NO317882B1 - Sykliske aminoforbindelser, farmasoytisk preparat inneholdende en slik forbindelse og anvendelse av en slik forbindelse for fremstilling av et medikament - Google Patents

Info

Publication number

NO317882B1

NO317882B1 NO20004279A NO20004279A NO317882B1 NO 317882 B1 NO317882 B1 NO 317882B1 NO 20004279 A NO20004279 A NO 20004279A NO 20004279 A NO20004279 A NO 20004279A NO 317882 B1 NO317882 B1 NO 317882B1

Authority

NO

Norway

Prior art keywords

group

denotes

groups

cyclopropylcarbonyl

substituted

Prior art date

1998-02-27

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• 150000001875 compounds Chemical class 0.000 title claims description 275
• 239000003814 drug Substances 0.000 title claims description 13
• 238000004519 manufacturing process Methods 0.000 title claims description 4
• 239000000825 pharmaceutical preparation Substances 0.000 title claims 2
• 229940079593 drug Drugs 0.000 title description 3
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 53
• 150000003839 salts Chemical class 0.000 claims abstract description 49
• 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 10
• 208000005189 Embolism Diseases 0.000 claims abstract description 9
• 208000007536 Thrombosis Diseases 0.000 claims abstract description 9
• -1 Cyclic amino compound Chemical class 0.000 claims description 178
• 125000001424 substituent group Chemical group 0.000 claims description 109
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 60
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 50
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 45
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 44
• 125000003277 amino group Chemical group 0.000 claims description 36
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 32
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 29
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 28
• 125000001153 fluoro group Chemical group F* 0.000 claims description 28
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
• 229910052801 chlorine Inorganic materials 0.000 claims description 25
• 229910052731 fluorine Inorganic materials 0.000 claims description 25
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 25
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 24
• 125000005843 halogen group Chemical group 0.000 claims description 23
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
• 229910052717 sulfur Inorganic materials 0.000 claims description 22
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 20
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 20
• 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 20
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 20
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 19
• 125000004434 sulfur atom Chemical group 0.000 claims description 19
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 18
• 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 13
• 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 13
• 125000004122 cyclic group Chemical group 0.000 claims description 12
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 12
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 9
• 206010003210 Arteriosclerosis Diseases 0.000 claims description 9
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 9
• 238000002360 preparation method Methods 0.000 claims description 9
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 230000002265 prevention Effects 0.000 claims description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
• 125000001246 bromo group Chemical group Br* 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000006637 cyclobutyl carbonyl group Chemical group 0.000 claims description 6
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
• 239000011737 fluorine Substances 0.000 claims description 6
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
• 125000002252 acyl group Chemical group 0.000 claims description 5
• 125000002642 gamma-glutamyl group Chemical group 0.000 claims description 5
• QEGZWPDJIVRZEX-UHFFFAOYSA-N 1-cyclopropyl-2-(2-fluorophenyl)-2-(4-methylsulfinylsulfanylpiperidin-1-yl)ethanone Chemical compound C1CC(SS(=O)C)CCN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 QEGZWPDJIVRZEX-UHFFFAOYSA-N 0.000 claims description 4
• NLIJNPFMJMIDBH-UHFFFAOYSA-N 1-cyclopropyl-2-(2-fluorophenyl)-2-[4-(4-methoxyphenyl)sulfonylsulfanylpiperidin-1-yl]ethanone Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)SC1CCN(C(C(=O)C2CC2)C=2C(=CC=CC=2)F)CC1 NLIJNPFMJMIDBH-UHFFFAOYSA-N 0.000 claims description 4
