CN1124957A - 血小板聚集抑制剂 - Google Patents
血小板聚集抑制剂 Download PDFInfo
- Publication number
- CN1124957A CN1124957A CN94192290A CN94192290A CN1124957A CN 1124957 A CN1124957 A CN 1124957A CN 94192290 A CN94192290 A CN 94192290A CN 94192290 A CN94192290 A CN 94192290A CN 1124957 A CN1124957 A CN 1124957A
- Authority
- CN
- China
- Prior art keywords
- amino
- phenyl
- oxo
- ethanoyl
- imino methyl
- 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.)
- Granted
Links
- -1 1-amidinophenyl-pyrrolidones piperidinones Chemical class 0.000 title claims description 107
- 229940127218 antiplatelet drug Drugs 0.000 title 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 179
- 150000001875 compounds Chemical class 0.000 claims abstract description 172
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 241000124008 Mammalia Species 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 312
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 248
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 176
- 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 claims description 104
- 229910052799 carbon Inorganic materials 0.000 claims description 103
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 87
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 74
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- UQPOLPWFZXUCOT-UHFFFAOYSA-N ethyl propanoate;2,2,2-trifluoroacetic acid Chemical compound CCOC(=O)CC.OC(=O)C(F)(F)F UQPOLPWFZXUCOT-UHFFFAOYSA-N 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 30
- HVAMZGADVCBITI-UHFFFAOYSA-N pent-4-enoic acid Chemical compound OC(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-N 0.000 claims description 25
- DYWOPZYICSJYMT-UHFFFAOYSA-N propanoic acid;2,2,2-trifluoroacetic acid Chemical compound CCC(O)=O.OC(=O)C(F)(F)F DYWOPZYICSJYMT-UHFFFAOYSA-N 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 22
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 18
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 16
- 125000003368 amide group Chemical group 0.000 claims description 15
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 claims description 15
- MLBYLEUJXUBIJJ-UHFFFAOYSA-N pent-4-ynoic acid Chemical compound OC(=O)CCC#C MLBYLEUJXUBIJJ-UHFFFAOYSA-N 0.000 claims description 15
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- DDJDJYICKCWLHD-DAFXYXGESA-N CCOC(=O)[C@H](CC=C)NC(=O)CC1CCCN(C1=O)C2=CC=C(C=C2)C=NN Chemical compound CCOC(=O)[C@H](CC=C)NC(=O)CC1CCCN(C1=O)C2=CC=C(C=C2)C=NN DDJDJYICKCWLHD-DAFXYXGESA-N 0.000 claims description 9
- 125000004423 acyloxy group Chemical group 0.000 claims description 9
- 239000003146 anticoagulant agent Substances 0.000 claims description 9
- 229940127219 anticoagulant drug Drugs 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 235000019260 propionic acid Nutrition 0.000 claims description 9
- 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 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- KTCIDVULKRHVRD-WUJWULDRSA-N (2S)-2-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopyrrolidin-3-yl]acetyl]amino]pent-4-enoic acid Chemical compound NN=CC1=CC=C(C=C1)N1C(C(CC1)CC(=O)N[C@H](C(=O)O)CC=C)=O KTCIDVULKRHVRD-WUJWULDRSA-N 0.000 claims description 7
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- YVOOMFLKCLBVIK-UHFFFAOYSA-N ethyl butanoate 2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCCC(=O)OCC YVOOMFLKCLBVIK-UHFFFAOYSA-N 0.000 claims description 6
- UCIZAUTZEBGXLY-UHFFFAOYSA-N ethyl hexanoate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCCCCC(=O)OCC UCIZAUTZEBGXLY-UHFFFAOYSA-N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- XWDAERJIFZLPHF-UHFFFAOYSA-N 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]-3-thiophen-3-ylpropanoic acid Chemical compound C1=CC(C=NN)=CC=C1N1C(=O)C(CC(=O)NC(CC(O)=O)C2=CSC=C2)CCC1 XWDAERJIFZLPHF-UHFFFAOYSA-N 0.000 claims description 5
- IFGRDMOQTOYIRO-DAFXYXGESA-N C1CC(C(=O)N(C1)C2=CC=C(C=C2)C=NN)CC(=O)N[C@@H](CC3=COC=C3)C(=O)O Chemical compound C1CC(C(=O)N(C1)C2=CC=C(C=C2)C=NN)CC(=O)N[C@@H](CC3=COC=C3)C(=O)O IFGRDMOQTOYIRO-DAFXYXGESA-N 0.000 claims description 5
- ZDSXEXMRSMYZIE-DAFXYXGESA-N CCOC(=O)[C@H](CC#C)NC(=O)CC1CCCN(C1=O)C2=CC=C(C=C2)C=NN Chemical compound CCOC(=O)[C@H](CC#C)NC(=O)CC1CCCN(C1=O)C2=CC=C(C=C2)C=NN ZDSXEXMRSMYZIE-DAFXYXGESA-N 0.000 claims description 5
- HUTZDNPDMJFVTO-LWKPJOBUSA-N CCOC(=O)[C@H](CC#C)NC(=O)CC1CCN(C1=O)C2=CC=C(C=C2)C=NN Chemical compound CCOC(=O)[C@H](CC#C)NC(=O)CC1CCN(C1=O)C2=CC=C(C=C2)C=NN HUTZDNPDMJFVTO-LWKPJOBUSA-N 0.000 claims description 5
- VCTXSFDDGLDPSN-LYKKTTPLSA-N CCOC(=O)[C@H](CC=C)NC(=O)NC1CCN(C1=O)C2=CC=C(C=C2)C=NN Chemical compound CCOC(=O)[C@H](CC=C)NC(=O)NC1CCN(C1=O)C2=CC=C(C=C2)C=NN VCTXSFDDGLDPSN-LYKKTTPLSA-N 0.000 claims description 5
- SMWOOPXJZAGCNM-UHFFFAOYSA-N FC(C(=O)O)(F)F.C1(=CC=CC=C1)C(C(=O)O)C Chemical compound FC(C(=O)O)(F)F.C1(=CC=CC=C1)C(C(=O)O)C SMWOOPXJZAGCNM-UHFFFAOYSA-N 0.000 claims description 5
- 239000005864 Sulphur Substances 0.000 claims description 5
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 5
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 5
- 125000005239 aroylamino group Chemical group 0.000 claims description 5
- 125000005110 aryl thio group Chemical group 0.000 claims description 5
- SQIIOMYKKDNKJQ-UHFFFAOYSA-N butanoic acid;2,2,2-trifluoroacetic acid Chemical compound CCCC(O)=O.OC(=O)C(F)(F)F SQIIOMYKKDNKJQ-UHFFFAOYSA-N 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- YVWYEJVEWOHNNW-UHFFFAOYSA-N 3-(furan-2-yl)-3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]propanoic acid Chemical compound C1=CC(C=NN)=CC=C1N1C(=O)C(CC(=O)NC(CC(O)=O)C=2OC=CC=2)CCC1 YVWYEJVEWOHNNW-UHFFFAOYSA-N 0.000 claims description 4
- HWELRYDLBHRHPE-UHFFFAOYSA-N 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]-5-phenylpent-4-ynoic acid Chemical compound C1=CC(C=NN)=CC=C1N1C(=O)C(CC(=O)NC(CC(O)=O)C#CC=2C=CC=CC=2)CCC1 HWELRYDLBHRHPE-UHFFFAOYSA-N 0.000 claims description 4
- GBEGINCXPOBIGG-UHFFFAOYSA-N 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]-6,6-dimethylhept-4-ynoic acid Chemical compound O=C1C(CC(=O)NC(CC(O)=O)C#CC(C)(C)C)CCCN1C1=CC=C(C=NN)C=C1 GBEGINCXPOBIGG-UHFFFAOYSA-N 0.000 claims description 4
- GHFWTPWGKULBET-UHFFFAOYSA-N 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]butanoic acid Chemical compound O=C1C(CC(=O)NC(CC(O)=O)C)CCCN1C1=CC=C(C=NN)C=C1 GHFWTPWGKULBET-UHFFFAOYSA-N 0.000 claims description 4
- JZCPJJKHDRGSFY-UHFFFAOYSA-N 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]propanoic acid Chemical compound C1=CC(C=NN)=CC=C1N1C(=O)C(CC(=O)NCCC(O)=O)CCC1 JZCPJJKHDRGSFY-UHFFFAOYSA-N 0.000 claims description 4
- PMCLZZYRGICVSK-UHFFFAOYSA-N 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopyrrolidin-3-yl]acetyl]amino]butanoic acid Chemical compound O=C1C(CC(=O)NC(CC(O)=O)C)CCN1C1=CC=C(C=NN)C=C1 PMCLZZYRGICVSK-UHFFFAOYSA-N 0.000 claims description 4
- XOSJQOZJKLYWQZ-UHFFFAOYSA-N 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopyrrolidin-3-yl]acetyl]amino]propanoic acid Chemical compound C1=CC(C=NN)=CC=C1N1C(=O)C(CC(=O)NCCC(O)=O)CC1 XOSJQOZJKLYWQZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000002905 alkanoylamido group Chemical group 0.000 claims description 4
- BULRYVCEKWWJLH-UHFFFAOYSA-N ethyl 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]-5-phenylpent-4-ynoate Chemical compound C=1C=CC=CC=1C#CC(CC(=O)OCC)NC(=O)CC(C1=O)CCCN1C1=CC=C(C=NN)C=C1 BULRYVCEKWWJLH-UHFFFAOYSA-N 0.000 claims description 4
- DMYZZNALHBSAPH-UHFFFAOYSA-N ethyl 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]-6,6-dimethylhept-4-ynoate Chemical compound O=C1C(CC(=O)NC(CC(=O)OCC)C#CC(C)(C)C)CCCN1C1=CC=C(C=NN)C=C1 DMYZZNALHBSAPH-UHFFFAOYSA-N 0.000 claims description 4
- ISZWGQPNVQONJF-UHFFFAOYSA-N ethyl 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopyrrolidin-3-yl]acetyl]amino]-3-phenylpropanoate Chemical compound C=1C=CC=CC=1C(CC(=O)OCC)NC(=O)CC(C1=O)CCN1C1=CC=C(C=NN)C=C1 ISZWGQPNVQONJF-UHFFFAOYSA-N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 3
- MZZOLYLOZZWWGL-UHFFFAOYSA-N ethyl 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]pent-4-ynoate Chemical compound NN=CC1=CC=C(C=C1)N1C(C(CCC1)CC(=O)NC(CC(=O)OCC)C#C)=O MZZOLYLOZZWWGL-UHFFFAOYSA-N 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 45
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 12
- UOTVYRCVNKFZCR-LWKPJOBUSA-N CCOC(=O)[C@H](CC=C)NC(=O)CC1CCN(C1=O)C2=CC=C(C=C2)C=NN Chemical compound CCOC(=O)[C@H](CC=C)NC(=O)CC1CCN(C1=O)C2=CC=C(C=C2)C=NN UOTVYRCVNKFZCR-LWKPJOBUSA-N 0.000 claims 8
- MGFMERGXPMAWJR-UHFFFAOYSA-N ethyl 3-[[2-[1-(4-methanehydrazonoylphenyl)-2-oxopiperidin-3-yl]acetyl]amino]-3-phenylpropanoate Chemical compound C=1C=CC=CC=1C(CC(=O)OCC)NC(=O)CC(C1=O)CCCN1C1=CC=C(C=NN)C=C1 MGFMERGXPMAWJR-UHFFFAOYSA-N 0.000 claims 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims 1
- 229960003328 benzoyl peroxide Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 14
- 230000005764 inhibitory process Effects 0.000 abstract description 12
- 208000010110 spontaneous platelet aggregation Diseases 0.000 abstract description 9
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 195
- 238000002360 preparation method Methods 0.000 description 120
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 238000004458 analytical method Methods 0.000 description 65
- 238000005481 NMR spectroscopy Methods 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 46
- 230000008569 process Effects 0.000 description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 37
- 235000019439 ethyl acetate Nutrition 0.000 description 34
- 238000001228 spectrum Methods 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 238000004007 reversed phase HPLC Methods 0.000 description 33
