mL, 10 vol eq.) and water (490 mL, 5 vol
eq.), mixed and organic layer separated. Organics washed further with water (1 x 250 mL), brine
(250 mL), dried (MgSO4), filtered and concentrated in vacuo to leave crude product as a dark red
viscous oil, 185.3g.
The obtained product oil (185.3g) was dissolved in THF (882.0 mL) and HCl (545.5 mL
of 2 M, 1.091 mol) was added. The resulting mixture was stirred at room temperature for 20 mins.
THF was removed in vacuo then onal (HCl (2M) (588.0 mL) was added. The aqueous was
washed twice with EtOAc (294.0 mL). A large amount of a yellow precipitate formed during
extraction in both c and aqueous phase, the solid from both the c and aqueous phase was
collected by ion and dried by suction. The mixed organic and s filtrate was added to
separating funnel, extracted with 2M HCl (2 x 200 mL). All aqueous phases plus solid collected on
sinter (product) were combined to give a suspension. The pH was adjusted to 6 using 2M NaOH and
extracted with DCM (3 x 600 mL). The organics were combined, dried (MgSO4), filtered and
concentrated in vacuo to leave a pale orange waxy solid, . This solid was slurried in MeCN
(200 mL), d for 10 mins then solid collected by filtration, washed with minimal MeCN and
dried by suction to leave product 27 as a white solid (66.8 g, 83% yield). 1H NMR (500 MHz,
DMSO—d6) 5 7.82 (d, 1H), 7.63 (d, 1H), 5.22 (s, 2H), 3.11 — 3.00 (m, 2H), 2.91 (tt, 2H), 2.36 (tt,
1H), 1.88 — 1.83 (m, 2H), 1.79 — 1.71 (m, 2H), 1.43 (s, 9H). MS (ES+) 297.1.
Scheme 7b: Alternative a roach to s nthesize tert-but l 1- 3-aminofluoro-4—
rid l i eridinecarbox late
DIPA thCNH
(CCI3)2 Br dba)s
N N KF DMSO
\ xanphos F|/
I \
I Me4NCI
/ / 4M HCI
F Br F Br 100c Br DIPEA
2MeTHF
room
temp
31 18
32 26 270k
Step I: 3-br0m0chlorofluor0pyridine hydrochloride 18
A solution of diisopropylamine (101.2 g, 140.2 mL, 1.000 mol) in tetrahydrofuran (1.148
L) was cooled to between —25°C and —20°C. Butyllithium (2.5M in hexanes) (400 mL of 2.5 M,
1.000 mol) was added at such a rate as to maintain the reaction temperature below -20°C (addition 20
minutes). The mixture was then allowed to warm to 4°C over 1 hour, then re—cooled to —78°C. 3—
bromo—5—fiuoro—pyridine (153.0 g, 869.6 mmol) in tetrahydrofuran (3 82.5 mL) was added over 40
minutes. The mixture was stirred for 90 minutes, then a solution of 1,1,1,2,2,2-hexachloroethane
(205.9 g, 869.6 mmol) in ydrofuran (350.0 mL) was added dropwise over 40 minutes. Once the
addition was complete the mixture was allowed to warm to ambient overnight. The mixture was
cooled to 0°C then transferred into cold water (2 L), stirred for 20 mins then MTBE (2.5 L) added
and stirred vigorously for 30 mins then transferred to separating funnel and organic layer separated.
Aqueous was transferred back to reaction vessel and further extracted with MTBE (2.5 L), stirred for
mins vigorously then erred to separating funnel and organic layer separated. Organics were
ed, dried ), filtered and concentrated to a brown oil. The oil was dissolved in pentane
(500 ml) and ether (300ml). HCl (2M in ether) (434.8 mL of 2 M, 869.6 mmol) was added slowly
with stirring. On te addition the mixture was stirred for 20 mins then solid collected by
filtration, washed with ether and dried under vacuum for 1hr. to leave product 18 as a beige solid
(148.9g, 69%); 1H NMR (500 MHz, DMSO—d6) 5 8.77 (2H, s); 19F NMR (500 MHz, DMSO—d6) 5 —
124.8; MS 210.8.
Step 2: tert—butyl I-(3-br0m0fluor0pyridinyl)piperidinecarb0xylate 26
3—bromo—4—chloro—5—fluoro—pyridine hydrochloride 18 (62 g, 251.1 mmol) was suspended
in DCM (600 mL) and stirred. The mixture was cooled in an ice bath and sodium hydroxide (276.2
mL of 1 M, 276.2 mmol) was added slowly. The resulting mixture was stirred for 1 hour. The
e was phase-separated. More DCM/water was added to aid phase separation. Some tarry
particulates remained in the aqueous phase. The organic phase was washed with brine, dried
(MgSO4), filtered and concentrated. The residue was triturated with heptane. The heptane on
was filtered through a florsil pad, eluting with heptane. The filtrate was concentrated to an oil which
fied. This gave 41g of free base.
A thoroughly stirred mixture of o—4—chloro—5—fluoropyridine free base (55 g, 0.26
mol), potassium fluoride (31 g, 0.53 mol) and Me4NCl (5.8 g, 53 mmol) in DMSO (400 mL) was
heated to 130°C for 2 hours. The reaction mixture was cooled to room temperature and tert—butyl
piperidinecarboxylate hloride 22 (66 g, 0.30 mol) and DIPEA (65 g, 0.50 mol) were added.
The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in
vacuo. The residue was portioned between DCM/water. The organic layer was washed with water
(3x), dried over NaZSO4, and filtered over silica gel using DCM as . The filtrated was
evaporated to give tert—butyl 1—(3 —bromo-5 -fluoropyridinyl)piperidine—4-carboxylate 26 (61 g,
65%) as a light yellow solid; 1H NMR (500 MHz, DMSO-d6) 5 8.47 (s, 1H), 8.41 (d, 1H), 3.39 —
3.36 (m, 2H), 3.12 (tt, 2H), 2.49 — 2.43 (m, 1H), 1.91 — 1.87 (m, 2H), 1.71 — 1.64 (m, 2H) and 1.43
(s, 9H); 19F NMR (500 MHz, DMSO—d6) 5 —135.2; MS (ES+) 361.0.
Step 3: utyl I-(3-aminofluor0pyridinyl)pmeridine-él-carboxylate 27
Tert—butyl 1—(3—bromo—5—fluoropyridinyl)piperidinecarboxylate 26 (800g, 2.23mol)
was dissolved in 1,4-dioxane (7.5L). Diphenylmethanimine (484g, 2.67mol) was added in one
portion followed by cesium carbonate (1.45kg, 4.45mol), Xantphos (129g, 223mmol) and Pd2(dba)3
(102g, 111mmol). Additional 1,4—dioxane (2.9L) was added and the e heated to 95°C under
nitrogen until the reaction was complete (determined by HPLC analysis). The mixture was cooled to
°C and ethyl acetate (8L) and water (4L) were added. The organic phase was isolated and washed
with water (4L) and brine (3.5L) and dried over magnesium sulphate and filtered. The filtrate was
concentrated to a brown oil (1 .3Kg). The oil was dissolved in 2-methyltetrahydrofuran (7.2L) and
2M HCl was added at 20°C and the mixture stirred for 30 minutes. The aqueous layer was ed
and the organic layer extracted with 2M HCl (1.2L). The ed aqueous was neutralised with 2M
NaOH (5.4L, pH 8—9). The product was extracted into yltetrahydrofuran (14L then 2x5L). The
combined extracts were washed with water (1.6L) and the organic solution concentrated. The e
was slurried in acetonitrile (2L), filtered and dried. This gave the product 27 as a white solid (568.7g,
86.5%); 1H NMR (500 MHz, DMSO—dg) 5 7.82 (d, 1H), 7.63 (d, 1H), 5.22 (s, 2H), 3.11 — 3.00 (m,
2H), 2.91 (tt, 2H), 2.36 (tt, 1H), 1.88 — 1.83 (m, 2H), 1.79 — 1.71 (m, 2H), 1.43 (s, 9H); 19F NMR
(500 MHz, DMSO—d6) 5 — 140.0; MS (ES+) 297.1.
Pre aration 8: S nthesis of tert-but l i eridinecarbox late
CBz tBuOH, EDCI CBz H
N N
DMAP Pd/C 10%, H2 N
DCMRT, 12h EtOAc, RT, 12h
(91%) (91%)
0 OH 0 OtBu o OtBu
22
Step I: I-benzyltert—bulyl piperidine-1,4-dicarb0xylate 21
In a 5L flange flask was charged 1-benzyloxycarbonylpiperidinecarboxylic acid 20
(200 g, 759.6 mmol) in DCM (500.0 mL) followed by additional DCM (2.000 L), t—butanol (140.8 g,
181.7 mL, 1.899 mol) and DMAP (46.40 g, 379.8 mmol). The mixture was cooled on ice/salt/water
bath (internal -3.4°C). 3-(ethyliminomethyleneamino)-N,N—dimethyl-propanamine (Hydrochloric
Acid (1)) (145.6 g, 759.6 mmol) was added nwise over 15 mins, with addition funnel rinsed
with DCM (500.0 mL). Mixture was stirred on ice bath for 2hr. Ice bath was then removed (internal
3°C) and d to warm to room temperature overnight. Mixture was washed with 5% citric acid
(2 x 500 mL), then sat. NaHCO3 (500 mL), water (500 mL), and cs dried over MgSO4, which
was then filtered and concentrated in vacuo to leave t 21 as a viscous light yellow oil which
turned to a white solid on standing. (246. 1 g, 101%). 1H NMR (500 MHz, DMSO-d6) 5 7.40 — 7.31
(m, 5H), 5.08 (s, 2H), 3.90 (dt, 2H), 2.93 (br s, 2H), 2.43 (tt, 1H), 1.80 — 1.76 (m, 2H) and 1.45 —
1.37 (m, 11H).
Step 2: utylpzperidinecarb0xylate 22
To a 3L flask under nitrogen was d Pd on C, wet, Degussa (10%Pd, 50% water)
(8.120 g, 76.30 mmol) then EtOAc (1.706 L). The mixture was degassed via Nz/vacuum cycles (3x),
then a solution of 1-benzyltert—butyl piperidine-1,4-dicarboxylate 21 (243.7 g, 763.0 mmol) in
EtOAc (243.7 mL) was added. Mixture was stirred under a hydrogen atmosphere overnight.
Hydrogen was replenished and mixture was d for a r 3.5hr. Methanol (60 mL) was added
to aid dissolution of precipitate then filtered through celite, washing h with methanol. Filtrate
concentrated in vacuo to leave a brown oil with a slight suspension of a white solid, 138.6g. Solid
removed by filtration, and washed with minimal EtOAc. te was concentrated in vacuo to leave
desired product as a light brown oil (129g, 91%). 1H NMR (500 MHz, DMSO—d6) 5 2.88 (dt, 2H),
2.44 (td, 2H), 2.23 (tt, 1H), 1.69 — 1.64 (m, 2H) and 1.41 — 1.33 (m, 11H).
Pre aration 9: S nthesis of 1- oxetan l i erazine
oxetanone 1.2 eq
NaBH(OAc)3 2 eq 9 Pd/C 10%, H2
N THF N 130323302”
E j 0°C to RT, o/n E j ’ /—\
i N wN<>O
o 020 100%
83/.
O O
D b 25
23 24
Step I: benzyl 4-(oxetan-S-ybpiperazine-I—carboxylate 24
Benzyl piperazine-l-carboxylate 23 (27.3 mL, 142.2 mmol) was dissolved in dry THF
(313.1 mL) and oxetan—3—one (12.29 g, 10.93 mL, 170.6 mmol) was added. The resulting solution
was cooled in an ice—bath. NaBH(Oac)3 (59.99 g, 284.4 mmol) was added portionwise over 30 mins,
about a quarter was added. Mixture removed from ice bath, allowed to warm to room temperature
then ued adding the NaBH(Oac)3 nwise over 30 mins. On complete addition, an
exotherm from 22°C slowly to 32°C was observed, whereby the mixture was subsequently cooled on
an ice bath until an internal of 22°C was d. The ice bath was removed and the reaction
mixture’s internal temp was steady at 22°C. The mixture was stirred at room temperature overnight.
