JP4842262B2 - レニン阻害剤としてのピペリジン誘導体 - Google Patents

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Publication number

JP4842262B2

JP4842262B2 JP2007519812A JP2007519812A JP4842262B2 JP 4842262 B2 JP4842262 B2 JP 4842262B2 JP 2007519812 A JP2007519812 A JP 2007519812A JP 2007519812 A JP2007519812 A JP 2007519812A JP 4842262 B2 JP4842262 B2 JP 4842262B2

Authority

JP

Japan

Prior art keywords

alkoxy

alkyl

phenyl

benzo

dihydro

Prior art date

2004-07-09

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

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• 239000002461 renin inhibitor Substances 0.000 title description 6
• 229940086526 renin-inhibitors Drugs 0.000 title description 5
• 150000003053 piperidines Chemical class 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims description 167
• 150000003839 salts Chemical class 0.000 claims description 18
• -1 3-acetamidomethylpyrrolidinyl Chemical group 0.000 description 318
• 239000000243 solution Substances 0.000 description 76
• DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 74
• 238000000034 method Methods 0.000 description 70
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 68
• 239000000203 mixture Substances 0.000 description 65
• 229910004298 SiO 2 Inorganic materials 0.000 description 54
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
• 239000011541 reaction mixture Substances 0.000 description 54
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 53
• 238000003818 flash chromatography Methods 0.000 description 52
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
• 229910052938 sodium sulfate Inorganic materials 0.000 description 46
• 235000011152 sodium sulphate Nutrition 0.000 description 46
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 44
• 239000012267 brine Substances 0.000 description 42
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 42
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 38
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 35
• RWJKKARAQBPRFE-UHFFFAOYSA-N 4-[4-[1-(3-fluorophenyl)pyrrolidin-3-yl]oxyphenyl]-5-[[4-(3-methoxypropyl)-2,3-dihydro-1,4-benzoxazin-6-yl]methoxy]piperidin-3-ol Chemical compound C1=C2N(CCCOC)CCOC2=CC=C1COC1CNCC(O)C1C(C=C1)=CC=C1OC(C1)CCN1C1=CC=CC(F)=C1 RWJKKARAQBPRFE-UHFFFAOYSA-N 0.000 description 33
• 239000012230 colorless oil Substances 0.000 description 32
• 238000001704 evaporation Methods 0.000 description 32
• 230000008020 evaporation Effects 0.000 description 32
• 239000003921 oil Substances 0.000 description 32
• 235000019198 oils Nutrition 0.000 description 32
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
• 239000007858 starting material Substances 0.000 description 30
• 239000012074 organic phase Substances 0.000 description 29
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 27
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 26
• 235000019439 ethyl acetate Nutrition 0.000 description 25
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 24
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 20
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 20
• IQOIMKMZQVCXMK-UHFFFAOYSA-N 6-(chloromethyl)-4-(3-methoxypropyl)-1,4-benzoxazin-3-one Chemical compound C1=C(CCl)C=C2N(CCCOC)C(=O)COC2=C1 IQOIMKMZQVCXMK-UHFFFAOYSA-N 0.000 description 20
• DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 20
• 229910021529 ammonia Inorganic materials 0.000 description 19
• 238000006243 chemical reaction Methods 0.000 description 18
• 125000000623 heterocyclic group Chemical group 0.000 description 17
• 239000001257 hydrogen Substances 0.000 description 17
• 229910052739 hydrogen Inorganic materials 0.000 description 17
• 229920006395 saturated elastomer Polymers 0.000 description 17
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 17
• 235000017557 sodium bicarbonate Nutrition 0.000 description 17
• 229910052736 halogen Inorganic materials 0.000 description 15
• 150000002367 halogens Chemical class 0.000 description 15
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 15
• 238000010992 reflux Methods 0.000 description 15
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 14
• 125000003118 aryl group Chemical group 0.000 description 14
• 125000000217 alkyl group Chemical group 0.000 description 13
• 229910052757 nitrogen Inorganic materials 0.000 description 13
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 12
• LFWGXIVKBPLQMD-UHFFFAOYSA-N benzyl 3-hydroxy-4-(4-hydroxyphenyl)-5-tri(propan-2-yl)silyloxypiperidine-1-carboxylate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OC1CN(C(=O)OCC=2C=CC=CC=2)CC(O)C1C1=CC=C(O)C=C1 LFWGXIVKBPLQMD-UHFFFAOYSA-N 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• 238000007429 general method Methods 0.000 description 11
