ES2881776T3 - Compuestos tricíclicos útiles para tratar las infecciones por ortomixovirus - Google Patents

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Publication number

ES2881776T3

ES2881776T3 ES17711349T ES17711349T ES2881776T3 ES 2881776 T3 ES2881776 T3 ES 2881776T3 ES 17711349 T ES17711349 T ES 17711349T ES 17711349 T ES17711349 T ES 17711349T ES 2881776 T3 ES2881776 T3 ES 2881776T3

Authority

ES

Spain

Prior art keywords

alkyl

ring

haloalkyl

halo

benzyloxy

Prior art date

2016-03-08

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.)

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 173
• 208000009620 Orthomyxoviridae Infections Diseases 0.000 title description 4
• -1 hydroxy, amino Chemical group 0.000 claims abstract description 170
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 101
• 150000003839 salts Chemical class 0.000 claims abstract description 69
• 125000005843 halogen group Chemical group 0.000 claims abstract description 62
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 60
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 55
• 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims abstract description 51
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 48
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 45
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 30
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 24
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 23
• 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims abstract description 22
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 20
• 239000012453 solvate Substances 0.000 claims abstract description 19
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 17
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 17
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 14
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 13
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 12
• 150000001345 alkine derivatives Chemical class 0.000 claims abstract description 12
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims abstract description 11
• 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims abstract description 8
• 125000004122 cyclic group Chemical group 0.000 claims abstract description 7
• 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims abstract description 5
• 150000004292 cyclic ethers Chemical group 0.000 claims abstract description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 4
• 125000004076 pyridyl group Chemical group 0.000 claims abstract description 4
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims abstract 2
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract 2
• 125000003545 alkoxy group Chemical group 0.000 claims description 29
• 239000008194 pharmaceutical composition Substances 0.000 claims description 28
• 206010022000 influenza Diseases 0.000 claims description 25
• 239000003814 drug Substances 0.000 claims description 23
• 229910052739 hydrogen Inorganic materials 0.000 claims description 19
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
• 239000003937 drug carrier Substances 0.000 claims description 9
• 229910005965 SO 2 Inorganic materials 0.000 claims description 5
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 4
• 150000003536 tetrazoles Chemical class 0.000 claims description 4
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 3
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 3
• 150000003852 triazoles Chemical class 0.000 claims description 3
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
• ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 2
• WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 2
• VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 claims description 2
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 33
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract description 15
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 4
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract description 2
• RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 146
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 107
• 239000000203 mixture Substances 0.000 description 105
• 238000006243 chemical reaction Methods 0.000 description 99
• 239000000243 solution Substances 0.000 description 93
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 92
• 235000019439 ethyl acetate Nutrition 0.000 description 75
• 238000000034 method Methods 0.000 description 74
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 66
• 239000000543 intermediate Substances 0.000 description 65
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 58
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 54
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 51
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
• 238000005160 1H NMR spectroscopy Methods 0.000 description 45
• 239000011541 reaction mixture Substances 0.000 description 44
• 238000011282 treatment Methods 0.000 description 41
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 40
• 229910052938 sodium sulfate Inorganic materials 0.000 description 40
• 235000011152 sodium sulphate Nutrition 0.000 description 40
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 37
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
• 125000001424 substituent group Chemical group 0.000 description 33
• 239000000047 product Substances 0.000 description 32
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 32
• 239000012267 brine Substances 0.000 description 31
• 238000010898 silica gel chromatography Methods 0.000 description 31
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
• 239000010410 layer Substances 0.000 description 29
• 239000007787 solid Substances 0.000 description 27
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
• 239000002904 solvent Substances 0.000 description 26
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
• 238000000746 purification Methods 0.000 description 24
• LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 23
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
• 208000037797 influenza A Diseases 0.000 description 22
• 239000007832 Na2SO4 Substances 0.000 description 21
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 21
• 125000003118 aryl group Chemical group 0.000 description 20
• 239000002585 base Substances 0.000 description 20
• 239000012044 organic layer Substances 0.000 description 20
• 230000015572 biosynthetic process Effects 0.000 description 19
• 239000003795 chemical substances by application Substances 0.000 description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 19
• 0 C*C(C(C[n]1c(C(C(C(O)=CNC)=O)=N)nnc1*)O)I Chemical compound C*C(C(C[n]1c(C(C(C(O)=CNC)=O)=N)nnc1*)O)I 0.000 description 18
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 18
• 238000003786 synthesis reaction Methods 0.000 description 18
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
• 239000000706 filtrate Substances 0.000 description 17
• 208000037798 influenza B Diseases 0.000 description 17
• 208000037799 influenza C Diseases 0.000 description 17
• 238000007792 addition Methods 0.000 description 16
