CN1043344C - 杂环化合物,制备方法,药物组合物和用途 - Google Patents
杂环化合物,制备方法,药物组合物和用途 Download PDFInfo
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- CN1043344C CN1043344C CN94105013A CN94105013A CN1043344C CN 1043344 C CN1043344 C CN 1043344C CN 94105013 A CN94105013 A CN 94105013A CN 94105013 A CN94105013 A CN 94105013A CN 1043344 C CN1043344 C CN 1043344C
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- Prior art keywords
- rudimentary
- glycyl
- alkenoyl
- phenyl
- alkyl
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- 150000002391 heterocyclic compounds Chemical class 0.000 title description 9
- 238000000034 method Methods 0.000 claims abstract description 111
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 101800004538 Bradykinin Proteins 0.000 claims abstract description 8
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 102100035792 Kininogen-1 Human genes 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 7
- -1 carbonylamino-phenyl Chemical group 0.000 claims description 762
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 346
- 125000000217 alkyl group Chemical group 0.000 claims description 280
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 223
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 183
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 167
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 96
- 125000002252 acyl group Chemical group 0.000 claims description 91
- 150000003839 salts Chemical class 0.000 claims description 81
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 70
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 60
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 59
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 49
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 47
- 125000003545 alkoxy group Chemical group 0.000 claims description 45
- 239000000376 reactant Substances 0.000 claims description 44
- 125000003282 alkyl amino group Chemical group 0.000 claims description 42
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 38
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 17
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 16
- 238000006467 substitution reaction Methods 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 239000004202 carbamide Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 150000003254 radicals Chemical class 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 8
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 8
- 125000001118 alkylidene group Chemical group 0.000 claims description 8
- 125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 7
- 150000002118 epoxides Chemical class 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- AKUSZFPCJFNRSZ-UHFFFAOYSA-N 3,4-dimethyl-1,2-oxazole Chemical compound CC1=CON=C1C AKUSZFPCJFNRSZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000676 alkoxyimino group Chemical group 0.000 claims description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000002541 furyl group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 claims description 2
- JTSFIVQMXUDGAB-UHFFFAOYSA-N 4-thiomorpholin-4-ylmorpholine Chemical compound C1COCCN1N1CCSCC1 JTSFIVQMXUDGAB-UHFFFAOYSA-N 0.000 claims description 2
- KDISMIMTGUMORD-UHFFFAOYSA-N N-acetylpiperidine Natural products CC(=O)N1CCCCC1 KDISMIMTGUMORD-UHFFFAOYSA-N 0.000 claims description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 125000005030 pyridylthio group Chemical group N1=C(C=CC=C1)S* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims 15
- 150000002431 hydrogen Chemical class 0.000 claims 5
- SVBBBGKQAZGLQE-UHFFFAOYSA-N 2-oxo-n-phenylpiperidine-1-carboxamide Chemical compound C1CCCC(=O)N1C(=O)NC1=CC=CC=C1 SVBBBGKQAZGLQE-UHFFFAOYSA-N 0.000 claims 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims 1
- 125000006501 nitrophenyl group Chemical group 0.000 claims 1
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical class C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims 1
- 206010061218 Inflammation Diseases 0.000 abstract description 5
- 208000002193 Pain Diseases 0.000 abstract description 5
- 230000004054 inflammatory process Effects 0.000 abstract description 5
- 230000036407 pain Effects 0.000 abstract description 5
- 206010020751 Hypersensitivity Diseases 0.000 abstract description 4
- 208000026935 allergic disease Diseases 0.000 abstract description 4
- 230000007815 allergy Effects 0.000 abstract description 4
- 230000002265 prevention Effects 0.000 abstract description 4
- 230000001404 mediated effect Effects 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 821
- 125000000539 amino acid group Chemical group 0.000 description 430
- 239000002585 base Substances 0.000 description 239
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 231
- WORJEOGGNQDSOE-ASTXPPQBSA-N trichloro(deuterio)methane;trideuterio(deuteriooxy)methane Chemical compound [2H]C(Cl)(Cl)Cl.[2H]OC([2H])([2H])[2H] WORJEOGGNQDSOE-ASTXPPQBSA-N 0.000 description 220
- 239000000203 mixture Substances 0.000 description 169
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 124
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 90
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 77
- 239000000243 solution Substances 0.000 description 70
- 235000002639 sodium chloride Nutrition 0.000 description 67
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 64
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 52
- 125000000623 heterocyclic group Chemical group 0.000 description 50
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 40
- 229940093499 ethyl acetate Drugs 0.000 description 37
- KBEBGUQPQBELIU-UHFFFAOYSA-N cinnamic acid ethyl ester Natural products CCOC(=O)C=CC1=CC=CC=C1 KBEBGUQPQBELIU-UHFFFAOYSA-N 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- 239000012044 organic layer Substances 0.000 description 34
- OKKJLVBELUTLKV-MZCSYVLQSA-N CD3OD Substances [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 31
- KBEBGUQPQBELIU-CMDGGOBGSA-N Ethyl cinnamate Chemical compound CCOC(=O)\C=C\C1=CC=CC=C1 KBEBGUQPQBELIU-CMDGGOBGSA-N 0.000 description 31
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
- 235000019341 magnesium sulphate Nutrition 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 28
- 235000013985 cinnamic acid Nutrition 0.000 description 27
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 26
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 26
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 23
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 23
- 229930016911 cinnamic acid Natural products 0.000 description 23
- 125000005544 phthalimido group Chemical group 0.000 description 23
- 239000000843 powder Substances 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 22
- 238000001816 cooling Methods 0.000 description 21
- 239000005457 ice water Substances 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 20
- 238000005406 washing Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 19