• RXEKWAMWQDYRBH-UHFFFAOYSA-N 1-cyclopropyl-2-[4-[(2,4-dinitrophenyl)disulfanyl]piperidin-1-yl]-2-(2-fluorophenyl)ethanone Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC=C1SSC1CCN(C(C(=O)C2CC2)C=2C(=CC=CC=2)F)CC1 RXEKWAMWQDYRBH-UHFFFAOYSA-N 0.000 claims description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
• LTYNRPSTKQGLFG-UHFFFAOYSA-N 1-cyclopropyl-2-(2-fluorophenyl)-2-(4-methylsulfonylsulfanylpiperidin-1-yl)ethanone Chemical compound C1CC(SS(=O)(=O)C)CCN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 LTYNRPSTKQGLFG-UHFFFAOYSA-N 0.000 claims description 3
• CGBGIPTWNMMHDZ-UHFFFAOYSA-N 1-cyclopropyl-2-(2-fluorophenyl)-2-[3-(4-methylphenyl)sulfonylsulfanylpyrrolidin-1-yl]ethanone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)SC1CN(C(C(=O)C2CC2)C=2C(=CC=CC=2)F)CC1 CGBGIPTWNMMHDZ-UHFFFAOYSA-N 0.000 claims description 3
• TVMUYLIQNCEKCN-UHFFFAOYSA-N 1-cyclopropyl-2-(2-fluorophenyl)-2-[4-(4-fluorophenyl)sulfonylsulfanylpiperidin-1-yl]ethanone Chemical compound C1=CC(F)=CC=C1S(=O)(=O)SC1CCN(C(C(=O)C2CC2)C=2C(=CC=CC=2)F)CC1 TVMUYLIQNCEKCN-UHFFFAOYSA-N 0.000 claims description 3
• QSKQQHNQLMSZQY-UHFFFAOYSA-N 1-cyclopropyl-2-(2-fluorophenyl)-2-[4-(4-methylphenyl)sulfonylsulfanylpiperidin-1-yl]ethanone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)SC1CCN(C(C(=O)C2CC2)C=2C(=CC=CC=2)F)CC1 QSKQQHNQLMSZQY-UHFFFAOYSA-N 0.000 claims description 3
• LKOANQFXGZLVAV-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)sulfonylsulfanylpiperidin-1-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone Chemical compound FC1=CC=CC=C1C(C(=O)C1CC1)N1CCC(SS(=O)(=O)C=2C=CC(Cl)=CC=2)CC1 LKOANQFXGZLVAV-UHFFFAOYSA-N 0.000 claims description 3
• 125000001931 aliphatic group Chemical group 0.000 claims description 3
• HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 3
• XZPRLCRUBAAKIG-OBGWFSINSA-N methyl 2-(2-chlorophenyl)-2-[(3e)-3-(2-ethoxy-2-oxoethylidene)-4-(4-methylphenyl)sulfonylsulfanylpiperidin-1-yl]acetate Chemical compound CCOC(=O)\C=C1/CN(C(C(=O)OC)C=2C(=CC=CC=2)Cl)CCC1SS(=O)(=O)C1=CC=C(C)C=C1 XZPRLCRUBAAKIG-OBGWFSINSA-N 0.000 claims description 3
• MZPSKJWUACDADS-UHFFFAOYSA-N methyl 2-(2-fluorophenyl)-2-[4-(4-methylphenyl)sulfonylsulfanylpiperidin-1-yl]acetate Chemical compound C=1C=CC=C(F)C=1C(C(=O)OC)N(CC1)CCC1SS(=O)(=O)C1=CC=C(C)C=C1 MZPSKJWUACDADS-UHFFFAOYSA-N 0.000 claims description 3
• JAGCORPGQVAXSS-UHFFFAOYSA-N methyl 3-[[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidin-4-yl]disulfanyl]propanoate Chemical compound C1CC(SSCCC(=O)OC)CCN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 JAGCORPGQVAXSS-UHFFFAOYSA-N 0.000 claims description 3
• 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 2
• 229910052757 nitrogen Inorganic materials 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• 125000000217 alkyl group Chemical group 0.000 claims 2
• AMPOCARAOGXMMH-DGVXAMKHSA-N (2r)-2-amino-3-[[(3z)-3-(carboxymethylidene)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidin-4-yl]disulfanyl]propanoic acid Chemical compound C1\C(=C\C(O)=O)C(SSC[C@H](N)C(O)=O)CCN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 AMPOCARAOGXMMH-DGVXAMKHSA-N 0.000 claims 1
• 125000004432 carbon atom Chemical group C* 0.000 claims 1
• DYIFDZHNKXUDOY-CAPFRKAQSA-N ethyl (2e)-2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-(4-methylphenyl)sulfonylsulfanylpiperidin-3-ylidene]acetate Chemical compound CCOC(=O)\C=C1/CN(C(C(=O)C2CC2)C=2C(=CC=CC=2)F)CCC1SS(=O)(=O)C1=CC=C(C)C=C1 DYIFDZHNKXUDOY-CAPFRKAQSA-N 0.000 claims 1
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
• 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 13
• 239000003146 anticoagulant agent Substances 0.000 abstract description 4
• 230000003449 preventive effect Effects 0.000 abstract description 4
• 230000002776 aggregation Effects 0.000 abstract description 2
• 238000004220 aggregation Methods 0.000 abstract description 2
• 230000000694 effects Effects 0.000 abstract description 2
• 230000000702 anti-platelet effect Effects 0.000 abstract 1
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
• 238000006243 chemical reaction Methods 0.000 description 188
• 229910052739 hydrogen Inorganic materials 0.000 description 186
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 102
• 238000001819 mass spectrum Methods 0.000 description 96
• 230000002829 reductive effect Effects 0.000 description 85
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 81
• 239000000203 mixture Substances 0.000 description 79
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 79
