TWI546305B - 製備異喹啉酮之方法及異喹啉酮之固體形式 - Google Patents

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Publication number

TWI546305B

TWI546305B TW101100966A TW101100966A TWI546305B TW I546305 B TWI546305 B TW I546305B TW 101100966 A TW101100966 A TW 101100966A TW 101100966 A TW101100966 A TW 101100966A TW I546305 B TWI546305 B TW I546305B

Authority

TW

Taiwan

Prior art keywords

group

compound

polymorphic form

formula

polymorphic

Prior art date

2011-01-10

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• 238000000034 method Methods 0.000 title claims description 150
• 239000007787 solid Chemical group 0.000 title claims description 53
• VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical group C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims description 398
• -1 2,2,2-trichloroethoxycarbonyl Chemical group 0.000 claims description 305
• 239000000203 mixture Substances 0.000 claims description 273
• 239000002904 solvent Substances 0.000 claims description 183
• 125000000217 alkyl group Chemical group 0.000 claims description 115
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 105
• 238000000634 powder X-ray diffraction Methods 0.000 claims description 102
• 125000001072 heteroaryl group Chemical group 0.000 claims description 96
• 125000003118 aryl group Chemical group 0.000 claims description 90
• 229910052799 carbon Inorganic materials 0.000 claims description 79
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 78
• 125000003342 alkenyl group Chemical group 0.000 claims description 69
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 68
• 125000000304 alkynyl group Chemical group 0.000 claims description 64
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 62
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 59
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 55
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 55
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 54
• 125000001424 substituent group Chemical group 0.000 claims description 53
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 50
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 45
• 125000003545 alkoxy group Chemical group 0.000 claims description 45
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 45
• 150000001412 amines Chemical class 0.000 claims description 44
• 125000000623 heterocyclic group Chemical group 0.000 claims description 42
• 239000008194 pharmaceutical composition Substances 0.000 claims description 42
• 229910052739 hydrogen Inorganic materials 0.000 claims description 41
• 239000001257 hydrogen Substances 0.000 claims description 40
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
• XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 39
• 150000002148 esters Chemical class 0.000 claims description 37
• 239000002253 acid Substances 0.000 claims description 35
• 239000007788 liquid Substances 0.000 claims description 35
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 34
• 238000002360 preparation method Methods 0.000 claims description 31
• 125000004104 aryloxy group Chemical group 0.000 claims description 30
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 29
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 29
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 26
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
• 239000012296 anti-solvent Substances 0.000 claims description 25
• 239000003795 chemical substances by application Substances 0.000 claims description 25
• 230000008569 process Effects 0.000 claims description 24
• JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 24
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
• 238000006243 chemical reaction Methods 0.000 claims description 22
• 125000006239 protecting group Chemical group 0.000 claims description 22
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 21
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
• 238000001816 cooling Methods 0.000 claims description 21
• 238000000113 differential scanning calorimetry Methods 0.000 claims description 20
• 239000003153 chemical reaction reagent Substances 0.000 claims description 19
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 19
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
• 239000002002 slurry Substances 0.000 claims description 18
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 17
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 17
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 17
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 16
• 239000011734 sodium Substances 0.000 claims description 15
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
• 125000000000 cycloalkoxy group Chemical group 0.000 claims description 14
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 14
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 13
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 12
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
• 239000003125 aqueous solvent Substances 0.000 claims description 11
• 125000005587 carbonate group Chemical group 0.000 claims description 11
• 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 11