The resulting white suspension was quenched by addition of 2M sodium carbonate
solution (approx 150 mL) (pH = 8) and concentrated under reduced pressure to remove THF. Product
was then extracted with EtOAc (3 x 250 mL). Organics were combined, dried over MgSO4, filtered
and concentrated under reduced pressure to leave product 24 as a white solid (32.7g 83% . 1H
NMR (500 MHz, DMSO-d6) 5 7.39 — 7.30 (m, 5H), 5.07 (s, 2H), 4.52 (t, 2H), 4.42 (t, 2H), 3.43 —
3.39 (m, 5H) and 2.22 (t, 4H). MS (ES+) 276.8.
Step 2: tan-S-priperazine 25
In a 1L flask was added Pd(OH)2 (1.661 g, 2.366 mmol) under nitrogen. MeOH (130.8
mL) and EtOAc (261.6 mL) were added and the mixture degassed via vacuum/nitrogen cycles (3x).
Benzyl 4-(oxetan-3 -yl)piperazine-l-carboxylate 24 (32.7 g, 1183 mmol) was then added and the
mixture stirred under a hydrogen atmosphere over the weekend. e was filtered through a pad
of Celite, washing through with EtOAc then methanol. Filtrate was concentrated in vacuo to leave
product 25 as an orange oil l(8.lg, quantitative yield). 1H NMR (500 MHz, DMSO—d6) 5 4.51 (t,
2H), 4.41 (t, 2H), 3.36 — 3.30 (masked signal, 1H), 2.69 (t, 4H) and 2.14 (br s, 4H).
Com ound 1-2 and 2-amin0fluoro-N- 5—flu0r0-4— 4- 2 2 3 3 5 5 6 deuter0-4— oxetan-
N\ NH NH2
2 O
/ i) M (1/3) /
N/ Pyridine \ / N \ / triethylsilane
‘N / N H
90°C 12h “ii/K0 NF/ I1 12h
N N N
II) 4M HCI NMP RT 20min /,
\ N
/ </\
F F\/:NZ:PF .HCI
OtBu
OtBu OH
6a* 27 29
D3“ DD NH2 NH2
0 0
/N /N
”D l ”D “(I \’ regime“: “I“ \/
o N H c)3, C I
gaETEtBN F F
N/ // N N Dill” \ N N
N / u \ \ / /
RT18h RTISII
D D '_l
29 1-2
Step I: tert—bulyl I-(3-(2-amin0fluor0pyrazolo[1,5-a]pyrimidinecarb0xamid0)flu0r0pyridin-
4-yl)pzperidine—4-carb0xylate 28
A e of (6-chlorobenzotriazolyl) 2-aminofluoro-pyrazolo[1,5-a]pyrimidine
carboxylate 621* (41.69 g, 119.9 mmol) and tert—butyl 1-(3-aminofluoropyridyl)piperidine
carboxylate 27 (32.2 g, 109.0 mmol) in pyridine (483 mL) was heated at 90°C for 12h. The reaction
was cooled to RT, EtOH was added (322 mL), and the mixture stirred at RT for 10 mins. The solid
was collected by filtration, washed well with ethanol and dried by suction to leave 28 as a yellow
solid (33g, 64%).
Step 2: Z-aminofluor0pyrazolo[1,5-a]pyrimidine-S-carboxamido)flu0r0pyridin
eridinecarb0xylic acid 29
To a sion of tert—butyl 1—[3—[(2—aminofluoro-pyrazolo[1,5—a]pyrimidine—3—
carbonyl)amino]fluoropyridyl]piperidinecarboxylate 28 (69.7 g, 147.2 mmol) in DCM
(348.5 mL) were added triethylsilane (18.83 g, 25.87 mL, 161.9 mmol) followed by TFA (151.1 g,
102.1 mL, 1.325 mol). The resulting solution was d at RT for 12h. The mixture was
concentrated in vacuo to leave an orange solid which was triturated in DCM (200 mL) for 20 mins.
The solid was collected by filtration, washed with minimal DCM and dried by suction to afford the
desired the trifluoroactate product as a yellow solid (75.2g, 96%).
To a solution of 1-[3-[(2-aminofluoro-pyrazolo[1,5-a]pyrimidine-3 -carbonyl)amino]
4-pyridyl]piperidinecarboxylic acid trifluoroacetate (73 g, 124.7 mmol) in NMP (662.7
mL) was added hydrogen chloride (4M in dioxane) (37.4 mL of 4 M, 149.6 mmol). The reaction
was stirred at RT for 20 mins then the solid was collected by filtration, washed with minimal NMP
then MTBE, dried by suction to afford pure product hydrochloride 29 as a light yellow solid.
Step 3: 2-amin0fluor0-N-(5-fluor0(4-(2,2, 3, 3,5, 5, 6, 6-octadeuter0-piperazine-I -
przperidin-I-yl)pyridyl)pyrazolo[1,5-a]pyrimidine-S-carboxamide (Compound I-2)
(Benzotriazolyloxy-dimethylamino-methylene)-dimethyl-ammonium roborate
(127.3 mg, 0.3966 mmol) was added to a mixture of 1—[3—[(2-amino—6—fluoro—pyrazolo[1,5—
a]pyrimidinecarbonyl)amino]fluoropyridyl]piperidinecarboxylic acid hydrochloride 29
(150 mg, 0.3305 mmol) 1.652 mmol) and Et3N
, 2,2,3,3,5,5,6,6—octadeuteriopiperazine (155.6 mg,
(83.6 mg, 115.2 uL, 0.8262 mmol) in DMF (5 mL). The reaction mixture was stirred at RT for 18h.
The crude mixture was purified by preparative HPLC to afford I-2 as a white solid (114mg, 48%).
Step 4: 2-amin0fluor0-N-(5-fluor0(4-(2,2, 3,3, 5, 5, 6, 6-octadeuter0(oxetan-S-przperazine-I -
carbonprzperidin-I-yl)pyridineyl)pyrazolo[1,5-a]pyrimidine-S-carboxamide (Compound I-3)
Sodium triacetoxyborohydride (24.67 mg, 0.1164 mmol) was added to a solution of
oxetan—3—one (7.271 mg, 0.1009 mmol), 2—amino—6—fluoro—N—(5—fluoro—4—(4—(2,2,3,3,5,5,6,6—
WO 85132
octadeutero-piperazinecarbonyl)piperidinyl)pyridine-3 -yl)pyrazolo[1,5 -a]pyrimidine-3 -
carboxamide 13 (56 mg, 0.07761 mmol) and acetic acid (13.98 mg, 13.24 uL, 0.2328 mmol) in
DMF (2 mL). The reaction mixture was stirred at RT for 18h. The solution was quenched with
methanol and water and the crude mixture was purified by preparative HPLC to afford the desired
product I-3 (20mg, 46%). 1H NMR (500 MHz, DMSO—d6) 5 10.64 (s, 1H), 9.67 (s, 1H), 9.48 (dd,
1H), 9.26 (dd, 1H), 8.26 (d, 1H), 6.79 (s, 2H), 4.55 (t, 2H), 4.47 (t, 2H), 3.63 (m, 1H), 3.20 (m, 2H),
3.15 (m, 2H), 2.95 (m, 1H), 2.10 (m, 2H), 1.74 (d, 2H); ES+ 550.4.
nd Analytical Data
H NMR (500 MHz, ol-d4) 5 1.87 (2H, m), 2.27-
2.33 (2H, m), 2.55 (4H, m), 2.97—3.03 (1H, m), 3.18 (2H,
m), 3.70—3.85 (4H, m), 4.67—4.70 (2H, m), 4.75—4.78 (2H,
m), 8.16 (1H, d), 9.00 (1H, dd), 9.17 (1H, dd), 9.68 (1H, s),
.65 (1H, s).
1H NMR (500 MHz, DMSO—d6) 5 10.64 (s, 1H), 9.67 (s,
1H), 9.48 (dd, 1H), 9.26 (dd, 1H), 8.26 (d, 1H), 6.79 (s,
2H), 3.20—3.25 (m, 2H), 3.05—3.07 (m, 2H), 2.95-2.98 (m,
1H), 2.07—2.12 (m, 2H), 1.74 (d, 2H).
1H NMR (500 MHz, DMSO—d6) 5 10.64 (s, 1H), 9.67 (s,
1H), 9.48 (dd, 1H), 9.26 (dd, 1H), 8.26 (d, 1H), 6.79 (s,
2H), 4.55 (t, 2H), 4.47 (t, 2H), 3.63 (m, 1H), 3.20 (m, 2H),
3.15 (m, 2H), 2.95 (m, 1H), 2.10 (m, 2H), 1.74 (d, 2H).
Solid Forms of Compound I-1
] Compound I-1 has been prepared in various solid forms, including salts, solvates,
hydrates, and anhydrous forms. The solid forms of the present ion are useful in the
manufacture of medicaments for the treatment of cancer. One embodiment es use of a solid
form described herein for treating cancer. In some embodiments, the cancer is triple negative breast
cancer, pancreatic cancer, small cell lung cancer, ctal cancer, ovarian cancer, or non-small cell
lung cancer. Another embodiment provides a pharmaceutical composition comprising a solid form
described herein and a pharmaceutically acceptable carrier.
2014/068713
] ants be herein a plurality of novel solid forms of Compound I-1. The names
and stoichiometry for each of these solid forms are provided in Table 2 below:
Table2
Examole 5 0 ethanol e 1:0.72
Exam-166a 1:45
Examle 6b ———————
Exam-167 N/A
Exam-168 —
Exam-169 N/A
Exam-1610 N/A
Exam-1611 1:1
Exam-1612 1:13
Exam-1613 1:0.44
Example 14 Compound I isopropanol solvate 1:0.35
ssNMR Experimental Method
Solid state NMR spectra were acquired on the Bruker—Biospin 400 MHz Advance III
wide—bore spectrometer equipped with Bruker—Biospin 4mm HFX probe. Samples were packed into
4mm ZrOz rotors (approximately 70mg or less, depending on sample bility). Magic angle
spinning (MAS) speed of typically 12.5 kHz was applied. The temperature of the probe head was set
to 275K to minimize the effect of frictional heating during spinning. The proton relaxation time was
measured using 1H MAS T1 saturation recovery relaxation experiment in order to set up proper
recycle delay of the 13C cross-polarization (CP) MAS experiment. The recycle delay of 13C CPMAS
experiment was adjusted to be at least 1.2 times longer than the measured 1H T1 tion time in
order to maximize the carbon spectrum signal-to-noise ratio. The CP contact time of 13C CPMAS
experiment was set to 2 ms. A CP proton pulse with linear ramp (from 50% to 100%) was
employed. The Hartmann-Hahn match was optimized on external reference sample (glycine).
Fluorine spectra were acquired using proton decoupled MAS setup with recycled delay set to
approximately 5 times of the measured 19F T1 relaxation time The fluorine relaxation time was
measured using proton decoupled 19F MAS T1 tion recovery relaxation experiment. Both
carbon and fluorine spectra were ed with SPINAL 64 decoupling was used with the field
strength of approximately 100 kHz. The chemical shift was referenced against external standard of
adamantane with its upfield resonance set to 29.5 ppm.
Example 5: Compound I-1 [ethanol solvate]
Compound I-1 ethanol solvate can be prepared according to the s described in
Example 1, Step 4.
XRPD of Compound I-1 {ethanol solvate)
The XRPD pattern of Compound I-1° ethanol e was ed at room temperature in
reflection mode using a ticaZ diffractometer equipped with an Empyrean tube source and a
PIXcel 1D detector (PANaZyticaZ, The Netherlands). The X-ray generator was operating at a voltage
of 45 kV and a current of 40 mA. The powder sample was placed in a silicon holder. The data were
over the range of 3°-39° 2 theta with a step size of 0.0130 and a dwell time of 121s per step. Figure
la shows the X-ray powder diffractogram of the sample which is characteristic of crystalline drug
substance.