• 150000002431 hydrogen Chemical class 0.000 description 11
• 125000004093 cyano group Chemical group *C#N 0.000 description 10
• 229910052760 oxygen Inorganic materials 0.000 description 10
• 125000004076 pyridyl group Chemical group 0.000 description 10
• 239000000126 substance Substances 0.000 description 10
• 239000000725 suspension Substances 0.000 description 10
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
• 125000002252 acyl group Chemical group 0.000 description 9
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 9
• 239000010410 layer Substances 0.000 description 9
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
• YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
• 125000005605 benzo group Chemical group 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 8
• 238000012360 testing method Methods 0.000 description 8
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 8
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 7
• 101800000734 Angiotensin-1 Proteins 0.000 description 7
• 102400000344 Angiotensin-1 Human genes 0.000 description 7
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
• 125000003545 alkoxy group Chemical group 0.000 description 7
• ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 7
• 125000004432 carbon atom Chemical group C* 0.000 description 7
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 7
• 125000002757 morpholinyl group Chemical group 0.000 description 7
• 125000000168 pyrrolyl group Chemical group 0.000 description 7
• 229910052717 sulfur Inorganic materials 0.000 description 7
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 6
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
• LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
• 125000001624 naphthyl group Chemical group 0.000 description 6
• 239000001301 oxygen Substances 0.000 description 6
• 239000000546 pharmaceutical excipient Substances 0.000 description 6
• 125000003386 piperidinyl group Chemical group 0.000 description 6
• 229910000027 potassium carbonate Inorganic materials 0.000 description 6
• 239000012312 sodium hydride Substances 0.000 description 6
• 229910000104 sodium hydride Inorganic materials 0.000 description 6
• 239000007787 solid Substances 0.000 description 6
• 238000003756 stirring Methods 0.000 description 6
• 239000011593 sulfur Substances 0.000 description 6
• 125000001544 thienyl group Chemical group 0.000 description 6
• 239000001993 wax Substances 0.000 description 6
• 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 description 5
• 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 description 5
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 5
• 235000019502 Orange oil Nutrition 0.000 description 5
• 108090000783 Renin Proteins 0.000 description 5
• 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 5
• 239000000706 filtrate Substances 0.000 description 5
• 238000004128 high performance liquid chromatography Methods 0.000 description 5
• 239000003112 inhibitor Substances 0.000 description 5
• 239000010502 orange oil Substances 0.000 description 5
• 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 5
• 125000004193 piperazinyl group Chemical group 0.000 description 5
• 238000002360 preparation method Methods 0.000 description 5
• 229940002612 prodrug Drugs 0.000 description 5
• 239000000651 prodrug Substances 0.000 description 5
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 5
• 125000003831 tetrazolyl group Chemical group 0.000 description 5
• 125000004568 thiomorpholinyl group Chemical group 0.000 description 5
• 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 4
• 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 description 4
• LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 4
• INXKVYFOWNAVMU-UHFFFAOYSA-N 2,5-difluorophenol Chemical compound OC1=CC(F)=CC=C1F INXKVYFOWNAVMU-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
• 102000005862 Angiotensin II Human genes 0.000 description 4
• 101800000733 Angiotensin-2 Proteins 0.000 description 4
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
• 101000579218 Homo sapiens Renin Proteins 0.000 description 4
• CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 4
• 102100028255 Renin Human genes 0.000 description 4
• 125000005907 alkyl ester group Chemical group 0.000 description 4
• 229950006323 angiotensin ii Drugs 0.000 description 4
• 239000008346 aqueous phase Substances 0.000 description 4
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 4
• 230000036772 blood pressure Effects 0.000 description 4
• 239000003814 drug Substances 0.000 description 4
• 150000002148 esters Chemical class 0.000 description 4