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 18
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000007864 aqueous solution Substances 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 16
- 229910052801 chlorine Inorganic materials 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000010828 elution Methods 0.000 description 15
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 14
- 125000006325 2-propenyl amino group Chemical group [H]C([H])=C([H])C([H])([H])N([H])* 0.000 description 14
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- 229910052731 fluorine Inorganic materials 0.000 description 13
- 239000011737 fluorine Substances 0.000 description 13
- 238000001556 precipitation Methods 0.000 description 13
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methylthiourea Natural products CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 235000011121 sodium hydroxide Nutrition 0.000 description 11
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- 125000001980 alanyl group Chemical group 0.000 description 10
- 235000009508 confectionery Nutrition 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 9
- 229910052794 bromium Inorganic materials 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 125000003435 aroyl group Chemical group 0.000 description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 150000003927 aminopyridines Chemical class 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- CCRCUPLGCSFEDV-UHFFFAOYSA-N cinnamic acid methyl ester Natural products COC(=O)C=CC1=CC=CC=C1 CCRCUPLGCSFEDV-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 6
- 125000006260 ethylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])C([H])([H])[H] 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 239000011630 iodine Substances 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 5
- RYECOJGRJDOGPP-UHFFFAOYSA-N Ethylurea Chemical group CCNC(N)=O RYECOJGRJDOGPP-UHFFFAOYSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 5
- 229940054066 benzamide antipsychotics Drugs 0.000 description 5
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- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000003452 oxalyl group Chemical group *C(=O)C(*)=O 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005646 oximino group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 208000027753 pain disease Diseases 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 201000001245 periodontitis Diseases 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- BZCGWAXQDLXLQM-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O.ClP(Cl)(Cl)=O BZCGWAXQDLXLQM-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000011295 pitch Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 208000026440 premature labor Diseases 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical group [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 125000005942 tetrahydropyridyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
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- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract
本发明涉及具有作为缓激肽拮抗剂活性的式Ⅰ的杂环化合物及其药物上可接受的盐,其制备方法,含有它们的药物组合物以及使用它们预防和/或治疗人体或动物体中缓激肽或其类似物介导的疾病的方法。式Ⅰ中各取代基的定义见说明书。
Description
本发明涉及新的杂环化合物及其药物上可接受的盐。
更具体地说,本发明涉及具有作为缓激肽拮抗剂活性的新的杂环化合物及其药物上可接受的盐,其制备方法,含有该化合物或其盐的药物组合物,以及在治疗上用其预防和/或治疗人体或动物体中缓激肽或其类似物介导的疾病如变态反应、炎症、自体免疫疾病、休克、疼病等的方法。
本发明的一个目的是提供具有作为缓激肽拮抗剂活性的新的、有用的杂环化合物及其药物上可接受的盐。
本发明的另一个目的是提供制备所述的化合物及其盐的方法。
本发明的再一个目的是提供含有所述的杂环化合物及其药物上可接受的盐作为有效成分的药物组合物。
本发明的再一个目的是提供一种使用所述的杂环化合物及其药物上可接受的盐预防和/或治疗缓激肽或其类似物介导的疾病如变态反应、炎症、自体免疫疾病、休克、疼痛等的方法。
一些杂环化合物是已知的,例如在EP-A-224,086,EP-A-261,539,化学文摘90:34849g(1979),或化学文摘97:18948c(1982)中有述。然而,所述的化合物具有作为缓激肽拮抗剂活性是未知的。
X2是N或C-R7,
X3是N或C-R8,
R1是氢或卤素,
R2是卤素,
R3是氢、硝基、可选择性地带有适宜取代基的氨基或可选择性地带有适宜取代基的杂环基,
R4和R5各自为氢或卤素,
R6和R8各自为氢、卤素、低级烷基、羟基、低级烷硫基、可被低级烷基选择性取代的氨基、或可被下列取代基选择性取代的低级烷氧基:羟基、低级烷氧基、氨基、低级烷氨基和被低级烷氧基选择性取代的芳基,
R7是氢或低级烷基,
A是低级亚烷基,
Q是O或N-R9,其中R9是氢或酰基,条件是当X1是C-R6,其中R6是氢时,R3不是氢。
目的化合物〔1〕或其盐可按照如下列反应流程所示的方法制备。
R11是酰基,
R11a是带有氨基的酰基,
R11b是带有酰氨基的酰基,
R12是氢、低级烷基、低级烷氧(低级)烷基、低级烷氨(低级烷基)、杂环(低级)烷基、杂环基、低级链烯基、低级炔基、低级烷基氨基甲酰氧基(低级)烷基、低级烷氧羰基(低级)烷基、羧基(低级)烷基、低级烷基氨基甲酰基(低级)烷基、低级烷氧羰基-芳(低级)烷基、羧基-芳(低级)烷基、低级烷基氨基甲酰基-芳(低级)烷基、被保护或未保护的羟基(低级)烷基或被低级烷氨基选择性取代的芳基,R13是氢、低级烷基、低级烷氧(低级)烷基或被保护或未保护的羟基(低级)烷基,或R12或R13与相连的氮原子一起形成可选择性地带有适宜取代基的杂环基,
(AA)是氨基酸残基,
X是离去基团,
Y是NH或低级亚烷基,
Z是CH或N,
R1,R2,R3,R4,R5,X1,X2,X3,Q和A各自如上所定义。
下面详细解释包括于本发明范围之内的本说明书上下文中所述的各种不同定义的适宜的实例。
术语“低级”除非另外指明,是指具有1-6个碳原子的基团。
在这一点上,各种不同定义中的低级链烯基部分、低级炔基部分和芳(低级)链烯基部分中的“低级”一词是指具有2-6个碳原子的基团。
此外,各种不同定义中的低级链烯酰基部分、低级炔酰基部分、环(低级)烷基部分、环(低级)链烯基部分、芳(低级)链烯酰基部分、芳(低级)炔酰基部分和杂环(低级)链烯酰基部分中的“低级”一词是指具有3-6个碳原子的基团。
适宜的“卤素”可以是氟、氯、溴和碘。
适宜的“芳基”和术语“芳(低级)链烯酰基”中的芳基部分可以是苯基、萘基、被低级烷基取代的苯基〔例如甲苯基、二甲苯基、_基、枯烯基、二(叔丁基)苯基,等〕等等,其中优选的是苯基、萘基和甲苯基。
适宜的“低级烷基”和术语“杂环(低级)烷基”、“低级烷硫基”和“低级烷氨基”中的低级烷基部分可以是直链或支链的低级烷基如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基或类似的基团,其中优选的是C1-C4烷基如甲基、乙基、丙基、异丁基或叔丁基。
适宜的“低级亚烷基”可以是直链或支链的基团如亚甲基、亚乙基、三亚甲基、甲基亚甲基、四亚甲基、乙基亚乙基、亚丙基、五亚甲基、六亚甲基或类似的基团,其中最优选的是亚甲基。
适宜的“低级烷氧基”可以是直链或支链的基团如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、己氧基或类似的基团,其中优选的是C1-C4烷氧基如甲氧基、乙氧基或异丙氧基。
适宜的“低级亚烯基”可以是直链或支链的C2-C6亚烯基如1,2-亚乙烯基,甲基亚乙烯基、亚丙烯基、1,3-亚丁二烯基或类似的基团,其中最优选的是1,2-亚乙烯基。
适宜的“酰基”可以是取代的或未取代的烷酰基如烷酰基〔例如甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、己酰基、庚酰基、3,3-二甲基丁酰基,等〕,卤(低级)烷酰基〔例如氯乙酰基、三氟乙酰基、溴乙酰基、溴丁酰基、七氟丁酰基,等〕,羟基(低级)烷酰基〔例如乙醇酰、乳酰、3-羟基丙酰基、甘油酰,等〕,低级烷磺酰氧基(低级)烷酰基〔例如,甲磺酰氧基乙酰基、乙磺酰氧基乙酰基、甲磺酰氧基丙酰基,等〕,低级烷氧(低级)烷酰基〔例如甲氧乙酰基、乙氧乙酰基、甲氧丙酰基、乙氧丙酰基、丙氧丙酰基、甲氧丁酰基,等〕,低级烷硫基(低级)烷酰基〔例如甲硫基乙酰基、乙硫基乙酰基、甲硫基丙酰基、乙硫基丙酰基、丙硫基丙酰基、甲硫基丁酰基,等〕,低级烷酰氧基(低级)烷酰基〔例如乙酰氧基乙酰基、乙酰氧基丙酰基、丙酰氧基乙酰基,等〕,芳氧基(低级)烷酰基〔例如苯氧乙酰基、苯氧丙酰基、甲苯氧乙酰基、萘氧乙酰基,等〕,芳酰基(低级)烷酰基〔例如苯基草酰基、苯甲酰乙酰基、苯甲酰丙酰基,等〕,羧基(低级)烷酰基〔例如草酰、羧基乙酰基、3-羧基丙酰基、3-羧基丁酰基、4-羧基丁酰基,等〕,酯化羧基(低级)烷酰基,例如,低级烷氧羰基(低级)烷酰基〔例如甲氧羰基乙酰基、乙氧羰基乙酰基、甲氧羰基丙酰基、乙氧羰基丙酰基、等〕,氨基甲酰(低级)烷酰基〔例如,氨基甲酰乙酰基、氨基甲酰丙酰基,等〕,低级烷基氨基甲酰(低级)烷酰基〔例如甲基氨基甲酰乙酰基、甲基氨基甲酰丙酰基、乙基氨基甲酰丙酰基、二甲基氨基甲酰丙酰基、(N-甲基-N-乙基氨基甲酰)丙酰基,等〕,芳(低级)烷酰基〔例如苯基乙酰基、甲苯基乙酰基、萘基乙酰基、2-苯基丙酰基、3-苯基丙酰基、4-苯基丁酰基、三苯甲基羰基,等〕,选择性取代的杂环(低级)烷酰基〔例如吗啉代乙酰基、硫代吗啉代乙酰基、吗啉代丙酰基、硫代吗啉代丙酰基、哌啶子基丙酰基、哌嗪子基丙酰基、吡啶基乙酰基、吡咯烷基丙酰基、咪唑烷基丙酰基、哌啶子基乙酰基、吡咯烷基乙酰基、六亚甲基亚氨基乙酰基、六亚甲基亚氨基丙酰基、咪唑基乙酰基、呋喃基乙酰基、噻吩基乙酰基、甲基哌嗪基乙酰基、吡啶基哌嗪基乙酰基,等〕,杂环硫代(低级)烷酰基〔例如吡啶基硫代乙酰基、嘧啶基硫代乙酰基、咪唑基硫代丙酰基,等〕,等等,低级链烯酰基〔例如丙烯酰基、巴豆酰基、异巴豆酰基、3-丁烯酰基、3-戊烯酰基、4-戊烯酰基、异丁烯酰基,等〕,低级炔酰基〔例如丙炔酰基、2-丁炔酰基、3-丁炔酰基,等〕,环(低级)烷基羰基〔例如环丙基羰基、环丁基羰基、环戊基羰基、环己基羰基,等〕,环(低级)链烯基羰基〔例如环戊烯基羰基、环己烯基羰基,等〕,羧基,酯化羧基如低级烷氧羰基〔例如甲氧羰基、乙氧羰基、丙氧羰基、异丙氧羰基、丁氧羰基、异丁氧羰基、叔丁氧羰基、戊氧羰基、己氧羰基,等〕,芳氧羰基〔例如苯氧羰基,等〕,等等,取代或未取代的芳酰基如芳酰基〔例如苯甲酰基、甲苯酰基、二甲苯酰基、萘酰基,等〕,低级烷氧芳酰基〔例如甲氧苯甲酰基,等〕,卤芳酰基〔例如氯苯甲酰基、氟苯甲酰基,等〕,酰基芳酰基,例如,低级烷氧羰基芳酰基〔例如甲氧羰基苯甲酰基,等〕,等等,取代或未取代的芳(低级)链烯酰基如芳(低级)链烯酰基〔例如肉桂酰基、别肉桂酰基、2-甲基肉桂酰基、4-甲基肉桂酰基,等〕,低级烷氧基-芳(低级)链烯酰基〔例如甲氧基肉桂酰基、乙氧基肉桂酰基、二甲氧基肉桂酰基,等〕,低级亚烷基二氧基-芳(低级)链烯酰基〔例如亚甲二氧基肉桂酰基、亚乙二氧基肉桂酰基,等〕,硝基-芳(低级)链烯酰基〔例如硝基肉桂酰基,等〕,氰基-芳(低级)链烯酰基〔例如氰基肉桂酰基,等〕,卤-芳(低级)链烯酰基〔例如氟肉桂酰基、氟肉桂酰基,等〕,羟基-芳(低级)链烯酰基〔例如羟基肉桂酰基,等〕,羟基(低级)烷氧-芳(低级)链烯酰基〔例如羟基甲氧肉桂酰基、羟基乙氧肉桂酰基,等〕,氨基(低级)烷氧-芳(低级)链烯酰基〔例如氨基乙氧肉桂酰基,等〕,低级烷氨基(低级)烷氧-芳(低级)链烯酰基〔例如甲氨基乙氧肉桂酰基、二甲氨基乙氧肉桂酰基,等〕,杂环(低级)烷氧基-芳(低级)链烯酰基〔例如吡啶基甲氧肉桂酰基,等〕,选择性取代的杂环-芳(低级)链烯酰基〔例如吗啉代肉桂酰基、甲基哌嗪基肉桂酰基、吡咯烷基肉桂酰基、氧代吡咯烷基肉桂酰基、氧代哌啶子基肉桂酰基、二氧代吡咯烷基肉桂酰基、氧代噁唑烷基肉桂酰基、吡咯基肉桂酰基、四唑基肉桂酰基,等〕,氨基-芳(低级)链烯酰基〔例如氨基肉桂酰基,等〕,低级烷氨基-芳(低级)链烯酰基〔例如甲氨基肉桂酰基、二甲氨基