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 77
• 239000002904 solvent Substances 0.000 description 77
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
• 239000000460 chlorine Substances 0.000 description 58
• 238000000034 method Methods 0.000 description 52
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 46
• 238000002329 infrared spectrum Methods 0.000 description 45
• 239000003921 oil Substances 0.000 description 44
• 235000019198 oils Nutrition 0.000 description 44
• 239000000243 solution Substances 0.000 description 43
• 239000011541 reaction mixture Substances 0.000 description 39
• 238000002844 melting Methods 0.000 description 35
• 230000008018 melting Effects 0.000 description 35
• 239000007787 solid Substances 0.000 description 35
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
• 238000004587 chromatography analysis Methods 0.000 description 27
• 239000012442 inert solvent Substances 0.000 description 27
• 239000000741 silica gel Substances 0.000 description 27
• 229910002027 silica gel Inorganic materials 0.000 description 27
• 239000007788 liquid Substances 0.000 description 26
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 26
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 25
• 239000012156 elution solvent Substances 0.000 description 25
• 239000012528 membrane Substances 0.000 description 25
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical class [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
• 238000001816 cooling Methods 0.000 description 22
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
• 239000013078 crystal Substances 0.000 description 19
• 238000001914 filtration Methods 0.000 description 16
• SPRFTLSCKAIIHW-UHFFFAOYSA-N 1-cyclopropyl-2-(2-fluorophenyl)-2-(4-sulfanylpiperidin-1-yl)ethanone;hydrochloride Chemical compound Cl.FC1=CC=CC=C1C(C(=O)C1CC1)N1CCC(S)CC1 SPRFTLSCKAIIHW-UHFFFAOYSA-N 0.000 description 15
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 15
• 239000003795 chemical substances by application Substances 0.000 description 15
• 208000010110 spontaneous platelet aggregation Diseases 0.000 description 15
• LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 14
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
• 239000002585 base Substances 0.000 description 14
• 150000008282 halocarbons Chemical class 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 14
• 238000001035 drying Methods 0.000 description 13
• 229910052740 iodine Inorganic materials 0.000 description 13
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 12
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 12
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
• 238000004440 column chromatography Methods 0.000 description 12
• 150000002170 ethers Chemical class 0.000 description 12
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
• 239000012046 mixed solvent Substances 0.000 description 12
• 239000003960 organic solvent Substances 0.000 description 12
• 238000001953 recrystallisation Methods 0.000 description 12
• 239000007858 starting material Substances 0.000 description 12
• 238000003756 stirring Methods 0.000 description 12
• 239000002253 acid Substances 0.000 description 11
• 230000002378 acidificating effect Effects 0.000 description 11
• 150000001298 alcohols Chemical class 0.000 description 11
• 150000001408 amides Chemical class 0.000 description 11
• 150000001412 amines Chemical class 0.000 description 11
• 239000011630 iodine Substances 0.000 description 11
• 229910000027 potassium carbonate Inorganic materials 0.000 description 11
• 235000011181 potassium carbonates Nutrition 0.000 description 11
• 239000000843 powder Substances 0.000 description 11
• 239000000047 product Substances 0.000 description 11
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
• 238000012360 testing method Methods 0.000 description 10
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
• 229910052783 alkali metal Inorganic materials 0.000 description 9
• 230000002401 inhibitory effect Effects 0.000 description 9
• 239000002198 insoluble material Substances 0.000 description 9
• 210000004623 platelet-rich plasma Anatomy 0.000 description 9
• 150000003462 sulfoxides Chemical class 0.000 description 9
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
• LLPWRIFVAQIMBS-UHFFFAOYSA-N 1-cyclopropyl-2-(2-fluorophenyl)-2-(4-hydroxypiperidin-1-yl)ethanone Chemical compound C1CC(O)CCN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 LLPWRIFVAQIMBS-UHFFFAOYSA-N 0.000 description 8
• XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 8
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
• 230000001419 dependent effect Effects 0.000 description 8
• GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 8
• BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
• 125000006239 protecting group Chemical group 0.000 description 8
• 230000035484 reaction time Effects 0.000 description 8
• PQJRECLQFGWWDV-UHFFFAOYSA-N s-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]piperidin-4-yl] ethanethioate Chemical compound C1CC(SC(=O)C)CCN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 PQJRECLQFGWWDV-UHFFFAOYSA-N 0.000 description 8
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 7
• 229910000288 alkali metal carbonate Inorganic materials 0.000 description 7
• 150000008041 alkali metal carbonates Chemical class 0.000 description 7
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
• 239000012230 colorless oil Substances 0.000 description 7
• 238000004128 high performance liquid chromatography Methods 0.000 description 7
• 150000002825 nitriles Chemical class 0.000 description 7
• 239000001301 oxygen Substances 0.000 description 7
• 229910052760 oxygen Inorganic materials 0.000 description 7
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
• 229910000029 sodium carbonate Inorganic materials 0.000 description 7
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• CZUJZKZRXMQVFR-VHPXAQPISA-N methyl 2-(2-chlorophenyl)-2-[(3e)-3-(2-ethoxy-2-oxoethylidene)-4-sulfanylpiperidin-1-yl]acetate;hydrochloride Chemical compound Cl.C1CC(S)C(=C/C(=O)OCC)/CN1C(C(=O)OC)C1=CC=CC=C1Cl CZUJZKZRXMQVFR-VHPXAQPISA-N 0.000 description 1
• BQUDIDJPHGGDMS-LBEJWNQZSA-N methyl 2-(2-chlorophenyl)-2-[(3e)-3-(2-methoxy-2-oxoethylidene)-4-sulfanylpiperidin-1-yl]acetate;hydrochloride Chemical compound Cl.C1CC(S)C(=C/C(=O)OC)/CN1C(C(=O)OC)C1=CC=CC=C1Cl BQUDIDJPHGGDMS-LBEJWNQZSA-N 0.000 description 1
• FJKYCRYZJMUMJN-ACCUITESSA-N methyl 2-(2-chlorophenyl)-2-[(3e)-3-[2-(dimethylamino)-2-oxoethylidene]-4-methylsulfonyloxypiperidin-1-yl]acetate Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)OC)N1CCC(OS(C)(=O)=O)\C(=C\C(=O)N(C)C)C1 FJKYCRYZJMUMJN-ACCUITESSA-N 0.000 description 1
• QKVQKJIKGOCATR-PKNBQFBNSA-N methyl 2-(2-chlorophenyl)-2-[(3e)-4-hydroxy-3-[2-(methylamino)-2-oxoethylidene]piperidin-1-yl]acetate Chemical compound C1CC(O)C(=C/C(=O)NC)/CN1C(C(=O)OC)C1=CC=CC=C1Cl QKVQKJIKGOCATR-PKNBQFBNSA-N 0.000 description 1
• HNDLRHCOPQOGQS-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-2-[4-(4-methylphenyl)sulfonylsulfanylpiperidin-1-yl]acetate Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)OC)N(CC1)CCC1SS(=O)(=O)C1=CC=C(C)C=C1 HNDLRHCOPQOGQS-UHFFFAOYSA-N 0.000 description 1
• RPVDJNLNZOOCRY-UHFFFAOYSA-N methyl 2-(2-fluorophenyl)-2-(4-hydroxypiperidin-1-yl)acetate Chemical compound C=1C=CC=C(F)C=1C(C(=O)OC)N1CCC(O)CC1 RPVDJNLNZOOCRY-UHFFFAOYSA-N 0.000 description 1
• UJPRFZGNAPIEEA-UHFFFAOYSA-N methyl 2-(2-fluorophenyl)-2-(4-sulfanylpiperidin-1-yl)acetate;hydrochloride Chemical compound Cl.C=1C=CC=C(F)C=1C(C(=O)OC)N1CCC(S)CC1 UJPRFZGNAPIEEA-UHFFFAOYSA-N 0.000 description 1
• JGFPMASSAQLFMN-LVZFUZTISA-N methyl 2-[(3e)-3-(2-butoxy-2-oxoethylidene)-4-(4-methylphenyl)sulfonylsulfanylpiperidin-1-yl]-2-(2-chlorophenyl)acetate Chemical compound CCCCOC(=O)\C=C1/CN(C(C(=O)OC)C=2C(=CC=CC=2)Cl)CCC1SS(=O)(=O)C1=CC=C(C)C=C1 JGFPMASSAQLFMN-LVZFUZTISA-N 0.000 description 1
• ANXXRJDFMOQMLB-SDNWHVSQSA-N methyl 2-[(3e)-4-acetylsulfanyl-3-(2-ethoxy-2-oxoethylidene)piperidin-1-yl]-2-(2-chlorophenyl)acetate Chemical compound C1CC(SC(C)=O)C(=C/C(=O)OCC)/CN1C(C(=O)OC)C1=CC=CC=C1Cl ANXXRJDFMOQMLB-SDNWHVSQSA-N 0.000 description 1
• JILMPHBWGHVZJX-UHFFFAOYSA-N methyl 2-bromo-2-(2-fluorophenyl)acetate Chemical compound COC(=O)C(Br)C1=CC=CC=C1F JILMPHBWGHVZJX-UHFFFAOYSA-N 0.000 description 1
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• IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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• UUPRSFAQEHTNDS-RVDMUPIBSA-N s-[(3e)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-[2-(methylamino)-2-oxoethylidene]piperidin-4-yl] ethanethioate Chemical compound C1CC(SC(C)=O)C(=C/C(=O)NC)/CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 UUPRSFAQEHTNDS-RVDMUPIBSA-N 0.000 description 1
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• KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
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• LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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