Table 3a depicts representative XRPD peaks from Compound I-1° ethanol solvate:
Table 3a: Representative XRPD Peaks
2 12.7 6.4
3 13.6 12.2
4 14.3 7.5
14.9 9.5
7 16.2 15.7
8* 50.6
* 19.7 35.3
11 25.2
12 23-1
13 3.5
22.8 11.2
16 18.2
18 23.8 91.4
* 24.4 72.8
21 15.1
23 26.3 6.0
24 27.5 5.8
* 29.0 44.9
26 30.0 9.7
NN 00\l 30.9 4.6
31.5 4.5
Thermo Analysis of Compound I-1 (ethanol solvate)
A thermal gravimetric analysis of Compound I-1° ethanol solvate was performed to
determine the percent weight loss as a function of temperature using the Discovery TGA (TA
Instruments Trios). A sample (8.338 mg) was added to a pre-tared aluminum pan and heated from
ambient temperature to 310°C at 20°C/min. The TGA results seen in Figure 2a show a large weight
loss of 5.76% between 166°C (onset) and 219°C (end point). This weight loss corresponds to
imately 0.72 molar equivalents of l. The subsequent weight loss seen at 290°C is a
result of melting/degradation.
ential Scanning Calorimetg of Compound I-1 {ethanol e)
Differential scanning calorimetry of Compound I-1° ethanol solvate was measured using
the TA Instrument DSC Q2000. A sample (1.84 mg) was weighed in a pre—punched e
aluminum ic pan and heated from ambient temperature to 300°C at 20°C/min. The DSC
results seen in Figure 3a show a desolvation endotherm at 169 °C ) followed by a single
melting endotherm at 258°C (onset).
ssNMR of Compound I-1 {ethanol solvate)
A solid state 13C NMR spectrum of Compound I ethanol e is shown in Figure 4a.
Table 3b provides chemical shifts of the relevant peaks.
Table 3b: Solid State 13C NMRspectrum of Compound I-1 (ethanol solvate)
Peak # Intensity
1* 175.4 53.9
2 162.4 58.4
3 160.0 14.1
4 157.4
150.7
6 148.2
7 145.8
8 140.1
9* 138.0
136.1
11 134.3
12* 123.1
13 89.0
14 76.8
76.1
16* 57.8
17 51.6
18 48.9
19* 44.0
42.2
21 38.8
22 30.9
23 28.7
24* 19.5
A solid state 19F NMR spectrum of nd Iethanol solvate is shown in Figure 5a.
Table 3c provides chemical shifts of the relevant peaks.
Table 3c: Solid State 19F NMR um of Compund I-1 (ethanol solvate)
436-0
451-6
Example 6a: Compound I-1 [hydrate I]
Compound I-1° ethanol solvate (lOOOmg), prepared according to the methods described in
Example 1, Step 4, was slurried in water (20mL) for 4 days at room temperature. The sion
was fuged and the residual solids were isolated then dried ght in a 35°C vacuum oven to
afford Compound I hydrate I as a yellow powder.
XRPD of Compound I-1 [hydrate I]
The XRPD pattern of Compound I-1° hydrate I was recorded at room temperature in
reflection mode using a Bruker D8 Discover diffractometer equipped with a sealed tube source and a
Hi-Star area detector (Bruker AXS, Madison, WI, Asset V012842). The X-ray generator was
operating at a voltage of 40 kV and a current of 35 mA. The powder sample was placed in a nickel
holder. Two frames were ered with an exposure time of 120 seconds each. The data were
subsequently integrated over the range of 3.5°—3 9° 2—theta with a step size of 0.020 and merged into
one continuous pattern. Figure lb shows the X-ray powder diffractogram of the sample which is
characteristic of crystalline drug substance.
Table 4a depicts representative XRPD peaks from Compound I-1° hydrate I:
Table 4a: Representative XRPD Peaks
1 1.4
2 3.0
3 7.8
4 100.0
* 51.0
6 3.0
7 10.5
8 10.4 10.8
9 11.2 5.9
11.5 8.7
11 11.5
12* 16.0
13* 10.9
14 7.2
9.2
16 10.5
17 14.8
18* 10.8
19 14.1
11.6
21 10.2
22 4.5
23 7.8
24* 13.6
10.9
26 4.9
27 32.3 2.2
Thermo Analysis of Compound I-1 ghydrate I)
A thermal gravimetric analysis of Compound I-1° hydrate I was performed to determine
the percent weight loss as a function of time using the TA Instrument TGA Q5000 (Asset V014258).
A sample (7.380 mg) was added to a pre-tared um pan and heated from ambient ature
to 350°C at 10°C/min. The TGA results seen in Figure 2b show a large initial weight loss up to
100°C followed by a small amount of additional weight loss prior to melting/degradation. The initial
weight loss of 14.56% corresponds to approximately 4.5 molar lents of water. The onset
temperature of melting/degradation is 292°C.
Differential Scanning Calorimetg of Compound I-1 [hydrate I]
Differential scanning calorimetry of nd I-1° hydrate I was measured using the TA
Instrument DSC Q200 (Asset 2). A sample (5.598 mg) was weighed in a pre—punched
pinhole aluminum hermetic pan and heated from t temperature to 350°C at 10°C/min. The
DSC results seen in Figure 3b show an initial broad endothermic event that corresponds to de—
hydration and subsequent melting to an amorphous form. ing the melt there is a Tg at 125°C,
re-crystallization at 180°C, a melt at 257°C, then a final melt/degradation event at 278°C.
Example 6b: Compound I-1 [hydrate II]
Compound I-1° l solvate (1000mg), prepared according to the methods described in
Example 1, Step 4, was slurried in water (20mL) for 4 days at room temperature. The suspension
was centrifuged and the residual solids were isolated to afford Compound I hydrate II as a yellow
paste.
XRPD of Compound I-1 te II]
The XRPD pattern of Compound I-1°hydrate II was recorded at room temperature in
reflection mode using a Bruker D8 Discover diffractometer equipped with a sealed tube source and a
r area detector (Bruker AXS, Madison, WI, Asset V012842). The X-ray generator was
operating at a voltage of 40 kV and a current of 35 mA. The powder sample was placed in a nickel
holder. Two frames were ered with an exposure time of 120 seconds each. The data were
subsequently integrated over the range of 9O 2—theta with a step size of 0.020 and merged into
one continuous pattern. Figure 4b shows the X-ray powder diffractogram of the sample which is
characteristic of crystalline drug substance.
Table 4b depicts representative XRPD peaks from Compound I-1° hydrate II:
Table 4b: Representative XRPD Peaks
8* 11.9 29.9
9 45.6
25.2
11 22.2
12 19.7
13 17.2
14 39.7
21.1
16* 24.7
17 10.3
18 28.6
19 12.0
8.8
21* 13.0
22 12.6
23 5.3
24 12.2
9.5
26 9.2
27 14.9
ssNMR of Compound I-1 {hydrate 111
] A solid state 13C NMR spectrum of Compoun I-1° hydrate II is shown in Figure 5b. Table
40 provides Chemical shifts of the relevant peaks.
Table 4c: Solid State 13C NMRspectrum of Compoun I-1 (hydrate II)
Intensity
49.2
24.9
3 161.3
4 160.9
159.7
6* 158-2
7 151-9
8 149-1
9* 142-9
136-3
12 132-9 40.1
13 130.5
14 122-8
* 85-1
16 76-9
2014/068713
17 76.4
18* 58.9
19 50.2
49.5
21 48.5
22 45.0
23 41 .8
24 37.2
* 31 .9
26 28.9
] A solid state 19F NMR spectrum of Compound Ihydrate II is shown in Figure 6b. Table
4d provides Chemical shifts of the relevant peaks.
Table 4d: Solid State 19F NMR um of Compoun I-1° hydrate II
Intensity
1* -138.0 8.2
2* -152.7 12.5
e 7: Compound I-1 [anhydrous form A]
Compound I-1° l e (lOOOmg), prepared according to the methods described in
Example 1, Step 4, was slurried in THF (20mL) for 72hr at room temperature. The suspension was
centrifuged and the residual solids were isolated then dried overnight in a 35°C vacuum oven to
afford compound I anhydrous form A (“form A”) as a yellow powder.
In an alternative process, compound I-1° amorphous form (15. lg; 0.028mol), prepared
according to the method in Example 2, step 3, was suspended in a mixture of 2-propanol (300mL)
and water (lOOmL). The mixture was stirred and heated to C and filtered whilst hot. The
resulting clear filtrate was heated and distilled and solvent replaced with 2-propanol until the
contents temperature reached 825°C. The resulting suspension was cooled to 15°C over 10 hours
and stirred for a r 5 hours. The solids were collected by filtration, dried by suction for 1 hour
then dried in a vacuum oven for 20 hours at 60°C to give compound I-1° anhydrous form A (13.9g;
92%).
A number of other solvents may be utilized to prepare compound I anhydrous form A.
Table 5a below summarizes the methods.
Table 5a: Solvents Used to Prepare Form A
Anisole Slurry
2—Butanone Slurry
Slurry
Ethyl e
Slurry
Heptane
Hot Slurry
Isopropanol
Slurry
Isopropyl acetate
TBME Slurry
THF Slurry
XRPD of Compound I-1 ganhydrous form A1
The XRPD pattern of Compound I-1° anhydrous form A was recorded at room
temperature in reflection mode using a Bruker D8 Discover diffractometer ed with a sealed
tube source and a Hi—Star area detector (Bruker AXS, Madison, WI, Asset V012842). The X—ray
generator was operating at a voltage of 40 kV and a t of 35 mA. The powder sample was
placed in a nickel holder. Two frames were ered with an exposure time of 120 seconds each.
The data were subsequently integrated over the range of 3.50—3 9° 2—theta with a step size of 0.020
and merged into one continuous pattern. Figure 1c shows the X-ray powder diffractogram of the
sample which is characteristic of crystalline drug substance.
Table 5b depicts representative XRPD peaks form Compound I anhydrous form A:
Table 5b: Representative XRPD Peaks
18* 31.8 16.0
Thermo Analysis of Compound I-1 (anhydrous form A)
A thermal gravimetric analysis of Compound I-1° anhydrous form A was performed to
determine the percent weight loss as a on of time using the TA Instrument TGA Q5000 (Asset
V01425 8). A sample (7.377 mg) was added to a pre-tared aluminum pan and heated from ambient
temperature to 350°C at in. The TGA results seen in Figure 2c show very little observed
weight loss prior to melting or thermal degradation. From ambient temperature to 265°C, the weight
loss is 0.96%. The onset temperature of degradation is 292°C.
Differential Scanning Calorimetfl of Compound I-1 {anhydrous form A)
] Differential scanning calorimetry of Compound I-1° anhydrous form A was measured
using the TA Instrument DSC Q2000 (Asset V014259). A sample (3.412 mg) was d in a pre-
punched pinhole aluminum hermetic pan and heated from ambient ature to 350°C at
°C/min. The DSC results seen in Figure 3c show a single ermic melting event at 262°C.
There are two distinct peaks contained within the melting event which are separated by about 1°C.
Composition and Preparation ofactive Tablets Containing Anhydrous Form A
Composition of Form A 10 mg tablet
The formulation compositions for both the dry granulation and tablet blends of the active
Form A 10 mg tablets are described in Tables 5c and 5d. The overall composition ication of
the tablets is described in Table 5e.