肉桂酰基,等〕,酰氨基-芳(低级)链烯酰基,例如,低级烷酰氨基-芳(低级)链烯酰基〔例如,乙酰氨基肉桂酰基、丙酰氨基肉桂酰基、异丁酰氨基肉桂酰基,等〕,环烷基(低级)烷酰氨基-芳(低级)链烯酰基〔例如环戊基乙酰氨基肉桂酰基、环己基乙酰氨基肉桂酰基、金刚烷基乙酰氨基肉桂酰基,等〕,环烷基羰基氨基-芳(低级)链烯酰基〔例如环丙基羰基氨基肉桂酰基、环戊基羰基氨基肉桂酰基、环己基羰基氨基肉桂酰基、金刚烷基羰基氨基肉桂酰基,等〕,低级链烯酰氨基-芳(低级)链烯酰基〔例如丙烯酰氨基肉桂酰基、巴豆酰氨基肉桂酰基,等〕,低级烷氧羰基氨基-芳(低级)链烯酰基〔例如甲氧羰基氨基肉桂酰基、乙氧羰基氨基肉桂酰基,等〕,羟基(低级)烷氨基-芳(低级)链烯酰基〔例如羟基乙酰氨基肉桂酰基、羟基丙酰氨基肉桂酰基,等〕,低级烷氧(低级)烷酰氨基-芳(低级)链烯酰基〔例如甲氧乙酰氨基肉桂酰基、甲氧丙酰氨基肉桂酰基,等〕,卤(低级)烷酰氨基-芳(低级)链烯酰基〔例如氯乙酰氨基肉桂酰基、溴丁酰氨基肉桂酰基、三氟乙酰氨基肉桂酰基,等〕,氨基(低级)烷酰氨基-芳(低级)链烯酰基〔例如氨基乙酰氨基肉桂酰基、氨基丙酰氨基肉桂酰基,等〕,低级烷氨基(低级)烷酰氨基-芳(低级)链烯酰基〔例如甲氨基乙酰氨基肉桂酰基、二甲氨基乙酰氨基肉桂酰基,等〕,低级烷酰氨基(低级)烷酰氨基-芳(低级)链烯酰基〔例如乙酰氨基乙酰氨基肉桂酰基、乙酰氨基丙酰氨基肉桂酰基,等〕,羧基(低级)烷酰氨基-芳(低级)链烯酰基〔例如羧基乙酰氨基肉桂酰基,羧基丙酰氨基肉桂酰基,等〕,低级烷氧羰基(低级)烷酰氨基-芳(低级)链烯酰基〔例如乙氧羰基乙酰氨基肉桂酰基、乙氧羰基丙酰氨基肉桂酰基,等〕,低级烷氧羰基(低级)链烯酰氨基-芳(低级)链烯酰基〔例如乙氧羰基丙烯酰氨基肉桂酰基,等〕,卤(低级)烷氧羰基氨基-芳(低级)链烯酰基〔例如氯乙氧羰基氨基肉桂酰基,等〕,选择性取代的杂环(低级)烷酰氨基-芳(低级)链烯酰基〔例如吡啶基乙酰氨基肉桂酰基、噻吩基乙酰氨基肉桂酰基、甲基吡咯基乙酰氟基肉桂酰基,等〕,芳酰氨基-芳(低级)链烯酰基〔例如苯甲酰氨基肉桂酰基,等〕,选择性取代的杂环羰基氨基-芳(低级)链烯酰基〔例如吡啶基羰基氨基肉桂酰基、吗啉代羰基氨基肉桂酰基、呋喃基羰基氨基肉桂酰基、噻吩基羰基氨基肉桂酰基、噁唑基羰基氨基肉桂酰基、甲基噁唑基羰基氨基肉桂酰基、二甲基异噁唑基羰基氨基肉桂酰基、咪唑基羰基氨基肉桂酰基、甲基咪唑基羰基氨基肉桂酰基、哌啶基羰基氨基肉桂酰基、乙基哌啶基羰基氨基肉桂酰基、乙酰基哌啶基羰基氨基肉桂酰基、吡咯烷基羰基氨基肉桂酰基、乙酰基吡咯烷基羰基氨基肉桂酰基、叔丁氧羰基吡咯烷基羰基氨基肉桂酰基,等〕,低级烷基磺酰氨基-芳(低级)链烯酰基〔例如甲磺酰氨基肉桂酰基、乙磺酰氨基肉桂酰基,等〕,等等,N-(低级烷酰基)-N-(低级烷基)氨基-芳(低级)链烯酰基〔例如N-乙酰-N-甲氨基肉桂酰基、N-乙酰-N-乙氨基肉桂酰基、N-丙酰-N-甲氨基肉桂酰基,等〕,N-〔低级烷氧(低级)烷酰基〕-N-(低级烷基)氨基-芳(低级)链烯酰基〔例如N-甲氧乙酰-N-甲氨基肉桂酰基、N-甲氧丙酰-N-甲氨基肉桂酰基,等〕,N-(低级烷酰基)-N-〔杂环(低级)烷基〕氨基-芳(低级)链烯酰基〔例如N-乙酰-N-吡啶基甲氨基肉桂酰基,等〕,N-(低级烷酰基)-N-〔低级烷氧(低级)烷基〕氨基-芳(低级)链烯酰基〔例如N-乙酰-N-甲氧乙氨基肉桂酰基、N-乙酰-N-甲氧甲氨基肉桂酰基、N-丙酰-N-甲氧乙氨基肉桂酰基,等〕,N-(低级烷酰基)-N-〔低级烷氧羰基(低级)烷基〕氨基-芳(低级)链烯酰基〔例如N-乙酰-N-叔丁氧羰基甲氨基肉桂酰基、N-乙酰-N-叔丁氧羰基乙氨基肉桂酰基、N-丙酰-N-叔丁氧羰基甲氨基肉桂酰基,等〕,N-(低级烷酰基)-N-〔羧基(低级)烷基〕氨基-芳(低级)链烯酰基〔例如N-乙酰-N-羧甲氨基肉桂酰基、N-乙酰-N-羧乙氨基肉桂酰基、N-丙酰-N-羧甲氨基肉桂酰基,等〕,N-〔低级烷氧(低级)烷酰基〕-N-〔杂环(低级)烷基〕氨基-芳(低级)链烯酰基〔例如N-甲氧乙酰-N-吡啶基甲氨基肉桂酰基,N-甲氧丙酰-N-吡啶基甲氨基肉桂酰基,等〕,N-〔杂环羰基〕-N-〔低级烷氧(低级)烷基〕氨基-芳(低级)链烯酰基〔例如N-吡啶基羰基-N-甲氧甲氨基肉桂酰基、N-吡啶基羰基-N-甲氧乙氨基肉桂酰基、N-噻吩基羰基-N-甲氧乙氨基肉桂酰基,等〕,脲基-芳(低级)链烯酰基〔例如脲基肉桂酰基,等〕,低级烷基脲基-芳(低级)链烯酰基〔例如甲基脲基肉桂酰基、乙基脲基肉桂酰基、二甲基脲基肉桂酰基,等〕,杂环脲基-芳(低级)链烯酰基〔例如吡啶基脲基肉桂酰基、嘧啶基脲基肉桂酰基、噻吩基脲基肉桂酰基,等〕,酰基-芳(低级)链烯酰基,例如,低级烷酰基-芳(低级)链烯酰基〔例如甲酰肉桂酰基、乙酰肉桂酰基,丙酰肉桂酰基,等〕,羧基-芳(低级)链烯酰基〔例如羧基肉桂酰基,等〕,低级烷氧羰基-芳(低级)链烯酰基〔例如甲氧羰基肉桂酰基、乙氧羰基肉桂酰基,等〕,氨基甲酰基-芳(低级)链烯酰基〔例如氨基甲酰基肉桂酰基,等〕,低级烷基氨基甲酰基-芳(低级)链烯酰基〔例如甲基氨基甲酰基肉桂酰基、乙基氨基甲酰基肉桂酰基、二甲基氨基甲酰基肉桂酰基、丙基氨基甲酰基肉桂酰基、异丙基氨基甲酰基肉桂酰基、二乙基氨基甲酰基肉桂酰基、N-甲基-N-乙基氨基甲酰基肉桂酰基,等〕,羟基(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如羟乙基氨基甲酰基肉桂酰基、二(羟乙基)氨基甲酰基肉桂酰基,等〕,N-〔羟基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)链烯酰基〔例如N-羟乙基-N-甲基氨基甲酰基肉桂酰基,等〕,低级烷氧(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如甲氧甲基氨基甲酰基肉桂酰基、甲氧乙基氨基甲酰基肉桂酰基、二(甲氧乙基)氨基甲酰基肉桂酰基、乙氧乙基氨基甲酰基肉桂酰基、甲氧丙基氨基甲酰基肉桂酰基、二(乙氧乙基)氨基甲酰基肉桂酰基,等〕,N-〔低级烷氧(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)链烯酰基〔例如甲氧乙基-N-甲基氨基甲酰基肉桂酰基、N-乙氧乙基-N-甲基氨基甲酰基肉桂酰基,等〕,杂环(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如吡啶基甲基氨基甲酰基肉桂酰基、呋喃基甲基氨基甲酰基肉桂酰基、噻吩基甲基氨基甲酰基肉桂酰基,等〕,N-〔杂环(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)链烯酰基〔例如N-吡啶基甲基-N-甲基氨基甲酰基肉桂酰基,等〕,杂环氨基甲酰基-芳(低级)链烯酰基〔例如吗啉基氨基甲酰基肉桂酰基、噻吩基氨基甲酰基肉桂酰基、吡啶基氨基甲酰基肉桂酰基、嘧啶基氨基甲酰基肉桂酰基、四唑基氨基甲酰基肉桂酰基,等〕,选择性取代的杂环羰基-芳(低级)链烯酰基〔例如吗啉代羰基肉桂酰基、吡咯烷基羰基肉桂酰基、哌啶子基羰基肉桂酰基、四氢吡啶基羰基肉桂酰基、甲基哌嗪基羰基肉桂酰基,等〕,低级链烯基氨基甲酰基-芳(低级)链烯酰基〔例如乙烯基氨基甲酰基肉桂酰基、烯丙基氨基甲酰基肉桂酰基、甲基丙烯基氨基甲酰基肉桂酰基,等〕,低级炔基氨基甲酰基-芳(低级)链烯酰基〔例如乙炔基氨基甲酰基肉桂酰基、丙炔基氨基甲酰基肉桂酰基,等〕,氨基(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如氨基甲基氨基甲酰基肉桂酰基、氨基乙基氨基甲酰基肉桂酰基,等〕,低级烷氨基(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如甲氨基甲基氨基甲酰基肉桂酰基、甲氨基乙基氨基甲酰基肉桂酰基、乙氨基乙基氨基甲酰基肉桂酰基、二甲氨基乙基氨基甲酰基肉桂酰基,等〕,低级烷基氨基甲酰氧基(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如甲基氨基甲酰氧基甲基氨基甲酰基肉桂酰基、甲基氨基甲酰氧基乙基氨基甲酰基肉桂酰基、乙基氨基甲酰氧基乙基氨基甲酰基肉桂酰基、二甲基氨基甲酰氧基乙基氨基甲酰基肉桂酰基,等〕,低级烷基氨基甲酰基(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如甲基氨基甲酰基甲基氨基甲酰基肉桂酰基、甲基氨基甲酰基乙基氨基甲酰基肉桂酰基、乙基氨基甲酰基乙基氨基甲酰基肉桂酰基、二甲基氨基甲酰基乙基氨基甲酰基肉桂酰基,等〕,低级烷氧羰基(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如甲氧羰基甲基氨基甲酰基肉桂酰基、甲氧羰基乙基氨基甲酰基肉桂酰基、乙氧羰基甲基氨基甲酰基肉桂酰基、乙氧羰基乙基氨基甲酰基肉桂酰基,等〕,羧基(低级)烷基氨基甲酰基-芳(低级)链烯酰基〔例如羧甲基氨基甲酰基肉桂酰基、羧乙基氨基甲酰基肉桂酰基,等〕,(低级烷基氨基甲酰基-芳(低级)烷基〕氨基甲酰基-芳(低级)链烯酰基〔例如(甲基氨基甲酰基-苯乙基)氨基甲酰基肉桂酰基。(乙基氨基甲酰基-笨乙基)氨基甲酰基肉桂酰基,(乙基氨基甲酰基-苯乙基)氨基甲酰基肉桂酰基,等〕,〔低级烷氧羰基-芳(低级)烷基〕氨基甲酰基-芳(低级)链烯酰基〔例如(甲氧羰基-苯乙基)-氨基甲酰基肉桂酰基、(乙氧羰基-苯乙基)氨基甲酰基肉桂酰基,等〕,〔羧基-芳(低级)烷基〕氨基甲酰基-芳(低级)链烯酰基〔例如羧基-苯乙基)氨基甲酰基肉桂酰基,等〕,N-〔低级烷基氨基甲酰基(低级)烷基〕-N-(低级烷基)氯基甲酰基-芳(低级)链烯酰基〔例如N-(甲基氨基甲酰基甲基)-N-甲基氨基甲酰基肉桂酰基、N-(甲基氨基甲酰基乙基)-N-甲基氨基甲酰基肉桂酰基、N-(乙基氨基甲酰基乙基)-N-甲基氨基甲酰基肉桂酰基、N-(二甲基氨基甲酰基乙基)-N-甲基氨基甲酰基肉桂酰基,等〕,N-〔低级烷氧羰基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)链烯酰基〔例如N-甲氧羰基甲基-N-甲基氨基甲酰基肉桂酰基、N-甲氧羰基乙基-N-甲基氨基甲酰基肉桂酰基、N-乙氧羰基甲基-N-甲基氨基甲酰基肉桂酰基,N-乙氧羰基乙基-N-甲基氨基甲酰基肉桂酰基,等〕,N-(羧基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)链烯酰基〔例如N-羧甲基-N-甲基氨基甲酰基肉桂酰基、N-羧乙基-N-甲基氨基甲酰基肉桂酰基,等〕,芳基氨基甲酰基-芳(低级)链烯酰基〔例如苯基氨基甲酰基肉桂酰基、萘基氨基甲酰基肉桂酰基,等〕,等等,等等,芳(低级)炔酰基〔例如苯基丙炔酰基,等〕,取代或未取代的杂环(低级)链烯酰基如杂环(低级)链烯酰基〔例如吗啉基丙烯酰基、吡啶基丙烯酰基、噻吩基丙烯酰基,等〕,氨基-杂环(低级)链烯酰基〔例如氨基吡啶基丙烯酰基,等〕,低级烷氨基-杂环(低级)链烯酰基〔例如甲氨基吡啶基丙烯酰基、二甲氨基吡啶基同丙烯酰基,等〕,酰氨基-杂环(低级)链烯酰基,例如,低级烷酰氨基-杂环(低级)链烯酰基〔例如乙酰氨基吡啶基丙烯酰基、丙酰氨基吡啶基丙烯酰基,等〕,低级链烯酰氨基-杂环(低级)链烯酰基〔例如丙烯酰氨基吡啶基丙烯酰基、巴豆酰氨基吡啶基丙烯酰基,等〕,杂环(低级)烷酰氨基-杂环(低级)链烯酰基〔例如吡啶基乙酰氨基吡啶基丙烯酰基、噻吩基乙酰氨基吡啶基丙烯酰基,等〕,杂环羰基氨基-杂环(低级)链烯酰基〔例如吡啶基羰基氨基吡啶基丙烯酰基、呋喃基羰基氨基吡啶基丙烯酰基,等〕低级烷酰氨基(低级)烷酰氨基-杂环(低级)链烯酰基〔例如乙酰氨基乙酰氨基吡啶基丙烯酰基、乙酰氨基丙酰氨基吡啶基丙烯酰基,等〕,低级烷氧羰基(低级)烷酰氨基-杂环(低级)链烯酰基〔例如乙氧羰基乙酰氨基吡啶基丙烯酰基、乙氧羰基丙酰氨基吡啶基丙烯酰基,等〕、低级烷氧(低级)烷酰氨基-杂环(低级)链烯酰基〔例如甲氧乙酰氨基吡啶基丙烯酰基、甲氧丙酰氨基吡啶基丙烯酰基、乙氧丙酰氨基吡啶基丙烯酰基,等〕,等等,低级烷基脲基-杂环(低级)链烯酰基〔例如甲基脲基吡啶基丙烯酰基,等〕,酰基-杂环(低级)链烯酰基,例如,羧基杂环(低级)链烯酰基〔例如羧基吡啶基丙烯酰基,等〕,低级烷氧羰基-杂环(低级)链烯酰基〔例如,乙氧羰基吡啶基丙烯酰基,等〕,低级烷基氨基甲酰基-杂环(低级)链烯酰基〔例如甲基氨基甲酰基吡啶基丙烯酰基、乙基氨基甲酰基吡啶基丙烯酰基、二甲基氨基甲酰基吡啶基丙烯酰基、二乙基氨基甲酰基吡啶基丙烯酰基、异丙基氨基甲酰基吡啶基丙烯酰基、N-乙基-N-甲基氨基甲酰基吡啶基丙烯酰基,等〕,低级烷氧(低级)烷基氨基甲酰基-杂环(低级)链烯酰基〔例如甲氧甲基氨基甲酰基吡啶基丙烯酰基、甲氧乙基氨基甲酰基吡啶基丙烯酰基、甲氧丙基氨基甲酰基吡啶基丙烯酰基、乙氧乙基氨基甲酰基吡啶基丙烯酰基、二(甲氧乙基)氨基甲酰基吡啶基丙烯酰基,等〕,羟基(低级)烷基氨基甲酰基-杂环(低级)链烯酰基〔例如羟甲基氨基甲酰基吡啶基丙烯酰基、羟乙基氨基甲酰基吡啶基丙烯酰基、二(羟乙基)氨基甲酰基吡啶基丙烯酰基,等〕,杂环氨基甲酰基-杂环(低级)链烯酰基〔例如吡啶基氨基甲酰基吡啶基丙烯酰基、吗啉基氨基甲酰基吡啶基丙烯酰基、噻吩基氨基甲酰基吡啶基丙烯酰基、嘧啶基氨基甲酰基吡啶基丙烯酰基,等〕,杂环(低级)烷基氨基甲酰基-杂环(低级)链烯酰基〔例如吡啶基甲基氨基甲酰基吡啶基丙烯酰基、呋喃基甲基氨基甲酰基吡啶基丙烯酰基、噻吩基甲基氨基甲酰基吡啶基丙烯酰基,等〕,杂环羰基-杂环(低级)链烯酰基〔例如吗啉代羰基吡啶基丙烯酰基、吡咯烷基羰基吡啶基丙烯酰基、哌啶子基羰基吡啶基丙烯酰基,等〕,低级链烯基氨基甲酰基-杂环(低级)链烯酰基〔例如乙烯基氨基甲酰基吡啶基丙烯酰基、烯丙基氨基甲酰基吡啶基丙烯酰基,等〕,低级炔基氨基甲酰基-杂环(低级)链烯酰基〔例如乙炔基氨基甲酰基吡啶基丙烯酰基、丙炔基氨基甲酰基吡啶基丙烯酰基,等〕,等等,等等,可被取代基所取代的杂环羰基〔例如呋喃甲酰、噻吩甲酰、烟酰、异烟酰、吗啉代羰基、哌啶子基羰基、4-甲基-1-哌嗪基羰基、4-乙基-1-哌嗪基羰基、二甲氨基哌啶子基羰基、4-甲基氨基甲酰基-1-哌嗪基羰基、1,2,3,6-四氢吡啶基羰基、吡咯烷基羰基、吲哚基羰基,等〕,可被硝基取代的芳氧羰基〔例如苯氧羰基、硝基苯氧羰基,等〕,可被硝基取代的芳(低级)烷氧羰基〔例如苄氧羰基、硝基苄氧羰基,等〕,取代或未取代的氨基甲酰基或硫代氨基甲酰基如氨基甲酰基、低级烷基氨基甲酰基〔例如甲基氨基甲酰基、乙基氨基甲酰基、丙基氨基甲酰基、异丙基氨基甲酰基、丁基氨基甲酰基、异丁基氨基甲酰基、叔丁基氨基甲酰基、戊基氨基甲酰基、二甲基氨基甲酰基、二乙基氨基甲酰基、N-乙基-N-甲基氨基甲酰基,等〕,羧基(低级)烷基氨基甲酰基〔例如羧甲基氨基甲酰基、羧乙基氨基甲酰基,等〕,酯化羧基(低级)烷基氨基甲酰基,例如,低级烷氧羰基(低级)烷基氨基甲酰基〔例如甲氧羰基甲基氨基甲酰基、乙氧羰基甲基氨基甲酰基、乙氧羰基乙基氨基甲酰基,等〕,低级链烯基氨基甲酰基〔例如乙烯基氨基甲酰基、烯丙基氨基甲酰基,等〕,环(低级)烷基氨基甲酰基〔例如环丙基氨基甲酰基、环丁基氨基甲酰基、环戊基氨基甲酰基、环己基氨基甲酰基,等,卤(低级)烷酰氨基甲酰基〔例如三氯乙酰氨基甲酰基,等〕,取代或未取代的芳基氨基甲酰基,例如,芳基氨基甲酰基〔例如苯基氨基甲酰基、甲苯基氨基甲酰基、二甲苯基氨基甲酰基、萘基氨基甲酰基、乙基苯基氨基甲酰基,等〕,芳硫基氨基甲酰基〔例如苯硫基氨基甲酰基,等〕,低级烷氧-芳基氨基甲酰基〔例如甲氧苯基氨基甲酰基,等〕,卤-芳基氨基甲酰基〔例如氟苯基氨基甲酰基、氯苯基氨基甲酰基,等〕,卤(低级)烷基芳基氨基甲酰基〔例如三氟甲基苯基氨基甲酰基,等〕,硝基-芳基氨基甲酰基〔例如硝基苯基氨基甲酰基,等〕,氰基-芳基氨基甲酰基〔例如氰基苯基氨基甲酰基,等〕,羟基(低级)烷基-芳基氨基甲酰基〔例如羟甲基苯基氨基甲酰基、羟乙基苯基氨基甲酰基,等〕,氨基-芳基氨基甲酰基〔例如氨基苯基氨基甲酰基,等〕,低级烷氨基-芳基氨基甲酰基〔例如甲氨基苯基氨基甲酰基、乙氨基苯基氨基甲酰基、二甲氨基苯基氨基甲酰基,等〕,低级烷酰氨基-芳基氨基甲酰基〔例如乙酰氨基苯基氨基甲酰基、丙酰氨基苯基氨基甲酰基,等〕,N-(低级烷酰基)-N-(低级烷基)氨基-芳基氨基甲酰基〔例如N-乙酰-N-甲氨基苯基氨基甲酰基、N-丙酰-N-甲氨基苯基氨基甲酰基,等〕,低级烷氧