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 11
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 11
• 238000001556 precipitation Methods 0.000 claims description 11
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 11
• 229910052744 lithium Inorganic materials 0.000 claims description 10
• 229940098779 methanesulfonic acid Drugs 0.000 claims description 10
• WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 9
• 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 9
• 125000004849 alkoxymethyl group Chemical group 0.000 claims description 9
• 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
• 125000006612 decyloxy group Chemical group 0.000 claims description 9
• CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 claims description 9
• 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 9
• 229940016286 microcrystalline cellulose Drugs 0.000 claims description 9
• 239000008108 microcrystalline cellulose Substances 0.000 claims description 9
• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
• GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 8
• XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 8
• 239000008101 lactose Substances 0.000 claims description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
• VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 8
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 7
• 108091007960 PI3Ks Proteins 0.000 claims description 7
• 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims description 7
• 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims description 7
• 239000011575 calcium Substances 0.000 claims description 7
• 229910052791 calcium Inorganic materials 0.000 claims description 7
• 238000001914 filtration Methods 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 7
• ZHGNHOOVYPHPNJ-UHFFFAOYSA-N Amigdalin Chemical compound FC(F)(F)C(=O)OCC1OC(OCC2OC(OC(C#N)C3=CC=CC=C3)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C2OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C(OC(=O)C(F)(F)F)C1OC(=O)C(F)(F)F ZHGNHOOVYPHPNJ-UHFFFAOYSA-N 0.000 claims description 6
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
• 206010028980 Neoplasm Diseases 0.000 claims description 6
• GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 6
• DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
• HKVFISRIUUGTIB-UHFFFAOYSA-O azanium;cerium;nitrate Chemical compound [NH4+].[Ce].[O-][N+]([O-])=O HKVFISRIUUGTIB-UHFFFAOYSA-O 0.000 claims description 6
• 229910000420 cerium oxide Inorganic materials 0.000 claims description 6
• 229940125782 compound 2 Drugs 0.000 claims description 6
• MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 claims description 6
• BLHLJVCOVBYQQS-UHFFFAOYSA-N ethyllithium Chemical compound [Li]CC BLHLJVCOVBYQQS-UHFFFAOYSA-N 0.000 claims description 6
• 238000005984 hydrogenation reaction Methods 0.000 claims description 6
• XBEREOHJDYAKDA-UHFFFAOYSA-N lithium;propane Chemical compound [Li+].CC[CH2-] XBEREOHJDYAKDA-UHFFFAOYSA-N 0.000 claims description 6
• DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 6
• 239000007800 oxidant agent Substances 0.000 claims description 6
• BMMGVYCKOGBVEV-UHFFFAOYSA-N oxo(oxoceriooxy)cerium Chemical compound [Ce]=O.O=[Ce]=O BMMGVYCKOGBVEV-UHFFFAOYSA-N 0.000 claims description 6
• 239000011541 reaction mixture Substances 0.000 claims description 6
• 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
• 229920002472 Starch Polymers 0.000 claims description 5
• WXZIKFXSSPSWSR-UHFFFAOYSA-N [Li]CCCCC Chemical compound [Li]CCCCC WXZIKFXSSPSWSR-UHFFFAOYSA-N 0.000 claims description 5
• 201000011510 cancer Diseases 0.000 claims description 5
• 229910017604 nitric acid Inorganic materials 0.000 claims description 5
• 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 5
• 229920000136 polysorbate Polymers 0.000 claims description 5
• 238000004537 pulping Methods 0.000 claims description 5
• 239000008107 starch Substances 0.000 claims description 5
• 235000019698 starch Nutrition 0.000 claims description 5
• 229940032147 starch Drugs 0.000 claims description 5
• 239000007818 Grignard reagent Substances 0.000 claims description 4
• WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
• CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
• 229930006000 Sucrose Natural products 0.000 claims description 4
• 235000019359 magnesium stearate Nutrition 0.000 claims description 4
• 239000005720 sucrose Substances 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 3
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
• 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 3
• 229930195725 Mannitol Natural products 0.000 claims description 3
• 235000021355 Stearic acid Nutrition 0.000 claims description 3
• 125000002252 acyl group Chemical group 0.000 claims description 3
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
• 239000004337 magnesium citrate Substances 0.000 claims description 3
• 229960005336 magnesium citrate Drugs 0.000 claims description 3
• 235000002538 magnesium citrate Nutrition 0.000 claims description 3
• 239000000594 mannitol Substances 0.000 claims description 3
• 235000010355 mannitol Nutrition 0.000 claims description 3
