CN100369896C - 环胺化合物 - Google Patents
环胺化合物 Download PDFInfo
- Publication number
- CN100369896C CN100369896C CNB998055786A CN99805578A CN100369896C CN 100369896 C CN100369896 C CN 100369896C CN B998055786 A CNB998055786 A CN B998055786A CN 99805578 A CN99805578 A CN 99805578A CN 100369896 C CN100369896 C CN 100369896C
- Authority
- CN
- China
- Prior art keywords
- prco
- group
- meoco
- carbonyl
- atom
- Prior art date
- 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 - Lifetime
Links
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 58
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 15
- 208000005189 Embolism Diseases 0.000 claims abstract description 13
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 13
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 10
- -1 cyclic amine compound Chemical class 0.000 claims description 306
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 106
- 229910052731 fluorine Inorganic materials 0.000 claims description 93
- 150000003053 piperidines Chemical class 0.000 claims description 88
- 229910052801 chlorine Inorganic materials 0.000 claims description 66
- 125000001153 fluoro group Chemical group F* 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 57
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 53
- 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 42
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 41
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 40
- 239000011737 fluorine Substances 0.000 claims description 36
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 33
- 125000005843 halogen group Chemical group 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 239000003814 drug Substances 0.000 claims description 20
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 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 18
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 16
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 125000001246 bromo group Chemical group Br* 0.000 claims description 14
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 14
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 14
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 11
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000002228 disulfide group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 7
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- GTESIFDIWKFRRF-UHFFFAOYSA-N 1-methylsulfanylpiperidine Chemical class CSN1CCCCC1 GTESIFDIWKFRRF-UHFFFAOYSA-N 0.000 claims description 5
- 125000006637 cyclobutyl carbonyl group Chemical group 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims 3
- ACALWZKOOXPOMQ-UHFFFAOYSA-N COC(C(C(C=CC=C1)=C1F)N(CC1)CCC1SS(C1=CC=C(CN)C=C1)(=O)=O)=O Chemical class COC(C(C(C=CC=C1)=C1F)N(CC1)CCC1SS(C1=CC=C(CN)C=C1)(=O)=O)=O ACALWZKOOXPOMQ-UHFFFAOYSA-N 0.000 claims 2
- HNTSFOROFMYKGO-UHFFFAOYSA-N COC(C(C(C=CC=C1)=C1Cl)N(CC1)CCC1SS(C1=CC=C(CN)C=C1)(=O)=O)=O Chemical class COC(C(C(C=CC=C1)=C1Cl)N(CC1)CCC1SS(C1=CC=C(CN)C=C1)(=O)=O)=O HNTSFOROFMYKGO-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
- 230000003449 preventive effect Effects 0.000 abstract description 4
- 230000002776 aggregation Effects 0.000 abstract 1
- 238000004220 aggregation Methods 0.000 abstract 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract 1
- 230000000702 anti-platelet effect Effects 0.000 abstract 1
- 239000003146 anticoagulant agent Substances 0.000 abstract 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 786
- 150000001875 compounds Chemical class 0.000 description 228
- 238000006243 chemical reaction Methods 0.000 description 191
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 139
- 239000002904 solvent Substances 0.000 description 112
- 238000001819 mass spectrum Methods 0.000 description 94
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 93
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 85
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 77
- 238000000034 method Methods 0.000 description 68
- 239000002585 base Substances 0.000 description 62
- 230000006837 decompression Effects 0.000 description 56
- 239000000243 solution Substances 0.000 description 47
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 38
- 239000000178 monomer Substances 0.000 description 37
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 35
- 229920002554 vinyl polymer Polymers 0.000 description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- 238000001035 drying Methods 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical class CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 239000003921 oil Substances 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 28
- 239000012442 inert solvent Substances 0.000 description 27
- 230000002829 reductive effect Effects 0.000 description 27
- 238000010898 silica gel chromatography Methods 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 26
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 26
- 229940086542 triethylamine Drugs 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 23
- 229960001701 chloroform Drugs 0.000 description 23
- 125000001424 substituent group Chemical group 0.000 description 23
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 19
- 239000002253 acid Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 18
- 239000003513 alkali Substances 0.000 description 17
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000007670 refining Methods 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 150000008282 halocarbons Chemical class 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 13
- 238000000605 extraction Methods 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 206010013786 Dry skin Diseases 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 150000001298 alcohols Chemical class 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 150000002170 ethers Chemical class 0.000 description 12
- 239000003960 organic solvent Substances 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- 238000000638 solvent extraction Methods 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 235000015320 potassium carbonate Nutrition 0.000 description 10
- 101000783577 Dendroaspis angusticeps Thrombostatin Proteins 0.000 description 9
- 101000783578 Dendroaspis jamesoni kaimosae Dendroaspin Proteins 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
- 229940127218 antiplatelet drug Drugs 0.000 description 9
- 229960004756 ethanol Drugs 0.000 description 9
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 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
- 150000001335 aliphatic alkanes Chemical class 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 229940052308 general anesthetics halogenated hydrocarbons Drugs 0.000 description 8
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical class CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 8
- 229910052740 iodine Inorganic materials 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical group OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 239000012230 colorless oil Substances 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 235000008504 concentrate Nutrition 0.000 description 7
- 230000018044 dehydration Effects 0.000 description 7
- 238000006297 dehydration reaction Methods 0.000 description 7
- 239000011630 iodine Substances 0.000 description 7
- 150000002825 nitriles Chemical class 0.000 description 7
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 235000017550 sodium carbonate Nutrition 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- LMCZCCDXOZGIND-UHFFFAOYSA-N 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone Chemical compound FC1=CC=CC=C1C(Br)C(=O)C1CC1 LMCZCCDXOZGIND-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 150000007960 acetonitrile Chemical class 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 210000001772 blood platelet Anatomy 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000001913 cellulose Substances 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- 238000006386 neutralization reaction Methods 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 6
- CLASDMKBOIFHNY-UHFFFAOYSA-N 2-methylidenepiperidine Chemical class C=C1CCCCN1 CLASDMKBOIFHNY-UHFFFAOYSA-N 0.000 description 5
- 125000003164 beta-aspartyl group Chemical group 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 229910052736 halogen Inorganic materials 0.000 description 5
- 230000002140 halogenating effect Effects 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- 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 description 5
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 5
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 4
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 4
- 150000002081 enamines Chemical class 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 238000003810 ethyl acetate extraction Methods 0.000 description 4
- 238000005187 foaming Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 150000002430 hydrocarbons Chemical class 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical class OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 229950004288 tosilate Drugs 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 4
- LXUNZSDDXMPKLP-UHFFFAOYSA-N 2-Methylbenzenethiol Chemical compound CC1=CC=CC=C1S LXUNZSDDXMPKLP-UHFFFAOYSA-N 0.000 description 3
- DKIDEFUBRARXTE-UHFFFAOYSA-M 3-mercaptopropionate Chemical compound [O-]C(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-M 0.000 description 3
- NTSFJZORNYYLFW-UHFFFAOYSA-N 4-methylbenzenesulfonyl bromide Chemical compound CC1=CC=C(S(Br)(=O)=O)C=C1 NTSFJZORNYYLFW-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 3
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- FCLZCOCSZQNREK-UHFFFAOYSA-N Pyrrolidine, hydrochloride Chemical compound Cl.C1CCNC1 FCLZCOCSZQNREK-UHFFFAOYSA-N 0.000 description 3
- 235000005291 Rumex acetosa Nutrition 0.000 description 3
- 240000007001 Rumex acetosella Species 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 150000001340 alkali metals Chemical group 0.000 description 3
- 239000010953 base metal Substances 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 3
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- HMBUCZUZRQQJQD-UHFFFAOYSA-N methyl 2-bromo-2-(2-chlorophenyl)acetate Chemical compound COC(=O)C(Br)C1=CC=CC=C1Cl HMBUCZUZRQQJQD-UHFFFAOYSA-N 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 235000003513 sheep sorrel Nutrition 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 238000005991 sulfenylation reaction Methods 0.000 description 3
- 230000006103 sulfonylation Effects 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- NZBUCABTIWJWAN-UHFFFAOYSA-N tetrabromomethane;triphenylphosphane Chemical class BrC(Br)(Br)Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NZBUCABTIWJWAN-UHFFFAOYSA-N 0.000 description 3
- 150000003613 toluenes Chemical class 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N 1,1-Diethoxyethane Chemical class CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- RAVIQFQJZMTUBX-AWEZNQCLSA-N 1-[(3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxypiperidin-1-yl]-2-(3,4-dichlorophenyl)ethanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CCC1)C(CC1=CC(=C(C=C1)Cl)Cl)=O RAVIQFQJZMTUBX-AWEZNQCLSA-N 0.000 description 2
- ICWLEFBCBJYIGN-UHFFFAOYSA-N 2,4-dinitrobenzenesulfinyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)=O)C([N+]([O-])=O)=C1 ICWLEFBCBJYIGN-UHFFFAOYSA-N 0.000 description 2
- VLUWLNIMIAFOSY-UHFFFAOYSA-N 2-methylbenzenesulfinic acid Chemical compound CC1=CC=CC=C1S(O)=O VLUWLNIMIAFOSY-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- WSNKEJIFARPOSQ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-(1-benzothiophen-2-ylmethyl)benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NCC2=CC3=C(S2)C=CC=C3)C=CC=1 WSNKEJIFARPOSQ-UHFFFAOYSA-N 0.000 description 2
- PJNDLVDONAGUTF-LSDHHAIUSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[(1S,2R)-2-hydroxycyclopentyl]benzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)N[C@@H]2[C@@H](CCC2)O)C=CC=1 PJNDLVDONAGUTF-LSDHHAIUSA-N 0.000 description 2
- ZMCQQCBOZIGNRV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-[2-(1,2,4-triazol-1-yl)ethyl]benzamide Chemical compound NCC1=CC(OC2=CC=CC(=C2)C(=O)NCCN2C=NC=N2)=NC(=C1)C(F)(F)F ZMCQQCBOZIGNRV-UHFFFAOYSA-N 0.000 description 2
- HAEQAUJYNHQVHV-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylbenzamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)NC2=CC=CC=C2)C=CC=1 HAEQAUJYNHQVHV-UHFFFAOYSA-N 0.000 description 2
- KDIWEKJFLYTKPI-UHFFFAOYSA-N 4-methyl-3,8-dithiatricyclo[5.1.0.02,4]oct-5-ene Chemical compound C12(C(C3C(C=C1)S3)S2)C KDIWEKJFLYTKPI-UHFFFAOYSA-N 0.000 description 2
- NRLQBVLOUUPAMI-UHFFFAOYSA-N 8-[3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxybenzoyl]-1-oxa-3,8-diazaspiro[4.5]decan-2-one Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C(=O)N2CCC3(CNC(O3)=O)CC2)C=CC=1 NRLQBVLOUUPAMI-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- UEOQGGDCTJBMII-UHFFFAOYSA-M C(C)OC([O-])=O.[Cl+] Chemical compound C(C)OC([O-])=O.[Cl+] UEOQGGDCTJBMII-UHFFFAOYSA-M 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- CETBSQOFQKLHHZ-UHFFFAOYSA-N Diethyl disulfide Chemical compound CCSSCC CETBSQOFQKLHHZ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical group OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 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 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- JBZRLVKMCLOFLG-UHFFFAOYSA-N O=S=Cl Chemical compound O=S=Cl JBZRLVKMCLOFLG-UHFFFAOYSA-N 0.000 description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical class OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical class [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical class [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- YKKPYMXANSSQCA-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3-pyrazol-1-ylazetidin-1-yl)methanone Chemical compound N1(N=CC=C1)C1CN(C1)C(=O)C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F YKKPYMXANSSQCA-UHFFFAOYSA-N 0.000 description 2
- LJHFUFVRZNYVMK-ZDUSSCGKSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3S)-3-hydroxypyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@H](CC1)O LJHFUFVRZNYVMK-ZDUSSCGKSA-N 0.000 description 2
- BDKZHNJTLHOSDW-UHFFFAOYSA-N [Na].CC(O)=O Chemical class [Na].CC(O)=O BDKZHNJTLHOSDW-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 229910000323 aluminium silicate Inorganic materials 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 229960004676 antithrombotic agent Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical class [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- IODDQGMEFSNLGV-UHFFFAOYSA-N butane;hydrochloride Chemical compound Cl.CCCC IODDQGMEFSNLGV-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical class CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- 150000001728 carbonyl compounds Chemical class 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000006639 cyclohexyl carbonyl group Chemical class 0.000 description 2
- 125000006638 cyclopentyl carbonyl group Chemical class 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- SDJHDRMYZQFJJO-UHFFFAOYSA-N ethanethioic s-acid;potassium Chemical compound [K].CC(S)=O SDJHDRMYZQFJJO-UHFFFAOYSA-N 0.000 description 2
- ASCHBOWFKWDVGW-UHFFFAOYSA-N fluorobenzene;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.FC1=CC=CC=C1 ASCHBOWFKWDVGW-UHFFFAOYSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- GMPNCPFQIMYMEO-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-2-(4-hydroxypiperidin-1-yl)acetate Chemical compound C=1C=CC=C(Cl)C=1C(C(=O)OC)N1CCC(O)CC1 GMPNCPFQIMYMEO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 210000004623 platelet-rich plasma Anatomy 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000001103 potassium chloride Chemical class 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000001235 sensitizing effect Effects 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- NBNBICNWNFQDDD-UHFFFAOYSA-N sulfuryl dibromide Chemical compound BrS(Br)(=O)=O NBNBICNWNFQDDD-UHFFFAOYSA-N 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- QEJZCKJXVYGWMY-UHFFFAOYSA-N (cyclopentyldisulfanyl)cyclopentane Chemical group C1CCCC1SSC1CCCC1 QEJZCKJXVYGWMY-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- XABWIIKINKLNDO-UHFFFAOYSA-N 1-(1-hydroxyethyl)piperidin-4-one Chemical compound OC(C)N1CCC(CC1)=O XABWIIKINKLNDO-UHFFFAOYSA-N 0.000 description 1
- LMCOZBHJIOVSPA-UHFFFAOYSA-N 1-[3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxybenzoyl]azetidine-3-carbonitrile Chemical compound NCC1=CC(OC2=CC=CC(=C2)C(=O)N2CC(C2)C#N)=NC(=C1)C(F)(F)F LMCOZBHJIOVSPA-UHFFFAOYSA-N 0.000 description 1
- SJZKULRDWHPHGG-UHFFFAOYSA-N 1-benzylpiperidin-4-one Chemical compound C1CC(=O)CCN1CC1=CC=CC=C1 SJZKULRDWHPHGG-UHFFFAOYSA-N 0.000 description 1
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 1
- NXCKJENHTITELM-UHFFFAOYSA-N 1-nitro-2-[(2-nitrophenyl)disulfanyl]benzene Chemical group [O-][N+](=O)C1=CC=CC=C1SSC1=CC=CC=C1[N+]([O-])=O NXCKJENHTITELM-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical class NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical class CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- ARVVVVWAVZGHFV-UHFFFAOYSA-N 4-phenyl-3,8-dithiatricyclo[5.1.0.02,4]oct-5-ene Chemical class S1C2C3SC3C=CC21C1=CC=CC=C1 ARVVVVWAVZGHFV-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical class CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000256844 Apis mellifera Species 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WGHIPQMYAPDVOL-UHFFFAOYSA-N C1(=CC=CC=C1)C(C1=CC=CC=C1)C1=CC=CC=C1.[Cl] Chemical compound C1(=CC=CC=C1)C(C1=CC=CC=C1)C1=CC=CC=C1.[Cl] WGHIPQMYAPDVOL-UHFFFAOYSA-N 0.000 description 1
- SLFDKQSZHFHDGA-UHFFFAOYSA-N C1(=CC=CC=C1)N1CCCCC1.C[O] Chemical class C1(=CC=CC=C1)N1CCCCC1.C[O] SLFDKQSZHFHDGA-UHFFFAOYSA-N 0.000 description 1
- JBUUXBWAANKTBB-UHFFFAOYSA-N C1=CC(=CC=C1CN)S(=O)(=O)Br Chemical compound C1=CC(=CC=C1CN)S(=O)(=O)Br JBUUXBWAANKTBB-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229910052684 Cerium Inorganic materials 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical class C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- ODHAQPXNQDBHSH-UHFFFAOYSA-N Dicyclohexyl disulfide Chemical group C1CCCCC1SSC1CCCCC1 ODHAQPXNQDBHSH-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- YYMCYJLIYNNOMK-UHFFFAOYSA-N Nor-psi-tropine Chemical compound C1C(O)CC2CCC1N2 YYMCYJLIYNNOMK-UHFFFAOYSA-N 0.000 description 1
- FVHAJRLAQGDMMU-UHFFFAOYSA-N O=S(=O)=Br.C1=CC=CC=C1 Chemical compound O=S(=O)=Br.C1=CC=CC=C1 FVHAJRLAQGDMMU-UHFFFAOYSA-N 0.000 description 1
- DIGGWMOTBUMCTG-UHFFFAOYSA-N P.[C] Chemical compound P.[C] DIGGWMOTBUMCTG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 241000241413 Propolis Species 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- XZCVVAVJEXDQJO-UHFFFAOYSA-N S(=O)(=O)(Br)Br.ClC1=CC=CC=C1 Chemical compound S(=O)(=O)(Br)Br.ClC1=CC=CC=C1 XZCVVAVJEXDQJO-UHFFFAOYSA-N 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 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 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- PJXUTWGNUWGDOC-UHFFFAOYSA-N [K].S(=S)(=O)O.C1(=CC=CC=C1)C Chemical compound [K].S(=S)(=O)O.C1(=CC=CC=C1)C PJXUTWGNUWGDOC-UHFFFAOYSA-N 0.000 description 1
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 description 1
- QVMHUALAQYRRBM-UHFFFAOYSA-N [P].[P] Chemical compound [P].[P] QVMHUALAQYRRBM-UHFFFAOYSA-N 0.000 description 1
- NZHXEWZGTQSYJM-UHFFFAOYSA-N [bromo(diphenyl)methyl]benzene Chemical class C=1C=CC=CC=1C(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 NZHXEWZGTQSYJM-UHFFFAOYSA-N 0.000 description 1
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical class [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000001243 alanino group Chemical group 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000003162 alpha-aspartyl group Chemical group 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical class [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- RJGDLRCDCYRQOQ-UHFFFAOYSA-N anthrone Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3CC2=C1 RJGDLRCDCYRQOQ-UHFFFAOYSA-N 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 125000002867 asparto group Chemical group 0.000 description 1
- GMWFCJXSQQHBPI-UHFFFAOYSA-N azetidin-3-ol Chemical compound OC1CNC1 GMWFCJXSQQHBPI-UHFFFAOYSA-N 0.000 description 1
- UPABQMWFWCMOFV-UHFFFAOYSA-N benethamine Chemical class C=1C=CC=CC=1CNCCC1=CC=CC=C1 UPABQMWFWCMOFV-UHFFFAOYSA-N 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical group C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- XFEIRVZQVUQECX-UHFFFAOYSA-N bromo ethyl carbonate Chemical compound CCOC(=O)OBr XFEIRVZQVUQECX-UHFFFAOYSA-N 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 150000004652 butanoic acids Chemical class 0.000 description 1
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical class [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000012241 calcium silicate Nutrition 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical class [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- ODYJZKDNEJGBSE-UHFFFAOYSA-N calcium;2-methylpropan-2-olate Chemical class [Ca+2].CC(C)(C)[O-].CC(C)(C)[O-] ODYJZKDNEJGBSE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- GWXLDORMOJMVQZ-UHFFFAOYSA-N cerium Chemical compound [Ce] GWXLDORMOJMVQZ-UHFFFAOYSA-N 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 150000001868 cobalt Chemical class 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 150000001896 cresols Chemical class 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- JEQRBTDTEKWZBW-UHFFFAOYSA-N dehydroacetic acid Chemical compound CC(=O)C1=C(O)OC(C)=CC1=O JEQRBTDTEKWZBW-UHFFFAOYSA-N 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 229940052303 ethers for general anesthesia Drugs 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- DBPFRRFGLYGEJI-UHFFFAOYSA-N ethyl glyoxylate Chemical compound CCOC(=O)C=O DBPFRRFGLYGEJI-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 150000002301 glucosamine derivatives Chemical class 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 125000002684 glutamo group Chemical group 0.000 description 1
- 125000000267 glycino group Chemical group [H]N([*])C([H])([H])C(=O)O[H] 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- CUILPNURFADTPE-UHFFFAOYSA-N hypobromous acid Chemical compound BrO CUILPNURFADTPE-UHFFFAOYSA-N 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 229950003188 isovaleryl diethylamide Drugs 0.000 description 1
- 150000002597 lactoses Chemical class 0.000 description 1
- 125000003217 leucino group Chemical group [H]OC(=O)C([H])(N([H])[*])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical class [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 1
- RHDUOFVTCTUTFX-UHFFFAOYSA-N methanesulfinic acid;sodium Chemical compound [Na].CS(O)=O RHDUOFVTCTUTFX-UHFFFAOYSA-N 0.000 description 1
- OCUKIRHXHKSPMR-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-2-(4-sulfanylpiperidin-1-yl)acetate;hydrochloride Chemical compound Cl.C=1C=CC=C(Cl)C=1C(C(=O)OC)N1CCC(S)CC1 OCUKIRHXHKSPMR-UHFFFAOYSA-N 0.000 description 1
- HNDLRHCOPQOGQS-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-2-[4-(4-methylphenyl)sulfonylsulfanylpiperidin-1-yl]acetate Chemical class 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
- MZPSKJWUACDADS-UHFFFAOYSA-N methyl 2-(2-fluorophenyl)-2-[4-(4-methylphenyl)sulfonylsulfanylpiperidin-1-yl]acetate Chemical class 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 description 1
- ICNBQWACEJQOCN-UHFFFAOYSA-N methyl 2-(4-acetylsulfanylpiperidin-1-yl)-2-(2-chlorophenyl)acetate Chemical class C=1C=CC=C(Cl)C=1C(C(=O)OC)N1CCC(SC(C)=O)CC1 ICNBQWACEJQOCN-UHFFFAOYSA-N 0.000 description 1
- BAVNUJSUDYAQKD-UHFFFAOYSA-N methyl 2-(4-acetylsulfanylpiperidin-1-yl)-2-(2-fluorophenyl)acetate Chemical class C=1C=CC=C(F)C=1C(C(=O)OC)N1CCC(SC(C)=O)CC1 BAVNUJSUDYAQKD-UHFFFAOYSA-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
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical class COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- ACTNHJDHMQSOGL-UHFFFAOYSA-N n',n'-dibenzylethane-1,2-diamine Chemical class C=1C=CC=CC=1CN(CCN)CC1=CC=CC=C1 ACTNHJDHMQSOGL-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- KMTUBAIXCBHPIZ-UHFFFAOYSA-N pentane-1,5-dithiol Chemical compound SCCCCCS KMTUBAIXCBHPIZ-UHFFFAOYSA-N 0.000 description 1
- FDOHPUYPQQKECS-UHFFFAOYSA-N pentanoyl bromide Chemical group CCCCC(Br)=O FDOHPUYPQQKECS-UHFFFAOYSA-N 0.000 description 1
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical group CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000000405 phenylalanyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical class BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- QRKVRHZNLKTPGF-UHFFFAOYSA-N phosphorus pentabromide Chemical class BrP(Br)(Br)(Br)Br QRKVRHZNLKTPGF-UHFFFAOYSA-N 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- BIWOSRSKDCZIFM-UHFFFAOYSA-N piperidin-3-ol Chemical compound OC1CCCNC1 BIWOSRSKDCZIFM-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical class [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940069949 propolis Drugs 0.000 description 1
- QQKDTTWZXHEGAQ-UHFFFAOYSA-N propyl carbonochloridate Chemical compound CCCOC(Cl)=O QQKDTTWZXHEGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical class CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 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
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- MJIKIYZXUTXUMS-UHFFFAOYSA-N tert-butyl 3-ethylidene-4-oxopiperidine-1-carboxylate Chemical compound CC=C1CN(C(=O)OC(C)(C)C)CCC1=O MJIKIYZXUTXUMS-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical class BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical class Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 125000001796 valino group Chemical group 0.000 description 1
- 125000002114 valyl group Chemical group 0.000 description 1
- 238000004073 vulcanization Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/54—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Lubricants (AREA)
- Saccharide Compounds (AREA)
- Cosmetics (AREA)
Abstract
具有通式(1)结构的环胺化合物环胺化合物或其药理上可容许的盐,〔式中,R1表示可取代的苯基、R2表示可取代的脂肪族酰基、可取代的苯甲酰基或者烷氧羰基、R3是具有取代基的可稠环饱和氨基〕具有优良的抑制血小板凝聚作用,作为栓塞症、血栓症及动脉硬化症的预防及治疗药是非常有用的。
Description
技术领域
本发明涉及具有优良的血小板凝聚抑制作用或者动脉硬化发展抑制作用等的环胺化合物、及其药理上可容许的盐、含有上述化合物的用于预防或治疗栓塞症、血栓症或者动脉硬化症的组合物、在制造为预防或治疗栓塞症、血栓症或者动脉硬化症药物中上述化合物的使用、将上述化合物或组合物的药理上有效量给药于温血动物的栓塞症、血栓症或者动脉硬化症的预防方法或治疗方法、或者上述化合物的制造方法。
技术背景
具有血小板凝聚抑制作用等的环胺化合物,例如氢化吡啶衍生物,是已知的。〔例如美国专利第4,051,141号、特开昭59-27895号公报(EP99802)、特开平6-41139号公报(EP542411)、WO98/08811等〕。
发明的公开
本发明者等长年地研究了环胺化合物的药理作用。其结果,发现了特异的环胺化合物具有优良的血小板凝聚抑制作用或者动脉硬化进展抑制作用等(特别是血小板凝聚抑制作用),作为预防或治疗栓塞症、血栓症或者动脉硬化症(特别是栓塞症或血栓症)的预防剂或治疗剂(特别是治疗剂)是有用的,从而完成了本发明。
本发明提供了具有优良的血小板凝聚抑制作用或者动脉硬化进展抑制作用等的环胺化合物、及其药理上可容许的盐、含有上述化合物的用于预防或治疗栓塞症、血栓症或者动脉硬化症的组合物、在制造为预防或治疗栓塞症、血栓症或者动脉硬化症药物中上述化合物的使用、将上述化合物或组合物的药理上有效量给药于温血动物的栓塞症、血栓症或者动脉硬化症的预防方法或治疗方法、或者上述化合物的制造方法。
本发明的环胺化合物具有通式(I)的结构。
上式中,
R1表示可有任意取代的苯基(该取代基是卤原子、C1-C4烷基、氟取代C1-C4烷基、C1-C4烷氧基、氟取代C1-C4烷氧基、氰基或硝基。)、
R2表示可有任意取代的C1-C8脂肪族酰基(该取代基是卤原子、C1-C4烷氧基或氰基。);可有任意取代的苯甲酰基(该取代基是卤原子、C1-C4烷基或C1-C4烷氧基。);或者(C1-C4烷氧基)羰基、
R3是可任意稠环的、取代3-7元环状饱和氨基{该取代基的必须条件是具有通式-S-X-R4的基〔式中,R4是可有任意取代的苯基(该取代基是卤原子、C1-C4烷基、C1-C4烷氧基、硝基或氰基。);可有任意取代的C1-C6烷基〔该取代基是氨基、羟基、羧基、(C1-C4烷氧基)羰基、具有通式-NH-A1的基(式中A1表示α-氨基酸残基。)或者具有通式-CO-A2的基(式中A2表示α-氨基酸残基。)〕;或者表示C3-C8环烷基、X表示硫原子、亚磺酰基或者磺酰基。〕、
希望的是具有通式=CR5R6的基〔式中R5及R6相同或不同地表示氢原子、C1-C4烷基、羧基、(C1-C4烷氧基)羰基、氨基甲酰基、(C1-C4烷基)氨基甲酰基或二(C1-C4烷基)氨基甲酰基。〕。}。
上述R1的定义中,可有任意取代的苯基中的作为取代基的“卤原子”,可以是氟原子、氯原子、溴原子或碘原子,优选的是氟原子、氯原子或溴原子,特别优选的是氟原子或氯原子。
R1的定义中,可有任意取代的苯基中的作为取代基的“C1-C4烷基”可以是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基类的直链或支链的碳原子数1-4个的烷基,优选的是甲基或乙基,特别优选的是甲基。
R1的定义中,可有任意取代的苯基中的作为取代基的“氟取代C1-C4烷基”可以是氟甲基、二氟甲基、三氟甲基、2-氟乙基、2-氟丙基、3-氟丙基、2-氟丁基、3-氟丁基、或4-氟丁基类的直链或支链的碳原子数1-4个的氟取代烷基,优选的是二氟甲基或三氟甲基,特别优选的是三氟甲基。
R1的定义中,可有任意取代的苯基中的作为取代基的“C1-C4烷氧基”可以是甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、或叔丁氧基类的直链或支链的碳原子数1-4个的烷氧基,优选的是甲氧基或乙氧基,特别优选的是甲氧基。
R1的定义中,可有任意取代的苯基中的作为取代基的“氟取代C1-C4烷氧基”,可以是氟甲氧基、二氟甲氧基、三氟甲氧基、2-氟乙氧基、2-氟丙氧基、3-氟丙氧基、2-氟异丙氧基、或4-氟丁氧基类的直链或支链的碳原子数1-4个的氟取代烷氧基,优选的是二氟甲氧基或三氟甲氧基,特别优选的是三氟甲氧基。
R1的定义中,可有任意取代的苯基中的取代基,优选的是卤原子、甲基、乙基、二氟甲基、三氟甲基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、氰基或硝基,更优选的是氟原子、氯原子、溴原子、三氟甲基、二氟甲氧基、三氟甲氧基、氰基或硝基,特别优选的是氟原子或氯原子。该取代基的数优选的是1-3,更优选的是1或2,特别优选的是1。另外取代基的位置优选的是2位或4位,特别优选的是2位。
R2的定义中,可有任意取代的C1-C8脂肪族酰基中的“脂肪族酰基”部分,可以是甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、三甲基乙酰基、己酰基、庚酰基或辛酰基类的直链或支链的C1-C8烷酰基;或者,环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基或环庚基羰基类的(C3-C7环烷基)羰基,优选的是C2-C4烷酰基或者(C3-C6环烷基)羰基,更优选的是乙酰基、丙酰基、异丁酰基、环丙基羰基或者环丁基羰基,最优选的是丙酰基或环丙基羰基,特别优选的是环丙基羰基。
脂肪族酰基的取代基的“卤原子”及“C1-C4烷氧基”的定义是与上述的R1的“可有任意取代的苯基”中的取代基的定义相同,脂肪族酰基的取代基,优选的是氟原子、氯原子、甲氧基、乙氧基或氰基,更优选的是氟原子或氯原子,特别优选的是氟原子。该取代基的数,优选的是1-3,更优选的是1或2,特别优选的是1。
“取代脂肪族酰基”的具体例是,如氟代乙酰基、二氟乙酰基、三氟乙酰基、氯代乙酰基、三氯乙酰基、溴代乙酰基、碘代乙酰基、3-氟丙酰基、3-氯丙酰基、3-溴丙酰基、3-碘丙酰基、4-氟丁酰基、4-氯丁酰基、5-氟戊酰基、甲氧基乙酰基、3-甲氧基丙酰基、4-甲氧基丁酰基、5-甲氧基戊酰基、乙氧基乙酰基、3-乙氧基丙酰基、4-乙氧基丁酰基、5-乙氧基戊酰基、氰基乙酰基、3-氰基丙酰基、4-氰基丁酰基、5-氰基戊酰基、2-氟环丙基羰基、2,2-二氟环丙基羰基、2-氯环丙基羰基、2-溴环丙基羰基、2-氟环丁基羰基、2-氯环丁基羰基、2-氟环戊基羰基、2-氯环戊基羰基、2-氟环己基羰基、2-氯环己基羰基、2-甲氧基环丙基羰基、2-甲氧基环丁基羰基、2-甲氧基环戊基羰基、2-甲氧基环己基羰基、2-乙氧基环丙基羰基、2-乙氧基环丁基羰基、2-乙氧基环戊基羰基、2-乙氧基环己基羰基、2-氰基环丙基羰基、2-氰基环丁基羰基、2-氰基环戊基羰基、或2-氰基环己基羰基,
优选的是,氟代乙酰基、二氟乙酰基、三氟乙酰基、氯代乙酰基、3-氟丙酰基、3-氯丙酰基、甲氧基乙酰基、3-甲氧基丙酰基、乙氧基乙酰基、氰基乙酰基、3-氰基丙酰基、2-氟环丙基羰基、2,2-二氟环丙基羰基、2-氯环丙基羰基、2-氟环丁基羰基、2-氯环丁基羰基、2-氟环戊基羰基、2-氟环己基羰基、2-甲氧基环丙基羰基、2-乙氧基环丙基羰基或者2-氰基环丙基羰基,
更优选的是,氟代乙酰基、二氟乙酰基、三氟乙酰基、氯代乙酰基、3-氟丙酰基、2-氟环丙基羰基、2-氯环丙基羰基或者2-氟环丁基羰基,
特别优选的是,氟代乙酰基、二氟乙酰基、三氟乙酰基、3-氟丙酰基或者2-氟环丙基羰基。
R2的定义中,可有任意取代的苯甲酰基中的作为取代基的“卤原子”、“C1-C4烷基”及“C1-C4烷氧基”的定义是与上述的R1的“可有任意取代的苯基”的取代基定义相同,苯甲酰基的取代基,优选的是,氟原子、氯原子、甲基、乙基、甲氧基或乙氧基,更优选的是氟原子或氯原子,特别优选的是氟原子。该取代基的数,优选的是1-3,更优选的是1或2,特别优选的是1。
R2的定义中的“(C1-C4烷氧基)羰基”,可以是甲氧基羰基、乙氧基羰基、丙氧基羰基、异丙氧基羰基、丁氧基羰基、异丁氧基羰基、仲丁氧基羰基或叔丁氧基羰基,优选的是甲氧基羰基或乙氧基羰基,特别优选的是甲氧基羰基。
R3的定义中的“可以稠环的、被取代的3-7元环状饱和氨基”的“环状饱和氨基”部分,可以是1-氮杂环丙烷基、1-氮杂环丁烷基、1-吡咯烷基、1-哌啶基、2H-六氢氮杂卓-1-基、7-氮杂双环〔3.1.1〕庚烷-7-基、8-氮杂双环〔3.2.1〕辛烷-8-基、9-氮杂双环〔3.3.1〕壬烷-9-基、4-吗啉基、4-硫代吗啉基或4-哌嗪基类的、可以稠环的、可以含有氧、氮或硫原子的、碳原子数2-8个的环状饱和氨基,优选的是1-氮杂环丁烷基、1-吡咯烷基、1-哌啶基、7-氮杂双环〔3.1.1〕庚烷-7-基、8-氮杂双环〔3.2.1〕辛烷-8-基、9-氮杂双环〔3.3.1〕壬烷-9-基、4-吗啉基或4-硫代吗啉基,更优选的是1-氮杂环丁烷基、1-吡咯烷基、1-哌啶基、8-氮杂双环〔3.2.1〕辛烷-8-基或9-氮杂双环〔3.3.1〕壬烷-9-基,最优选的是,1-氮杂环丁烷基、1-吡咯烷基、1-哌啶基或8-氮杂双环〔3.2.1〕辛烷-8-基,特别优选的是1-氮杂环丁烷基、1-吡咯烷基、1-哌啶基。此外,该基可通过环上的氮原子与相邻的碳原子(与R1、R2结合的碳原子)结合。
R3的定义中的“可以稠环的、取代3-7元环状饱和氨基”,优选的是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、3-或4-(-S-X-R4)-1-哌啶基、4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基或8-氮杂-3-(-S-X-R4)-双环〔3.2.1〕辛烷-8-基,特别优选的是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基。
R4的定义中,“可有任意取代的苯基”中的作为取代基的“卤原子”、“C1-C4烷基”及“C1-C4烷氧基”的定义是与上述R1的“可有任意取代的苯基”中的取代基定义相同,R4的可有任意取代的苯基中的取代基,优选的是,卤原子、甲基、乙基、甲氧基、乙氧基、硝基或氰基,更优选的是氟原子、氯原子、溴原子、甲基、甲氧基、硝基或氰基,特别优选的是氟原子、氯原子、甲基、甲氧基或硝基。该取代基的数,优选的是1-3,更优选的是1或2,特别优选的是1。
R4的定义中,“可有任意取代的C1-C6烷基”的“C1-C6烷基”部分,可以是上述R1的“可有任意取代的苯基”中的取代基定义相同的C1-C4烷基或者戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基或2-乙基丁基类的直链或支链状的碳原子数1-6个的烷基,优选的是甲基、乙基、丙基、丁基、戊基或己基类的直链状的C1-C6烷基,更优选的是,甲基、乙基、丙基、丁基类的直链状的C1-C6烷基,特别优选的是甲基、乙基或丙基。
R4的定义中,“可有任意取代的C1-C6烷基”的作为取代基的“(C1-C4烷氧基)羰基”的定义是与上述R2中的定义相同,优选的是甲氧基羰基或乙氧基羰基。
R4的定义中,“可有任意取代的C1-C6烷基”的作为取代基的具有通式-NH-A1基中的A1的“α-氨基酸残基”是甘氨酰基、丙氨酰基、缬氨酰基、亮氨酰基、苯基甘氨酰基、苯基丙氨酰基、α-天冬氨酰基、β-天冬氨酰基、α-谷氨酰基或r-谷氨酰基类的从α-氨基酸的羧基除去羟基的具有部分结构的氨基酸残基,优选的是甘氨酰基、丙氨酰基、β-天冬氨酰基或r-谷氨酰基,更优选的是甘氨酰基或r-谷氨酰基,特别优选的是r-谷氨酰基。
R4的定义中,“可有任意取代的C1-C6烷基”的作为取代基的具有通式-CO-A2基中的A2的“α-氨基酸残基”可以是甘氨酸残基(glycino)、丙氨酸残基(alanino)、缬氨酸残基(valino)、亮氨酸残基(leucino)、苯基甘氨酸残基、苯基丙氨酸残基、天冬氨酸残基(asparto)或谷氨酸残基(glutamo)类的、从α-氨基酸的氨基除去氢原子的具有部分结构的氨基酸残基,优选的是甘氨酸残基、丙氨酸残基、缬氨酸残基、亮氨酸残基、苯基甘氨酸残基、苯基丙氨酸残基、更优选的是甘氨酸残基、丙氨酸残基或缬氨酸残基,最优选的是甘氨酸残基。
R4的“可有任意取代的C1-C6烷基”的取代基,
优选的是氨基、羟基、羧基、(C1-C4烷氧基)羰基、具有通式-NH-A1a的基(式中,A1a表示甘氨酰基、丙氨酰基、β-天冬氨酰基或r-谷氨酰基。)或者具有通式-CO-A2a的基(式中,A2a表示甘氨酸残基、丙氨酸残基、缬氨酸残基、亮氨酸残基、苯基甘氨酸残基、苯基丙氨酸残基。)、
更优选的是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1b的基(式中,A1b表示甘氨酰基或r-谷氨酰基。)或者具有通式-CO-A2b的基(式中,A2b表示甘氨酸残基、丙氨酸残基或缬氨酸残基。)、
最优选的是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1c的基(式中,A1c表示r-谷氨酰基。)或具有通式-CO-A2c的基(式中,A2c是谷氨酸残基。)、
特别优选的是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1c的基(式中,A1c表示与上述相同的定义。)或具有通式-CO-A2c的基(式中,A2c表示与上述相同的定义。)。
R4的定义中,“可有任意取代的C1-C6烷基”的取代基数,优选的是1或2,取代基的数是2时,具有氨基、羟基或者通式-NH-A1的基,与结合着具有羧基或通式-CO-A2基的同一碳原子结合的是特别优选的。
R4的定义中,“C3-C8环烷基”可以是环丙基、环丁基、环戊基、环己基、环庚基或环辛基,优选的是环丁基、环戊基、环己基、或环庚基,特别优选的是环戊基、环己基。
R5及R6的定义中,“C1-C4烷基”与上述R1的“可有任意取代的苯基”的取代基的定义相同。
R5及R6的定义中,“(C1-C4烷基)氨基甲酰基”可以是甲基氨基甲酰基、乙基氨基甲酰基、丙基氨基甲酰基、异丙基氨基甲酰基、丁基氨基甲酰基、异丁基氨基甲酰基、仲丁基氨基甲酰基或叔丁基氨基甲酰基,优选的是甲基氨基甲酰基或乙基氨基甲酰基,特别优选的是甲基氨基甲酰基。
