CA2615611C - Indazole derivatives - Google Patents

Info

Publication number

CA2615611C

CA2615611C CA2615611A CA2615611A CA2615611C CA 2615611 C CA2615611 C CA 2615611C CA 2615611 A CA2615611 A CA 2615611A CA 2615611 A CA2615611 A CA 2615611A CA 2615611 C CA2615611 C CA 2615611C

Authority

CA

Canada

Prior art keywords

isopropyl

group

indazole

carboxamide

pyrrolidin

Prior art date

2005-07-22

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

Links

• Espacenet
• Global Dossier
• CIPO
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• 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 242
• 150000003839 salts Chemical class 0.000 claims abstract description 30
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
• 238000011282 treatment Methods 0.000 claims abstract description 14
• 201000010099 disease Diseases 0.000 claims abstract description 13
• 201000006549 dyspepsia Diseases 0.000 claims abstract description 12
• 208000002551 irritable bowel syndrome Diseases 0.000 claims abstract description 8
• 230000001404 mediated effect Effects 0.000 claims abstract description 8
• 208000035475 disorder Diseases 0.000 claims abstract description 6
• 208000021302 gastroesophageal reflux disease Diseases 0.000 claims abstract description 5
• 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 4
• 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 4
• 206010010774 Constipation Diseases 0.000 claims abstract description 4
• 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 4
• 206010019280 Heart failures Diseases 0.000 claims abstract description 4
• 208000019695 Migraine disease Diseases 0.000 claims abstract description 4
• 206010028813 Nausea Diseases 0.000 claims abstract description 4
• 208000012902 Nervous system disease Diseases 0.000 claims abstract description 4
• 208000025966 Neurological disease Diseases 0.000 claims abstract description 4
• 206010030216 Oesophagitis Diseases 0.000 claims abstract description 4
• 208000002193 Pain Diseases 0.000 claims abstract description 4
• 206010047700 Vomiting Diseases 0.000 claims abstract description 4
• 206010003119 arrhythmia Diseases 0.000 claims abstract description 4
• 230000006793 arrhythmia Effects 0.000 claims abstract description 4
• 208000015114 central nervous system disease Diseases 0.000 claims abstract description 4
• 208000010877 cognitive disease Diseases 0.000 claims abstract description 4
• 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 4
• 208000010643 digestive system disease Diseases 0.000 claims abstract description 4
• 208000006881 esophagitis Diseases 0.000 claims abstract description 4
• 230000030135 gastric motility Effects 0.000 claims abstract description 4
• 208000018685 gastrointestinal system disease Diseases 0.000 claims abstract description 4
• 206010027599 migraine Diseases 0.000 claims abstract description 4
• 230000008693 nausea Effects 0.000 claims abstract description 4
• 201000002859 sleep apnea Diseases 0.000 claims abstract description 4
• -1 METHYLSULFONYL Chemical class 0.000 claims description 140
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 38
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 36
• 125000000623 heterocyclic group Chemical group 0.000 claims description 33
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 29
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 26
• MUBZPKHOEPUJKR-UHFFFAOYSA-L Oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 claims description 22
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 15
• 108091005482 5-HT4 receptors Proteins 0.000 claims description 11
• 230000000694 effects Effects 0.000 claims description 11
• WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical class [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 11
• 125000000217 alkyl group Chemical group 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 9
• 229910052731 fluorine Chemical group 0.000 claims description 9
• 125000005843 halogen group Chemical group 0.000 claims description 9
• 125000001424 substituent group Chemical group 0.000 claims description 8
• 125000001153 fluoro group Chemical group F* 0.000 claims description 7
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
• 241000124008 Mammalia Species 0.000 claims description 4
• 239000013543 active substance Substances 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 claims description 4
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• XNFVQTPDQLIWKO-IRXDYDNUSA-N n-[(3s,6s)-6-[(4-hydroxyoxan-4-yl)methyl]piperidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C([C@@H]1CC[C@@H](CN1)NC(=O)C1=NN(C2=CC=CC=C21)C(C)C)C1(O)CCOCC1 XNFVQTPDQLIWKO-IRXDYDNUSA-N 0.000 claims description 3
• UCILVXWJAFETDW-KBPBESRZSA-N 5-fluoro-n-[(3s,5s)-5-(2-hydroxy-2-methylpropyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC(F)=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CC(C)(C)O)C1 UCILVXWJAFETDW-KBPBESRZSA-N 0.000 claims description 2