- 239000012467 final product Substances 0.000 description 32
- 239000011541 reaction mixture Substances 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 30
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 29
- 150000001721 carbon Chemical group 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
- 239000012264 purified product Substances 0.000 description 22
- 108090000371 Esterases Proteins 0.000 description 21
- 210000004185 liver Anatomy 0.000 description 21
- 210000001772 blood platelet Anatomy 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- RYJHOPWTZAFUQQ-UHFFFAOYSA-N 2-[1-(4-cyanophenyl)-2-oxopyrrolidin-3-yl]acetic acid Chemical compound O=C1C(CC(=O)O)CCN1C1=CC=C(C#N)C=C1 RYJHOPWTZAFUQQ-UHFFFAOYSA-N 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- 238000005406 washing Methods 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 15
- 229910052794 bromium Inorganic materials 0.000 description 15
- 239000012141 concentrate Substances 0.000 description 15
- LRTRXDSAJLSRTG-UHFFFAOYSA-N 4-bromobutanoyl chloride Chemical compound ClC(=O)CCCBr LRTRXDSAJLSRTG-UHFFFAOYSA-N 0.000 description 13
- 210000004369 blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000011161 development Methods 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 10
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 9
- LDRBRYURDQQPMN-LURJTMIESA-N ethyl (2s)-2-aminopent-4-enoate Chemical compound CCOC(=O)[C@@H](N)CC=C LDRBRYURDQQPMN-LURJTMIESA-N 0.000 description 9
- 239000012299 nitrogen atmosphere Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- GWEQMFFMXGCPJZ-ZCFIWIBFSA-N ethyl (3s)-3-aminopent-4-enoate Chemical compound CCOC(=O)C[C@H](N)C=C GWEQMFFMXGCPJZ-ZCFIWIBFSA-N 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 208000007536 Thrombosis Diseases 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 102000008186 Collagen Human genes 0.000 description 6
- 108010035532 Collagen Proteins 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 229940000635 beta-alanine Drugs 0.000 description 6
- 235000013877 carbamide Nutrition 0.000 description 6
- 238000000605 extraction Methods 0.000 description 6
- 150000002460 imidazoles Chemical class 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000003825 pressing Methods 0.000 description 6
- 102000008946 Fibrinogen Human genes 0.000 description 5
- 108010049003 Fibrinogen Proteins 0.000 description 5
- 230000005587 bubbling Effects 0.000 description 5
- 239000004202 carbamide Substances 0.000 description 5
- 229940012952 fibrinogen Drugs 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
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- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
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- 125000006168 tricyclic group Chemical group 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- 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
-
- 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
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
-
- 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
- C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—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 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon 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
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Abstract
本发明涉及用于抑制血小板聚集的具有如下通式的化合物或其可药用盐:
本发明还涉及这些苯基脒衍生物的药物组合物以及通过施用这些化合物和组合物抑制哺乳动物血小板聚集的方法。
Description
本发明的领域
本发明涉及抑制哺乳动物血小板聚集的药物制剂(化合物)。
本发明的背景
纤维蛋白原是作为血浆正常成分存在的糖蛋白,它参与血凝块过程中的血小板聚集和纤维蛋白的形成。
血小板是存在于全血中的细胞单元,它也参与血凝固。在血凝固过程中与血小板结合的纤维蛋白原对正常的血小板功能来说非常重要,当血管受到损伤时,与纤维蛋白原结合的血小板开始聚集并形成血栓。纤维蛋白原与血小板相互作用是通过称为GP IIb/IIIa的膜糖蛋白配合物发生的,这是血小板功能的一个重要特征,这种相互作用的抑制剂可用于调节血小板血栓形成。
还已知其他大糖蛋白(称为纤维结合素,为主要的细胞外基质蛋白)与血小板相互作用,现已发现在纤维结合素的与细胞结合区域中的各种相对大的多肽片段具有连接细胞的活性,参见美国专利4,517,686;4,589,881;和4,661,111。某些同样分子的相对短的肽片段当被固定在底物上时可促进细胞与底物连接或当处于被溶解或悬浮形式时可以抑制连接,参见美国专利4,578,079和4,614,517。
在美国专利4,683,291中公开了用合成肽抑制血小板功能,这种合成肽被用作与血小板结合的纤维蛋白原的高亲和力的拮抗剂。美国专利4,857,508公开了用作血小板聚集抑制剂的四肽。
在下列文献中公开了其他合成的肽和作为与血小板结合的纤维蛋白原的抑制剂:Koczewiak等人,Biochem.23,1767-1774(1984);Plow等人,Proc.Natl.Acad.Sci.82,8057-8061(1985);Ruggeri等人,Ibid.83,5708-5712(1986);Ginsberg等人J.Biol.Chem.260(7),3931-3936(1985);Haverstick等人,Blood 66(4),946-952(1985);和Ruoslahti &Pierschbacher,Science 238,491-497(1987)。欧洲专利申请275,748和298,820公开了另外一些抑制剂肽。
欧洲专利申请512,831公开了抑制纤维蛋白原与血小板结合的哌啶基烷基氮杂环烷酮,因此可用于抑制血小板的聚集。
欧洲专利申请503,548公开了用于抑制细胞相互作用的环脲衍生物(咪唑酮和三唑酮),因此可用于治疗或预防血栓形成、栓塞和肿瘤转移。
欧洲专利申请496,378公开了抑制细胞-细胞和细胞-基质相互作用的脒基联苯基化合物,因此可用于治疗血栓形成、脑血管疾病、肺栓塞、心肌梗塞形成、动脉硬化、骨质疏松症和肿瘤转移。
欧洲专利申请445,96公开了对粘性蛋白与血小板的结合以及对血小板聚集和细胞-细胞粘接具有抑制作用的乙酸衍生物。
欧洲专利申请372,486公开了N-酰基β氨基酸衍生物及其盐,所述化合物可用于在治疗血栓形成、中风、心肌梗塞形成、炎症和动脉硬化中抑制血小板聚集以及抑制转移。
欧洲专利申请381,033公开了用于治疗血栓形成、中风、心肌梗塞形成、炎症和动脉硬化和肿瘤的脒基或胍基芳基取代的链烷酸衍生物。
美国专利申请07/847,260;07/777,811和07/777,875公开了用作血小板聚集抑制剂的脒基苯氨基琥珀酸衍生物。
美国专利申请07/904,237公开了用作血小板聚集抑制剂的苯基脒酸链烷酸和内酯类化合物。
本发明的概述
Z1和Z2独立选自氢、1-6个碳原子的烷基、羟基、卤代和1-6个碳原子的烷氧基;
R1选自氢、1-6个碳原子的低级烷基、2-6个碳原子的低级链烯基2-6个碳原子的低级炔基、烷氧羰氧烷基、脂环烃基和芳族烃基,它们可被羟基、1-6个碳原子的低级烷氧基、1-6个碳原子的低级烷基、卤代、硝基、氨基、酰氧基、苯基或萘基任意取代;
R2选自氢、1-6个碳原子的低级烷基、2-6个碳原子的低级链烯基、2-6个碳原子的低级炔基、环烷基、芳基、单环、双环或三环杂环基团其中存在1-3个独立选自氧、氮或硫的杂原子,其中所述杂环基团被一个或多个取代基任意取代,取代基选自羟基、1-6个碳原子的低级烷氧基、1-6个碳原子的低级烷基、卤代、硝基、氰基、叠氮基、脲基、取代脲基、羧基、羰基衍生基团、三氟甲基、酰氧基、烷硫基、芳硫基、烷基亚磺酰基、芳基亚磺酰基、烷基磺酰基、芳基磺酰基、氨基、烷基氨基、三烷基甲硅烷基、氨基磺酰基、二烷基氨基、链烷酰氨基、芳酰基氨基、苯基和萘基;
R3选自氢、1-6个碳原子的烷基、1-6碳原子的烷氧基、氟、氨基、一烷基氨基、二烷基氨基、酰氨基、烷基磺酰基氨基、芳基磺酰基氨基、羟基、烷氧羰基和烷氧羰基烷基;
m为1-4的整数;
n为0-4的整数;以及
p为0或1,其中n和p不均为0。
本发明的另一目的是提供含有式I化合物的药物组合物。这些化合物和组合物可用作血小板聚集的调节剂和/或抑制剂。本发明还涉及治疗性地抑制或调节需要如此治疗的哺乳动物的血小板聚集。
本发明的详细描述
本发明涉及如上所述的式(I)表示的一类化合物。
本发明的优选的方案是式(I)化合物或其可用药盐,其中:
R1选自氢或1-6个碳原子的低级烷基;
R2选自氢、1-6个碳原子的低级烷基、2-6个碳原子的低级链烯基、2-6个碳原子的低级炔基和苯基,它们均可被苯基或三烷基甲硅烷基任意取代;
Z1和Z2为氢;
n为0或1的整数;
m为2或3的整数。
本发明列举的方案为下列化合物:
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸一盐酸盐;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体A;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸一盐酸盐,对映体富集的异构体A;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体B;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸,对映体富集的异构体B;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2氧代-3-吡咯烷基]乙酰基]氨基]丁酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸乙酯;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸;
1-[4-(氨基亚氨基甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸一盐酸盐;
1-[4-(氨基亚氨基甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸乙酯三氟乙酸盐;3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三甲基甲硅烷基)-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三甲基甲硅烷基)-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基-4-庚炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基-4-庚炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-苯基-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-苯基-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸;
3-[[[1-[4-(氨基亚氨在甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-丙酸三氟乙酸盐,对映体富集的异构体B;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-噻吩基)丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-呋喃基)丙酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-呋喃基)丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸,对映体富集的异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯,对映体富集的异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸,对映体富集的异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸乙酯;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸乙酯;
3S-[[[4-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体A;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体A;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B;
3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸乙酯三氟乙酸盐,对映体富集的异构体B;
3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸三氟乙酸盐,对映体富集的异构体B;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;以及
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B。
本文所用的术语“烷基”是指具有1-6个碳原子的直链或支链烃基。这些烷基的实例为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、新戊基、己基、异己基等。
本文所用的术语“烷氧基”包括式-OR4的含有氧的直链或支链基团,其中R4为如上定义的烷基部分。这些基团的实例为甲氧基、乙氧基、正丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、异丙氧基等。
本文所用的术语“卤代”或“卤素”是指氯(Cl)、氟(F)、溴(Br)或碘(I)基团。
本文所用的术语“链烯基”是指含有至少一条双键和2-6个碳原子的不饱和无环烃基,相对于在双键碳原子上的取代的基团,在链烯基部分中的碳-碳双键可为顺式或反式几何构型。这些基团的实例为乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基、己烯基等。
本文所用的术语“炔基”是指含有一条或多条三键和2-6个碳原子的无环烃基。这些基团的实例为乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。
本文所用的术语“具有1-6个碳原子的烷氧羰基”是指基团
,其中R表示具有1-6个碳原子的烷基。这些基团的实例为甲氧羰基、乙氧羰基、丙氧羰基、戊氧羰基等。
本文所用的术语“环烷基”是指含有3-6个碳原子的饱和环碳基团。合适的环烷基的实例包括环丙基、环丙烯基、环丁基、环戊基、环己基、2-环己烯-1-基等。
本文所用的术语“氨基”是指式-NH2基团。本文所用的术语“一烷基氨基”或“烷基氨基”可用基团-NHR4表示,其中R4为如上所述的烷基。本文所用的术语“二烷基氨基”可用基团-NR4R5表示,其中R4和R5为相同或不同的上面定义的烷基。
术语“三烷基甲硅烷基”包括通过硅原子与式I的环连接的基团,并且硅原子被相同或不同的上面定义的三个末端烷基取代。
术语“烷硫基”包括含有与二价硫原子连接的1-6个碳原子的直链或支链烷基的基团,该基团通过硫部分与式I的环连接。
术语“亚磺酰基”和“磺酰基”,不管是单独使用或与其他术语如“烷基”联用都分别表示-SO-和-SO2-。
本文所用的术语“芳基”和“芳烃”表示由一个或多个芳环组成的碳环芳环体系。优选的芳基为由一个、二个或三个苯环组成的芳基。术语“芳基”包括芳族基团如苯基、萘基或联苯基。本文所用的术语“芳硫基”表示与二价硫原子连接的芳基,该基团通过硫原子与式I的环连接,例如苯硫基。
本文所用的术语“氰基”可用式-CN基团表示。
本文所用的术语“羟”和“羟基”为同义词,可用式-OH基团表示。
本文所用的术语“硝基”可用式-NO2基团表示。
本文所用的术语“酰氧基”可用式
基团表示,其中R4为上面定义的烷基。本文所用的术语“烷氧羰氧烷基”表示式基团,其中R12为氢或上面定义的烷基和R6为上面定义的烷基或环烷基。本文所用的术语“酰氨基”可用式
基团表示,其中R12为氢或上面定义的烷基和R4为被上面定义的芳基任意取代的烷基或烷氧基。
术语“烷基磺酰氨基”和“芳磺酰氨基”表示式R7-SO2-NR12-基团,其中R7为上面定义的烷基或芳基,R12为H或上面定义的烷基。
本文所用的术语“烷氧羰氧基”表示式R4O-C(O)O-基团,其中R4为上面定义的烷基。
本文所用的术语“杂环基”包括含有1-3个选自氧、氮和硫的杂原子的单环、稠合双环和稠合三环基团。术语“羧”或“羧基”表示式-COOH基团。本文所用的术语“羰基衍生基团”可用式
的基团表示,其中羰基与式I的环连接,R8表示选自H、烷基、芳基、环烷基、氨基、一烷基氨基和二烷基氨基(如上定义)的基团。本文所用的术语“叠氮基”可用基团-N3表示。本文所用的术语“脲基”为脲衍生的基团,它可用式的(氨基羰基)氨基表示。
本文所用的术语“三氟甲基”可用式-CF3基团表示。
术语“烷基亚磺酰基”和“芳基亚磺酰基”可用式R13-SO-基团表示,其中R13为如上所定义的烷基或芳基。本文所用的术语“芳基磺酰基”和“烷基磺酰基”和“氨基磺酰基”可用式R10-SO2-基团表示,其中R10为如上所定义的氨基、烷基或芳基。本文所用的术语“链烷酰基氨基”是指式
的基团,其中R4为如上所定义的烷基。术语“芳酰基氨基”可用式
的基团表示,其中R11为如上所定义的芳基。
本文所用的术语“组合物”是指将多种组分或成分混合或组合而成的产物。
本文所用的术语“可药用载体”是指可药用物质、组合物或载体如液体或固体填料、稀释剂、赋形剂、溶剂或用于胶囊的物质包括携带或输送药剂的物质。
术语“治疗有效量”是指激发被研究者或临床医师所用的组织、系统或动物的生物或医学应答的药物或药剂的量。