R5及R6的定义中,“二-(C1-C4烷基)氨基甲酰基”可以是N,N-二甲基氨基甲酰基、N-乙基-N-甲基氨基甲酰基、N,N-二乙基氨基甲酰基、N,N-二丙基氨基甲酰基、N,N-二异丙基氨基甲酰基、N,N-二丁基氨基甲酰基、N,N-二异丁基氨基甲酰基、N,N-二-仲丁基氨基甲酰基、N,N-二-叔丁基氨基甲酰基,优选的是N,N-二甲基氨基甲酰基或N,N-二乙基氨基甲酰基,特别优选的是N,N-二甲基氨基甲酰基。
R5及R6的定义中,“(C1-C4烷氧基)羰基”与上述R2中的定义相同。
具有通式=CR5R6的基,优选的是R5及R6相同或不同地表示氢原子、甲基、乙基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基、乙基氨基甲酰基、N,N-二甲基氨基甲酰基或N,N-二乙基氨基甲酰基,更优选的是,R5是氢原子,R6是氢原子、甲基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基或N,N-二甲基氨基甲酰基,特别优选的是,R5是氢原子,R6是羧基、甲氧羰基或乙氧羰基。
X优选的是硫原子或者磺酰基。
本发明化合物(I)中,R1结合的碳原子等可以是不对称碳原子,所以存在光学异构体,其异构体及这些混合物也都包括在本发明的化合物中。另外,化合物(I)的分子中含有双键和/或环烷基或者环胺基上含有两个取代基时,则存在基于此的顺式/反式几何异构体,其异构体及这些混合物也都包括在本发明的化合物中。
本发明化合物(I)中,R5或R6是羧基时,用碱处理可容易地得到药理上可容许的盐。作为这些盐,例如纳盐、钾盐、锂盐类的碱金属盐、钙盐、镁盐类的碱土金属盐,铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等的金属盐;铵盐类的无机盐、叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡萄糖胺盐、胍盐、二乙基胺盐、三乙基胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙胺盐、哌嗪盐、四甲基胺盐、三(羟基甲基)氨基甲烷盐类的有机盐等的胺盐,优选的是碱金属盐(特别是钠盐或钾盐)。
用酸处理本发明化合物(I)可容易地变换成药理上可容许的盐。这些盐有盐酸盐、硫酸盐、硝酸盐、磷酸盐类的无机盐,醋酸盐、丙酸盐、丁酸盐、苯甲酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐类的有机酸盐,优选的是盐酸盐、硫酸盐、硝酸盐、草酸盐、琥珀酸盐、富马酸盐或甲磺酸盐。
进而,化合物(I)或者其盐的水合物也包括在本发明中。
本发明的具有上述通式(I)的化合物中,优选的是,
(1)R1是被取代了的苯基(该取代基是卤原子、甲基、乙基、二氟甲基、三氟甲基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、氰基或硝基)化合物、
(2)R1是被取代了的苯基(该取代基是氟原子、氯原子、溴原子、三氟甲基、二氟甲氧基、三氟甲氧基、氰基或硝基。)化合物、
(3)R1是被取代了的苯基(该取代基是氟原子、氯原子)化合物、
(4)R1的被取代了苯基的取代基数是1-3的化合物、
(5)R1的被取代了苯基的取代基数是1或2的化合物、
(6)R1的被取代了苯基的取代基的取代位置是2位或4位的化合物、
(7)R2是可有任意取代的C2-C4烷酰基或(C3-C6环烷基)羰基(该取代基是氟原子、氯原子、甲氧基、乙氧基或氰基);可有任意取代的苯甲酰基(该取代基是氟原子、氯原子、甲基、乙基、甲氧基或乙氧基。);或是(C1-C4烷氧基)羰基化合物、
(8)R2是可有用氟原子或氯原子任意取代的C2-C4烷酰基或(C3-C6环烷基)羰基;苯甲酰基或(C1-C4烷氧基)羰基化合物、
(9)R2是可有用氟原子任意取代的乙酰基、丙酰基、异丁酰基、环丙羰基、环丁羰基、甲氧羰基或乙氧羰基化合物、
(10)R2是丙酰基、环丙羰基、甲氧羰基或乙氧羰基化合物、
(11)R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、3-或4-(-S-X-R4)-1-哌啶基、4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基或8-氮杂-3-(-S-X-R4)-双环〔3.2.1〕辛烷-8-基、
R4是可有任意取代的苯基(该取代基是卤原子、甲基、乙基、甲氧基、乙氧基、硝基或氰基);可有任意取代的直链状的C1-C6烷基[该取代基是氨基、羟基、羧基、(C1-C4烷氧基)羰基、具有通式-NH-A1a的基(式中,A1a表示甘氨酰基、丙氨酰基、β-天冬氨酰基或r-谷氨酰基。)或者具有通式-CO-A2a的基(式中,A2a表示甘氨酸残基、丙氨酸残基、缬氨酸残基、亮氨酸残基、苯基甘氨酸残基、或苯基丙氨酸残基。)];或环丁基、环戊基、环己基或环庚基、
R5及R6相同或不同地表示氢原子、C1-C4烷基、羧基、(C1-C4烷氧基)羰基、氨基甲酰基、(C1-C4烷基)氨基甲酰基或二-(C1-C4烷基)氨基甲酰基、
X是硫原子、磺酰基或亚磺酰基的化合物。
(12)R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基、
R4是可有任意取代的苯基(该取代基是氟原子、氯原子、溴原子、甲基、甲氧基、硝基或氰基);可有任意取代的直链状的C1-C4烷基[该取代基是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1b的基(式中,A1b表示甘氨酰基或r-谷氨酰基。)或者具有通式-CO-A2b的基(式中,A2b表示甘氨酸残基、丙氨酸残基或缬氨酸残基。)];或环戊基或环己基、
R5及R6相同或不同地表示氢原子、甲基、乙基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基、乙基氨基甲酰基、N,N-二甲基氨基甲酰基或N,N-二乙基氨基甲酰基、
X是硫原子、亚磺酰基或磺酰基的化合物。
(13)R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基、4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基、
R4是可有任意取代的苯基(该取代基是氟原子、氯原子、甲基、甲氧基或硝基。);可有任意取代的甲基、乙基或丙基[该取代基是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1c的基(式中,A1c表示r-谷氨酰基。)或具有通式-CO-A2c的基(式中,A2c是谷氨酸残基。)〕或环戊基、环己基、
R5是氢原子、
R6是氢原子、甲基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基或N,N-二甲基氨基甲酰基、
X是硫原子、亚磺酰基或磺酰基的化合物。
(14)R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基、4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基、
R4是可有任意取代的苯基(该取代基是氟原子、氯原子、甲基、甲氧基或硝基。);可有任意取代的甲基、乙基或丙基[该取代基是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1c的基(式中,A1c表示r-谷氨酰基。)或具有通式-CO-A2c的基(式中,A2c是谷氨酸残基。)];或者环戊基或环己基、
R5是氢原子、
R6是羧基、甲氧羰基或乙氧羰基、
X是硫原子或磺酰基化合物。
关于R1的优选顺序是(1)~(3)及(4)~(6)、R2的优选顺序是(7)~(10)、R3的优选顺序是(11)~(14),分别依次理优选。
本发明还涉及药物组合物,其含有治疗有效量的具有上述通式(I)的环胺化合物或其药理上可容许的盐。
作为具有上述通式(I)的环胺化合物或其药理上容许的盐或含有这些的药剂,可举出从(1)~(3)、(4)~(6)、(7)~(10)及(11)~(14)群中选出2~4个、将这些任意组合、作为其组合优选的是,例如,
(15)R1是被取代了的苯基(该取代基是卤原子、甲基、乙基、二氟甲基、三氟甲基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、氰基或硝基。)、
R1的被取代了的苯基的取代基数是1~3、
R2是可有任意取代的C2-C4烷酰基或(C3-C6环烷基)羰基(该取代基是氟原子、氯原子、甲氧基、乙氧基或氰基);可有任意取代的苯甲酰基(该取代基是氟原子、氯原子、甲基、乙基、甲氧基或乙氧基。);或是(C1-C4烷氧基)羰基的化合物、
(16)R1是被取代了的苯基(该取代基是氟原子、氯原子、溴原子、三氟甲基、二氟甲氧基、三氟甲氧基、氰基或硝基。)、
R1的被取代了的苯基的取代基数是1或2、
R2是可有氟原子或氯原子任意取代的C2-C4烷酰基或(C3-C6环烷基)羰基;苯甲酰基;或(C1-C4烷氧基)羰基的化合物、
(17)R1是被取代了的苯基(该取代基是氟原子、氯原子、溴原子、三氟甲基、二氟甲氧基、三氟甲氧基、氰基或硝基。)、
R1的被取代了的苯基的取代基的位置是2位或4位、
R2是可有氟原子或氯原子任意取代的C2-C4烷酰基或(C3-C6环烷基)羰基、苯甲酰基、或(C1-C4烷氧基)羰基;
R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、3-或4-(-S-X-R4)-1-哌啶基、4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基或8-氮杂-3-(-S-X-R4)-双环〔3.2.1〕辛烷-8-基、
R4是可有任意取代的苯基(该取代基是卤原子、甲基、乙基、甲氧基、乙氧基、硝基或氰基);可有任意取代的直链状的C1-C6烷基[该取代基是氨基、羟基、羧基、(C1-C4烷氧基)羰基、具有通式-NH-A1a的基(式中,A1a表示甘氨酰基、丙氨酰基、β-天冬氨酰基或r-谷氨酰基。)或者具有通式-CO-A2a的基(式中,A2a表示甘氨酸残基、丙氨酸残基、缬氨酸残基、亮氨酸残基、苯基甘氨酸残基或苯基丙氨酸残基。)];或环丁基、环戊基、环己基或环庚基、
R5及R6相同或不同地表示氢原子、C1-C4烷基、羧基、(C1-C4烷氧基)羰基、氨基甲酰基、(C1-C4烷基)氨基甲酰基或二-(C1-C4烷基)氨基甲酰基、
X是硫原子、亚磺酰基或磺酰基的化合物。
(18)R1是被取代了的苯基(该取代基是氟原子、氯原子。)、
R1的被取代了苯基的取代基的取代位置是2位或4位、
R2是可有氟原子任意取代的乙酰基、丙酰基、异丁酰基、环丙羰基、环丁羰基、甲氧羰基或乙氧羰基、
R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基、或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基、
R4是可有任意取代的苯基(该取代基是氟原子、氯原子、溴原子、甲基、甲氧基、硝基或氰基);可有任意取代的直链状的C1-C4烷基[该取代基是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1b的基(式中,A1b表示甘氨酰基或r-谷氨酰基。)或者具有通式-CO-A2b的基(式中,A2b表示甘氨酸残基、丙氨酸残基或缬氨酸残基。)];或环戊基或环己基、
R5及R6相同或不同地表示氢原子、甲基、乙基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基、乙基氨基甲酰基、N,N-二甲基氨基甲酰基或N,N-二乙基氨基甲酰基、
X是硫原子、亚磺酰基或磺酰基的化合物。
(19)R1是被取代了的苯基(该取代基是氟原子、氯原子)、
R1的被取代了苯基的取代基的取代位置是2位或4位、
R2是丙酰基、环丙羰基、甲氧羰基或乙氧羰基、
R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基、
R4是可有任意取代的苯基(该取代基是氟原子、氯原子、甲基、甲氧基或硝基。);可有任意取代的甲基、乙基或丙基[该取代基是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1c的基(式中,A1c表示r-谷氨酰基。)或具有通式-CO-A2c的基(式中,A2c是谷氨酸残基。)];或者环戊基或环己基、
R5是氢原子、
R6是氢原子、甲基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基或N,N-二甲基氨基甲酰基、
X是硫原子、亚磺酰基或磺酰基的化合物、
(20)R1是被取代了的苯基(该取代基是氟原子或氯原子)、
R1的被取代了苯基的取代基的取代位置是2位或4位、
R2是丙酰基、环丙羰基、甲氧羰基或乙氧羰基、
R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基、
R4是可有任意取代的苯基(该取代基是氟原子、氯原子、甲基、甲氧基或硝基。);可有任意取代的甲基、乙基或丙基[该取代基是氨基、羟基、羧基、甲氧羰基、乙氧羰基、具有通式-NH-A1c的基(式中,A1c表示r-谷氨酰基。)或具有通式-CO-A2c的基(式中,A2c是谷氨酸残基。)];或者环戊基或环己基、
R5是氢原子、
R6是羧基、甲氧羰基或乙氧羰基、
X是硫原子、或磺酰基的化合物,关于上述的优选顺序是(15)~(20)依次更优选。
作为本发明的代表化合物如以下表所示,但是本发明不受这些化合物的限制。
表中的略号如下。
Ala : 丙氨酰基
Asp : 天冬氨酰基
Bu : 丁基
c-Bu : 环丁基
Et : 乙基
Glu : 谷氨酰基
Gly : 甘氨酸残基
Gly : 甘氨酰基
Hx : 己基
c-Hx : 环己基
Me : 甲基
Ph : 苯基
Pn : 戊基
c-Pn : 环戊基
Pr : 丙基
c-Pr : 环丙基
Prop : 丙酰基
【表1】
示例化合物号 | R<sup>1</sup> | R<sup>2</sup> | -S-X-R<sup>4</sup> |
1-1 | 2-F-Ph | Prop | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-2 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-3 | 2-NO<sub>2</sub>-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-4 | 2-CN-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-5 | 2-CF<sub>3</sub>-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-6 | 2-F-Ph | 2-F-c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-7 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-8 | 4-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-9 | 2,4-diF-Ph | c-BuCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-10 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-11 | 2-F-Ph | EtOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-12 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) |
1-13 | 2-Cl-Ph | c-PrCO | 4-S-SO-(4-Me-Ph) |
1-14 | 2-F-Ph | c-PrCO | 4-S-SO-(4-Me-Ph) |
1-15 | 2-F-Ph | MeOCO | 4-S-SO-(4-Me-Ph) |
1-16 | 2-Cl-Ph | MeOCO | 4-S-SO-(4-Me-Ph) |
1-17 | 2-F-Ph | c-PrCO | 4-S-S-(4-Me-Ph) |
1-18 | 2-Cl-Ph | c-PrCO | 4-S-S-(4-Me-Ph) |
1-19 | 2-F-Ph | MeOCO | 4-S-S-(4-Me-Ph) |
1-20 | 2-Cl-Ph | MeOCO | 4-S-S-(4-Me-Ph) |
1-21 | 2-F-Ph | Prop | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-22 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-23 | 2-NO<sub>2</sub>-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-24 | 2-CN-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-25 | 2-CF<sub>3</sub>-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-26 | 2-F-Ph | 2-F-c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-27 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-28 | 4-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-29 | 2,4-diF-Ph | c-BuCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-30 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-31 | 2-F-Ph | EtOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-32 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-33 | 2-Cl-Ph | c-PrCO | 4-S-SO-(4-Cl-Ph) |
1-34 | 2-F-Ph | c-PrCO | 4-S-SO-(4-Cl-Ph) |
1-35 | 2-F-Ph | MeOCO | 4-S-SO-(4-Cl-Ph) |
1-36 | 2-Cl-Ph | MeOCO | 4-S-SO-(4-Cl-Ph) |
1-37 | 2-F-Ph | c-PrCO | 4-S-S-(4-Cl-Ph) |
1-38 | 2-Cl-Ph | c-PrCO | 4-S-S-(4-Cl-Ph) |
1-39 | 2-F-Ph | MeOCO | 4-S-S-(4-Cl-Ph) |
1-40 | 2-Cl-Ph | MeOCO | 4-S-S-(4-Cl-Ph) |
1-41 | 2-F-Ph | Prop | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-42 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-43 | 2-NO<sub>2</sub>-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-44 | 2-CN-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-45 | 2-CF<sub>3</sub>-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-46 | 2-F-Ph | 2-F-c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-47 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-48 | 4-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-49 | 2,4-diF-Ph | c-BuCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-50 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-51 | 2-F-Ph | EtOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-52 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) |
1-53 | 2-Cl-Ph | c-PrCO | 4-S-SO-(4-F-Ph) |
1-54 | 2-F-Ph | c-PrCO | 4-S-SO-(4-F-Ph) |
1-55 | 2-F-Ph | MeOCO | 4-S-SO-(4-F-Ph) |
1-56 | 2-Cl-Ph | MeOCO | 4-S-SO-(4-F-Ph) |
1-57 | 2-F-Ph | c-PrCO | 4-S-S-(4-F-Ph) |
1-58 | 2-Cl-Ph | c-PrCO | 4-S-S-(4-F-Ph) |
1-59 | 2-F-Ph | MeOCO | 4-S-S-(4-F-Ph) |
1-60 | 2-Cl-Ph | MeOCO | 4-S-S-(4-F-Ph) |
1-61 | 2-F-Ph | Prop | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-62 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-63 | 2-NO<sub>2</sub>-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-64 | 2-CN-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-65 | 2-CF<sub>3</sub>-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-66 | 2-F-Ph | 2-F-c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-67 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-68 | 4-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-69 | 2,4-diF-Ph | c-BuCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-70 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-71 | 2-F-Ph | EtOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-72 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-73 | 2-Cl-Ph | c-PrCO | 4-S-SO-(4-MeO-Ph) |
1-74 | 2-F-Ph | c-PrCO | 4-S-SO-(4-MeO-Ph) |
1-75 | 2-F-Ph | MeOCO | 4-S-SO-(4-MeO-Ph) |
1-76 | 2-Cl-Ph | MeOCO | 4-S-SO-(4-MeO-Ph) |
1-77 | 2-F-Ph | c-PrCO | 4-S-S-(4-MeO-Ph) |
1-78 | 2-Cl-Ph | c-PrCO | 4-S-S-(4-MeO-Ph) |
1-79 | 2-F-Ph | MeOCO | 4-S-S-(4-MeO-Ph) |
1-80 | 2-Cl-Ph | MeOCO | 4-S-S-(4-MeO-Ph) |
1-81 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph |
1-82 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph |
1-83 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph |
1-84 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph |
1-85 | 2-Cl-Ph | c-PrCO | 4-S-SO-Ph |
1-86 | 2-F-Ph | c-PrCO | 4-S-SO-Ph |
1-87 | 2-Cl-Ph | MeOCO | 4-S-SO-Ph |
1-88 | 2-Cl-Ph | c-PrCO | 4-S-S-Ph |
1-89 | 2-F-Ph | c-PrCO | 4-S-S-Ph |
1-90 | 2-Cl-Ph | MeOCO | 4-S-S-Ph |
1-91 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
1-92 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
1-93 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
1-94 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
1-95 | 2-Cl-Ph | c-PrCO | 4-S-SO-(4-NO<sub>2</sub>-Ph) |
1-96 | 2-F-Ph | c-PrCO | 4-S-SO-(4-NO<sub>2</sub>-Ph) |
1-97 | 2-Cl-Ph | MeOCO | 4-S-SO-(4-NO<sub>2</sub>-Ph) |
1-98 | 2-Cl-Ph | c-PrCO | 4-S-S-(4-NO<sub>2</sub>-Ph) |
1-99 | 2-F-Ph | c-PrCO | 4-S-S-(4-NO<sub>2</sub>-Ph) |
1-100 | 2-Cl-Ph | MeOCO | 4-S-S-(4-NO<sub>2</sub>-Ph) |
1-101 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
1-102 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
1-103 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
1-104 | 2-Cl-Ph<sup>-</sup> | MeOCO | 4-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
1-105 | 2-Cl-Ph | c-PrCO | 4-S-SO-(2-NO<sub>2</sub>-Ph) |
1-106 | 2-F-Ph | c-PrCO | 4-S-SO-(2-NO<sub>2</sub>-Ph) |
1-107 | 2-Cl-Ph | MeOCO | 4-S-SO-(2-NO<sub>2</sub>-Ph) |
1-108 | 2-Cl-Ph | c-PrCO | 4-S-S-(2-NO<sub>2</sub>-Ph) |
1-109 | 2-F-Ph | c-PrCO | 4-S-S-(2-NO<sub>2</sub>-Ph) |
1-110 | 2-Cl-Ph | MeOCO | 4-S-S-(2-NO<sub>2</sub>-Ph) |
1-111 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(2-Cl-Ph) |
1-112 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(2-Cl-Ph) |
1-113 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(2-Cl-Ph) |
1-114 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(2-Cl-Ph) |
1-115 | 2-Cl-Ph | c-PrCO | 4-S-SO-(2-Cl-Ph) |
1-116 | 2-F-Ph | c-PrCO | 4-S-SO-(2-Cl-Ph) |
1-117 | 2-Cl-Ph | MeOCO | 4-S-SO-(2-Cl-Ph) |
1-118 | 2-Cl-Ph | c-PrCO | 4-S-S-(2-Cl-Ph) |
1-119 | 2-F-Ph | c-PrCO | 4-S-S-(2-Cl-Ph) |
1-120 | 2-Cl-Ph | MeOCO | 4-S-S-(2-Cl-Ph) |
1-121 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(2-F-Ph) |
1-122 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(2-F-Ph) |
1-123 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(2-F-Ph) |
1-124 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(2-F-Ph) |
1-125 | 2-Cl-Ph | c-PrCO | 4-S-SO-(2-F-Ph) |
1-126 | 2-F-Ph | c-PrCO | 4-S-SO-(2-F-Ph) |
1-127 | 2-Cl-Ph | MeOCO | 4-S-SO-(2-F-Ph) |
1-128 | 2-Cl-Ph | c-PrCO | 4-S-S-(2-F-Ph) |
1-129 | 2-F-Ph | c-PrCO | 4-S-S-(2-F-Ph) |
1-130 | 2-Cl-Ph | MeOCO | 4-S-S-(2-F-Ph) |
1-131 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
1-132 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
1-133 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
1-134 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
1-135 | 2-Cl-Ph | c-PrCO | 4-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
1-136 | 2-F-Ph | c-PrCO | 4-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
1-137 | 2-Cl-Ph | MeOCO | 4-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
1-138 | 2-Cl-Ph | c-PrCO | 4-S-S-(2,4-diNO<sub>2</sub>-Ph) |
1-139 | 2-F-Ph | c-PrCO | 4-S-S-(2,4-diNO<sub>2</sub>-Ph) |
1-140 | 2-Cl-Ph | MeOCO | 4-S-S-(2,4-diNO<sub>2</sub>-Ph) |
1-141 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me |
1-142 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me |
1-143 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-Me |
1-144 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Me |
1-145 | 2-Cl-Ph | c-PrCO | 4-S-SO-Me |
1-146 | 2-F-Ph | c-PrCO | 4-S-SO-Me |
1-147 | 2-Cl-Ph | MeOCO | 4-S-SO-Me |
1-148 | 2-Cl-Ph | c-PrCO | 4-S-S-Me |
1-149 | 2-F-Ph | c-PrCO | 4-S-S-Me |
1-150 | 2-Cl-Ph | MeOCO | 4-S-S-Me |
1-151 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Et |
1-152 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Et |
1-153 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-Et |
1-154 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Et |
1-155 | 2-Cl-Ph | c-PrCO | 4-S-SO-Et |
1-156 | 2-F-Ph | c-PrCO | 4-S-SO-Et |
1-157 | 2-Cl-Ph | MeOCO | 4-S-SO-Et |
1-158 | 2-Cl-Ph | c-PrCO | 4-S-S-Et |
1-159 | 2-F-Ph | c-PrCO | 4-S-S-Et |
1-160 | 2-Cl-Ph | MeOCO | 4-S-S-Et |
1-161 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Pr |
1-162 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Pr |
1-163 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-Pr |
1-164 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Pr |
1-165 | 2-Cl-Ph | c-PrCO | 4-S-SO-Pr |
1-166 | 2-F-Ph | c-PrCO | 4-S-SO-Pr |
1-167 | 2-Cl-Ph | MeOCO | 4-S-SO-Pr |
1-168 | 2-Cl-Ph | c-PrCO | 4-S-S-Pr |
1-169 | 2-F-Ph | c-PrCO | 4-S-S-Pr |
1-170 | 2-Cl-Ph | MeOCO | 4-S-S-Pr |
1-171 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Bu |
1-172 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Bu |
1-173 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-Bu |
1-174 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Bu |
1-175 | 2-Cl-Ph | c-PrCO | 4-S-SO-Bu |
1-176 | 2-F-Ph | c-PrCO | 4-S-SO-Bu |
1-177 | 2-Cl-Ph | MeOCO | 4-S-SO-Bu |
1-178 | 2-Cl-Ph | c-PrCO | 4-S-S-Bu |
1-179 | 2-F-Ph | c-PrCO | 4-S-S-Bu |
1-180 | 2-Cl-Ph | MeOCO | 4-S-S-Bu |
1-181 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Pn |
1-182 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Pn |
1-183 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-c-Pn |
1-184 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-c-Pn |
1-185 | 2-Cl-Ph | c-PrCO | 4-S-SO-c-Pn |
1-186 | 2-F-Ph | c-PrCO | 4-S-SO-c-Pn |
1-187 | 2-Cl-Ph | MeOCO | 4-S-SO-c-Pn |
1-188 | 2-Cl-Ph | c-PrCO | 4-S-S-c-Pn |
1-189 | 2-F-Ph | c-PrCO | 4-S-S-c-Pn |
1-190 | 2-Cl-Ph | MeOCO | 4-S-S-c-Pn |
1-191 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Hx |
1-192 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Hx |
1-193 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-c-Hx |
1-194 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-c-Hx |
1-195 | 2-Cl-Ph | c-PrCO | 4-S-SO-c-Hx |
1-196 | 2-F-Ph | c-PrCO | 4-S-SO-c-Hx |
1-197 | 2-Cl-Ph | MeOCO | 4-S-SO-c-Hx |
1-198 | 2-Cl-Ph | c-PrCO | 4-S-S-c-Hx |
1-199 | 2-F-Ph | c-PrCO | 4-S-S-c-Hx |
1-200 | 2-Cl-Ph | MeOCO | 4-S-S-c-Hx |
1-201 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
1-202 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>COOEt |
1-203 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
1-204 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>COOEt |
1-205 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
1-206 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
1-207 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
1-208 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
1-209 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
1-210 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
1-211 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
1-212 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
1-213 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
1-214 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
1-215 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
1-216 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
1-217 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
1-218 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
1-219 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
1-220 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
1-221 | 2-Cl-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
1-222 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
1-223 | 2-F-Ph | MeOCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
1-224 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
1-225 | 2-Cl-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
1-226 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
1-227 | 2-F-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
1-228 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
1-229 | 2-Cl-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
1-230 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
1-231 | 2-F-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
1-232 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
1-233 | 2-Cl-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-234 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-235 | 2-F-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-236 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-237 | 2-Cl-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-238 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-239 | 2-F-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-240 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-241 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
1-242 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
1-243 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
1-244 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
1-245 | 2-F-Ph | c-PrCO | 3-S-SO-(4-Me-Ph) |
1-246 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-Me-Ph) |
1-247 | 2-F-Ph | c-PrCO | 3-S-S-(4-Me-Ph) |
1-248 | 2-Cl-Ph | MeOCO | 3-S-S-(4-Me-Ph) |
1-249 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-250 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-251 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-252 | 2-Cl-Ph<sup>-</sup> | MeOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-253 | 2-F-Ph | c-PrCO | 3-S-SO-(4-Cl-Ph) |
1-254 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-Cl-Ph) |
1-255 | 2-F-Ph | c-PrCO | 3-S-S-(4-Cl-Ph) |
1-256 | 2-Cl-Ph | MeOCO | 3-S-S-(4-Cl-Ph) |
1-257 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
1-258 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
1-259 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
1-260 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
1-261 | 2-F-Ph | c-PrCO | 3-S-SO-(4-F-Ph) |
1-262 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-F-Ph) |
1-263 | 2-F-Ph | c-PrCO | 3-S-S-(4-F-Ph) |
1-264 | 2-Cl-Ph | MeOCO | 3-S-S-(4-F-Ph) |
1-265 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-266 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-267 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-268 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-269 | 2-F-Ph | c-PrCO | 3-S-SO-(4-MeO-Ph) |
1-270 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-MeO-Ph) |
1-271 | 2-F-Ph | c-PrCO | 3-S-S-(4-MeO-Ph) |
1-272 | 2-Cl-Ph | MeOCO | 3-S-S-(4-MeO-Ph) |
1-273 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Ph |
1-274 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Ph |
1-275 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Ph |
1-276 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Ph |
1-277 | 2-F-Ph | c-PrCO | 3-S-SO-Ph |
1-278 | 2-Cl-Ph | MeOCO | 3-S-SO-Ph |
1-279 | 2-F-Ph | c-PrCO | 3-S-S-Ph |
1-280 | 2-Cl-Ph | MeOCO | 3-S-S-Ph |
1-281 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
1-282 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
1-283 | 2-F-Ph | c-PrCO | 3-S-SO-(4-NO<sub>2</sub>-Ph) |
1-284 | 2-F-Ph | c-PrCO | 3-S-S-(4-NO<sub>2</sub>-Ph) |
1-285 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
1-286 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
1-287 | 2-F-Ph | c-PrCO | 3-S-SO-(2-NO<sub>2</sub>-Ph) |
1-288 | 2-F-Ph | c-PrCO | 3-S-S-(2-NO<sub>2</sub>-Ph) |
1-289 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
1-290 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
1-291 | 2-F-Ph | c-PrCO | 3-S-SO-(2-Cl-Ph) |
1-292 | 2-F-Ph | c-PrCO | 3-S-S-(2-Cl-Ph) |
1-293 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
1-294 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
1-295 | 2-F-Ph | c-PrCO | 3-S-SO-(2-F-Ph) |
1-296 | 2-F-Ph | c-PrCO | 3-S-S-(2-F-Ph) |
1-297 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
1-298 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
1-299 | 2-F-Ph | c-PrCO | 3-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
1-300 | 2-F-Ph | c-PrCO | 3-S-S-(2,4-diNO<sub>2</sub>-Ph) |
1-301 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Me |
1-302 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Me |
1-303 | 2-F-Ph | c-PrCO | 3-S-SO-Me |
1-304 | 2-F-Ph | c-PrCO | 3-S-S-Me |
1-305 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Et |
1-306 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Et |
1-307 | 2-F-Ph | c-PrCO | 3-S-SO-Et |
1-308 | 2-F-Ph | c-PrCO | 3-S-S-Et |
1-309 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Pr |
1-310 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Pr |
1-311 | 2-F-Ph | c-PrCO | 3-S-S-Pr |
1-312 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Bu |
1-313 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Bu |
1-314 | 2-F-Ph | c-PrCO | 3-S-S-Bu |
1-315 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Pn |
1-316 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Pn |
1-317 | 2-F-Ph | c-PrCO | 3-S-S-c-Pn |
1-318 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Hx |
1-319 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Hx |
1-320 | 2-F-Ph | c-PrCO | 3-S-S-c-Hx |
1-321 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
1-322 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>COOEt |
1-323 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
1-324 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>COOEt |
1-325 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
1-326 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
1-327 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
1-328 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
1-329 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
1-330 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
1-331 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
1-332 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
1-333 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
1-334 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
1-335 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
1-336 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
1-337 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
1-338 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
1-339 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
1-340 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
1-341 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
1-342 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
1-343 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
1-344 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
1-345 | 2-Cl-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
1-346 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
1-347 | 2-F-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
1-348 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
1-349 | 2-Cl-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
1-350 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
1-351 | 2-F-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
1-352 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
1-353 | 2-Cl-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-354 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-355 | 2-F-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-356 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-357 | 2-Cl-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-358 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-359 | 2-F-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-360 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-361 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
1-362 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
1-363 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
1-364 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
1-365 | 2-F-Ph | c-PrCO | 2-S-SO-(4-Me-Ph) |
1-366 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-Me-Ph) |
1-367 | 2-F-Ph | c-PrCO | 2-S-S-(4-Me-Ph) |
1-368 | 2-Cl-Ph | MeOCO | 2-S-S-(4-Me-Ph) |
1-369 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-370 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-371 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-372 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
1-373 | 2-F-Ph | c-PrCO | 2-S-SO-(4-Cl-Ph) |
1-374 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-Cl-Ph) |
1-375 | 2-F-Ph | c-PrCO | 2-S-S-(4-Cl-Ph) |
1-376 | 2-Cl-Ph | MeOCO | 2-S-S-(4-Cl-Ph) |
1-377 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
1-378 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
1-379 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
1-380 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
1-381 | 2-F-Ph | c-PrCO | 2-S-SO-(4-F-Ph) |
1-382 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-F-Ph) |
1-383 | 2-F-Ph | c-PrCO | 2-S-S-(4-F-Ph) |
1-384 | 2-Cl-Ph | MeOCO | 2-S-S-(4-F-Ph) |
1-385 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-386 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-387 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-388 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
1-389 | 2-F-Ph | c-PrCO | 2-S-SO-(4-MeO-Ph) |
1-390 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-MeO-Ph) |
1-391 | 2-F-Ph | c-PrCO | 2-S-S-(4-MeO-Ph) |
1-392 | 2-Cl-Ph | MeOCO | 2-S-S-(4-MeO-Ph) |
1-393 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Ph |
1-394 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Ph |
1-395 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-Ph |
1-396 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Ph |
1-397 | 2-F-Ph | c-PrCO | 2-S-SO-Ph |
1-398 | 2-Cl-Ph | MeOCO | 2-S-SO-Ph |
1-399 | 2-F-Ph | c-PrCO | 2-S-S-Ph |
1-400 | 2-Cl-Ph<sup>-</sup> | MeOCO | 2-S-S-Ph |
1-401 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
1-402 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
1-403 | 2-F-Ph | c-PrCO | 2-S-SO-(4-NO<sub>2</sub>-Ph) |
1-404 | 2-F-Ph | c-PrCO | 2-S-S-(4-NO<sub>2</sub>-Ph) |
1-405 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
1-406 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
1-407 | 2-F-Ph | c-PrCO | 2-S-SO-(2-NO<sub>2</sub>-Ph) |
1-408 | 2-F-Ph | c-PrCO | 2-S-S-(2-NO<sub>2</sub>-Ph) |
1-409 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-Cl-Ph) |
1-410 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-Cl-Ph) |
1-411 | 2-F-Ph | c-PrCO | 2-S-SO-(2-Cl-Ph) |
1-412 | 2-F-Ph | c-PrCO | 2-S-S-(2-Cl-Ph) |
1-413 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-F-Ph) |
1-414 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-F-Ph) |
1-415 | 2-F-Ph | c-PrCO | 2-S-SO-(2-F-Ph) |
1-416 | 2-F-Ph | c-PrCO | 2-S-S-(2-F-Ph) |
1-417 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
1-418 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
1-419 | 2-F-Ph | c-PrCO | 2-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
1-420 | 2-F-Ph | c-PrCO | 2-S-S-(2,4-diNO<sub>2</sub>-Ph) |
1-421 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Me |
1-422 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Me |
1-423 | 2-F-Ph | c-PrCO | 2-S-SO-Me |
1-424 | 2-F-Ph | c-PrCO | 2-S-S-Me |
1-425 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Et |
1-426 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Et |
1-427 | 2-F-Ph | c-PrCO | 2-S-SO-Et |
1-428 | 2-F-Ph | c-PrCO | 2-S-S-Et |
1-429 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Pr |
1-430 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Pr |
1-431 | 2-F-Ph | c-PrCO | 2-S-S-Pr |
1-432 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Bu |
1-433 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Bu |
1-434 | 2-F-Ph | c-PrCO | 2-S-S-Bu |
1-435 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-c-Pn |
1-436 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-c-Pn |
1-437 | 2-F-Ph | c-PrCO | 2-S-S-c-Pn |
1-438 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-c-Hx |
1-439 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-c-Hx |
1-440 | 2-F-Ph | c-PrCO | 2-S-S-c-Hx |
1-441 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
1-442 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>COOEt |
1-443 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
1-444 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>COOEt |
1-445 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
1-446 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
1-447 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
1-448 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sup>2</sup>COOH |
1-449 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
1-450 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
1-451 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
1-452 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
1-453 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
1-454 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
1-455 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
1-456 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
1-457 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
1-458 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
1-459 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
1-460 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
1-461 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
1-462 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
1-463 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
1-464 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
1-465 | 2-Cl-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
1-466 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
1-467 | 2-F-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