Table 5c: Form A (10mg) ranular Blending
Form A 10.00 10.26
Lactose Monoh drate, #316, NF, PhEur, JP 27.50 28.20
Avicel PH- 101 (microcrystalline cellulose),
55.00 56.41
NF, PhEur, JP
Ac—Di—Sol
WO 85132
(croscarmellose sodium), NF, PhEur, JP
Sodium Stea lFumarate, NF, PhEur, JP 2.00 2.05
97.50 100.00
Table 5d: Form A (10mg) Tablet Composition
Form A Intragranular Blend
(Milled)
Ac—Di—Sol
(croscarmellose sodium), NF, PhEur, JP
Sodium Stearyl Fumarate,
NF, PhEur, JP
Total
Table 5e: Form A (10mg) Tablet Overall Composition
Form A
Lactose Monohydrate, #316, NF, PhEur, JP
intra Avicel PH-101, NF, PhEur, JP
granular Ac-Di-Sol, NF, PhEur, JP
Sodium Stea lFumarate, NF, PhEur, JP
_ranules:
extra Ac-Di-Sol, NF, PhEur, JP 1.50
granular Sodium Stearyl Fumarate, NF, PhEur, JP 1.00
total core tablet: 100.00
ition of Form A 50 mg tablet
The formulation compositions for both the dry granulation and tablet blends of the active
Form A 50 mg tablets are bed in Tables 5f and 5g. The overall composition specification of
the tablets is described in Table 5h.
Table 5f: Form A (50mg) Intragranular Blending
Lactose Monoh drate, #316, NF, PhEur, JP 137.50 28.20
Avicel PH- 101 (microcrystalline ose),
275.00 56.41
NF, PhEur, JP
Ac—Di—Sol
'00
croscarmellose sodium JP
, NF, PhEur,
Sodium Stearyl Fumarate, NF, PhEur, JP 10.00 2.05
Total 487.50 100.00
Table 5g: Form A (50mg) Tablet Composition
Form A lntragranular Blend
487.50 97.50
Milled
Ac-Di-Sol
1.50
(croscarmellose sodium), NF, PhEur, JP
Sodium Stearyl Fumarate,
1 00
NF, PhEur, JP ‘
Total 100.00
Table 5h: Form A (50mg) Tablet Overall Composition
Lactose Monohydrate, #316, NF, PhEur, JP
intra AVicel PH-101, NF, PhEur, JP
granular Ac-Di-Sol, NF, PhEur, JP
Sodium Stearyl Fumarate, NF, PhEur, JP
total _ranules:
extra Ac-Di-Sol, NF, PhEur, JP 1.50
granular Sodium Stearyl Fumarate, NF, PhEur, JP 1.00
total core tablet: 100.00
Process for Preparing Form A 10 mg and 50 mg Tablets
Step I. anulation Mixing:
] Form A was passed through a cone mill assembled with a 24R round holed screen and a
rounded edge type impeller at an impeller rate of 1500 rpms. Lactose drate, microcrystalline
ose, and granular croscarmellose sodium were screened through a #30 mesh sieve. The
cone milled Form A and all the screened components were then blended for 10 minutes at 26 rpm.
Sodium stearyl fumarate was hand sieved through a 60 mesh screen and then charged into the
blender and blended with the materials for 3 minutes at 26 rpm. Samples were pulled for blend
uniformity analysis.
Step II. Dry Granulation:
The blend was dry granulated on a s Minipactor. The blend was passed through the
roller compactor, assembled with a combination of smooth faced and knurled faced compaction rolls,
at a 2 rpm roll speed with 5KN/cm roll force and a 2 mm roll gap. Compacted powder was then
granulated with a ed type milling roll through a 1 mm screen with 80 rpm mill speed.
Step III. Final Blending:
Extra—granular croscarmellose sodium and sodium stearyl te were hand sieved
through 30 and 60 mesh screens, respectively. Extra—granular croscarmellose sodium was blended
with the dry granulate for 5 s at 32 rpm. Extra-granular sodium stearyl fumarate was then
added to the bulk mixture and mixed for 3 minutes at 32 rpm. Samples were pulled for blend
uniformity analysis. The blend was sealed in double Low Density Polyethylene bags within a hard
secondary container to protect from puncture.
Step IV. Tablet Compression:
A tablet compression machine (Piccola D—8 Rotatory Press) was partially tooled (2 stations
out of 8 stations) with a 0.25” standard round concave tooling for 10 mg th and 0.568” x
0.2885” caplet tooling for 50 mg strength. Turret speed was 25—35 rpm. The in—process control
testing for tablets included average weight, individual weight, and hardness, as shown in Table 5i.
Table 5i: Form A (10mg and 50 mg) Tablet Compression In-process Control Specifications
we1ht m
Cgstal Preparation of Form A
Form A was crystallized from a DCM/ e mixture by slow evaporation of the
solvents. A colorless needle shaped l with dimensions 0.10 x 0.02 x 0.02 mm was chosen for
the ction experiment on a Bruker APEX ll CCD diffractometer with Cu Ka radiation at room
temperature. The structure was solved by direct methods and d by the SHELXTL package.
Form A Crystal Experimental:
The crystal shows monoclinic cell with P21/c centrosymmetric space group. The lattice
parameters are a = 3)A, b = 2)A, c= 14.48(3)A, or = 90°, E = 107.22(3)°, y = 90°,
volume = 2573(9)A3. The refinement gave the R factor of 6.9%. Conformational plots of nd
I-1° anhydrous form A based on single crystal X-ray analyses are shown in Figures 4c and 5c.
Compound I-1° anhydrous form A s ordered in the asymmetric unit (Figure 4c). As shown in
Figure 5c, Compound I-1° anhydrous form A molecules form a one-dimensional chain along the b-
axis that is stabilized by the inter—molecular hydrogen bonds between the amine and pyridine groups.
Multiple chains stack in three dimensions with approximately 4.3A layer spacing.
Table 5j: Crystal data for Form A
C25H29F2N903 Z = 4
Mr=541.57 F(000)= 1136
inic, P21/c Dx = 1.398 Mg m'3
a = 15.29 (3) A Cu K01 radiation, 7» = 1.54178 A
7(2)A u=0.89 mm'l
c= 14.48 (3)A T=296K
[3 = 107.22 (3)0 Needle, colorless
V= 2573 (9) A3 0.10 X 0.02 X 0.02 mm
Geometry: All esds (except the esd in the dihedral angle between two l.s. planes) are
estimated using the full covariance . The cell esds are taken into account individually in the
estimation of esds in distances, angles and torsion angles; correlations between esds in cell
parameters are only used when they are defined by crystal symmetry. An approximate (isotropic)
treatment of cell esds is used for estimating esds involving ls. planes.
Table 5k: Data collection parameters for Form A crystal
Bruker APEX II CCD Rim = 0.084
diffractometer
Radiation source: sealed tube Gmax = 53.60, 0min = 3.00
oscillation photos around 00 and (1) scans h — —15—>15
9104 measured reflections k = —12—> 1 1
293 9 independent reflections Z = —1 1—> 14
Data collection: Apex 11; cell refinement: Apex II; data reduction: Apex II; program(s)
used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure:
SHELXL97 (Sheldrick, 1997); molecular graphics: Mercury; software used to prepare al for
publication: publCIF.
Table 5m: Refinement parameters for Form A crystal
Least-squares matrix: full Hydrogen site location: inferred from
neighbouring sites
<F2>1=oow
more) = 0.179 w = 10020002) -— 1021
where P = (F02 -- 2Fc2)/3
S = 0.94 (A/o)max < 0.001
2939 refiectlons A>max = 0.23 e A 3
352 parameters A>min = —0.26 e A'3
ent: Refinement of F2 against ALL reflections. The weighted R-factor wR and
goodness of fit S are based on F2, conventional R—factors R are based on F, with F set to zero for
negative F2. The threshold expression of F2 > 2sigma(F2) is used only for calculating R-factors(gt)
etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are
statistically about twice as large as those based on F, and R-factors based on ALL data will be even
ssNMR of Compound I-1 [anhydrous form A]
A solid state C NMR spectrum of Compoun I anhydrous form A is shown in Figure
6c. Table 5n es chemical shifts of the relevant peaks.
Table 5n: Solid State 13C ctrum of Form A
Intensity
67.9
46.9
59.1
18.1
9 139.8
* 138.9
11 135.8
12 134.3
13 122.6
14 89.3
76.2
16* 74.1
17 59.8
18 51.7 77.2
19 50.3 98.8
49.4 91.4
21* 42.8 100.0
22 38.4 97.7
23* 31.5 84.2
24 28.3 85.4
] A solid state 19F NMR spectrum of Compound Ianhydrous form A is shown in Figure
7c. Table 5p provides chemical shifts of the relevant peaks.
Table 5p: Solid State 19F NMR um of Form A
O Om
436.8 .1.
455.7
Example 8: Compound I-1 [anhydrous form B]
d Compound I-1° amorphous (3.50g), prepared according to the methods described
in Example 2, Step 3, was placed in a 250mL 3-neck flask, THF (70mL) was added, and ed
using an overhead stirrer at ambient temperature overnight (e.g., at least 12 hr.). The suspension was
filtered under vacuum (4.25cm diameter Whatman filter paper), washed with THF (7mL), and pulled
under vacuum for about 35 minutes to give a fairly hard yellow solid (2.25 g). Dried the solids under
vacuum with a good bleed at 35°C overnight affording 1.92 lg of nd I anhydrous form B
as a yellow solid.
XRPD of Compound I-1 [anhydrous form B]
The XRPD pattern of Compound I anhydrous form B was recorded at room
temperature in reflection mode using a Bruker D8 Discover diffractometer equipped with a sealed
tube source and a Hi—Star area detector (Bruker AXS, Madison, WI, Asset V012842). The X—ray
generator was operating at a voltage of 40 kV and a current of 35 mA. The powder sample was
placed in a nickel holder. Two frames were registered with an exposure time of 300 s each.
The data were subsequently integrated over the range of 3.50—3 9° 2—theta with a step size of 0.020
and merged into one continuous pattern. Figure 1d shows the X-ray powder diffractogram of the
sample which is characteristic of crystalline drug substance.
Table 6a depicts representative XRPD peaks form Compound I ous form B:
Table 6a: Representative XRPD Peaks
00 UL)
Thermo Analysis of Compound I-1 {anhydrous form B)
A thermal gravimetric analysis of Compound I-1° anhydrous form B was performed to
ine the percent weight loss as a function of time using the TA Instrument TGA Q500 (Asset
V014840). A sample (2.728 mg) was added to a pre-tared platinum pan and heated from ambient
temperature to 350°C at in. The TGA results seen in Figure 2d show two distinct weight loss
events totaling 2.5% up to 175°C. The onset temperature of g/degradation is 284°C.
Differential Scanning Calorimetgg of nd I-1 (anhydrous form B)
Differential scanning calorimetry of Compound I-1° anhydrous form B was measured
using the TA ment DSC Q2000 (Asset V0123 90). A sample (2.125 mg) was weighed in a pre—
punched pinhole aluminum hermetic pan and heated from 30°C to 350°C at 3°C/min, modulating ::
1°C every 60 seconds. The DSC results seen in Figure 3d show an exothermic event at 177°C (likely
a slight re-arrangement of the crystal structure), an endothermic melt at 257°C, stallization at
8°C, then a final melt/degradation event at 280°C.
ssNMR Compound I-1 {anhydrous form B1
A solid state 13C NMR spectrum of Compoun I-1°anhydrous form B is shown in Figure 4d. Table 6b
provides chemical shifts of the relevant peaks.
Table 6b: Solid State 13C NMR spectrum of Form B
Peak # Intensity
1* 173.4
2* 164.5
3 162.3
4 159.9
157.4
6 151.8
7 149.5
8 144.9
9 141.6
136.3
11* 133-5
12* 130.8
13 124.4
14 86.9
74.9
16 72.0
17* 67.7
18 59.5
19 50.8
* 45.3
21 40.4
22 37.9 mm.
23 30.3
24* 25.9
2014/068713
A solid state 19F NMR spectrum of Compound Ianhydrous form B is shown in Figure
5d. Table 6c provides chemical shifts of the relevant peaks.
Table 6c: Solid State 19F NMR Spectrum of Form B
Intensity
Example 9: nd I-1 rous form C]
Compound I-1° anhydrous form B ), prepared according to the method described
in Example 8, was added to pre-punched pinhole aluminum hermetic pans and heated via DSC to
265°C at a rate of 5°C/min (3 pans, ~5mg each) to afford compound I-1° anhydrous form C as a dark
yellow powder.