(低级)烷酰氨基-芳基氨基甲酰基〔例如甲氧乙酰氨基苯基氨基甲酰基、甲氧丙酰氨基苯基氨基甲酰基,等〕,低级烷氧羰基(低级)烷酰氨基-芳基氨基甲酰基〔例如乙氧羰基乙酰氨基苯基氨基甲酰基、甲氧羰基丙酰氨基苯基氨基甲酰基,等〕,羧基氨基-芳基氨基甲酰基〔例如羧基氨基苯基氨基甲酰基,等〕,低级烷氧羰基氨基-芳基氨基甲酰基〔例如乙氧羰基氨基苯基氨基甲酰基,等〕,芳酰氨基-芳基氨基甲酰基〔例如苯甲酰氨基苯基氨基甲酰基,等〕,杂环羰基氨基-芳基氨基甲酰基〔例如吡啶基羰基氨基苯基氨基甲酰基、呋喃基羰基氨基苯基氨基甲酰基、吗啉代羰基氨基苯基氨基甲酰基,等〕,杂环(低级)烷酰氨基-芳基氨基甲酰基〔例如吡啶基乙酰氨基苯基氨基甲酰基、噻吩基乙酰氨基苯基氨基甲酰基,等〕,脲基-酰基氨基甲酰基〔例如脲基苯基氨基甲酰基,等〕,低级烷基脲基-芳基氨基甲酰基〔例如甲基脲基苯基氨基甲酰基、乙基脲基苯基氨基甲酰基,等〕,羟亚氨基(低级)烷基-芳基氨基甲酰基〔例如羟亚氨基乙基苯基氨基甲酰基,等〕,低级烷氧亚氨基(低级)烷基-芳基氨基甲酰基〔例如甲氧亚氨基乙基苯基氨基甲酰基,等〕,低级烷基亚肼基(低级)烷基-芳基氨基甲酰基〔例如甲基亚肼基乙基苯基氨基甲酰基、二甲基亚肼基乙基苯基氨基甲酰基,等〕,选择性取代的杂环-芳基氨基甲酰基〔例如氧代吡咯烷基苯基氨基甲酰基、氧代哌啶子基苯基氨基甲酰基、二氧代吡咯烷基苯基氨基甲酰基、氧代噁唑烷基苯基氨基甲酰基、吡咯基苯基氨基甲酰基,等〕,酰基-芳基氨基甲酰基,例如,羧基-芳基氨基甲酰基〔例如羧苯基氨基甲酰基,等〕,低级烷氧羰基-芳基氨基甲酰基〔例如乙氧羰基苯基氨基甲酰基,等〕,杂环羰基-芳基氨基甲酰基〔例如吗啉代羰基苯基氨基甲酰基、吡咯烷基羰基苯基氨基甲酰基、哌啶子基羰基苯基氨基甲酰基、1,2,3,6-四氢吡啶基羰基苯基氨基甲酰基、哌嗪基羰基苯基氨基甲酰基、硫代吗啉代羰基苯基氨基甲酰基,等〕,被低级烷基取代的杂环羰基-芳基氨基甲酰基〔例如甲基哌嗪基羰基苯基氨基甲酰基、乙基哌嗪基羰基苯基氨基甲酰基,等〕,被芳基取代的杂环羰基-芳基氨基甲酰基〔例如苯基哌嗪基羰基苯基氨基甲酰基,等〕,被杂环基取代的杂环羰基-芳基氨基甲酰基〔例如吡啶基哌嗪基羰基苯基氨基甲酰基,等〕,被低级烷酰基取代的杂环羰基-芳基氨基甲酰基〔例如乙酰哌嗪基羰基苯基氨基甲酰基,等〕,被低级烷氧羰基取代的杂环羰基-芳基氨基甲酰基〔例如乙氧羰基哌嗪基羰基苯基氨基甲酰基,等〕,被低级烷氨基取代的杂环羰基-芳基氨基甲酰基〔例如甲氨基哌嗪基羰基-苯基氨基甲酰基、二甲氨基哌啶子基羰基苯基氨基甲酰基,等〕,被低级烷基氨基甲酰基取代的杂环羰基-芳基氨基甲酰基〔例如甲基氨基甲酰基哌嗪基羰基苯基氨基甲酰基,等〕,氨基甲酰基-芳基氨基甲酰基〔例如氨基甲酰基苯基氨基甲酰基,等〕,低级烷基氨基甲酰基-芳基氨基甲酰基〔例如甲基氨基甲酰基苯基氨基甲酰基、乙基氨基甲酰基苯基氨基甲酰基、丙基氨基甲酰基苯基氨基甲酰基、二甲基氨基甲酰基苯基氨基甲酰基、二乙基氨基甲酰基苯基氨基甲酰基、N-乙基-N-甲基氨基甲酰基苯基氨基甲酰基、N-异丙基-N-甲基氨基甲酰基苯基氨基甲酰基,等〕,羟基(低级)烷基氨基甲酰基-芳基氨基甲酰基〔例如羟甲基氨基甲酰基苯基氨基甲酰基、羟乙基氨基甲酰基苯基氨基甲酰基、二(羟乙基)氨基甲酰基苯基氨苯基甲酰基,等〕,N-〔羟基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基〔例如N-(羟乙基)-N-甲基氨基甲酰基苯基氨基甲酰基,等〕,低级烷氧(低级)烷基氨基甲酰基-芳基氨基甲酰基〔例如甲氧甲基氨基甲酰基苯基氨基甲酰基、甲氧乙基氨基甲酰基苯基氨基甲酰基、乙氧乙基氨基甲酰基苯基氨基甲酰基、二(甲氧乙基)氨基甲酰基苯基氨基甲酰基、二(乙氧乙基)氨基甲酰基苯基氨基甲酰基,等〕,N-〔低级烷氧(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基〔例如N-(甲氧乙基)-N-甲基氨基甲酰基苯基氨基甲酰基、N-(甲氧丙基)-N-甲基氨基甲酰基苯基氨基甲酰基,等〕,低级烷氨基(低级)烷基氨基甲酰基-芳基氨基甲酰基〔例如甲氨基乙基氨基甲酰基苯基氨基甲酰基、二甲氨基乙基氨基甲酰基苯基氨基甲酰基,等〕,N-(低级)烷氨基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基〔例如N-(二甲氨基甲基)-N-甲基氨基甲酰基苯基氨基甲酰基、N-(二甲氨基丙基)-N-甲基氨基甲酰基苯基氨基甲酰基,等〕,杂环氨基甲酰基-芳基氨基甲酰基〔例如吗啉基氨基甲酰基苯基氨基甲酰基、噻吩基氨基甲酰基苯基氨基甲酰基、吡啶基氨基甲酰基苯基氨基甲酰基、嘧啶基氨基甲酰基苯基氨基甲酰基,等〕,N-(杂环)-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基〔例如N-吡啶基-N-甲基氨基甲酰基苯基氨基甲酰基,等〕,杂环(低级)烷基氨基甲酰基-芳基氨基甲酰基〔例如吡啶基甲基氨基甲酰基苯在氨基甲酰基、吡啶基乙基氨基甲酰基苯基氨基甲酰基,噻吩基甲基氨基甲酰基苯基氨基甲酰基,等〕,N-〔杂环(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基〔例如N-吡啶基甲基-N-甲基氨基甲酰基苯基氨基甲酰基,等〕,N-〔杂环(低级)烷基〕-N-〔低级烷氧(低级)烷基〕氨基甲酰基-芳基氨基甲酰基〔例如N-吡啶基甲基-N-甲氧乙基氨基甲酰基苯基氨基甲酰基,等〕,芳基氨基甲酰基-芳基氨基甲酰基〔例如苯基氨基甲酰基苯基氨基甲酰基,等〕,低级烷氨基-芳基氨基甲酰基-芳基氨基甲酰基〔例如二甲氨基苯基氨基甲酰基苯基氨基甲酰基,等〕,低级烷酰基-芳基氨基甲酰基〔例如乙酰苯基氨基甲酰基、丙酰苯基氨基甲酰基,等〕,等等,等等,芳(低级)烷基氨基甲酰基〔例如苄基氨基甲酰基、苯乙基氨基甲酰基,等〕,杂环氨基甲酰基〔例如呋喃基氨基甲酰基、噻吩基氨基甲酰基、吡啶基氨基甲酰基、喹啉基氨基甲酰基、异喹啉基氨基甲酰基、嘧啶基氨基甲酰基、吡唑基氨基甲酰基,等〕,杂环(低级)烷基氨基甲酰基〔例如吡啶基甲基氨基甲酰基、吡啶基乙基氨基甲酰基、呋喃基甲基氨基甲酰基、噻吩基甲基氨基甲酰基,等〕,芳氨基氨基甲酰基〔例如苯氨基氨基甲酰基,等〕,芳酰基氨基甲酰基〔例如苯甲酰基氨基甲酰基,等〕,等等,低级烷基磺酰基〔例如甲磺酰基、乙磺酰基、丙磺酰基、异丙磺酰基、叔丁磺酰基、戊磺酰基,等〕,芳基磺酰基〔例如甲苯磺酰基、苯磺酰基,等〕,芳(低级)烷基磺酰基〔例如苯甲磺酰基、苯乙磺酰基,等〕,芳(低级)链烯基磺酰基〔例如苯乙烯基磺酰基、肉桂酰基磺酰基,等〕,邻苯二甲酰基,下面提到的取代或未取代的氨基酸残基,或类似的基团。
适宜的“氨基酸残基”可包括天然的或人造的氨基酸,这样的氨基酸可以是甘氨酸、肌氨酸、丙氨酸、β-丙氨酸、缬氨酸、正缬氨酸、亮氨酸、异亮氨酸、正亮氨酸、丝氨酸、苏氨酸、米胱氨酸、甲硫氨酸、苯丙氨酸、苯基甘氨酸、色氨酸、酪氨酸、脯氨酸、羟脯氨酸、谷氨酸、天冬氨酸、谷氨酰胺、天冬酰胺、赖氨酸、精氨酸、组氨酸、乌氨酸、或其类似物,其中较优选的是甘氨酸、肌氨酸、丙氨酸、β-丙氨酸和脯氨酸,最优选的是甘氨酸。所述的氨基酸残基可被适宜的取代基所取代,这样的取代基如上述的低级烷基,上述的芳基,上述的酰基,芳(低级)烷基〔例如苄基、苯乙基、三苯甲基,等〕,环烷基〔例如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基,等〕,下述的杂环基,杂环(低级)烷基〔例如吡啶基甲基、吡啶基乙基、咪唑基甲基、呋喃基甲基、噻吩基甲基、吗啉代甲基、哌啶子基甲基,等〕,取代或未取代的脒基〔例如脒基、甲基脒基、N-乙基-N’-氰基脒基,等〕,或类似的基团。
所述的被适宜的取代基所取代的氨基酸残基的优选实例可以是被低级烷基取代的氨基酸残基〔例如乙基甘氨酰、异丙基甘氨酰、二甲基甘氨酰、二乙基甘氨酰、乙基肌氨酰、异丙基氨酰、甲基丙氨酰、甲基-β-丙氨酰、二甲基-β-丙氨酰,等〕,被芳基取代的氨基酸残基〔例如N-苯基甘氨酰、N-甲苯基甘氨酰、N-苯基丙氨酰、N-苯基肌氨酰,等〕,被芳(低级)烷基取代的氨基酸残基〔例如苯甲基甘氨酰、三苯甲基甘氨酰、苯乙基甘氨酰、苯甲基肌氨酰、苯甲基丙氨酰,等〕,被杂环基取代的氨基酸残基〔例如吗啉代甘氨酰、哌啶子基甘氨酰、吡啶基甘氨酰,等〕,被杂环(低级)烷基取代的氨基酸残基〔例如吡啶基甲基甘氨酰、咪唑基甲基甘氨酰、呋喃基甲基甘氨酰、噻吩基甲基甘氨酰,等〕,被环烷基取代的氨基酸残基〔例如环丙基甘氨酰、环丁基甘氨酰、环戊基甘氨酰、环己基甘氨酰、环庚基甘氨酰、环辛基甘氨酰、金刚烷基甘氨酰、环己基肌氨酰、环庚基肌氨酰、环己基丙氨酰,等〕,被选择性取代的脒基取代的氨基酸残基〔例如脒基甘氨酰、甲基脒基甘氨酰、N-乙基-N’-氰基脒基甘氨酰,等〕,被酰基取代的氨基酸残基如被烷酰基取代的氨基酸残基〔例如甲酰甘氨酰、乙酰甘氨酰、乙酰肌氨酰、乙酰丙氨酰、乙酰-β-丙氨酰、丙酰甘氨酰、丁酰甘氨酰、异丁酰甘氨酰、戊酰甘氨酰、异戊酰甘氨酰、新戊酰甘氨酰、己酰甘氨酰、庚酰甘氨酰,等〕,被卤(低级)烷酰基取代的氨基酸残基〔例如三氟乙酰甘氨酰、三氟乙酰肌氨酰、三氟乙酰丙氨酰、溴乙酰甘氨酰、七氟丁酰甘氨酰,等〕,被羟基(低级)烷酰基取代的氨基酸残基〔例如乙醇酰甘氨酰、乙醇酰肌氨酰、乳酰甘氨酰、乳酰丙氨酰,等〕,被低级烷基磺酰氧基(低级)烷酰基取代的氨基酸残基〔例如甲磺酰氧基乙酰甘氨酰、乙磺酰氧基乙酰甘氨酰、甲磺酰氧基乙酰肌氨酰,等〕,被低级烷氧(低级)烷酰基取代的氨基酸残基〔例如甲氧乙酰甘氨酰、乙氧乙酰甘氨酰、甲氧乙酰肌氨酰、甲氧丙酰甘氨酰,等〕,被芳氧基(低级)烷酰基取代的氨基酸残基〔例如苯氧乙酰甘氨酰、苯氧丙酰甘氨酰、苯氧乙酰肌氨酰,等〕,被低级烷硫基(低级)烷酰基取代的氨基酸残基〔例如甲硫基乙酰甘氨酰、甲硫基丙酰甘氨酰,等〕,被低级烷基氨基甲酰基(低级)烷酰基取代的氨基酸残基〔例如甲基氨基甲酰基丙酰甘氨酰、甲基氨基甲酰基丙酰丙氨酰,等〕,被低级烷酰氧基(低级)烷酰基取代的氨基酸残基〔例如乙酰氧基乙酰甘氨酰、乙酰氧基乙酰肌氨酰、丙酰氧基乙酰甘氨酰、乙酰氧基丙酰丙氨酰,等〕,被羟基(低级)烷酰基取代的氨基酸残基〔例如羰基乙酰甘氨酰、羧基丙酰甘氨酰、羧基丙酰肌氨酸、羧基乙酰丙氨酰,等〕,被低级烷氧羰基(低级)烷酰基取代的氨基酸残基〔例如甲氧羰基乙酰甘氨酰、乙氧羰基丙酰甘氨酰、甲氧羰基乙酰肌氨酰,等〕,被芳(低级)烷酰基取代的氨基酸残基〔例如苯基乙酰甘氨酰、苯基乙酰肌氨酰、苯基丙酰丙氨酰、苯基丙酰甘氨酰、萘基乙酰甘氨酰、苯基丁酰甘氨酰,等〕,被选择性取代的杂环(低级)烷酰基取代的氨基酸残基〔例如吗啉代乙酰甘氨酰、硫代吗啉代乙酰甘氨酰、其氧化物或二氧化物、吡啶基乙酰甘氨酰、吗啉代丙酰丙氨酰、咪唑基乙酰甘氨酰、哌啶子基乙酰甘氨酰、吡咯烷基乙酰甘氨酰、六亚甲基亚氨基乙酰甘氨酰、甲基哌嗪基乙酰甘氨酰、吡啶基哌嗪基乙酰甘氨酰,等〕,被低级链烯酰基取代的氨基酸残基〔例如丙烯酰甘氨酰、巴豆酰甘氨酰、3-戊烯酰甘氨酰、3-丁烯酰甘氨酰、4-戊烯酰甘氨酰、3-丁烯酰肌氨酰,等〕,被芳(低级)链烯酰基取代的氨基酸残基〔例如肉桂酰甘氨酰、别肉桂酰甘氨酰、α-甲基肉桂酰甘氨酰、4-甲基肉桂酰甘氨酰、肉桂酰肌氨酰,等〕,被低级烷氧-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氧肉桂酰甘氨酰、乙氧肉桂酰甘氨酰、二甲氧肉桂酰甘氨酰,等〕,被低级亚烷基二氧基-芳(低级)链烯酰基取代的氨基酸残基〔例如亚甲基二氧基肉桂酰甘氨酰、亚乙基二氧基肉桂酰甘氨酰,等〕,硝基-芳(低级)链烯酰基〔例如硝基肉桂酰甘氨酰,等〕,被氰基-芳(低级)链烯酰基取代的氨基酸残基〔例如氰基肉桂酰甘氨酰,等〕,被卤-芳(低级)链烯酰基取代的氨基酸残基〔例如氯肉桂酰甘氨酰、氟肉桂酰甘氨酰,等〕,被羟基-芳(低级)链烯酰基取代的氨基酸残基〔例如羟基肉桂酰甘氨酰,等〕,被羟基(低级)烷氧-芳(低级)链烯酰基取代的氨基酸残基〔例如羟基甲氧肉桂酰甘氨酰、羟基乙氧肉桂酰甘氨酰,等〕,被氨基(低级)烷氧-芳(低级)链烯酰基取代的氨基酸残基〔例如氨基乙氧肉桂酰甘氨酰,等〕,被低级烷氨基(低级)烷氧-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氨基甲氧肉桂酰甘氨酰、二甲氨基乙氧肉桂酰甘氨酰,等〕,被杂环(低级)烷氧-芳(低级)链烯酰基取代的氨基酸残基〔例如吡啶基甲氧肉桂酰甘氨酰,等〕,被选择性取代的杂环-芳(低级)链烯酰基取代的氨基酸残基〔例如吗啉代肉桂酰甘氨酰、甲基哌嗪基肉桂酰甘氨酰、吡咯烷基肉桂酰甘氨酰、氧代吡咯烷基肉桂酰甘氨酰、氧代哌啶子基肉桂酰甘氨酰、二氧代吡咯烷基肉桂酰甘氨酰、氧代噁唑烷基肉桂酰甘氨酰、吡咯基肉桂酰甘氨酰、四唑基肉桂酰甘氨酰,等〕,被氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如氨基肉桂酰甘氨酰,等〕,被低级烷氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氨基肉桂酰甘氨酰、二甲氨基肉桂酰甘氨酰,等〕,被酰基氨基-芳(低级)链烯酰基取代的氨基酸残基,例如,被低级烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如乙酰氨基肉桂酰甘氨酰、丙酰氨基肉桂酰甘氨酰、异丁酰氨基肉桂酰甘氨酰,等〕,被环烷基(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如环戊基乙酰氨基肉桂酰甘氨酰、环己基乙酸氨基肉桂酰甘氨酰、金刚烷基乙酰氨基肉桂酰甘氨酰,等〕,被环烷基羰基氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如环丙基羰基氨基肉桂酰甘氨酰、环戊基羰基氨基肉桂酰甘氨酰、环己基羰基氨基肉桂酰甘氨酰、金刚烷基羰基氨基肉桂酰甘氨酰,等〕,被低级链烯酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如丙烯酰氨基肉桂酰甘氨酰、巴豆酰氨基肉桂酰甘氨酰,等〕,被低级烷氧羰基氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氧羰基氨基肉桂酰甘氨酰、乙氧羰基氨基肉桂酰甘氨酰,等〕,被羟基(低级)烷酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如羟基乙酰氨基肉桂酰甘氨酰、羟基丙酰氨基肉桂酰甘氨酰,等〕,被低级烷氧(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氧乙酰氨基肉桂酰甘氨酰、甲氧丙酰氨基肉桂酰甘氨酰,等〕,被卤(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如氯乙酰氨基肉桂酰甘氨酰、三氟乙酰氨基肉桂酰甘氨酰、溴丁酰氨基肉桂酰甘氨酰,等〕,被氨基(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如氨基乙酰氨基肉桂酰甘氨酰、氨基丙酰氨基肉桂酰甘氨酰,等〕,被低级烷氨基(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氨基乙酰氨基肉桂酰甘氨酰、二甲氨基乙酰氨基肉桂酰甘氨酰,等〕,被低级烷酰氨基(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如乙酰氨基乙酰氨基肉桂酰甘氨酰、乙酰氨基丙酰氨基肉桂酰甘氨酰,等〕,被羧基(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如羧乙酰氨基肉桂酰甘氨酰、羧丙酰氨基肉桂酰甘氨酰,等〕,被低级烷氧羰基(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如乙氧羰基乙酰氨基肉桂酰甘氨酰、乙氧羰基丙酰氨基肉桂酰甘氨酰,等〕,被低级烷氧羰基(低级)链烯酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如乙氧羰基丙烯酰氨基肉桂酰甘氨酰,等〕,被卤(低级)烷氧羰基氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如氯乙氧羰基氨基肉桂酰甘氨酰,等〕,被选择性取代的杂环(低级)烷酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如吡啶基乙酰氨基肉桂酰甘氨酰、噻吩基乙酰氨基肉桂酰甘氨酰、甲基吡咯基乙酰氨基肉桂酰甘氨酰,等〕,被芳酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如苯甲酰氨基肉桂酰甘氨酰,等〕,被选择性取代的杂环羰基氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如吡啶基羰基氨基肉桂酰甘氨酰、吗啉代羰基氨基肉桂酰甘氨酰、呋喃基羰基氨基肉桂酰甘氨酰、噻吩基羰基氨基肉桂酰甘氨酰、噁唑基羰基氨基肉桂酰甘氨酰、甲基噁唑基羰基氨基肉桂酰甘氨酰、二甲基异噁唑基羰基氨基肉桂酰甘氨酰、咪唑基羰基氨基肉桂酰甘氨酰、甲基咪唑基羰基氨基肉桂酰甘氨酰、哌啶基羰基氨基肉桂酰甘氨酰、乙基哌啶基羰基氨基肉桂酰甘氨酰、乙酰哌啶基羰基氨基肉桂酰甘氨酰、吡咯烷基羰基氨基肉桂酰甘氨酰、乙酰吡咯烷基羰基氨基肉桂酰甘氨酰、叔丁氧羰基吡咯烷基羰基氨基肉桂酰甘氨酰,等〕,被低级烷基磺酰氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲磺酰氨基肉桂酰甘氨酰、乙磺酰氨基肉桂酰甘氨酰,等〕,等等,被N-(低级烷酰)-N-(低级烷基)氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如N乙酰-N-甲氨基肉桂酰甘氨酰、N-乙酰-N-乙氨基肉桂酰甘氨酰、N-丙酰-N-甲氨基肉桂酰甘氨酰,等〕,被N-〔低级烷氧(低级)烷酰〕-N-(低级烷基)氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-甲氧乙酰-N-甲氨基肉桂酰甘氨酰、N-甲氧丙酰-N-甲氨基肉桂酰甘氨酰,等〕,被N-(低级烷酰)-N-〔杂环(低级)烷基〕氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-乙酰-N-吡啶基甲氨基肉桂酰甘氨酰,等〕,被N-(低级烷酰)-N-〔低级烷氧(低级)烷基〕氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-乙酰-N-甲氧乙氨基肉桂酰甘氨酰、N-乙酰-N-甲氧甲氨基肉桂酰甘氨酰、N-丙酰-N-甲氧乙氨基肉桂酰甘氨酰,等〕,被N-(低级烷酰)-N-〔低级烷氧羰基(低级)烷基〕氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-乙酰-N-叔丁氧羰基甲氨基肉桂酰甘氨酰、N-乙酰-N-叔丁氧羰基乙氨基肉桂酰甘氨酰、N-丙酰-N-叔丁氧羰基甲氨基肉桂酰甘氨酰,等〕,被N-(低级烷酰基)-N-〔羧基(低级)烷基〕氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-乙酰-N-羧甲氨基肉桂酰甘氨酰、N-乙酰-N-羧乙氨基肉桂酰甘氨酰、N-丙酰-N-羧甲氨基肉桂酰甘氨酰,等〕,被N-〔低级烷氧(低级)烷酰〕-N-〔杂环(低级)烷基〕氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-甲氧乙酰-N-吡啶基甲氨基肉桂酰甘氨酰、N-甲氧丙酰-N-吡啶基甲氨基肉桂酰甘氨酰,等〕,被N-〔杂环羰基〕-N-〔低级烷氧(低级)烷基〕氨基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-吡啶基羰基-N-甲氧甲氨基肉桂酰甘氨酰、N-吡啶基羰基-N-甲氧乙氨基肉桂酰甘氨酰、N-噻吩基羰基-N-甲氧乙氨基肉桂酰甘氨酰,等〕,被脲基-芳(低级)链烯酰基取代的氨基酸残基〔例如脲基肉桂酰甘氨酰,等〕,被低级烷脲基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲脲基肉桂酰甘氨酰、乙脲基肉桂酰甘氨酰、二甲脲基肉桂酰甘氨酰,等〕,被杂环脲基-芳(低级)链烯酰基取代的氨基酸残基〔例如吡啶基脲基肉桂酰甘氨酰、嘧啶基脲基肉桂酰甘氨酰、噻吩基脲基肉桂酰甘氨酰,等〕,被酰基-芳(低级)链烯酰基取代的氨基酸残基,例如,被低级烷酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲酰肉桂酰甘氨酰、乙酰肉桂酰甘氨酰、丙酰肉桂酰甘氨酰,等〕,被羧基-芳(低级)链烯酰基取代的氨基酸残基〔例如羧基肉桂酰甘氨酰,等〕,被低级烷氧羰基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氧羰基肉桂酰甘氨酰、乙氧羰基肉桂酰甘氨酰,等〕,被氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如氨基甲酰基肉桂酰甘氨酰,等〕,被低级烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲基氨基甲酰基肉桂酰甘氨酰、乙基氨基甲酰基肉桂酰甘氨酰、二甲基氨基甲酰基肉桂酰甘氨酰、丙基氨基甲酰基肉桂酰甘氨酰、异丙基氨基甲酰基肉桂酰甘氨酰、二乙基氨基甲酰基肉桂酰甘氨酰、N-甲基-N-乙基氨基甲酰基肉桂酰甘氨酰,等〕,被羟基(低级)烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如羟乙基氨基甲酰基肉桂酰甘氨酰、二(羟乙基)氨基甲酰基肉桂酰甘氨酰,等〕,被N-〔羟基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-羟乙基-N-甲基氨基甲酰基肉桂酰甘氨酰,等〕,被低级烷氧(低级)烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氧甲基氨基甲酰基肉桂酰甘氨酰、甲氧乙基氨基甲酰基肉桂酰甘氨酰、二(甲氧乙基)氨基甲酰基肉桂酰甘氨酰、乙氧乙基氨基甲酰基肉桂酰甘氨酰、甲氧丙基氨基甲酰基肉桂酰甘氨酰、二(乙氧乙基)氨基甲酰基肉桂酰甘氨酰,等〕,被N-〔低级烷氧(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-甲氧乙基-N-甲基氨基甲酰基肉桂酰甘氨酰,等〕,被杂环(低级)烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如吡啶基甲基氨基甲酰基肉桂酰甘氨酰、呋喃基甲基氨基甲酰基肉桂酰甘氨酰、噻吩基甲基氨基甲酰基肉桂酰甘氨酰,等〕,被N-〔杂环(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如N-吡啶基甲基-N-甲基氨基甲酰基肉桂酰甘氨酰,等〕,被杂环氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如吗啉基氨基甲酰基肉桂酰甘氨酰、噻吩基氨基甲酰基肉桂酰甘氨酰、吡啶基氨基甲酰基肉桂酰甘氨酰、嘧啶基氨基甲酰基肉桂酰甘氨酰、四唑基氨基甲酰基肉桂酰甘氨酰,等〕,被选择性取代的杂环羰基-芳(低级)链烯酰基取代的氨基酸残基〔例如吗啉代羰基肉桂酰甘氨酰、吡咯烷基羰基肉桂酰甘氨酰、哌啶子基羰基肉桂酰甘氨酰、四氢吡啶基羰基肉桂酰甘氨酰、甲基哌嗪基羰基肉桂酰甘氨酰,等〕,被低级链烯基氨基甲酰基芳(低级)链烯酰基取代的氨基酸残基〔例如乙烯基氨基甲酰基肉桂酰甘氨酰、烯丙基氨基甲酰基肉桂酰甘氨酰、甲基丙烯基氨基甲酰基肉桂酰甘氨酰,等〕,被低级炔基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如乙炔基氨基甲酰基肉桂酰甘氨酰、丙炔基氨基甲酰基肉桂酰甘氨酰,等〕,被氨基(低级)烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如氨基甲基氨基甲酰基肉桂酰甘氯酰、氨基乙基氨基甲酰基肉桂酰甘氨酰,等〕,被低级烷氨基(低级)烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氨基甲基氨基甲酰基肉桂酰甘氨酰、甲氨基乙基氨基甲酰基肉桂酰甘氨酰、乙氨基乙基氨基甲酰基肉桂酰甘氨酰、二甲氨基乙基氨基甲酰基肉桂酰甘氨酰,等〕,被低级烷基氨基甲酰氧基(低级)烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲基氨基甲酰氧基甲基氨基甲酰基肉桂酰甘氨酰、甲基氨基甲酰氧基乙基氨基甲酰基肉桂酰甘氨酰、乙基氨基甲酰氧基乙基氨基甲酰基肉桂酰甘氨酰、二甲基氨基甲酰氧基乙基氨基甲酰基肉桂酰甘氨酰,等〕,被低级烷基氨基甲酰基(低级)烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲基氨基甲酰甲基氨基甲酰肉桂酰甘氨酰、甲基氨基甲酰乙基氨基甲酰肉桂酰甘氨酰、乙基氨基甲酰乙基氨基甲酰肉桂酰甘氨酰、二甲基氨基甲酰乙基氨基甲酰肉桂酰甘氨酰,等〕,被低级烷氧羰基(低级)烷基氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如甲氧羰基甲基氨基甲酰肉桂酰甘氨酰、甲氧羰基乙基氨基甲酰肉桂酰甘氨酰、乙氧羰基甲基氨基甲酰肉桂酰甘氨酰、乙氧羰基乙基氨基甲酰肉桂酰甘氨酰,等〕,被羧基(低级)烷基氨基甲酰-芳(低级)链烯酰基取代的氨基酸残基〔例如羧甲基氨基甲酰肉桂酰甘氨酰、羧乙基氨基甲酰肉桂酰甘氨酰,等〕,被〔低级烷基氨基甲酰-芳(低级)烷基〕氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如(甲基氨基甲酰-苯乙基)氨基甲酰肉桂酰甘氨酰、(乙基氨基甲酰-苯乙基)氨基甲酰肉桂酰甘氨酰,等〕,被〔低级烷氧羰基-芳(低级)烷基〕氨基甲酰基-芳(低级)链烯酰基取代的氨基酸残基〔例如,(甲氧基羰基-苯乙基)氨基甲酰基肉桂酰基甘氨酰基,(乙氧基羰基-苯乙基)氨基甲酰基肉桂酰基甘氨酰基,等),被〔羧基-芳(低级)烷基〕氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基〔例如,(羧基-苯乙基)氨基甲酰基肉桂酰基甘氨酰基,等〕,被N-〔低级烷基氨基甲酰基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基〔例如,N-(甲基氨基甲酰基甲基)-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-(甲基氨基甲酰基乙基)-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-(乙基氨基甲酰基乙基)-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-(二甲基氨基甲酰基乙基)-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等〕,被N-〔低级烷氧基羰基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基〔例如,N-甲氧基羰基甲基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-甲氧基羰基乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基、N-乙氧基羰基甲基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-乙氧基羰基乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等〕,被N-〔羧基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基〔例如,N-羧甲基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-羧乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等〕,被芳基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基〔例如,苯基氨基甲酰基肉桂酰基甘氨酰基,萘基氨基甲酰基肉桂酰基甘氨酰基,等〕,等,被芳(低级)烯酰基取代的氨基酸残基〔例如,苯基丙烯酰基甘氨酰基,等〕,被杂环基(低级)烯酰基取代的氨基酸残基〔例如吗啉基丙烯酰基甘氨酰基,吡啶基丙烯酰基甘氨酰基,噻吩基丙烯酰基甘氨酰基,等〕,被氨基-杂环基(低级)烯酰基取代的氨基酸残基〔例如氨基吡啶基丙烯酰基甘氨酰基,等〕,被低级烷基氨基-杂环基(低级)烯酰基取代的氨基酸残基〔例如甲基氨基吡啶基丙烯酰基甘氨酰基,二甲基氨基吡啶基丙烯酰基甘氨酰基,等〕,被酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基,例如,被低级烷酰基氨基-杂环基(低级)烯基取代的氨基酸残基〔例如,乙酰基氨基吡啶基丙烯酰基甘氨酰基,丙酰基氨基吡啶基丙烯酰基甘氨酰基,等〕,被低级烯酰基氨基一杂环基(低级)烯酰基取代的氨基酸残基〔例如丙烯酰基氨基吡啶基丙烯酰基甘氨酰基,巴豆酰基氨基吡啶基丙烯酰基甘氨酰基,等〕,被杂环基(低级)烷酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基〔例如吡啶基乙酰基氨基吡啶基丙烯酰基甘氨酰基,噻吩基乙酰基氨基吡啶基丙烯酰基甘氨酰基,等〕,被杂环基羰基氨基-杂环基(低级)烯酰基取代的氨基酸残基〔例如吡啶基羰基氨基吡啶基丙烯酰基甘氨酰基,呋喃基氨基甲酰基氨基吡啶基丙烯酰基甘氨酰基,等〕,被低级烷酰基氨基-(低级)烷酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基〔例如乙酰基氨基乙酰基氨基吡啶基丙烯酰基甘氨酰基,乙酰基氨基丙酰基氨基吡啶基丙烯酰基甘氨酰基,等〕,被低级烷氧基羰基-(低级)烷酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基〔例如乙氧基羰基乙酰基氨基吡啶基丙烯酰基甘氨酰基,乙氧基羰基丙酰基氨基吡啶基丙烯酰基甘氨酰基,等〕,被低级烷氧基(低级)烷酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基〔例如甲氧基乙酰基氨基吡啶基丙烯酰基甘氨酰基,甲氧基丙酰基氨基吡啶基丙烯酰基甘氨酰基,乙氧基丙酰基氨基吡啶基丙烯酰基甘氨酰基,等〕,等,被低级烷基脲基-杂环基(低级)烯酰基取代的氨基酸残基〔例如甲基脲基吡啶基丙烯酰基甘氨酰基,等〕,被酰基-杂环基(低级)烯酰基取代的氨基酸残基,例如,被羧基-杂环基(低级)烯酰基取代的氨基酸残基〔例如羧基吡啶基丙烯酰基甘氨酰基,等〕,被低级烷氧基羰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如乙氧基羰基吡啶基丙烯酰基甘氨酰基,等〕,被低级烷基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,乙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,二甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,二乙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,异丙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,N-乙基-N-甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等〕,被低级烷氧基(低级)烷基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如甲氧基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,甲氧基乙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,甲氧基丙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