1-468 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
1-469 | 2-Cl-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
1-470 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
1-471 | 2-F-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
1-472 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
1-473 | 2-Cl-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-474 | 2-F-Ph- | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-475 | 2-F-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-476 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
1-477 | 2-Cl-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-478 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-479 | 2-F-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
1-480 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
【表2】
示例化合物号 | R<sup>1</sup> | R<sup>2</sup> | -S-X-R<sup>4</sup> |
2-1 | 2-F-Ph | Prop | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-2 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-3 | 2-NO<sub>2</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-4 | 2-CN-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-5 | 2-CF<sub>3</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-6 | 2-F-Ph | 2-F-c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-7 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-8 | 4-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-9 | 2,4-diF-Ph | c-BuCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-10 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-11 | 2-F-Ph | EtOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-12 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
2-13 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-Me-Ph) |
2-14 | 2-F-Ph | c-PrCO | 3-S-SO-(4-Me-Ph) |
2-15 | 2-F-Ph | MeOCO | 3-S-SO-(4-Me-Ph) |
2-16 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-Me-Ph) |
2-17 | 2-F-Ph | c-PrCO | 3-S-S-(4-Me-Ph) |
2-18 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-Me-Ph) |
2-19 | 2-F-Ph | MeOCO | 3-S-S-(4-Me-Ph) |
2-20 | 2-Cl-Ph | MeOCO | 3-S-S-(4-Me-Ph) |
2-21 | 2-F-Ph | Prop | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-22 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-23 | 2-NO<sub>2</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-24 | 2-CN-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-25 | 2-CF<sub>3</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-26 | 2-F-Ph | 2-F-c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-27 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-28 | 4-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-29 | 2,4-diF-Ph | c-BuCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-30 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-31 | 2-F-Ph | EtOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-32 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-33 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-Cl-Ph) |
2-34 | 2-F-Ph | c-PrCO | 3-S-SO-(4-Cl-Ph) |
2-35 | 2-F-Ph | MeOCO | 3-S-SO-(4-Cl-Ph) |
2-36 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-Cl-Ph) |
2-37 | 2-F-Ph | c-PrCO | 3-S-S-(4-Cl-Ph) |
2-38 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-Cl-Ph) |
2-39 | 2-F-Ph | MeOCO | 3-S-S-(4-Cl-Ph) |
2-40 | 2-Cl-Ph | MeOCO | 3-S-S-(4-Cl-Ph) |
2-41 | 2-F-Ph | Prop | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-42 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-43 | 2-NO<sub>2</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-44 | 2-CN-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-45 | 2-CF<sup>3</sup>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-46 | 2-F-Ph | 2-F-c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-47 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-48 | 4-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-49 | 2,4-diF-Ph | c-BuCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-50 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-51 | 2-F-Ph | EtOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-52 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
2-53 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-F-Ph) |
2-54 | 2-F-Ph | c-PrCO | 3-S-SO-(4-F-Ph) |
2-55 | 2-F-Ph | MeOCO | 3-S-SO-(4-F-Ph) |
2-56 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-F-Ph) |
2-57 | 2-F-Ph | c-PrCO | 3-S-S-(4-F-Ph) |
2-58 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-F-Ph) |
2-59 | 2-F-Ph | MeOCO | 3-S-S-(4-F-Ph) |
2-60 | 2-Cl-Ph | MeOCO | 3-S-S-(4-F-Ph) |
2-61 | 2-F-Ph | Prop | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-62 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-63 | 2-NO<sub>2</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-64 | 2-CN-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-65 | 2-CF<sub>3</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-66 | 2-F-Ph | 2-F-c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-67 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-68 | 4-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-69 | 2,4-diF-Ph | c-BuCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-70 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-71 | 2-F-Ph | EtOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-72 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-73 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-MeO-Ph) |
2-74 | 2-F-Ph | c-PrCO | 3-S-SO-(4-MeO-Ph) |
2-75 | 2-F-Ph | MeOCO | 3-S-SO-(4-MeO-Ph) |
2-76 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-MeO-Ph) |
2-77 | 2-F-Ph | c-PrCO | 3-S-S-(4-MeO-Ph) |
2-78 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-MeO-Ph) |
2-79 | 2-F-Ph | MeOCO | 3-S-S-(4-MeO-Ph) |
2-80 | 2-Cl-Ph | MeOCO | 3-S-S-(4-MeO-Ph) |
2-81 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Ph |
2-82 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Ph |
2-83 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Ph |
2-84 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Ph |
2-85 | 2-Cl-Ph | c-PrCO | 3-S-SO-Ph |
2-86 | 2-F-Ph | c-PrCO | 3-S-SO-Ph |
2-87 | 2-Cl-Ph | MeOCO | 3-S-SO-Ph |
2-88 | 2-Cl-Ph | c-PrCO | 3-S-S-Ph |
2-89 | 2-F-Ph | c-PrCO | 3-S-S-Ph |
2-90 | 2-Cl-Ph | MeOCO | 3-S-S-Ph |
2-91 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
2-92 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
2-93 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
2-94 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
2-95 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-NO<sub>2</sub>-Ph) |
2-96 | 2-F-Ph | c-PrCO | 3-S-SO-(4-NO<sub>2</sub>-Ph) |
2-97 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-NO<sub>2</sub>-Ph) |
2-98 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-NO<sub>2</sub>-Ph) |
2-99 | 2-F-Ph | c-PrCO | 3-S-S-(4-NO<sub>2</sub>-Ph) |
2-100 | 2-Cl-Ph | MeOCO | 3-S-S-(4-NO<sub>2</sub>-Ph) |
2-101 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
2-102 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
2-103 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
2-104 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
2-105 | 2-Cl-Ph | c-PrCO | 3-S-SO-(2-NO<sub>2</sub>-Ph) |
2-106 | 2-F-Ph | c-PrCO | 3-S-SO-(2-NO<sub>2</sub>-Ph) |
2-107 | 2-Cl-Ph | MeOCO | 3-S-SO-(2-NO<sub>2</sub>-Ph) |
2-108 | 2-Cl-Ph | c-PrCO | 3-S-S-(2-NO<sub>2</sub>-Ph) |
2-109 | 2-F-Ph | c-PrCO | 3-S-S-(2-NO<sub>2</sub>-Ph) |
2-11O | 2-Cl-Ph | MeOCO | 3-S-S-(2-NO<sub>2</sub>-Ph) |
2-111 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
2-112 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
2-113 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
2-114 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
2-115 | 2-Cl-Ph | c-PrCO | 3-S-SO-(2-Cl-Ph) |
2-116 | 2-F-Ph | c-PrCO | 3-S-SO-(2-Cl-Ph) |
2-117 | 2-Cl-Ph | MeOCO | 3-S-SO-(2-Cl-Ph) |
2-118 | 2-Cl-Ph | c-PrCO | 3-S-S-(2-Cl-Ph) |
2-119 | 2-F-Ph | c-PrCO | 3-S-S-(2-Cl-Ph) |
2-120 | 2-Cl-Ph | MeOCO | 3-S-S-(2-Cl-Ph) |
2-121 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
2-122 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
2-123 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
2-124 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
2-125 | 2-Cl-Ph | c-PrCO | 3-S-SO-(2-F-Ph) |
2-126 | 2-F-Ph | c-PrCO | 3-S-SO-(2-F-Ph) |
2-127 | 2-Cl-Ph | MeOCO | 3-S-SO-(2-F-Ph) |
2-128 | 2-Cl-Ph | c-PrCO | 3-S-S-(2-F-Ph) |
2-129 | 2-F-Ph | c-PrCO | 3-S-S-(2-F-Ph) |
2-130 | 2-Cl-Ph | MeOCO | 3-S-S-(2-F-Ph) |
2-131 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
2-132 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
2-133 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
2-134 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
2-135 | 2-Cl-Ph | c-PrCO | 3-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
2-136 | 2-F-Ph | c-PrCO | 3-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
2-137 | 2-Cl-Ph | MeOCO | 3-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
2-138 | 2-Cl-Ph | c-PrCO | 3-S-S-(2,4-diNO<sub>2</sub>-Ph) |
2-139 | 2-F-Ph | c-PrCO | 3-S-S-(2,4-diNO<sub>2</sub>-Ph) |
2-140 | 2-Cl-Ph | MeOCO | 3-S-S-(2,4-diNO<sub>2</sub>-Ph) |
2-141 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Me |
2-142 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Me |
2-143 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Me |
2-144 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Me |
2-145 | 2-Cl-Ph | c-PrCO | 3-S-SO-Me |
2-146 | 2-F-Ph | c-PrCO | 3-S-SO-Me |
2-147 | 2-Cl-Ph | MeOCO | 3-S-SO-Me |
2-148 | 2-Cl-Ph | c-PrCO | 3-S-S-Me |
2-149 | 2-F-Ph | c-PrCO | 3-S-S-Me |
2-150 | 2-Cl-Ph | MeOCO | 3-S-S-Me |
2-151 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Et |
2-152 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Et |
2-153 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Et |
2-154 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Et |
2-155 | 2-Cl-Ph | c-PrCO | 3-S-SO-Et |
2-156 | 2-F-Ph | c-PrCO | 3-S-SO-Et |
2-157 | 2-Cl-Ph | MeOCO | 3-S-SO-Et |
2-158 | 2-Cl-Ph | c-PrCO | 3-S-S-Et |
2-159 | 2-F-Ph | c-PrCO | 3-S-S-Et |
2-160 | 2-Cl-Ph | MeOCO | 3-S-S-Et |
2-161 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Pr |
2-162 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Pr |
2-163 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Pr |
2-164 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Pr |
2-165 | 2-Cl-Ph | c-PrCO | 3-S-SO-Pr |
2-166 | 2-F-Ph | c-PrCO | 3-S-SO-Pr |
2-167 | 2-Cl-Ph | MeOCO | 3-S-SO-Pr |
2-168 | 2-Cl-Ph | c-PrCO | 3-S-S-Pr |
2-169 | 2-F-Ph | c-PrCO | 3-S-S-Pr |
2-170 | 2-Cl-Ph | MeOCO | 3-S-S-Pr |
2-171 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Bu |
2-172 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Bu |
2-173 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Bu |
2-174 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Bu |
2-175 | 2-Cl-Ph | c-PrCO | 3-S-SO-Bu |
2-176 | 2-F-Ph | c-PrCO | 3-S-SO-Bu |
2-177 | 2-Cl-Ph | MeOCO | 3-S-SO-Bu |
2-178 | 2-Cl-Ph | c-PrCO | 3-S-S-Bu |
2-179 | 2-F-Ph | c-PrCO | 3-S-S-Bu |
2-180 | 2-Cl-Ph | MeOCO | 3-S-S-Bu |
2-181 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Pn |
2-182 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Pn |
2-183 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Pn |
2-184 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Pn |
2-185 | 2-Cl-Ph | c-PrCO | 3-S-SO-c-Pn |
2-186 | 2-F-Ph | c-PrCO | 3-S-SO-c-Pn |
2-187 | 2-Cl-Ph | MeOCO | 3-S-SO-c-Pn |
2-188 | 2-Cl-Ph | c-PrCO | 3-S-S-c-Pn |
2-189 | 2-F-Ph | c-PrCO | 3-S-S-c-Pn |
2-190 | 2-Cl-Ph | MeOCO | 3-S-S-c-Pn |
2-191 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Hx |
2-192 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Hx |
2-193 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Hx |
2-194 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Hx |
2-195 | 2-Cl-Ph | c-PrCO | 3-S-SO-c-Hx |
2-196 | 2-F-Ph | c-PrCO | 3-S-SO-c-Hx |
2-197 | 2-Cl-Ph | MeOCO | 3-S-SO-c-Hx |
2-198 | 2-Cl-Ph | c-PrCO | 3-S-S-c-Hx |
2-199 | 2-F-Ph | c-PrCO | 3-S-S-c-Hx |
2-200 | 2-Cl-Ph | MeOCO | 3-S-S-c-Hx |
2-201 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
2-202 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>COOEt |
2-203 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
2-204 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>COOEt |
2-205 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
2-206 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
2-207 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
2-208 | 2-Cl-Ph<sup>-</sup> | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
2-209 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
2-210 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
2-211 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
2-212 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
2-213 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
2-214 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
2-215 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
2-216 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
2-217 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
2-218 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
2-219 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
2-220 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
2-221 | 2-C1-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
2-222 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
2-223 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
2-224 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
2-225 | 2-Cl-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
2-226 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
2-227 | 2-F-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
2-228 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
2-229 | 2-Cl-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
2-230 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
2-231 | 2-F-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
2-232 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
2-233 | 2-Cl-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
2-234 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
2-235 | 2-F-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
2-236 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
2-237 | 2-Cl-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
2-238 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
2-239 | 2-F-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
2-240 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
2-241 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
2-242 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
2-243 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
2-244 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
2-245 | 2-F-Ph | c-PrCO | 2-S-SO-(4-Me-Ph) |
2-246 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-Me-Ph) |
2-247 | 2-F-Ph | c-PrCO | 2-S-S-(4-Me-Ph) |
2-248 | 2-Cl-Ph | MeOCO | 2-S-S-(4-Me-Ph) |
2-249 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-250 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-251 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-252 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
2-253 | 2-F-Ph | c-PrCO | 2-S-SO-(4-Cl-Ph) |
2-254 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-Cl-Ph) |
2-255 | 2-F-Ph | c-PrCO | 2-S-S-(4-Cl-Ph) |
2-256 | 2-Cl-Ph | MeOCO | 2-S-S-(4-Cl-Ph) |
2-257 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
2-258 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
2-259 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
2-260 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
2-261 | 2-F-Ph | c-PrCO | 2-S-SO-(4-F-Ph) |
2-262 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-F-Ph) |
2-263 | 2-F-Ph | c-PrCO | 2-S-S-(4-F-Ph) |
2-264 | 2-Cl-Ph | MeOCO | 2-S-S-(4-F-Ph) |
2-265 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-266 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-267 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-268 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
2-269 | 2-F-Ph | c-PrCO | 2-S-SO-(4-MeO-Ph) |
2-270 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-MeO-Ph) |
2-271 | 2-F-Ph | c-PrCO | 2-S-S-(4-MeO-Ph) |
2-272 | 2-Cl-Ph | MeOCO | 2-S-S-(4-MeO-Ph) |
2-273 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Ph |
2-274 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Ph |
2-275 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-Ph |
2-276 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Ph |
2-277 | 2-F-Ph | c-PrCO | 2-S-SO-Ph |
2-278 | 2-Cl-Ph | MeOCO | 2-S-SO-Ph |
2-279 | 2-F-Ph | c-PrCO | 2-S-S-Ph |
2-280 | 2-Cl-Ph | MeOCO | 2-S-S-Ph |
2-281 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
2-282 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
2-283 | 2-F-Ph | c-PrCO | 2-S-SO-(4-NO<sub>2</sub>-Ph) |
2-284 | 2-F-Ph | c-PrCO | 2-S-S-(4-NO<sub>2</sub>-Ph) |
2-285 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
2-286 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
2-287 | 2-F-Ph | c-PrCO | 2-S-SO-(2-NO<sub>2</sub>-Ph) |
2-288 | 2-F-Ph | c-PrCO | 2-S-S-(2-NO<sub>2</sub>-Ph) |
2-289 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-Cl-Ph) |
2-290 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-Cl-Ph) |
2-291 | 2-F-Ph | c-PrCO | 2-S-SO-(2-Cl-Ph) |
2-292 | 2-F-Ph | c-PrCO | 2-S-S-(2-Cl-Ph) |
2-293 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-F-Ph) |
2-294 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-F-Ph) |
2-295 | 2-F-Ph | c-PrCO | 2-S-SO-(2-F-Ph) |
2-296 | 2-F-Ph | c-PrCO | 2-S-S-(2-F-Ph) |
2-297 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
2-298 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
2-299 | 2-F-Ph | c-PrCO | 2-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
2-300 | 2-F-Ph | c-PrCO | 2-S-S-(2,4-diNO<sub>2</sub>-Ph) |
2-301 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Me |
2-302 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Me |
2-303 | 2-F-Ph | c-PrCO | 2-S-SO-Me |
2-304 | 2-F-Ph | c-PrCO | 2-S-S-Me |
2-305 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Et |
2-306 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Et |
2-307 | 2-F-Ph | c-PrCO | 2-S-SO-Et |
2-308 | 2-F-Ph | c-PrCO | 2-S-S-Et |
2-309 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Pr |
2-310 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Pr |
2-311 | 2-F-Ph | c-PrCO | 2-S-S-Pr |
2-312 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Bu |
2-313 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Bu |
2-314 | 2-F-Ph | c-PrCO | 2-S-S-Bu |
2-315 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-c-Pn |
2-316 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-c-Pn |
2-317 | 2-F-Ph | c-PrCO | 2-S-S-c-Pn |
2-318 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-c-Hx |
2-319 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-c-Hx |
2-320 | 2-F-Ph | c-PrCO | 2-S-S-c-Hx |
2-321 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
2-322 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>COOEt |
2-323 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
2-324 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>COOEt |
2-325 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
2-326 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
2-327 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
2-328 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
2-329 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
2-330 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
2-331 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
2-332 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
2-333 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
2-334 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
2-335 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
2-336 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
2-337 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
2-338 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
2-339 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
2-340 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
2-341 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
2-342 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
2-343 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
2-344 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
2-345 | 2-Cl-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
2-346 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
2-347 | 2-F-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
2-348 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
2-349 | 2-Cl-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
2-350 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
2-351 | 2-F-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
2-352 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
2-353 | 2-Cl-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
2-354 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
2-355 | 2-F-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
2-356 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
2-357 | 2-Cl-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
2-358 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
2-359 | 2-F-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
2-360 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
【表3】
示例化合物号 | R<sup>1</sup> | R<sup>2</sup> | -S-X-R<sup>4</sup> |
3-1 | 2-F-Ph | Prop | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-2 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-3 | 2-NO<sub>2</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-4 | 2-CN-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-5 | 2-CF<sub>3</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-6 | 2-F-Ph | 2-F-c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-7 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-8 | 4-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-9 | 2,4-diF-Ph | c-BuCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-10 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-11 | 2-F-Ph | EtOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-12 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
3-13 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-Me-Ph) |
3-14 | 2-F-Ph | c-PrCO | 3-S-SO-(4-Me-Ph) |
3-15 | 2-F-Ph | MeOCO | 3-S-SO-(4-Me-Ph) |
3-16 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-Me-Ph) |
3-17 | 2-F-Ph | c-PrCO | 3-S-S-(4-Me-Ph) |
3-18 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-Me-Ph) |
3-19 | 2-F-Ph | MeOCO | 3-S-S-(4-Me-Ph) |
3-20 | 2-Cl-Ph | MeOCO | 3-S-S-(4-Me-Ph) |
3-21 | 2-F-Ph | Prop | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-22 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-23 | 2-NO<sub>2</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-24 | 2-CN-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-25 | 2-CF<sub>3</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-26 | 2-F-Ph | 2-F-c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-27 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-28 | 4-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-29 | 2,4-diF-Ph | c-BuCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-30 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-31 | 2-F-Ph | EtOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-32 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-33 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-Cl-Ph) |
3-34 | 2-F-Ph | c-PrCO | 3-S-SO-(4-Cl-Ph) |
3-35 | 2-F-Ph | MeOCO | 3-S-SO-(4-Cl-Ph) |
3-36 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-Cl-Ph) |
3-37 | 2-F-Ph | c-PrCO | 3-S-S-(4-Cl-Ph) |
3-38 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-Cl-Ph) |
3-39 | 2-F-Ph | MeOCO | 3-S-S-(4-Cl-Ph) |
3-40 | 2-Cl-Ph | MeOCO | 3-S-S-(4-Cl-Ph) |
3-41 | 2-F-Ph | Prop | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-42 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-43 | 2-NO<sub>2</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-44 | 2-CN-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-45 | 2-CF<sub>3</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-46 | 2-F-Ph | 2-F-c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-47 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-48 | 4-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-49 | 2,4-diF-Ph | c-BuCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-50 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-51 | 2-F-Ph | EtOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-52 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
3-53 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-F-Ph) |
3-54 | 2-F-Ph | c-PrCO | 3-S-SO-(4-F-Ph) |
3-55 | 2-F-Ph | MeOCO | 3-S-SO-(4-F-Ph) |
3-56 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-F-Ph) |
3-57 | 2-F-Ph | c-PrCO | 3-S-S-(4-F-Ph) |
3-58 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-F-Ph) |
3-59 | 2-F-Ph | MeOCO | 3-S-S-(4-F-Ph) |
3-60 | 2-Cl-Ph | MeOCO | 3-S-S-(4-F-Ph) |
3-61 | 2-F-Ph | Prop | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-62 | 2-Cl-Ph<sup>-</sup> | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-63 | 2-NO<sub>2</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-64 | 2-CN-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-65 | 2-CF<sub>3</sub>-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-66 | 2-F-Ph | 2-F-c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-67 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-68 | 4-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-69 | 2,4-diF-Ph | c-BuCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-70 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-71 | 2-F-Ph | EtOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-72 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-73 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-MeO-Ph) |
3-74 | 2-F-Ph | c-PrCO | 3-S-SO-(4-MeO-Ph) |
3-75 | 2-F-Ph | MeOCO | 3-S-SO-(4-MeO-Ph) |
3-76 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-MeO-Ph) |
3-77 | 2-F-Ph | c-PrCO | 3-S-S-(4-MeO-Ph) |
3-78 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-MeO-Ph) |
3-79 | 2-F-Ph | MeOCO | 3-S-S-(4-MeO-Ph) |
3-80 | 2-Cl-Ph | MeOCO | 3-S-S-(4-MeO-Ph) |
3-81 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Ph |
3-82 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Ph |
3-83 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Ph |
3-84 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Ph |
3-85 | 2-Cl-Ph | c-PrCO | 3-S-SO-Ph |
3-86 | 2-F-Ph | c-PrCO | 3-S-SO-Ph |
3-87 | 2-Cl-Ph | MeOCO | 3-S-SO-Ph |
3-88 | 2-Cl-Ph | c-PrCO | 3-S-S-Ph |
3-89 | 2-F-Ph | c-PrCO | 3-S-S-Ph |
3-90 | 2-Cl-Ph | MeOCO | 3-S-S-Ph |
3-91 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
3-92 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
3-93 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
3-94 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
3-95 | 2-Cl-Ph | c-PrCO | 3-S-SO-(4-NO<sub>2</sub>-Ph) |
3-96 | 2-F-Ph | c-PrCO | 3-S-SO-(4-NO<sub>2</sub>-Ph) |
3-97 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-NO<sub>2</sub>-Ph) |
3-98 | 2-Cl-Ph | c-PrCO | 3-S-S-(4-NO<sub>2</sub>-Ph) |
3-99 | 2-F-Ph | c-PrCO | 3-S-S-(4-NO<sub>2</sub>-Ph) |
3-100 | 2-Cl-Ph | MeOCO | 3-S-S-(4-NO<sub>2</sub>-Ph) |
3-101 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
3-102 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
3-103 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
3-104 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
3-105 | 2-Cl-Ph | c-PrCO | 3-S-SO-(2-NO<sub>2</sub>-Ph) |
3-106 | 2-F-Ph | c-PrCO | 3-S-SO-(2-NO<sub>2</sub>-Ph) |
3-107 | 2-Cl-Ph | MeOCO | 3-S-SO-(2-NO<sub>2</sub>-Ph) |
3-108 | 2-Cl-Ph | c-PrCO | 3-S-S-(2-NO<sub>2</sub>-Ph) |
3-109 | 2-F-Ph | c-PrCO | 3-S-S-(2-NO<sub>2</sub>-Ph) |
3-110 | 2-Cl-Ph | MeOCO | 3-S-S-(2-NO<sub>2</sub>-Ph) |
3-111 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
3-112 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
3-113 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
3-114 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
3-115 | 2-Cl-Ph | c-PrCO | 3-S-SO-(2-Cl-Ph) |
3-116 | 2-F-Ph | c-PrCO | 3-S-SO-(2-Cl-Ph) |
3-117 | 2-Cl-Ph | MeOCO | 3-S-SO-(2-Cl-Ph) |
3-118 | 2-Cl-Ph | c-PrCO | 3-S-S-(2-Cl-Ph) |
3-119 | 2-F-Ph | c-PrCO | 3-S-S-(2-Cl-Ph) |
3-120 | 2-Cl-Ph | MeOCO | 3-S-S-(2-Cl-Ph) |
3-121 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
3-122 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
3-123 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
3-124 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
3-125 | 2-Cl-Ph | c-PrCO | 3-S-SO-(2-F-Ph) |
3-126 | 2-F-Ph | c-PrCO | 3-S-SO-(2-F-Ph) |
3-127 | 2-Cl-Ph | MeOCO | 3-S-SO-(2-F-Ph) |
3-128 | 2-Cl-Ph | c-PrCO | 3-S-S-(2-F-Ph) |
3-129 | 2-F-Ph | c-PrCO | 3-S-S-(2-F-Ph) |
3-130 | 2-Cl-Ph | MeOCO | 3-S-S-(2-F-Ph) |
3-131 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
3-132 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
3-133 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
3-134 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
3-135 | 2-Cl-Ph | c-PrCO | 3-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
3-136 | 2-F-Ph | c-PrCO | 3-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
3-137 | 2-Cl-Ph | MeOCO | 3-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
3-138 | 2-Cl-Ph | c-PrCO | 3-S-S-(2,4-diNO<sub>2</sub>-Ph) |
3-139 | 2-F-Ph | c-PrCO | 3-S-S-(2,4-diNO<sub>2</sub>-Ph) |
3-140 | 2-Cl-Ph | MeOCO | 3-S-S-(2,4-diNO<sub>2</sub>-Ph) |
3-141 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Me |
3-142 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Me |
3-143 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Me |
3-144 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Me |
3-145 | 2-Cl-Ph | c-PrCO | 3-S-SO-Me |
3-146 | 2-F-Ph | c-PrCO | 3-S-SO-Me |
3-147 | 2-Cl-Ph | MeOCO | 3-S-SO-Me |
3-148 | 2-Cl-Ph | c-PrCO | 3-S-S-Me |
3-149 | 2-F-Ph | c-PrCO | 3-S-S-Me |
3-150 | 2-Cl-Ph | MeOCO | 3-S-S-Me |
3-151 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Et |
3-152 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Et |
3-153 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Et |
3-154 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Et |
3-155 | 2-Cl-Ph | c-PrCO | 3-S-SO-Et |
3-156 | 2-F-Ph | c-PrCO | 3-S-SO-Et |
3-157 | 2-Cl-Ph | MeOCO | 3-S-SO-Et |
3-158 | 2-Cl-Ph | c-PrCO | 3-S-S-Et |
3-159 | 2-F-Ph | c-PrCO | 3-S-S-Et |
3-160 | 2-Cl-Ph | MeOCO | 3-S-S-Et |
3-161 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Pr |
3-162 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Pr |
3-163 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Pr |
3-164 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Pr |
3-165 | 2-Cl-Ph | c-PrCO | 3-S-SO-Pr |
3-166 | 2-F-Ph | c-PrCO | 3-S-SO-Pr |
3-167 | 2-Cl-Ph | MeOCO | 3-S-SO-Pr |
3-168 | 2-Cl-Ph | c-PrCO | 3-S-S-Pr |
3-169 | 2-F-Ph | c-PrCO | 3-S-S-Pr |
3-170 | 2-Cl-Ph | MeOCO | 3-S-S-Pr |
3-171 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Bu |
3-172 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Bu |
3-173 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Bu |
3-174 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Bu |
3-175 | 2-Cl-Ph | c-PrCO | 3-S-SO-Bu |
3-176 | 2-F-Ph | c-PrCO | 3-S-SO-Bu |
3-177 | 2-Cl-Ph | MeOCO | 3-S-SO-Bu |
3-178 | 2-Cl-Ph | c-PrCO | 3-S-S-Bu |
3-179 | 2-F-Ph | c-PrCO | 3-S-S-Bu |
3-180 | 2-Cl-Ph | MeOCO | 3-S-S-Bu |
3-181 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Pn |
3-182 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Pn |
3-183 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Pn |
3-184 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Pn |
3-185 | 2-Cl-Ph | c-PrCO | 3-S-SO-c-Pn |
3-186 | 2-F-Ph | c-PrCO | 3-S-SO-c-Pn |
3-187 | 2-Cl-Ph | MeOCO | 3-S-SO-c-Pn |
3-188 | 2-Cl-Ph | c-PrCO | 3-S-S-c-Pn |
3-189 | 2-F-Ph | c-PrCO | 3-S-S-c-Pn |
3-190 | 2-Cl-Ph | MeOCO | 3-S-S-c-Pn |
3-191 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Hx |
3-192 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Hx |
3-193 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Hx |
3-194 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Hx |
3-195 | 2-Cl-Ph | c-PrCO | 3-S-SO-c-Hx |
3-196 | 2-F-Ph | c-PrCO | 3-S-SO-c-Hx |
3-197 | 2-Cl-Ph | MeOCO | 3-S-SO-c-Hx |
3-198 | 2-Cl-Ph | c-PrCO | 3-S-S-c-Hx |
3-199 | 2-F-Ph | c-PrCO | 3-S-S-c-Hx |
3-200 | 2-Cl-Ph | MeOCO | 3-S-S-c-Hx |
3-201 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