XRPD of Compound I-1 [anhydrous form C]
The XRPD pattern of Compound I anhydrous form C was recorded at room
temperature in reflection mode using a Bruker D8 Discover diffractometer equipped with a sealed
tube source and a Hi—Star area detector (Bruker AXS, Madison, WI, Asset V012842). The X—ray
generator was operating at a e of 40 kV and a current of 35 mA. The powder sample was
placed in a nickel holder. Two frames were registered with an exposure time of 120 seconds each.
The data were subsequently integrated over the range of 3.50—3 9° 2—theta with a step size of 0.020
and merged into one uous pattern. Figure 1e shows the X-ray powder diffractogram of the
sample which is characteristic of lline drug substance.
Table 7a depicts representative XRPD peaks form Compound I anhydrous form C:
Table 7a: Representative XRPD Peaks
8* 13.4 29.1
9 14.2 51.8
Thermo Analysis of Compound I-1 rous form C1
A thermal gravimetric analysis of Compound I-1° anhydrous form C was performed to
determine the percent weight loss as a function of time using the TA Instrument TGA Q500 (Asset
V014840). A sample (3.363 mg) was added to a pre—tared platinum pan and heated from ambient
temperature to 350°C at 10°C/min. The TGA results seen in Figure 2e show no distinct weight loss
events prior to melting/degradation. The onset temperature of melting/degradation is 292°C.
ential Scanning Calorimetg of Compound I-1 {anhydrous form C)
Differential scanning calorimetry of nd I-1° anhydrous form C was measured
using the TA Instrument DSC Q2000 (Asset V0123 90). A sample (4.100 mg) was weighed in a pre—
punched pinhole aluminum hermetic pan and heated from 30°C to 350°C at 3°C/min, modulating ::
1°C every 60 seconds. The DSC results seen in Figure 3e show a single endothermic
melting/degradation event at 281°C.
ssNMR
] A solid state C NMR spectrum of n I-1°anhydrous form C form is shown in
Figure 4e. Table 7b provides chemical shifts of the relevant peaks.
Table 7b: Solid State 13C NMRspectrum of Form C
Peak#
1* 175.2
2 163.3
3 162.1
4 158.2
152.4
6 149.9
7 144.9
8* 142.5
9 137.9
135.7
11* 129.6
12 123-6
13 86.5
14 76.6
* 73.5
16 59.6
17* 54.0
18 51.2
19 49.7
* 46.7
21 42.3
22 37.2
23 31.4
24 28.9
A solid state 19F NMR spectrum of Compound hydrous form C is shown in Figure
5e. Table 7c es chemical shifts of the relevant peaks.
Table 7c: Solid State 19F NMR Spectrum of Form C
Intensity
1* -131.2 4.8
2* -150.7 12.5
e 10: Compound I-1 [amorphous form]
Compound I-1° amorphous form was prepared according to the methods described in
Example 2, Step 3, or in Example 3, Step 3, above.
XRPD of Compound I-1 [amomhous form]
The XRPD pattern of Compound I-1° amorphous form was recorded at room temperature
in reflection mode using a PANalyticaZ diffractometer equipped with an Empyrean Cu tube source
and a PIXcel 1D detector (PANaZyticaZ, The Netherlands). The X-ray tor was operating at a
voltage of 45 kV and a current of 40 mA. The powder sample was placed in a silicon holder. The
data were over the range of 3°—3 9° 2 theta with a step size of 0.013° and a dwell time of 0.5s per step.
Figure 1f shows the X-ray powder diffractogram of the sample which is characteristic of amorphous
drug substance.
Differential Scanning Calorimetg of Compound I-1 {amorphous form)
Differential scanning calorimetry of Compound I-1° amorphous form was measured using
the TA Instrument DSC Q2000. A sample (2.61 mg) was weighed in an aluminum non-hermetic pan
and heated using the modulated mode from t temperature to 350°C at a g rate of 2°C
/min, with a modulation ude of +/—0.5°C and a period of 60s. The DSC results seen in Figure
2f show a glass transition (Tg) at 128°C (onset) with heat capacity change of 0.3 J/(g.°C). Glass
transition was ed by a crystallization exotherm at 174°C (onset), which was in turn followed
by a melt/ degradation event at 250°C.
ssNMR of Compound I-1 (amorphous)
A solid state C NMR spectrum of Compoun I amorphous form is shown in Figure
3f Table 8a provides al shifts of the relevant peaks.
Table 8a: Solid State 13C NMRspectrum of amorphous form
IntenSIty
1* 173-8
2 162-3
3 157.6
4 149.3
* 144.2
6 134-7
7 123-1
8* 87.5
9 75.6
59.4
11 50.8
12* 45-6
13 41-8
14 38.3
* 29-5
A solid state 19F NMR spectrum of Compound orphous is shown in Figure 4f.
Table 8b provides chemical shifts of the relevant peaks.
Table 8b: Solid State 19F NMR Spectrum of amorphous form
Intensity
1 .0* 9.8
12.5
Example 11: Compound I-1 (DMSO solvate)
Compound I-1° anhydrous form A (10.0g; 18.47mmol), prepared according to the
s described in Example 7, was suspended in DMSO ) and heated to 55°C. The
mixture was filtered whilst hot. The hot filtrate was stirred in a clean flask and cooled to 20—25°C
then stirred for an additional 2 hours. The solids were collected by filtration, washed with DMSO
(10mL), dried by n then dried in a vacuum oven for 14 hours at 40—45°C to give compound I-
1- DMSO solvate (7.23g; 63%). 1H NMR (500 MHz, DMSO—d6) 5 10.63 (s, 1H), 9.66 (s, 1H), 9.47
(dd, 1H), 9.24 (dd, 1H), 8.24 (d, 1H), 6.78 (s, 2H), 4.54 (t, 2H), 4.46 (t, 2H), 3.60 (dt, 4H), 3.43 (m,
1H), 3.18 (m, 2H), 2.97 (m, 3H), 2.54 (s, 6H), 2.26 (dt, 4H), 2.12 (qd, 2H), 1.73 (d, 2H); 19F NMR
(500 MHz, DMSO—d6) 5 —136.1, —152.8.
XRPD of Compound I-1 (DMSO solvate)
] The XRPD pattern of compound I-1° DMSO solvate was recorded at room temperature in
reflection mode using a PANalyticaZ diffractometer ed with an Empyrean tube source and a
PIXcel 1D detector (PANaZyticaZ, The Netherlands). The X-ray generator was operating at a
voltage of 45 kV and a current of 40 mA. The powder sample was placed in a silicon . The
data was recorded over the range of 30—390 2 theta with a step size of 0.0130 and a dwell time of 121s
per step. Figure 1 g shows the X-ray powder diffractogram of the sample which is characteristic of
crystalline drug substance.
] Table 9 depicts representative XRPD peaks form Compound I DMSO solvate:
Table 9: Representative XRPD Peaks
7.0034
8.9204
.4007
12.4735 6.81
12.7962 12.32
13.3976 —12.25
14.8102 —29.16
.439 —15.1
7 —14.37
16.5454 82.57
—15.34
—20.25
—29.71
—3.68
.9143
21.3593
22.1801
22.8306
23.3866
23.8312
22 24.5088 —15.65
—11.53
—8.95
—5.69
—8.63
—6.42
—8.71
33.2165
34.1902
34.6067
.45
38.6972
Thermo Analysis of Compound I-1 {DMSO solvate)
A thermal graVimetric analysis of compound I-1° DMSO solvate was performed to
ine the percent weight loss as a function of temperature using the Discovery TGA (TA
Instruments Trios). A sample (3.26 mg) was added to a pre-tared aluminum pan and heated from
ambient temperature to 350°C at 10°C/min. The TGA s seen in Figure 2g show a large weight
loss of 12.44% between 146°C (onset) and 156°C (end point). This weight loss corresponds to
approximately 1 molar equivalents of DMSO. A second weight loss of 0.52% was then seen
between 254°C ) and 262°C (end point). The subsequent weight loss seen at 304°C is a result
of g/degradation.
Differential Scanning Calorimetgg of Compound I-1 [DMSO solvate]
] ential scanning calorimetry of compound I DMSO solvate was measured using
the TA Instrument DSC Q2000. A sample (1.77 mg) was weighed in a pinholed um hermetic
pan and heated from ambient temperature to 350°C at 10°C/min. The DSC results seen in Figure 3g
show a desolvation endotherm at 143°C (onset) followed by a single melting endotherm at 258°C
(onset).
Example 12: nd I-1 [DMAC solvate]
Compound I-1° anhydrous form A (100mg; 0.18 mmol), prepared according to the
methods described in Example 7, was suspended in DMAC (2000uL) and stirred for 20 hours at 20—
°C. The solids were collected by filtration, washed with DMAC (500uL), dried by suction then
dried in a vacuum oven at 40—50°C to give compound I-1° DMAC solvate (84mg). 1H NMR (500
MHz, DMSO-d6) 5 10.62 (s, 1H), 9.66 (s, 1H), 9.46 (dd, 1H), 9.26 — 9.22 (m, 1H), 8.24 (d, 1H), 6.77
(s, 2H), 4.54 (t, 2H), 4.46 (t, 2H), 3.66 — 3.54 (m, 4H), 3.43 (p, 1H), 3.18 (tt, 2H), 2.94 (s, 8H), 2.78
(s, 4H), 2.26 (dt, 4H), 2.12 (qd, 2H), 1.96 (s, 4H), 1.76 — 1.69 (m, 2H).
XRPD of Compound I-1 [DMAC e]
The XRPD pattern of compound I-1° DMAC solvate was recorded at room ature in
reflection mode using a PANalyticaZ diffractometer equipped with an Empyrean tube source and a
PIXcel 1D detector (PANaZyticaZ, The Netherlands). The X-ray generator was operating at a
voltage of 45 kV and a current of 40 mA. The powder sample was placed in a silicon holder. The
data were recorded over the range of 3°—3 9° 2 theta with a step size of 0.013° and a dwell time of
121s per step. Figure 1h shows the X-ray powder diffractogram of the sample which is characteristic
of crystalline drug substance.
] Table 10 depicts representative XRPD peaks form Compound I DMAC solvate:
Table 10: Representative XRPD Peaks
2 7.5182
3 8.5957
4 9.7593
10.9655
12.0406 12. 17
—20.85
—71.07
—0.92
—82.12
18.1371
18.5857
19.0786
19.745
.3531
.7384
21.2654
—100
—39.15
—10.68
—15.9
28.763
29.5534
.5467
31.4852
32.228
44 34.7188
47 2
Thermo Analysis of Compound I-1 gDMAC solvate)
A thermograVimetric analysis of compound I-1° DMAC solvate was performed to
determine the percent weight loss as a function of temperature using the Discovery TGA (TA
Instruments Trios). A sample (5.12mg) was added to a pre—tared aluminum pan and heated from
ambient temperature to 350°C at 10°C/min. The TGA s seen in Figure 2h show a large weight
loss of 17.76% between 85°C (onset) and 100°C (end . This weight loss corresponds to
approximately 1.3 molar equivalents of DMAC. The subsequent weight loss seen at 306°C is a result
of melting/degradation.
Differential Scanning Calorimetg of Compound I-1 [DMAC e]
Differential scanning calorimetry of compound I-1° DMAC solvate was measured using
the TA Instrument DSC Q2000. A sample (1.93 mg) was weighed in a pinholed aluminum hermetic
pan and heated from ambient temperature to 350°C at 10°C/min. The DSC results seen in Figure 3h
show a desolvation endotherm at 81°C (onset) followed by a single melting endotherm at 261°C
(onset).
Example 13: nd I-1 [acetone e]
Compound I-1° amorphous (100mg; 0.18mmol), prepared according to the methods
described in Example 2, Step 3, above, was suspended in e (2000uL) and stirred for 22 hours.
nd I-1° acetone solvate was collected by filtration. 1H NMR (500 MHz, DMSO—d6) 5 10.63
(s, 1H), 9.66 (s, 1H), 9.46 (dd, 1H), 9.24 (dd, 1H), 8.24 (d, 1H), 6.78 (s, 2H), 4.54 (t, 2H), 4.46 (t,
2H), 3.65 — 3.54 (m, 4H), 3.43 (p, 1H), 3.19 (tt, 2H), 3.06 — 2.90 (m, 3H), 2.26 (dt, 4H), 2.18 — 2.05
(m, 3H), 1.72 (d, 2H).