• LWENXMUXSIMIEC-LIOBNPLQSA-N N-[(3S,5R)-5-(2-acetamidoethyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide oxalic acid Chemical compound OC(=O)C(O)=O.C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CCNC(C)=O)C1 LWENXMUXSIMIEC-LIOBNPLQSA-N 0.000 claims description 2
• QYKKHBBHHHUQRG-LIOBNPLQSA-N N-[(3S,6S)-6-(3-hydroxypropyl)piperidin-3-yl]-1-propan-2-ylindazole-3-carboxamide oxalic acid Chemical compound OC(=O)C(O)=O.C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@H]1CC[C@@H](CCCO)NC1 QYKKHBBHHHUQRG-LIOBNPLQSA-N 0.000 claims description 2
• USUOIHWHSLQKEA-CABCVRRESA-N n-[(3s,5r)-5-(3-hydroxy-3-methylbutyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CCC(C)(C)O)C1 USUOIHWHSLQKEA-CABCVRRESA-N 0.000 claims description 2
• GCLUDMXIZPSJBO-KGLIPLIRSA-N n-[(3s,5r)-5-(3-hydroxypropyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CCCO)C1 GCLUDMXIZPSJBO-KGLIPLIRSA-N 0.000 claims description 2
• BIRATPPIBVTVLX-HOTGVXAUSA-N n-[(3s,5s)-5-(2-ethyl-2-hydroxybutyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C1N[C@H](CC(O)(CC)CC)C[C@@H]1NC(=O)C1=NN(C(C)C)C2=CC=CC=C12 BIRATPPIBVTVLX-HOTGVXAUSA-N 0.000 claims description 2
• AJDANZDKBLQXLM-KBPBESRZSA-N n-[(3s,5s)-5-(2-hydroxy-2-methylpropyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CC(C)(C)O)C1 AJDANZDKBLQXLM-KBPBESRZSA-N 0.000 claims description 2
• NZMWDGPDPDDZQZ-OLZOCXBDSA-N n-[(3s,5s)-5-(2-hydroxyethyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CCO)C1 NZMWDGPDPDDZQZ-OLZOCXBDSA-N 0.000 claims description 2
• CUUNOWAFGVOBCI-KBPBESRZSA-N n-[(3s,5s)-5-(acetamidomethyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CNC(C)=O)C1 CUUNOWAFGVOBCI-KBPBESRZSA-N 0.000 claims description 2
• BQMABOCCEDSSTI-STQMWFEESA-N n-[(3s,5s)-5-(methanesulfonamidomethyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CNS(C)(=O)=O)C1 BQMABOCCEDSSTI-STQMWFEESA-N 0.000 claims description 2
• RQDXEGNGZYADNP-GJZGRUSLSA-N n-[(3s,5s)-5-[(2-hydroxy-2-methylpropoxy)methyl]pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](COCC(C)(C)O)C1 RQDXEGNGZYADNP-GJZGRUSLSA-N 0.000 claims description 2
• CFCMRKXACCTYSD-KBPBESRZSA-N n-[(3s,5s)-5-[2-(dimethylamino)-2-oxoethyl]pyrrolidin-3-yl]-5-fluoro-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC(F)=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CC(=O)N(C)C)C1 CFCMRKXACCTYSD-KBPBESRZSA-N 0.000 claims description 2
• VRPFURCSCWZOBP-GJZGRUSLSA-N n-[(3s,6s)-6-(2-hydroxy-2-methylpropyl)piperidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@H]1CC[C@@H](CC(C)(C)O)NC1 VRPFURCSCWZOBP-GJZGRUSLSA-N 0.000 claims description 2
• NNMHDMNVMSTROF-KBPBESRZSA-N n-[(3s,6s)-6-(2-hydroxyethyl)piperidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@H]1CC[C@@H](CCO)NC1 NNMHDMNVMSTROF-KBPBESRZSA-N 0.000 claims description 2
• KJEUARLXPXDRDF-HOTGVXAUSA-N 1-ethyl-n-[(3s,6s)-6-[(4-hydroxyoxan-4-yl)methyl]piperidin-3-yl]indazole-3-carboxamide Chemical compound C([C@@H]1CC[C@@H](CN1)NC(=O)C1=NN(C2=CC=CC=C21)CC)C1(O)CCOCC1 KJEUARLXPXDRDF-HOTGVXAUSA-N 0.000 claims 1
• SIASQZCBDFKLJF-QJHJCNPRSA-N OC(=O)C(O)=O.C([C@H]1NC[C@H](CC1)NC(=O)C=1C2=CC=CC=C2N(C2CCC2)N=1)C1(O)CCOCC1 Chemical compound OC(=O)C(O)=O.C([C@H]1NC[C@H](CC1)NC(=O)C=1C2=CC=CC=C2N(C2CCC2)N=1)C1(O)CCOCC1 SIASQZCBDFKLJF-QJHJCNPRSA-N 0.000 claims 1
• GWCFJLDJXKSNPJ-HOTGVXAUSA-N n-[(3s,5s)-5-(2-morpholin-4-yl-2-oxoethyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C([C@H]1NC[C@H](C1)NC(=O)C1=NN(C2=CC=CC=C21)C(C)C)C(=O)N1CCOCC1 GWCFJLDJXKSNPJ-HOTGVXAUSA-N 0.000 claims 1
• YUCYQTXDEKGEEC-RYUDHWBXSA-N n-[(3s,5s)-5-(hydroxymethyl)pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](CO)C1 YUCYQTXDEKGEEC-RYUDHWBXSA-N 0.000 claims 1
• BNGCYFRHRTXPEY-STQMWFEESA-N n-[(3s,5s)-5-[2-(methylamino)-2-oxoethyl]pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C1N[C@H](CC(=O)NC)C[C@@H]1NC(=O)C1=NN(C(C)C)C2=CC=CC=C12 BNGCYFRHRTXPEY-STQMWFEESA-N 0.000 claims 1
• UILOWMSUNTVCPN-GJZGRUSLSA-N n-[(3s,5s)-5-[[2-(dimethylamino)-2-oxoethoxy]methyl]pyrrolidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@@H]1CN[C@H](COCC(=O)N(C)C)C1 UILOWMSUNTVCPN-GJZGRUSLSA-N 0.000 claims 1
• DDYYHPCXODSNRX-HOTGVXAUSA-N n-[(3s,6s)-6-(3-hydroxy-3-methylbutyl)piperidin-3-yl]-1-propan-2-ylindazole-3-carboxamide Chemical compound C12=CC=CC=C2N(C(C)C)N=C1C(=O)N[C@H]1CC[C@@H](CCC(C)(C)O)NC1 DDYYHPCXODSNRX-HOTGVXAUSA-N 0.000 claims 1
• 239000000203 mixture Substances 0.000 abstract description 137
• 101710150225 5-hydroxytryptamine receptor 4 Proteins 0.000 abstract description 9
• 230000001270 agonistic effect Effects 0.000 abstract description 5
• 229910052739 hydrogen Inorganic materials 0.000 description 443
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 178
• 238000006243 chemical reaction Methods 0.000 description 145
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
• 238000000034 method Methods 0.000 description 100
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 96
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 79