,乙氧基乙基氨基甲酰基吡啶基丙烯酰基甘氯酰基,二(甲氧基乙基)氨基甲酰基吡啶基丙烯酰基甘氨酰基,等〕,被羟基(低级)烷基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如羟甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,羟乙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,二(羟乙基)氨基甲酰基吡啶基丙烯酰基甘氨酰基,等〕,被杂环基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如吡啶基氨基甲酰基吡啶基丙烯酰基甘氨酰基,吗啉基氨基甲酰基吡啶基丙烯酰基甘氨酰基,噻吩基氨基甲酰基吡啶基丙烯酰基甘氨酰基,嘧啶基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等〕,被杂环基(低级)烷基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如吡啶基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,呋喃基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,噻吩基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等〕,被杂环基羰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如吗啉代羰基吡啶基丙烯酰基甘氨酰基,吡咯烷基羰基吡啶基丙烯酰基甘氨酰基,哌啶基羰基吡啶基丙烯酰基甘氨酰基,等〕,被低级链烯基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如乙烯基氨基甲酰基吡啶基丙烯酰基甘氨酰基,烯丙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等〕,被低级炔基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基〔例如乙炔基氨基甲酰基吡啶基丙烯酰基甘氨酰基,丙炔基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等〕,等,被杂环基硫代(低级)烷酰基取代的氨基酸残基〔例如吡啶基硫代乙酰基甘氨酰基,嘧啶基硫代乙酰基甘氨酰基,咪唑基硫代丙酰基甘氨酰基,等〕,被选择性取代的杂环基羰基取代的氨基酸残基〔例如吗啉代羰基甘氨酰基,吲哚基羰基甘氨酰基,4-甲基-1-哌嗪基羰基甘氨酰基,等〕,被环(低级)烷基羰基取代的氨基酸残基〔例如环丙基羰基甘氨酰基,环戊基羰基甘氨酰基,环己基羰基甘氨酰基,环己基羰基肌氨酰基,等〕,被低级烷氧基羰基取代的氨基酸残基〔例如甲氧基羰基甘氨酰基,叔丁氧基羰基甘氨酰基,叔丁氧基羰基肌氨酰基,叔丁氧基羰基丙氨酰基,等〕,被芳氧基羰基取代的氨基酸残基〔例如苯氧基羰基甘氨酰基,等〕,被芳酰基(低级)烷酰基取代的氨基酸残基〔例如苯基草酰基甘氨酰基,苯基苯甲酰基丙酰基甘氨酰基,等〕,被芳酰基取代的氨基酸残基〔例如苯甲酰基甘氨酰基,萘甲酰基甘氨酰基,苯甲酰基肌氨酰基,苯甲酰基丙氨酰基,等〕,被硝基-芳基氧基羰基取代的氨基酸残基〔例如硝基苯基氧基羰基甘氨酰基,等〕,被氨基甲酰基取代的氨基酸残基〔例如氨基甲酰基甘氨酰基,氨基甲酰基丙氨酰基,氨基甲酰基肌氨酰基,氨基甲酰基-β-丙氨酰基,等〕,被低级烷基氨基甲酰基取代的氨基酸残基〔例如甲基氨基甲酰基甘氨酰基,乙基氨基甲酰基甘氨酰基,丙基氨基甲酰基甘氨酰基,异丙基氨基甲酰基甘氨酰基,甲基氨基甲酰基肌氨酰基,乙基氨基甲酰基丙氨酰基,异丙基氨基甲酰基-β-丙氨酰基,戊基氨基甲酰基甘氨酰基,等〕,被低级烷氧基羰基(低级)烷基氨基甲酰基取代的氨基酸残基〔例如甲氧基羰基甲基氨基甲酰基甘氨酰基,乙氧基羰基甲基氨基甲酰基甘氯酰基,等〕,被低级烯基氨基甲酰基取代的氨基酸残基〔例如乙烯基氨基甲酰基甘氨酰基,烯丙基氨基甲酰基甘氯酰基,烯丙基氨基甲酰基肌氨酰基,等〕,被环(低级)烷基氨基甲酰基取代的氨基酸残基〔例如环丙基氨基甲酰基甘氨酰基,环己基氨基甲酰基甘氨酰基,环己基氨基甲酰基肌氨酰基,等〕,被芳基氨基甲酰基取代的氨基酸残基〔例如苯基氨基甲酰基甘氨酰,萘基氨基甲酰基甘氨酰基,甲苯基氨基甲酰基甘氨酰基,乙基苯基氨基甲酰基甘氨酰基,苯基氨基甲酰基丙氨酰基,苯基氨基甲酰基肌氨酰基,等〕,被低级烷氧基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲氧基苯基氨基甲酰基甘氨酰基,乙氧基苯基氨基甲酰基甘氨酰基,甲氧基苯基氨基甲酰基丙氨酰基,等〕,被卤代(低级)烷基-芳基氨基甲酰基取代的氨基酸残基〔例如三氟甲基苯基氨基甲酰基甘氨酰基,三氟甲基苯基氨基甲酰基丙氨酰基,三氟甲基苯基氨基甲酰基肌氟酰基,等〕,被卤代-芳基氨基甲酰基取代的氨基酸残基〔例如,氯代苯基氨基甲酰基甘氨酰基,氟代苯基氨基甲酰基甘氨酰基,氟代苯基氨基甲酰基丙氨酰基,等〕,被羟基(低级)烷基-芳基氨基甲酰基取代的氨基酸残基〔例如,羟甲基苯基氨基甲酰基甘氨酰基,羟乙基苯基氨基甲酰基甘氨酰基,羟乙基苯基氨基甲酰基丙氨酰基,等〕,被硝基-芳基氨基甲酰基取代的氨基酸残基〔例如,硝基苯基氨基甲酰基甘氨酰基,等〕,被氰基-芳基氨基甲酰基取代的氨基酸残基〔例如,氰基苯基氨基甲酰基甘氨酰基,等〕,被氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,氨基苯基氨基甲酰基甘氨酰基,等〕,被低级烷基氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲基氨基苯基氨基甲酰基甘氨酰基,乙基氨基苯基氨基甲酰基甘氨酰基,二甲基氨基苯基氨基甲酰基甘氨酰基,等〕,被低级烷酰基氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,乙酰基氨基苯基氨基甲酰基甘氨酰基,丙酰基氨基苯基氨基甲酰基甘氨酰基,等〕,被N-(低级烷酰基)-N-(低级烷基)氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,N-乙酰基-N-甲基氨基苯基氨基甲酰基甘氨酰基,N-丙酰基-N-甲基氨基苯基氨基甲酰基甘氨酰基,等〕,被低级烷氧基(低级)烷酰基氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲氧基乙酰基氨基苯基氨基甲酰基甘氨酰基,甲氧基丙酰基氨基苯基氨基甲酰基甘氨酰基,等〕,被低级烷氧基羰基(低级)烷酰基氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,乙氧基羰基乙酰基氨基苯基氨基甲酰基甘氨酰基,甲氧基羰基丙酰基氨基苯基氨基甲酰基甘氨酰基,等〕,被羧基氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,羧基氨基苯基氨基甲酰基甘氨酰基,等〕,被低级烷氧基羰基氨基芳基氨基甲酰基取代的氨基酸残基〔例如,乙氧基羰基氨基苯基氨基甲酰基甘氨酰基,等〕,被芳酰基氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,苯甲酰基氨基苯基氨基甲酰基甘氨酰基,等〕,被杂环基羰基氨基芳基氨基甲酰基取代的氨基酸残基〔例如,吡啶基羰基氨基苯基氨基甲酰基甘氨酰基,呋喃基羰基氨基苯基氨基甲酰基甘氨酰基,吗啉代羰基氨基苯基氨基甲酰基甘氨酰基,等〕,被杂环基(低级)烷酰基氨基-芳基氨基甲酰基取代的氨基酸残基〔例如,吡啶基乙酰基氨基苯基氨基甲酰基甘氨酰基,噻吩基乙酰基氨基苯基氨基甲酰基甘氨酰基,等〕,被脲基-芳基氨基甲酰基取代的氨基酸残基〔例如,脲基苯基氨基甲酰基甘氨酰基,等〕,被低级烷基脲基芳基氨基甲酰基取代的氨基酸残基〔例如,甲基脲基苯基氨基甲酰基甘氨酰基,乙基脲基苯基氨基甲酰基甘氨酰基,等〕,被羟基亚氨基(低级)烷基-芳基氨基甲酰基取代的氨基酰基氨基酸残基〔例如,羟基亚氨基乙基苯基氨基甲酰基甘氨酰基,等〕,被低级烷氧基亚氨基(低级)烷基芳基氨基甲酰基取代的氨基酸残基〔例如,甲氧基亚氨基乙基苯基氨基甲酰基甘氨酰基,等〕,被低级烷基肼叉(低级)烷基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲基肼叉乙基苯基氨基甲酰基甘氨酰基,二甲基亚肼基乙基苯基氨基甲酰基甘氨酰基,等〕,被选择性取代的杂环-芳基氨基甲酰基取代的氨基酸-残基〔例如,氧代吡咯烷基苯基氨基甲酰基甘氨酰基,氧代哌啶基苯基氨基甲酰基甘氨酰基,二氧代吡咯烷基苯基氨基甲酰基甘氨酰基,氧代噁唑烷基苯基氨基甲酰基甘氨酰基,吡咯基苯基氨基甲酰基甘氨酰基,等〕,被酰基-芳基氨基甲酰基取代的氨基酸残基,例如,被低级烷酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,乙酰基苯基氨基甲酰基甘氨酰基,丙酰基苯基氨基甲酰基甘氨酰基,等〕,被杂环基羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,吗啉代羰基苯基氨基甲酰基甘氨酰基,哌啶基羰基苯基氨基甲酰基甘氨酰基,哌嗪基羰基苯基氨基甲酰基甘氨酰基,硫代吗啉代羰基苯基氨基甲酰基丙氨酰基,吡咯烷基羰基苯基氨基甲酰基甘氨酰基,1,2,3,6-四氢吡啶基羰基苯基氨基甲酰基甘氨酰基,等〕,被羧基-芳基氨基甲酰基取代的氨基酸残基〔例如,羧基苯基氨基甲酰基甘氨酰基,等〕,被低级烷氧基羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲氧基羰基苯基氨基甲酰基甘氨酰基,乙氧基羰基苯基氨基甲酰基甘氨酰基,等〕,被氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被低级烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,丙基氨基甲酰基苯基氨基甲酰基甘氨酰基,二甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,二乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,N-乙基-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,N-异丙基-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被具有低级烷基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲基哌嗪基羰基苯基氨基甲酰基甘氨酰基,乙基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等〕,被具有芳基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,苯基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等〕,被具有-个杂环基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,吡啶基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等〕,被具有低级烷酰基的杂环羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,乙酰基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等〕,被具有低级烷氧基羰基的杂环羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,乙氧基羰基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等〕,被具有低级烷基氨基的杂环羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲基氨基哌嗪基羰基苯基氨基甲酰基甘氨酰基,二甲基氨基哌啶基羰基苯基氨基甲酰基甘氨酰基,等〕,被具有低级烷基氨基甲酰基的杂环羰基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲基氨基甲酰基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等〕,被羟基(低级)烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,羟甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,羟乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,二(羟乙基)氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被N-〔羟基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,N-(羟乙基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被低级烷氧基(低级)烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲氧基甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,甲氧基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,乙氧基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,二(甲氧基乙基)氨基甲酰基苯基氨基甲酰基甘氨酰基,二(乙氧基乙基)氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被N-〔低级烷氧基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,N-(甲氧基乙基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,N-(甲氧基丙基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被低级烷基氨基(低级)烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,甲基氨基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,二甲基氨基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被N-〔低级烷基氨基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,N-(二甲基氨基乙基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,N-(二甲基氨基丙基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被杂环基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,吗啉基氨基甲酰基苯基氨基甲酰基甘氨酰基,噻吩基氨基甲酰基苯基氨基甲酰基甘氨酰基,吡啶基氨基甲酰基苯基氨基甲酰基甘氨酰基,嘧啶基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被N-(杂环基)-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如N-吡啶基-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