XRPD of nd I-1 ne solvate]
The XRPD pattern of compound I-1° acetone solvate was recorded at room temperature in
reflection mode using a PANalyticaZ diffractometer equipped with an Empyrean tube source and a
PIXcel 1D detector (PANaZyticaZ, The Netherlands). The X-ray generator was operating at a
voltage of 45 kV and a current of 40 mA. The powder sample was placed in a silicon . The
data were recorded over the range of 3°—3 9° 2 theta with a step size of 0.0130 and a dwell time of
121s per step. Figure 1i shows the X-ray powder diffractogram of the sample which is characteristic
of crystalline drug substance.
Table 11 depicts representative XRPD peaks form Compound I-1° acetone solvate:
Table 10: Representative XRPD Peaks
7.38
—-1m
* 16.6652 —22.77
11 17.1217 —6.15
12 17.9563 —10.57
18.1349
18.589
19.5447
.8656
21.3488
22.2722
22 23.465
—3.74
—2.49
—4.74
—13.52
—8.03
—6.04
.6427
31.36
32.2601
33.3871
33.8459
34.2253
.6517
39 35.9083
40 36.4752
Thermo Analysis of Compound I-1 ne solvate)
A thermograVimetric analysis of compound I-1° acetone solvate was performed to
determine the percent weight loss as a function of temperature using the Discovery TGA (TA
Instruments . A sample (2.45mg) was added to a pre-tared aluminum pan and heated from
ambient temperature to 350°C at 10°C/min. The TGA results seen in Figure 2i show an initial
2014/068713
weight loss of 1.46%. A larger weight loss of 4.55% was then seen n 124°C ) and
151°C (end point), which corresponds to approximately 0.44 molar equivalents of Acetone. The
uent weight loss seen at 302°C is a result of melting/degradation.
Differential Scanning Calorimetg of Compound I-1 [acetone solvate]
Differential scanning calorimetry of compound I-1° acetone solvate was ed using
the TA Instrument DSC Q2000. A sample (1.42 mg) was weighed in a pinholed aluminum hermetic
pan and heated from ambient temperature to 350°C at 10°C/min. The DSC results seen in Figure 3i
show a desolvation endotherm at 136 °C (onset) followed by a melting endotherm at 166°C (onset).
This was in turn followed by immediate recrystallization exotherm at 175°C. Another g
endotherm was then recorded at 259°C. This was also followed by a recrystallization exotherm at
261°C. A final g erm was observed at 279°C.
Example 14: Compound I-1 [isopropanol solvate]
Compound I-1° amorphous (100mg; 0.18mmol), prepared according to the methods
described in Example 2, Step 3, above, was suspended in 2—propanol (2000uL) and stirred for 22
hours at 20—25°C. Compound I-1° isopropanol solvate was collected by tion.
XRPD of Compound I-1 [isopropanol solvate)
The XRPD pattern of compound I panol solvate was recorded at room
temperature in ion mode using a PANaZytical diffractometer equipped with an Empyrean tube
source and a PIXcel 1D detector (PANaZyticaZ, The Netherlands). The X—ray generator was
operating at a voltage of 45 kV and a current of 40 mA. The powder sample was placed in a silicon
holder. The data were recorded over the range of 3°—39° 2 theta with a step size of 0.013° and a dwell
time of 121s per step. Figure 1j shows the X-ray powder diffractogram of the sample which is
characteristic of crystalline drug substance.
Table 12 depicts representative XRPD peaks form Compound I-1° isopropanol solvate:
Table 12: Representative XRPD Peaks
6.937
— 11.0107
— 12.8255
13.6694 3.53
6 2.27
.- 14.8878
16.1846
17.1027 18.84
2014/068713
9* 172424
180956 047
272638
28.8751
32.9263
34.4773
.6844
27 37.3825
Thermo Analysis of Compound I-1 [isopropanol solvate]
A thermograVimetric analysis of Compound I-1° isopropanol solvate was performed to
determine the percent weight loss as a function of temperature using the Discovery TGA (TA
Instruments Trios). A sample (3.39mg) was added to a pre-tared aluminum pan and heated from
ambient temperature to 300°C at 10°C/min. The TGA results seen in Figure 2j show a large weight
loss of 3.76% between 136°C ) and 180°C (end point). This weight loss corresponds to
approximately 0.35 molar equivalents of IPA. The subsequent weight loss seen at 278°C is a result
of melting/degradation.
Differential Scanning metg of Compound I-1 [isopropanol solvate)
ential scanning metry of compound I-1° isopropanol solvate was measured
using the TA Instrument DSC Q2000. A sample (1.03 mg) was weighed in a T-zero aluminum pan
and heated from ambient ature to 320°C at 10°C/min. The DSC results seen in Figure 3j
show a broad desolvation endotherm at 135°C (onset) followed by a single melting endotherm at
258°C (onset).
Example 15: Cellular ATR Inhibition Assay:
Compounds can be screened for their ability to inhibit intracellular ATR using an
immunofluorescence microscopy assay to detect phosphorylation of the ATR substrate histone
H2AX in hydroxyurea treated cells. HT29 cells are plated at 14,000 cells per well in 96—well black
WO 85132
imaging plates (BD 353219) in McCoy’s 5A media (Sigma M8403) supplemented with 10% foetal
bovine serum (JRH Biosciences 12003), Penicillin/Streptomycin solution diluted 1:100 (Sigma
P7539), and 2mM L-glumtamine (Sigma G7513), and allowed to adhere overnight at 37°C in 5%
C02. Compounds are then added to the cell media from a final concentration of 25uM in 3—fold
serial dilutions and the cells are incubated at 37°C in 5% C02. After 15min, hydroxyurea (Sigma
H8627) is added to a final concentration of 2mM.
After 45min of treatment with hydroxyurea, the cells are washed in PBS, fixed for 10min
in 4% formaldehyde diluted in PBS (Polysciences Inc 18814), washed in 0.2% Tween—20 in PBS
(wash buffer), and permeabilised for 10min in 0.5% Triton X-100 in PBS, all at room temperature.
The cells are then washed once in wash buffer and blocked for 30min at room temperature in 10%
goat serum (Sigma G9023) diluted in wash buffer (block buffer). To detect H2AX phosphorylation
levels, the cells are then incubated for 1hr. at room ature in primary dy (mouse
monoclonal anti-phosphorylated histone H2AX Ser139 antibody; Upstate 05—636) d 1:250 in
block . The cells are then washed five times in wash buffer before incubation for 1hr. at room
temperature in the dark in a mixture of ary antibody (goat anti-mouse Alexa Fluor 488
conjugated antibody; Invitrogen A11029) and Hoechst stain (Invitrogen H3570); diluted 1:500 and
1:5000, respectively, in wash buffer. The cells are then washed five times in wash buffer and finally
100ul PBS is added to each well before imaging.
Cells are imaged for Alexa Fluor 488 and Hoechst intensity using the BD Pathway 855
ger and Attovision software (BD Biosciences, Version 1.6/855) to quantify phosphorylated
H2AX Ser139 and DNA staining, respectively. The percentage of phosphorylated ositive
nuclei in a montage of 9 images at 20x magnification is then calculated for each well using BD
Image Data Explorer re (BD Biosciences Version 2.2.15). Phosphorylated H2AX—positive
nuclei are defined as Hoechst-positive regions of interest containing Alexa Fluor 488 intensity at
1.75-fold the average Alexa Fluor 488 intensity in cells not d with hydroxyurea. The percentage
of H2AX positive nuclei is finally plotted against concentration for each compound and IC50s for
intracellular ATR inhibition are determined using Prism software (GraphPad Prism version 3.0cx for
osh, GraphPad Software, San Diego California, USA).
The compounds described herein can also be tested according to other methods known in
the art (@ Sarkaria et al, “Inhibition ofATM and ATR Kinase ties by the Radiosensitizing
Agent, Caffeine: Cancer Research 59: 4375—53 82 (1999); Hickson et al, “Identification and
Characterization of a Novel and Specific Inhibitor of the Ataxia-Telangiectasia d Kinase
ATM” Cancer Research 64: 9152—9159 (2004); Kim et al, “Substrate Specificities and Identification
of Putative Substrates ofATM Kinase Family Members” The Journal ofBiological try,
274(53): 3753 8—3 7543 (1999); and Chiang et al, “Determination of the catalytic ties of mTOR
and other s of the phosphoinositide-3 -kinase—related kinase family” s Mol. Biol.
281 : 125—41 (2004)).
Example 16: ATR Inhibition Assay:
Compounds can be screened for their ability to inhibit ATR kinase using a radioactive—
phosphate incorporation assay. Assays are carried out in a e of 50mM Tris/HCl (pH 7.5),
10mM MgClz and 1mM DTT. Final substrate concentrations are 10uM [y-33P]ATP (3mCi 33P
ATP/mmol ATP, Perkin Elmer) and 800 [1M target peptide (ASELPASQPQPFSAKKK).
Assays are carried out at 25°C in the presence of 5 nM full-length ATR. An assay stock
buffer solution is prepared containing all of the reagents listed above, with the exception of ATP and
the test compound of interest. 13.5 [1L of the stock solution is placed in a 96 well plate followed by
addition of 2 [1L of DMSO stock containing serial dilutions of the test compound (typically starting
from a final concentration of 15 [1M with 3-fold serial dilutions) in duplicate (final DMSO
concentration 7%). The plate is pre-incubated for 10 minutes at 25°C and the reaction initiated by
addition of 15 [LL [y-33P]ATP (final tration 10 uM).
The reaction is stopped after 24 hours by the addition of 30uL 0.1M phosphoric acid
ning 2mM ATP. A multiscreen phosphocellulose filter 96-well plate (Millipore, Cat no.
MAPHNOB50) is pretreated with 100uL 0.2M phosphoric acid prior to the addition of 45 [LL of the
stopped assay mixture. The plate is washed with 5 x 200uL 0.2M phosphoric acid. After drying,
100 [1L Optiphase ‘SuperMix’ liquid scintillation cocktail (Perkin Elmer) is added to the well prior to
scintillation counting (1450 Microbeta Liquid Scintillation Counter, Wallac).
After removing mean background values for all of the data points, Ki(app) data are
ated from non-linear regression is of the initial rate data using the Prism software
package (GraphPad Prism version 3.0cx for Macintosh, ad Software, San Diego California,
USA).
] In general, the nds of the present invention are effective for inhibiting ATR.
Compounds I-1 and L3 inhibit ATR at Ki values below 1 uM.
Example 17: Cisplatin Sensitization Assay
nds can be screened for their y to sensitize HCT116 colorectal cancer cells to
Cisplatin using a 96h cell viability (MTS) assay. HCT116 cells, which possess a defect in ATM
signaling to Cisplatin (see, Kim et al.; Oncogene 21:3 864 (2002); see also, Takemura et al.; JBC
281 :30814 (2006)) are plated at 470 cells per well in 96—well polystyrene plates (Costar 3596) in
150ul of McCoy’s 5A media (Sigma M8403) supplemented with 10% foetal bovine serum (JRH
Biosciences 12003), Penicillin/Streptomycin solution diluted 1:100 (Sigma P753 9), and 2mM L-
mine (Sigma , and allowed to adhere overnight at 37°C in 5% C02. Compounds and
Cisplatin are then both added simultaneously to the cell media in 2-fold serial dilutions from a top
final concentration of 10uM as a full matrix of concentrations in a final cell volume of 200ul, and the
cells are then incubated at 37°C in 5% C02. After 96h, 40ul of MTS t ga G358a) is
added to each well and the cells are incubated for 1hr. at 37°C in 5% C02. y, absorbance is
measured at 490nm using a SpectraMax Plus 384 reader (Molecular Devices) and the concentration
of compound required to reduce the IC50 of Cisplatin alone by at least 3—fold (to 1 decimal place)
can be reported.