3-202 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>COOEt |
3-203 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
3-204 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>COOEt |
3-205 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
3-206 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
3-207 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
3-208 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
3-209 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
3-210 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
3-211 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
3-212 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
3-213 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
3-214 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
3-215 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
3-216 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
3-217 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
3-218 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
3-219 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
3-220 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
3-221 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
3-222 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
3-223 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
3-224 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
3-225 | 2-Cl-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
3-226 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
3-227 | 2-F-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
3-228 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
3-229 | 2-Cl-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
3-230 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
3-231 | 2-F-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
3-232 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
3-233 | 2-Cl-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
3-234 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
3-235 | 2-F-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
3-236 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
3-237 | 2-Cl-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
3-238 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
3-239 | 2-F-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
3-240 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
3-241 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
3-242 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
3-243 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
3-244 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
3-245 | 2-F-Ph | c-PrCO | 2-S-SO-(4-Me-Ph) |
3-246 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-Me-Ph) |
3-247 | 2-F-Ph | c-PrCO | 2-S-S-(4-Me-Ph) |
3-248 | 2-Cl-Ph | MeOCO | 2-S-S-(4-Me-Ph) |
3-249 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-250 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-251 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-252 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
3-253 | 2-F-Ph | c-PrCO | 2-S-SO-(4-Cl-Ph) |
3-254 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-Cl-Ph) |
3-255 | 2-F-Ph | c-PrCO | 2-S-S-(4-Cl-Ph) |
3-256 | 2-Cl-Ph | MeOCO | 2-S-S-(4-Cl-Ph) |
3-257 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
3-258 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
3-259 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
3-260 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
3-261 | 2-F-Ph | c-PrCO | 2-S-SO-(4-F-Ph) |
3-262 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-F-Ph) |
3-263 | 2-F-Ph | c-PrCO | 2-S-S-(4-F-Ph) |
3-264 | 2-Cl-Ph | MeOCO | 2-S-S-(4-F-Ph) |
3-265 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-266 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-267 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-268 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
3-269 | 2-F-Ph | c-PrCO | 2-S-SO-(4-MeO-Ph) |
3-270 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-MeO-Ph) |
3-271 | 2-F-Ph | c-PrCO | 2-S-S-(4-MeO-Ph) |
3-272 | 2-Cl-Ph | MeOCO | 2-S-S-(4-MeO-Ph) |
3-273 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Ph |
3-274 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Ph |
3-275 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-Ph |
3-276 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Ph |
3-277 | 2-F-Ph | c-PrCO | 2-S-SO-Ph |
3-278 | 2-Cl-Ph | MeOCO | 2-S-SO-Ph |
3-279 | 2-F-Ph | c-PrCO | 2-S-S-Ph |
3-280 | 2-Cl-Ph | MeOCO | 2-S-S-Ph |
3-281 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
3-282 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
3-283 | 2-F-Ph | c-PrCO | 2-S-SO-(4-NO<sub>2</sub>-Ph) |
3-284 | 2-F-Ph | c-PrCO | 2-S-S-(4-NO<sub>2</sub>-Ph) |
3-285 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
3-286 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
3-287 | 2-F-Ph | c-PrCO | 2-S-SO-(2-NO<sub>2</sub>-Ph) |
3-288 | 2-F-Ph | c-PrCO | 2-S-S-(2-NO<sub>2</sub>-Ph) |
3-289 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-Cl-Ph) |
3-290 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-Cl-Ph) |
3-291 | 2-F-Ph | c-PrCO | 2-S-SO-(2-Cl-Ph) |
3-292 | 2-F-Ph | c-PrCO | 2-S-S-(2-Cl-Ph) |
3-293 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-F-Ph) |
3-294 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-F-Ph) |
3-295 | 2-F-Ph | c-PrCO | 2-S-SO-(2-F-Ph) |
3-296 | 2-F-Ph | c-PrCO | 2-S-S-(2-F-Ph) |
3-297 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
3-298 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
3-299 | 2-F-Ph | c-PrCO | 2-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
3-300 | 2-F-Ph | c-PrCO | 2-S-S-(2,4-diNO<sub>2</sub>-Ph) |
3-301 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Me |
3-302 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Me |
3-303 | 2-F-Ph | c-PrCO | 2-S-SO-Me |
3-304 | 2-F-Ph | c-PrCO | 2-S-S-Me |
3-305 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Et |
3-306 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Et |
3-307 | 2-F-Ph | c-PrCO | 2-S-SO-Et |
3-308 | 2-F-Ph | c-PrCO | 2-S-S-Et |
3-309 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Pr |
3-310 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Pr |
3-311 | 2-F-Ph | c-PrCO | 2-S-S-Pr |
3-312 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Bu |
3-313 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Bu |
3-314 | 2-F-Ph | c-PrCO | 2-S-S-Bu |
3-315 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-c-Pn |
3-316 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-c-Pn |
3-317 | 2-F-Ph | c-PrCO | 2-S-S-c-Pn |
3-318 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-c-Hx |
3-319 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-c-Hx |
3-320 | 2-F-Ph | c-PrCO | 2-S-S-c-HX |
3-321 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
3-322 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>COOEt |
3-323 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
3-324 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>COOEt |
3-325 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
3-326 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
3-327 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
3-328 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
3-329 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
3-330 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
3-331 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
3-332 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
3-333 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
3-334 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
3-335 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
3-336 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
3-337 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
3-338 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
3-339 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
3-340 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
3-341 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
3-342 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
3-343 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
3-344 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
3-345 | 2-Cl-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
3-346 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
3-347 | 2-F-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
3-348 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
3-349 | 2-Cl-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
3-350 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
3-351 | 2-F-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
3-352 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
3-353 | 2-Cl-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
3-354 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
3-355 | 2-F-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
3-356 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
3-357 | 2-Cl-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
3-358 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
3-359 | 2-F-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
3-360 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
【表4】
示例化合物号 | R<sup>1</sup> | R<sup>2</sup> | -S-X-R<sup>4</sup> |
4-1 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
4-2 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
4-3 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
4-4 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Me-Ph) |
4-5 | 2-F-Ph | c-PrCO | 2-S-SO-(4-Me-Ph) |
4-6 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-Me-Ph) |
4-7 | 2-F-Ph | c-PrCO | 2-S-S-(4-Me-Ph) |
4-8 | 2-Cl-Ph | MeOCO | 2-S-S-(4-Me-Ph) |
4-9 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-10 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-11 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-12 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-13 | 2-F-Ph | c-PrCO | 2-S-SO-(4-Cl-Ph) |
4-14 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-Cl-Ph) |
4-15 | 2-F-Ph | c-PrCO | 2-S-S-(4-Cl-Ph) |
4-16 | 2-Cl-Ph | MeOCO | 2-S-S-(4-Cl-Ph) |
4-17 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
4-18 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
4-19 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
4-20 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-F-Ph) |
4-21 | 2-F-Ph | c-PrCO | 2-S-SO-(4-F-Ph) |
4-22 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-F-Ph) |
4-23 | 2-F-Ph | c-PrCO | 2-S-S-(4-F-Ph) |
4-24 | 2-Cl-Ph | MeOCO | 2-S-S-(4-F-Ph) |
4-25 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-26 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-27 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-28 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-29 | 2-F-Ph | c-PrCO | 2-S-SO-(4-MeO-Ph) |
4-30 | 2-Cl-Ph | MeOCO | 2-S-SO-(4-MeO-Ph) |
4-31 | 2-F-Ph | c-PrCO | 2-S-S-(4-MeO-Ph) |
4-32 | 2-Cl-Ph | MeOCO | 2-S-S-(4-MeO-Ph) |
4-33 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Ph |
4-34 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Ph |
4-35 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-Ph |
4-36 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Ph |
4-37 | 2-F-Ph | c-PrCO | 2-S-SO-Ph |
4-38 | 2-Cl-Ph | MeOCO | 2-S-SO-Ph |
4-39 | 2-F-Ph | c-PrCO | 2-S-S-Ph |
4-40 | 2-Cl-Ph | MeOCO | 2-S-S-Ph |
4-41 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
4-42 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
4-43 | 2-F-Ph | c-PrCO | 2-S-SO-(4-NO<sub>2</sub>-Ph) |
4-44 | 2-F-Ph | c-PrCO | 2-S-S-(4-NO<sub>2</sub>-Ph) |
4-45 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
4-46 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
4-47 | 2-F-Ph | c-PrCO | 2-S-SO-(2-NO<sub>2</sub>-Ph) |
4-48 | 2-F-Ph | c-PrCO | 2-S-S-(2-NO<sub>2</sub>-Ph) |
4-49 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-Cl-Ph) |
4-50 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-Cl-Ph) |
4-51 | 2-F-Ph | c-PrCO | 2-S-SO-(2-Cl-Ph) |
4-52 | 2-F-Ph | c-PrCO | 2-S-S-(2-Cl-Ph) |
4-53 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2-F-Ph) |
4-54 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2-F-Ph) |
4-55 | 2-F-Ph | c-PrCO | 2-S-SO-(2-F-Ph) |
4-56 | 2-F-Ph | c-PrCO | 2-S-S-(2-F-Ph) |
4-57 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
4-58 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
4-59 | 2-F-Ph | c-PrCO | 2-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
4-60 | 2-F-Ph | c-PrCO | 2-S-S-(2,4-diNO<sub>2</sub>-Ph) |
4-61 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Me |
4-62 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Me |
4-63 | 2-F-Ph | c-PrCO | 2-S-SO-Me |
4-64 | 2-F-Ph | c-PrCO | 2-S-S-Me |
4-65 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Et |
4-66 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Et |
4-67 | 2-F-Ph | c-PrCO | 2-S-SO-Et |
4-68 | 2-F-Ph | c-PrCO | 2-S-S-Et |
4-69 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Pr |
4-70 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Pr |
4-71 | 2-F-Ph | c-PrCO | 2-S-S-Pr |
4-72 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-Bu |
4-73 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-Bu |
4-74 | 2-F-Ph | c-PrCO | 2-S-S-Bu |
4-75 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-c-Pn |
4-76 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-c-Pn |
4-77 | 2-F-Ph | c-PrCO | 2-S-S-c-Pn |
4-78 | 2-F-Ph | c-PrCO | 2-S-SO<sub>2</sub>-c-Hx |
4-79 | 2-Cl-Ph | MeOCO | 2-S-SO<sub>2</sub>-c-Hx |
4-80 | 2-F-Ph | c-PrCO | 2-S-S-c-Hx |
4-81 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
4-82 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>COOEt |
4-83 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
4-84 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>COOEt |
4-85 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
4-86 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
4-87 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
4-88 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
4-89 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
4-90 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
4-91 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
4-92 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
4-93 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
4-94 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
4-95 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
4-96 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
4-97 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
4-98 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
4-99 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
4-100 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
4-101 | 2-Cl-Ph | c-PrCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
4-102 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
4-103 | 2-F-Ph | MeOCO | 2-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
4-104 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
4-105 | 2-Cl-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
4-106 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
4-107 | 2-F-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
4-108 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
4-109 | 2-Cl-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
4-110 | 2-F-Ph | c-PrCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
4-111 | 2-F-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
4-112 | 2-Cl-Ph | MeOCO | 2-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
4-113 | 2-Cl-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-114 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-115 | 2-F-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-116 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-117 | 2-Cl-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-118 | 2-F-Ph | c-PrCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-119 | 2-F-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-120 | 2-Cl-Ph | MeOCO | 2-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-121 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
4-122 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
4-123 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
4-124 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Me-Ph) |
4-125 | 2-F-Ph | c-PrCO | 3-S-SO-(4-Me-Ph) |
4-126 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-Me-Ph) |
4-127 | 2-F-Ph | c-PrCO | 3-S-S-(4-Me-Ph) |
4-128 | 2-Cl-Ph | MeOCO | 3-S-S-(4-Me-Ph) |
4-129 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-130 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-131 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-132 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-133 | 2-F-Ph | c-PrCO | 3-S-SO-(4-Cl-Ph) |
4-134 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-Cl-Ph) |
4-135 | 2-F-Ph | c-PrCO | 3-S-S-(4-Cl-Ph) |
4-136 | 2-Cl-Ph | MeOCO | 3-S-S-(4-Cl-Ph) |
4-137 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
4-138 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
4-139 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
4-140 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-F-Ph) |
4-141 | 2-F-Ph | c-PrCO | 3-S-SO-(4-F-Ph) |
4-142 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-F-Ph) |
4-143 | 2-F-Ph | c-PrCO | 3-S-S-(4-F-Ph) |
4-144 | 2-Cl-Ph | MeOCO | 3-S-S-(4-F-Ph) |
4-145 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-146 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-147 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-148 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-149 | 2-F-Ph | c-PrCO | 3-S-SO-(4-MeO-Ph) |
4-150 | 2-Cl-Ph | MeOCO | 3-S-SO-(4-MeO-Ph) |
4-151 | 2-F-Ph | c-PrCO | 3-S-S-(4-MeO-Ph) |
4-152 | 2-Cl-Ph | MeOCO | 3-S-S-(4-MeO-Ph) |
4-153 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Ph |
4-154 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Ph |
4-155 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-Ph |
4-156 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Ph |
4-157 | 2-F-Ph | c-PrCO | 3-S-SO-Ph |
4-158 | 2-Cl-Ph | MeOCO | 3-S-SO-Ph |
4-159 | 2-F-Ph | c-PrCO | 3-S-S-Ph |
4-160 | 2-Cl-Ph | MeOCO | 3-S-S-Ph |
4-161 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
4-162 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
4-163 | 2-F-Ph | c-PrCO | 3-S-SO-(4-NO<sub>2</sub>-Ph) |
4-164 | 2-F-Ph | c-PrCO | 3-S-S-(4-NO<sub>2</sub>-Ph) |
4-165 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
4-166 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
4-167 | 2-F-Ph | c-PrCO | 3-S-SO-(2-NO<sub>2</sub>-Ph) |
4-168 | 2-F-Ph | c-PrCO | 3-S-S-(2-NO<sub>2</sub>-Ph) |
4-169 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
4-170 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-Cl-Ph) |
4-171 | 2-F-Ph | c-PrCO | 3-S-SO-(2-Cl-Ph) |
4-172 | 2-F-Ph | c-PrCO | 3-S-S-(2-Cl-Ph) |
4-173 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
4-174 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2-F-Ph) |
4-175 | 2-F-Ph | c-PrCO | 3-S-SO-(2-F-Ph) |
4-176 | 2-F-Ph | c-PrCO | 3-S-S-(2-F-Ph) |
4-177 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
4-178 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
4-179 | 2-F-Ph | c-PrCO | 3-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
4-180 | 2-F-Ph | c-PrCO | 3-S-S-(2,4-diNO<sub>2</sub>-Ph) |
4-181 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Me |
4-182 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Me |
4-183 | 2-F-Ph | c-PrCO | 3-S-SO-Me |
4-184 | 2-F-Ph | c-PrCO | 3-S-S-Me |
4-185 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Et |
4-186 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Et |
4-187 | 2-F-Ph | c-PrCO | 3-S-SO-Et |
4-188 | 2-F-Ph | c-PrCO | 3-S-S-Et |
4-189 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Pr |
4-190 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Pr |
4-191 | 2-F-Ph | c-PrCO | 3-S-S-Pr |
4-192 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-Bu |
4-193 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-Bu |
4-194 | 2-F-Ph | c-PrCO | 3-S-S-Bu |
4-195 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Pn |
4-196 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Pn |
4-197 | 2-F-Ph | c-PrCO | 3-S-S-c-Pn |
4-198 | 2-F-Ph | c-PrCO | 3-S-SO<sub>2</sub>-c-Hx |
4-199 | 2-Cl-Ph | MeOCO | 3-S-SO<sub>2</sub>-c-Hx |
4-200 | 2-F-Ph | c-PrCO | 3-S-S-c-Hx |
4-201 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
4-202 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>COOEt |
4-203 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
4-204 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>COOEt |
4-205 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
4-206 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
4-207 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
4-208 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
4-209 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
4-210 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
4-211 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
4-212 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
4-213 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
4-214 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
4-215 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sup>3</sup>COOEt |
4-216 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
4-217 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
4-218 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
4-219 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
4-220 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
4-221 | 2-Cl-Ph | c-PrCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
4-222 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
4-223 | 2-F-Ph | MeOCO | 3-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
4-224 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
4-225 | 2-Cl-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
4-226 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
4-227 | 2-F-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
4-228 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
4-229 | 2-Cl-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
4-230 | 2-F-Ph | c-PrCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
4-231 | 2-F-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
4-232 | 2-Cl-Ph | MeOCO | 3-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
4-233 | 2-Cl-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-234 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-235 | 2-F-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-236 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-237 | 2-Cl-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-238 | 2-F-Ph | c-PrCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-239 | 2-F-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-240 | 2-Cl-Ph | MeOCO | 3-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-241 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-Me-Ph) |
4-242 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-Me-Ph) |
4-243 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-Me-Ph) |
4-244 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-Me-Ph) |
4-245 | 2-F-Ph | c-PrCO | 6-S-SO-(4-Me-Ph) |
4-246 | 2-Cl-Ph | MeOCO | 6-S-SO-(4-Me-Ph) |
4-247 | 2-F-Ph | c-PrCO | 6-S-S-(4-Me-Ph) |
4-248 | 2-Cl-Ph | MeOCO | 6-S-S-(4-Me-Ph) |
4-249 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-250 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-251 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-252 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-Cl-Ph) |
4-253 | 2-F-Ph | c-PrCO | 6-S-SO-(4-Cl-Ph) |
4-254 | 2-Cl-Ph | MeOCO | 6-S-SO-(4-Cl-Ph) |
4-255 | 2-F-Ph | c-PrCO | 6-S-S-(4-Cl-Ph) |
4-256 | 2-Cl-Ph | MeOCO | 6-S-S-(4-Cl-Ph) |
4-257 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-F-Ph) |
4-258 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-F-Ph) |
4-259 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-F-Ph) |
4-260 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-F-Ph) |
4-261 | 2-F-Ph | c-PrCO | 6-S-SO-(4-F-Ph) |
4-262 | 2-Cl-Ph | MeOCO | 6-S-SO-(4-F-Ph) |
4-263 | 2-F-Ph | c-PrCO | 6-S-S-(4-F-Ph) |
4-264 | 2-Cl-Ph | MeOCO | 6-S-S-(4-F-Ph) |
4-265 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-266 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-267 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-268 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-MeO-Ph) |
4-269 | 2-F-Ph | c-PrCO | 6-S-SO-(4-MeO-Ph) |
4-270 | 2-Cl-Ph | MeOCO | 6-S-SO-(4-MeO-Ph) |
4-271 | 2-F-Ph | c-PrCO | 6-S-S-(4-MeO-Ph) |
4-272 | 2-Cl-Ph | MeOCO | 6-S-S-(4-MeO-Ph) |
4-273 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-Ph |
4-274 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-Ph |
4-275 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-Ph |
4-276 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-Ph |
4-277 | 2-F-Ph | c-PrCO | 6-S-SO-Ph |
4-278 | 2-Cl-Ph | MeOCO | 6-S-SO-Ph |
4-279 | 2-F-Ph | c-PrCO | 6-S-S-Ph |
4-280 | 2-Cl-Ph | MeOCO | 6-S-S-Ph |
4-281 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
4-282 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) |
4-283 | 2-F-Ph | c-PrCO | 6-S-SO-(4-NO<sub>2</sub>-Ph) |
4-284 | 2-F-Ph | c-PrCO | 6-S-S-(4-NO<sub>2</sub>-Ph) |
4-285 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
4-286 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(2-NO<sub>2</sub>-Ph) |
4-287 | 2-F-Ph | c-PrCO | 6-S-SO-(2-NO<sub>2</sub>-Ph) |
4-288 | 2-F-Ph | c-PrCO | 6-S-S-(2-NO<sub>2</sub>-Ph) |
4-289 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(2-Cl-Ph) |
4-290 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(2-Cl-Ph) |
4-291 | 2-F-Ph | c-PrCO | 6-S-SO-(2-Cl-Ph) |
4-292 | 2-F-Ph | c-PrCO | 6-S-S-(2-Cl-Ph) |
4-293 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(2-F-Ph) |
4-294 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(2-F-Ph) |
4-295 | 2-F-Ph | c-PrCO | 6-S-SO-(2-F-Ph) |
4-296 | 2-F-Ph | c-PrCO | 6-S-S-(2-F-Ph) |
4-297 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
4-298 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-(2,4-diNO<sub>2</sub>-Ph) |
4-299 | 2-F-Ph | c-PrCO | 6-S-SO-(2,4-diNO<sub>2</sub>-Ph) |
4-300 | 2-F-Ph | c-PrCO | 6-S-S-(2,4-diNO<sub>2</sub>-Ph) |
4-301 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-Me |
4-302 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-Me |
4-303 | 2-F-Ph | c-PrCO | 6-S-SO-Me |
4-304 | 2-F-Ph | c-PrCO | 6-S-S-Me |
4-305 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-Et |
4-306 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-Et |
4-307 | 2-F-Ph | c-PrCO | 6-S-SO-Et |
4-308 | 2-F-Ph | c-PrCO | 6-S-S-Et |
4-309 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-Pr |
4-310 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-Pr |
4-311 | 2-F-Ph | c-PrCO | 6-S-S-Pr |
4-312 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-Bu |
4-313 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-Bu |
4-314 | 2-F-Ph | c-PrCO | 6-S-S-Bu |
4-315 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-c-Pn |
4-316 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-c-Pn |
4-317 | 2-F-Ph | c-PrCO | 6-S-S-c-Pn |
4-318 | 2-F-Ph | c-PrCO | 6-S-SO<sub>2</sub>-c-HX |
4-319 | 2-Cl-Ph | MeOCO | 6-S-SO<sub>2</sub>-c-Hx |
4-320 | 2-F-Ph | c-PrCO | 6-S-S-c-Hx |
4-321 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
4-322 | 2-F-Ph | c-PrCO | 6-S-S-CH<sub>2</sub>COOEt |
4-323 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-CH<sub>2</sub>COOH |
4-324 | 2-Cl-Ph | MeOCO | 6-S-S-CH<sub>2</sub>COOEt |
4-325 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
4-326 | 2-F-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
4-327 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOH |
4-328 | 2-Cl-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>COOH |
4-329 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
4-330 | 2-F-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
4-331 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOMe |
4-332 | 2-Cl-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe |
4-333 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
4-334 | 2-F-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
4-335 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>COOEt |
4-336 | 2-Cl-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>COOEt |
4-337 | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
4-338 | 2-F-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
4-339 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>OH |
4-340 | 2-Cl-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>OH |
4-34l | 2-Cl-Ph | c-PrCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
4-342 | 2-F-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
4-343 | 2-F-Ph | MeOCO | 6-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>3</sub>NH<sub>2</sub> |
4-344 | 2-Cl-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NH<sub>2</sub> |
4-345 | 2-Cl-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
4-346 | 2-F-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
4-347 | 2-F-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGly |
4-348 | 2-Cl-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NHAla |
4-349 | 2-Cl-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
4-350 | 2-F-Ph | c-PrCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
4-351 | 2-F-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NH-β-Asp |
4-352 | 2-Cl-Ph | MeOCO | 6-S-S-(CH<sub>2</sub>)<sub>2</sub>NHGlu |
4-353 | 2-Cl-Ph | c-PrCO | 6-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-354 | 2-F-Ph | c-PrCO | 6-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-355 | 2-F-Ph | MeOCO | 6-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-356 | 2-Cl-Ph | MeOCO | 6-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH |
4-357 | 2-Cl-Ph | c-PrCO | 6-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-358 | 2-F-Ph | c-PrCO | 6-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-359 | 2-F-Ph | MeOCO | 6-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
4-360 | 2-Cl-Ph | MeOCO | 6-S-S-CH<sub>2</sub>CH(NHGlu)COgly |
【表5】
示例化合物号 | R<sup>1</sup> | R<sup>2</sup> | -S-X-R<sup>4</sup> | =CR<sup>5</sup>R<sup>6</sup> |
5-1 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOMe |
5-2 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOMe |
5-3 | 2-F-Ph | c-PrCO | 4-S-S-(4-Me-Ph) | =CHCOOMe |
5-4 | 2-Cl-Ph | MeOCO | 4-S-S-(4-Me-Ph) | =CHCOOMe |
5-5 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOMe |
5-6 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOMe |
5-7 | 2-F-Ph | c-PrCO | 4-S-S-(4-Cl-Ph) | =CHCOOMe |
5-8 | 2-Cl-Ph | MeOCO | 4-S-S-(4-Cl-Ph) | =CHCOOMe |
5-9 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOMe |
5-10 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOMe |
5-11 | 2-F-Ph | c-PrCO | 4-S-S-(4-F-Ph) | =CHCOOMe |
5-12 | 2-Cl-Ph | MeOCO | 4-S-S-(4-F-Ph) | =CHCOOMe |
5-13 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOMe |
5-14 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOMe |
5-15 | 2-F-Ph | c-PrCO | 4-S-S-(4-MeO-Ph) | =CHCOOMe |
5-16 | 2-Cl-Ph | MeOCO | 4-S-S-(4-MeO-Ph) | =CHCOOMe |
5-17 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOMe |
5-18 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOMe |
5-19 | 2-F-Ph | c-PrCO | 4-S-S-Ph | =CHCOOMe |
5-20 | 2-Cl-Ph | MeOCO | 4-S-S-Ph | =CHCOOMe |
5-21 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) | =CHCOOMe |
5-22 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) | =CHCOOMe |
5-23 | 2-F-Ph | c-PrCO | 4-S-S-(4-NO<sub>2</sub>-Ph) | =CHCOOMe |
5-24 | 2-Cl-Ph | MeOCO | 4-S-S-(4-NO<sub>2</sub>-Ph) | =CHCOOMe |
5-25 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me | =CHCOOMe |
5-26 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Me | =CHCOOMe |
5-27 | 2-F-Ph | c-PrCO | 4-S-S-Me | =CHCOOMe |
5-28 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Et | =CHCOOMe |
5-29 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Et | =CHCOOMe |
5-30 | 2-F-Ph | c-PrCO | 4-S-S-Et | =CHCOOMe |
5-31 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Pr | =CHCOOMe |
5-32 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Pr | =CHCOOMe |
5-33 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Pn | =CHCOOMe |
5-34 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Hx | =CHCOOMe |