被杂环(低级)烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,吡啶基甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,吡啶基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,噻吩基甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被N-〔杂环基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,N-吡啶基甲基-N-甲基氨基甲酰基-苯基氨基甲酰基甘氨酰基,等〕,被N-〔杂环基(低级)烷基〕-N-〔低级烷氧基(低级)烷基〕氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,N-吡啶基甲基-N-甲氧基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被芳基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,苯基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,被低级烷基氨基芳基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基〔例如,二甲基氨基苯基氨基甲酰基苯基氨基甲酰基甘氨酰基,等〕,等,被芳硫基氨基甲酰基取代的氨基酸残基〔例如,苯基硫基氨基甲酰基甘氨酰基,萘硫基氨基甲酰基甘氨酰基,苯硫式氨基甲酰基丙氨酰基,苯硫基氨基甲酰基肌氨酰基,等〕,被芳(低级)烷基氨基甲酰基取代的氨基酸残基〔例如,苄基氨基甲酰基甘氨酰基,苄基氨基甲酰基肌氨酰基,苄基氨基甲酰基丙氨酰基,等〕,被芳酰基氨基甲酰基取代的氨基酸残基〔例如,苯甲酰基氨基甲酰基甘氨酰基,等〕,被杂环基氨基甲酰基取代的氨基酸残基〔吡啶基氨基甲酰基甘氨酰基,吡啶基氨基甲酰基丙氨酰基,吡啶基氨基甲酰基肌氨酰基,噻吩基氨基甲酰基甘氨酰基,吡唑基氨基甲酰基甘氨酰基,嘧啶基氨基甲酰基甘氨酰基,喹啉基氨基甲酰基甘氨酰基,异喹啉基氨基甲酰基甘氨酰基,等〕,被杂环基(低级)烷基氨基甲酰基取代的氨基酸残基〔例如,吡啶基甲基氨基甲酰基甘氨酰基,吡啶基乙基氨基甲酰基甘氨酰基,噻吩基甲基氨基甲酰基甘氨酰基,等〕,被芳基氨基氨基甲酰基取代的氨基酸残基〔例如,苯基氨基氨基甲酰基甘氨酰基,等〕,被芳(低级)烯基磺酰基取代的氨基酸残基〔例如,苯乙烯基磺酰基甘氨酰基,肉桂酰基磺酰基甘氨酰基,等〕,被低级烷基磺酰基取代的氨基酸残基〔例如,甲磺酰基甘氨酰基,乙基磺酰基甘氨酰基,甲磺酰基肌氨酰基,甲磺酰基丙氨酰基,等〕,被苯二甲酰基取代的氨基酸基〔例如,苯二甲酰基甘氨酰基,苯二甲酰基丙氨酰基,苯二甲酰基-β-丙氨酰基,等〕,具有未被取代的氨基酸残基的氨基酸残基〔例如,甘氨酰基甘氨酰基,丙氨酰基甘氨酰基,肌氨酰基甘氨酰基,脯氨酰基甘氨酰基,甘氨酰基肌氨酰基,脯氨酰基肌氨酰基,等〕,具有被取代的氨基酸残基的氨基酸残基〔例如,具有被低级烷基取代的氨基酸残基的氨基酸残基〔例如,二甲基甘氨酰基甘氨酰基,二乙基甘氨酰基甘氨酰基,二甲基甘氨酰基肌氨酰基,乙基肌氨酰基甘氨酰基,异丙基肌氨酰基甘氨酰基,乙基甘氨酰基甘氨酰基,丙基甘氨酰基甘氨酰基,异丙基甘氨酰基甘氨酰基,乙基甘氨酰基丙氨酰基,二甲基甘氨酰基丙氨酰基,二甲基丙氨酰基甘氨酰基,二甲基-β-丙氨酰基甘氨酰基,等〕,具有被杂环基团取代的氨基酸残基的氨基酸残基〔例如,吗啉基甘氨酰基甘0滨#基,哌啶基甘氨酰基甘氨酰基,吡啶基甘氨酰基甘氨酰基,哌啶基肌氨酰基甘氨酰基,等〕,具有被杂环基(低级)烷基取代的氨基酸残基的氨基酸残基〔例如,吡啶基甲基甘氨酰基甘氨酰基,咪唑基甲基甘氨酰基甘氨酰基,呋喃基甲基甘氨酰基甘氨酰基,噻吩基甲基肌氨酰基甘氨酰基,等〕,具有被环烷基取代的氨基酸残基的氨基酸残基〔例如,环丙基甘氨酰基甘氨酰基,环丁基甘氨酰基甘氨酰基,环戊基甘氨酰基甘氨酰基,环己基甘氨酰基甘氨酰基,环庚基甘氨酰基甘氨酰基,环辛基甘氨酰基甘氨酰基,金刚烷基甘氨酰基甘氨酰基,环己基肌氨酰基甘氨酰基,环庚基肌氨酰基甘氨酰基,环己基甘氨酰基肌氨酰基,环己基甘氨酰基丙氨酰基,等〕,具有被芳基取代的氨基酸残基的氨基酸残基〔例如,苯基甘氨酰基甘氨酰基,苯基肌氨酰基甘氨酰基,等〕,具有被酰基取代的氨基酸残基的氨基酸残基〔例如,具有被烷酰基取代的氨基酸残基的氨基酸残基〔例如,乙酰基甘氨酰基甘氨酰基,乙酰基脯氨酰基甘氨酰基,丙酰基甘氨酰基甘氨酰基,乙酰基丙氨酰基甘氨酰基,等〕,具有被低级烷氧基羰基取代的氨基酸残基的氨基酸残基〔例如,叔丁氧基羰基甘氨酰基甘氨酰基,叔丁氧基羰基脯氨酰基甘氨酰基,等〕,具有被酞酰基取代的氨基酸残基的氨基酸残基〔例如,酞酰基甘氨酰基甘氨酰基,等〕,等},具有被芳(低级)烷基取代的氨基酸残基的氨基酸残基〔例如,苄基甘氨酰基甘氨酰基,等),等〕,等。
适宜的“具有氨基的酰基”可以是未取代的氨基酸残基,具有未取代的氨基酸残基的氨基酸残基,等,它们的优选的实例可以参考上面的例证。
适宜的“具有酰基氨基的酰基”可以是被酰基取代的氨基酸残基,具有被酰基取代的氨基酸残基的氨基酸残基,等,和它们的优选的实例可参考上面的那些例证。
在术语“选择性具有适宜的取代基的氨基”中适宜的取代基可以是上述的低级烷基,上述的酰基,芳(低级)烷基〔例如,苄基,苯乙基,三苯甲基,等〕,羧基(低级)烷基〔例如,羧甲基,羧基乙基,羰基丙基,等〕,低级烷氧基羰基(低级)烷基〔例如,甲氧基羰基甲基,乙氧基羰基甲基,甲氧基羰基乙基,乙氧基羰基丙基,等〕,杂环基(低级)烷基〔例如,吡啶基甲基,吡啶基乙基,等〕,等。
适宜的“被保护的或未被保护的羟基(低级)烷基”可以是羟甲基,羟乙基,羟丙基,苄氧基甲基,叔丁基二苯基甲硅烷基氧基乙基或类似基团。
适宜的“低级烷氧基(低级)烷基”可以是甲氧基甲基,甲氧基乙基,甲氧基丙基,乙氧基甲基,乙氧基乙基,等。
适宜的“低级烷基氨基(低级)烷基”可以是甲基氨基甲基,甲基氨基乙基,甲基氨基丙基,二甲基氨基甲基,二甲基氨基乙基,二甲基氨基丙基,二乙基氨基乙基,等。
适宜的“低级链烯基”可以是乙烯基,烯丙基甲基丙烯基,丁烯基,戊烯基等。
适宜的“低级炔基”可以是乙炔基,丙炔基,丁炔基,戊炔基等。
适宜的“低级烷基氨基甲酰基氧基(低级)烷基”可以是甲基氨基甲酰基氧基甲基,甲基氨基甲酰基氧基乙基,乙基氨基甲酰基氧基乙基,二甲基氨基甲酰基氧基乙基等。
适宜的“低级烷氧基羰基(低级)烷基”可以是甲氧基羰基甲基,甲氧基羰基乙基,乙氧基羰基甲基,乙氧基羰基乙基等。
适宜的“羧基(低级)烷基”可以是羧甲基,羧基乙基,羧基丙基等。
适宜的“低级烷基氨基甲酰基(低级)烷基”可以是甲基氨基甲酰基甲基,甲基氨基甲酰基乙基,乙基氨基甲酰基乙基,二甲基氨基甲酰基乙基等。
适宜的“低级烷氧基羰基-芳(低级)烷基”可以是甲氧基羰基-苄基,甲氧基羰基-苯乙基,乙氧基羰基-苯乙基,等。
适宜的“羧基-芳(低级)烷基”可以是羧基-苄基,羧基-苯乙基等。
适宜的“低级烷基氨基甲酰基-芳(低级)烷基”可以是甲基氨基甲酰基-苄基,甲基氨基甲酰基-苯乙基,乙基氨基甲酰基-苯乙基等。
适宜的“杂环基团”和在本说明书和权利要求中述及的各种定义中的所有杂环部分如在术语“杂环基(低级)烷基”,“杂环基(低级)烯酰基”等中述及的,可以包括饱和的或不饱和的,单环或多环每个环上含有至少一个如氮原子,氧原子或硫原子的杂原子,较好的是N、O和/或S含有5或6员的杂环基团,其中较好的杂环是吗啉基,哌嗪基,吡啶基,四氢吡啶基,嘧啶基,哌啶基,噻吩基,呋喃基,噁唑基,异噁唑基,噻唑基,四唑基,咪唑基,吡咯烷基,吡咯基等。
在术语“选择性具有适宜取代基的杂环基团”中适宜的取代基可以是上述的卤素,上述的低级烷基,上述的酰基,上述的芳基,氧代,硝基,氨基,芳(低级)烷基〔例如,苄基,苯乙基,三苯甲基,等〕,低级烷氧基羰基(低级)烷基〔例如甲氧基羰基甲基,乙氧基羰基甲基,甲氧基羰基乙基,乙氧基羰基丙基,等〕,等。
由R12,R13和连接的氮原子形成的适宜的“杂环基团”可以是吗啉代,硫代吗啉代,吡咯烷-1-基,哌啶基,1,2,3,6-四氢吡啶-1-基,哌嗪-1-基,等。和所述的杂环基团可以是被适宜的取代基所取代的,这些基团如上述的低级烷基,上述的杂环基,上述的酰基,低级烷基氨基,上述的芳基。等。
“杂环基(低级)烷基”的优选的实例可以是吗啉基甲基,吗啉基乙基,吡啶基甲基,吡啶基乙基,噻吩基甲基,哌啶基甲基,吡咯基甲基,咪唑基甲基,呋喃基甲基,等。
尤其是,X1,X2,X3,R1,R2,R3,R4,R5,Q和A的优选的实施案例如下:
式-X3=X2-X2=N-的基团是下式的基团:其中R6和R8均是氢;卤素如氟,氯,溴和碘;低级烷基如甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基和己基;羟基;低级烷硫基如甲硫基,乙硫基,丙基硫基,异丙基硫基和丁基硫基;氨基;低级烷基氨基如甲基氨基,乙基氨基,丙基氨基,二甲基氨基和二乙基氨基;低级烷氧基如甲氧基,乙氧基,丙氧基,异丙氧基和丁氧基;低级烷氧基(低级)烷氧基如甲氧基甲氧基和甲氧基乙氧基;低级烷基氨基(低级)烷氧基如甲基氨基乙氧基和二甲基氨基乙氧基;或被低级烷氧基取代的芳(低级)烷氧基如二甲氧基苄氧基;R7是氢;或低级烷基如甲基,乙基,丙基,异丙基和丁基;R1是氢;或卤素如氟、氯、溴和碘;R2是卤素如氟、氯、溴和碘;R3是氢;硝基;
如下式基团:其中Ra10是氢;低级烷基如甲基,乙基,丙基和丁基;羧基(低级)烷基如羧甲基和羧乙基;低级烷氧基羰基(低级)烷基如甲氧基羰基甲基,甲氧基羰基乙基和乙氧基羰基甲基;芳(低级)烷基如苄氧基和苯乙基;和酰基如低级烷酰基〔例如,甲酰基,乙酰基,丙酰基,等〕,羧基和酯化的羧基〔例如,低级烷氧基羰基(例如,甲氧基羰基,乙氧基羰基,叔丁氧基羰基,等),等〕,Rc11是氢;低级烷基如甲基,乙基,丙基,异丙基和丁基;芳(低级)烷基如苄基;杂环基(低级)烷基如吡啶基(低级)烷基〔例如,吡啶基甲基,吡啶基乙基,等〕;和酰基如低级烷酰基〔例如,甲酰基,乙酰基,丙酰基,丁酰基,异丁酰基,等〕,卤代(低级)烷酰基〔例如,三氟乙酰基,等〕,羧基,酯化的羧基〔例如,低级烷氧基羰基(例如,甲氧基羰基,乙氧基羰基,叔丁氧基羰基,等),等〕,羟基(低级)烷酰基〔例如,乙醇酰基,丙醇酰基,3-羟基丙酰基,等〕,低级烷酰氧基(低级)烷酰基〔例如,乙酰氧基乙酰基,乙酰氧基丙酰基,等〕,低级烷氧基(低级)烷酰基〔例如,甲氧基乙酰基,甲氧基丙酰基,等〕,苯甲酰基,甲苯酰基,被低级烷氧基取代的苯甲酰基〔例如,甲氧基苯甲酰基,等〕,被酯化的羧基取代的苯甲酰基〔例如,低级烷氧基羰基苯甲酰基(例如,甲氧基羰基苯甲酰基,叔丁氧基羰基苯甲酰基,等),等〕,被卤素取代的苯甲酰基〔例如氯代苯甲酰基,氟代苯甲酰基,等〕,被硝基选择性取代的苯氧基羰基,低级烷基磺酰基〔例如,甲磺酰基,乙基磺酰基,等〕,氨基甲酰基,低级烷基氨基甲酰基〔例如,甲基氨基甲酰基,乙基氨基甲酰基,异丙基氨基甲酰基,等〕,卤代(低级)烷酰基氨基甲酰基〔例如,三氯乙酰基氨基甲酰基,等〕,苯基氨基甲酰基,未取代的氨基酸残基〔例如,甘氨酰基,肌氨酰基,丙氨酰基,β-丙氨酰基,等〕和取代的氨基酸残基〔例如,被低级烷基取代的氨基酸残基(例如,乙基甘氨酰基,异丙基甘氨酰基,二甲基甘氨酰基,二乙基甘氨酰基,乙基肌氨酰基,异丙基肌氨酰基,甲基丙氨酰基,甲基-β-丙氨酰基,等),被选择性取代的脒基取代的氨基酸残基(例如,脒基甘氨酰基,N-乙基-N’-氰基脒基甘氨酰基,等),被酰基取代的氨基酸残基〔例如,被烷酰基取代的氨基酸残基(例如,甲酰基甘氨酰基,乙酰基甘氨酰基,乙酰基肌氨酰基,乙酰基丙氨酰,乙酰基-β-丙氨酰,丙酰基甘氨酰基,丁酰基甘氨酰基,异丁酰基甘氨酰基,戊酰基甘氨酰基,异戊酰基甘氨酰基,特戊酰基甘氨酰基,己酰基甘氨酰基,庚酰基甘氨酰基,等),被卤代(低级)烷酰基取代的氨基酸残基(例如,三氟乙酰基甘氨酰基,三氟乙酰基肌氨酰基,三氟乙酰基丙氨酰基,溴代乙酰基甘氨酰基,七氟丁酰基甘氨酰基,等),被羟基(低级)烷酰基取代的氨基酸残基(例如,乙醇酰基甘氨酰基,乙醇酰基肌氨酰基,丙醇酰基甘氨酰基,丙醇酰基丙氨酰基,等),被低级烷基磺酰氧基(低级)烷酰基取代的氨基酸残基(例如,甲磺酰氧基乙酰基甘氨酰基,乙磺酰氧基乙酰基甘氨酰基,甲磺酰氧基乙酰基肌氨酰基,等),被低级烷氧基(低级)烷酰基取代的氨基酸残基〔例如,甲氧基乙酰基甘氨酰基,乙氧基乙酰基甘氨酰基,甲氧基乙酰基肌氨酰基,甲氧基丙酰基丙氨酰基,等),被芳氧基(低级)烷酰基取代的氨基酸残基〔例如,苯氧基乙酰基甘氨酰基,苯氧基丙酰基甘氨酰基,苯氧基乙酰基肌氨酰基,等),被低级烷硫基(低级)烷酰基取代的氨基酸残基〔例如,甲硫基乙酰基甘氨酰基,甲硫基丙酰基甘氨酰基,等),被低级烷基氨基甲酰基(低级)烷酰基取代的氨基酸残基(例如,甲基氨基甲酰基丙酰基甘氨酰基,甲基氨基甲酰基丙酰基丙氨酰基,等),被低级烷酰氧基(低级)烷酰基取代的氨基酸残基(例如,乙酰氧基乙酰基甘氨酰基,乙酰氧基乙酰基肌氨酰基,丙酰基氧基乙酰基甘氨酰基,乙酰氧基丙酰基丙氨酰基,等),被羧基(低级)烷酰基取代的氨基酸残基(例如,羧基乙酰基甘氨酰基,羧基丙酰基甘氨酰基,羧基丙酰基肌氨酰基,羧基乙酰基丙氨酰基,等),被低级烷氧基羰基(低级)烷酰基取代的氨基酸残基(例如,甲氧基羰基乙酰基甘氨酰基,乙氧基羰基丙酰基甘氨酰基,甲氧基羰基乙酰基肌氨酰基,等),被芳(低级)烷酰基取代的氨基酸残基(例如,苯基乙酰基甘氨酰基,苯基丙酰基甘氨酰基,苯基丁酰基甘氨酰基,苯基乙酰基肌氯酰基,苯基丙酰基丙氨酰基,萘基乙酰基甘氨酰基,等),被选择性取代的杂环基(低级)烷酰基取代的氨基酸残基(例如,吗啉代乙酰基甘氨酰基,吡啶基乙酰基甘氨酰基,吗啉代丙酰基丙氨酰基,咪唑基乙酰基甘氨酰基,哌啶基乙酰基甘氨酰基,吡咯烷基乙酰基甘氨酰基,六次甲基亚氨基乙酰基甘氨酰基,甲基哌嗪基乙酰基甘氨酰基,吡啶基哌嗪基乙酰基甘氨酰基,硫代吗啉代乙酰基甘氨酰基,它的氧化物或二氧化物,等),被低级烯酰基取代的氨基酸残基(例如,丙烯酰基甘氨酰基,巴豆酰基甘氨酰基,3-戊烯酰基甘氨酰基,3-丁烯酰基甘氨酰基,4-戊烯酰基甘氨酰基,3-丁烯酰基肌氨酰基,等),被芳(低级)烯酰基取代的氨基酸残基(例如,肉桂酰基甘氨酰基,α甲基肉桂酰基甘氨酰基,4-甲基肉桂酰基甘氨酰基,等),被低级烷氧基-芳(低级)烯酰基取代的氨基酸残基(例如,甲氧基肉桂酰基甘氨酰基,乙氧基肉桂酰基甘氨酰基,二甲氧基肉桂酰基甘氨酰基,等),被烷撑二氧基-芳(低级)烯酰基取代的氨基酸残基(例如,甲二氧基肉桂酰基甘氨酰基,乙二氧基肉桂酰基甘氨酰基,等),被硝基-芳(低级)烯酰基取代的氨基酸残基(例如,硝基肉桂酰基甘氨酰基,等),被氰基-芳(低级)烯酰基取代的氨基酸残基(例如,氰基肉桂酰基甘氨酰基,等),被卤代-芳(低级)烯酰基取代的氨基酸残基(例如,氯代肉桂酰基甘氨酰基,氟代肉桂酰基甘氨酰基,等),被羟基-芳(低级)烯酰基取代的氨基酸残基(例如,羟基肉桂酰基甘氨酰基,等),被羟基(低级)烷氧基-芳(低级)烯酰基取代的氨基酸残基(例如,羟基甲氧基肉桂酰基甘氨酰基,羟基乙氧基肉桂酰基甘氨酰基,等),被氨基(低级)烷氧基-芳(低级)烯酰基取代的氨基酸残基(例如,氨基乙氧基肉桂酰基甘氨酰基,等),被低级烷基氨基(低级)烷氧基-芳(低级)烯酰基取代的氨基酸残基(例如,甲基氨基甲氧基肉桂酰基甘氨酰基,二甲基氨基乙氧基肉桂酰基甘氨酰基,等),被杂环基(低级)烷氧基-芳(低级)烯酰基取代的氨基酸残基(例如,吡啶基甲氧基肉桂酰基甘氨酰基,等),被选择性取代的杂环基-芳(低级)烯酰基取代的氨基酸残基(例如,吗啉基肉桂酰基甘氨酰,甲基哌嗪基肉桂酰基甘氨酰基,吡咯烷基肉桂酰基甘氨酰基,氧代吡咯烷基肉桂酰基甘氨酰基,氧代哌啶基肉桂酰基甘氨酰基,二氧代吡咯烷基肉桂酰基甘氨酰基,氧代噁唑烷基肉桂酰基甘氨酰基,吡咯基肉桂酰基甘氨酰基,四唑基肉桂酰基甘氨酰基,等),被氨基-芳(低级)烯酰基取代的氨基酸残基(例如,氨基肉桂酰基甘氨酰基,等),被低级烷基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,甲基氨基肉桂酰基甘氨酰基,二甲基氨基肉桂酰基甘氨酰基,等),被低级烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