In general, the compounds of the present invention are effective for sensitizing cancer cells
to Cisplatin. Compounds I-1 and L3 have Cisplatin sensitization values of < 0.2 uM.
Example 18: Single Agent HCT116 Activity
Compounds can be screened for single agent activity against HCT116 colorectal cancer
cells using a 96h cell viability (MTS) assay. HCT116 are plated at 470 cells per well in 96-well
yrene plates (Costar 3596) in 150ul of McCoy’s 5A media (Sigma M8403) supplemented with
% foetal bovine serum (JRH Biosciences 12003), Penicillin/ Streptomycin solution d 1:100
(Sigma P7539), and 2mM L-glumtamine (Sigma G7513), and allowed to adhere ght at 37°C in
% C02. Compounds are then added to the cell media in 2—fold serial dilutions from a top final
concentration of 10uM as a full matrix of trations in a final cell volume of 200ul, and the cells
are then incubated at 37°C in 5% C02. After 96h, 40ul of MTS reagent (Promega G358a) is added to
each well and the cells are incubated for 1hr. at 37°C in 5% C02. Finally, absorbance is measured at
490nm using a SpectraMax Plus 384 reader (Molecular Devices) and IC50 values can be calculated.
Example 19: ATR-complex Inhibition Assay
Compounds were screened for their y to inhibit ATR kinase, in the presence of
partner proteins ATRIP, CLK2 and TopBPl, using a radioactive-phosphate incorporation
assay. Assays were carried out in a mixture of 50 mM Tris/HCl (pH 7.5), 10 mM MgClz and 1 mM
DTT. Final substrate concentrations were 10 ”M [g-33P]ATP (3.5 ”Ci 33P ATP/nmol ATP, Perkin
Elmer, Massachusetts, USA) and 800 ”M target peptide (ASELPASQPQPFSAKKK, Isca
Biochemicals, Cambridgeshire, UK).
2014/068713
] Assays were carried out at 25°C in the presence of 4 nM full—length ATR, 40 nM full-
length ATRIP, 40 nM full-length CLK2 and 600 nM TopBP1(A891-S1105). An enzyme stock
buffer solution was prepared containing all of the reagents listed above, with the exception of target
peptide, ATP and the test compound of interest. This enzyme stock was pre—incubated for 30
minutes at 25°C. 8.5 uL of the enzyme stock on was placed in a 96—well plate followed by
addition of 5ul of target peptide and 2 uL of DMSO stock containing serial dilutions of the test
compound (typically starting from a final concentration of 1.5 ”M with 2.5-fold serial dilutions) in
duplicate (final DMSO concentration 7%). The plate was pre-incubated for 10 minutes at 25°C and
the reaction ted by on of 15 uL [g-33P]ATP (final concentration 10 uM).
The on was stopped after 20 hours by the addition of 30 uL 0.3 M phosphoric acid
containing 2 mM ATP. A phosphocellulose filter 96-well plate (Multiscreen HTS MAPHNOB50,
Merck-Millipore, Massachusetts, USA) was ated with 100 uL 0.1 M phosphoric acid prior to
the addition of 45 uL of the stopped assay mixture. The plate was washed with 5 x 200 ”L 0.1 M
phosphoric acid. After drying, 50 uL Optiphase ‘SuperMix’ liquid scintillation cocktail (Perkin
Elmer, Massachusetts, USA) was added to the well prior to scintillation counting (Wallac 1450
Microbeta Liquid Scintillation Counter, Perkin Elmer, Massachusetts, USA).
After ng mean background values for all of the data points, Ki(app) data were
calculated from non-linear regression analysis of the initial rate data using the Prism software
package (GraphPad Prism version 6.0c for Macintosh, GraphPad Software Inc., San Diego, USA).
While we have described a number of embodiments of this invention, it is apparent that
our basic examples may be altered to provide other ments that utilize the compounds,
methods, and processes of this invention. Therefore, it will be appreciated that the scope of this
invention is to be defined by the ed claims rather than by the c embodiments that have
been represented by way of example herein.
Claims (68)
1. A solid form of a compound of formula I-1: wherein the form is selected from the group consisting of Compound I-1 hydrate I, Compound I-1 ous form A, Compound I-1 anhydrous form B, Compound I-1 anhydrous form C, Compound I-1 DMSO solvate, Compound I-1 DMAC solvate, Compound I-1 acetone solvate, or Compound I-1 isopropanol solvate, wherein Compound I-1 hydrate I is crystalline Compound I-1 hydrate I characterized by one or more peaks sed in 2-theta ± 0.2 at 6.5, 12.5, 13.7, 18.8, and 26.0 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation, Compound I-1 anhydrous form A is crystalline Compound I-1 anhydrous form A characterized by one or more peaks expressed in 2-theta ± 0.2 at 6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X-Ray powder ction pattern ed using Cu K alpha radiation, Compound I-1 anhydrous form B is crystalline Compound I-1 anhydrous form B characterized by two or more peaks expressed in 2-theta ± 0.2 at 7.2, 8.3, 12.9, 19.5, and 26.6 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation, Compound I-1• anhydrous form C is crystalline Compound I-1• anhydrous form C terized by two or more peaks sed in a ± 0.2 at 6.8, 13.4, 15.9, 30.9, and 32.9 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation.
2. The solid form of claim 1, n the form is crystalline Compound I-1• hydrate I.
3. The solid form of claim 2, wherein the crystalline Compound I-1• hydrate I has a Compound I-1 to H2O ratio of about 1:4.5.
4. The solid form of claim 2, characterized by a weight loss of from about 14.56% in a temperature range of from about 25 °C to about 100 °C as determined by a thermal gravimetric analysis.
5. The solid form of claim 2, terized as having the following peaks in a X-ray powder diffraction pattern Angle Intensity % (2-Theta ± 0.2) 4.0 1.4 4.8 3.0 5.7 7.8 6.3 100.0 6.5 51.0 9.1 3.0 10.1 10.5 10.4 10.8 11.2 5.9 11.5 8.7 11.8 11.5 12.5 16.0 13.7 10.9 14.3 7.2 15.0 9.2 15.5 10.5 16.9 14.8 18.8 10.8 20.1 14.1 20.6 11.6 22.6 10.2 23.9 4.5 24.7 7.8 26.0 13.6 27.3 10.9 28.6 4.9 32.3 2.2.
6. The solid form of claim 1, wherein the form is crystalline nd I-1• anhydrous form A.
7. The solid form of claim 6, characterized by a weight loss of from about 0.96 % in a temperature range of from about 25 °C to about 265 °C as determined by a thermal gravimetric analysis.
8. The solid form of claim 6, characterized as having the following peaks in a X-ray powder diffraction pattern Angle Intensity % (2-theta ± 0.2) 3.6 12.5 3.9 17.4 6.1 51.0 9.7 20.5 12.2 22.8 14.0 23.5 14.5 22.2 16.4 33.5 17.1 25.0 17.8 36.0 19.1 21.5 20.2 26.5 21.3 16.1 22.3 31.6 24.4 23.7 25.3 100.0 28.4 11.9 31.8 16.0.
9. The solid form of claim 6, characterized as having one or more peaks corresponding to 175.9 ± 0.3 ppm, 138.9 ± 0.3 ppm, 74.1 ± 0.3 ppm, 42.8 ± 0.3 ppm, and 31.5± 0.3 ppm in a 13C ssNMR
10. The solid form of claim 6, characterized as having one or more peaks corresponding to -136.8 ± 0.3 ppm and -155.7 ± 0.3 ppm in an 19F ssNMR spectrum.
11. The solid form of claim 1, wherein the form is lline Compound I-1• anhydrous form B.
12. The solid form of claim 11, characterized by a weight loss of from about 2.5 % in a temperature range of from about 25 °C to about 175 °C as determined by a thermal gravimetric analysis.
13. The solid form of claim 11, characterized as having the following peaks in a X-ray powder diffraction pattern Angle (2-theta ± 0.2) Intensity % 5.2 19.0 5.9 33.8 7.2 52.9 8.3 79.0 9.8 88.8 11.1 60.8 11.7 65.4 12.9 62.9 14.8 62.0 15.6 100.0 16.3 62.7 16.8 57.1 18.0 52.6 19.5 33.9 20.4 11.5 21.3 8.3 23.2 22.1 25.2 39.9 25.9 27.3 26.6 22.9 27.4 30.0 28.0 44.8 28.9 26.9 30.6 18.0 32.2 11.6 36.0 3.1.
14. The solid form of claim 11, characterized as having one or more peaks corresponding to 173.4 ± 0.3 ppm, 164.5 ± 0.3 ppm, 133.5 ± 0.3 ppm, 130.8 ± 0.3 ppm, 67.7 ± 0.3 ppm, 45.3 ± 0.3 ppm, and 25.9 ± 0.3 ppm in a 13C ssNMR spectrum.
15. The solid form of claim 11, characterized as having one or more peaks corresponding to - 138.0 ± 0.3 ppm and -153.5 ± 0.3 ppm in an 19F ssNMR spectrum.
16. The solid form of claim 1, wherein the form is crystalline Compound I-1• anhydrous form C.
17. The solid form of claim 16, characterized as having the following peaks in a X-ray powder diffraction n Angle (2-theta ± 0.2) Intensity % 3.6 1.1 4.0 1.1 6.8 44.8 7.6 11.1 8.1 12.7 10.3 13.3 11.4 100.0 13.4 29.1 14.2 51.8 14.9 23.8 15.9 31.1 16.3 14.2 16.7 17.6 17.0 26.9 18.2 37.9 19.1 50.4 20.7 31.7 22.6 3.8 23.3 16.0 23.9 15.0 24.5 10.1 25.5 24.0 25.8 33.3 27.1 17.3 27.9 23.8 29.1 19.2 30.9 22.3 32.0 12.9 32.9 12.8 33.7 7.5 35.1 4.5.
18. The solid form of claim 16, characterized as having one or more peaks ponding to 175.2 ± 0.3 ppm, 142.5 ± 0.3 ppm, 129.6 ± 0.3 ppm, 73.5± 0.3 ppm, 54.0 ± 0.3 ppm, and 46.7 ± 0.3 ppm in a 13C ssNMR spectrum.
19. The solid form of claim 16, characterized as having one or more peaks corresponding to - 131.2 ± 0.3 ppm and -150.7 ± 0.3 ppm in an 19F ssNMR spectrum.
20. The solid form of claim 1, wherein the form is Compound I-1• DMSO solvate.
21. The solid form of claim 1, wherein the form is crystalline Compound I-1• DMSO solvate.
22. The solid form of claim 21, wherein the crystalline Compound I-1• DMSO e has a compound I-1 to DMSO ratio of about 1:1.
23. The solid form of claim 21, characterized by a weight loss of from about 12.44% in a temperature range of from about 146°C to about 156°C as determined by a thermal gravimetric analysis.
24. The solid form of claim 21, characterized by one or more peaks sed in 2-theta ± 0.2 at 8.9, 14.8, 16.5, 18.6, 20.9, 22.2, and 23.4 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation.
25. The solid form of claim 21, characterized as having the following peaks in a X-ray powder diffraction pattern Angle (2-theta ± 0.2) Intensity % 7.0034 8.33 8.9204 11.28 10.4007 10.11 12.4735 6.81 12.7962 12.32 13.3976 12.25 14.8102 29.16 15.439 15.1 15.7477 14.37 16.5454 82.57 17.051 15.34 18.1033 20.25 4 29.71 19.593 3.68 20.1178 6.42 20.9143 35.76 21.3593 11.65 22.1801 100 22.8306 25.4 23.3866 51.08 23.8312 16.31 24.5088 15.65 25.6545 25.59 27.0136 3.06 27.4405 2.43 1 3.27 28.5715 8.73 28.9693 11.53 29.555 8.95 30.1186 5.69 30.5402 8.63 31.2969 6.42 32.0663 8.71 33.2165 3.04 34.1902 7.02 34.6067 3.57 35.45 1.47 36.5669 3.23 38.6972 2.19.