• 229910052805 deuterium Inorganic materials 0.000 description 16
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 229940124597 therapeutic agent Drugs 0.000 description 15
• 230000009385 viral infection Effects 0.000 description 15
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 14
• 239000002253 acid Substances 0.000 description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
• 229910000027 potassium carbonate Inorganic materials 0.000 description 14
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 13
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 12
• 201000010099 disease Diseases 0.000 description 12
• 125000006413 ring segment Chemical group 0.000 description 12
• 241000712461 unidentified influenza virus Species 0.000 description 12
• 208000036142 Viral infection Diseases 0.000 description 11
• 239000004480 active ingredient Substances 0.000 description 11
• 238000003556 assay Methods 0.000 description 11
• 229940015043 glyoxal Drugs 0.000 description 11
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
• 229910000024 caesium carbonate Inorganic materials 0.000 description 10
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 10
• 238000010348 incorporation Methods 0.000 description 10
• 239000003921 oil Substances 0.000 description 10
• 235000019198 oils Nutrition 0.000 description 10
• 229920006395 saturated elastomer Polymers 0.000 description 10
• USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 9
• 239000005695 Ammonium acetate Substances 0.000 description 9
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 9
• CUQZQRIIFNWQSJ-UHFFFAOYSA-N FC(F)(F)[Cu].c1cnc2c(c1)ccc1cccnc21 Chemical compound FC(F)(F)[Cu].c1cnc2c(c1)ccc1cccnc21 CUQZQRIIFNWQSJ-UHFFFAOYSA-N 0.000 description 9
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 9
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
• 229940043376 ammonium acetate Drugs 0.000 description 9
• 235000019257 ammonium acetate Nutrition 0.000 description 9
• 125000004429 atom Chemical group 0.000 description 9
• 239000000284 extract Substances 0.000 description 9
• 239000000546 pharmaceutical excipient Substances 0.000 description 9
• 239000000725 suspension Substances 0.000 description 9
• 239000003826 tablet Substances 0.000 description 9
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
• KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 8
• 102100031780 Endonuclease Human genes 0.000 description 8
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 8
• 150000001299 aldehydes Chemical class 0.000 description 8
• 150000001721 carbon Chemical group 0.000 description 8
• 238000004128 high performance liquid chromatography Methods 0.000 description 8
• 239000012074 organic phase Substances 0.000 description 8
• 239000011591 potassium Substances 0.000 description 8
• 238000002953 preparative HPLC Methods 0.000 description 8
• JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 8
• 208000024891 symptom Diseases 0.000 description 8
• 230000002194 synthesizing effect Effects 0.000 description 8
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 7
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
• 108010042407 Endonucleases Proteins 0.000 description 7
• 238000005481 NMR spectroscopy Methods 0.000 description 7
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
• 238000010511 deprotection reaction Methods 0.000 description 7
• 208000035475 disorder Diseases 0.000 description 7
• 238000010438 heat treatment Methods 0.000 description 7
• 150000002430 hydrocarbons Chemical group 0.000 description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
• 238000002360 preparation method Methods 0.000 description 7
• 229910000104 sodium hydride Inorganic materials 0.000 description 7
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• 125000002947 alkylene group Chemical group 0.000 description 6
• 125000002619 bicyclic group Chemical group 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• 229910052801 chlorine Inorganic materials 0.000 description 6
• 239000000460 chlorine Chemical group 0.000 description 6
• 229910052731 fluorine Inorganic materials 0.000 description 6
• 239000011737 fluorine Substances 0.000 description 6
• 125000001188 haloalkyl group Chemical group 0.000 description 6
• 239000001257 hydrogen Substances 0.000 description 6
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
• 208000015181 infectious disease Diseases 0.000 description 6
• 230000003287 optical effect Effects 0.000 description 6
• 229910052763 palladium Inorganic materials 0.000 description 6
• 239000003755 preservative agent Substances 0.000 description 6
• 230000010076 replication Effects 0.000 description 6
• 238000004007 reversed phase HPLC Methods 0.000 description 6
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
• 235000017557 sodium bicarbonate Nutrition 0.000 description 6
• 239000007858 starting material Substances 0.000 description 6
• 230000001225 therapeutic effect Effects 0.000 description 6
• SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 5
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
• 229910004298 SiO 2 Inorganic materials 0.000 description 5
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
• 239000007864 aqueous solution Substances 0.000 description 5
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
• 229910052794 bromium Inorganic materials 0.000 description 5
• 238000001727 in vivo Methods 0.000 description 5
• 230000000155 isotopic effect Effects 0.000 description 5
• 238000003328 mesylation reaction Methods 0.000 description 5
• 125000002950 monocyclic group Chemical group 0.000 description 5
• XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 5
• 235000011181 potassium carbonates Nutrition 0.000 description 5
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• 239000011734 sodium Substances 0.000 description 5
• 239000012312 sodium hydride Substances 0.000 description 5
• 241000894007 species Species 0.000 description 5
• 239000003381 stabilizer Substances 0.000 description 5
• 238000012360 testing method Methods 0.000 description 5
• 238000002560 therapeutic procedure Methods 0.000 description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
• DZJJTSGLPYDYEU-XMMPIXPASA-N (8S)-8-benzhydryl-5-chloro-13-phenylmethoxy-3,6,9-triazatricyclo[7.4.0.02,6]trideca-1(13),2,4,10-tetraen-12-one Chemical compound C(C1=CC=CC=C1)(C1=CC=CC=C1)[C@@H]1N2C(C=3N(C1)C(=CN=3)Cl)=C(C(C=C2)=O)OCC1=CC=CC=C1 DZJJTSGLPYDYEU-XMMPIXPASA-N 0.000 description 4
• MBXXNUIUYMJMSO-UHFFFAOYSA-N 3-amino-1,1-diphenylpropan-2-ol Chemical compound C=1C=CC=CC=1C(C(O)CN)C1=CC=CC=C1 MBXXNUIUYMJMSO-UHFFFAOYSA-N 0.000 description 4
• KTZAKTCBKGPDAH-UHFFFAOYSA-N 4-oxo-5-phenylmethoxy-1-(2-trimethylsilylethoxymethyl)pyridazine-3-carbaldehyde Chemical compound C(C1=CC=CC=C1)OC=1C(C(=NN(C=1)COCC[Si](C)(C)C)C=O)=O KTZAKTCBKGPDAH-UHFFFAOYSA-N 0.000 description 4
• VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
• ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
• 241000124008 Mammalia Species 0.000 description 4
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• 229910052725 zinc Inorganic materials 0.000 description 1
• GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1