5-35 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCOOMe |
5-36 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCOOMe |
5-37 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCOOMe |
5-38 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCOOMe |
5-39 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly | =CHCOOMe |
5-40 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly | =CHCOOMe |
5-41 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOEt |
5-42 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOEt |
5-43 | 2-F-Ph | c-PrCO | 4-S-S-(4-Me-Ph) | =CHCOOEt |
5-44 | 2-Cl-Ph | MeOCO | 4-S-S-(4-Me-Ph) | =CHCOOEt |
5-45 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOEt |
5-46 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOEt |
5-47 | 2-F-Ph | c-PrCO | 4-S-S-(4-Cl-Ph) | =CHCOOEt |
5-48 | 2-Cl-Ph | MeOCO | 4-S-S-(4-Cl-Ph) | =CHCOOEt |
5-49 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOEt |
5-50 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOEt |
5-51 | 2-F-Ph | c-PrCO | 4-S-S-(4-F-Ph) | =CHCOOEt |
5-52 | 2-Cl-Ph | MeOCO | 4-S-S-(4-F-Ph) | =CHCOOEt |
5-53 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOEt |
5-54 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOEt |
5-55 | 2-F-Ph | c-PrCO | 4-S-S-(4-MeO-Ph) | =CHCOOEt |
5-56 | 2-Cl-Ph | MeOCO | 4-S-S-(4-MeO-Ph) | =CHCOOEt |
5-57 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOEt |
5-58 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOEt |
5-59 | 2-F-Ph | c-PrCO | 4-S-S-Ph | =CHCOOEt |
5-60 | 2-Cl-Ph | MeOCO | 4-S-S-Ph | =CHCOOEt |
5-61 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) | =CHCOOEt |
5-62 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) | =CHCOOEt |
5-63 | 2-F-Ph | c-PrCO | 4-S-S-(4-NO<sub>2</sub>-Ph) | =CHCOOEt |
5-64 | 2-Cl-Ph | MeOCO | 4-S-S-(4-NO<sub>2</sub>-Ph) | =CHCOOEt |
5-65 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me | =CHCOOEt |
5-66 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Me | =CHCOOEt |
5-67 | 2-F-Ph | c-PrCO | 4-S-S-Me | =CHCOOEt |
5-68 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Et | =CHCOOEt |
5-69 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Et | =CHCOOEt |
5-70 | 2-F-Ph | c-PrCO | 4-S-S-Et | =CHCOOEt |
5-71 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Pr | =CHCOOEt |
5-72 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Pr | =CHCOOEt |
5-73 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Pn | =CHCOOEt |
5-74 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Hx | =CHCOOEt |
5-75 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CHCOOMe | =CHCOOEt |
5-76 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CHCOOMe | =CHCOOEt |
5-77 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCOOEt |
5-78 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCOOEt |
5-79 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly | =CHCOOEt |
5-80 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly | =CHCOOEt |
5-81 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOH |
5-82 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOH |
5-83 | 2-F-Ph | c-PrCO | 4-S-S-(4-Me-Ph) | =CHCOOH |
5-84 | 2-Cl-Ph | MeOCO | 4-S-S-(4-Me-Ph) | =CHCOOH |
5-85 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOH |
5-86 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOH |
5-87 | 2-F-Ph | c-PrCO | 4-S-S-(4-Cl-Ph) | =CHCOOH |
5-88 | 2-Cl-Ph | MeOCO | 4-S-S-(4-Cl-Ph) | =CHCOOH |
5-89 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOH |
5-90 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOH |
5-91 | 2-F-Ph | c-PrCO | 4-S-S-(4-F-Ph) | =CHCOOH |
5-92 | 2-Cl-Ph | MeOCO | 4-S-S-(4-F-Ph) | =CHCOOH |
5-93 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOH |
5-94 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOH |
5-95 | 2-F-Ph | c-PrCO | 4-S-S-(4-MeO-Ph) | =CHCOOH |
5-96 | 2-Cl-Ph | MeOCO | 4-S-S-(4-MeO-Ph) | =CHCOOH |
5-97 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOH |
5-98 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOH |
5-99 | 2-F-Ph | c-PrCO | 4-S-S-Ph | =CHCOOH |
5-100 | 2-Cl-Ph | MeOCO | 4-S-S-Ph | =CHCOOH |
5-101 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) | =CHCOOH |
5-102 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-NO<sub>2</sub>-Ph) | =CHCOOH |
5-103 | 2-F-Ph | c-PrCO | 4-S-S-(4-NO<sub>2</sub>-Ph) | =CHCOOH |
5-104 | 2-Cl-Ph | MeOCO | 4-S-S-(4-NO<sub>2</sub>-Ph) | =CHCOOH |
5-105 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me | =CHCOOH |
5-106 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Me | =CHCOOH |
5-107 | 2-F-Ph | c-PrCO | 4-S-S-Me | =CHCOOH |
5-108 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Et | =CHCOOH |
5-109 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Et | =CHCOOH |
5-110 | 2-F-Ph | c-PrCO | 4-S-S-Et | =CHCOOH |
5-111 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Pr | =CHCOOH |
5-112 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Pr | =CHCOOH |
5-113 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Pn | =CHCOOH |
5-114 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-c-Hx | =CHCOOH |
5-115 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCOOH |
5-116 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCOOH |
5-117 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCOOH |
5-118 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCOOH |
5-119 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly | =CHCOOH |
5-120 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NHGlu)COgly | =CHCOOH |
5-121 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCONH<sub>2</sub> |
5-122 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCONH<sub>2</sub> |
5-123 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCONH<sub>2</sub> |
5-124 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCONH<sub>2</sub> |
5-125 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCONH<sub>2</sub> |
5-126 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me | =CHCONH<sub>2</sub> |
5-127 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCONH<sub>2</sub> |
5-128 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCONH<sub>2</sub> |
5-129 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCONHMe |
5-130 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCONHMe |
5-131 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCONHMe |
5-132 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCONHMe |
5-133 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCONHMe |
5-134 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me | =CHCONHMe |
5-135 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCONHMe |
5-136 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCONHMe |
5-137 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCONHEt |
5-138 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCONHEt |
5-139 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCONHEt |
5-140 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCONHEt |
5-141 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCONHEt |
5-142 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me | =CHCONHEt |
5-143 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCONHEt |
5-144 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCONHEt |
5-145 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCONMe<sub>2</sub> |
5-146 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCONMe<sub>2</sub> |
5-147 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCONMe<sub>2</sub> |
5-148 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCONMe<sub>2</sub> |
5-149 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCONMe<sub>2</sub> |
5-150 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me | =CHCONMe<sub>2</sub> |
5-151 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCONMe<sub>2</sub> |
5-152 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCONMe<sub>2</sub> |
5-153 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHMe |
5-154 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHMe |
5-155 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHMe |
5-156 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHMe |
5-157 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHMe |
5-158 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Me | =CHMe |
5-159 | 2-F-Ph | c-PrCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHMe |
5-160 | 2-F-Ph | c-PrCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHMe |
5-161 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOPr |
5-162 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOPr |
5-163 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOPr |
5-164 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOPr |
5-165 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOPr |
5-166 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOPr |
5-167 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOPr |
5-168 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOPr |
5-169 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOPr |
5-170 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOPr |
5-171 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOBu |
5-172 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCOOBu |
5-173 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOBu |
5-174 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCOOBu |
5-175 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOBu |
5-176 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCOOBu |
5-177 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOBu |
5-178 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCOOBu |
5-179 | 2-F-Ph | c-PrCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOBu |
5-180 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph | =CHCOOBu |
5-181 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCONHMe |
5-182 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCONHMe |
5-183 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCONHMe |
5-184 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCONHMe |
5-185 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph | =CHCONHMe |
5-186 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Me | =CHCONHMe |
5-187 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCONHMe |
5-188 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCONHMe |
5-189 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Me-Ph) | =CHCONMe<sub>2</sub> |
5-190 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-Cl-Ph) | =CHCONMe<sub>2</sub> |
5-191 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(4-F-Ph) | =CHCONMe<sub>2</sub> |
5-192 | 2-Cl-Pb | MeOCO | 4-S-SO<sub>2</sub>-(4-MeO-Ph) | =CHCONMe<sub>2</sub> |
5-193 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-Ph | =CHCONMe<sub>2</sub> |
5-194 | 2-Cl-Pb | MeOCO | 4-S-SO<sub>2</sub>-Me | =CHCONMe<sub>2</sub> |
5-195 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCONMe<sub>2</sub> |
5-196 | 2-Cl-Ph | MeOCO | 4-S-SO<sub>2</sub>-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCONMe<sub>2</sub> |
5-197 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCONHMe |
5-198 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCONHMe |
5-199 | 2-Cl-Ph | MeOCO | 4-S-S-(CH<sub>2</sub>)<sub>2</sub>COOMe | =CHCONMe<sub>2</sub> |
5-200 | 2-Cl-Ph | MeOCO | 4-S-S-CH<sub>2</sub>CH(NH<sub>2</sub>)COOH | =CHCONMe<sub>2</sub> |
上述表中优选的化合物号是1-2、1-6、1-7、1-10、1-12、1-13、1-14、1-16、1-17、1-20、1-22、1-27、1-30、1-32、1-34、1-36、1-37、1-40、1-42、1-47、1-50、1-52、1-54、1-56、1-57、1-60、1-62、1-67、1-70、1-72、1-74、1-76、1-77、1-80、1-81、1-82、1-83、1-84、1-86、1-87、1-89、1-90、1-109、1-110、1-112、1-114、1-122、1-124、1-139、1-140、1-142、1-144、1-145、1-146、1-152、1-1:54、1-182、1-184、1-189、1-192、1-194、1-199、1-202、1-204、1-206、1-210、1-214、1-216、1-222、1-225、1-230、1-234、1-236、1-238、1-242、1-244、1-250、1-252、1-258、1-260、1-266、1-268、1-274、1-276、1-301、1-305、1-315、1-318、1-354、1-356、2-2、2-7、2-10、2-12、2-14、2-16、2-17、2-20、2-22、2-27、2-30、2-32、2-34、2-36、2-37、2-40、2-42、2-47、2-50、2-52、2-54、2-56、2-57、2-60、2-62、2-67、2-70、2-72、2-74、2-76、2-77、2-80、2-82、2-84、2-86、2-89、2-109、2-112、2-114、2-122、2-124、2-139、2-140、2-142、2-144、2-145、2-152、2-154、2-182、2-192、2-202、2-206、2-210、2-214、2-222、2-230、2-234、2-236、2-238、3-7、3-12、3-17、3-20、3-27、3-32、3-37、3-40、3-47、3-52、3-57、3-60、3-67、3-72、3-77、3-80、3-82、3-84、3-86、3-89、3-109、3-122、3-124、3-139、3-142、3-144、3-145、3-152、3-182、3-192、3-202、3-206、3-210、3-214、3-234、3-236、3-238、4-2、4-4、4-10、4-12、4-18、4-20、4-26、4-28、4-34、4-36、4-61、4-65、4-75、4-78、4-114、4-116、5-1、5-2、5-5、5-6、5-9、5-10、5-13、5-14、5-17、5-25、5-35、5-37、5-39、5-41、5-42、5-45、5-46、5-49、5-50、5-53、5-54、5-57、5-65、5-75、5-77、5-79、5-81、5-82、5-85、5-86、5-89、5-90、5-93、5-94、5-97、5-105、5-115、5-117、5-119、5-121、5-125、5-126、5-129、5-133、5-134、5-137、5-141、5-145、5-149、5-150、5-153、5-157、5-158、5-161、5-162、5-169、5-170、5-171、5-172、5-179、5-180、5-181、5-185、5-186、5-189、5-193或5-194
更优选的化合物号是1-2、1-7、1-10、1-12、1-14、1-16、1-17、1-20、1-22、1-27、1-30、1-32、1-34、1-36、1-37、1-40、1-42、1-47、1-50、1-52、1-54、1-56、1-57、1-60、1-62、1-67、1-70、1-72、1-74、1-76、1-77、1-80、1-81、1-82、1-83、1-84、1-86、1-87、1-89、1-90、1-109、1-110、1-122、1-124、1-139、1-140、1-142、1-144、1-145、1-146、1-182、1-189、1-192、1-199、1-202、1-206、1-210、1-214、1-216、1-234、2-7、2-14、2-17、2-20、2-27、2-32、2-37、2-40、2-47、2-52、2-57、2-60、2-67、2-72、2-77、2-80、2-82、2-84、2-86、2-89、2-109、2-122、2-124、2-142、2-144、2-145、2-202、2-206、2-210、2-214、2-234、3-7、3-12、3-17、3-20、3-27、3-32、3-37、3-40、3-47、3-52、3-57、3-60、3-67、3-72、3-77、3-80、3-82、3-84、3-86、3-89、3-109、3-122、3-124、3-142、3-144、3-145、3-202、3-206、3-210、3-214、3-234、5-1、5-2、5-5、5-9、5-13、5-17、5-37、5-41、5-42、5-45、5-49、5-53、5-57、5-65、5-77、5-81、5-82、5-85、5-89、5-93、5-97、5-117、5-121、5-129、5-137、5-145、5-153、5-161、5-162、5-171、5-172、5-181或5-189
最优选的化合物号是1-7、1-10、1-12、1-14、1-17、1-27、1-32、1-34、1-37、1-47、1-52、1-54、1-57、1-67、1-72、1-74、1-77、1-82、1-84、1-86、1-109、1-139、1-142、1-145、1-148、1-189、1-199、1-210、2-7、2-14、2-27、2-32、2-47、2-52、2-67、2-72、2-82、2-142、3-7、3-12、3-27、3-32、3-47、3-52、3-67、3-72、3-82、3-142、5-2、5-5、5-9、5-13、5-17、5-41、5-42、5-45、5-49、5-53、5-57、5-65、5-81、5-82、5-85、5-89、5-93、5-97、5-117、5-129、5-145、5-171、5-172、5-181或5-189
特别合适的化合物可以举出以下的化合物,
示例化合物号1-7:1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯基磺酰硫基)哌啶、
示例化合物号1-10:1-(2-氟-α-甲氧基羰基苄基)-4-(4-甲基苯基磺酰硫基)哌啶、
示例化合物号1-12:1-(2-氯-α-甲氧基羰基苄基)-4-(4-甲基苯基磺酰硫基)哌啶、
示例化合物号1-14:1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯基亚磺酰硫基)哌啶、
示例化合物号1-17:1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯基二硫基(sulfanil))哌啶、
示例化合物号1-27:4-(4-氯苯基磺酰硫基)-1-(α-环丙基羰基-2-氟苄基)哌啶、
示例化合物号1-47:1-(α-环丙基羰基-2-氟苄基)-4-(4-氟苯基磺酰硫基)哌啶、
示例化合物号1-67:1-(α-环丙基羰基-2-氟苄基)-4-(4-甲氧基苯基磺酰硫基)哌啶、
示例化合物号1-82:1-(α-环丙基羰基-2-氟苄基)-4-苯基磺酰硫基哌啶、
示例化合物号1-109:1-(α-环丙基羰基-2-氟苄基)-4-(2-硝基苯基二硫基)哌啶、
示例化合物号1-139:1-(α-环丙基羰基-2-氟苄基)-4-(2,4-二硝基苯基二硫基)哌啶、
示例化合物号1-142:1-(α-环丙基羰基-2-氟苄基)-4-甲基磺酰硫基哌啶、
示例化合物号1-146:1-(α-环丙基羰基-2-氟苄基)-4-甲基亚磺酰硫基哌啶、
示例化合物号1-210:1-(α-环丙基羰基-2-氟苄基)-4-(2-甲氧基羰基乙基二硫基)哌啶、
示例化合物号2-7:1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯基磺酰硫基)吡咯烷、
示例化合物号2-14:1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯基亚磺酰硫基)吡咯烷、
示例化合物号3-7:1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯基磺酰硫基)氮杂环丁烷、
示例化合物号5-2:(E)-1-(2-氯-α-甲氧基羰基苄基)-3-甲氧基羰基亚甲基-4-(4-甲基苯基磺酰硫基)哌啶、
示例化合物号5-41:(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧基羰基亚甲基-4-(4-甲基苯基磺酰硫基)哌啶、
示例化合物号5-42:(E)-1-(2-氯-α-甲氧基羰基苄基)-3-乙氧基羰基亚甲基-4-(4-甲基苯基磺酰硫基)哌啶、或
示例化合物号5-117:(Z)-4-〔(R)-2-氨基-2-羧基乙基二硫基〕-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)哌啶。
具有本发明通式(I)的化合物通过以下的方法制造。
A法
上述式中,R1、R2、R3及R4表示与上述相同的定义。
R3a表示可以稠环、可取代的3-7元环状饱和氨基〔该取代基,作为必须的是羟基,希望的是具有通式=CR5aR6a的基(式中,R5a及R6a,除羧基外,分别表示与R5及R6相同的定义。)。〕、
R3b除了包含在R3a的羟基可以变换成卤原子(合适的是氯原子或溴原子)、可有用卤素任意取代的C1-C4烷磺酰氧基(合适的是甲磺酰氧基)或者是可有任意取代的苯磺酰氧基(该取代基是卤原子、C1-C4烷基、C1-C4烷氧基或硝基,优选的是氯原子、甲基、甲氧基或硝基,特别优选的是对甲基或者对硝基。)之外,其他与R3a具有相同的定义。
R3c除了含在R3a中的羟基可以变换成具有通式-S-COR7的基〔式中,R7表示C1-C4烷基(特别合适的是甲基。)。]之外,其他与R3a具有相同的定义。
R3d除了必须的取代基可以变换成巯基之外,其他与R3具有相同的定义。
R3e表示可以稠环、被取代的3-7元环状饱和氨基〔该取代基,作为必须的是具有通式-S-SO2-R4的基,希望的是具有通式=CR5aR6a的基(式中,R5a及R6a,与上述的具有相同的定义)〕、
M表示碱金属原子(例如可以是锂、钠、钾,优选的是钠或钾)。
A法是制造化合物(I)的方法。
第A1工序是制造具有通式(III)化合物的工序,是通过将具有通式(II)的化合物与卤化剂或者磺酰化剂反应而得到的。
使用的卤化剂,可以是亚硫酰氯、亚硫酰溴类的亚硫酰卤,三氯化磷、三溴化磷类的三卤化磷,五氯化磷、五溴化磷类的五卤化磷,氧氯化磷、氧溴化磷类的氧卤化磷,三苯基膦-四氯化碳、三甲苯基膦-四氯化碳、三苯基膦-四溴化碳类的三(可有用C1-C4烷基任意取代的苯基)膦-四卤化碳,优选的是亚硫酰氯、三氯化磷、三溴化磷、五氯化磷、三苯基膦-四氯化碳、三甲苯基膦-四氯化碳或者三苯基膦-四溴化碳,特别优选的是亚硫酰氯、三苯基膦-四氯化碳或者三苯基膦-四溴化碳。
使用的磺酰化剂,可以是可有用卤素任意取代的C1-C4烷磺酰卤、可有用卤素任意取代的C1-C4烷磺酸酐、可有任意取代的苯磺酰卤,优选的是可有用氟任意取代的C1-C4烷磺酰氯、C1-C4烷磺酰溴、可有用氟任意取代的C1-C4烷磺酸酐、可有任意取代的苯磺酰氯或者可有任意取代的苯磺酰溴,更优选的是C1-C2烷磺酰氯、三氟甲磺酰氯、C1-C2烷磺酸酐、三氟甲磺酸酐、苯磺酰氯、甲苯磺酰氯或硝基苯磺酰溴,特别优选的是甲磺酰氯、三氟甲磺酰氯、苯磺酰氯或者对甲苯磺酰氯。
化合物(II)和卤化剂的反应,是在惰性溶剂的存在下或不存在下进行的(优选的是存在下),所使用的惰性溶剂,只要是与反应无关,就没有特别的限制。例如,可以是己烷、苯、甲苯类的烃类;二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤代烃类;乙醚、四氢呋喃、二_烷类的醚类;丙酮、甲乙酮类的酮类;乙腈类的腈类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、六甲基磷酰胺类的酰胺类;二甲基亚砜类的砜类或者这些的混合溶剂,优选的是醚类或卤化烃类。
反应温度是根据原料化合物(II)、卤化剂及溶剂的种类而不同,通常是-10℃~200℃(优选的是0℃~100℃),反应时间是依反应温度等而不同,为30分钟~24小时(优选的是1小时~12小时)。
化合物(II)和磺酰化剂的反应,是在惰性溶剂中,碱的存在或不存在下进行的(优选的是存在下),所使用的惰性溶剂,与上述化合物(II)和卤化剂反应所使用的相同。
使用的碱,优选的是氢氧化锂、氢氧化钠、氢氧化钾类的碱金属氢氧化物;碳酸锂、碳酸钠、碳酸钾类的碱金属碳酸盐;碳酸氢钠、碳酸氢钾类的碱金属碳酸氢盐;甲醇锂、甲醇纳、乙醇钠、叔丁醇钙类的烷氧基碱金属;三乙胺、三丁胺、乙基二异丙胺、N-甲基吗啉、吡啶、4-二甲基氨基吡啶、甲基吡啶、二甲基吡啶、三甲基吡啶、1,5-二氮杂二环[4.3.0]-5-壬烯、1,8-二氮杂二环[5.4.0]-7-十一碳烯类的有机胺类、更优选的是碱金属碳酸盐或有机胺类,特别优选的是碳酸钠、碳酸钾、三乙胺、三丁胺、乙基二异丙胺、吡啶或二甲基吡啶。在使用液体的有机胺类时,也可兼有溶剂大大过量地使用。
反应温度是根据原料化合物(II)、磺酰化剂及溶剂的种类而不同,但通常是-10℃~100℃(优选的是0℃~50℃),反应时间是依反应温度等而不同,但是为30分钟~24小时(优选的是1小时~10小时)。
反应终了后,本反应的目的化合物,用常法从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
第A2工序是制造具有通式(V)化合物的工序,是通过在惰性溶剂中,将化合物(III)与具有通式(IV)的化合物反应而得到的。
所使用的惰性溶剂,只要是与反应无关,就没有特别的限制。例如,可以是乙醚、四氢呋喃、二_烷类的醚类;丙酮、甲乙酮类的酮类;醋酸乙酯、醋酸丁酯类的酯类;甲醇、乙醇、丙醇、异丙醇、丁醇类的醇类;乙腈类的腈类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、六甲基磷酰胺类的酰胺类;二甲基亚砜类的砜类或者这些的混合溶剂,优选的是醇类、酰胺类或亚砜类。
反应温度是根据原料化合物(III)、原料化合物(IV)及溶剂的种类而不同,但通常是0℃~200℃(优选的是20℃~150℃),反应时间是依反应温度等而不同,但是为30分钟~24小时(优选的是1小时~12小时)。
反应终了后,本反应的目的化合物,用常法从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
第A3工序是制造具有通式(VI)的化合物的工序,
该工序是包括:
反应(a):将包含在R3c中的、具有通式-S-COR7的基(式中,R7表示与上述的具有相同的定义。)变换成巯基的反应和,
根据需要,
反应(b):将含在R3c的烷氧羰基变换成羧基或其他的烷氧羰基的反应及
反应(C):包含基于含在R3c的双键的顺/反体异构化的反应,改变适宜地顺序,而进行的。
反应(a):
将反应(a)的、具有通式-S-COR7的基(式中,R7表示与上述的具有相同的定义。)变换成巯基的反应是使用酸或碱(合适的是酸),以有机合成化学公知的方法将相应的化合物水解或醇解,而进行的。另外,通过适宜选择本水解的反应条件(温度、酸或碱的种类和使用量及溶剂等),也可同时进行反应(a)和后述的反应(b)。
所使用的酸,例如可以是氯化氢、硝酸、盐酸、硫酸类的无机酸、醋酸、三氟乙酸、甲磺酸、对甲苯磺酸类的有机酸,优选的是氯化氢、盐酸、硫酸或三氟乙酸,特别优选的是氯化氢或盐酸。
所使用的碱,例如可以是氢氧化钠、氢氧化钾类的碱金属氢氧化物;碳酸钠、碳酸钾类的碱金属碳酸盐;碳酸氢钠、碳酸氢钾类的碱金属碳酸氢盐、优选的是碱金属氢氧化物(特别是氢氧化钠)。
所使用的惰性溶剂,只要是与反应无关,就没有特别的限制。例如,可以是己烷、苯、甲苯类的烃类;二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤代烃类;乙醚、四氢呋喃、二_烷类的醚类;丙酮、甲乙酮类的酮类;甲醇、乙醇、丙醇、异丙醇、丁醇类的醇类;甲酸、乙酸、丙酸、丁酸类的羧酸类;水或这些混合溶剂,优选的是,在使用酸的水解时,是醇类、羧酸类、水或这些的混合溶剂,在使用碱的水解时,是醇类或水。
反应温度是根据原料化合物(V)、酸、碱及溶剂的种类而不同,但通常是-10℃~70℃(优选的是0℃~50℃),反应时间是依反应温度等而不同,但是为30分钟~20天(优选的是1小时~12天)。
反应终了后,本反应的目的化合物,用常法从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,在反应液是酸性或碱性时,适宜中和,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
反应(b):
将反应(b)的包含在R3c中的烷氧羰基变换成羧基的反应是与将反应(a)的具有通式-S-COR7的基(式中,R7表示与上述的具有相同的定义。)变换成巯基的反应相同地进行。另外,在R3c和R2中都含有烷氧羰基时,通过适宜地选择水解条件或者使用两者烷氧基部分种类不同的化合物(例如,使用R2是甲氧羰基或乙氧羰基,含在R3c的烷氧羰基是叔丁氧羰基的化合物,在酸性条件下进行反应),与R2的烷氧羰基区别,只将含在R3c中的烷氧羰基选择性地变换成羧基。
将含在R3c的烷氧羰基变换成其他的烷氧羰基的反应,可通过使用希望的乙醇作为溶剂,在与上述相同条件下(优选的是酸性条件下,更优选的是氯化氢共存下)反应而容易地进行。
一般,由于反应(b)比反应(a)的反应条件严格,所以在反应(b)的条件下使化合物(V)反应,可使反应(a)和反应(b)同时进行。
反应终了后,本反应的目的化合物,可用常法从反应混合物中取出。在将烷氧羰基变换成羧基的反应中,例如在目的化合物析出时或者通过减压蒸出溶剂析出目的化合物时,将其适宜地过滤或者减压蒸出溶剂后,在残留物中加入酸,调节溶液的pH为酸性后,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。另一方面,在将烷氧羰基变换成其他的烷氧羰基的反应中,例如在存在不溶物时,可通过适宜地过滤,在反应液是酸性或碱性时,适宜地中和,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
反应(C):
将反应(C)中的基于含在R3c中的双键的顺/反体异构化的反应,是通过在惰性溶剂中,在敏化剂存在或不存在下(优选的是不存在下),光照射相应的化合物而进行的。
所使用的光照射的光源是低压水银灯(20W~100W,优选的是32W),敏化剂,例如是二苯甲酮、芴酮或蒽酮。
另外,以促进反应和/或抑制付反应等目的,添加二甲基二硫化物、二乙基二硫化物、二苯基二硫化物类的有机硫化物,也可进行本反应。
所使用的惰性溶剂,只要是与反应无关,就没有特别的限制。例如,可以是乙醚、四氢呋喃、二_烷类的醚类;醋酸乙酯、醋酸丁酯类的酯类;甲醇、乙醇、丙醇、异丙醇、丁醇类的醇类;乙腈类的腈类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、六甲基磷酰胺类的酰胺类;二甲基亚砜类的砜类;水或者这些的混合溶剂,优选的是醇类或腈类或者这些的混合溶剂。
反应温度是根据原料化合物、光源及溶剂的种类而不同,但通常是-20℃~100℃(优选的是0℃~50℃),反应时间是依反应温度等而不同,但是为5分钟~8小时(优选的是10分钟~3小时)。
反应终了后,本反应的目的化合物,用常法从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
第A4工序是制造具有通式(I)的目的化合物的工序,其反应大致如下:
反应(d):将含在R3d中的巯基磺酰化,变换成磺酰硫基的反应;
反应(e):将含在R3d中的巯基亚磺酰化,变换成亚磺酰硫基的反应及
反应(f):将含在R3d中的巯基硫化(sulfenylation),变换成二硫基的反应。
反应(d):
反应(d)的磺酰化反应是将化合物(VI)和具有通式R4SO2Y[式中,R4表示与上述相同定义,Y表示卤原子(优选的是氯或溴原子)。]的化合物,在惰性溶剂中,在碱的存在下或不存在下(优选的是存在下)反应而进行的。
所使用的惰性溶剂,只要是与反应无关,就没有特别的限制。例如,可以是己烷、苯、甲苯类的烃类;二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤代烃类;乙醚、四氢呋喃、二_烷类的醚类;丙酮、甲乙酮类的酮类;乙腈类的腈类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、六甲基磷酰胺类的酰胺类;二甲基亚砜类的砜类或者这些的混合溶剂,优选的是卤化烃类、烃类或醚类。
所使用的碱可以是碳酸锂、碳酸钠、碳酸钾类的碱金属碳酸盐;甲醇锂、甲醇钠、乙醇钠、叔丁醇钾类的烷氧基碱金属;三乙胺、三丁胺、乙基二异丙胺、N-甲基吗啉、吡啶、4-二甲基氨基吡啶、甲基吡啶、二甲基吡啶、三甲基吡啶、1,5-二氮杂二环[4.3.0]-5-壬烯、1,8-二氮杂二环[5.4.0]-7-(十一)碳烯类的有机胺类、优选的是烷氧基碱金属或有机胺类,更优选的是甲醇钠、乙醇钠、三乙胺、三丁胺、乙基二异丙胺、N-甲基吗啉、吡啶,特别优选的是三乙胺、三丁胺或乙基二异丙胺。
化合物R4SO2Y的使用量,通常对于化合物(VI),是当量摩尔~15倍摩尔,优选的是当量摩尔~10倍摩尔。
反应温度是根据化合物R4SO2Y的种类而不同,但通常是-10℃~100℃(优选的是0℃~50℃),反应时间是依反应温度等而不同,但是为30分钟~24小时(优选的是1小时~12小时)。
反应终了后,本反应的目的化合物,用常法从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
反应(e):
反应(e)的亚磺酰化反应是适宜地选择如下的反应方法而进行的,即使化合物(VI)与具有通式R4SO2H[式中,R4表示与上述的具有相同意义。]的化合物或其碱金属盐,在惰性溶剂中,在缩合剂的存在下反应的方法或者使化合物(VI)和具有通式R4SOY[式中,R4及Y表示与上述的具有相同定义。]的化合物,在惰性溶剂中,在碱的存在下反应的方法。
化合物(VI)和化合物R4SO2H的反应,通常使用对于化合物(VI),是当量摩尔~5倍摩尔(优选的是当量摩尔~3倍摩尔)的化合物R4SO2H而进行的,作为缩和剂,优选的是使用二环己基碳化二亚胺或1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺,其使用量,对于化合物R4SO2H是当量摩尔。
所使用的惰性溶剂,只要是与反应无关,就没有特别的限制。例如,可以是二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤代烃类;乙醚、四氢呋喃、二_烷、二甲氧基乙烷、二乙氧基乙烷类的醚类;乙腈类的腈类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、六甲基磷酰胺类的酰胺类;二甲基亚砜类的亚砜类或者这些的混合溶剂,优选的是卤化烃类、醚类或酰胺类。
反应温度通常是-10℃~100℃(优选的是0℃~50℃),反应时间是依反应温度等而不同,但是为30分钟~24小时(优选的是1小时~12小时)。
化合物(VI)和化合物R4SOY的反应,除了使用化合物R4SOY代替上述反应(d)的化合物R4SO2Y之外,其他可在与反应(d)相同条件下进行。
反应终了后,各反应的目的化合物,用常法从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
反应(f):
反应(f)的硫化反应是适宜地选择如下的反应方法而进行的,即使化合物(VI)与具有通式R4SYa[式中,R4表示与上述的具有相同定义、Ya表示卤原子(优选的是氯或溴原子)、烷基磺酰基(优选的是甲基磺酰基)、可有任意取代的苯基磺酰基(优选的是苯基磺酰基或4-甲基苯基磺酰基)或者硝基取代苯硫基(优选的是2,4-二硝基苯硫基、4-硝基苯硫基或2-硝基苯硫基)。]的化合物,在惰性溶剂中,在碱的存在下反应的方法或者使化合物(VI)和具有通式R4SH[式中,R4表示与上述的具有相同定义。]的化合物,在惰性溶剂中,在氧化剂的存在下反应的方法。
化合物(VI)和化合物R4SYa的反应,除了使用化合物R4SYa代替上述反应(d)的化合物R4SO2Y之外,其他可在与反应(d)相同条件下进行。另外,在Ya是硝基取代苯硫基时,在将化合物(VI)一旦变换成银盐后,与化合物R4SYa反应,也可容易进行,反应条件等可按照化学集第813页(1975年)[Chem.Lett.,813(1975).]所述的方法适应选择地进行。
化合物(VI)和化合物R4SH在氧化剂存在下的反应,通常使用过量(优选的是5~20倍摩尔)的化合物R4SH而进行。
所使用的氧化剂,优选的是碘、溴、次氯酸、次溴酸、过氧化氢,特别优选的是碘。氧化剂的使用量,对于(VI),通常是2~10倍摩尔(优选的是5~10摩尔)。
所使用的惰性溶剂,只要是与反应无关,就没有特别的限制。例如,可以是二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤代烃类;乙醚、四氢呋喃、二_烷、二甲氧基乙烷、二乙氧基乙烷类的醚类;甲醇、乙醇、丙醇、异丙醇、丁醇类的醇类;乙腈类的腈类;N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、六甲基磷酰胺类的酰胺类;二甲基亚砜类的亚砜类、水或者这些的混合溶剂,优选的是卤化烃类、醚类、醇类、水或这些的混合溶剂。
反应温度通常是-10℃~100℃(优选的是0℃~50℃),反应时间是依反应温度等而不同,但是为30分钟~24小时(优选的是1小时~12小时)。
另外,为了抑制付反应,也可在碱的共存下进行本反应,作为这些的盐可举出碱金属碳酸盐(优选的是碳酸钠或碳酸钾)或者有机胺类(优选的是三乙胺、三丁胺或乙基二异丙胺)。
反应终了后,各反应的目的化合物,用常法从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
第A5工序,是另一途径制造在化合物(I)中,X是磺酰基的、具有通式(Ia)化合物的方法,是通过在惰性溶剂中,在碱的存在或不存在下(优选的是存在下),将由第A2工序得到的化合物(III)与具有通式(XVII)的化合物反应而得到,除了使用化合物(XVII)代替化合物(IV)之外,其他在与上述第A2工序相同条件下进行。
化合物(I)有存在光学异构体或几何异构体的场合,在该场合时,可使用光学拆分或分离几何异构体的原料化合物,只得到目的化合物所要求的光学异构体或几何异构体。
在制造工序的适宜阶段中,通过通常的光学拆分法或分离法处理光学异构体或几何异构体混合物,也可得到各种异构体。
另外,化合物(1)可通过常法用酸进行处理,变换成药理上容许的盐。例如,在惰性溶剂(优选的是乙醚、四氢呋喃、二_烷类的醚类、甲醇、乙醇类的醇类、二氯甲烷、三氯甲烷类的卤化烃类)中,与相当的酸在室温下反应5分钟~1小时,减压蒸出溶剂而得到。
本发明的原料化合物(II)可按照以下的方法容易地制造。
B法
C法
D法
上述式中,R1、R2、R3a、R5a及R6a表示与上述的具有相同的定义,R8是氨基的保护基,在酸性条件下可除去,R9是氨基的保护基,在还原条件下可除去,Yb表示卤原子(优选的是氯或溴原子),m表示0~3,n表示1~2。
在酸性条件下可除去R8的氨基的保护基,例如可以是三苯甲基或叔丁氧羰基,在还原条件下可除去R9的氨基的保护基,例如可以是与上述的羟基的保护基相同的可有任意取代的苄基或可有任意取代的苄氧羰基,优选的是苄基、对甲氧基苄基、对氯苄基、苄氧羰基、对甲氧基苄氧羰基、对氯苄氧羰基,特别优选的是苄基或对甲氧基苄基。
B法是制造化合物(II)的方法。
第B1工序是制造化合物(II)的工序,是在惰性溶剂中(优选的是N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、六甲基磷酰胺类的酰胺类或二甲基亚砜类的亚砜类),在碱的存在或不存在下(优选的是在碳酸钠、碳酸钾类的碱金属碳酸盐的存在下),在0℃~200℃(优选的是20℃~150℃)下使具有通式(VII)的化合物和具有通式(VIII)的化合物反应1小时~24小时(优选的是2小时~15小时)而进行的。
另外,在化合物(II)中,将在R3a中含有烷氧羰基的化合物,与上述A法第A3工序的反应(b)相同地进行水解,制造羧酸衍生物,接着,使得到的羧酸衍生物与氯代碳酸甲酯、氯代碳酸乙酯、溴代碳酸乙酯、氯代碳酸丙酯、氯代碳酸丁酯、氯代碳酸异丁酯类的卤代碳酸C1-C2烷基酯在三乙胺或者乙基二异丙胺类的碱的存在下进行反应,制造活性酯衍生物,最后,使得到的活性酯衍生物与氨或或者二-C1-C4烷基胺,在惰性溶剂中(优选的是在二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤代烃类)、-10℃~100℃(优选的是10℃~50℃)下,反应1小时~24小时(优选的是2小时~10小时),可以制造相应的酰胺衍生物。
反应终了后,本反应的目的化合物,用常法从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,在反应液是酸性或碱性时,适宜地中和,减压蒸出溶剂或者减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
C法是制造在B法原料化合物(VII)中,具有通式=CR5aR6a取代基的化合物(VIIa)的方法(式中,R5a及R6a与上述的具有相同的定义)。
第C1工序是制造具有通式(X)化合物的工序,是在惰性溶剂中(优选的是二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤代烃类、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、六甲基磷酰胺类的酰胺类或二甲基亚砜类的亚砜类)、在碱的存在或不存在下(优选的是碳酸锂、碳酸钠、碳酸钾类的碱金属碳酸盐或三乙胺或者乙基二异丙胺类的有机胺类的存在下),在0℃~150℃(优选的是20℃~100℃)下,使三苯甲基氯、三苯甲基溴类的三苯甲基卤化物、叔丁基羰基氯、叔丁基羰基溴类的叔丁基羰基卤化物或二碳酸二叔丁酯,与具有通式(IX)的化合物反应1小时~24小时(优选的是2小时~10小时)。
第C2工序是制造具有通式(XII)化合物的工序,是在惰性溶剂中(优选的是苯、甲苯、二甲苯类的芳香族烃类),使二-C1-C4烷基胺或3~6元环胺(优选的是二甲胺、二乙胺、吡咯烷、哌啶或吗啉,特别优选的是吡咯烷、哌啶或吗啉)和化合物(X)一边进行共沸脱水,一边在60~200℃(优选的是80~150℃)下反应30分钟~15小时(优选的是1小时~10小时),制造烯胺衍生物,接着,将具有通式(XI)的化合物,与此烯胺衍生物和在惰性溶剂中(优选的是苯、甲苯、二甲苯类的芳香族烃类),一边进行共沸脱水,一边在60~200℃(优选的是80~150℃)下反应30分钟~10小时(优选的是1小时~5小时)而进行的。
第C3工序是制造具有通式(XIII)化合物的工序,是在惰性溶剂中(优选的是甲醇、乙醇类的醇类),使化合物(XII)和还原剂(优选的是硼氢化钠、氰基硼氢化钠类的硼氢化合物、在0~100℃(优选的是5~50℃)下反应10分钟~6小时(优选的是30分钟~3小时)而进行的。
第C4工序是制造具有通式(VIIa)化合物的工序,通过除去化合物(XIII)的氨基保护基来完成的,本工序中,采用了“有机合成保护基,第2版,第309页,T.W.格林和P.G.M瓦次著,JuhnWiley&Sons,Inc”中所记载的酸(优选的是对甲苯磺酸、三氟乙酸)而进行的。
反应终了后,本反应的各工序的目的化合物,用常法,从反应混合物中取出。例如,在存在不溶物时,可通过适宜地过滤,在反应液是酸性或碱性时,适宜地中和,减压蒸出溶剂或减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
D法是另外途径制造C法的中间体(XII)的方法。
第D1工序是制造具有通式(Xa)化合物的工序,是将化合物(IX)和可有任意取代的苄基卤或可有任意取代的苄氧羰基卤(优选的是氯)进行与上述C法第C1工序相同的反应。
第D2工序是制造具有通式(XIV)化合物的工序,是将化合物(Xa)和二-C1-C4烷基胺或者3~6元环胺(优选的是二甲胺、二乙胺、吡咯烷、哌啶或吗啉,特别优选的是吡咯烷、哌啶或吗啉)进行与C法第2工序的前段相同的反应,制造烯胺衍生物,接着此烯胺衍生物和具有通式(XI)的化合物,在惰性溶剂中(优选的是二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤化烃类)、酸催化剂的存在下(优选的是三氟硼-乙醚络合物、氯化铝、四氯化钛、四氯化锡类的路易斯酸),在-10℃~100℃(优选的是10℃~50℃)下,反应1小时~24小时(优选的是2小时~20小时)而进行的。
第D3工序是制造具有通式(XV)化合物的工序,是通过除去化合物(XIV)的氨基保护基而完成的,本工序中,采用了上述文献“有机合成中的保护基,第2版(Protective Groups in OrganicSynthesis,2nd edition)”中所记载氢还原方法。
第D4工序是制造具有通式(XVI)化合物的工序,是通过除去化合物(XV)的氨基保护基而完成的,本工序进行与上述C法第C1工序相同的反应。
第D5工序是制造具有通式(XII)化合物的工序,通过将化合物(XVI)与上述A法第A1工序相同的磺酰化,接着,将得到的磺酰氧基体,与碱(优选的是三乙胺、N-甲基吗啉、吡啶、4-二甲基氨基吡啶、1,5-二氮杂双环〔4.3.0〕-5-壬烯、1,8-二氮杂双环〔5.4.0〕-7-(十一碳)烯类的有机胺类)在惰性溶剂(优选的是二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷类的卤化烃类)中,在-10℃~100℃(优选的是10℃~50℃)下,反应30分钟~10小时(优选的是1小时~5小时)而进行的。
反应终了后,本反应的各工序的目的化合物,用常法,从反应混合物中取出。在存在不溶物时,可通过适宜地过滤,在反应液是酸性或碱性时,适宜地中和,减压蒸出溶剂或减压蒸出溶剂后,在残留物中加入水,用醋酸乙酯类的水不混合性有机溶剂萃取,用无水硫酸镁等干燥后,蒸出溶剂而得到,必要时,可用常法,例如重结晶、柱色谱等进一步精制。
原料化合物(VIII)是公知的或者用公知的方法来制造的〔例如,特开昭59-27895号公报(EP99802)、特开平6-41139号公报(EP542411)等〕。另外,原料化合物(VII)是公知的或者用公知的方法来制造的〔例如,有机化学杂志,第37卷、第3953页(1972年):J.Org.Chem.,37,3953(1972)等〕。
实施本发明的最佳方案
以下,用实施例、参考例、试验例及制剂例进一步详细地说明本发明,但是本发明的范围不受这些限制。
实施例1
1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号1-7)
(a)将1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶8.0g(28.9mmol)溶解在二氯甲烷50ml中,加入三乙胺2.92g(28.9mmol),进而在冰冷下滴入甲磺酰氯3.31g(28.9mmol)的二氯甲烷10ml的溶液,在室温下搅拌1小时。减压下蒸馏出溶剂,在得到的残渣中加入醋酸乙酯,过滤析出的三乙胺盐酸盐,减压下浓缩滤液,得到粗的1-(α-环丙基羰基-2-氟苄基)-4-甲基磺酰氧基哌啶。向此粗产物中加入二甲基亚砜(DMSO)50ml及硫代醋酸钾19.8g(170mmol),在50℃下搅拌4小时。在反应混合物中加入水,用醋酸乙酯萃取,用无水硫酸钠干燥。减压下蒸馏出溶剂,将得到的残渣加在硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=19/1),得到红褐色油状物。用己烷结晶化,得到4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)哌啶的浅褐色结晶3.6g(收率37%)。
熔点:78-80℃;
NMR谱(CDCl3,δ):0.79-0.87(2H,m),0.98-1.04(2H,m),1.66-1.80(2H,m),1.90-2.00(2H,m),2.16-2.22(2H,m),2.28(3H,s),2.32-2.35(1H,m),2.70-2.78(1H,m),2.80-2.88(1H,m),3.38-3.47(1H,m),4.62(1H,s),7.08-7.38(4H,m);
质谱(CI,m/z):336(M++1);
IR谱(KBr,vmaxcm-1):1689.
(b)将上述(a)得到的4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)哌啶2.00g(5.97mmol)溶解在乙醇50ml中,向此溶液中吹入适当量的氯化氢气。在室温下放置一夜。减压下蒸馏出溶剂,用乙醚使得到的残渣结晶,得到1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐的微褐色结晶1.95g(收率99%)。
熔点:135-140℃;
元素分析值(%):C16 -H20FNOS·HCl·1/4H2O
理论值:C,57.48%H,6.48%N,4.19%,
分析值:C,57.33%H,6.43%N,4.15%;
质谱(CI,m/z):294(M++1).
(c)将(4-甲基苯基)磺酰溴0.92g(3.9mmol)溶解在四氯化碳50ml中,在冰冷下滴入三乙胺0.395g(3.91mmol)。接着,在60分钟内滴入含有上述(b)得到的1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐1.29g(3.91mmol)和三乙胺0.49g(4.85mmol)的四氯化碳悬浮液30ml。冰冷下搅拌2小时后,加入水50ml,用氯仿萃取。有机层用硫酸镁干燥后,减压下蒸馏出溶剂,将得到的残渣加在硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=9/1),得到0.96g的淡黄色油状物。用二异丙基醚结晶化,得到白色固体的标题化合物0.85g(收率49%)。
熔点:63-69℃;
NMR谱(CDCl3,δ):0.70-0.93(2H,m),0.93-1.10(2H,m),1.45-2.38(9H,m),2.44(3H,s),2.57-2.85(2H,m),3.20-3.38(1H,m),4.61(1H,s),7.03-7.43(6H,m),7.78(2H,d,J=8.1Hz);
质谱(CI,m/z):448(M++1);
IR谱(KBr,vmaxcm-1):1701,1326,1142.
实施例2
1-(2-氯-α-甲氧羰基苄基)-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号1-12)
(a)使用1-(2-氯-α-甲氧羰基苄基)-4-羟基哌啶代替1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶,与实施例1(a)相同地进行反应,得到4-乙酰硫基-1-(2-氯-α-甲氧羰基苄基)哌啶的红褐色油状物(收率37%)。
NMR谱(CDCl3,δ):1.60-1.80(2H,m),1.85-2.00(2H,m),2.10-2.25(1H,m),2.30(3H,s),2.32-2.48(1H,m),2.55-2.75(1H,m),2.80-2.90(1H,m),3.40-3.60(1H,m),3.70(3H,s),4.70(1H,s),7.20-7.65(4H,m);
质谱(CI,m/z):342(M++1).
(b)使用由上述(a)得到的4-乙酰硫基-1-(2-氯-α-甲氧羰基苄基)哌啶代替4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)哌啶,与实施例1(b)相同地进行反应,定量地得到1-(2-氯-α-甲氧羰基苄基)-4-巯基哌啶盐酸盐的微褐色结晶。
熔点:134-140℃;
质谱(CI,m/z):300(M++1).
(c)使用由上述(b)得到的1-(2-氯-α-甲氧羰基苄基)-4-巯基哌啶盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,与实施例1(c)相同地进行反应,得到浅黄色油状物的标题化合物(收率62%)。
NMR谱(CDCl3,δ):1.59-1.80(2H,m),1.85-2.00(2H,m),2.22-2.41(2H,m),2.44(3H,s),2.57-2.69(1H,m),2.72-2.85(1H,m),3.28-3.42(1H,m),3.67(3H,s),4.67(1H,s),7.21-7.55(6H,m),7.78-7.82(2H,m);
质谱(CI,m/z):454(M++1);
IR谱(液膜法,vmaxcm-1):1743,1326,1142.
(d)将由上述(c)得到的淡黄色油状物,溶解在脱水乙醚中,在水浴中一边搅拌;一边加入氯化氢的乙醚溶液。过滤析出的结晶,用乙醚、己烷洗涤后减压干燥,得到白色固体的标题化合物盐酸盐。
熔点:100-115℃;
质谱(CI,m/z):454(M++1).
实施例3
1-(2-氟-α-甲氧羰基苄基)-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号1-10)
(a)使用1-(2-氟-α-甲氧羰基苄基)-4-羟基哌啶代替1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶,与实施例1(a)相同地进行反应,得到4-乙酰硫基-1-(2-氟-α-甲氧羰基苄基)哌啶的浅黄色固体(非晶形)(收率45.6%)。
NMR谱(CDCl3,δ):1.65-1.78(2H,m),1.88-1.99(2H,m),2.20-2.33(4H,m),2.39(1H,t,J=9.6Hz),2.75-2.86(2H,m),3.40-3.50(1H,m),3.71(3H,s),4.53(1H,s),7.04-7.49(4H,m);
质谱(CI,m/z):326(M++1).
(b)使用由上述(a)得到的4-乙酰硫基-1-(2-氟-α-甲氧羰基苄基)哌啶代替4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)哌啶,与实施例1(b)相同地进行反应,得到浅黄色固体(非晶形)的1-(2-氟-α-甲氧羰基苄基)-4-巯基哌啶盐酸盐(收率97.1%)。
NMR谱(CDCl3,δ):1.70-2.24(3H,m),2.47-3.13(3.5H,m),3.21-3.36(0.5H,m ),3.38-3.72(2.5H,m),3.83,3.84(计3H,各s),3.92-4.02(0.5H,m),5.21,5.24(计1H,各s),7.20-7.93(4H,m),12.91-13.34(1H,m);
质谱(CI,m/z):284(M++1).
(c)使用由上述(b)得到的1-(2-氟-α-甲氧羰基苄基)-4-巯基哌啶盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,以二氯甲烷作为溶剂,与实施例1(c)相同地进行反应,得到无色油状物的标题化合物(收率38%)。
NMR谱(CDCl3,δ):1.62-1.82(2H,m),1.85-2.04(2H,m),2.20-2.50(2H,m),2.44(3H,s),2.66-2.83(2H,m),3.25-3.38(2H,m),3.25-3.38(1H,m),3.68(3H,s),4.50(1H,s),7.01-7.45(6H,m),7.80(2H,d,J=8.1Hz);
质谱(CI,m/z):438(M++1);
IR谱(液膜法,vmaxcm-1):1747,1326,1142.
(d)使用由上述(c)得到的1-(2-氟-α-甲氧羰基苄基)-4-(4-甲基苯磺酰硫基)哌啶,与实施例2(d)相同地进行反应,得到白色固体的标题化合物的盐酸盐。
熔点:106-109℃;
质谱(CI,m/z):438(M++1).
实施例4
1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯磺酰硫基)吡咯烷(示例化合物号2-7)
(a)使用1-(α-环丙基羰基-2-氟苄基)-3-羟基吡咯烷代替1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶,与实施例1(a)相同地进行反应,得到褐色油状物的3-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)吡咯烷(收率51%)。
NMR谱(CDCl3,δ):0.78-0.85(2H,m),0.97-1.02(2H,m),1.75-1.78(1H,m ),2.09-2.15(1H,m),2.28(3H,s),2.32-3.39(1H,m),2.48-2.61(2H,m),2.72-2.80(1H,m),2.97-3.10(1H,m),3.91-3.97(1H,m),4.63,4.65(计1H,各s),7.06-7.48(4H,m);
质谱(CI,m/z):321(M++1);
IR谱(液膜,vmaxcm-1):1692.
(b)使用由上述(a)得到的3-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)吡咯烷代替4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)哌啶,与实施例1(b)相同地进行反应,得到微褐色固体(非晶形)的1-(α-环丙基羰基-2-氟苄基)-3-巯基吡咯烷盐酸盐(收率74%)。
质谱(CI,m/z):280(M++1);
IR谱(KBr,vmaxcm-1):1710.
(c)使用由上述(b)得到的1-(α-环丙基羰基-2-氟苄基)-3-巯基吡咯烷盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,以二氯甲烷作为溶剂,与实施例1(c)相同地进行反应,得到浅黄色油状物的标题化合物(收率46%)。
NMR谱(CDCl3,δ):0.71-0.88(2H,m),0.92-1.01(2H,m),1.72-1.82(1H,m),1.99-2.09(1H,m),2.25-2.60(6H,m),2.69-2.78(1H,m),2.87-3.07(1H,m),3.70-3.79(1H,m),4.59-4.65(1H,m),7.05-7.39(6H,m),7.75-7.79(2H,m);
质谱(CI,m/z):434(M++1);
IR谱(液膜法,vmaxcm-1):1705,1326,1142.
(d)使用由上述(c)得到的1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯磺酰硫基)吡咯烷,与实施例2(d)相同地进行反应,得到微灰棕色固体的标题化合物的盐酸盐。熔点:98-106℃;
质谱(CI,m/z):434(M++1).
实施例5
1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯磺酰硫基)氮杂环丁烷(示例化合物号3-7)
(a)使用1-(α-环丙基羰基-2-氟苄基)-3-羟基氮杂环丁烷代替1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶,与实施例1(a)相同地进行反应,得到浅黄色结晶的3-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)氮杂环丁烷(收率54%)。
熔点:49-52℃;
NMR谱(CDCl3,δ):0.74-0.87(2H,m),0.94-1.01(2H,m),1.92-1.98(1H,m),2.28(3H,s),3.06-3.19(2H,m),3.62(1H,dd,J=7.3Hz,7.9Hz),3.91(1H,dd,J=7.3Hz,7.9Hz),4.13-4.21(1H,m),4.62(1H,s),7.07-7.42(4H,m);
质谱(CI,m/z):308(M++1);
IR谱(KBr,vmaxcm-1):1695.