式I所示的化合物存在各种异构体,所有这些异构体都包括在本发明之中。本发明还包括互变异构体以及这些异构体和互变异构体的可药用盐。
在本文的结构和通式中,画在环键上的键可位于环上任何允许的原子上。
术语“可药用盐”是指式I化合物与酸反应制备的盐,该酸的阴离子一般被认为应适合人的消耗。可药用盐的实例包括盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、乙酸盐、丙酸盐、乳酸盐、马来酸盐、苹果酸盐、琥珀酸盐和酒石酸盐。所有这些可药用盐可用常规方法制备(可药用盐的其它实例参见J Pharm. Sci.,66(1),1-19(1977))。
本发明还涉及抑制血小板聚集的方法,更具体地,所涉及的治疗方法包括施用式I化合物和可药用载体以达到所述的抑制。
为了抑制血小板聚集,本发明的化合物可以含有常规可药用载体、辅助剂和赋形剂的单位剂型口服、肠胃外给药、或吸入喷雾给药、直肠给药或局部给药,本文所用的术语肠胃外包括例如皮下、静脉内、肌肉内、胸骨内、输注方法或腹膜内。
本发明的化合物可以任何合适的途径给药,优选采用适合这种途径的药物组合物形式以及使用治疗有效的剂量。预防或抑制病症发展所需的本发明化合物的治疗有效量对本领域技术人员来是说容易确定。
因此,本发明提供了一类新的药物组合物,包括一种或多种本发明的化合物和一种或多种无毒的可药用载体和/或稀释剂和/或辅助剂(本文统称为“载体”物质),如果需要的话,和其它活性成分。
用本发明的化合物和/或组合物治疗疾病的剂量范围取决于各种因素,包括病人的类型、年龄、体重、性别和病症;疾病的严重程度;给药途径;以及所使用的具体化合物。因此剂量可在较宽的范围内变化,用于治疗上述疾病的大约的剂量为约0.01mg至50mg/千克体重/天。
对于口服给药,药物组合物可采用片剂、胶囊剂、悬浮剂或液体制剂。药物组合物优选制成含有特定量的活性成分的单位剂型,它们含有的活性成分的量为大约1-500mg,优选大约25-350mg。哺乳动物的合适的日剂量随病人的状况和其它因素而有较大的变化。
活性成分也可以通过注射组合物给药,在组合物中,用盐水、葡萄糖或水作为合适的载体。注射的合适的日剂量一般为大约0.01-10mg/kg体重/天,根据所治疗的疾病可采用多次剂量。
为了给药,本发明的化合物通常与一种或多种适合于上述给药途径的辅助剂混合。本发明化合物可与下列物质混合:乳糖、蔗糖、淀粉、链烷酸的纤维素酯、纤维素烷基酯、滑石、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐和钙盐,明胶、阿拉伯胶、藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇以及为了便于给药的成片和胶囊化的物质。另外,本发明的化合物可溶于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄醇、氯化钠和/或各种缓冲剂。其它辅助剂和给药方式在制药领域是公知的。
药物组合物可制成固体形式如粒剂、粉剂或栓剂,或液体形式如溶液、悬浮液、乳液。药物组合物可以进行常规药物操作如灭菌和/或可含有常规药物辅助剂如防腐剂、稳定剂、湿润剂、乳化剂、缓冲剂等等。
本发明的血小板聚集抑制剂可用类似于溶液相肽合成的方法[参见:The Peptides:Analysis,Synthesis,Biology(E.Gross &J.Meienhofer等),Vol.1-5,Academic Press,New York)]与常规合成方法结合制备。下面的流程图说明制备本发明化合物的方法。
在流程A中概述了一般的合成步骤。以接近定量的产率经硫代亚氨酸酯将氰基转化为脒。首先用硫化氢(H2S)处理氰基化合物,接着用甲基碘烷基化制备硫代亚氢酸酯。然后用乙酸铵处理硫代亚氢酸酯得到脒的盐(HI),用反相高压液相色谱纯化得到用于生物试验的最终产物[High Performance Liquid ChromatographyProtein and Peptide Chemistry (F.Lottspeich A.Henscher,K.P.Hupe等)Walter DeGruyter,New York,1981]。
当X=酰胺或脲时,流程A中的相应的苄腈可按流程B所示制备。简而言之,使合适的取代的苄腈与ω-溴链烷酰氯在碱存在下反应进行酰化,接着用氢化钠处理形成内酰胺。用双三甲基甲硅烷基氨基锂(LiHMDS)脱质子化然后用ω-溴链烷醇叔丁酯烷基化使上述内酰胺烷基化。用三氟乙酸(TFA)处理使所得的烷基酯离解为烷基酸[ThePeptides:Analysis,Synthesis,Biology(E.Gross &J.Meienhofer,eds.),vol.1-5,Academic Press New York]。流程A中的苄腈衍生物其中X=酰胺可通过将用于肽偶合的酸活化(例如N,N-二琥珀酰亚氢基碳酸酯[DSC]),接着与合适的取代的β-氨基酯或酸反应来制备。流程A中的苄腈衍生物其中X=脲通过将烷基酸与二苯基磷酰基叠氮化物[(PhO)2PON3]反应[S.Yamada,K.Ninomiya &T.Shioiri Tetrahedron Lett.2343(1973);P.A.S.SmithOrg.React.Vol.3,337(1946);J.H.Saunders R.J.SlocombeChem.Rev.,V.43,203(1948)]接着用合适的取代的游离β-氨基酯捕获中间体异氰酸酯来制备。流程A中的苄腈衍生物其中P=0按流程C所述制备其中流程B中的内酰胺通过用双三甲基甲硅烷基氨基锂脱质子化然后与合适的取代的ω-卤代链烷醇酯反应而被烷基化。
β-氨基酸可以购买或使用如流程D所述的已知方法由市场上得到的起始原料制备。外消旋的β-芳基β-氨基酸可按流程D-方法1所示的方法由合适的芳基醛、丙二酸和乙酸铵制备(Johnson & LivakJ.Am.Chem.Soc.299(1936)),外消旋的β-烷基β-氨基酸可按流程D-方法2所示的方法由相应的链烯烃和氯磺酰基异氰酸酯(CSI)经β内酰胺中间体制备[W. A.Szabo Aldrichimica Acta 23(1977);R.Graf Angew.Chem.Internat.Edit.172(1968)]。如流程D所示,用无水盐酸的乙醇溶液处理β内酰胺使其开环成为乙基酯,例如在实施例1中使1,3-丁二烯与CSI反应生成相应的乙烯基β内酰胺,接着用无水HCl的乙醇溶液开环。制备外消旋的3-氨基酯的另一方法如流程D方法3所示。将亲核试剂加到4-苯甲酰氧基-2-氮杂环丁烷酮中,用无水HCl的乙醇溶液处理,得到各种3-取代的β-氨基酯。例如,将4-苯甲酰氧基-2-氮杂环丁烷酮与烯丙基三甲基硅烷在路易斯酸催化剂存在下反应[titanium tetrachloride-k.,Prasad等人,Vol.19 Heterocycles 2099(1982)]。外消旋的β-氨基酸可用文献中描述的常规方法折分[E.Fischer,H.Scheibler,R.GrohBer.2020(1910);E.Fischer,H.Scheibler Annalen 337(1911)]。
手性β-氨基酸可用许多不同的方法制备,包括下面方法:如流程D方法4所示,使用Arndt-Eistert反应同系化α氨基酸[Meier &Zeller Angew.Chem.Int.Ed.Eng.32-43(1975)][M.Rodriguez等人,Tetrahedron Lett.5153(1990);W.J.GreenleeJ.Med.Chem.434(1985),在此作为参考文献];如流程D方法5所示,使胺与带有手性辅助剂的α、β不饱和酯发生加成反应[J.d’Angelo & J.Maddaluno J.Am. Chem.Soc.8112-14(1986)];如流程D方法6所示,使脱氢氨基酸对映选择地氢化[参见:Asymmetric Synthesis,Vol.5,(J.D.Morrison,ed.)AcademicPress,New York,1985];如流程D方法7所示,使对映体纯的胺与α、β不饱和酯发生加成反应[参见:S.G.Davies & O.IchiharaTetrahedron:Asymmetry 183-186(1991)]。如流程D方法8所示,各种2-取代的β氨基酯的制备可通过用2.2当量的二异丙基氨基锂(LDA)处理苄氧羰基保护的β-氨基酯,接着按Seebach andcoworkers的方法用亲电子试剂(烷基卤、醛、偶氮化合物或α,β-不饱和硝基)骤停[V.H.Estermann & D.Seebach,HelveticaChimica Acta,V.71,1988)]。另一方法是用2-磺酰基氧氮杂丙啶骤停烯醇酯得到α-羟基酯(Davis,et al.,JOC,(1984)49,3243-3244)。
含有吡咯烷酮的代表性的化合物的合成如流程E所示。将可从市场上得到的氨基苄腈(Aldrich)用4-溴丁酰氯酰化得到酰胺1。用氢化钠处理产物得到内酰胺2,将内酰胺烷基化(LiHMDS,溴乙酸叔丁酯)然后水解叔丁基酯得到吡咯烷酮乙酸衍生物4,用N,N-二琥珀酰亚氨基碳酸酯[DSC]将酸转化为活性酯,然后与各种β-氨基酸偶合。在此实施例中,使用(3S)-3-氨基-4-戊烯酸乙酯得到偶合的产物5。使用三个步骤完成苄腈转化为苄脒6(H2S,然后MeI,然后NH4OAc)。用猪肝酯酶酶水解乙酯得到所需的目标产物7。
吡咯烷酮乙酸4的折分如流程F所示,可通过用乙腈结晶α-甲基-苄胺来完成。为富集非对映体对比例至91∶9需要进行12次重结晶。使化合物4的(+)酸和(-)酸各自与(3S)-3-氨基-4-戊烯酸乙酯偶合,然后按流程E描述的方法进行反应得到最终产物(例如,使用(+)-4得到7a)。
流程G描述了吡咯烷酮脲类的合成。将市场上得到的α-氨基-γ-丁内酯氢溴酸盐(Aldrich)转化为Boc保护的内酯(Boc2O,N-甲基吗啉),用2当量LiHMIDS处理产物和4-氨基苄腈得到羟基酰胺10,将产物10环化得到内酰胺11(Ph3P,偶氮二甲酸二乙酯(DEAD))并用无水HCl/EtOAc处理粗产物得到α-氨基内酰胺盐酸盐12,得到较高的总产率。按照流程E描述的方法,依次使用三光气[H.Eckert andB.Forsten,Angew.Chem.Int.Ed.Engl.894-895(1987)]和EtN(i-Pr)2然后(3S)-3-氨基-4-戊烯酸乙酯/EtN(i-Pr)2,由化合物12一罐法合成脲13,得到最终产物15。
流程H说明了用于合成吡咯烷酮己酸衍生物的方法,通过保护醇(叔丁基二甲基甲硅烷基氯(TBDMSCL),咪唑)接着用硼氢化钠处理臭氧分解,使市场上得到的(S)-(-)-β-香茅醇16(Aldrich)转化为醇17。碘化物18(I2,咪唑,Ph3P)用于烷基化烯醇酸锂2(LiHMDS),裂解甲硅烷基醚得到醇19,为手性非对映体的混合物,Jones氧化得到酸20,按照流程E描述的方法,将酸20转化为最终产物21。
下面实施例是用于说明本发明而不是对本发明范围的限制,本领域技术人员很容易理解下列制备方法的条件和步骤的已知的改变都可用于制备本发明的化合物。流程A流程B流程C(式I化合物基中p=0)流程D方法2方法3方法4 *表示手性中心立体化学的保留流程D方法5方法6方法7 *表示手性中心流程D方法8流程E a4-溴丁酰氯 Et3N;bNaH;cLiHMDS,溴乙酸叔丁酯;dTFA;eDSC,then 3(S)-乙烯基-丙氨酸HCl,Et3N;f1)H2S,Et3N;2)Mel;3)NH4OAc;g猪肝酯酶流程F a(R)-(+)-a-甲基苄胺 HCl;b(S)-(-)-a-甲基苄胺,HCl;cDSC,then3(S)乙烯基β丙氨酸HCl,Et3N;D1)H2S,Et3N;2)Mel;3)NH4OAc;e猪肝酯酶流程G aβBoc2O,N-甲基吗啉;b4-氨基苄腈,LlHMDS;cPh3P,DEAD;d无水HCl;e三光气然后3(S)乙烯基-β丙氨酸HCl,EtN(I-Pr)2;r1)H2S,Et3N;2)Mel;3)NH4OAc;g猪肝酯酶流程H aTBDMSCl,咪唑e;bO3,然后NaBH4;cPh3P,l2,咪唑;dLIHMDS,然后18;eTBAF;fJones试剂;g1)H2S,Et3N;2)Mel;3)NH4OAc.
实施例13S-[[[1-4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯A. N-(4-氰基苯基)-4-溴丁酰胺的制备
在氮气氛下向冰浴中冷却搅拌的4-氨基苄腈(12.7g,108mmol)和三乙胺(13.1g,129mmol)的100mlCH2Cl2的溶液中通过注射器加入纯的4-溴丁酰氯(24g,129mmol)。将反应混合物温热至室温。2小时后,混合物用CH2Cl2稀释,用1NNaHSO4、饱和NaCl洗涤,干燥(MgSO4)并且浓缩。用己烷研制得到27.7g(96%)产物,为浅黄色固体,可直接用于下一步反应, H NMR(d6-DMSO)δ2.14(m,2H),2.56(t,J=7Hz,2H),3.61(t,J=7Hz,2H),7.75(d,J=8Hz,2H),7.81(d,J=8Hz.2H).元素分析:计算值 C11H11N2OBr:C,49.46;H,4.15;N,10.49实测值:C,49.73;H,4.25;N,10.54B. 1-(4-氰基苯基)-吡咯烷酮的制备
向搅拌着的步骤A产物(27.7g,104mmo1)的150mlTHF溶液中加入NaH(4.77g,119mmol)(60%W/W的矿物油的分散液)。反应混合物在室温下搅拌3.5小时,然后用EtOAc稀释,用稀盐酸洗涤。有机相进一步用饱和NaCl洗涤、干燥(MgSO4)并浓缩。固体残余物用EtOAc/Et2O重结晶得到12.2g(63%)产物:
H NMR(CDCl3)δ2.22(m,2H),2.66(m,2H),3.88(m,2H),7.65(d,J=8Hz,2H),7.80(d,J=8Hz,2H).
元素分析:计算值 C11H10N2O:C,70.95;H,5.41:N,15.04实测值:C,70.72;H,5.67;N,15.04.C. 1-(4-氰基苯基)-2-氧代-3-吡咯烷基-3-乙酸叔丁酯的制备
在-75℃氮气氛下向搅拌着的步骤B的产物(1.86g,10mmol)的50ml无水THF溶液中通过注射器滴加入LiHMDS(1M于10mlTHF中)。15分钟后,通过注射器加入4ml无水HMPA,接着迅速加入溴乙酸叔丁酯(1.95g,10mmol)。在-75℃又15分钟后,将反应混合物倾入稀盐酸中并用EtOAc萃取(2X)。合并有机馏份,用水、饱和NaCl洗涤,干燥(MgSO4)并浓缩。固体残余物用热Et2O研制,然后用异丙醚沉淀得到2.1g(70%)产物:H NMR(CDCl3)δ1.45(s,3H),1.95(m,1H),2.50(m,2H),2.85(m,2H),3.03(m,1H),3.83(m,2H),7.64(d,J=8Hz,2H),7.81(d,J=8Hz,2H).D. 1-(4-氰基苯基)-2-氧代-3-吡咯烷基-3-乙酸的制备
将步骤C的产物(1.8g,6mmo1)溶于20mlTFA/H2O(9∶1)中并在室温下搅拌2小时,将反应混合物倾入碎冰中。过滤沉淀物,用水洗涤并干燥得到1.42g(97%)产物,可直接于下一步反应,
H NMR(CDCl3)δ1.96(m,1H).2.48-2.63(m,2H),2.95-(m,1H),3.07(m,1H),3.85(m,2H),7.66(d,J=8Hz,2H),7.80(d,J=sHz,2H).E. [1-(4-氰基苯基)-2-氧代-3-吡咯烷基]乙酰基-3(S)-乙烯基-β-丙氨酸乙酯的制备
向搅拌着的步骤D的产物(500mg,2.05mmol)和DMAP(50mg)的4mlDMF/吡啶(1∶1)溶液中加入N,N’-二琥珀酰亚氨基碳酸酯(DSC)(525mg,2.05mmol)。在室温下搅拌15分钟后,加入3(S)-乙烯基-β-丙氨酸盐酸盐(368mg,2.05mmol),接着加入三乙胺(207mg,2.05mmol)。在室温下再搅拌30分钟后,将反应混合物倾入饱和NaHCO3中,用EtOAc萃取。有机层用稀盐酸洗涤,干燥(MgSO4)并浓缩得到760mg(100%)产物,放置形成蜡状固体
H NMR(CDCl3)δ1.25(m,3H),1.98(m,1H),2.93-2.57(m,2H),2.63(m,2H),2.81(m,1H),3.10(m,1H),3.83(m,2H),4.14(q,J=7Hz,2H),4.86(m,1H),5.10-5.27(m,2H),5.84(m,1H),7.65(d,J=8Hz,2H),7.80(d,J=8Hz,2H).F. 3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯的制备
在室温下将硫化氢鼓泡通过步骤E的产物(756mg,2.05mmol)和三乙胺(1.24g,12.3mmol)的10ml吡啶溶液5分钟。塞住反应混合物并在室温下搅拌过夜。将反应混合物倾入稀盐酸中,过滤出黄色沉淀物,用水洗涤并干燥。向所得的硫代酰胺的丙酮(15ml)溶液中加入碘代甲烷(4.36g,31mmol),将反应混合物在65℃氮气氛下搅拌35分钟。减压下除去溶剂得到粗硫代亚氨酸酯氢碘化物。向此黄色残余物中加入无水乙酸铵(315mg,4.1mmol)和MeOH(15ml)。将混合物在65℃氮气氛下搅拌3.5小时,然后浓缩。残余物用反相色谱法在Water C-18 Delta Pak柱上纯化,用0.05%TFA/水∶乙腈梯度洗脱(95%的0.05%TFA/水∶乙腈至60%的0.05%TFA/水∶乙腈,30分钟)得到280mg(27%)标题化合物,为TFA盐:元素分析:计算值 C22H27N4O6F3·0.33H2O:C,52.17;H,5.51;N,11.06.实测值: C,52.16;H,5.36;N,11.06.
向实施例1步骤F的产物(503mg,1.0mmol)的15ml0.1M pH7.4磷酸盐缓冲液和0.2ml乙腈的悬浮液中加入猪肝酯酶的悬浮液(0.9ml)。将反应混合物在室温下搅拌2天。过滤出两性离子产物,用水洗涤并干燥。将白色固体悬浮于MeOH中,加入2N HCl(0.55ml),将所得溶液蒸发至干,残余物用乙腈研制得到275mg(70%)产物,为盐酸盐:(m. p.153-156℃)。元素分析:计算值 C18H23N4O4Cl.1/2H2O:C,53.53;H,5.99;N,13.87;Cl,8.78.实测值: C,53.49;H,6.05;N,13.71;Cl,8.63.
实施例33S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体AA.(-)-1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的制备
向实施例1步骤D的产物(970mg,3.97mmol)的热乙腈(100ml)溶液中加入(S)-(-)-α-甲基苄基胺(481mg,3.97mmol)。用乙腈重结晶12次后得到320mg手性盐([α]D 25=-40.4°MeOH)(m.p.171-174℃)。在EtOAc和稀盐酸之间分配后析出游离酸([α]D 25=-34.4°MeOH)(m.p.193-194℃)。在chiralpak-OD-R柱上用30/70乙腈/0.5M高氯酸钠2.5pH(流速=0.5ml/min)洗脱进行手性HPLC分析证明对映体过量(82%e.e.)。B.[1-(4-氰基苯基)-2-氧代-3-吡咯烷基]乙酰基-3(S)-乙烯基-β-丙氨酸乙酯,对映体富集的异构体A的制备
按类似于实施例1步骤A的方法,由步骤A的产物(240mg,0.98mmol)制备标题化合物,得到360mg(99%)产物。元素分析:计算值 C20H23N3O4:C,65.02;H,6.28;N,11.38.实测值: C,64.89;H,6.29;N,11.36C. 3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体A的制备
按类似于实施例1步骤F的方法,由步骤B的产物(350mg,0.95mmol)制备标题化合物,经反相色谱纯化后得到260mg(58%)产物,为TFA盐[m.p.232-233℃(分解)]。元素分析:计算值 C22H27N4O6F3:C,52.80;H,5.44;N,11.20.实测值: C,52.64;H,5.54;N,11.19.
按类似于实施例2的方法,由上面实施例的产物(250mg,0.50mmol)制备标题化合物,得到182mg(92%)产物[m.p.113-115℃(分解)]。元素分析:计算值 C18H21N4O4Cl.1/2H2O:C,53.53,H,5.99,N,13.87.实测值: C,53.78;H,6.22;N,13.47.
按类似于实施例2步骤A的方法,由实施例1步骤D的产物(1.93g,7.91mmol),用(R)-(+)-α-甲基苄胺代替(S)-(-)-α-甲基苄胺制备标题化合物,得到640mg手性盐([α]D 25=+37.3°MeOH)(m.p.171-174℃)。在EtOAc和稀盐酸之间分配后析出游离酸([α]D 25=+29.3°MeOH)(m.p.190-191.5℃)。在chiralpak:-OD-R柱上用30/70乙腈/0.05M高氯酸钠2.5pH(流速=0.5ml/min)洗脱进行手性HPLC分析证明对映体过量(82%e.e.)。B. [1-(4-氰基苯基)-2-氧代-3-吡咯烷基]乙酰基-3(S)-乙烯基-β-丙氨酸乙酯,对映体富集的异构体B的制备
按类似于实施例1步骤E的方法,由步骤A的产物(365mg,1.50mmol)制备标题化合物,用CH2Cl2/甲基叔丁基醚重结晶后得到450mg(81%)产物。(m.p.130-131℃)([α]D 25=+46.9°,CHCl3).元素分析:计算值 C20H23N3O4:C,65.02;H,6.28;N,11.38.实测值: C,65.09;H,6.31;N,11.37.C. 3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体B的制备
按类似于实施例1步骤F的方法,由步骤B的产物(500mg,1.22mmol)制备标题化合物,经反相色谱纯化后得到310mg(51%)产物,为TFA盐[m.p.217-218℃(分解)]。元素分析:计算值 C22H27N4O6F3:C,52.80;H,5.44;N,11.20.实测值: C,52.55;H,5.44;N,11.06.