• 239000006260 foam Substances 0.000 description 4
• ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 4
• 125000002541 furyl group Chemical group 0.000 description 4
• 125000005844 heterocyclyloxy group Chemical group 0.000 description 4
• 125000002883 imidazolyl group Chemical group 0.000 description 4
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 4
• 125000001041 indolyl group Chemical group 0.000 description 4
• 238000002347 injection Methods 0.000 description 4
• 239000007924 injection Substances 0.000 description 4
• 125000004433 nitrogen atom Chemical group N* 0.000 description 4
• 125000002971 oxazolyl group Chemical group 0.000 description 4
• BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 4
• 229920005862 polyol Polymers 0.000 description 4
• 150000003077 polyols Chemical class 0.000 description 4
• 125000000714 pyrimidinyl group Chemical group 0.000 description 4
• 125000001424 substituent group Chemical group 0.000 description 4
• 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 description 4
• 238000004809 thin layer chromatography Methods 0.000 description 4
• 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 description 3
• OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
• 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
• 230000029936 alkylation Effects 0.000 description 3
• 238000005804 alkylation reaction Methods 0.000 description 3
• 125000002947 alkylene group Chemical group 0.000 description 3
• 125000005530 alkylenedioxy group Chemical group 0.000 description 3
• 229910052786 argon Inorganic materials 0.000 description 3
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 3
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 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
• 238000001816 cooling Methods 0.000 description 3
• 239000013078 crystal Substances 0.000 description 3
• 238000002425 crystallisation Methods 0.000 description 3
• 230000008025 crystallization Effects 0.000 description 3
• 125000000753 cycloalkyl group Chemical group 0.000 description 3
• WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
• 125000000532 dioxanyl group Chemical group 0.000 description 3
• 125000005879 dioxolanyl group Chemical group 0.000 description 3
• 239000006185 dispersion Substances 0.000 description 3
• 125000005883 dithianyl group Chemical group 0.000 description 3
• 230000000694 effects Effects 0.000 description 3
• 238000001914 filtration Methods 0.000 description 3
• 229960003883 furosemide Drugs 0.000 description 3
• 239000007903 gelatin capsule Substances 0.000 description 3
• 238000000338 in vitro Methods 0.000 description 3
• 238000001727 in vivo Methods 0.000 description 3
• 239000007788 liquid Substances 0.000 description 3
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
• 125000004430 oxygen atom Chemical group O* 0.000 description 3
• 239000008194 pharmaceutical composition Substances 0.000 description 3
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 3
• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
• 239000000047 product Substances 0.000 description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
• 238000000746 purification Methods 0.000 description 3
• 125000003373 pyrazinyl group Chemical group 0.000 description 3
• 238000000926 separation method Methods 0.000 description 3
• 229910000029 sodium carbonate Inorganic materials 0.000 description 3
• 239000002904 solvent Substances 0.000 description 3
• 125000004434 sulfur atom Chemical group 0.000 description 3
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
• 125000001425 triazolyl group Chemical group 0.000 description 3
• 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 2
• 125000006590 (C2-C6) alkenylene group Chemical group 0.000 description 2
• 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 description 2
• 125000006621 (C3-C8) cycloalkyl-(C1-C6) alkyl group Chemical group 0.000 description 2
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
• GRPVXZDDHARJSD-UHFFFAOYSA-N 1-(3-bromopropoxy)-2-chlorobenzene Chemical compound ClC1=CC=CC=C1OCCCBr GRPVXZDDHARJSD-UHFFFAOYSA-N 0.000 description 2
• YZSNQEGPANCTAL-UHFFFAOYSA-N 1-(3-fluorophenyl)pyrrolidin-3-ol Chemical compound C1C(O)CCN1C1=CC=CC(F)=C1 YZSNQEGPANCTAL-UHFFFAOYSA-N 0.000 description 2
• AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 2
• JKIPXZABCHFCTD-UHFFFAOYSA-N 1-prop-2-enoxyadamantane Chemical compound C1C(C2)CC3CC2CC1(OCC=C)C3 JKIPXZABCHFCTD-UHFFFAOYSA-N 0.000 description 2
• PWVXRBWBVGKKHP-UHFFFAOYSA-N 2-(2,5-difluorophenoxy)ethoxy-tri(propan-2-yl)silane Chemical compound CC(C)[Si](C(C)C)(C(C)C)OCCOC1=CC(F)=CC=C1F PWVXRBWBVGKKHP-UHFFFAOYSA-N 0.000 description 2
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