(b)使用由上述(a)得到的3-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)氮杂环丁烷代替4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)哌啶,与实施例1(b)相同地进行反应,得到白色固体(非晶形)的1-(α-环丙基羰基-2-氟苄基)-3-巯基氮杂环丁烷盐酸盐(收率83%)。
质谱(CI,m/z):266(M++1);
IR谱(KBr,vmaxcm-1):1709;
元素分析值(%):C14H16FNOS·HCl·1/2H2O
理论值:C,54.10%H,5.84%N,4.51%,
分析值:C,53.95%H,5.68%N,4.45%.
(c)使用由上述(b)得到的1-(α-环丙基羰基-2-氟苄基)-3-巯基氮杂环丁烷盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,以二氯甲烷作为溶剂,与实施例1(c)相同地进行反应,得到浅黄色油状物的标题化合物。
NMR谱(CDCl3,δ):0.70-1.00(4H,m),1.81-1.88(1H,m),2.44(3H,s),3.03-3.14(2H,m),3.46-3.53(1H,m),3.86-3.90(1H,m),3.96-4.03(1H,m),4.59(1H,s),7.07-7.17(2H,m),7.27-7.33(4H,m),7.74-7.77(2H,m);
质谱(CI,m/z):420(M++1);
IR谱(液膜法,vmaxcm-1):1706,1329,1144.
(d)使用由上述(c)得到的1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯磺酰硫基)氮杂环丁烷,与实施例2(d)相同地进行反应,得到白色固体的标题化合物的盐酸盐。
熔点:80-86℃;
质谱(CI,m/z):420(M++1).
实施例6
(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-41)
(a)在无水二氯甲烷50ml中,溶解(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-羟基哌啶3.28g(9.1mmol),在室温下加入四溴化碳6.02g(18.2mmol),接着,一次性地加入三苯基膦2.62g(9.9mmol),在室温下搅拌1小时。浓缩反应液,用硅胶柱色谱(洗脱溶剂:甲苯/醋酸乙酯=19/1)精制,得到浅黄色油状物的(E)-4-溴-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基哌啶2.00g(收率52.1%)。
NMR谱(CDCl3,δ):0.75-0.88(2H,m),0.97-1.11(2H,m),1.22,1.25(计3H,各t,J=6.8Hz,J=7.3Hz),2.05-3.00(6H,m),4.11,4.13(计2H,各q,J=6.8Hz,J=7.3Hz),4.45,4.60(计1H,各d,J=13.6Hz,J=14.1Hz),4.77,4.78(计1H,各s),5.90(1H,s),7.05-7.43(4H,m);
质谱(CI,m/z):424(M++1).
在无水乙醇30ml中加入硫代醋酸钾2.14g(18.7mmol)、由上述得到的(E)-4-溴-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基哌啶1.98g(4.7mmol),在室温下搅拌1小时,进而在50℃下搅拌5小时。过滤反应液,除去析出的盐、浓缩。用硅胶柱色谱(洗脱溶剂:甲苯/醋酸乙酯=19/1)精制,得到浅黄色油状物的(E)-4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基哌啶0.95g(收率48.2%)。
NMR谱(CDCl3,δ):0.78-0.90(2H,m),0.99-1.10(2H,m),1.22,1.25(计3H,各t,J=6.8Hz,J=7.3Hz),1.82-1.94(1H,m),2.13-2.28(2H,m),2.30,2.31(计3H,各s),2.35-2.90(3H,m),3.40(1H,br.s),4.11,4.13(计2H,各q,J=6.8Hz,J=7.3Hz),4.25-4.40(1H,m),4.75,4.77(计1H,各s),5.93(1H,s),7.08-7.38(4H,m);
质谱(CI,m/z):420(M-+1),350.
(b)使用由上述(a)得到的(E)-4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基哌啶0.57g(1.3mmol),与实施例1(b)相同地进行反应,得到浅黄白色结晶的(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-巯基哌啶盐酸盐0.52g(收率92%)。
熔点:120-125℃;
NMR谱(CDCl3,δ):0.80-0.93(1H,m),0.94-1.06(1H,m),1.23(3H,t,J=7.3Hz),1.70-2.20(5H,m),2.80-3.06,3.11-3.39(计1H,各m),3.45-3.80(1H,m),3.90-4.25(2H,m),4.20(2H,q,J=7.3Hz),4.58,5.05(计1H,各m),5.49(1H,s),6.25(1H,s),7.15-8.10(4H,m);
质谱(CI,m/z):378(M++1),308;
IR谱(KBr,vmaxcm-1):1712.
(c)使用由上述(b)得到的(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-巯基哌啶盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,与实施例1(c)相同地进行反应,得到浅黄色油状物的标题化合物(收率74%)。
NMR谱(CDCl3,δ):0.75-0.92(2H,m),0.94-1.10(2H,m),1.13-1.28(3H,m),2.01-2.78(5H,m),2.42(3H,s),3.30(0.5H,d,J=13.5Hz),3.35(0.5H,d,J=13.5Hz),3.92-4.15(4H,m),4.69,4.72(计1H,各s),5.51(1H,s),7.05-7.45(6H,m),7.75(2H,d,J=8.1Hz);
质谱(CI,m/z):532(M++1);
IR谱(液膜法,vmaxcm-1):1712,1327,1142.
(d)使用由上述(c)得到的(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶,与实施例2(d)相同地进行反应,得到白色固体的标题化合物的盐酸盐。
熔点:94-103℃;
质谱(CI,m/z):532(M++1).
实施例7
(i)(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-42)及
(ii)(E)-1-(2-氯-α-甲氧羰基苄基)-3-甲氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-2)
(a)使用(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-羟基哌啶,代替(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-羟基哌啶,与实施例6(a)相同地进行反应,得到浅红褐色油状物的(E)-4-乙酰硫基-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基哌啶(收率35.3%)。
NMR谱(CDCl3,δ):1.21,1.23(计3H,各t,J=7.3Hz),1.75-1.92(1H,m ),2.15-2.30(1H,m),2.32(3H,s),2.52-2.85(2H,m),3.48(0.5H,d,J=13.9Hz),3.60(0.5H,d,J=13.9Hz),3.71,3.72(计3H,各s),4.05-4.14(2.5H,m),4.25(0.5H,d,J=13.9Hz),4.31-4.44(1H,m),4.83,4.85(计1H,各s),5.96(1H,s),7.15-7.70(4H,m);
质谱(CI,m/z):426(M++1)
(b)将由上述(a)得到的(E)-4-乙酰硫基-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基哌啶1.22g溶解在甲醇50ml中,向此溶液中吹入适当量的氯化氢气,在室温下放置一夜。在减压下蒸馏出溶剂,用乙醚结晶残渣、得到(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-巯基哌啶盐酸盐和(E)-1-(2-氯-α-甲氧羰基苄基)-4-巯基-3-甲氧羰基亚甲基哌啶盐酸盐的混合物1.25g。
(C)使用由上述(b)得到的(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-巯基哌啶盐酸盐和(E)-1-(2-氯-α-甲氧羰基苄基)-4-巯基-3-甲氧羰基亚甲基哌啶盐酸盐的混合物1.25g,代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶的盐酸盐,进行与实施例1(c)相同的反应,用硅胶柱色谱分离生成物,得到(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶0.22g(浅黄色油状物、收率13%)和(E)-1-(2-氯-α-甲氧羰基苄基)-3-甲氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶0.81g(白色固体、收率48%)。
(i)(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶
NMR谱(CDCl3,δ):1.16-1.28(2H,m),2.00-2.06(1H,m),2.14-2.20(1H,m),2.42(3H,s),2.60-2.71(2H,m),3.34(0.5H,d,J=14.8Hz),3.44(0.5H,d,J=14.8Hz),3.68(3H,s),4.02-4.10(3.5H,m),4.17(0.5H,d,J=14.8Hz),4.78,4.79(计1H,各s),5.52(1H,s),7.13-7.55(6H,m),7.75(2H,d,J=8.0Hz);
质谱(CI,m/z);538(M++1);
IR谱(液膜法,-vmaxcm-1):1715,1326,1141.
(ii)(E)-1-(2-氯-α-甲氧羰基苄基)-3-甲氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶
熔点:144-146℃;
NMR谱(CDCl3,δ):2.00-2.07(2H,m),2.15-2.23(2H,m),2.42(3H,s),2.60-2.70(2H,m),3.34(0.5H,d,J=15.2Hz),3.45(0.5H,d,J=15.2Hz),3.59(3H,s),3.70(3H,s),4.07-4.15(1.5H,m),4.18(0.5H,d,J=15.2Hz),4.78,4.79(计1H,各s),5.52(1H,s),7.16-7.55(6H,m),7.75(2H,d,J=8.3Hz);
质谱(CI,m/z):524(M++1);
IR谱(KBr,vmaxcm-1):1720,1326,1141.
(d)使用由上述(c)(i)得到的(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶,进行与实施例2(d)相同的反应,得到淡黄白色固体的(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-(4-甲基苯磺酰硫基)哌啶盐酸盐。
熔点:73-78℃;
质谱(CI,m/z):538(M++1).
实施例8
1-(α-环丙基羰基-2-氟苄基)-4-甲基磺酰硫基哌啶(示例化合物号1-142)
使用甲磺酰氯代替4-甲基苯磺酰溴,以二氯甲烷作为溶剂,进行与实施例1(c)相同的反应,以26.2%的收率得到白色结晶的标题化合物。
熔点:89-91℃;
NMR谱(CDCl3,δ):0.73-0.95(2H,m),0.98-1.11(2H,m),1.43-2.45(9H,m),2.75-2.98(2H,m),3.31(3H,s),3.37-3.53(1H,m),4.68(1H,s),7.05-7.40(4H,m);
质谱(CI,m/z):372(M++1);
IR谱(KBr,vmaxcm-1):1701,1322,1131.
实施例9
1-(α-环丙基羰基-2-氟苄基)-4-苯磺酰硫基哌啶(示例化合物号1-82)
(a)使用苯磺酰溴代替4-甲基苯磺酰溴,以二氯甲烷作为溶剂,进行与实施例1(c)相同的反应,以51%的收率得到浅黄色油状物的标题化合物。
NMR谱(CDCl3,δ):0.73-1.06(4H,m),1.60-2.32(7H,m),2.55-2.80(2H,m),3.25-3.39(1H,m),4.61(1H,s),7.04-7.17(2H,m),7.21-7.35(2H,m),7.38-7.65(3H,m),7.86-7.94(2H,m);
质谱(CI,m/z):434(M++1);
IR谱(液膜法,vmaxcm-1):1701,1325,1144.
(b)使用由上述(a)得到的1-(α-环丙基羰基-2-氟苄基)-4-苯磺酰硫基哌啶,进行与实施例2(d)相同的反应,得到微黄白色固体的标题化合物盐酸盐。
熔点:105-116℃;
质谱(CI,m/z):434(M++1).
实施例10
4-(4-氯苯磺酰硫基)-1-(α-环丙基羰基-2-氟苄基)哌啶(示例化合物号1-27)
(a)使用4-氯苯磺酰溴代替4-甲基苯磺酰溴,以二氯甲烷作为溶剂,进行与实施例1(c)相同的反应,以54%的收率得到浅黄色油状物的标题化合物。
NMR谱(CDCl3,δ):0.72-1.09(4H,m),1.66-2.38(7H,m),2.63-2.82(2H,m),3.25-3.36(1H,m),4.62(1H,s),7.05-7.36(4H,m),7.45-7.55(2H,m),7.79-7.89(2H,m);
质谱(CI,m/z):468(M++1);
IR谱(液膜法,vmaxcm-1):1701,1329,1145.
(b)使用由上述(a)得到的4-(4-氯苯磺酰硫基)-1-(α-环丙基羰基-2-氟苄基)哌啶,进行与实施例2(d)相同的反应,得到白色固体的标题化合物盐酸盐。
熔点:108-116℃;
质谱(CI,m/z):468(M++1).
实施例11
1-(α-环丙基羰基-2-氟苄基)-4-(4-氟苯磺酰硫基)哌啶(示例化合物号1-47)
(a)在二氯甲烷40ml中,溶解4-氟苯磺酰氯2.34g(12.0mmol),在冰冷下加入三乙胺0.44g(4.30mmol),接着,在1小时内滴入含有1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐0.67g(2.03mmol)和三乙胺0.22g(2.17mmol)的二氯甲烷10ml的悬浮液。在冰冷下进而搅拌1小时后,加入30ml水,用二氯甲烷50ml萃取二次。用饱和盐水20ml洗涤有机层后,用无水硫酸镁干燥。减压下蒸馏出溶剂,将得到的残渣加在硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=19/1),得到微黄色油状物的标题化合物0.42g(收率46%)。
NMR谱(CDCl3,δ):0.71-1.07(4H,m),1.59-2.34(7H,m),2.58-2.81(2H,m),3.21-3.36(1H,m),4.62(1H,s),7.00-7.39(6H,m),7.84-7.99(2H,m);
质谱(CI,m/z):452(M++1);
IR谱(液膜法,vmaxcm-1):1703,1330,1142.
(b)使用由上述(a)得到的1-(α-环丙基羰基-2-氟苄基)-4-(4-氟苯磺酰硫基)哌啶,进行与实施例2(d)相同的反应,得到微黄白色固体的标题化合物的盐酸盐。
熔点:110-121℃;
质谱(CI,m/z):452(M++1).
实施例12
1-(α-环丙基羰基-2-氟苄基)-4-(4-甲氧基苯磺酰硫基)哌啶(示例化合物号1-67)
(a)使用4-甲氧基苯磺酰氯代替4-氟苯磺酰氯,进行与实施例11(a)相同的反应,以37%的收率得到浅黄色油状物的标题化合物。
NMR谱(CDCl3,δ):0.72-1.07(4H,m),1.63-2.34(7H,m),2.60-2.80(2H,m),3.22-3.34(1H,m),3.88(3H,s),4.61(1H,s),6.92-7.35(6H,m),7.77-7.88(2H,m);
质谱(CI,m/z):464(M++1);
IR谱(液膜法,vmaxcm-1):1713,1327,1139.
(b)使用由上述(a)得到的1-(α-环丙基羰基-2-氟苄基)-4-(4-甲氧基苯磺酰硫基)哌啶,进行与实施例2(d)相同的反应,得到微黄白色固体的标题化合物的盐酸盐。
熔点:113-122℃;
质谱(CI,m/z):464(M++1).
实施例13
1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯亚磺酰硫基)哌啶(示例化合物号1-14)
(a)在二氯甲烷15ml中,溶解对甲苯亚磺酸0.48g(3.07mmol),在冰冷下加入1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺(EDC)盐酸盐0.59g(3.08mmol),接着,在20分钟内滴入含有1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐1.00g(3.03mmol)和三乙胺0.34g(3.37mmol)的二氯甲烷20ml的溶液。在冰冷下搅拌1小时后,加入25ml水,用二氯甲烷萃取。用饱和盐水30ml洗涤有机层后,用无水硫酸镁干燥。减压下蒸馏出溶剂,将得到的残渣加在硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=15/1),得到浅黄色油状物的标题化合物0.80g(收率61%)。
NMR谱(CDCl3,δ):0.78-0.90(2H,m),0.95-1.08(2H,m),1.85-2.38(7H,m),2.41(3H,s),2.79-2.99(2H,m),3.40-3.50(1H,m),4.63(1H,s),7.05-7.18(3H,m),7.22-7.39(3H,m),7.58-7.62(2H,m);
质谱(FAB,m/z):432(M++1);
IR谱(液膜法,vmaxcm-1):1702,1092.
(b)使用由上述(a)得到的1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯磺酰硫基)哌啶,进行与实施例2(d)相同的反应,得到微黄白色固体的标题化合物的盐酸盐。
熔点:110-118℃;
质谱(FAB,m/z):432(M++1).
实施例14
1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯亚磺酰硫基)吡咯烷(示例化合物号2-14)
(a)使用1-(α-环丙基羰基-2-氟苄基)-4-巯基吡咯烷盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,进行与实施例13(a)相同的反应,以62%的收率得到浅黄色油状物的标题化合物。
NMR谱(CDCl3,δ):0.76-0.85(2H,m),0.96-1.08(2H,m),1.90-1.94(1H,m),2.02-2.17(2H,m),2.40,2.41(计3H,各s),2.53-2.67(2H,m),2.73-2.84(1.5H,m),2.96-3.01(0.25H,m),3.13-3.18(0.5H,m),3.25-3.28(0.25H,m),3.25-4.03(1H,m),4.62,4.64,4.67,4.68(计1H,各s),7.06-7.62(4H,m);
质谱(FAB,m/z):418(M++1);
IR谱(液膜法,vmaxcm-1):1710,1090.
(b)使用上述(a)得到的1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯亚磺酰硫基)吡咯烷,进行与实施例2(d)相同的反应,得到微黄白色固体的标题化合物的盐酸盐。
熔点:87-100℃;
质谱(CI,m/z):418(M++1).
实施例15
1-(α-环丙基羰基-2-氟苄基)-4-甲基亚磺酰硫基哌啶(示例化合物号1-146)
(a)使用甲基亚磺酸钠代替对甲苯亚磺酸,进行与实施例13(a)相同的反应,以39%的收率得到浅黄色油状物的标题化合物。
NMR谱(CDCl3,δ):0.77-0.92(2H,m),0.95-1.09(2H,m),1.82-2.40(7H,m),2.75-3.02(2H,m),2.98(3H,s),3.30-3.46(1H,m),4.64(1H,s),7.04-7.41(4H,m);
质谱(CI,m/z):356(M++1);
IR谱(液膜法,vmaxcm-1):1700,1085.
(b)使用由上述(a)得到的1-(α-环丙基羰基-2-氟苄基)-4-甲基亚磺酰硫基)哌啶,进行与实施例2(d)相同的反应,得到白色固体的标题化合物盐酸盐。
熔点:105-111℃;
质谱(CI,m/z):356(M++1).
实施例16
1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯二硫基)哌啶(示例化合物号1-17)
(a)在对硫甲酚2.98g(24.0mmol)中加入吡啶90ml,接着加入醋酸银4.01g(24.0mmol),在室温下搅拌60分钟,过滤析出物,通过水洗、减压干燥,得到灰色粉末的对硫甲酚的银盐5.38g(23.3mmol、收率96.9%)。
在氮气氛下,将对硫甲酚的银盐3.70g(16.0mmol)和2,4-二硝基苯基亚磺酰氯3.75g(16.0mmol),在冰冷下,乙腈150ml的溶液中搅拌3小时。过滤反应液,减压下浓缩滤液后,将得到的残渣加在硅胶柱色谱中(洗脱溶剂:己烷/醋酸乙酯=5/1),得到黄色结晶物的2,4-二硝基苯基-对甲苯二硫1.64g(5.08mmol、收率31.8%)。
(b)在1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐0.83g(2.5mmol)的吡啶10ml溶液中,加入三乙胺0.38ml和醋酸银0.42g(2.5mmol),在室温下搅拌5小时。在反应液中加入30ml水,过滤析出的固体,接着用醋酸乙酯、己烷洗涤后,减压干燥,得到黄褐色固体的1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶的银盐0.67g(收率64%)。
(c)在氮气氛下,将由上述(a)得到的2,4-二硝基苯基-对甲苯二硫化物0.65g(2.02mmol),溶解在DMF13ml中,接着加入由上述(b)得到的1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶的银盐0.52g(1.30mmol),在室温下搅拌一夜,在反应液中加入30ml水,用甲苯100ml萃取后,用无水硫酸镁干燥有机层,减压下蒸馏出溶剂,将得到的残渣加在硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=15/1),得到浅黄色油状物的标题化合物0.20g(收率30%)。
NMR谱(CDCl3,δ):0.77-0.86(2H,m),0.97-1.04(2H,m),1.70-1.80(2H,m),1.94-2.05(3H,m),2.15-2.25(2H,m),2.32(3H,m),2.74-2.86(2H,m),2.87-2.98(1H,m),4.59(1H,s),7.04-7.16(4H,m),7.25-7.41(4H,m);
质谱(CI,m/z):416(M++1);
IR谱(液膜法,vmaxcm-1):1702.
(d)使用由上述(c)得到的1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯二硫基)哌啶,进行与实施例2(d)相同的反应,得到微黄白色固体的标题化合物的盐酸盐。
熔点:96-103℃;
质谱(CI,m/z):416(M++1).
实施例17
1-(α-环丙基羰基-2-氟苄基)-4-(2,4-二硝基苯基二硫基)哌啶(示例化合物号1-139)
(a)在二氯甲烷30ml中,溶解2,4-二硝基苯基亚磺酰氯0.71g(3.03mmol),在冰冷下在20分钟内滴入含有1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐1.00g(3.03mmol)和三乙胺0.34g(3.36mmol)的二氯甲烷悬浮溶液20ml。在冰冷下搅拌3小时后,加入30ml水,用二氯甲烷50ml萃取3次。用饱和盐水30ml洗涤有机层后,用无水硫酸镁干燥。减压下蒸馏出溶剂,将得到的残渣加在硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=20/1),得到黄色油状物的标题化合物0.50g(收率34%)。
NMR谱(CDCl3,δ):0.78-0.90(2H,m),0.95-1.05(2H,m),1.70-2.22(7H,m),2.79-3.01(3H,m),4.63(1H,s),7.05-7.19(2H,m),7.22-7.34(2H,m),8.40-8.53(2H,m),9.08-9.10(1H,m);
质谱(FAB,m/z):492(M++1);
IR谱(液膜法,vmaxcm-1):1700,1592,1339,1304.
(b)使用由上述(a)得到的1-(α-环丙基羰基-2-氟苄基)-4-(2,4-二硝基苯基二硫基)哌啶,进行与实施例2(d)相同的反应,得到浅黄色固体的标题化合物的盐酸盐。
熔点:120-127℃;
质谱(FAB,m/z):492(M++1).
实施例18
1-(α-环丙基羰基-2-氟苄基)-4-(2-硝基苯基二硫基)哌啶(示例化合物号1-109)
(a)使用2-二硝基苯基亚磺酰氯代替2,4-二硝基苯基亚磺酰氯,进行与实施例17(a)相同的反应,以59%的收率得到黄色泡状物的标题化合物。
NMR谱(CDCl3,δ):0.73-0.86(2H,m),0.93-1.08(2H,m),1.63-2.07(5H,m),2.08-2.23(2H,m),2.68-2.99(3H,m),4.61(1H,s),7.03-7.26(2H,m),7.27-7.36(3H,m),7.60-7.68(1H,m),8.21-8.30(2H,m);
质谱(CI,m/z):447(M++1);
IR谱(液膜法,vmaxcm-1):1699,1589,1337,1304.
(b)使用由上述(a)得到的1-(α-环丙基羰基-2-氟苄基)-4-(2-硝基苯基二硫基)哌啶,进行与实施例2(d)相同的反应,得到浅黄白色固体的标题化合物盐酸盐。
熔点:110-116℃;
质谱(CI,m/z):447(M++1).
实施例19
(Z)-4-[(R)-2-氨基-2-羧乙基二硫基]-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)哌啶(示例化合物号5-117)
(a)在醋酸15ml及浓盐酸10ml的混合液溶剂中,溶解(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-巯基哌啶0.44g(1.1mmol),在室温暗处放置12天。浓缩干固反应液,用乙醚结晶化,用硅胶柱色谱(洗脱溶剂:氯仿/甲醇=30/1)精制过滤了的结晶,得到浅黄白色结晶的(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐0.12g(收率27%)。
熔点:109-111℃;
NMRスペクトル(CDCl3,δ):0.74-0.92(1H,m),1.00-1.14(1H,m),1.62-1.75(1H,m),1.76-1.90(1H,m),1.94-2.08(2H,m),2.20-2.39(1H,m),2.50-2.70(2H,m),2.90-3.03,3.08-3.18(计1H,各m),3.41-3.80(3H,m),4.11-4.28(1H,m),4.90,5.03(计1H,各d,J=17.6Hz),5.98,6.12(计1H,各s),7.10-7.55(4H,m);
质谱(CI,m/z):350(M++1),280;
IR谱(KBr,vmaxcm-1):1712.
(b)在水-乙腈(1∶1)混合溶剂60ml中,溶解由上述(a)得到的(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐0.50g(1.3mmol)和二甲基二硫醚0.05ml,冰冷下用32W低压水银灯,进行光照射90分钟。反应终了后,减压浓缩,将残渣加入到高速液相色谱中[柱:TSK-GEL ODS-80TS、移动相:乙腈/水=3/7(含有0.016%三氟醋酸)、温度:室温],分别得到白色粉末(无晶形)的(Z)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶三氟醋酸盐的二个非对映异构体14.0mg(A体)及13.5mg(B体)。异构体A及异构体B的高速液相色谱的保持时间分别是16.5分钟及18.5分钟[柱:Inertsil ODS-2,移动相:乙腈/水=20/80(含有0.02%三氟醋酸)、温度:27℃、流速:1.5ml/min]。
A体
NMR谱(CD3CN,δ):0.80-1.10(4H,m),1.82-1.89(1H,m),1.92-2.02(1H,m),2.26-2.46(2H,m),3.11-3.29(2H,m),3.46(1H,d,J=13.6Hz),3.81(1H,d,J=14.2Hz),5.26(1H,s),5.38(1H,s),5.73(1H,s),7.27-7.59(4H,m);
质谱(CI,m/z):350(M++1),280.
B体
NMR谱(CD3CN,δ):0.80-1.11(4H,m),1.79-1.88(1H,m),1.95-2.04(1H,m),2.28-2.43(2H,m),2.86-3.01(1H,m),3.03-3.12(1H,m),3.52(1H,d,J=12.8Hz),3.87(1H,d,J=12.8Hz),5.24(1H,s),5.29(1H,s),5.68(1H,s),7.25-7.56(4H,m);
质谱(CI,m/z):350(M++1),280.
(c)在由上述(a)得到的(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐2.57g(6.67mmol)的水/乙腈(1/2.5)混合溶液中,加入盐酸,调节pH=2.9后,在冰冷下用32W低压水银灯,进行光照射120分钟。接着加入饱和醋酸钠水溶液,调节pH=5.17后,减压下浓缩。将残渣加入到高速液相色谱中[柱:TSK-GEL ODS-80TS、移动相:乙腈/水=3/7(含有0.012%三氟醋酸)、温度:室温],在得到的洗脱液中加入饱和醋酸钠水溶液中和后,在减压下浓缩。接着使用固相萃取筒将残渣进行脱盐处理、浓缩,得到白色粉末的(Z)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶的二非对映异构体混合物182mg(收率7.8%)。
NMR谱(D2O,δ):0.85-1.27(4H,m),1.80-1.94(1H,m),1.99-2.10(1H,m),2.21-2.49(1H,m),2.85-3.02(1H,m),3.10-3.30(1.5H,m),3.35-3.52(0.5H,m),3.62-3.93(1H,m),4.8(1H,m),5.35-5.58(1H,m),5.71,5.80(各0.5H,合计1H,各s),7.20-7.75(4H,m).
(d)在水8.8ml中,溶解L-半胱氨酸550.6mg(4.543mmol),加入由上述(c)得到的(Z)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶的二非对映异构体混合物117.1mg(0.3351mmol)的甲醇8.8ml溶液,接着加入碘到碘的颜色不消失为止后,在室温下搅拌2小时。反应终了后,过滤析出的胱氨酸,接着在减压下蒸馏出溶剂后,用高速液相色谱[TSK-GEL ODS-80TS,21.5×300mm,洗脱液:乙腈/水=1/3(含有0.03%三氟醋酸)]分取、精制目的物。从此洗脱液在减压下蒸去乙腈后,保持在固相萃取筒中(填充剂:C18 500mg)。水洗固相萃取筒,除去三氟醋酸后,用甲醇洗脱,在减压下蒸去甲醇,得到浅黄色固体的标题化合物(Z、E的混合物)60.8mg(收率38%)。
熔点:135-138℃;
NMR谱(DMSO-d6,δ):0.60-0.95(4H,m),1.80-1.99(1H,m),2.00-4.20(9H,m),4.21-4.46(0.5H,m),4.52-4.75(1H,m),5.15-5.30(0.5H,m),5.65-5.90(1H,m),7.12-7.28(2H,m),7.30-7.52(2H,m);
质谱(FAB,m/z):469(M++1);
IR谱(KBr,vmaxcm-1):1700,1642.
(e)在水15ml中,溶解L-半胱氨酸1.00g(8.25mmol),加入(Z)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶191mg(0.547mmol)的甲醇16ml溶液,接着加入碘到碘的颜色不消失为止后,在室温下搅拌1小时。反应终了后,过滤析出的胱氨酸,接着在减压下蒸馏出溶剂后,保持在固相萃取筒中(填充剂:C18 10g)。水洗固相萃取筒,接着用乙腈洗涤后,用甲醇洗脱目的物。在减压下蒸去甲醇,得到白色泡状物的标题化合物219mg(收率85.4%)。
NMR谱(CD3OD,δ):0.79-1.20(4H,m),1.86-2.10(1H,m),2.11-2.49(2.5H,m),2.60-2.98(2.5H,m),3.05-3.46(3H,m),3.80-3.90(1H,m),4.79-4.88(1H,m),5.35-5.44(1H,m),5.76,5.78,5.86,5.88(计1H,各s),7.10-7.29(2H,m),7.32-7.48(2H,m);
质谱(FAB,m/z):469(M++1).
实施例20
1-(α-环丙基羰基-2-氟苄基)-4-(2-甲氧羰基乙基二硫基)哌啶(示例化合物号1-210)
(a)在1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶0.50g(1.70mmol)的甲醇溶液中,加入3-巯基丙酸甲酯1.03g(8.53mmol)和三乙胺5.68g(56.09mmol)。在此溶液中,滴入碘的甲醇溶液到碘的颜色不消失为止,反应终了后,在减压下蒸馏出溶剂后,加入甲苯,过滤析出的三乙胺盐,再次减压下蒸馏出甲苯。将残渣加入到硅胶柱色谱(洗脱溶剂:甲苯/醋酸乙酯=50/1-19/1),得到黄橙色油状物的标题化合物0.563g(收率80%)。
NMR谱(CDCl3,δ):0.77-0.90(2H,m),0.93-1.08(2H,m),1.65-1.85(2H,m),1.92-2.08(3H,m),2.15-2.29(2H,m),2.64-2.75(3H,m),2.81-2.91(3H,m),2.93-3.03(1H,m),3.69(3H,s),4.61(1H,s),7.05-7.19(2H,m),7.27-7.41(2H,m);
质谱(CI,m/z):412(M++1);
IR谱(液膜法,vmaxcm-1):1740,1702.
实施例21
(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-甲基磺酰硫基哌啶(示例化合物号5-65)
(a)使用甲磺酰氯代替4-甲基苯磺酰氯,进行与实施例6(c)相同的反应,得到浅黄色油状物的标题化合物(收率14%)。
NMR谱(CDCl3,δ):0.75-0.92(2H,m),0.96-1.11(2H,m),1.21-1.30(3H,m),2.04-2.86(5H,m),3.21(3H,s),3.37-3.52(1H,m),4.01-4.33(4H,m),4.78,4.80(计1H,各s),5.98(1H,s),7.11-7.40(4H,m);
质谱(CI,m/z):456(M++1);
IR谱(液膜法,vmaxcm-1):1711,1324,1133.
(b)使用由上述(a)得到的(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-甲基磺酰硫基哌啶,进行与实施例2(d)相同的反应,得到浅黄白色固体的标题化合物盐酸盐。
熔点:98-115℃;
质谱(CI,m/z):456(M++1).
实施例22
4-环己基二硫基-1-(α-环丙基羰基-2-氟苄基)哌啶(示例化合物号1-199)
使用环己烷硫醇代替3-巯基丙酸甲酯,进行与实施例20(a)相同的反应,得到橙褐色油状物的标题化合物(收率86%)。
NMR谱(CDCl3,δ):0.77-0.90(2H,m),0.91-1.08(2H,m),1.12-1.37(5H,m),1.52-1.85(5H,m),1.90-2.10(5H,m),2.13-2.30(2H,m),2.58-2.72(2H,m),2.80-2.90(1H,m),2.91-3.01(1H,m),4.61(1H,s),7.02-7.22(2H,m),7.25-7.41(2H,m);
质谱(CI,m/z):408(M++1);
IR谱(液膜法,vmaxcm-1):2930,1702.
实施例23
4-环戊基二硫基-1-(α-环丙基羰基-2-氟苄基)哌啶(示例化合物号1-189)
使用环戊烷硫醇代替3-巯基丙酸甲酯,进行与实施例20(a)相同的反应,得到橙褐色油状物的标题化合物(收率84%)。
NMR谱(CDCl3,δ):0.75-0.90(2H,m),0.91-1.08(2H,m),1.45-1.84(8H,m),1.86-2.10(5H,m),2.12-2.30(2H,m),2.61-2.75(1H,m),2.79-2.90(1H,m),2.92-3.03(1H,m),3.18-3.29(1H,m),4.61(1H,s),7.01-7.20(2H,m),7.22-7.42(2H,m);
质谱(CI,m/z):394(M++1);
IR谱(液膜法,vmaxcm-1):2952,1702.
实施例24
(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-81)
(a)使用(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,以二氯甲烷作为溶剂,进行与实施例1(c)相同的反应,得到黄色泡状物的标题化合物(收率49%)。
NMR谱(CDCl3,δ):0.73-0.92(2H,m),0.95-1.09(2H,m),1.90-2.37(3H,m),2.38-2.63(4H,m),2.73-2.94(1H,m),3.05(0.5H,d,J=14.7Hz),3.50(0.5H,d,J=14.2Hz),3.86(0.5H,d,J=15.6Hz),4.01-4.08(1H,m),4.23(0.5H,d,J=14.7Hz),4.80,4.86(计1H,各s),5.55(1H,s),7.05-7.43(6H,m),7.67-7.80(2H,m).
(b)使用由上述(a)得到的(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯磺酰硫基)哌啶,进行与实施例2(d)相同的反应,得到浅黄色固体的标题化合物的盐酸盐。
质谱(FAB,m/z):504(M++1);
IR谱(KBr,vmaxcm-1):1713,1329,1143.
实施例25
(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-145)
(a)使用(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶,代替1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶,将反应溶剂从二甲基亚砜(DMSO)变更成N,N-二甲基甲酰胺(DMF)以外,进行与实施例1(a)相同的反应,以27.5%的收率得到红褐色油状物的(E)-4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)-3-(N,N-二甲基氨基甲酰)亚甲基哌啶。
NMR谱(CDCl3,δ):0.76-0.91(2H,m),0.95-1.09(2H,m),1.70-1.94(2H,m),2.15-2.50(5H,m),2.70-3.30(8H,m),3.55-3.80(1H,m),4.28-4.40(1H,m),4.68,4.75(计1H,各s),6.14(1H,s),7.05-7.80(4H,m);
质谱(CI,m/z):419(M++1).
(b)使用由上述(a)得到的(E)-4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)-3-(N,N-二甲基氨基甲酰)亚甲基哌啶代替4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)哌啶,进行与实施例1(b)相同的反应,以96.3%的收率得到浅褐色结晶的(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-巯基哌啶盐酸盐。
熔点:106-111℃;
NMR谱(CDCl3,δ):0.75-1.55(4H,m),1.60-2.50(4H,m),2.75-3.35(7H,m),3.40-4.80(4H,m),5.53(1H,s),6.31,6.60(计1H,各s),7.10-7.90(4H,m),12.9(1H,br.s);
质谱(CI,m/z):377(M++1).
(c)使用由上述(b)得到的(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-巯基哌啶盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,进行与实施例1(c)相同的反应,以23.2%的收率得到白色结晶的标题化合物。
熔点:48-52℃;
NMR谱(CDCl3,δ):0.73-0.89(2H,m),0.90-1.05(2H,m),1.94-2.04(1H,m),2.10-2.29(2H,m),2.43(3H,s),2.54-2.78(2H,m),2.83-2.97(6H,m),3.10-3.28(1H,m),3.37-3.65(1H,m),4.06-4.14(1H,m),4.63,4.68(计1H,各s),5.93(1H,s),7.03-7.40(6H,m),7.78(2H,d,J=8.3Hz);
质谱(FAB,m/z):531(M++1);
IR谱(KBr,vmaxcm-1):1699,1629,1324,1141.
实施例26
(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N-甲基氨基甲酰)亚甲基-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-129)
(a)使用(E)-1-(α-环丙基羰基-2-氟苄基)-4-羟基-3-(N-甲氨基甲酰)亚甲基哌啶,代替1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶,将反应溶剂从二甲基亚砜(DMSO)变更成N,N-二甲基甲酰胺(DMF)以外,进行与实施例1(a)相同的反应,以47.8%的收率得到浅褐色结晶的(E)-4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)-3-(N-甲基氨基甲酰)亚甲基哌啶。
NMR谱(CDCl3,δ):0.75-0.98(2H,m),0.98-1.13(2H,m),1.50-1.72(1H,m),1.72-1.90(1H,m),1.91-2.10(1H,m),2.10-2.45(5H,m),2.55-3.05(5H,m),3.05-3.35(1H,m),3.85-4.10(1H,m),4.26,4.28(计1H,各s),4.79,4.83(计1H,各s),5.90(1H,s),6.05(1H,br.s),7.05-7.50(4H,m);
质谱(CI,m/z):405(M++1).