按类似于实施例2的方法,由实施例5步骤C的产物(125mg,0.25mmol)制备标题化合物,得到72mg(73%)产物[m.p.135-137℃(分解)]。元素分析:计算值 C18H23N4O4Cl.1.33H2O:C,51.62,H,6.18,N,13.38.实测值: C,51.85;H,5.83;N,13.67.
实施例73-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯A. 1-[4-(硫代甲酰氨基)苯基]-2-吡咯烷酮-3-乙酸的制备
在室温下将硫化氢鼓泡通过实施例1步聚D的产物(2.25g,9.20mmol)和三乙胺(5.57g,55.2mmol)的12ml吡啶溶液5分钟。塞住反应混合物并在室温下搅拌过夜。将反应混合物倾入稀盐酸中,过滤出黄色沉淀物,用水洗涤并干燥,得到2.40g(94%)黄色产物,可直接于下一步反应:
H NMR(d6-DMSO)δ1.86(m,1H),2.34(m,1H),2.47(m,1H),2.69(m,1H),2.97(m,1H),3.82(m,2H),7.73(d,J=8Hz,2H),7.98(d,J=8Hz,2H),9.53(br.s,1H),9.76(br.s,1H).B. 3-[[[1-[4-(硫代甲酰氨基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸的制备
按类似于实例1步骤E的方法,由步骤A的产物(500mg,1.8mmol),用β-丙氨酸乙酯盐酸盐代替(3S)-乙烯基β-丙氨酸乙酯盐酸盐制备标题化合物,得到440mg(65%)产物:
H NMR(d6-DMSO)δ1.19(t,J=7Hz,3H),1.78(m,1H),2.25(m,2H),2.46(t,J=7Hz,2H),2.58(m,1H),2.93(m,1H),3.29(m,2H),3.80(m,2H),4.07(q,J=7Hz,2H),7.72(d,J=8Hz,2H),7.97(d,J=8Hz,2H).C. 3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-丙酸乙酯的制备
按类似于实施例1步骤F的方法,由本实施例步骤B的产物(400mg,1.06mmol)制备标题化合物,经反相色谱纯化后得到260mg(52%)产物,为TFA盐。
H NMR(d6-DMSO)δ1.19(t,J=7Hz,3H),1.81(m,1H),2.29(m,2H),2.46(t,J=7Hz,2H),2.58(m,1H),2.98(m,1H),3.28(m,2H),3.83(m,2H),4.07(q,J=7Hz,2H),7.87(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C20H25N4O6F3·0.25H2O:C,50.16;H,5.37;N,11.70.实测值: C,50.02;H,5.22;N,11.51.
实施例83-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸
按类似于实施例2的方法,由实施例7步骤C的产物(100mg,0.21mmol)制备标题化合物,经反相色谱纯化后得到60mg(64%)产物。
H NMR(d6-DMSO)δ1.81(m,1H),2.28(m,2H),2.39(t,J=7Hz,2H),2.58(m,1H),2.96(m,1H),3.25(m,2H),3.83(m,2H),7.85(d,J=8Hz,2H),7.92(d,J=8Hz,2H).元素分析:计算值 C18H21N4O6F3·0.25H2O:C,47.95;H,4.81;N,12.43.实测值: C,47.82;H,4.84;N,12.21.
实施例93-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸乙酯A. 3-[[[1-[4-(硫代甲酰氨基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸乙酯的制备
按类似于实施例7步骤B的方法,由实施例7步骤A的产物,用3-甲基-β-丙氨酸乙酯盐酸盐(260mg,1.54mmol)代替β-丙氨酸乙酯盐酸盐制备标题化合物,得到410mg(75%)产物:H NMR(d6-DMSO)δ 1.09(m,3H),1.18(t,J=7Hz,3H),1.78(m,1H),2.15-2.61(m,4H),2.93(m,1H),3.80(m,2H),4.00-4.17(m,3H),7.72(d,J=8Hz,2H),7.97(d,J=8Hz,2H).B. 3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-丁酸乙酯的制备
按类似于实施例1步骤F的方法,由本实施例步骤A的产物(400mg,1.03mmol)制备标题化合物,经反相色谱纯化后得到180mg(36%)产物,为TFA盐。H NMR(d6-DMSO)δ1.09(m,3H),1.18(t,J=7Hz,3H),1.81(m,1H),2.20-2.60(m,4H),2.96(m,1H),3.83(m,2H),4.05(q,J=7Hz,2H),4.05(q,J=7Hz,2H),4.10(m,1H),7.85(d,J=8Hz,2H),7.92(d,J=8Hz,2H).元素分析:计算值 C21H27N4O6F3:C,51.64;H,5.57;N,11.47.实测值: C,51.67;H,5.65;N,11.36.
实施例103-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸
按类似于实施例2的方法,由实施例9步骤B的产物(100mg,0.21mmol)制备标题化合物,经反相色谱纯化后得到55mg(58%)产物。
H NMR(d6-DMSO)δ1.09 (m,3H),1.72(m,1H),2.20-2.60(m,4H),2.96(m,1H),3.83(m,2H),4.08(m,1H),7.85(d,J=8Hz,2H),7.92(d,J=8Hz,2H).元素分析:计算值 C17H22N4O4·1.2TFA·H2O:C,46.49;H,5.07;N,11.18.实测值: C,46.75;H,4.81;N,10.92.
实施例113-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸乙酯A. 3-[[[4-[4-(硫代甲酰氨基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸乙酯的制备
按类似于实施例7步骤B的方法,由实施例7步骤A的产物,用3-苯基-β-丙氨酸乙酯盐酸盐(355mg,1.54mmol)代替β-丙氨酸乙酯盐酸盐制备标题化合物,得到460mg(73%)产物:H NMR(d6-DMSO)δ1.13(t,J=7Hz,3H),1.78(m,1H),2.15-2.45(m,2H),2.63(m,1H),2.75(d,J=8Hz,2H),2.93(m,1H),3.78(m,2H),4.02(m,2H),5.24(m,2H),7.20-7.38(m,5H),7.72(d,J=8Hz,2H),7.97(d,J=8Hz,2H).B. 3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸乙酯的制备
按类似于实施例1步骤F的方法,由本实施例9步骤A的产物(450mg,0.99mmol)制备标题化合物,经反相色谱纯化后得到250mg(46%)产物,为TFA盐:
H NMR(d6-DMSO)δ1.13(t,J=7Hz,3H),1.79(m,1H),2.15-2.40(m,2H),2.63(m,1H),2.66(d,J=8Hz,2H),2.95(m,1H),3.80(m,2H),4.03(q,J=7Hz,2H),5.24(m,2H),7.20-7.38(m,5H),7.87(d,J=8Hz,2H),7.90(d,J=8Hz,2H).元素分析:计算值 C26H29N4O6F3·0.5H2O:C,55.81;H,5.40;N,10.01.实测值: C,56.00;H,5.33;N,9.97.
实施例123-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸
按类似于实施例2的方法,由实施例11步骤B的产物(100mg,0.21mmol)制备标题化合物,经反相色谱纯化后得到53mg(56%)产物:
H NMR(400MHz,d6-DMSO)δ1.80(m,1H),2.15-2.45(m,2H),2.63(m,1H),2.68(d,J=8Hz,2H),2.95(m,1H),3.80(m,2H),5.22(m,2H),7.20-7.3 8(m,5H),7.84(d,J=8Hz,2H),7.91(d,J=8Hz,2H).元素分析:计算值C22N24N4O4·1.3TFA·H2O:C,51.41;H,4.79;N,9.75.实测值: C,51.21;H,4.53;N,9.49.
实施例133(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸乙酯A. 3(S)-[[[1-[4-(氰基苯基)]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸乙酯的制备
按类似于实施例1步骤E的方法,用[(3S)乙炔基]-β-丙氨酸乙酯盐酸盐(250mg,1.41mmol)代替[(3S)-乙烯基-β-丙氨酸乙酯盐酸盐制备标题化合物,得到450mg(87%)产物:
H NMR(CDCl3)δ1.27(m,3H),1.96(m,1H),2.27(m,1H),2.42-2.58(m,2H),2.63-2.85(m,3H),3.08(m,1H),3.83(m,2H),4.18(m,2H),5.12(m,1H),7.64(d,J=8Hz,2H),7.80(d,J=8Hz,2H).元素分析:计算值 C20N21N3O4:C,65.38;H,5.76;N,11.41.实测值: C,65.13;H,6.15;N,11.34.B. 3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸乙酯的制备
按类似于实施例1步骤F的方法,由步骤A的产物(150mg,0.40mmol)制备标题化合物,经反相色谱纯化后得到85mg(43%)产物,为TFA盐:
HNMR(d6-DMSO)δ1.18(m,3H),1.71(m,1H),2.24-2.38(m,2H),2.53-2.64(m,3H),2.98(m,1H),3.23(m,1H),3.83(m,2H),4.05(m,2H),4.85(m,1H),7.86(d,J=8Hz,2H),7.93(d,J=8Hz,2H).
按类似于实施例2的方法,由步骤B的产物(50mg,0.10mmol)制备标题化合物,经反相色谱纯化后得到35mg(74%)产物:
m.p.200-203°(分解);HNMR(d6-DMSO)δ1.71(m,1H),2.24-2.38(m,2H),2.53-2.64(m,3H),2.98(m,1H),3.23(m,1H),3.83(m,2H),4.85(m,1H),7.86(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C20H21N4O6F3·1H2O:C,50.10;H,4.63;N,11.69.实测值: C,50.01;H,4.53;N,11.57.
实施例153-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸乙酯A. 3-氨基-2(S)-(苯基甲氧基羰基氨基)丙酸乙酯盐酸盐的制备
将Na-Z-L-2,3-二氨基丙酸(2.00g,8.4mmol)的30ml饱和HCl/EtOH溶液室温下搅拌过夜,除去溶剂,残余物用Et2O研制得到2.4g(96%)产物:
H NMR(CD3OD)δ1.24(t,J=7Hz,3H),3.24(dd,J=8.13Hz,1H),3.45(dd,J=5.13Hz,1H),4.22(q,J=8Hz,2H),4.48(m,1H),5.14(s,2H),7.28-7.41(m,5H).B. 3(S)-[[[1-[4-氰基苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸乙酯的制备
按类似于实施例1步骤E的方法,由步骤A的产物(530mg,1.76mmol)制备标题化合物,得到665mg(85%)产物。H NMR(CDCl3)δ1.28,(t,J=7Hz,3H),1.92(m,1H),2.45(m,2H),2.68(m,2H),3.04(m,1H),3.68(m,2H),3.79(m,2H),4.18(m,2H),4.43(m,1H),5.09(m,2H),7.35(m,5H),7.57(m,2H),7.78(m,2H).C. 3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸乙酯的制备
按类似于实施例1步骤F的方法,由本实施例步骤B的产物(650mg,1.32mmol)制备标题化合物,经反相色谱纯化后得到400mg(48%)产物,为TFA盐。元素分析:计算值 C28N32N5O8F3·1/2H2O:C,53.16;H,5.26;N,11.07.实测值: C,53.12;H,5.09;N,10.99.
按类似于实施例2的方法,由实施例14步骤C的产物(100mg,0.16mmol)制备标题化合物,经反相色谱纯化后得到62mg(64%)产物:
H NMR(d6-DMSO)δ1.88(m,1H),2.30-2.45(m,2H),2.73(m,1H),3.03(m,1H),3.47 (m,1H),3.73(m,1H),3.83(m,2H),4.38(m,1H),5.09(m,2H),7.20-7.39(m,5H),7.81(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C26H28N5O8F3·1.5H2O:C,50.16;H,5.02;N,11.20.实测值: C,50.18;H,4.89;N,10.79.
向α-氨基-γ-丁内酯氢溴化物(1.82g,10mmol)的5mlH2O溶液中依次加入Boc2O(在10ml二噁烷中)和N-甲基吗啉(1.01g,10mmol)。将反应混合物在室温下搅拌3小时,用2NHCl酸化,用饱和NaCl稀释,用EtOAc萃取。将有机层干燥(MgSO4)并浓缩,用己烷研制残余物得到1.85g(92%)产物(m.p.113-114.5℃)。元素分析:计算值 C9N15NO4:C,53.72;H,7.51;N,6.96.实测值: C,53.48;H,7.70;N,6.85.B. N-(4-氰基苯基)-4-羟基-2-[(1,1-二甲基)乙氧羰基氨基]丁酰胺的制备
向步骤A的产物(1.52g,7.56mmol)和氨基苄腈(892mg,7.56mmol)的THF(20ml)溶液中加入LiHMDS(15ml 1M的THF溶液,15mmol),并在室温下搅拌30分钟,将溶液倾入稀盐酸中,用EtOAc萃取(2X),用饱和NaCl洗涤,干燥(MgSO4)并浓缩。将残余物进行硅胶色谱纯化(3∶1EtOAc/己烷,然后EtOAc)得到2.45g(90%)产物:
H NMR(CDCl3)δ1.47(s,9H),1.87(m,lH),2.16(m,1H),3.86(m,2H),4.54(m,1H),7.61(d,J=8Hz,2H),7.69(d,J=8Hz,2H).C. 3-氨基-1-(4-氰基苯基)-2-吡咯烷酮盐酸盐的制备
在-40℃氮气氛下向步骤B的产物(2.36g,7.40mmol)和三苯膦(2.13g,8.14mmol)的无水THF(30ml)溶液中加入偶氮二甲酸二乙酯(1.48g,8.51mmol)。撤去冰浴,将溶液在室温下搅拌1小时。浓缩反应混合物并再溶于EtOAc(70ml)中,在室温下将无水的HCl气体鼓泡通过溶液5分钟,将溶液再搅拌45分钟,过滤出所得沉淀物,用EtOAc洗涤并干燥得到1.50g(85%)产物:
H NMR(CDCl3/CD3OD)δ2.33(m,1H),2.81(m,1H),3.97(m,2H),4.23(m,1H),7.73(d,J=8Hz,2H),7.86(d,J=8Hz,2H).元素分析:计算值 C11H12N3OCl·0.33H2O:C,54.23;H,5.24;N,17.25.实测值: C,54.65;H,5.19;N,17.25.
通过在饱和NaHCO3和EtOAc之间分配,产物转化为游离碱,浓缩后可直接用于下一步反应。D. [1-(4-氰基苯基)-2-吡咯烷酮-3-氨基羰基]-[(3S)乙烯基]-β-丙氨酸的制备
向三光气(42mg,0.14mmol)的1,2-二氯乙烷(1ml)溶液中加入步骤C的产物(85mg,0.42mmol)和二异丙基乙胺(108mg,0.84mmol)的1,2-二氯乙烷(2ml)溶液。在室温下搅拌30分钟后,依次加入固体(3S)-乙烯基-β-丙氨酸盐酸盐(76mg,0.42mmol)和纯二异丙基乙胺(54mg,0.42mmol)。将反应混合物在65℃下搅拌2小时,倾入稀盐酸中,用EtOAc萃取。将有机馏份干燥(MgSO4),用硅胶过滤(EtOAc)并浓缩,残余物用Et2O研制并过滤得到110mg(70%)产物(m.p.113-115℃)。元素分析:计算值 C19H22N4O4:C,61.61;H,5.99;N,15.13.实测值: C,61.60;H,5.62;N,15.21.E. 3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸乙酯的制备
按类似于实施例1步骤F的方法,由步骤D的产物(440mg,1.19mmol)制备标题化合物,得到306mg(59%)产物。[m.p.203-205℃(分解)]:1H-NMR(300MHz,d6-DMSO)δ1.18(t,J=7Hz,3H),1.96(m,1H),2.35-2.55(m,3H),3.80(m,2H),4.06(q,J=7Hz,2H),4.39-4.56(m,2H),5.03-5.18(m,2H),5.84(m,1H),7.87(d,J=8Hz,2H),7.92(d,J=8Hz,2H).