26. The solid form of claim 1, n the form is nd I-1• DMAC solvate.
27. The solid form of claim 1, wherein the form is crystalline Compound I-1• DMAC solvate.
28. The solid form of claim 27, wherein the crystalline Compound I-1• DMAC solvate has a compound I-1 to DMAC ratio of about 1:1.3.
29. The solid form of claim 27, characterized by a weight loss of from about 17.76% in a temperature range of from about 85°C to about 100°C as determined by a thermal gravimetric analysis.
30. The solid form of claim 27, characterized by one or more peaks expressed in a ± 0.2 at 6.0, 15.5, 17.7, 18.1, 20.4, and 26.6 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation.
31. The solid form of claim 27, characterized as having the following peaks in a X-ray powder diffraction pattern Angle (2-theta ± 0.2) Intensity % 6.0169 75.51 7.5182 7.99 8.5957 32.29 9.7593 33.98 5 15.95 11.3688 7.25 12.0406 12.17 13.6703 19.18 14.1108 36.56 14.2831 23.2 14.5895 9.33 15.1755 25.52 15.4632 20.85 16.0919 71.07 16.9423 0.92 17.7117 82.12 18.1371 77.28 18.5857 4.73 19.0786 16.95 19.745 7.05 20.3531 40.38 20.7384 29.95 21.2654 10.22 21.7978 9.56 8 2.27 22.8051 5.51 23.3945 6.33 23.829 19.65 24.6486 3.69 25.343 5.43 2 7.83 26.6041 100 27.6488 39.15 28.1311 10.68 28.4779 15.9 28.763 13.68 29.2517 17.62 29.5534 13.91 29.9062 12.28 30.5467 7.27 31.4852 9.17 32.228 2.69 32.6692 3.7 34.7188 1.29 2 1.43 37.1111 1.9 38.0592 1.92.
32. The solid form of claim 1, wherein the form is Compound I-1• acetone solvate.
33. The solid form of claim 1, wherein the form is crystalline Compound I-1• acetone solvate.
34. The solid form of claim 33, wherein the crystalline Compound I-1• acetone e has a compound I-1 to acetone ratio of about 1:0.44.
35. The solid form of claim 33, characterized by a weight loss of from about 4.55% in a temperature range of from about 124°C to about 151°C as determined by a thermal gravimetric analysis.
36. The solid form of claim 33, characterized by one or more peaks expressed in 2-theta ± 0.2 at 8.9, 15.5, 15.8, 16.7, 22.3, 25.7, and 29.0 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation.
37. The solid form of claim 33, characterized as having the following peaks in a X-ray powder diffraction pattern Angle (2-theta ± 0.2) Intensity % 6.9871 31.75 8.9148 62.84 10.4145 7.38 12.4529 6.65 12.7486 9.09 13.4567 7.37 14.8093 10.97 15.528 35.3 15.826 19.22 16.6652 22.77 17.1217 6.15 17.9563 10.57 18.1349 9.4 18.589 7.22 19.5447 3.06 20.0055 2.55 20.8656 6.29 21.3488 6.36 2 100 5 13.43 22.9581 19.8 23.465 21.26 8 8.65 24.5843 8.65 25.7222 13.01 26.0003 3.74 27.696 2.49 28.7335 4.74 29.0658 13.52 29.6743 8.03 30.2154 6.04 30.6427 4.67 31.36 4.28 32.2601 3.86 33.3871 0.66 33.8459 1.15 34.2253 1.42 35.6517 2.34 35.9083 2 36.4752 2.17.
38. The solid form of claim 1, wherein the form is Compound I-1• isopropanol solvate.
39. The solid form of claim 1, wherein the form is lline Compound I-1• isopropanol solvate.
40. The solid form of claim 39, wherein the crystalline Compound I-1• isopropanol solvate has a compound I-1 to isopropanol ratio of about 1:0.35.
41. The solid form of claim 39, characterized by a weight loss of from about 3.76% in a ature range of from about 136°C to about 180°C as determined by a thermal gravimetric analysis.
42. The solid form of claim 39, characterized by one or more peaks sed in 2-theta ± 0.2 at 6.9, 17.1, 17.2, 19.1, 19.6, 23.7, 24.4, and 28.9 degrees in an X-Ray powder diffraction pattern ed using Cu K alpha radiation.
43. The solid form of claim 39, characterized as having the following peaks in a X-ray powder diffraction pattern Angle (2-theta ± 0.2) ity % 6.937 100 11.0107 7.85 5 8.34 13.6694 3.53 6 2.27 14.8878 7.9 16.1846 4.17 17.1027 18.84 17.2424 19.04 18.0956 0.47 19.1139 5.27 19.6437 15.33 20.3628 10.96 21.4978 1.13 22.769 5.81 23.6531 41.5 24.3573 39.72 24.8556 17.48 25.8121 8.63 27.2638 2.35 28.8751 21.82 30.0648 2.34 31.4229 1.58 32.9263 1.14 34.4773 2.29 35.6844 1.53 37.3825 0.46.
44. A composition comprising: a) Compound I-1, or a pharmaceutically acceptable salt thereof, wherein Compound I-1 is represented by the following structural formula: ; and b) one or more excipients, wherein at least 90% by weight of Compound I-1 is crystalline Compound I-1•anhydrous form A characterized by one or more peaks expressed in 2-theta ± 0.2 at 6.1, 12.2, 14.5, 22.3, and 31.8 s in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation.
45. The composition of claim 44, wherein the one or more excipients comprises one or more selected from the group consisting of one or more fillers, one or more wetting agents, one or more lubricants, and one or more egrants.
46. The composition of claims 44 or 45, wherein the one or more excipients comprise one or more fillers.
47. The composition of claim 46, wherein the one or more fillers is present in an amount in the range of about 10 wt% to about 88 wt% by the total weight of the composition.
48. The composition of claim 46 or 47, wherein the one or more fillers is selected from the group consisting of mannitol, lactose, e, se, maltodextrin, sorbitol, xylitol, ed cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, starch, pregelatinized starch, dibasic calcium phosphate, calcium e and calcium carbonate.
49. The composition of claim 48, wherein the one or more filler is selected from microcrystalline cellulose and lactose.
50. The composition of any one of claims 44-49, wherein the one or more excipients comprises one or more disintegrants.
51. The composition of claim 50, wherein one or more disintegrants is present in an amount in the range of about 1 wt% to about 15 wt% by the total weight of the composition.
52. The ition of claim 50 or 51, wherein the one or more disintegrants is selected from the group consisting of croscarmellose sodium, sodium alginate, calcium alginate, alginic acid, starch, pregelatinized starch, sodium starch glycolate, vidone, cellulose and its derivatives, carboxymethylcellulose calcium, ymethylcellulose sodium, soy polysaccharide, guar gum, an ion exchange resin, an effervescent system based on food acids and an alkaline carbonate component, and sodium bicarbonate.
53. The composition of claim 52, n the one or more disintegrants is croscarmellose sodium.
54. The composition of any one of claims 44-53, wherein the one or more ents comprises one or more lubricants.
55. The composition of claim 54, wherein the one or more lubricants is present in an amount in the range of about 0.1 wt% to about 10 wt% by the total weight of the composition.
56. The composition of claim 54 or 55, wherein the one or more lubricants is selected from the group consisting of talc, fatty acid, stearic acid, magnesium stearate, calcium stearate, sodium stearate, glyceryl monostearate, sodium lauryl sulfate, sodium stearyl fumarate, enated oils, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, leucine, sodium benzoate, and a combination thereof.
57. The composition of claim 56, wherein the one or more lubricants is sodium stearyl fumarate.
58. The composition of any one of claims 44-57, comprising: a) an amount of nd I-1 in the range of about 5 wt% to about 50 wt% by the total weight of the composition; b) an amount of one or more lubricants in the range of about 0.1 wt% to about 10 wt% by the total weight of the composition; c) an amount of one or more disintegrants in the range of about 1 wt% to about 15 wt% by the total weight of the composition; and d) an amount of one or more fillers in the range of about 10 wt% to about 90 wt% by the total weight of the composition.
59. The composition of any one of claims 44-58, comprising: a) an amount of Compound I-1 of 10.0 wt% by the total weight of the composition; b) an amount of lactose monohydrate of 27.5 wt% by the total weight of the composition; c) an amount of Avicel PH-101 (microcrystalline cellulose) of 55.0 wt% by the total weight of the composition; d) an amount of Ac-Di-Sol (croscarmellose sodium) of 4.5 wt% by the total weight of the composition; and e) an amount of sodium l fumarate of 3.0 wt% by the total weight of the composition.
60. The composition of any one of claims 44-59, wherein all of Compound I-1 is Form A.
61. The composition of any one of claims 44-59, wherein at least 95% by weight of Compound I- 1 is Form A.
62. The composition of claim 61, wherein at least 98% by weight of Compound I-1 is Form A.
63. A crystal form of nd I-1 having a monoclinic crystal system, a P21/c centrosymmetric space group, and the following unit cell parameters: a = 15.29(3)Å α = 90° b = 2)Å β = 107.22(3)° c = 14.48(3)Å γ = 90° wherein nd I-1 is represented by the following structural formula:
64. A s for preparing Compound I-1•anhydrous form A comprising stirring a suspension ning Compound I-1•ethanol solvate and tetrahydrofuran wherein Compound hydrous form A is crystalline Compound hydrous form A characterized by one or more peaks expressed in 2-theta ± 0.2 at 6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation, wherein Compound I-1 is ented by the following structural formula:
65. A process for preparing Compound I-1•anhydrous form A comprising stirring a sion containing Compound I-1•amorphous, isopropanol, and water, wherein Compound I-1•anhydrous form A is crystalline Compound I-1•anhydrous form A characterized by one or more peaks expressed in 2-theta ± 0.2 at 6.1, 12.2, 14.5, 22.3, and 31.8 degrees in an X-Ray powder diffraction pattern obtained using Cu K alpha radiation, wherein Compound I-1 is represented by the following structural formula:
66. The process of claim 65, wherein the suspension is heated to between about 65°C and about 80°C.
67. The process of claim 66, wherein the suspension is heated to n about 70°C and about 75°C.
68. A solid form of claim 1, substantially as herein described with reference to any one of the Examples and/or
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361912636P | 2013-12-06 | 2013-12-06 | |
US61/912,636 | 2013-12-06 | ||
US201462008220P | 2014-06-05 | 2014-06-05 | |
US62/008,220 | 2014-06-05 | ||
US201462058819P | 2014-10-02 | 2014-10-02 | |
US62/058,819 | 2014-10-02 | ||
PCT/US2014/068713 WO2015085132A1 (en) | 2013-12-06 | 2014-12-05 | 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof |
Publications (3)
Publication Number | Publication Date |
---|---|
NZ720909A NZ720909A (en) | 2020-10-30 |
NZ713645B2 true NZ713645B2 (en) | 2021-02-02 |
NZ720909B2 NZ720909B2 (en) | 2021-02-02 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11485739B2 (en) | Compounds useful as inhibitors of ATR kinase | |
EP2751099B1 (en) | Compounds useful as inhibitors of atr kinase | |
US8841337B2 (en) | Compounds useful as inhibitors of ATR kinase | |
US8841450B2 (en) | Compounds useful as inhibitors of ATR kinase | |
EP2569286B1 (en) | Compounds useful as inhibitors of atr kinase | |
NZ713645A (en) | Use of high acyl gellan in whipping cream | |
US20140275021A1 (en) | Compounds useful as inhibitors of atr kinase | |
US20150158868A1 (en) | Compounds useful as inhibitors of atr kinase | |
NZ713645B2 (en) | 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof | |
NZ720909B2 (en) | 2-amino-6-fluoro-n-[5-fluoro-pyridin-3-yl]pyrazolo[1,5-a]pyrimidin-3-carboxamide compound useful as atr kinase inhibitor, its preparation, different solid forms and radiolabelled derivatives thereof |