• 239000002904 solvent Substances 0.000 description 79
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 71
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 71
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 67
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 62
• 229910001868 water Inorganic materials 0.000 description 59
• 230000002829 reductive effect Effects 0.000 description 56
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
• 239000000243 solution Substances 0.000 description 55
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 50
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
• 238000005160 1H NMR spectroscopy Methods 0.000 description 41
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 38
• 239000003153 chemical reaction reagent Substances 0.000 description 38
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 37
• 239000000741 silica gel Substances 0.000 description 37
• 229910002027 silica gel Inorganic materials 0.000 description 37
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
• 239000012044 organic layer Substances 0.000 description 30
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 26
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 23
• 239000007858 starting material Substances 0.000 description 23
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• 239000002253 acid Substances 0.000 description 21
• 239000012230 colorless oil Substances 0.000 description 21
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 21
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 239000012267 brine Substances 0.000 description 18
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
• 229910052938 sodium sulfate Inorganic materials 0.000 description 17
• 235000011152 sodium sulphate Nutrition 0.000 description 17
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
• 238000010511 deprotection reaction Methods 0.000 description 16
• 239000003826 tablet Substances 0.000 description 16
• 239000000706 filtrate Substances 0.000 description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
• 235000019341 magnesium sulphate Nutrition 0.000 description 14
• 125000004429 atom Chemical group 0.000 description 13
• 210000004027 cell Anatomy 0.000 description 13
• 239000001257 hydrogen Substances 0.000 description 13
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 13
• 239000007787 solid Substances 0.000 description 13
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 12
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical group [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
• 150000001408 amides Chemical class 0.000 description 12
• 229940079593 drug Drugs 0.000 description 12
• 150000002170 ethers Chemical class 0.000 description 12
• 231100000989 no adverse effect Toxicity 0.000 description 12
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 12
• 230000007062 hydrolysis Effects 0.000 description 11
• 238000006460 hydrolysis reaction Methods 0.000 description 11
• 239000003921 oil Substances 0.000 description 11
• 235000019198 oils Nutrition 0.000 description 11
• 238000002360 preparation method Methods 0.000 description 11
• 125000006239 protecting group Chemical group 0.000 description 11
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
• ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
• 238000003786 synthesis reaction Methods 0.000 description 10
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
• 239000002585 base Substances 0.000 description 9
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 9
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 8
• 150000007513 acids Chemical class 0.000 description 8
• 238000007112 amidation reaction Methods 0.000 description 8
• 239000003795 chemical substances by application Substances 0.000 description 8
• 239000013078 crystal Substances 0.000 description 8
• 239000002552 dosage form Substances 0.000 description 8
• 238000009472 formulation Methods 0.000 description 8
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
• 238000010534 nucleophilic substitution reaction Methods 0.000 description 8
• 239000000651 prodrug Substances 0.000 description 8
• 229940002612 prodrug Drugs 0.000 description 8
• 230000009467 reduction Effects 0.000 description 8
• 239000000725 suspension Substances 0.000 description 8
• 238000005406 washing Methods 0.000 description 8
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
• 150000001298 alcohols Chemical class 0.000 description 7
• 230000009435 amidation Effects 0.000 description 7
• 239000007864 aqueous solution Substances 0.000 description 7
• 238000001816 cooling Methods 0.000 description 7
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 7
• 230000003287 optical effect Effects 0.000 description 7
• 238000000746 purification Methods 0.000 description 7
• 238000003756 stirring Methods 0.000 description 7
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