实施例183(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸
按类似于实施例2的方法,由实施例17步骤E的产物(280mg,0.56mmol)制备标题化合物,得到160mg(72%)产物,为盐酸盐[m.p.185-187℃(分解)]。元素分析:计算值 C17H22N5O4Cl·1.1H2O:C,49.12;H,5.87;N,16.85.实测值: C,49.01;H,5.76;N,16.41.
实施例191-[4-(氨基亚氨基甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸一盐酸盐A. [3(S),7-二甲基辛-6-烯氧基](1,1-二甲基乙基)(二甲基)硅烷的制备
将固体TBDMSCL(5.06g,33.65mmol)加到搅拌着的(S)-(-)-β-香茅醇(5.0g,32mmol)[Aldrich,[αD 25]=-5.3°(纯态)]和咪唑(4.60g,67.31mmol)的5mlDMF溶液中,在室温下搅拌过夜后,反应混合物用水稀释,用己烷萃取,干燥(MgSO4)并浓缩得到9.0g(104%)粗产物,可直接用于下一步反应。
H-NMR(CDCl3)δ0.06(s,6H),0.90(m,12H),1.17(m,1H),1.31(m,2H),1.56(m,2H),1.61(s,3H),1.69(s,3H),1.99(m,2H),3.65(m,2H),5.11(m,1H).B. [6-羟基-[3(S)-甲基己基]氧](1,1-二甲基乙基)(二甲基)硅烷的制备
在-78℃下将臭氧鼓泡通过步骤A的产物(32mmol)的30mlCH2Cl2/MeOH(1∶1)溶液中,直至持续为兰色,然后将氧气鼓泡通过直至兰色消失。加入固体NaBH4(3.0g,80mmol)并将反应混合物在0℃搅拌1小时,然后在室温下搅拌1小时。将反应混合物倾入稀盐酸中,用EtOAc萃取,用饱和NaCl洗涤,干燥(MgSO4)并浓缩得到8.30g(105%)粗产物,可直接用于下一步反应:
H NMR(CDCl3)δ0.06(s,6H),0.90(m,12H),1.19(m,1H),1.56(m,4H),3.64(m,4H).C. [6-碘-[3(S)-甲基己基]氧](1,1-二甲基乙基)(二甲基)硅烷的制备
将固体碘(2.79g,11mmol)分批加到搅拌着的步骤B的产物(2.46g,10mmol)、咪唑(748mg,11mmol)和三苯膦(2.75g,10.5mmol)的无水THF(30ml)中,30分钟后,再依次加入0.5当量的同样试剂使反应完成。30分钟后,反应混合物用己烷(60ml)稀释,用Et2O/己烷(2∶1)作为洗脱剂(300ml)经硅胶填料过滤,除去溶剂得到2.70g(76%)产物。
H-NMR(CDCl3)δ0.04(s,6H),0.90(m,12H),1.18-1.45(m,3H),1.58(m,2H),1.86(m,2H),3.64(m,2H).D. [1-(4-氰基苯基)-γS-甲基-2-氧代-3-吡咯烷己氧基](1,1-二甲基乙基)(二甲基)硅烷的制备
在-75℃氮气氛下向实施例1步骤B的产物(500mg,2.69mmol)的22mlTHF/HMPA(10∶1)溶液中加入LiHMDS(2.7ml 1M的THF溶液,2.7mmol),5分钟后,通过注射器加入纯的步骤C的产物(982mg,2.69mmol)。将反应混合物缓慢温热至室温历时2小时,将溶液倾入稀盐酸中,用EtOAc萃取。有机相用水、饱和NaCl洗涤,干燥(MgSO4)并浓缩,将残余物进行硅胶色谱纯化(35%EtOAc/己烷)得到530mg(48%)产物:
H NMR(CDCl3)δ0.04(s,6H),0.89(m,12H),1.18-1.68(m,8H),1.77-2.00(m,2H),2.37(m,1H),2.63(m,1H),3.64(m,2H),3.79(m,2H),7.65(d,J=8Hz,2H),7.80(d,J=8Hz,2H).E. [1-(4-氰基苯基)-γS-甲基2-氧代-3-吡咯烷己醇的制备
向步骤D的产物(530mg,1.28mmol)的THF(5ml)溶液中加入氟化四丁基铵(3.8ml 1M的THF溶液,3.80mmol),在室温下搅拌3小时后,将反应混合物用EtOAc稀释,依次用水(2X)、饱和NaCl洗涤,干燥(MgSO4)并浓缩,将残余物进行硅胶色谱纯化(CH2Cl2,然后EtOAc)得到310mg(81%)产物:
H NMR(CDCl3)δ0.92(d,J=7Hz,3H),1.18-1.52(m,7H),1.77-2.00(m,2H),2.37(m,1H),2.63(m,1H),3.68(m,2H),3.79(m,2H),7.65(d,J=8Hz,2H),7.80(d,J=8Hz,2H).F. [1-(4-氰基苯基)-βS-甲基-2-氧代-3-吡咯烷己酸的制备
向Jones试剂(0.57ml2.67M溶液,1.53mmol)的5ml丙酮溶液中缓慢步骤E的产物(300mg,1mmol)的2ml丙酮溶液,在室温下搅拌30分钟后,将反应混合物用EtOAc稀释,用水、饱和NaCl洗涤,干燥(MgSO4)并浓缩,得到320mg(100%)产物:
H NMR(CDCl3)δ1.00(d,J=7Hz,3H),1.18-1.55(m,5H),1.77-2.05(m,3H),2.19(m,1H),2.32-2.43(m,2H),2.63(m,1H),3.79(m,2H),7.65(d,J=8Hz,2H),7.80(d,J=8Hz,2H).G. 1-[4-(氨基亚氨在甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸一盐酸盐的制备
按类似于实施例1步骤F的方法,接着按改进的处理方法,由步骤F的产物(314mg,1mmol)制备标题合物。除去溶剂后,用1ml水接着用15ml丙酮处理残余物,过滤沉淀出的两性离子产物并用丙酮(80mg)洗涤。通过悬浮于2mlMeOH中并用0.13ml2NHCl处理将产物转化为盐酸盐。将所得的溶液蒸发并固化,用丙酮研制,得到50mg(14%)产物[m.p.103-110℃(分解)]。元素分析:计算值 C18H26N3O3Cl·0.33H2O:C,57.83;H,7.19;N,11.24.实测值: C,58.07;H,7.30;N,10.73.
向实施例19步骤F的产和(500mg,1.60mmol)溶液中加入Cs2CO3(779mg,2.39mmol)和乙基碘(373mg,2.39mmol)的3mlDMF溶液,在室温下搅拌过夜后,将反应混合物用EtOAc稀释,用水、饱和NaCl洗涤,干燥(MgSO4)并浓缩,得到510mg(93%)产物:
H NMR(CDCl3)δ0.96(d,J=7Hz,3H),1.27(m,4H),1.33-1.55(m,4H),1.80-2.05(m,3H),2.13(m,1H),2.25-2.45(m,2H),2.62(m,1H),3.79(m,2H),4.13(q,J=7Hz,2H),7.65(d,J=8Hz,2H),7.80(d,J=8Hz,2H).B. 1-[4-(氨基亚氨基甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸乙酯三氟乙酸盐的制备
按类似于实施例1步骤F的方法,由步骤A的产物(510mg,1.49mmol)制备标题化合物,经反相色谱纯化后得到287mg(41%)产物,为TFA盐[m.p.216-218℃(分解)]。元素分析:计算值 C22H30N3O5F3:C,55.80;H,6.39;N,8.87.实测值: C,55.89;H,6.56;N,8.87.
按实施例1的方法,用3-氨基-5-三甲基甲硅烷基戊-4-炔酸乙酯代替3(S)-氨基-4-戊烯酸乙酯以及用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ-1.0,13.8,22.7,26.9,37.6,39.2,40.7,39.6,51.6,61.1,70.6,77.8,119.0,127.3,128.4,148.6,166.6,171.5,171.6,173.3.
实施例223S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三氟甲基甲硅烷基)-4-戊炔酸
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ-1.6,22.1,26.2,37.0,38.5,40.7,39.1,39.8,51.0,70.6,77.8,119.0,126.7128.4,148.5,166.6,171.5,171.6,173.3.
实施例233-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯
在23℃氮气氛下,向实施例21的最终产物(332mg,0.772mmol)的THF溶液(30ml)中加入2当量氟化四丁基铵(1.544mmol,1M的THF溶液)。1小时后,将反应混合物真空浓缩,按实施例1步骤F所述的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ12.7,21.7,26.0,36.7,37.4,38.7,39.6,50.7,60.2,70.9,81.4,126.1,126.4,128.1,148.2,166.8,169.1,171.0,172.9.
实施例243-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸
按实施例2的方法,用猪肝酯酶处理下面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被氢谱证实:
H NMR(CD3OD)δ1.63-1.94(m,2-CH2),2.48-2.78(m,2-CH2),3.52-3.71(m,CH2),4.76-4.94(m,CHN),7.42-7.72(m,PhH).元素分析:计算值 C19N22H4O4+1.3CF3CO2H·1.4H2O:C,47.70;H,4.84;N,10.30.实测值: C,47.56;H,4.53;N,10.42.
实施例253-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基4-庚炔酸乙酯
按实施例1的方法,用3-氨基-6,6-二甲基-4-戊炔酸乙酯代替(S)-3-氨基-4-戊烯酸乙酯制备标题化合物。使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ12.4,21.2,25.4,29.1,36.3,37.3,38.3,39.9,50.2,59.6,75.6,91.3,125.3,125.9,127.6,128.2,166.7,168.9,171.6,172.8.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ20.7,24.8,28.6,36.6,37.6,37.7,39.1.,49.7,75.6,91.3,25.1,125.7,127.4,146.7,166.7,168.9,171.6,172.8.
按实施例1的方法,用3-氨基-5-苯基-4-戊炔酸乙酯代替(S)-3-氨基-4-戊烯酸乙酯制备标题化合物。使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ13.8,22.7,27.0,37.7,39.1,39.2,39.7,39.7,40.7,40.8,51.7,61.2,82.8,87.7,123.7,127.1,127.3,127.4,128.7,128.9,129.0,131.9,149.2,166.8,170.4,172.3,173.9.FAB 质谱 (MH+)=475.元素分析:计算值 C27H30N4O4+1.2CF3CO2H:C,57.76;H,5.14;N,9.16.实测值:C,57.78;H,4.80;N,9.18.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ21.4,25.6,29.8,34.9,50.4,81.3,86.6,121.8,125.3,126.0,127.3,127.5,1.27.7,130.6,148.2,166.7,170.9,171.2,172.8.元素数分析:计算值 C25H26N4O4+1.0CF3CO2H:C,55.36;H,5.13;N,9.56. 实测值:C,55.32;H,4.94;N,9.49.
按实施例1的方法,用3-氨基丁酸乙酯代替(S)-3-氨基-4-戊烯酸乙酯制备标题化合物。使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:C NMR(CD3OD)δ13.8,19.7,22.7,27.0,38.0,39.8,41.1,43.1,51.7,60.9,127.1,127.4,129.1,140.5,166.8,170.4,172.3,173.9.元素分析:计算值 C20N28N4O4+1CF3CO2H:C,52.59;H,5.82;N,11.15.实测值:C,52.38;H,6.13;N,11.56.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ19.2,22.2,26.5,37.4,39.2,40.3,42.5,51.2,126.4,126.9,128.6,140.5,166.7,170.9,171.2,172.8.元素分析:计算值 C18H24N4O4+1CF3CO2H和0.5H2O:C,49.69;H,5.42 ;N,11.59.实测值:C,49.46;H,4.95;N,11.42.
按实施例1的方法,用3-氨基-3-苯基丙酸乙酯代替(S)-3-氨基-4-戊烯酸乙酯制备标题化合物。使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ12.5,21.5,25.8,36.7,38.6,40.0,49.7,50.5,59.9,125.4,125.7,126.2,126.7,127.7,127.9,140.7,14 8.0,166.8,170.3,171.2,172.4.元素分析:计算值 C25H30N4O4+1CF3CO2H和10.5H2O:
C,56.54;H,5.62;N,9.77实测值: C,56.86;H,5.25;N,9.92.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)22.7,26.8,37.9,39.8,40.9,50.8,51.7,126.5,126.8,126.9,127.3,127.4,127.7,128.8,129.0,141.8,149.2,166.8,172.4,173.0,173.9.元素分析:计算值 C23H26N4O4+1.1CF3CO2H和1.0H2O:
C,53.48;H,5.18;N,9.90实测值: C,53.75;H,4.78;N,9.87.
实施例333(S)-[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯
按实施例1的方法,用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物,产物被氢谱证实:
H NMR(CD3OD,2diast.)δ1.11( 重叠 t,J=6Hz,CH3),1.59-1.98(m,2CH2),2.38-2.72(m,2-CH2),3.52-3.73(m,CH2),3.96( 重叠 q,J=6Hz),4.64-4.74(m,CHN),4.95-5.14(m,CH2=).5.67-5.80(m,CH),7.42(d,J=8Hz,PhH),7.69(d,J=8Hz,PhH),9.08和9.28(2s,NH).
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被氢谱证实:
H NMR(CD3OD)δ1.59-1.98(m,2CH2),2.28-2.85(m,2-CH2),3.62-3.81(m,CH2),4.59-4.74(m,CHN),5.03-5.19(m,CH2=).5.67-5.91(m,CH),7.58(d,J=8Hz,PhH),7.84(d,J=8Hz,phH),9.08和9.28(2s,NH).
实施例34A3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-丙酸乙酯,对映体富集的异构体B
按实施例1的方法,用β-丙氨酸代替3(S)-氨基-4-戊烯酸乙酯以及用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。按实施例5折分1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法折分1-(4-氰基苯基)-2-哌啶酮-3-乙酸,它具有如下的旋光度([α]D 25=+42.5°,c0.521,MeOH)。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物([α]D 25=+30.9°,c0.110,MeOH),产物被碳谱证实:
C NMR(CD3OD)δ13.7,22.7,26.9,34.2,35.6,37.8,39.7,51.6,60.9,126.6,127.3,129.0,148.6,172.5,173.3,174.2.元素分析:计算值 C19H26N4O4+1.1CF3CO2H和1.5H2O:
C,48.33;H,5.76;N,10.63.实测值: C,48.50;H,5.40;N,10.56.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物([α]D 25=+35.1°,c0.163,MeOH),产物被碳谱证实:
CNMR(CD3OD)δ22.6,26.9,33.9,35.6,37.8,39.7,51.6,126.3,127.3,129.0,166.7,173.3,173.9,174.2.元素分析:计算值 C17H22N4O4+1.2CF3CO2H和1H2O:
C,46.49;H,5.07;N,11.18.实测值: C,46.61;H,4.70;N,11.16.
按实施例1的方法,用3-氨基-3-(3-噻吩基)丙酸乙酯代替3(S)-氨基-4-戊烯酸乙酯以及用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。按实施例5折分1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法折分1-(4-氰基苯基)-2-哌啶酮-3-乙酸。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物,产物被氢谱证实:
H NMR(CD3OD)δ1.52-1.63(m,2CH2),2.04-2.46(m,2-CH2),3.14-3.38(m,CH2),4.95-5.08(m,CHN),6.61-6.82(m,3H,ArH),7.05-7.14(m,2H,ArH),7.31-7.46(m,2H,ArH).元素分析:计算值 C21H24N4O4S+1.3CF3CO2H和1.5H2O:
C,46.95;H,4.72;N,9.28.实测值: C,47.00;H,4.33;N,9.49.
按实施例1的方法,用3(S)-氨基-3-(3-呋喃基)丙酸乙酯代替3(S)-氨基-4-戊烯酸乙酯以及用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。按实施例5折分1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法折分1-(4-氰基苯基)-2-哌啶酮-3-乙酸。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物([α]D 25=-2.2°,c0.045,MeOH),产物被碳谱证实:
C NMR(CD3OD)δ12.8,21.7,26.1,37.0,38.9,39.4,42.2,60.2,108.6,125.6,126.4,128.2,139.0,143.0,148.2,166.7,170.7,171.6,173.0.元素分析:计算值 C23N28N4O5+1.2CF3CO2H和1.1H2O:
C,51.09;H,5.30;N,9.38.实测值: C,50.73;H,4.89;N,9.12.