(b)使用由上述(a)得到的(E)-4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)-3-(N-甲基氨基甲酰)亚甲基哌啶代替4-乙酰硫基-1-(α-环丙基羰基-2-氟苄基)哌啶,进行与实施例1(b)相同的反应,以93.3%的收率得到浅褐色结晶的(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N-甲基氨基甲酰)亚甲基-4-巯基哌啶盐酸盐。
熔点:133-141℃;
NMR谱(CDCl3,δ):0.80-1.15(2H,m),1.13-1.40(2H,m),1.60-2.08(5H,m),2.50-3.05(3H,m),3.06-4.50(5H,m),5.41,5.42(计1H,各S),6.09,6.18(计1H,各S),7.15-7.98(4H,m),8.61,8.81(计1H,各br.s),12.90(1H,br.s);
质谱(CI,m/z):363(M++1).
(c)使用由上述(b)得到的(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N-甲基氨基甲酰)亚甲基-4-巯基哌啶盐酸盐代替1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶盐酸盐,进行与实施例1(c)相同的反应,以2.2%的收率得到浅黄色结晶的标题化合物。
熔点:69-73℃;
NMR谱(CDCl3,δ):0.74-0.90(2H,m),0.94-1.11(2H,m),1.90-2.11(1H,m),2.35-2.50(4H,m),2.53-2.69(1H,m),2.72-2.83(3H,m),3.03-3.27(1H,m),3.67-3.87(1H,m),3.99-4.14(1H,m),4.70,4.75(计1H,各s),5.57(1H,s),5.74,5.90(计1H,各br.s),7.03-7.40(6H,m),7.75(2H,dd,J=2.1,8.1Hz);
质谱(FAB,m/z):517(M++1);
IR谱(KBr,vmaxcm-1):1700,1670,1324,1140.
实施例27
(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-189)
(a)将(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶4.55g(12.4mmol)溶解在二氯甲烷30ml中,加入N-乙基二异丙胺1.76g(13.6mmol),进而在冰冷下滴入甲磺酰氯1.56g(13.6mmol)的二氯甲烷10ml的溶液,在室温下搅拌1小时。减压下蒸馏出溶剂,得到粗的(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-甲磺酰氧基哌啶。向此粗产物中加入N,N-二甲基甲酰胺(DMF)50ml及对甲苯硫磺酸钾7.02g(31.0mmol),在60℃下搅拌4小时。在反应混合物中加入水,用甲苯萃取后,用无水硫酸钠干燥萃取液。减压下蒸馏出溶剂,将得到的残渣加在硅胶柱色谱中(洗脱溶剂:氯仿/甲醇=100/1),进而(洗脱溶剂:甲苯/醋酸乙酯=6/4),得到浅黄色结晶的标题化合物0.58g(收率8.7%)。
NMR谱(CDCl3,δ):1.88-2.05(1H,m),2.10-2.27(1H,m),2.43(3H,s),2.55-2.75(2H,m),2.83,2.85(计3H,各s),2.88,2.89(计3H,各s),3.29(0.5H,d,J=13.5Hz),.3.31(0.5H,d,J=13.5Hz),3.57(0.5H,d,J=13.5Hz),3.61(0.5H,d,J=13.5Hz),3.67(3H,s),4.09-4.18(1H,m),4.75,4.76(计1H,各s),5.90(1H,s),7.15-7.55(6H,m),7.80(2H,dd,J=2.0,8.0Hz);
质谱(FAB,m/z):537(M+);
IR谱(KBr,vmaxcm-1):1741,1630,1325,1140.
(b)将上述(a)得到的(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰基)亚甲基-4-(4-甲基苯磺酰硫基)哌啶0.39g(0.73mmol),溶解在乙醚30ml中,向此溶液中加入预先吹入氯化氢气的乙醚溶液,放置30分钟。过滤析出的结晶、真空干燥,得到白色粉末的标题化合物的盐酸盐0.30g(收率72%)。
熔点:89-93℃;
质谱(FAB,m/z):537(M+).
实施例28
(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N-甲基氨基甲酰)亚甲基-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-181)
(a)使用(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N-甲基氨基甲酰)亚甲基-4-羟基哌啶代替(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶,进行与实施例27(a)相同的反应,以10%的收率得到浅黄白色结晶的标题化合物。
NMR谱(CDCl3,δ):1.88-2.02(1H,m),2.11-2.23(1H,m),2.44(3H,s),2.47-2.81(5H,m),3.31(0.5H,d,J=14.4Hz),3.44(0.5H,d,J=14.4Hz),3.68(3H,s),3.89-4.13(2H,m),4.76,4.81(计1H,各s),5.50(1H,br.s),5.57,5.59(计1H,各s),7.11-7.55(6H,m),7.77(2H,dd,J=1.2,8.3Hz);
质谱(FAB,m/z):523(M+);
IR谱(KBr,vmaxcm-1):1740,1670,1324,1140.
(b)使用由上述(a)得到的(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N-甲基氨基甲酰基)亚甲基-4-(4-甲基苯磺酰硫基)哌啶,进行与实施例27(b)相同的反应,得到白色固体的标题化合物盐酸盐。
熔点:108-114℃.
实施例29
(E)-3-丁氧羰基亚甲基-1-(2-氯-α-甲氧羰基苄基)-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-172)
(a)使用(E)-3-丁氧羰基亚甲基-1-(2-氯-α-甲氧羰基苄基)-4-羟基哌啶代替(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶,进行与实施例27(a)相同的反应,以16%的收率得到褐色油状的标题化合物。
NMR谱(CDCl3,δ):0.94(3H,t,J=7.1Hz),1.23-1.41(2H,m),1.45-1.64(2H,m),1.95-2.08(1H,m),2.14-2.28(1H,m),2.42,2.44(计3H,各s),2.55-2.77(2H,m),3.33(0.5H,d,J=15.4Hz),3.45(0.5H,d,J=15.4Hz),3.68,3.69(计3H,各s),3.86-4.20(4H,m),4.78,4.79(计1H,各s),5.53,5.55(计1H,各s),7.17-7.58(6H,m),7.75(2H,dd,J=1.8,8.1Hz);
质谱(FAB,m/z):566(M+);
IR谱(液膜法,vmaxcm-1):1740,1715,1327,1142.
(b)使用由上述(a)得到的(E)-3-丁氧羰基亚甲基-1-(2-氯-α-甲氧羰基苄基)-4-(4-甲基苯磺酰硫基)哌啶,进行与实施例27(b)相同的反应,得到黄色固体的标题化合物盐酸盐。
熔点:59-63℃.
实施例30
(E)-3-丁氧羰基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯磺酰硫基)哌啶(示例化合物号5-171)
(a)使用(E)-3-丁氧羰基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶代替(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶,进行与实施例27(a)相同的反应,以8.3%的收率得到褐色油状的标题化合物。
NMR谱(CDCl3,δ):0.67-1.13(7H,m),1.25-1.46(2H,m),1.50-1.69(2H,m),1.96-2.82(8H,m),3.14(0.5H,d,J=14.3Hz),3.28(0.5H,d,J=14.3Hz),3.88-4.17(4H,m),4.68,4.71(计1H,各s),5.52(1H,s),7.03-7.40(6H,m),7.75(2H,d,J=8.3Hz);
质谱(FAB,m/z):560(M++1);
IR谱(液膜法,vmaxcm-1):1713,1653,1329,1142.
(b)使用由上述(a)得到的(E)-3-丁氧羰基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯磺酰硫基)哌啶,进行与实施例27(b)相同的反应,得到黄色固体的标题化合物盐酸盐。
熔点:84-87℃.
实施例31
(E)-4-[(R)-2-氨基-2-羧乙基二硫基]-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)哌啶(示例化合物号5-117)
在水15ml中,溶解L-半胱氨酸1.00g(8.25mmol),加入(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-巯基哌啶191mg(0.547mmol)的甲醇15ml溶液,加入碘的甲醇溶液到碘的颜色不消失为止后,在室温下搅拌30分钟。反应终了后,过滤析出的胱氨酸,接着在减压下蒸馏出甲醇后,保持在固相萃取筒中(填充剂:C18 10g)。水洗固相萃取筒,除去碘化氢,接着用乙腈洗脱杂质后,用甲醇洗脱目的物。在减压下蒸去甲醇,得到微黄色泡状物的标题化合物0.16g(收率62%)。
NMR谱(CD3OD,δ):0.79-1.20(4H,m),1.89-2.10(1H,m),2.15-2.54(2.5H,m),2.65-2.88(2H,m),2.92-3.01(0.5H,m),3.10-3.42(2H,m),3.72-3.89(2H,m),4.47(0.25H,d,J=14.2Hz),4.50(0.25H,d,J=13.7Hz),4.56-4.65(0.5H,m),4.73-4.80(1H,m),5.83,5.85,5.95,5.96(计1H,各s),7.11-7.27(2H,m),7.33-7.50(2H,m);
质谱(FAB,m/z):469(M++1).
参考例1
1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶
将4-羟基哌啶3.13g(31mmol),溶解在二甲基甲酰胺(DMF)30ml中,加入α-环丙基羰基-2-氟苄基溴7.94g(31mmol)及碳酸钾4.7g(34mmol),在室温下搅拌2小时。在反应混合物中加入水,用甲苯萃取,用无水硫酸钠干燥得到的有机层。在减压下浓缩溶剂,将得到的残渣用硅胶柱色谱(洗脱溶剂:氯仿/甲醇=19/1)精制,得到褐色油状物的标题化合物8.00g(收率93%)。
NMR谱(CDCl3,δ):0.79-0.87(2H,m),0.98-1.04(2H,m),1.50-1.72(2H,m),1.82-1.98(2H,m),2.02-2.15(1H,m),2.18-2.30(2H,m),2.70-2.90(2H,m),3.60-3.74(1H,m),4.62(1H,s),7.05-7.45(4H,m);
质谱(CI,m/2):278(M++1).
参考例2
1-(2-氯-α-甲氧羰基苄基)-4-羟基哌啶
使用2-氯-α-甲氧羰基苄基溴代替α-环丙基羰基-2-氟苄基溴,进行与参考例1相同的反应,以95%的收率得到无色油状的标题化合物。
NMR谱(CDCl3,δ):1.55-1.70(2H,m),1.80-2.00(2H,m),2.22-2.45(2H,m),2.65-2.82(1H,m),2.83-2.98(1H,m),3.70(3H,s),3.72-3.80(1H,m),4.70(1H,s),7.20-7.70(4H,m);
质谱(CI,m/z):284(M++1).
参考例3
1-(α-环丙基羰基-2-氟苄基)-3-羟基哌啶
使用3-羟基哌啶代替4-羟基哌啶,进行与参考例1相同的反应,大致定量地得到褐色油状物的标题化合物。
NMR谱(CDCl3,δ):0.75-0.95(2H,m),1.00-1.10(2H,m),1.45-1.68(3H,m),1.72-1.95(1H,m),2.02-2.20(1H,m),2.30-2.70(4H,m),3.80-3.90(1H,m),4.72(1H,s),7.05-7.45(4H,m);
质谱(CI,m/z):278(M++1).
参考例4
1-(α-环丙基羰基-2-氟苄基)-3-羟基吡咯烷
使用3-羟基吡咯烷代替4-羟基哌啶,进行与参考例1相同的反应,以97%的收率得到黄色油状物的标题化合物。
NMR谱(CDCl3,δ):0.79-0.90(2H,m),1.00-1.03(2H,m),1.70-1.90(1H,m),2.02-2.20(2H,m),2.41-3.08(5H,m),4.28-4.40(1H,m),4.71,4.72(计1H,各s),7.07-7.46(4H,m);
质谱(CI,m/z):264(M++1).
参考例5
1-(α-环丙基羰基-2-氟苄基)-3-羟基氮杂环丁烷
使用3-羟基氮杂环丁烷代替4-羟基哌啶,进行与参考例1相同的反应,以66%的收率得到白色结晶的标题化合物。
NMR谱(CDCl3,δ):0.69-0.88(2H,m),0.90-1.07(2H,m),1.87-1.96(1H,m),2.94-3.03(2H,m),3.17(1H,br.s),3.44(1H,dd,J=6.1,6.7Hz),3.83(1H,dd,J=6.7,7.3Hz),4.45-4.53(1H,m),4.62(1H,s),7.07-7.38(4H,m);
质谱(CI,m/z):250(M++1).
参考例6
8-(α-环丙基羰基-2-氟苄基)-3-羟基-8-氮杂双环
〔3.2.1〕辛烷
使用3-羟基-8-氮杂双环〔3.2.1〕辛烷(外向和内向的异构体混合物)代替4-羟基哌啶,进行与参考例1相同的反应,用硅胶柱色谱(洗脱溶剂:甲苯/醋酸乙酯=100/3)分离,分别以45.2%及24.6%的收率得到标题化合物的二个异构体A-1及异构体B-1。将异构体A-1及异构体B-1,加在高速液相色谱上(柱:TSK-GEL ODS-80TM、移动相:乙腈/12mM KH2PO4=45/55、温度:35℃、流速:1.0ml/分钟),分别显示保持时间是4.0分钟及4.3分钟。
异构体A-1
形状:浅黄色固体;
NMR谱(CDCl3,δ):0.68-1.06(4H,m),1.35(1H,s),1.62(1H,d,J=13.9Hz),1.72(1H,d,J=13.9Hz),1.82-2.32(6H,m),2.39-2.54(1H,m),3.05(1H,s),3.22(1H,s),4.13(1H,s),4.64(1H,s),6.95-7.80(4H,m);
质谱(CI,m/z):304(M++1).
异构体B-1
形状:浅黄油状物;
NMR谱(CDCl3,δ):0.68-1.08(4H,m),1.25(1H,s),1.46-2.35(8H,m),2.38-2.54(1H,m),3.18(1H,s),3.26(1H,s),3.89-4.05(1H,m),4.72(1H,s),6.96-7.95(4H,m);
质谱(CI,m/z):304(M++1).
参考例7
(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-羟基哌啶
(a)(E)-3-乙氧羰基亚甲基-1-三苯基甲基-4-哌啶
在4-哌啶酮一水合物盐酸盐10.0g(65.1mmol)和三乙胺20.0g(198mmol)的二甲基甲酰胺150ml的溶液中,60℃、搅拌下,一点点地加入氯三苯基甲烷18.1g(65.1mmol)后,在该温度下进而搅拌5小时。冷却后,过滤析出的三乙胺盐酸盐,减压浓缩滤液。向残渣内加入150ml水,用醋酸乙酯300ml萃取,接着用饱和盐水洗涤有机层后,用无水硫酸镁干燥。减压下浓缩溶剂,得到1-三苯基甲基-4-哌啶酮23.0g(收率98.3%)。
将上述生成物23.0g和吡咯烷4.63g(65.0mmol)的苯溶液300ml,用水分离器,在加热回流下共沸脱水2小时。接着,加入乙醛酸乙酯(聚合物型)6.63g(65.0mmol)的苯溶液50ml,再次,进行90分钟的加热回流共沸脱水。冷却后加入200ml水,洗涤,用无水硫酸镁干燥有机层。减压浓缩溶剂,将得到的残渣用硅胶柱色谱(洗脱溶剂:甲苯/醋酸乙酯=19/1)精制,得到浅黄色油状物的标题化合物16.6g(收率60.2%)。
NMR谱(CDCl3,δ):1.15(3H,t,J=6.3Hz),2.57-2.68(2H,m),2.72-2.81(2H,m),3.61-3.79(2H,m),4.08(2H,q,J=6.3Hz),6.55(1H,s),7.15-7.60(15H,m);
质谱(CI,m/z):426(M++1).
(b)(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-羟基哌啶
在(E)-3-乙氧羰基亚甲基-1-三苯基甲基-4-哌啶酮16.6g(39.1mmol)的甲醇溶液150ml中,在冰冷下一点点地加入硼氢化钠1.48g(39.1mmol)后,在室温下搅拌1小时。减压下浓缩反应液后,加入水50ml和醋酸乙酯150ml进行萃取。用饱和盐水洗涤有机层,用无水硫酸镁干燥。减压下蒸馏出溶剂,得到褐色油状物的(E)-3-乙氧羰基亚甲基-4-羟基-1-三苯基甲基哌啶16.8g(收率100%)。
在上述生成物中加入四氢呋喃200ml和对甲苯磺酸1水合物6.70g(35.2mmol),在50℃下搅拌1小时。反应终了后,减压下蒸馏出溶剂,用甲苯洗涤得到的残渣,得到3-乙氧羰基亚甲基-4-羟基哌啶的对甲苯磺酸盐10.8g(收率86.6%)。
接着将上述生成物溶解在二甲基甲酰胺80ml中,进而,加入α-环丙基羰基-2-氟苄基溴7.84g(30.5mmol)和碳酸钾9.27g(67.0mmol)后,室温下搅拌1小时及50℃下搅拌3小时。反应终了后,加入150ml水,用醋酸乙酯萃取,用饱和盐水洗涤有机层,用无水硫酸镁干燥。减压下蒸馏出溶剂,将得到的残渣用硅胶柱色谱(洗脱溶剂:甲苯/醋酸乙酯=9/1~4/1)精制,得到浅黄色油状物的标题化合物7.63g(收率69.3%)。
NMR谱(CDCl3,δ):0.74-0.88(2H,m),0.97-1.10(2H,m),1.22,1.25(计3H,各t,J=6.8Hz,J=7.3Hz),1.75-1.87(1H,m),2.00-2.65(4H,m),2.89-3.09(2H,m),4.11,4.13(计2H,各q,J=6.8Hz,J=7.3Hz),4.46,4.58(计1H,各d,J=13.6Hz,J=14.1Hz),4.77,4.78(计1H,各s),6.00(1H,s),7.05-7.43(4H,m);
质谱(CI,m/z):362(M++1),292.
参考例8
(E)-1-(2-氯-α-甲氧羰基苄基)-3-乙氧羰基亚甲基-4-羟基哌啶
使用2-氯-α-甲氧羰基苄基溴代替α-环丙基羰基-2-氟苄基溴,进行与参考例7(b)相同的反应,以62.1%的收率得到黄色油状物的标题化合物。
NMR谱(CDCl3,δ):1.10-1.35(3H,m),1.70-1.89(1H,m),1.91-2.10(1H,m),2.41-2.74(2H,m),2.82-2.96(1H,m),3.14(0.5H,d,J=13.9Hz),3.21(0.5H,d,J=13.9Hz),3.70,3.71(计3H,各s),4.00-4.22(2H,m),4.52(0.5H,d,J=13.9Hz),4.61(0.5H,d,J=13.9Hz),4.82,4.87(计1H,各s),5.99,6.01(计1H,各s),7.1-7.7(4H,m);
质谱(CI,m/z):368(M++1).
参考例9
(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶
在浓盐酸75ml及醋酸180ml的混酸中溶解(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧羰基亚甲基-4-羟基哌啶9.72g(26.9mmol),室温下放置7天。减压浓缩干固,加在硅胶柱色谱中(洗脱溶剂:氯仿/甲醇=100/3~2/1),得到(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶5.11g(收率57%)。
在上述的生成物中加入二氯甲烷50ml及三乙胺3.25g(32.2mmol),冷却到-5℃~0℃后,滴入氯碳酸乙酯1.66g(15.3mmol)。反应液回到室温,搅拌30分钟后,冷却到10℃,加入二甲胺盐酸盐1.25g(15.3mmol),接着加入三乙胺1.54g(15.3mmol),室温下搅拌5小时。加入二氯甲烷-水,分离二氯甲烷层,用无水硫酸镁干燥后,减压浓缩,用硅胶柱色谱(洗脱溶剂:氯仿/甲醇=10/3)精制,得到浅黄色油状物的标题化合物3.56g(收率64.4%)。
NMR谱(CDCl3,δ):0.75-0.90(2H,m),0.93-1.06(2H,m),1.62-1.83(1H,m),1.85-2.10(1H,m),2.10-2.59(2H,m),2.75(0.5H,d,J=13.gHz),2.83(0.5H,d,J=13.9Hz),2.89,2.92,3.04(计5H,各s),3.12-3.40(1H,m),3.66(0.5H,d,J=13.9Hz),3.84(0.5H,d,J=13.9Hz),4.00-4.13(1H,m),4.68,4.71(计1H,各s),6.13(1H,s),7.00-7.48(4H,m);
质谱(CI,m/z):361(M++1).
参考例10
(E)-1-(α-环丙基羰基-2-氟苄基)-3-(N-甲基氨基甲酰)亚甲基-4-羟基哌啶
使用甲胺盐酸盐代替二甲胺盐酸盐,进行与参考例9相同的反应,以55.1%的收率得到白色固体的标题化合物。
NMR谱(CDCl3,δ):0.72-0.93(2H,m),0.94-1.12(2H,m),1.65-1.85(1H,m),1.85-2.12(2H,m),2.15-2.34(0.5H,m),2.4-2.68(1H,m),2.70-3.00(4.5H,m),3.95-4.20(2H,m),4.79(0.5H,s),4.85(0.5H,s),5.96(0.5H,s),5.97(0.5H,s),6.60(0.5H,br.s),6.83(0.5H,br.s),7.05-7.45(4H,m);
质谱(CI,m/2):347(M++1).
参考例11
1-(α-环丙基羰基-2-氟苄基)-3-亚乙基-4-羟基哌啶
(a)1-(叔丁氧羰基)-3-亚乙基-4-哌啶酮
将1-苄基-4-哌啶酮10.0g(52.9mmol)和吗啉4.61g(52.9mmol)的甲苯溶液100ml,用水分离器,在加热回流下共沸脱水5小时。反应终了后,减压下蒸馏出溶剂,定量地得到1-苄基-4-吗啉代基-1,2,5,6-四氢吡啶13.7g。在氩气氛下将乙醛1.52g(34.6mmol)的二氯甲烷20ml溶液冷却到-40℃,接着滴入三氟化硼-醚络合物5.3ml(43mmol)和由上述得到的1-苄基-4-吗啉代基-1,2,5,6-四氢吡啶7.44g(28.8mmol)。滴下终了后,慢慢地升高温度,在室温下放置一夜,加入水,停止反应后,用二氯甲烷萃取,用饱和盐水洗涤有机层后,用无水硫酸钠干燥。在减压下浓缩,将得到的残渣加入到硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=4/1),得到黄褐色油状物的1-苄基-3-(1-羟基乙基)-4-哌啶酮4.68g(收率69.7%)。
NMR谱(CDCl3,δ):1.11-1.14(3H,d,J=6Hz),2.35-2.95(7H,m),3.54-3.70(2H,m),4.02-4.22(1H,m),7.28-7.36(5H,m).
将由上述得到的1-苄基-3-(1-羟基乙基)-4-哌啶酮4.68g(20mmol),溶解在乙醇100ml中,加入5%的钯-碳0.5g,在氢气氛下、60℃下搅拌8小时。反应终了后,用硅藻土过滤钯-碳后,减压下蒸馏出溶剂,定量地得到无色油状物的3-(1-羟基乙基)-4-哌啶酮2.98g。
接着,将上述生成物溶解到二氯甲烷20ml中,加入15%的碳酸钾水溶液20ml,进而在搅拌下,加入二碳酸二叔丁酯4.6g(21mmol)后,室温下搅拌3小时。反应终了后,用二氯甲烷萃取,用饱和盐水洗涤有机层后,用无水硫酸钠干燥。在减压下浓缩,将得到的残渣加入到硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=4/1),得到无色油状物的1-(叔丁氧羰基)-3-(1-羟基乙基)-4-哌啶酮1.86g(收率38.3%)。
NMR谱(CDCl3,δ):1.21(1.5H,d,J=7Hz),1.25(1.5H,d,J=6Hz),1.50(9H,s),2.40-2.49(3H,m),2.98-3.08(0.5H,m),3.26-3.33(1H,m),3.40-3.90(2.5H,m),3.95-3.98(0.5H,m),4.08-4.28(1.5H,m);
质谱(CI,m/z):188,144.
在由上述得到的1-(叔-丁氧羰基)-3-(1-羟基乙基)-4-哌啶酮1.86g(7.6mmol)的二氯甲烷20ml溶液中,加入三乙胺0.77g(7.6mmol),接着在冰冷下,加入甲磺酰氯0.88g(7.6mmol)后,在室温下搅拌1小时。减压下蒸馏出溶剂,在残渣中加入醋酸乙酯,过滤析出的固体后,再次减压浓缩。接着溶解在氯仿20ml中,在室温下加入1,8-二氮杂双环[5.4.0](十一碳)-7-烯(DBU)1.16g(7.6mmol),在该温度下搅拌2小时。反应终了后,减压下浓缩,将残渣加入到硅胶柱色谱中(洗脱溶剂:甲苯/醋酸乙酯=19/1),得到无色油状物的标题化合物1.32g(收率77.2%)。
NMR谱(CDCl3,δ):1.49(9H,s),1.80(3H,d,J=7Hz),2.54(2H,t,J=6Hz),3.71(2H,t,J=6Hz),4.35(2H,br.s),6.86(1H,br.q);
质谱(CI,m/z):170.
(b)1-(α-环丙基羰基-2-氟苄基)-3-亚乙基-4-羟基哌啶
在1-(叔-丁氧羰基)-3-亚乙基-4-哌啶酮1.32g(5.9mmol)的甲醇10ml溶液中,在冰冷下加入氯化铈.7水合物2.19g(5.9mmol),接着加入硼氢化钠0.22g(5.9mmol)后,在室温下搅拌1小时。减压下蒸馏出溶剂后,加入水,用醋酸乙酯萃取。用无水硫酸钠干燥有机层后,减压下浓缩,将残渣加入到硅胶柱色谱中(洗脱溶剂:氯仿),定量地得到无色油状物的1-(叔-丁氧羰基)-3-亚乙基-4-羟基哌啶1.33g。
NMR谱(CDCl3,δ):1.46(9H,s),1.60-1.69(1H,m),1.71(3H,d,J=7Hz),1.80-1.90(1H,m),3.50-3.65(2H,m),4.04(1H,br.s),4.23(1H,br.t),5.54(1H,q,J=7Hz);
质谱(CI,m/z):172,154.
在二氯甲烷20ml溶液中,溶解1-(叔-丁氧羰基)-3-亚乙基-4-羟基哌啶1.51g(6.7mmol),在冰冷下加入三氟醋酸5ml后,在室温下搅拌2小时。接着,在冰冷下加入三乙胺11ml和α-环丙基羰基-2-氟苄基溴1.70g(6.7mmol),在室温下搅拌2小时。减压下蒸馏出溶剂,在残渣中加入醋酸乙酯,过滤析出的固体后,再次减压浓缩。将残渣加入到硅胶柱色谱中(洗脱溶剂:氯仿/甲醇=100/1),得到黄色油状物的标题化合物1.52g(收率74.9%)。
NMR谱(CDCl3,δ):0.80-0.88(2H,m),0.96-1.06(2H,m),1.23(3H,d,J=6Hz),2.20-2.27(3H,m),2.40-2.73(2H,m),2.98-3.17(2H,m),4.17-4.19(1H,m),4.73(0.5H,s),4.74(0.5H,s),5.73(1H,br.s),7.08-7.18(2H,m),7.28-7.33(1H,m),7.41-7.48(1H,m);
质谱(CI,m/z):304(M++1).
参考例12
1-(2-氟-α-甲氧羰基苄基)-4-羟基哌啶
使用2-氟-α-甲氧羰基苄基溴代替α-环丙基羰基-2-氟苄基溴,进行与参考例1相同的反应,以91.7%的收率得到无色油状物的标题化合物。
NMR谱(CDCl3,δ):1.54-1.74(2H,m),1.83-1.97(2H,m),2.16-2.35(2H,m),2.73-2.88(2H,m),3.55-3.78(1H,m),3.70(3H,s),4.53(1H,s),7.02-7.53(4H,m);
质谱(CI,m/z):268(M++1).
参考例13
(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶
(a)(E)-3-羧基亚甲基-4-羟基-1-三苯基甲基哌啶
将(E)-3-乙氧羰基亚甲基-4-羟基-1-三苯基甲基哌啶1.0g(2.3mmol)溶解在乙醇15ml中,加入16.7%的氢氧化钠水溶液6.0g(25mmol),在室温下搅拌15小时。在反应溶液中加入醋酸1.8g(30mmol),中和后,加入水,用氯仿萃取,用饱和盐水洗涤萃取液后,用无水硫酸钠干燥。减压下蒸馏出溶剂,得到白色粉末的(E)-3-羧基亚甲基-4-羟基-1-三苯基甲基哌啶0.92g(收率98%)。
NMR谱(CDCl3,δ):1.69-1.99(2H,m),2.03-2.23(2H,m),3.01(1H,d,J=10.0Hz),3.93-4.05(1H,m),4.61(1H,d,J=10.0Hz),6.11(1H,s),7.05-7.56(15H,m);
IR谱(KBr,vmaxcm-1):1695.
(b)(E)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基-1-哌啶的对甲苯磺酸盐
在上述生成物中加入二氯甲烷20ml及三乙胺0.35g(3.5mmol),冷却到-5℃~0℃后,滴入氯碳酸乙酯0.28g(2.6mmol)。反应液回到室温,搅拌30分钟后,加入二甲胺盐酸盐0.21g(2.6mmol),接着加入三乙胺0.28g(2.8mmol),室温下搅拌5小时。加入氯仿及水,用无水硫酸镁干燥分离了的有机层。减压下蒸馏出溶剂,用硅胶柱色谱(洗脱溶剂:氯仿/甲醇=100/3)精制,得到白色粉末的(E)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基-1-三苯基甲基哌啶0.56g(收率57%)。
NMR谱(CDCl3,δ):1.68-1.93(2H,m),1.95-2.20(2H,m),2.90(3H,s),2.91-3.03(1H,m),3.13(3H,s),3.68-3.84(1H,m),3.87-4.00(1H,m),6.18(1H,s),7.06-7.53(15H,m);
IR谱(KBr,vmaxcm-1):1613.
在上述生成物中加入四氢呋喃50ml和对甲苯磺酸1水合物0.25g(1.3mmol),在50℃下搅拌1小时后,放置一夜-反应终了后,减压下蒸馏出溶剂,用甲苯洗涤得到的残渣,得到白色固体的(E)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶的对甲苯磺酸盐0.55g(收率100%)。
NMR谱(CD3OD,δ):1.78-1.93(1H,m),2.11-2.24(1H,m),2.37(3H,s),2.98(3H,s),3.07(3H,s),3.17-3.33(1H,m),3.41-3.52(1H,m),3.81(1H,d,J=13.8Hz),4.32-4.40(2H,m),6.59(1H,s),7.22(2H,dd,J=1.8,8.4Hz),7.70(2H,dd,J=1.8,8.4Hz);
IR谱(KBr,vmaxcm-1):1616.
(c)(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶
将(E)-3-(N,N-二甲基氨基甲酰)亚甲基-4-羟基哌啶的对甲苯磺酸盐7.95g(22.3mmol),溶解在N,N-二甲基甲酰胺(DMF)50ml中,加入2-氯-α-甲氧羰基苄基溴7.35g(纯度80.0%,22.3mmol)及碳酸钾7.40g(53.5mmol),在室温下搅拌15小时。反应终了后,加入水150ml,用甲苯及醋酸乙酯萃取,减压下蒸馏出溶剂,将得到的残渣用硅胶柱色谱(洗脱溶剂:氯仿/甲醇=9/1~4/1)精制,得到黄褐色油状物的标题化合物6.38g(收率77.9%)。
NMR谱(CDCl3,δ):1.58-1.77(1H,m),1.89-2.04(1H,m),2.41-2.62(1H,m),2.77-3.06(7H,m),3.61-3.75(4H,m),3.92-4.19(2H,m),4.74,4.79(|计1H,各s),6.06,6.13(计1H,各s),7.17-7.60(4H,m);
质谱(CI,m/z):367(M++1);
IR谱(KBr,vmaxcm-1):1743,1667,1612.
参考例14
(E)-1-(2-氯-α-甲氧羰基苄基)-3-(N-甲基氨基甲酰)亚甲基-4-羟基哌啶
除了使用甲胺盐酸盐代替参考例13(b)的二甲胺盐酸盐之外,进行与参考例13相同的反应,以57.7%的收率得到浅黄褐色粉末物的标题化合物。
NMR谱(CDCl3,δ):1.58-1.81(1H,m),1.91-2.06(1H,m),2.33-2.46(0.5H,m),2.52-2.61(0.5H,m),2.77(1.5H,d,J=4.9Hz),2.80(1.5H,d,J=4.9Hz),2.87-3.15(2H,m),3.70(3H,s),4.05-4.30(2H,m),4.77,4.87(计1H,各s),5.95(1H,s),6.22(1H,br.s),7.19-7.61(4H,m);
质谱(CI,m/z):353(M++1);
IR谱(KBr,vmaxcm-1):1740,1670,1635.
参考例15
(E)-3-丁氧羰基亚甲基-1-(2-氯-α-甲氧羰基苄基)-4-羟基哌啶
在(E)-3-羧基亚甲基-4-羟基-1-三苯基甲基哌啶5.44g(13.6mmol)中,加入1-丁醇50ml,吹入盐酸气后,在60℃下加热搅拌1小时。反应终了后,减压下蒸馏出溶剂,将得到的残渣用甲苯洗涤,得到白色固体的(E)-3-丁氧羰基亚甲基-4-羟基哌啶的盐酸盐3.43g(收率100%)。
NMR谱(CD3OD,δ):0.96(3H,t,J=7.3Hz),1.33-1.49(2H,m),1.58-1.71(2H,m),1.81-1.95(1H,m),2.11-2.27(1H,m),3.17-3.33(1H,m),3.40-3.56(1H,m),4.05(1H,d,J=13.9Hz),4.16(2H,d,J=6.6Hz),4.30-4.43(1H,m),4.92(1H,d,J=13.9Hz),6.25(1H,s),7.04-7.24(1H,m);
质谱(CI,m/z):214(M++1).
使用上述盐酸盐,进行与参考例13(c)相同的反应,得到浅黄色油状物的标题化合物(收率61.7%)。
NMR谱(CDCl3,δ):0.92(3H,t,J=7.3Hz),1.29-1.43(2H,m),1.50-1.64(2H,m),1.71-1.87(1H,m),1.96-2.08(1H,m),2.48-2.69(1H,m),2.83-2.96(1H,m),3.16(0.5H,d,J=13.9Hz),3.24(0.5H,d,J=13.9Hz),3.70,3.72(计3H,各s),4.00-4.08(2H,m),4.10-4.21(1H,m),4.52(0.5H,d,J=13.9Hz),4.61(0.5H,d,J=13.9Hz),4.83,4.87(计1H,各s),5.99,6.00(计1H,各s),7.15-7.61(4H,m);
质谱(CI,m/z):396(M++1);
IR谱(液膜法,vmaxcm-1):1741,1715,1662.
参考例16
(E)-3-丁氧羰基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶
在(E)-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)-4-羟基哌啶3.19g(9.58mmol)中,加入1-丁醇150ml,接着吹入盐酸气直到溶液呈酸性。在室温下放置2小时后,加入苯100ml,共沸脱水2小时。反应终了后,减压下蒸馏出溶剂,在得到的残渣中,加入甲苯及碳酸氢钠水溶液,用无水硫酸镁干燥分离了的甲苯层后,在减压下蒸馏出溶剂,用硅胶柱色谱(洗脱溶剂:甲苯/醋酸乙酯=4/1)精制,得到浅黄色油状物的标题化合物2.75g(收率73.7%)。
NMR谱(CDCl3,δ):0.74-1.11(7H,m),1.30-1.46(2H,m),1.50-1.64(2H,m),1.74-1.90(1H,m),1.96-2.08(1H,m),2.11-2.24(1H,m),2.82-3.05(2H,m),3.98-4.16(4H,m),4.46(0.5H,d,J=12.2Hz),4.60(0.5H,d,J=12.2Hz),4.76,4.77(计1H,各s),6.00(1H,s),7.05-7.39(4H,m);
质谱(CI,m/z):390(M++1);
IR谱(液膜法,vmaxcm-1):1713,1663.