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
• OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
• 229920001983 poloxamer Polymers 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
• 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
• 239000000600 sorbitol Substances 0.000 claims description 3
• 235000010356 sorbitol Nutrition 0.000 claims description 3
• 239000008117 stearic acid Substances 0.000 claims description 3
• 239000000454 talc Substances 0.000 claims description 3
• 229910052623 talc Inorganic materials 0.000 claims description 3
• 235000012222 talc Nutrition 0.000 claims description 3
• PLSARIKBYIPYPF-UHFFFAOYSA-H trimagnesium dicitrate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O PLSARIKBYIPYPF-UHFFFAOYSA-H 0.000 claims description 3
• FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
• 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
• MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
• 230000004968 inflammatory condition Effects 0.000 claims description 2
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
• 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
• RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims 4
• CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Substances Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims 3
• 229920002785 Croscarmellose sodium Polymers 0.000 claims 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 claims 2
• 229960001681 croscarmellose sodium Drugs 0.000 claims 2
• 229960000913 crospovidone Drugs 0.000 claims 2
• 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims 2
• KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims 2
• UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims 2
• 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 2
• 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 2
• 206010025323 Lymphomas Diseases 0.000 claims 1
• MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 claims 1
• 230000001363 autoimmune Effects 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 claims 1
• 208000032839 leukemia Diseases 0.000 claims 1
• DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 claims 1
• 230000001404 mediated effect Effects 0.000 claims 1
• 229960004274 stearic acid Drugs 0.000 claims 1
• 229940071138 stearyl fumarate Drugs 0.000 claims 1
• 125000000446 sulfanediyl group Chemical group *S* 0.000 claims 1
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
• UGNWTBMOAKPKBL-UHFFFAOYSA-N tetrachloro-1,4-benzoquinone Chemical class ClC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O UGNWTBMOAKPKBL-UHFFFAOYSA-N 0.000 claims 1
• 150000003839 salts Chemical class 0.000 description 179
• 239000012453 solvate Substances 0.000 description 135
• 239000002585 base Substances 0.000 description 67
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 59
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 56
• 125000001188 haloalkyl group Chemical group 0.000 description 51
• 238000002425 crystallisation Methods 0.000 description 45
• 230000008025 crystallization Effects 0.000 description 45
• 125000005842 heteroatom Chemical group 0.000 description 42
• 125000004432 carbon atom Chemical group C* 0.000 description 34
• 125000005843 halogen group Chemical group 0.000 description 32
• 150000004677 hydrates Chemical class 0.000 description 32
• 150000002431 hydrogen Chemical group 0.000 description 31
• 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 30
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
• 235000019441 ethanol Nutrition 0.000 description 29
• 125000004149 thio group Chemical group *S* 0.000 description 29
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 28
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 27
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 26
• 238000002411 thermogravimetry Methods 0.000 description 26
• 229910052757 nitrogen Inorganic materials 0.000 description 25
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
• 229910019142 PO4 Inorganic materials 0.000 description 24
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 24
• 235000021317 phosphate Nutrition 0.000 description 24
• 239000010452 phosphate Substances 0.000 description 23
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 23
• 239000000651 prodrug Substances 0.000 description 23
• 229940002612 prodrug Drugs 0.000 description 23
• 239000000243 solution Substances 0.000 description 23
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 22
• 125000004093 cyano group Chemical group *C#N 0.000 description 22
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
• 125000006413 ring segment Chemical group 0.000 description 22
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• 239000013078 crystal Substances 0.000 description 21
• 239000001301 oxygen Substances 0.000 description 21
• 229910052760 oxygen Inorganic materials 0.000 description 21
• 239000000126 substance Substances 0.000 description 21
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 19
• 150000005829 chemical entities Chemical class 0.000 description 18
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
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