按实施例5的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物([α]D 25=+5.1°,c0.039,MeOH),产物被碳谱证实:
CNMR(CD3OD)δ22.7,26.9,37.8,39.7,39.9,43.0,51.6,109.4,126.6,127.2,127.3,129.0,139.8,143.7,149.1,166.7,172.3,173.2,173.9.元素分析:计算值 C21H24N4O5+1.2CF3CO2H和0.1HI:
C,50.00;H,4.54;N,9.97.实测值: C,50.26;H,4.08;N,9.99.
实施例34F3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸乙酯,非对映体按实施例1的方法,用3-氨基-3-(2-呋喃基)丙酸乙酯代替3(S)-氨基-4-戊烯酸乙酯以及用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。按实施例5折分1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法折分1-(4-氰基苯基)-2-哌啶酮-3-乙酸。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)12.7,21.6,25.8,36.8,37.5,38.7,50.6,60.1,105.5,109.5,126.1,126.3,128.0,141.5,148.0,166.7,170.1,171.5,172.8.元素分析:计算值 C23H28N4O5+1.0CF3CO2H和0.5H2O:
C,53.28;H,5.37;N,9.94.实测值: C,52.94;H,4.98;N,9.85.
实施例34G3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸,非对映体
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ22.7,26.9,37.9,38.3,39.8,44.8,47.8,51.8,106.6,110.6,127.4,127.5,129.1,142.6,149.2,166.7,172.6,173.1,174.0.元素分析:计算值 C21H24N4O5+1.1CF3CO2H和1.0H2O:
C,50.13;H,4.91;N,10.08.实测值: C,49.77;H,4.60;N,9.99.
实施例34H3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸乙酯
按实施例1的方法,用3-氨基-3-(4-甲氧基苯基)丙酸乙酯代替(S)-3-氨基-4-戊烯酸乙酯制备标题化合物。使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ13.6,22.6,26.9,37.8,39.6,41.1,50.2,51.6,60.9,114.1,12 6.8,127.3,128.0,129.0,149.0,159.4,166.7,171.5,172.2,173.8.元素分析:计算值 C26H32N4O5+1.8CF3CO2H和0.5H2O:
C,51.17;H,5.05;N,8.06.实测值: C,51.29;H,4.68;N,8.46.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ1.57-2.07(m,2 CH2),2.54-2.92(m,2-CH2),3.62-3.83(m,CH2),5.28-5.38(m,CHN),6.83-6.91(m,2H,ArH),1(m,2H,ArH),7.23-7.33(m,2H,ArH),7.4 6-7.58(m,2H,ArH),7.78-7.84(m,2H,ArH).元素分析:计算值 C24H28N4O5+1.0CF3CO2H和1.5H2O:
C,52.61;H,5.43;N,9.44.实测值: C,52.69;H,5.02;N,9.43.
按实施例1的方法,用1-(4-氰基苯基)-2-哌啶酮3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。除了用乙酸乙酯代替乙腈之外,按实施例5折分1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法折分1-(4-氰基苯基)-2-哌啶酮-3-乙酸。按实施例2的方法,用猪肝酯酶处理上面步骤的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物([α]D 25=-109.8°,c0.051,MeOH),产物被碳谱证实:
C NMR(CD3OD)δ21.9,26.1,37.1,38.5,38.9,48.0,50.9,114.1,126.6,128.2,136.8,166.7,172.1,172.5,173.2.
按实施例1的方法,用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-1-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。按实施例5折分1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法折分1-(4-氰基苯基)-2-哌啶酮-3-乙酸。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ13.6,22.5,26.8,37.8,39.3,39.6,48.0,51.5,60.9,114.9,126.3,127.2,128.9,137.2,166.7.172.5,172.4,173.8.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ22.5,26.8,37.8,39.1,39.6,51.6,112.0,114.9,117.3,127.2,128.9,129.9,137.4,149.0,166.7,172.4,173.3,173.8.
实施例34M3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯,对映体富集的异构体B
按实施例1的方法,用3(S)-氨基-4-戊炔酸乙酯代替3(S)-氨基-4-戊烯酸乙酯以及用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。按实施例5折分1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法折分1-(4-氰基苯基)-2-哌啶酮-3-乙酸。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)δ13.3,22.1,26.4,37.5,37.9,39.3,51.4,60.9,71.6,81.6,114.7,127.0,128.8,148.6,166.7,170.4,172.1,173.5.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化物得到标题化合物,产物被氢谱证实:
H NMR(CD3OD)δ1.72-2.14(m,2CH2),2.54-2.92(m,2CH2),3.37(d,J=1.5Hz,CC-H),3.54-3.83(m,CH2),4.97-5.07(m,CHN),7.57(d,2H,J=8Hz,ArH),7.83(d,2H,J=8Hz,ArH).
按实施例1的方法,用3(S)-氨基丁酸乙酯代替3(S)-氨基-4-戊烯酸乙酯制备标题化合物。使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)13.7,19.6,22.6,26.9,27.6,37.9,39.6,40.9,43.0,51.7,60.8,126.6,127.3,129.0,149.1,172.3,172.4,173.9.
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)19.7,22.8,26.9,37.8,39.7,40.74,42.9,51.7,105.5,126.5,127.4,129.1,174.0.
按实施例1的方法,用3(S)-氨基-3-苯基丙酸乙酯代替3(S)-氨基-4-戊烯酸乙酯制备标题化合物。使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被氢谱证实:
H NMR(CD3OD)1.2(t,3-CH3),1.8-2.05(m,CH2),2.7(m,CH2)2.8-2.9(m,CH2),3.6-3.9(m,CH2),4.1(q,2-CH2),5.4(t,NH),7.2-7.85(m,PhH).
按实施例2的方法,用猪肝酯酶处理上面实施例的最终产物制备标题化合物,使用实施例1的条件通过反相HPLC纯化产物得到标题化合物,产物被碳谱证实:
C NMR(CD3OD)22.0,26.1,37.0,39.0,40.2,50.0,50.9,96.8,125.9,126.1,126.6,126.9,128.1,128.3,141.4,148.4,171.6,172.6,173.2.
按实施例1的方法,用3-氨基-3-(3-塞吩基)丙酸乙酯代替3(S)-氨基-4-戊烯酸乙酯以及用1-(4-氰基苯基)-2-哌啶酮-3-乙酸代替实施例1步骤E的1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸制备标题化合物。按实施例1中制备1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法,用5-溴戊酰氯代替实施例1步骤A的4-溴丁酰氯制备1-(4-氰基苯基)-2-哌啶酮-3-乙酸。按实施例5折分1-(4-氰基苯基)-2-吡咯烷酮-3-乙酸的同样方法折分1-(4-氰基苯基)-2-哌啶酮-3-乙酸。使用实施例1的条件通过反相HPLC纯化最终产物得到标题化合物,产物被氢谱证实:
H NMR(dias.CD3OD)δ1.20,1.21(2t,CH3),1.72-1.83(m,2-CH2),2.55-2.93(m,2-CH2),3.63-3.87(m,CH2),4.06-4.15(2q,CH2),5.46-5.53(m,CHN),7.07-7.83(m,7H,ArH).
实施例353-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体BA. 3-[[[[1-(4-氰基苯基)]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯,对映体富集的异构体B的制备
按类似于实施例1的方法,由实施例5步骤A的产物(550mg,2.25mmol)和β-丙氨酸乙酯盐酸盐(380mg,2.47mmol)制备标题化合物,得到690mg(89%)产物。
1H-NMR(CDCl3)δ1.27(t,J=7Hz,3H),1.97(m,1H),2.40-2.58(m,4H),2.77(dd,J=5Hz,J=15Hz,1H),3.08(m,1H),3.53(q,J=7Hz,2H),3.83(m,2H),4.15(q,J=7Hz,2H),7.66(d,J=8Hz,2H),7.80(d,J=8Hz,2H).B. 3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯,对映体富集的异构体B的制备
按类似于实施例1步骤F的方法,由步骤A的产物(680mg,1.98mmol)制备标题化合物,经反相色谱纯化后得到630mg(67%)产物,为TFA盐:1H-NMR(d6-DMSO)δ1.19(t,J=7Hz,3H),1.81(m,1H),2.29(m,2H),2.46(t,J =7Hz,2H),2.58(m,1H)2.98(m,1H),3.28(m,2H),3.83(m,2H),4.07(q,J=7Hz,2H),7.87(d,J=8Hz,2H),7.93(d,J=8Hz,2H).
元素分析:计算值 C22H25N4O6F3:C,50.63;H,5.31;N,11.81.实测值:C,50.64;H,5.31;N,11.77.
按类似于实施例2的方法,由实施例35步骤B的产物(150mg,0.316mmol)制备标题化合物,经反相色谱纯化后得到78mg(55%)产物,为TFA盐:1H-NMR(d6-DMSO)δ1.81(m,1H),2.28(m,2H),2.39(t,J=7Hz,2H),2.58(m,1H),2.96(m,1H),3.25(m,2H),3.83(m,2H),7.85(d,J=8Hz,2H),7.92(d,J=8Hz,2H).元素分析:计算值 C18H21N4O6F3·1H2O:
C,46.55;H,4.99;N,12.06.实测值: C,46.42;H,4.69;N,12.23.
实施例373-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐A. 3-[[[[1-[4-(氰基苯基)-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯的制备
按类似于实施例17步骤D的方法,由实施例17步骤C的产物(322mg,1.60mmol),用β-丙氨酸盐酸盐代替(3S)-乙烯基-β-丙氨酸盐酸盐制备标题化合物,用Et2O研制后得到340mg(62%)产物:
1H-NMR(CDCl3)δ1.27(t,J=7Hz,3H),2.06(m,1H),2.54(t,J=6Hz,2H),2.82(m,1H),3.49(m,2H),3.76-3.88(m,2H),4.14(q,J=7Hz,2H),4.48(m,1H),7.67(d,J=8Hz,2H),7.81(d,J=8Hz,2H).元素分析:计算值 C17H20N4O4·0.25H2O:
C,58.52:H,5.92;N,16.06.实测值: C,58.59;H,6.08;N,15.92.B. 3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐的制备
按类似于实施例1步骤F的方法,由步骤A的产物(210mg,0.52mmol)制备标题化合物,经反相色谱纯化后得到187mg(76%)产物,为TFA盐:1H-NMR(d6-DMSO)δ1.20(t,J=7Hz,3H),1.95(m,1H),2.35-2.48(m,3H),3.24(m,2H),3.75-3.87(m,2H),4.07(q,J=7Hz,2H),4.45(m,1H),7.87(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C19H24N5O6F3:C,48.00;H,5.09;N,14.73.实测值:C,47.81;H,5.23;N,14.59.
按类似于实施例2的方法,由实施例37步骤B的产物(100mg,0.21mmol)制备标题化合物,经反相色谱纯化后得到33mg(35%)产物,为TFA盐:1H-NMR(d6-DMSO)δ1.95(m,2H),2.32-2.48(m,3H),3.22(m,2H),3.75-3.87(m,2H),4.55(m,1H),7.86(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C17H20N5O6F3·0.75H2O:
C,44.30;H,4.70;N,15.20.实测值: C,44.67;H,4.54;N,14.65.
实施例393-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-氮杂环丁烷基]乙酰基]氨基]-4-戊烯酸乙酯A. N-(4-氰基苯基)-3-溴丙酰胺的制备
将4-氨基苄腈(12.5g,106mmol)和二甲基苯胺(14.3g,121mmol)的600mlCH2Cl2溶液在冰浴中在氮气氛下冷却,在20分钟内滴加入3-溴丙酰氯(18.1g,106mmol)。将反应混合物温热至室温,2小时后,混合物用CH2Cl2稀释,用1NHCl、饱和NaCl洗涤,干燥(MgSO4)并浓缩。标题化合物被碳谱证实:
C NMR(CD3OD)δ25.6,38.9,117.8,118.9,132.2,141.7,168.B. 1-(4-氰基苯基)-2-氮杂环丁烷酮的制备
在3.5小时内向搅拌着的NaH(0.264g,11.0mmol)(60%W/W矿物油分散液)的DMF/CH2Cl2(20ml/80ml)溶液加入步骤A的产物(2.52g,10.0mmol)的DMF/CH2Cl2(20ml/80ml)溶液。将反应混合物在室温下搅拌3.5小时,用EtOAc(300ml)稀释并用1NKHSO4洗涤,有机相进一步用饱和NaCl洗涤,干燥(MgSO4)并浓缩。
C NMR(CDCl3)δ35.9,38.0,116.1,118.5,133.0.141.8.168.5.C. 3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-氮杂环丁烷基]乙酰基]氨基]-4-戊烯酸乙酯的制备
按实施例1的步骤C-F的方法,用1-(4-氰基苯基)-2-氮杂环丁烷酮代替步骤C的1-(4-氰苯基)-2-吡咯烷酮,制备标题化合物。最终产物被H NMR证实。
实施例403-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体AA. 1-(4-氰基苯基)-3-氨基吡咯烷-2-酮,对映体富集的异构体A的制备
向实施例17步骤C的产物(4.75g,20mmol)的饱和NaCl(20ml)悬浮液中加入1NNaOH(20ml,20mmol)。混合物用EtOAc萃取3X,洗涤(饱和NaCl),干燥(MgSO4)。向滤液(大约250ml)中加入(S)-(-)-扁桃酸EtOAc(50ml)溶液,过滤出白色沉淀,用EtOAc洗涤并干燥。产物用EtOH重结晶7X得到940mg产物[m.p.172-173℃,[α]D 25=+38.6°,(MeOH,C=9.58mg/ml)],按上面所述的方法将产物转化为游离碱,得到480mg产物(m.p.106-107℃,[α]D 25=+19.5,(MeOH,C=10.25mg/ml)94%e.e.)。使用Crownpak CR(-)柱(15cmX4.0mm)用1%HClO4水溶液以1.2ml/min流速异构化洗脱,测定对映体纯度,测量器被置于254nm。B. 3-[[[[1-(4-氰基苯基)-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯,对映体富集的异构体A的制备
在5℃氮气氛下向1,1-羰基咪唑(572mg,3.55mmol)的吡啶(2.5ml)悬浮液中加入固体3-氨基丙酸乙酯盐酸盐(545mg,3.55mmol)。将所得溶液在5℃下搅拌15分钟,用2.5mlDMF稀释,撤除冰浴。一起加入步骤A的产物(700mg,2.96mmol),并将反应混合物在75-80℃下搅拌2小时,冷却至室温后,所得溶液用15ml1NHCl稀释,过滤出白色沉淀,用H2O洗涤并干燥。用甲基叔丁基醚研制并过滤得到844mg产物(m.p.168.5-169℃)。用EtOAc萃取滤液得到另外的110mg产物(94%总产率)。
1H-NMR(CDCl3)δ1.27(t,J=7Hz,3H),2.06(m,1H),2.54(t,J=6Hz,2H),2.82(m,1H),3.49(m,2H),3.76-3.88(m,2H),4.14(q,J=7Hz,2H),4.48(m,1H),7.67(d,J=8Hz,2H),7.81(d,J=8Hz,2H).元素析:计算值 C17H20N4O4:C,59.29;H,5.85;N,16.27.实测值: C,58.94;H,5.71;N,16.13.C. 3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体A的制备
按类似于实施例1步骤F的方法,由步骤B的产物(600mg,1.74mmol)制备标题化合物,经反相色谱纯化后得到600mg(73%)产物,为TFA盐:[m.p.229-229.5(dec.)]. 1H-NMR(d6-DMSO)δ1.20(t,J=7Hz,3H),1.95(m,1H),2.35-2.48(m,3H),3.24(m,2H),3.75-3.87(m,2H),4.07(q,J=7Hz,2H),4.45(m,1H),7.87(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C19N24N5O6F3:C,48.00;H,5.09;N,14.73.实测值: C,47.86;H,4.71;N,14.56.
按类似于实施例2的方法,由实施例40步骤C的产物(0.50g,1.25mmol)制备标题化合物,经反相色谱纯化后得到400mg(71%)产物,为TFA盐:[m.p.222-223℃(dec.)]. 1H-NMR(d6-DMSO)δ1.95(m,2H),2.32-2.48(m,3H),3.22(m,2H),3.75-3.87(m,2H),4.55(m,1H),7.86(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值C17H20N5O6F3·1/4H2O:C,45.18;H,4.57;N,15.50.实测值: C,45.05;H,4.22;N,15.29.