试验例1
人的血小板凝聚抑制作用
血小板凝聚是使用部分地修改G.V.R.Born的方法[Nature,194,927-929(1962)]的自动血小板凝聚测定装置(PAM-8C、Mebanix)测定的。以3.8%柠檬酸钠溶液作为抗凝剂(添加采血量的1/9的量),从前2周不服药剂的健康成人的正肘部静脉采血。使用离心机(CR5DL、日立),在室温下离心(200xg)得到的加入柠檬酸盐的血15分钟,分离上层的富血小板血浆(Platelet-richPlasma、PRP)。进而在室温下离心(2,000xg)下层10分钟,分离贫血小板血浆(Platelet-Poor Plasma、PPP)。用自动血球测定装置(K-1000、东亚医用电子)测定PRP中的血小板数后,使用PPP将PRP中的血小板数调节成3×108/ml,用于血小板凝聚试验。将添加了被检药物的PRP(0.24ml),分别注入到比色杯中,放在自动血小板凝聚测定装置中。预热1.5分钟(37℃)后,添加0.01ml的腺苷二磷酸(ADP)溶液(0.25mM),引起血小板凝聚。测定血小板凝聚10分钟。
被检测药物的血小板的凝聚抑制作用,是以相对于空白(未添加被检测药物)的抑制率(%)而求出的,其结果表示在表6中。
表6
被测药物 | 试验例1(%抑制) | ||
10μg/ml | 30μg/ml | 100μg/ml | |
实施例1(c) | 36.5 | 99.6 | 100 |
实施例2(d) | 32.8 | 97.1 | 98 |
实施例3(d) | 24.4 | 89.3 | 99.8 |
实施例4(d) | 30.6 | 77.6 | 99.5 |
实施例5(d) | 37.1 | 98.4 | 99.6 |
实施例5(d) | 22.5 | 53.2 | 100 |
实施例7(c)(ii) | 34.5 | 81.5 | - |
实施例7(d) | 24.6 | 60 | 99.1 |
实施例8 | 19.5 | 88 | 100 |
实施例9(b) | 23.4 | 97.3 | 94 |
实施例10(b) | 35.2 | 96.2 | 98.8 |
实施例11(b) | 15.5 | 98 | 92.5 |
实施例12(b) | 19.2 | 93.9 | 100 |
实施例13(b) | 13.3 | 40 | 91.8 |
实施例14(b) | 28.6 | 64 | 95.8 |
实施例15(b) | 12.3 | 28.1 | 71.1 |
试验例2
大鼠的血小板凝聚抑制作用
血小板凝聚是使用部分地修改G.V.R.Born的方法[Nature,194,927-929(1962)]的自动血小板凝固测定装置(PAM-8C、Mebanix)测定的。作为试验动物,使用SD系雄性大鼠(日本SLC)。将被检测药物从静脉注射到大鼠体内1小时后,在麻醉下,以3.8%的柠檬酸钠溶液作为抗凝剂(添加采血量的1/9的量)从腹部大动脉采血。使用离心机(CR5DL、日立),在室温下离心(230xg)得到的加入柠檬酸盐的血15分钟,分离上层的PRP。进而在室温下离心(2,000xg)下层10分钟,分离PPP。用自动血球测定装置(K-1000、东亚医用电子)测定PRP中的血小板数后,使用PPP将PRP中的血小板数调节成5×108/ml,用于血小板凝聚试验。将PRP(0.24ml),分别注入到比色杯中,放在自动血小板凝聚测定装置中。预热1.5分钟(37℃)后,添加0.01ml的ADP溶液(0.075mM),引起血小板凝聚。测定血小板凝聚8分钟。
被检测药物的血小板的凝聚抑制作用(%抑制),是与对照组大鼠(未给与被检测药物)的最大凝聚率比较而求出的,其结果表示在表7中。
表7
被测药物 | 试验例2(%抑制) |
10mg/kg | |
实施例6(d) | 51.8 |
实施例7(d) | 59.0 |
实施例19(d) | 89.2 |
制剂例1
硬胶囊剂
将50mg的粉末状的实施例7(d)的化合物、128.7mg的乳糖、70mg的纤维素及1.3g的硬脂酸镁进行混合,通过60目的筛后,将此粉末加入到250mg的3号明胶胶囊中作成胶囊剂。
制剂例2
片剂
将50mg的粉末状的实施例7(d)的化合物、124mg的乳糖、25mg的纤维素及1mg的硬脂酸镁进行混合,用压片机进行压片,制成1片是200mg的片。必要时在此片剂上加上糖衣。
产业上的可利用性
本发明的具有上述通式(1)的化合物,具有优良的血小板凝聚抑制作用或动脉硬化进展抑制作用等(特别是血小板凝聚抑制作用),由于毒性小,作为栓塞症、血栓症或者动脉硬化症(特别是栓塞症或血栓症)的预防药或治疗药(特别是治疗药)是有用的。
在将本发明的化合物(I)及其药理上容许的盐类作为上述疾病的治疗或预防药使用时,可混合其本身或者适宜的药理学容许的赋形剂、稀释剂等,作成片剂、胶囊剂、颗粒剂、散剂或者糖浆制剂的经口或注射或者栓剂的非经口的给药。
这些制剂可使用赋形剂(例如可举出乳糖、白糖、葡萄糖、甘露糖醇、山梨糖醇类的糖衍生物;玉米淀粉、土豆淀粉、α淀粉、糊精淀粉类的淀粉衍生物;结晶纤维素类的纤维素衍生物;阿拉伯胶;葡聚糖;茁霉多糖类的有机系赋形剂及轻质无水硅酸、合成硅酸铝、硅酸钙、偏硅铝酸镁类的硅酸盐衍生物;磷酸氢钙类的磷酸盐;碳酸钙类的碳酸盐;硫酸钙类的硫酸盐等的无机类赋形剂。)、润滑剂(例如可举出硬脂酸、硬脂酸钙、硬脂酸镁类的硬脂酸金属盐;滑石;胶体硅;蜂腊、鲸腊类的腊;硼酸;己二酸;硫酸钠类的硫酸盐;乙二醇;富马酸;苯甲酸钠;DL亮氨酸;月桂基硫酸钠、月桂基硫酸镁类的月桂基硫酸盐;无水硅酸、硅酸水合物类的硅酸类及上述淀粉衍生物。)、结合剂(例如可举出羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮、聚乙二醇及与上述赋形剂相同的化合物。)、崩解剂(如低取代度羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、内部交联羧甲基纤维素钠类的纤维素衍生物;羧甲基淀粉、羧甲基淀粉钠、交联聚乙烯吡咯烷酮类的化学修饰了的淀粉.纤维素类。)、乳化剂(如膨润土、蜂胶类粘性土;氢氧化镁、氢氧化铝类的金属氢氧化物;月桂基硫酸钠、硬脂酸钙类的阴离子表面活性剂;氯化苄烷铵类的阳离子表面活性剂;及聚氧乙烯烷基醚、聚氧乙烯山梨糖醇酐脂肪酸酯、蔗糖脂肪酸酯类的非表表面活性剂)、稳定剂(如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯类的对羟基苯甲酸酯类;氯丁醇、苄醇、苯乙醇类的醇类;二甲基苄基氯化铵;苯酚、甲酚类的酚类;乙基汞硫代水杨酸钠;脱氢醋酸;及山梨酸。)、矫味矫臭剂(如通常使用的甜味料、酸味料、香料等)、稀释剂等的添加剂,用公知的方法制造。
其使用量依症状、年龄等而不同,但是对于成人,口服时,每次的下限量为1mg(合适的是10mg)、上限量为1000mg(合适的是500mg),静脉给药时,每次的下限量为0.5mg(合适的是5mg)、上限量为500mg(合适的是250mg),根据症状每日1~6次进行给药。
Claims (30)
1.具有通式(I)结构的环胺化合物,或其药理学上可容许的盐,
式中,R1表示可任选被至少一个选自卤原子、C1-C4烷基、氟取代C1-C4烷基、C1-C4烷氧基、氟取代C1-C4烷氧基、氰基和硝基的取代基取代的苯基;
R2表示可任选被至少一个选自卤原子、C1-C4烷氧基和氰基的取代基取代的C1-C8脂肪族酰基,可任选被至少一个选自卤原子、C1-C4烷基和C1-C4烷氧基的取代基取代的苯甲酰基,或者(C1-C4烷氧基)羰基;
R3表示具有3-7环原子的饱和环氨基,所述饱和环氨基被具有通式-S-X-R4的基取代、其中R4和X如下所述,所述饱和环氨基通过其环氮原子与带有R1和R2取代基的相邻碳原子相连,
R4表示可任选被至少一个选自卤原子、C1-C4烷基、C1-C4烷氧基、硝基和氰基的取代基取代的苯基,可任选被至少一个选自氨基、羟基、羧基和(C1-C4烷氧基)羰基的取代基取代的C1-C6烷基,或者表示C3-C8环烷基;
X表示硫原子、亚磺酰基或者磺酰基;且
所述环氨基可任选进一步被具有通式=CR5R6的基取代,式中R5及R6可相同或不同,分别独立地表示氢原子、C1-C4烷基、羧基、(C1-C4烷氧基)羰基、氨基甲酰基、(C1-C4烷基)氨基甲酰基或二-(C1-C4烷基)氨基甲酰基。
2.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1是被至少一个选自卤原子、甲基、乙基、二氟甲基、三氟甲基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、氰基和硝基的取代基取代的苯基。
3.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1是被至少一个选自氟原子、氯原子、溴原子、三氟甲基、二氟甲氧基、三氟甲氧基、氰基和硝基的取代基取代苯基。
4.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1是被至少一个选自氟原子或氯原子取代的苯基。
5.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示的取代苯基的取代基个数是1~3。
6.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示的取代苯基的取代基个数是1或2。
7.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示的取代苯基取代位置是2位或4位。
8.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R2表示C2-C4烷酰基或者(C3-C6环烷基)羰基,所述基团可任选被至少一个选自氟原子、氯原子、甲氧基、乙氧基和氰基的取代基取代;
苯甲酰基,其可任选被至少一个选自氟原子、氯原子、甲基、乙基、甲氧基和乙氧基的取代基取代;
或(C1-C4烷氧基)羰基。
9.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R2表示C2-C4烷酰基或者(C3-C6环烷基)羰基,所述基团可任选被至少一个氟原子或氯原子取代;
苯甲酰基;或
(C1-C4烷氧基)羰基。
10.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R2表示乙酰基、丙酰基、异丁酰基、环丙基羰基或环丁基羰基,所述基团可任选被至少一个氟原子取代;
甲氧基羰基;或
乙氧基羰基。
11.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R2是丙酰基、环丙基羰基、甲氧基羰基或乙氧基羰基。
12.权利要求1-11任一项所述的环胺化合物或其药理上可容许的盐,其中R3表示3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、3-或4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基,其中
R4表示苯基,其可任选被至少一个选自卤原子、甲基、乙基、甲氧基、乙氧基、硝基和氰基的取代基取代,
直链C1-C6烷基,其可任选被至少一个选自下述的取代基取代:氨基、羟基、羧基和(C1-C4烷氧基)羰基,或
环丁基、环戊基、或环庚基;
R5及R6相同或不同,分别独立地表示氢原子、C1-C4烷基、羧基、(C1-C4烷氧基)羰基、氨基甲酰基、(C1-C4烷基)氨基甲酰基或二-(C1-C4烷基)氨基甲酰基;且
X是硫原子、亚磺酰基或者磺酰基。
13.权利要求1-11任一项所述的环胺化合物或其药理上可容许的盐,其中R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基,其中
R4表示苯基,其可任选被至少一个选自氟原子、氯原子、溴原子、甲基、甲氧基、硝基或氰基的取代基取代,
直链C1-C4烷基,其可任选被至少一个选自下述的取代基取代:氨基、羟基、羧基、甲氧羰基和乙氧羰基,或
环戊基或环己基;
R5及R6相同或不同,分别独立地表示氢原子、甲基、乙基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基、乙基氨基甲酰基、N,N-二甲基氨基甲酰基或N,N-二乙基氨基甲酰基、
X是硫原子、亚磺酰基或者磺酰基。
14.权利要求1-11任一项所述的环胺化合物或其药理上可容许的盐,其中R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基,其中
R4表示苯基,其可任选被至少一个选自氟原子、氯原子、甲基、甲氧基和硝基的取代基取代,
甲基、乙基或丙基,其可任选被至少一个选自氨基、羟基、羧基、甲氧羰基和乙氧羰基的取代基取代,或
环戊基或己基;
R5是氢原子、
R6表示氢原子、甲基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基或N,N-二甲基氨基甲酰基;
X是硫原子、亚磺酰基或者磺酰基。
15.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基,其中
R4表示苯基,其可任选被至少一个选自氟原子、氯原子、甲基、甲氧基和硝基的取代基取代,
甲基、乙基或丙基,其可任选被至少一个选自氨基、羟基、羧基、甲氧羰基和乙氧羰基的取代基取代,或
环戊基或环己基;
R5是氢原子;
R6表示羧基、甲氧羰基或乙氧羰基;且
X是硫原子或磺酰基。
16.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示被1-3个选自卤原子、甲基、乙基、二氟甲基、三氟甲基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、氰基和硝基的取代基取代的苯基;
R2表示C2-C4烷酰基或者(C3-C6环烷基)羰基,所述基团可任选被至少一个选自氟原子、氯原子、甲氧基、乙氧基和氰基的取代基取代,
苯甲酰基,其可任选被至少一个选自氟原子、氯原子、甲基、乙基、甲氧基和乙氧基的取代基取代,或者
(C1-C4烷氧基)羰基。
17.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示被1-2个选自氟原子、氯原子、溴原子、三氟甲基、二氟甲氧基、三氟甲氧基、氰基和硝基的取代基取代的苯基;
R2表示C2-C4烷酰基或者(C3-C6环烷基)羰基,所述基团可任选被至少一个氟原子或氯原子取代,
苯甲酰基,或者
(C1-C4烷氧基)羰基。
18.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示在2位或4位取代的苯基,该取代基选自氟原子、氯原子、溴原子、三氟甲基、二氟甲氧基、三氟甲氧基、氰基和硝基;
R2表示C2-C4烷酰基或者(C3-C6环烷基)羰基,其可任选被至少一个氟原子或氯原子取代,
苯甲酰基,或者
(C1-C4烷氧基)羰基;
R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、3-或4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基,其中
R4是苯基,其可任选被至少一个选自卤原子、甲基、乙基、甲氧基、乙氧基、硝基和氰基的取代基取代,
直链C1-C6烷基,其可任选被至少一个选自氨基、羟基、羧基和(C1-C4烷氧基)羰基的取代基取代,或
环丁基、环戊基、环己基或环庚基;
R5及R6相同或不同,分别独立地表示氢原子、(C1-C4烷基)、羧基、(C1-C4烷氧基)羰基、氨基甲酰基、(C1-C4烷基)氨基甲酰基或二(C1-C4烷基)氨基甲酰基;
X是硫原子、亚磺酰基或者磺酰基。
19.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示在2位或4位被氟原子或氯原子取代的苯基;
R2表示可任选被至少一个氟原子取代的乙酰基、丙酰基、异丁酰基、环丙基羰基或环丁基羰基,
甲氧羰基,或者
乙氧羰基;且
R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基、
R4是苯基,其可任选被至少一个选自氟原子、氯原子、溴原子、甲基、甲氧基、硝基和氰基的取代基取代,
直链C1-C4烷基,其可任选被至少一个选自氨基、羟基、羧基、甲氧羰基和乙氧羰基的取代基取代,或
环戊基,或
环己基;
R5及R6相同或不同,分别独立地表示氢原子、甲基、乙基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基、乙基氨基甲酰基、N,N-二甲基氨基甲酰基或N,N-二乙基氨基甲酰基;
X是硫原子、亚磺酰基或者磺酰基。
20.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示在2位或4位被氟原子或氯原子取代的苯基;
R2表示丙酰基、环丙基羰基、甲氧羰基、或者乙氧羰基;且
R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基、
R4是苯基,其可任选被至少一个选自氟原子、氯原子、甲基、甲氧基和硝基的取代基取代,
甲基、乙基或丙基,其可任选被至少一个选自氨基、羟基、羧基、甲氧羰基和乙氧羰基的取代基取代,或
环戊基,或
环己基;
R5是氢原子;
R6是氢原子、甲基、羧基、甲氧羰基、乙氧羰基、氨基甲酰基、甲基氨基甲酰基或N,N-二甲基氨基甲酰基;
X是硫原子、亚磺酰基或者磺酰基。
21.权利要求1所述的环胺化合物或其药理上可容许的盐,其中R1表示在2位或4位被氟原子或氯原子取代的苯基;
R2表示丙酰基、环丙基羰基、甲氧羰基、或者乙氧羰基;
R3是3-(-S-X-R4)-1-氮杂环丁烷基、3-(-S-X-R4)-1-吡咯烷基、4-(-S-X-R4)-1-哌啶基或4-(-S-X-R4)-3-(=CR5R6)-1-哌啶基,其中
R4是苯基,其可任选被至少一个选自氟原子、氯原子、甲基、甲氧基和硝基的取代基取代,
甲基、乙基或丙基,其可任选被至少一个选自氨基、羟基、羧基、甲氧羰基和乙氧羰基的取代基取代,或
环戊基,或
环己基;
R5是氢原子;
R6是羧基、甲氧羰基或乙氧羰基;
X是硫原子或者磺酰基。
22.权利要求1所述的环胺化合物或其药理上可容许的盐,其选自下述组中:
1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯基磺酰硫基)哌啶、
1-(2-氟-α-甲氧基羰基苄基)-4-(4-甲基苯基磺酰硫基)哌啶、
1-(2-氯-α-甲氧基羰基苄基)-4-(4-甲基苯基磺酰硫基)哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯基亚磺酰硫基)哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯基二硫基)哌啶、
4-(4-氯苯基磺酰硫基)-1-(α-环丙基羰基-2-氟苄基)哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-(4-氟苯基磺酰硫基)哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-(4-甲氧基苯基磺酰硫基)哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-苯基磺酰硫基哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-(2-硝基苯基二硫基)哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-(2,4-二硝基苯基二硫基)哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-甲基磺酰硫基哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-甲基亚磺酰硫基哌啶、
1-(α-环丙基羰基-2-氟苄基)-4-(2-甲氧基羰基乙基二硫基)哌啶、
1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯基磺酰硫基)吡咯烷、
1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯基亚磺酰硫基)吡咯烷、
1-(α-环丙基羰基-2-氟苄基)-3-(4-甲基苯基磺酰硫基)氮杂环丁烷、
(E)-1-(2-氯-α-甲氧基羰基苄基)-3-甲氧基羰基亚甲基-4-(4-甲基苯基磺酰硫基)哌啶、
(E)-1-(α-环丙基羰基-2-氟苄基)-3-乙氧基羰基亚甲基-4-(4-甲基苯基磺酰硫基)哌啶、
(E)-1-(2-氯-α-甲氧基羰基苄基)-3-乙氧基羰基亚甲基-4-(4-甲基苯基磺酰硫基)哌啶、
(Z)-4-〔(R)-2-氨基-2-羧基乙基二硫基〕-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)哌啶。
23.权利要求22所述的环胺化合物或其药理上可容许的盐,其为1-(α-环丙基羰基-2-氟苄基)-4-(4-甲基苯基磺酰硫基)哌啶或其药理上可容许的盐。
24.权利要求22所述的环胺化合物或其药理上可容许的盐,其为1-(2-氟-α-甲氧基羰基苄基)-4-(4-甲基苯基磺酰硫基)哌啶或其药理上可容许的盐。
25.权利要求22所述的环胺化合物或其药理上可容许的盐,其为1-(α-环丙基羰基-2-氟苄基)-4-(4-甲氧基苯基亚磺酰硫基)哌啶或其药理上可容许的盐。
26.权利要求22所述的环胺化合物或其药理上可容许的盐,其为Z)-4-〔(R)-2-氨基-2-羧基乙基二硫基〕-3-羧基亚甲基-1-(α-环丙基羰基-2-氟苄基)哌啶或其药理上可容许的盐。
27.药物组合物,其含有治疗有效量的权利要求1~26中任何一项所述的环胺化合物或其药理上可容许的盐。
28.权利要求1~26中任何一项所述的环胺化合物或其药理上可容许的盐在制造预防或治疗栓塞症的药物中的应用。
29.权利要求1~26中任何一项所述的环胺化合物或其药理上可容许的盐在制造预防或治疗血栓症的药物中的应用。
30.权利要求1~26中任何一项所述的环胺化合物或其药理上可容许的盐在制造预防或治疗动脉硬化栓塞症的药物中的应用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP4692198 | 1998-02-27 | ||
JP46921/98 | 1998-02-27 | ||
JP46921/1998 | 1998-02-27 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1298389A CN1298389A (zh) | 2001-06-06 |
CN100369896C true CN100369896C (zh) | 2008-02-20 |
Family
ID=12760807
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB998055786A Expired - Lifetime CN100369896C (zh) | 1998-02-27 | 1999-02-26 | 环胺化合物 |
Country Status (23)
Country | Link |
---|---|
US (1) | US6610708B1 (zh) |
EP (1) | EP1063230B1 (zh) |
KR (1) | KR100567950B1 (zh) |
CN (1) | CN100369896C (zh) |
AT (1) | ATE238279T1 (zh) |
AU (1) | AU737303B2 (zh) |
BR (1) | BRPI9908319B8 (zh) |
CA (1) | CA2322171C (zh) |
CZ (1) | CZ300821B6 (zh) |
DE (1) | DE69907166T2 (zh) |
DK (1) | DK1063230T3 (zh) |
ES (1) | ES2196772T3 (zh) |
HU (1) | HU225741B1 (zh) |
ID (1) | ID25589A (zh) |
IL (1) | IL138068A (zh) |
MX (1) | MXPA00008439A (zh) |
NO (1) | NO317882B1 (zh) |
NZ (1) | NZ506574A (zh) |
PL (1) | PL200666B1 (zh) |
PT (1) | PT1063230E (zh) |
RU (1) | RU2203887C2 (zh) |
TR (1) | TR200002505T2 (zh) |
WO (1) | WO1999043648A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107921135A (zh) * | 2015-04-30 | 2018-04-17 | 密歇根大学董事会 | 噻吩并吡啶化合物的混合二硫共轭物及其用法 |
Families Citing this family (61)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20060108691A (ko) * | 2003-11-28 | 2006-10-18 | 상꾜 가부시키가이샤 | 헤테로아릴고리를 갖는 고리상 아민 유도체 |
US20060009491A1 (en) * | 2004-06-24 | 2006-01-12 | Incyte Corporation | Amido compounds and their use as pharmaceuticals |
EP1758580A4 (en) | 2004-06-24 | 2008-01-16 | Incyte Corp | N-SUBSTITUTED PIPERIDINE AND ITS USE AS A MEDICAMENT |
CA2609852A1 (en) * | 2005-05-27 | 2006-11-30 | Daiichi Sankyo Company, Limited | Cyclic amine derivative having substituted alkyl group |
WO2014037832A2 (en) | 2012-09-06 | 2014-03-13 | Mahesh Kandula | Compositions and methods for the treatment of epilepsy and neurological diseases |
US9399634B2 (en) | 2012-05-07 | 2016-07-26 | Cellix Bio Private Limited | Compositions and methods for the treatment of depression |
CA2873093A1 (en) | 2012-05-07 | 2013-11-14 | Cellixbio Private Limited | Compositions and methods for treatment of neuromuscular disorders and neurodegenerative disorders |
JP2015519333A (ja) | 2012-05-07 | 2015-07-09 | セリックスビオ プライヴェート リミテッド | 神経疾患の治療のための組成物および方法 |
WO2013167992A1 (en) | 2012-05-08 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of inflammatory disorders |
WO2013167991A1 (en) | 2012-05-08 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of metabolic disorders |
WO2013168022A1 (en) * | 2012-05-08 | 2013-11-14 | Mahesh Kandula | Compositions and methods for treating atherothrombosis |
WO2013168025A1 (en) | 2012-05-08 | 2013-11-14 | Mahesh Kandula | Compositions and methods for treatment of blood clotting disorders |
US9434704B2 (en) | 2012-05-08 | 2016-09-06 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurological degenerative disorders |
US9266823B2 (en) | 2012-05-08 | 2016-02-23 | Cellix Bio Private Limited | Compositions and methods for the treatment of parkinson's disease |
US9346742B2 (en) | 2012-05-10 | 2016-05-24 | Cellix Bio Private Limited | Compositions and methods for the treatment of fibromyalgia pain |
US9573927B2 (en) | 2012-05-10 | 2017-02-21 | Cellix Bio Private Limited | Compositions and methods for the treatment of severe pain |
US9499526B2 (en) | 2012-05-10 | 2016-11-22 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurologic diseases |
WO2013167997A2 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of metabolic syndrome |
WO2013168005A2 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of restless leg syndrome and fibromyalgia |
WO2013168015A1 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of asthma and allergy |
SG11201407318UA (en) | 2012-05-10 | 2014-12-30 | Cellix Bio Private Ltd | Compositions and methods for the treatment of metabolic syndrome |
US9273061B2 (en) | 2012-05-10 | 2016-03-01 | Cellix Bio Private Limited | Compositions and methods for the treatment of chronic pain |
US9315461B2 (en) | 2012-05-10 | 2016-04-19 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurologic diseases |
US9233161B2 (en) | 2012-05-10 | 2016-01-12 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurological conditions |
WO2013168014A1 (en) | 2012-05-10 | 2013-11-14 | Mahesh Kandula | Compositions and methods for the treatment of familial amyloid polyneuropathy |
US9321775B2 (en) | 2012-05-10 | 2016-04-26 | Cellix Bio Private Limited | Compositions and methods for the treatment of moderate to severe pain |
US9242939B2 (en) | 2012-05-10 | 2016-01-26 | Cellix Bio Private Limited | Compositions and methods for the treatment of respiratory disorders |
WO2013175344A2 (en) | 2012-05-23 | 2013-11-28 | Mahesh Kandula | Compositions and methods for the treatment of periodontitis and rheumatoid arthritis |
WO2013175376A2 (en) | 2012-05-23 | 2013-11-28 | Mahesh Kandula | Compositions and methods for the treatment of local pain |
US9498461B2 (en) | 2012-05-23 | 2016-11-22 | Cellix Bio Private Limited | Compositions and methods for the treatment of inflammatory bowel disease |
EP2852569B1 (en) | 2012-05-23 | 2020-10-14 | Cellixbio Private Limited | Compositions and methods for the treatment of multiple sclerosis |
WO2013175377A2 (en) | 2012-05-23 | 2013-11-28 | Mahesh Kandula | Compositions and methods for the treatment of mucositis |
US9227974B2 (en) | 2012-05-23 | 2016-01-05 | Cellex Bio Private Limited | Compositions and methods for the treatment of respiratory disorders |
US9108942B1 (en) | 2014-11-05 | 2015-08-18 | Mahesh Kandula | Compositions and methods for the treatment of moderate to severe pain |
US9187427B2 (en) | 2012-08-03 | 2015-11-17 | Cellix Bio Private Limited | N-substituted nicotinamide compounds and compositions for the treatment migraine and neurologic diseases |
US9624168B2 (en) | 2012-09-06 | 2017-04-18 | Cellix Bio Private Limited | Compositions and methods for the treatment inflammation and lipid disorders |
EP2892878A4 (en) | 2012-09-08 | 2016-02-24 | Cellix Bio Private Ltd | COMPOSITIONS AND METHODS FOR TREATING INFLAMMATION AND LIPID DISORDER |
AU2014205629B2 (en) | 2013-01-09 | 2016-12-22 | The Regents Of The University Of Michigan | Mixed disulfide conjugates of thienopyridine compounds and uses thereof |
US9333187B1 (en) | 2013-05-15 | 2016-05-10 | Cellix Bio Private Limited | Compositions and methods for the treatment of inflammatory bowel disease |
WO2014195961A1 (en) | 2013-06-04 | 2014-12-11 | Mahesh Kandula | Compositions and methods for the treatment of diabetes and pre-diabetes |
US9096537B1 (en) | 2014-12-31 | 2015-08-04 | Mahesh Kandula | Compositions and methods for the treatment of mucositis |
WO2016046835A1 (en) | 2014-09-26 | 2016-03-31 | Cellix Bio Private Limited | Compositions and methods for the treatment of epilepsy and neurological disorders |
CN107207403A (zh) | 2014-09-29 | 2017-09-26 | 塞尔利克斯生物私人有限公司 | 用于治疗多发性硬化的组合物和方法 |
CN107108535B (zh) | 2014-10-27 | 2020-04-28 | 塞尔利克斯生物私人有限公司 | 用于治疗多发性硬化的富马酸单甲酯与哌嗪或乙二胺的三组分盐 |
US9290486B1 (en) | 2014-11-05 | 2016-03-22 | Cellix Bio Private Limited | Compositions and methods for the treatment of epilepsy |
US9173877B1 (en) | 2014-11-05 | 2015-11-03 | Cellix Bio Private Limited | Compositions and methods for the treatment of local pain |
US9284287B1 (en) | 2014-11-05 | 2016-03-15 | Cellix Bio Private Limited | Compositions and methods for the suppression of carbonic anhydrase activity |
US10208014B2 (en) | 2014-11-05 | 2019-02-19 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurological disorders |
US9150557B1 (en) | 2014-11-05 | 2015-10-06 | Cellix Bio Private Limited | Compositions and methods for the treatment of hyperglycemia |
US9321716B1 (en) | 2014-11-05 | 2016-04-26 | Cellix Bio Private Limited | Compositions and methods for the treatment of metabolic syndrome |
US9175008B1 (en) | 2014-11-05 | 2015-11-03 | Cellix Bio Private Limited | Prodrugs of anti-platelet agents |
US9932294B2 (en) | 2014-12-01 | 2018-04-03 | Cellix Bio Private Limited | Compositions and methods for the treatment of multiple sclerosis |
US9206111B1 (en) | 2014-12-17 | 2015-12-08 | Cellix Bio Private Limited | Compositions and methods for the treatment of neurological diseases |
JP6679616B2 (ja) | 2015-01-06 | 2020-04-22 | セリックス バイオ プライヴェート リミテッドCellix Bio Private Limited | 炎症及び疼痛の治療のための組成物及び方法 |
CN106554369A (zh) * | 2015-09-25 | 2017-04-05 | 陕西合成药业股份有限公司 | 噻吩并吡啶类衍生物及其制备方法和用途 |
CN106554302A (zh) * | 2015-09-25 | 2017-04-05 | 陕西合成药业股份有限公司 | 噻吩并吡啶类衍生物及其制备方法和用途 |
CN106554368A (zh) * | 2015-09-25 | 2017-04-05 | 陕西合成药业股份有限公司 | 噻吩并吡啶类衍生物及其制备方法和用途 |
US11642335B2 (en) * | 2019-09-26 | 2023-05-09 | Board Of Regents, The University Of Texas System | Chemical synthesis of clopidogrel active metabolites and disulfide conjugate prodrugs |
CN111484446A (zh) * | 2020-04-02 | 2020-08-04 | 北京翼方生物科技有限责任公司 | 氯吡格雷代谢活性体二硫衍生物、其制备方法及医药用途 |
CN111848497A (zh) * | 2020-07-28 | 2020-10-30 | 内蒙古医科大学 | 氯吡格雷活性代谢物衍生物、其前药及其制备方法与应用 |
CN112851570A (zh) * | 2021-01-13 | 2021-05-28 | 北京沃邦医药科技有限公司 | 不饱和环胺半胱氨酸二硫衍生物制备方法及其医药用途 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US555854A (en) * | 1896-03-03 | Brush-handle attachment | ||
WO1998008811A1 (fr) * | 1996-08-28 | 1998-03-05 | Sankyo Company, Limited | Derives cycliques d'amines |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3647796A (en) * | 1968-12-23 | 1972-03-07 | Parke Davis & Co | Cyclicamino alkylaminothioacridine |
FR2215948B1 (zh) | 1973-02-01 | 1976-05-14 | Centre Etd Ind Pharma | |
FR2530247B1 (fr) | 1982-07-13 | 1986-05-16 | Sanofi Sa | Nouveaux derives de la thieno (3, 2-c) pyridine, leur procede de preparation et leur application therapeutique |
FR2576901B1 (fr) | 1985-01-31 | 1987-03-20 | Sanofi Sa | Nouveaux derives de l'acide a-(oxo-2 hexahydro-2,4,5,6,7,7a thieno (3,2-c) pyridyl-5) phenyl acetique, leur procede de preparation et leur application therapeutique |
FI101150B (fi) | 1991-09-09 | 1998-04-30 | Sankyo Co | Menetelmä lääkeaineina käyttökelpoisten tetrahydrotienopyridiinin johd annaisten valmistamiseksi |
AU3351293A (en) * | 1992-01-21 | 1993-08-03 | Glaxo Group Limited | Piperidineacetic acid derivatives as inhibitors of fibrinogen-dependent blood platelet aggregation |
ATE181832T1 (de) | 1993-04-23 | 1999-07-15 | Hoechst Ag | Pyrido-pyrimidindione, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
AU698748B2 (en) | 1993-09-17 | 1998-11-05 | Brigham And Women's Hospital | Use of nitric oxide-adducts to prevent thrombosis on artificial and vascular surfaces |
-
1999
- 1999-02-26 TR TR2000/02505T patent/TR200002505T2/xx unknown
- 1999-02-26 EP EP99906508A patent/EP1063230B1/en not_active Expired - Lifetime
- 1999-02-26 CN CNB998055786A patent/CN100369896C/zh not_active Expired - Lifetime
- 1999-02-26 AT AT99906508T patent/ATE238279T1/de active
- 1999-02-26 ES ES99906508T patent/ES2196772T3/es not_active Expired - Lifetime
- 1999-02-26 HU HU0100950A patent/HU225741B1/hu unknown
- 1999-02-26 ID IDW20001635A patent/ID25589A/id unknown
- 1999-02-26 AU AU26413/99A patent/AU737303B2/en not_active Expired
- 1999-02-26 DE DE69907166T patent/DE69907166T2/de not_active Expired - Lifetime
- 1999-02-26 IL IL13806899A patent/IL138068A/xx not_active IP Right Cessation
- 1999-02-26 PL PL342573A patent/PL200666B1/pl unknown
- 1999-02-26 BR BRPI9908319-1 patent/BRPI9908319B8/pt not_active IP Right Cessation
- 1999-02-26 NZ NZ506574A patent/NZ506574A/xx not_active IP Right Cessation
- 1999-02-26 DK DK99906508T patent/DK1063230T3/da active
- 1999-02-26 PT PT99906508T patent/PT1063230E/pt unknown
- 1999-02-26 CA CA002322171A patent/CA2322171C/en not_active Expired - Lifetime
- 1999-02-26 WO PCT/JP1999/000924 patent/WO1999043648A1/ja active IP Right Grant
- 1999-02-26 MX MXPA00008439A patent/MXPA00008439A/es active IP Right Grant
- 1999-02-26 KR KR1020007009485A patent/KR100567950B1/ko not_active IP Right Cessation
- 1999-02-26 RU RU2000122434/04A patent/RU2203887C2/ru active
- 1999-02-26 CZ CZ20003119A patent/CZ300821B6/cs not_active IP Right Cessation
-
2000
- 2000-08-24 US US09/622,849 patent/US6610708B1/en not_active Expired - Lifetime
- 2000-08-25 NO NO20004279A patent/NO317882B1/no not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US555854A (en) * | 1896-03-03 | Brush-handle attachment | ||
WO1998008811A1 (fr) * | 1996-08-28 | 1998-03-05 | Sankyo Company, Limited | Derives cycliques d'amines |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107921135A (zh) * | 2015-04-30 | 2018-04-17 | 密歇根大学董事会 | 噻吩并吡啶化合物的混合二硫共轭物及其用法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100369896C (zh) | 环胺化合物 | |
TW475931B (en) | A substituted condensed heterocyclic compound | |
BRPI0909535A2 (pt) | "4-(3-alquilsulfinilbenzoil)pirazol da formula ou seu sal, composição herbicida, método de controle de plantas indesejadas, uso de um composto da fórmula e composto" | |
EP2459528B1 (de) | 2-(3-alkylthiobenzoyl)cyclohexandione und ihre verwendung als herbizide | |
BR112013001368B1 (pt) | 4-(4-halogenalquil-3-tiobenzoil)pirazol, seu uso como herbicidas, e seu intermediário | |
TW499295B (en) | Pyrazole compounds and plant disease control agent | |
US11051515B2 (en) | 3-acyl-benzamides and their use as herbicides | |
AU666590B2 (en) | Alpha, omega-diarylalkane derivatives, their preparation and their use in the treatment and prevention of circulatory diseases and psychosis | |
JP2009019013A (ja) | 新規ヘテロアリールピペリジン誘導体 | |
JPH11310570A (ja) | 環状アミノ化合物 | |
JP2001131067A (ja) | 血小板凝集抑制剤又は動脈硬化進展抑制剤 | |
CN1328278C (zh) | N-酰基氨基酸酰胺化合物及其制造中间体 | |
US6620961B1 (en) | Biarylalkylenecarbamic acid derivatives and bacteriocides for agricultural and horticultural use | |
TW397827B (en) | Pyrimidin-4-one derivatives, their use, intermediates for their production, and processes for producing these intermediates | |
JP2004256525A (ja) | N−[1−置換−2−(アリールアミノ)エチル]アミド誘導体 | |
JP2004131499A (ja) | 水溶性トリアゾール化合物 | |
EA040316B1 (ru) | 3-ацилбензамиды и их применение в качестве гербицидов | |
JP2005263636A (ja) | 水溶性トリアゾール医薬組成物 | |
TW200410948A (en) | Water soluble triazole compounds |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C41 | Transfer of patent application or patent right or utility model | ||
TR01 | Transfer of patent right |
Effective date of registration: 20170111 Address after: Tokyo, Japan, Japan Patentee after: Daiichi Sankyo Co., Ltd. Patentee after: Ube Industries, Ltd. Address before: Tokyo, Japan, Japan Patentee before: Sankyo Co., Ltd. Patentee before: Ube Industries, Ltd. |
|
CX01 | Expiry of patent term | ||
CX01 | Expiry of patent term |
Granted publication date: 20080220 |