实施例423-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体BA. 1-(4-氰基苯基)-3-氨基吡咯烷-2-酮,对映体富集的异构体A的制备
按类似于实施例40步骤A的方法,由实施例17步骤C的产物(1.42g,7.08mmol),用(R)-(+)扁桃酸代替(S)-(-)-扁桃酸,制备标题化合物。产物用MeOH重结晶3X得到800mg产物[m.p.172-175℃,[α]D 25=-63.7,(MeOH,C=9.26mg/ml)],将产物悬浮于H2O(5ml)中,用1当量1NNaOH(2.23ml)中和,过滤出沉淀的游离碱,用水洗涤并干燥,得到410mg产物(m.p.104.5-105.5℃,[α]D 25=-18.9,(MeOH,C=10.59mg/ml),)99%e.e.)。使用Crownpak CR(-)柱(15cmX4.0mm)用1%HClO4水溶液以1.2ml/min流速异构化洗脱,测定对映体纯度,测量器被置于254nm。B. 3-[[[[1-(4-氰基苯基)-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯,对映体富集的异构体B的制备
按类似于实施例40步骤B的方法,由步骤A的产物(400mg,1.99mmol)制备标题化合物,得到560mg(82%)产物:[m.p.170.5-171℃,[α]D 25=+16.9(CHCl3,c=14.46mg/mL)].1H-NMR(CDCl3)δ1.27(t,J=7Hz,3H),2.06(m,1H),2.54(t,J=6Hz,2H),2.82(m,1H),3.49(m,2H),3.76-3.88(m,2H),4.14(q,J=7Hz,2H),4.48(m,1H),7.67(d,J=8Hz,2H),7.81(d,J=8Hz,2H).元素分析:计算值 C17H20N4O4:C,59.29;H,5.85;N,16.27.实测值: C,59.09;H,5.79;N,16.20.C. 3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B的制备
按类似于实施例1步骤F的方法,由步骤B的产物(560mg,1.63mmol)制备标题化合物,经反相色谱纯化后得到590mg(76%)产物,为TFA盐:[m.p.22 3-224℃(dec.)]. 1H-NMR(d6-DMSO)δ1.20(t,J=7Hz,3H),1.95(m,1H),2.35-2.48(m,3H),3.24(m,2H),3.75-3.87(m,2H),4.07(q,J=7Hz,2H),4.45(m,1H),7.87(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C19H24N5O6F3:C,48.00;H,5.09;N,14.73.实测值: C,47.64;H,4.72;N,14.55.
按类似于2的方法,由实施例42步骤C的产物(0.10g,0.21mmol)制备标题化合物,经反相色谱纯化后得到55mg(56%)产物,为TFA盐:
[m.p.222-223℃(dec.)].1H-NMR(d6-DMSO)δ1.95(m,2H),2.32-2.48(m,3H),3.22(m,2H),3.75-3.87(m,2H),4.55(m,1H),7.86(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C17H20N5O6F3:C,45.64;H,4.51;N,15.66.实测值: C,45.51;H,4.36;N,15.78.
将3-氨基丁酸乙酯盐酸盐(4.5g,26.8mmol)的27ml1NNaOH溶液用EtOAc萃取2X,将有机馏份干燥(Na2SO4)并在减压下浓缩,用EtOAc重结晶3X残余物得到1.93g(51%)产物,经NMR谱测定为单一非对映体:
(m.p.125-125℃). 1H-NMR(300MHz,CDCl3)δ1.00(d,J=7Hz,3H),1.27(t,J=7Hz,3H),2.23-2.45(m,2H),3.13(m,1H),4.13(q,J=7Hz,2H),4.85(s,1H),7.17-7.33(m,3H),7.41(d,J=8Hz,2H).元素分析:计算值 C14H21NO5:C,59.35;H,7.47;N,4.94.实测值: C,59.03,H,7.51;N,4.83.B. 3(R)-[[[[1-(4-氰基苯基)-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸乙酯,对映体富集的异构体B的制备
按类似于实施例40步骤E的方法,由步骤A的产物(375mg,1.32mmol)和实施例42步骤A的产物(260mg,1.1mmol)制备标题化合物,得到295mg(73%)产物:
(m.p.177.5-179℃).1H-NMR(300MHz,CDCl3)δ1.20-1.30(m,6H),2.05(m,1H),2.53(m,2H),2.83(m,1H),3.83(m,2H),4.15(q,J=7Hz,2H),4.19(m,1H),4.48(m,1H),7.68(d,J=8Hz,2H),7.82(d,J=8Hz,2H).元素分析:计算值C18H22N4O4·0.1H2O:C,60.02;H,6.21;N,15.56.实测值: C,60.29;H,6.21;N,15.06.C. 3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸乙酯三氟乙酸盐,对映体富集的异构体B的制备
按类似于实施例1步骤F的方法,由步骤B的产物(600mg,1.68mmol)制备标题化合物,经反相色谱纯化后得到440mg(55%)产物,为TFA盐:
[m.p.220-221℃(dec.)].1H-NMR(d6-DMSO)δ1.08(d,J=7Hz,3H),1.98(t,J=7Hz,3H),1.95(m,1H),2.32(dd,J=7Hz,J=15Hz,1H),2.45-2.50(m,2H),3.75-3.87(m,2H),3.95(m,1H),4.06(q,J=7Hz,2H),4.41(m,1H),7.87(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值C20H26N5O6F3:C,49.08;H,5.35;N,14.31.实测值: C,48.83;H,5.54;N,13.97.
按类似于实施例2的方法,由实施例44步骤C的产物(70mg,0.14mmol)制备标题化合物,经反相色谱纯化后得到48mg(73%)产物,为TFA盐:[m.p.179-181℃(dec.)]. 1H-NMR(d6-DMSO)δ1.08(d,J=7Hz,3H),2.94(m,1H),2.27(dd,J=7Hz,J=15Hz,1H),2.35-2.50(m,2H),3.75-3.87(m,2H),3.93(m,1H),4.43(m,1H),7.86(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值C18H22N5O6F3·1.5H2O:C,44.26;H,5.16;N,14.34.实测值: C,44.00;H,4.69;N,14.06.
实施例463(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸乙酯三氟乙酸盐,对映体富集的异构体BA. 3(S)-[[(1,1-二甲基乙氧基)羰基]氨基]苯丙酸乙酯的制备
在0℃下向搅拌着的N-Boc-D-苯基甘氨酸(5.02g,20mmol)、N-甲基吗啉(2.02g,20mmol)的EtOAc(100ml)的溶液中加入氯甲酸异丁酯(2.73g,20mmol),15分钟后,过滤反应混合物除去胺盐,然后加入二偶氮甲烷的乙醚溶液(60ml,30mmol),撤除冷浴,并将反应混合物在室温下搅拌2小时,用氮气冲洗反应混合物,除去过量的二偶氮甲烷,反应混合物用EtOAc稀释,用1NHCl、饱和NaHCO3洗涤并干燥(MgSO4)。蒸发溶剂得到粗二偶氮酮,将其溶于EtOH(100ml)中,然后依次用AgO2CPh(1.6g,7mmol)和三乙胺(6.06g,60mmol)处理,20小时后将反应混合物浓缩并色谱纯化(硅胶,15%EtOAc/己烷)得到4.90g(85%)产物,为无色油状物。
1H-NMR(300MHz,CDCl3)δ1.17(t,J=7Hz,3H),1.43(s,9H),2.73-2.92(m,2H),4.07(q,J=7Hz,2H),5.10(m,1H),5.48(m,1H),7.22-7.39(m,5H).B. 3(S)-氨基苯丙酸乙酯盐酸盐的制备
在室温下将无水HCl气体鼓泡通过步骤A的产物(3.0g,10.2mmol)的EtOAc(50ml)溶液15分钟,再搅拌30分钟后,减压下除去溶剂得到2.30g(98%)产物,为黄色油状物。
1H-NMR(300MHz,d6-DMSO)δ1.03(t,J=7Hz,3H),3.02(dd,J=10Hz,J=15Hz,1H),3.25(dd,J=6Hz,J=15Hz,1H),3.96(m,2H),4.55(m,1H),7.3-7.6(m,5H),8.93(s,3H).C. 3(S)-[[[[1-[4-(氰基苯基)-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸乙酯三氟乙酸盐,对映体富集的异构体B的制备
按类似于实施例40步骤B的方法,由步骤B的产物(685mg,2.9mmol)和实施例42步骤A的产物(600mg,2.9mmol)制备标题化合物,得到564mg(47%)产物,(m.p.108-109℃). 1H-NMR(300MHz,CDCl3)δ1.16(t,J=7Hz,3H),2.00(m,lH),2.77-2.93(m,3H),3.81(m,2H),4.05(q,J=7Hz,2H),4.50(m,1H),5.26(m,1H),7.20-7.35(m,5H),7.66(d,J=8Hz,2H),7.80(d,J=8Hz,2H).元素分析:计算值C23H24N4O4·1/3H2O:C,64.79;H,5.83;N,13.14实测值: C,64.65;H,5.58;N,13.18.D. 3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸乙酯三氟乙酸盐,对映体富集的异构体B的制备
按类似于实施例1步骤F的方法,由步骤C的产物(450mg,1.07mmol)制备标题化合物,经反相色谱纯化后得到430mg(73%)产物,为TFA盐:[m.p.223-224℃(dec.)]. 1H-NMR(d6-DMSO)δ1.14(t,J=7Hz,3H),2.03(m,1H),2.47(m,1H),2.80(m,2H),3.84(m,2H),4.04(m,2H),4.50(m,1H);5.05(t,J=7Hz,1H),7.23-7.44(m,5H),7.92(d,J=8Hz,2H),7.97(d,J=8Hz,2H).
实施例473 (S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸三氟乙酸盐,对映体富集的异构体B
按类似于实施例2的方法,由实施例46步骤D的产物(105mg,0.18mmol)制备标题化合物,经反相色谱纯化后得到46mg(46%)产物,为TFA盐:[m.p.198-199℃(dec.)]. 1H-NMR(d6-DMSO)δ1.94(m,1H),2.40(m,1H),2.68(m,2H),3.80(m,2H),4.44(m,1H),5.05(q,J=7Hz,1H),7.20-7.44(m,5H),7.92(d,J=8Hz,2H),7.97(d,J=8Hz,2H).元素分析:计算值C21H23N5O4F3.2H2O:C,49.37;H,5.04;N,12.52.实测值: C,49.07;H,5.62;N,12.43.
实施例483-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸乙三氟乙酸盐,对映体富集的异构体BA. 3-氨基-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸乙酯盐酸盐的制备
向搅拌着的Na-Z-L-2,3-二氨基丙酸(0.50g,2.10mmol)的EtOH(20ml)悬浮液中加入亚磺酰氯(310μl,4.2mmol),将所得溶液在室温下搅拌5小时,除去溶剂,固体残余物用Et2O研制得到573mg(90%)产物(m.p.134-136℃)。元素分析:计算值C13H19N2O4Cl·1/4H2O:C,50.82;H,6.40;N,9.12.实测值: C,50.87;H,6.57;N,8.95.B. 3-[[[[1-(4-(氰基苯基)-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸乙酯,对映体富集的异构体B的制备
按类似于实施例40步骤E的方法,由步骤A的产物(300mg,0.99mmol)和实施例42步骤A的产物(280mg,1.19mmol)制备标题化合物,得到341mg(70%)产物:
(m.p.177-178℃).1H-NMR(300MHz,DMSO)δ1.18(t,J=7Hz,3H),1.92(m,1H),2.39(m,1H),3.24(m,1H),3.48(m,1H),3.78(m,2H),4.09(m,3H),4.47(m,1H),5.04(s,2H),7.25-7.40(m,5H),7.83-7.93(m,4H).元素分析:计算值C18H27N5O6·1/4H2O:C,60.29;H,5.57;N,14.06.实测值: C,60.34;H,5.77;N,14.04.C. 3-[[[[1-[4-(氨基氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B的制备
按类似于实施例1步骤F的方法,由步骤B的产物(625mg,1.25mmol)制备标题化合物,经反相色谱纯化后得到487mg(62%)产物,为TFA盐:[m.p.197-198℃,(dec.)].1H-NMR(300MHz,DMSO)δ1.19(tJ=7Hz,3H),1.95(m,1H),2.40)(m,1H),3.25(m,1H),3.45(m,1H),3.80(m,2H),4.09(m,3H),4.47(m,1H),5.05(s,2H),7.25-7.40(m,5H),7.87(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值C27N31N6O8F3·3
/4H2O:C,50.82;H,5.13;N,13.17.实测值: C,50.82;H,5.03;N,13.10.
实施例493-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B
按类似于实施例2的方法,由实施例48步骤C的产物(100mg,0.16mmol)制备标题化合物,经反相色谱纯化后得到52mg(55%)产物,为TFA盐:[m.p.169-170.5℃(dec.)]. 1H-NMR(d6-DMSO)δ1.94(m,1H),2.42(m,1H),3.21(m,1H),3.49(m,1H),3.82(m,2H),4.03(m,1H),4.48(m,1H),5.04(s,2H),7.28-7.40(m,5H),7.87(d,J=8Hz,2H),7.93(d,J=8Hz,2H).元素分析:计算值 C25H27N6O8F3·1H2O:C,48.86;H,4.76;N,13.68.实测值: C,48.70;H,4.54;N,13.46.
实施例503 (S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-(3-呋喃基)丙酸乙酯三氟乙酸盐,对映体富集的异构体BA. 3(S)-[[[1-[4-(氰基苯基)-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-(3-呋喃基)丙酸乙酯,对映体富集的异构体B的制备
按类似于实施例1步骤E的方法,由实施例5的产物(550mg,2.25mmol)和3(S)-氨基-3-(3-呋喃基)丙酸乙酯三氟乙酸盐(740mg,2.50mmol)制备标题化合物,得到900mg(98%)产物,可直接用于下一步反应:
1H-NMR(300MHz,CDCl3)δ1.20(t,J=7Hz,3H),1.94(m,1H),2.37-2.50(m,3H),2.72-2.88(m,2H),3.08(m,1H),3.80(m,2H),4.08(q,J=7Hz,2H),5.42(m,1H),6.39(m,1H),7.34(m,1H),7.40(m,1H),7.61(d,J=8Hz,2H),7.80(d,J=8Hz,2H).B. 3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-(3-呋喃基)丙酸乙酯三氟乙酸盐,对映体富集的异构体B的制备
按类似于实施例1步骤F的方法,由步骤A的产物(900mg,2.20mmol)制备标题化合物,经反相色谱纯化后得到200mg(17%)产物,为TFA盐[m.p.207-208℃(dec.)].1H-NMR(300MHz,d6-DMSO)δ1.16(t,J=7Hz,3H),1.83(m,1H),2.20-2.40(m,2H),2.60(m,1H),2.74(m,2H),2.98(m,1H);3.83(m,2H),4.05(t,J=7Hz,2H),5.22(m,1H),6.46(m,1H),7.55(m,1H),7.60(m,1H),7.87(d,J=8Hz,2H),7.92(d,J=8Hz,2H).元素分析:计算值C24H27N4O7F3·3/4H2O:C,52.03;H,5.18;N,10.11.实测值: C,51.96;H,4.96;N,9.94.
按类似于实施例2的方法,由实施例50步骤B的产物(150mg,0.28mmol)制备标题化合物,经反相色谱纯化后得到62mg(45%)产物,为TFA盐:[m.p.200-201(dec.)].1H-NMR(300MHz,d6-DMSO)δ1.85(m,1H),2.20-2.38(m,2H),2.55-2.73(m,3H),2.98(m,1H),3.83(m,2H),5.18(m,1H),6.45(m,1H),7.53(m,1H),7.58(m,1H),7.87(d,J=8Hz,2H),7.92(d,J=8Hz,2H).元素分析:计算值C22H23N4O7F3·1H2O:C,49.81;H,4.75;N,10.56.实测值: C,49.59;H,4.53;N,10.29.用下面的试验证明本发明化合物的血小板结合抑制活性。人血小板聚集(PRP)的抑制
用从肘前的静脉(n=1)抽出的被柠檬酸化的全血(3.8%柠檬酸钠,1∶10,30ml血)制备血小板富集的血浆,通过将全血在1000Xg离心(Sorvall RC3C,DuPont,Wilmington,DE)3分钟,无制动下使离心停止,从而制得PRP。通过将PRP在2000Xg下离心10分钟制得血小板贫乏的血浆(PPP)。从选择具有血小板计数为2.5-3.5×108/ml并且聚集应答为大约70-80单位的供血者取血。用四通道集合度计(PAP-4C型,Bio/Data Corp.,Hatboro,PA)测定聚集,用等份试样的PPP标定集合度计测定最大的光透射度,以光透射度增加来测定血小板聚集。用50μl各种浓度的化合物(溶于10%ETOH/水中,浓度为10-3M,用0.9%NaCl将化合物稀释至所需浓度)在37℃下在900rpm下搅拌在集合度计中预先培养PRP(430μl部分)2分钟。按1∶10比例用5%葡萄糖和水溶液稀释原料胶原蛋白(Chronolog,Havertown,PA,马腱)。通过将20μl稀释的胶原蛋白加到未处理的等份试样PRP+50μl盐水中得到载体对照应答,最终胶原蛋白的浓度为4μg/ml。在加入胶原蛋白后记录聚集3分钟(最大聚集在2分钟内达到)。通过比较处理和对照的胶原蛋白计算抑制的百分数,通过比较处理和对照的试样计算抑制的百分数。由剂量-应答曲线用图解法计算IC50,用各个试验的IC50计算平均值和标准误差,用不对称方差不成对Student t试验进行统计分析[MinitabReference Manual,Minitab Inc.,State College,PA(1988)],当发现p<0.05时则认为具有统计意义。PRP(狗)的体外血小板聚集
在抽血之前将健康的雄性或雌性狗禁食8小时,然后使用蝶型针和30cc塑料注射器并用6ml0.129M缓冲的柠檬酸钠(3.8%)收集60ml全血(从至少3只狗体上抽取并将血混合),当将抽取的血与柠檬酸盐混合时小心旋转注射器。在室温下在975Xg下离心3.17分钟,无制动下惯性旋转使离心停止,从而制得血小板富集的血浆(PRP)。用塑料移液管从血液中移出PRP,然后放入有塑料罩的50ml Corning圆锥型无菌离心试管中,并置于室温下。在室温下将剩余的血在2000Xg下离心,无制动下惯性旋转使离心停止,从而制得血小板贫乏的血浆(PPP)。在PRP中血小板计数为大约2-4X108血小板/ml,将400μl PRP制剂和50μl被试验的化合物或盐水在37℃下在BioData集合度计(BioData,Horsham,PA)中预先培养2分钟,将50μl胶原蛋白(按1∶3比例用5%葡萄糖和水溶液稀释,33μg/ml最终浓度,马腱,Chronolog,Havertown,PA.)加到小杯中,测定聚集3分钟。所有化合物都试验两次,结果计算如下:
对照样的百分数=[(化合物的最大的OD-初始的OD)/(对照盐水的OD-初始的OD)]×100,抑制的%=100-(对照样的百分数)。
本发明化合物的试验结果及其中间的抑制浓度记录于表I中,由剂量-应答曲线用图解法计算IC50(如果化合物显示出50%的抑制),在下表中的NT表示未试验。表I
狗 PRP 人 PRP实施例 IC50(μM) IC50(μM)2 0.072 NT4 0.052 0.0556 1.6 0.858 0.18 0.1810 0.17 0.2612 0.39 0.2914 0.12 NT16 0.10 0.3118 0.17 0.1019 0.15 0.0922 0.18 NT24 0.19 NT26 0.59 NT28 0.17 0.1930 0.38 0.2832 0.25 0.1634 0.12 NT实施例
狗PRP 人 PRP
IC50 (μM) IC50(μM)34B 0.24 NT34C 0.16 NT34E 0.070 NT34G 0.19 NT34I 0.18 NT34J 13%@1μM NT34L 0.059 NT34N 0.059 NT36 0.091 0.1138 0.125 NT41 30%@1μM 0.1543 0.090 NT45 0.039 NT47 0.062 NT49 0.054 NT51 0.050 NT
Claims (19)
Z1和Z2独立选自氢、1-6个碳原子的烷基、羟基、卤代和1-6个碳原子的烷氧基;
R1选自氢、1-6个碳原子的低级烷基、2-6个碳原子的低级链烯基、2-6个碳原子的低级炔基、烷氧羰氧烷基、3-6个碳原子的环烷基和芳基,它们可被羟基、1-6个碳原子的低极烷氧基、1-6个碳原子的低级烷基、卤代、硝基、氨基、酰氧基、苯基或萘基任意取代;
R2选自氢,1-6个碳原子的低级烷基,2-6个碳原子的低级链烯基,2-6个碳原子的低级炔基,环烷基,芳基,单环、双环或三环杂环基团其中的1-3个杂原子独立选自氧、氮或硫,并且所述杂环基团被一个或多个取代基任意取代,取代基选自羟基、1-6个碳原子的低级烷氧基、1-6个碳原子的低级烷基、卤代、硝基、氰基、叠氮基、脲基、取代的脲基、羧基、羰基衍生基团、三氟甲基、酰氧基、烷硫基、芳硫基、烷基亚磺酰基、芳基亚磺酰基、烷基磺酰基、芳基磺酰基、氨基、烷基氨基、三烷基甲硅烷基、氨基磺酰基、二烷基氨基、链烷酰氨基、芳酰基氨基、苯基和萘基;
3、根据权利要求2的化合物,其中m为2。
4、根据权利要求3的化合物,其中n为1。
5、根据权利要求4的化合物,选自:
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸一盐酸盐;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体A;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸一盐酸盐,对映体富集的异构体A;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸,对映体富集的异构体B;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-丙酸三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-(3-呋喃基)丙酸乙酯三氟乙酸盐,对映体富集的异构体B;以及
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-(3-呋喃基)丙酸三氟乙酸盐,对映体富集的异构体B。
6、根据权利要求2的化合物,其中m为3。
7、根据权利要求6的化合物,其中n为1。
8、根据权利要求7的化合物,选自:
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三甲基甲硅烷基)-4-戊炔酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三甲基甲硅烷基)-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基-4-庚炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基-4-庚炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-苯基-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-苯基-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-丁酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-丁酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-噻吩基)丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-呋喃基)丙酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-呋喃基)丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸乙酯;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸乙酯;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸。
9、根据权利要求1的化合物,其中X为和p为1。
10、根据权利要求9的化合物,其中n为0。
11、根据权利要求10的化合物,其中m为2。
12、根据权利要求11的化合物,选自:
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸乙酯;
3S-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体A;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体A;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B;
3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸乙酯三氟乙酸盐,对映体富集的异构体B;
3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸三氟乙酸盐,对映体富集的异构体B;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;以及
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B。
13、根据权利要求1的化合物,其中n为1-4的整数;而p为0。
14、根据权利要求13的化合物,其中m为2。
15、根据权利要求14的化合物,选自:
1-[4-(氨基亚氨基甲基)苯基]-3S-甲基-2-氧代-3-吡咯烷己酸一盐酸盐;和
1-[4-(氨基亚氨基甲基)苯基]-3S-甲基-2-氧代-3-吡咯烷己酸乙酯三氟乙酸盐。
Z1和Z2独立选自氢、1-6个碳原子的烷基、羟基、卤代和1-6个碳原子的烷氧基;
R1选自氢、1-6个碳原子的低级烷基、2-6个碳原子的低级链烯基、2-6个碳原子的低级炔基、烷氧羰氧烷基、3-6个碳原子的环烷基和芳基,它们可被羟基、1-6个碳原子的低级烷氧基、1-6个碳原子的低级烷基、卤代、硝基、氨基、酰氧基、苯基或萘基任意取代;
R2选自氢,1-6个碳原子的低级烷基,2-6个碳原子的低级链烯基,2-6个碳原子的低级炔基,环烷基,芳基,单环、双环或三环杂环基团其中的1-3个杂原子独立选自氧、氮或硫,并且所述杂环基团被一个或多个取代基任意取代,取代基选自羟基、1-6个碳原子的低级烷氧基、1-6个碳原子的低级烷基、卤代、硝基、氰基、叠氮基、脲基、取代的脲基、羧基、羰基衍生基团、三氟甲基、酰氧基、烷硫基、芳硫基、烷基亚磺酰基、芳基亚磺酰基、烷基磺酰基、芳基磺酰基、氨基、烷基氨基、三烷基甲硅烷基、氨基磺酰基、二烷基氨基、链烷酰氨基、芳酰基氨基、苯基和萘基;
R3选自氢、1-6个碳原子的烷基、1-6碳原子的烷氧基、卤代、氨基、一烷基氨基、二烷基氨基、酰氨基、烷基磺酰基氨基和芳基磺酰基氨基、羟基、烷氧羰基和烷氧羰基烷基;
X选自:
m为1-4的整数;
n为0-4的整数;以及
p为0或1,其中n和p不均为0。
17、根据权利要求16的药物组合物,其中化合物选自:
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸一盐酸盐;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体A;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸一盐酸盐,对映体富集的异构体A;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯乙酯,对映体富集的异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸,对映体富集的异构体B;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酸基]氨基]-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸乙酯;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸;
3-[[[[1-[4-(氨基亚基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐;
1-[4-(氨基亚氨基甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸一盐酸盐;
1-[4-(氨基亚氨基甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸乙酯三氟乙酸盐;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三甲基甲硅烷基)-4-戊炔酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三甲基甲硅烷基)-4-戊炔酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基-4-庚炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基-4-庚炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-苯基-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-苯基-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-丁酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-丁酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-噻吩基)丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-呋喃基)丙酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-呋喃基)丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸乙酯;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸乙酯;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体A;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体A;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B;
3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸乙酯三氟乙酸盐,对映体富集的异构体B;
3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸三氟乙酸盐,对映体富集的异构体B;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;以及
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B。
Z1和Z2独立选自氢、1-6个碳原子的烷基、羟基、卤代和1-6个碳原子的烷氧基;
R1选自氢、1-6个碳原子的低极烷基、2-6个碳原子的低极链烯基、2-6个碳原子的低级炔基、烷氧羰氧烷基、3-6个碳原子的环烷基和芳基,它们可被羟基、1-6个碳原子的低级烷氧基、1-6个碳原子的低级烷基、卤代、硝基、氨基、酰氧基、苯基或萘基任意取代;
R2选自氢,1-6个碳原子的低级烷基,2-6个碳原子的低级链烯基,2-6个碳原子的低级炔基,环烷基,芳基,单环、双环或三环杂环基团其中的1-3个杂原子独立选自氧、氮或硫,并且所述杂环基团被一个或多个取代基任意取代,取代基选自羟基、1-6个碳原子的低级烷氧基、1-6个碳原子的低级烷基、卤代、硝基、氰基、叠氮基、脲基、取代的脲基、羧基、羰基衍生基团、三氟甲基、酰氧基、烷硫基、芳硫基、烷基亚磺酰基、芳基亚磺酰基、烷基磺酰基、芳基磺酰基、氨基、烷基氨基、三烷基甲硅烷基、氨基磺酰基、二烷基氨基、链烷酰氨基、芳酰基氨基、苯基和萘基;
R3选自氢、1-6个碳原子的烷基、1-6碳原子的烷氧基、卤代、氨基、一烷基氨基、二烷基氨基、酰氨基、烷基磺酰基氨基,芳基磺酰基氨基、羟基、烷氧羰基和烷氧烷基烷基;
n为0-4的整数;以及
p为0或1,其中n和p不均为0。
19、根据权利要求18的方法,其中化合物选自:
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸一盐酸盐;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体A;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸一盐酸盐,对映体富集的异构体A;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸乙酯,对映体富集的异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊烯酸,对映体富集的异构体B;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丁酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-3-苯基丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]-N-[(苯基甲氧基)羰基]-L-丙氨酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]乙酰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-4-戊烯酸乙酯;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐;
1-[4-(氨基亚氨基甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸一盐酸盐;
1-[4-(氨基亚氨基甲基)苯基]-βS-甲基-2-氧代-3-吡咯烷己酸乙酯三氟乙酸盐;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三甲基甲硅烷基)-4-戊炔酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-(三甲基甲硅烷基)-4-戊炔酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基-4-庚炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-6,6-二甲基-4-庚炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-苯基-4-戊炔酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-5-苯基-4-戊炔酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-丁酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-丁酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丙酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-噻吩基)丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-呋喃基)丙酸乙酯;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(3-呋喃基)丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(2-呋喃基)丙酸;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸乙酯;
3-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-(4-甲氧基苯基)丙酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸乙酯,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊烯酸,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸乙酯,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-4-戊炔酸,异构体B;
3(S)-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸乙酯;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]丁酸;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸乙酯;
3S-[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-哌啶基]乙酰基]氨基]-3-苯基丙酸;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体A;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体A;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B;
3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸乙酯三氟乙酸盐,对映体富集的异构体B;
3(R)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]丁酸三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸乙酯三氟乙酸盐,对映体富集的异构体B;
3(S)-[[[[1-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]苯丙酸三氟乙酸盐,对映体富集的异构体B;
3-[[[[4-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基)羰基]氨基]丙酸乙酯三氟乙酸盐,对映体富集的异构体B;以及
3-[[[[4-[4-(氨基亚氨基甲基)苯基]-2-氧代-3-吡咯烷基]氨基]羰基]氨基]-2(S)-[[(苯基甲氧基])羰基]氨基]丙酸三氟乙酸盐,对映体富集的异构体B。
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US4143393A | 1993-03-31 | 1993-03-31 | |
US08/041433 | 1993-03-31 |
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CN1124957A true CN1124957A (zh) | 1996-06-19 |
CN1054842C CN1054842C (zh) | 2000-07-26 |
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US (1) | US5721366A (zh) |
EP (1) | EP0691953B1 (zh) |
JP (1) | JP3034046B2 (zh) |
KR (1) | KR100257837B1 (zh) |
CN (1) | CN1054842C (zh) |
AT (1) | ATE195117T1 (zh) |
AU (1) | AU681396B2 (zh) |
CA (1) | CA2159450C (zh) |
DE (1) | DE69425431T2 (zh) |
DK (1) | DK0691953T3 (zh) |
ES (1) | ES2150489T3 (zh) |
FI (1) | FI111007B (zh) |
GR (1) | GR3034520T3 (zh) |
NO (1) | NO305950B1 (zh) |
PT (1) | PT691953E (zh) |
WO (1) | WO1994022820A1 (zh) |
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- 1994-03-30 JP JP6522208A patent/JP3034046B2/ja not_active Expired - Fee Related
- 1994-03-30 DE DE69425431T patent/DE69425431T2/de not_active Expired - Fee Related
- 1994-03-30 CN CN94192290A patent/CN1054842C/zh not_active Expired - Fee Related
- 1994-03-30 PT PT94913308T patent/PT691953E/pt unknown
- 1994-03-30 KR KR1019950704253A patent/KR100257837B1/ko not_active IP Right Cessation
- 1994-03-30 DK DK94913308T patent/DK0691953T3/da active
- 1994-03-30 WO PCT/US1994/003259 patent/WO1994022820A1/en active IP Right Grant
- 1994-03-30 ES ES94913308T patent/ES2150489T3/es not_active Expired - Lifetime
- 1994-03-30 US US08/436,404 patent/US5721366A/en not_active Expired - Fee Related
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CN103462967A (zh) * | 2013-09-22 | 2013-12-25 | 南京广康协生物医药技术有限公司 | Incarviatone A在抗疱疹病毒的药物中的应用 |
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DE69425431D1 (en) | 2000-09-07 |
NO953844L (no) | 1995-11-20 |
WO1994022820A1 (en) | 1994-10-13 |
NO953844D0 (no) | 1995-09-28 |
FI954609A0 (fi) | 1995-09-28 |
EP0691953B1 (en) | 2000-08-02 |
AU681396B2 (en) | 1997-08-28 |
CA2159450C (en) | 2002-01-08 |
CN1054842C (zh) | 2000-07-26 |
EP0691953A1 (en) | 1996-01-17 |
DE69425431T2 (de) | 2001-02-08 |
FI111007B (fi) | 2003-05-15 |
AU6552294A (en) | 1994-10-24 |
FI954609A (fi) | 1995-10-23 |
JPH08508732A (ja) | 1996-09-17 |
NO305950B1 (no) | 1999-08-23 |
PT691953E (pt) | 2001-01-31 |
KR100257837B1 (ko) | 2000-07-01 |
JP3034046B2 (ja) | 2000-04-17 |
ES2150489T3 (es) | 2000-12-01 |
ATE195117T1 (de) | 2000-08-15 |
DK0691953T3 (da) | 2000-09-04 |
US5721366A (en) | 1998-02-24 |
GR3034520T3 (en) | 2000-12-29 |
CA2159450A1 (en) | 1994-10-13 |
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