,乙酰基氨基肉桂酰基甘氨酰基,丙酰基氨基肉桂酰基甘氨酰基,异丁酰基氨基肉桂酰基甘氨酰基,等),被环烷基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,环戊基乙酰基氨基肉桂酰基甘氨酰基,环己基乙酰基氨基肉桂酰基甘氨酰基,金刚烷基乙酰基氨基肉桂酰基甘氨酰基,等),被环烷基羰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,环丙基羰基氨基肉桂酰基甘氯酰基,环戊基羰基氨基肉桂酰基甘氨酰基,环己基羰基氨基肉桂酰基甘氨酰基,金刚烷基羰基氨基肉桂酰基甘氨酰基,等),被低级烯酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,丙烯酰基氨基肉桂酰基甘氨酰基,巴豆酰基氨基肉桂酰基甘氨酰基,等),被低级烷氧基羰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,甲氧基羰基氨基肉桂酰基甘氨酰基,乙氧基羰基氨基肉桂酰基甘氨酰基,等),被羟基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,羟乙酰基氨基肉桂酰基甘氨酰基,羟丙酰基氨基肉桂酰基甘氨酰基,等),被低级烷氧基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,甲氧基乙酰基氨基肉桂酰基甘氨酰基,甲氧基丙酰基氨基肉桂酰基甘氨酰基,等),被卤代(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,氯乙酰基氨基肉桂酰基甘氨酰基,三氟乙酰基氨基肉桂酰基甘氨酰基,溴丁酰基氨基肉桂酰基甘氨酰基,等),被氨基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,氨基乙酰基氨基肉桂酰基甘氨酰基,氨基丙酰基氨基肉桂酰基甘氨酰基,等),被低级烷基氨基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,甲基氨基乙酰基氨基肉桂酰基甘氨酰基,二甲基氨基乙酰基氨基肉桂酰基甘氨酰基,等),被低级烷酰基氨基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,乙酰基氨基乙酰基氨基肉桂酰基甘氨酰基,乙酰基氨基丙酰基氨基肉桂酰基甘氨酰基,等),被羧基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,羧基乙酰基氨基肉桂酰基甘氨酰基,羧基丙酰基氨基肉桂酰基甘氨酰基,等),被低级烷氧基羰基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,乙氧基羰基乙酰基氨基肉桂酰基甘氨酰基,乙氧基羰基丙酰基氨基肉桂酰基甘氨酰基,等),被低级烷氧基羰基(低级)烯酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,乙氧基羰基丙烯酰基氨基肉桂酰基甘氨酰基,等),被卤代(低级)烷氧基羰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,氟代乙氧基羰基氨基肉桂酰基甘氨酰基,等),被选择性取代的杂环基(低级)烷酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,吡啶基乙酰基氨基肉桂酰基甘氨酰基,噻吩基乙酰基氨基肉桂酰基甘氨酰基,甲基吡咯基乙酰基氨基肉桂酰基甘氨酰基,等),被芳酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,苯甲酰基氨基肉桂酰基甘氨酰基,等),被选择性取代的杂环基羰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,吡啶基羰基氨基肉桂酰基甘氨酰基,吗啉代羰基氨基肉桂酰基甘氨酰基,呋喃基羰基氨基肉桂酰基甘氨酰基,噻吩基羰基氨基肉桂酰基甘氨酰基,噁唑基羰基氨基肉桂酰基甘氨酰基,甲基噁唑基羰基氨基肉桂酰基甘氨酰基,二甲基异噁唑基羰基氨基肉桂酰基甘氨酰基,咪唑基羰基氨基肉桂酰基甘氨酰基,甲基咪唑基羰基氨基肉桂酰基甘氨酰基,哌啶基羰基氨基肉桂酰基甘氨酰基、乙基哌啶基羰基氨基肉桂酰基甘氨酰基,乙酰基哌啶基羰基氨基肉桂酰基甘氨酰基,吡咯烷基羰基氨基肉桂酰基甘氨酰基,乙酰基吡咯烷基羰基氨基肉桂酰基甘氨酰基,叔丁氧基羰基吡咯烷基羰基氨基肉桂酰基甘氨酰基,等),被低级烷基磺酰基氨基-芳(低级)烯酰基取代的氨基酸残基(例如,甲磺酰基氨基肉桂酰基甘氨酰基,乙基磺酰基氨基肉桂酰基甘氨酰基,等),被N-(低级烷酰基)-N-(低级烷基)氨基-芳(低级)烯酰基取代的氨基酸残基(例如,N-乙酰基-N-甲基氨基肉桂酰基甘氨酰基,N-乙酰基-N-乙基氨基肉桂酰基甘氨酰基,N-丙酰基-N-甲基氨基肉桂酰基甘氨酰基,等),被N-〔低级烷氧基(低级)烷酰基〕-N-(低级烷基)氨基-芳(低级)烯酰基取代的氨基酸残基(例如,N-甲氧基乙酰基-N-甲基氨基肉桂酰基甘氨酰基,N-甲氧基丙酰基-N-甲基氨基肉桂酰基甘氨酰基,等),被N-(低级烷酰基)-N-〔杂环基(低级)烷基〕氨基-芳〔低级)烯酰基取代的氨基酸残基〔例如,N-乙酰基-N-吡啶基甲基氨基肉桂酰基甘氨酰基,等〕,被N-(低级烷酰基)-N-〔低级烷氧基(低级)烷基〕氨基-芳(低级)烯酰基取代的氨基酸残基(例如,N-乙酰基-N-甲氧基乙基氨基肉桂酰基甘氨酰基,N-乙酰基-N-甲氧基甲基氨基肉桂酰基甘氨酰基,N-丙酰基-N-甲氧基乙基氨基肉桂酰基甘氨酰基,等),被N-(低级烷酰基)-N-〔低级烷氧基羰基(低级)烷基〕氨基-芳(低级)烯酰基取代的氨基酸残基(例如,N-乙酰基-N-叔丁氧基羰基甲基氨基肉桂酰基甘氨酰基,N-乙酰基-N-叔丁氧基羰基乙基氨基肉桂酰基甘氨酰基,N-丙酰基-N-叔丁氧基羰基甲基氨基肉桂酰基甘氨酰基,等),被N-(低级烷酰基)-N-〔羧基(低级)烷基〕氨基-芳(低级)烯酰基取代的氨基酸残基(例如,N-乙酰基-N-羧甲基氨基肉桂酰基甘氨酰基,N-乙酰基-N-羧基乙基氨基肉桂酰基甘氨酰基,N-丙酰基-N-羧甲基氨基肉桂酰基甘氨酰基,等),被N-〔低级烷氧基(低级)烷酰基〕-N〔杂环基(低级)烷基〕氨基-芳(低级)烯酰基取代的氨基酸残基(例如,N-甲氧基乙酰基-N-吡啶基甲基氨基肉桂酰基甘氨酰基,N-甲氧基丙酰基-N-吡啶基甲基氨基肉桂酰基甘氨酰基,等),被N-〔杂环基羰基〕-N-〔低级烷氧基(低级)烷基〕氨基-芳(低级)烯酰基取代的氨基酸残基(例如,N-吡啶基羰基-N-甲氧基甲基氨基肉桂酰基甘氨酰基,N-吡啶基羰基-N-甲氧基乙基氨基肉桂酰基甘氨酰基,N-噻吩基羰基-N-甲氧基乙基氨基肉桂酰基甘氨酰基,等),被脲基-芳(低级)烯酰基取代的氨基酸残基(例如,脲基肉桂酰基甘氨酰基,等),被低级烷基脲基-芳(低级)烯酰基取代的氨基酸残基(例如,甲基脲基肉桂酰基甘氨酰基,乙基脲基肉桂酰基甘氨酰基,二甲基脲基肉桂酰基甘氨酰基,等),被杂环基脲基-芳(低级)烯酰基取代的氨基酸残基(例如,吡啶基脲基肉桂酰基甘氨酰基,嘧啶基脲基肉桂酰基甘氨酰基,噻吩基脲基肉桂酰基甘氨酰基,等),被低级烷酰基-芳(低级)烯酰基取代的氨基酸残基(例如,甲酰基肉桂酰基甘氨酰基,乙酰基肉桂酰基甘氨酰基,丙酰基肉桂酰基甘氨酰基,等),被羧基-芳(低级)烯酰基取代的氨基酸残基(例如,羧基肉桂酰基甘氨酰基,等),被低级烷氧基羰基-芳(低级)烯酰基取代的氨基酸残基(例如,甲氧基羰基肉桂酰基甘氨酰基,乙氧基羰基肉桂酰基甘氨酰基,等),被氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基〔例如,氨基甲酰基肉桂酰基甘氨酰基,等),被低级烷基氯基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,甲基氨基甲酰基肉桂酰基甘氨酰基,乙基氨基甲酰基肉桂酰基甘氨酰基,二甲基氨基甲酰基肉桂酰基甘氨酰基,丙基氨基甲酰基肉桂酰基甘氨酰基,异丙基氨基甲酰基肉桂酰基甘氨酰基,二乙基氨基甲酰基肉桂酰基甘氨酰基,N-甲基-N-乙基氨基甲酰基肉桂酰基甘氨酰基,等),被羟基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,羟乙基氨基甲酰基肉桂酰基甘氨酰基,二(羟乙基)氨基甲酰基肉桂酰基甘氨酰基,等),被N-〔羟基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,N-羟乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等),被低级烷氧基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,甲氧基甲基氨基甲酰基肉桂酰基甘氨酰基,甲氧基乙基氨基甲酰基肉桂酰基甘氨酰基,二(甲氧基乙基)氨基甲酰基肉桂酰基甘氨酰基,乙氧基乙基氨基甲酰基肉桂酰基甘氨酰基,甲氧基丙基氨基甲酰基肉桂酰基甘氨酰基,二(乙氧基乙基)氨基甲酰基肉桂酰基甘氨酰基,等),被N-〔低级烷氧基(低级)烷基〕-N(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,N-甲氧基乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-乙氧基乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等),被杂环基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,吡啶基甲基氨基甲酰基肉桂酰基甘氨酰基,呋喃基甲基氨基甲酰基肉桂酰基甘氨酰基,噻吩基甲基氨基甲酰基肉桂酰基甘氨酰基,等),被N-〔杂环基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,N-吡啶基甲基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等),被杂环基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,吗啉基氨基甲酰基肉桂酰基甘氨酰基,噻吩基氨基甲酰基肉桂酰基甘氨酰基,吡啶基氨基甲酰基肉桂酰基甘氨酰基,嘧啶基氨基甲酰基肉桂酰基甘氨酰基,四唑基氨基甲酰基肉桂酰基甘氨酰基,等),被杂环基羰基-芳(低级)烯酰基取代的氨基酸残基(例如,吗啉基羰基肉桂酰基甘氨酰基,吡咯烷基羰基肉桂酰基甘氨酰基,哌啶基羰基肉桂酰基甘氨酰基,四氢吡啶基羰基肉桂酰基甘氨酰基,甲基哌嗪基羰基肉桂酰基甘氨酰基,等),被低级烯基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,乙烯基氨基甲酰基肉桂酰基甘氨酰基,烯丙基氨基甲酰基肉桂酰基甘氨酰基,甲基丙烯基氨基甲酰基肉桂酰基甘氨酰基,等),被低级炔基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,乙炔基氨基甲酰基肉桂酰基甘氨酰基,丙炔基氨基甲酰基肉桂酰基基氨酰基,等),被氨基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,氨基甲基氨基甲酰基肉桂酰基甘氨酰基,氨基乙基氨基甲酰基肉桂酰基甘氨酰基,等),被低级烷基氨基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,甲基氨基甲基氨基甲酰基肉桂酰基甘氨酰基,甲基氨基乙基氨基甲酰基肉桂酰基甘氨酰基,乙基氨基乙基氨基甲酰基肉桂酰基甘氨酰基,二甲基氨基乙基氨基甲酰基肉桂酰基甘氨酰基,等),被低级烷基氨基甲酰基氧基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,甲基氨基甲酰基氧基甲基氨基甲酰基肉桂酰基甘氨酰基,甲基氨基甲酰基氧基乙基氨基甲酰基肉桂酰基甘氨酰基,乙基氨基甲酰基氧基乙基氨基甲酰基肉桂酰基甘氨酰基,二甲基氨基甲酰基氧基乙基氨基甲酰基肉桂酰基甘氨酰基,等),被低级烷基氨基甲酰基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,甲基氨基甲酰基甲基氨基甲酰基肉桂酰基甘氨酰基,甲基氨基甲酰基乙基氨基甲酰基肉桂酰基甘氨酰基,乙基氨基甲酰基乙基氨基甲酰基肉桂酰基甘氨酰基,二甲基氨基甲酰基乙基氨基甲酰基肉桂酰基甘氨酰基,等),被低级烷氧基羰基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,甲氧基羰基甲基氨基甲酰基肉桂酰基甘氨酰基,甲氧基羰基乙基氨基甲酰基肉桂酰基甘氨酰基,乙氧基羰基甲基氨基甲酰基肉桂酰基甘氨酰基,乙氧基羰基乙基氨基甲酰基肉桂酰基甘氨酰基,等),;被羧基(低级)烷基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,羧甲基氨基甲酰基肉桂酰基甘氨酰基,羧基乙基氨基甲酰基肉桂酰基甘氨酰基,等),被〔低级烷基氨基甲酰基-芳(低级)烷基〕氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基〔例如,(甲基氨基甲酰基-苯乙基)氨基甲酰基-肉桂酰基甘氨酰基,(乙基氯基甲酰基-苯乙基)氨基甲酰基肉桂酰基甘氨酰基,等),被〔低级烷氧基羰基-芳(低级)烷基〕氨基甲酰基-芳〔低级)烯酰基取代的氨基酸残基〔例如,(甲氧基羰基-苯乙基)氨基甲酰基肉桂酰基甘氨酰基,(乙氧基羰基-苯乙基)氨基甲酰基肉桂酰基甘氨酰基,等),被〔羧基-芳(低级)烷基〕氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基〔例如,(羧基-苯乙基)氨基甲酰基肉桂酰基甘氨酰基,等),被N-〔低级烷基氨基甲酰基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,N-(甲基氨基甲酰基甲基)-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-(甲基氨基甲酰基乙基)-N-甲基氯基甲酰基肉桂酰基甘氨酰基,N-(乙基氨基甲酰基乙基)-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-(二甲基氨基甲酰基乙基)-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等),被N-〔低级烷氧基羰基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,N-甲氧基羰基甲基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-甲氧基羰基乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-乙氧基羰基甲基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-乙氧基羰基乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等),被N-〔羧基(低级)烷基〕-N-(低级烷基)氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,N-羧基甲基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,N-羧基乙基-N-甲基氨基甲酰基肉桂酰基甘氨酰基,等),被芳基氨基甲酰基-芳(低级)烯酰基取代的氨基酸残基(例如,苯基氧基甲酰基肉桂酰基甘氨酰基,苯基氨基甲酰基肉桂酰基甘氨酰基,等),被芳(低级)炔酰基取代的氨基酸残基(例如,苯基丙炔基甘氨酰基,等),被杂环基(低级)烯酰基取代的氨基酸残基(例如,吗啉代丙烯酰基甘氨酰基,吡啶基内烯酰基甘氨酰基,噻吩基丙烯酰基甘氨酰基,等),被氨基杂环基(低级)烯酰基取代的氨基酸残基(例如,氨基吡啶基丙烯酰基甘氨酰基,等),被低级烷基氨基-杂环基(低级)烯酰基取代的氨基酸残基(例如,甲基氨基吡啶基丙烯酰基甘氨酰基,二甲基氨基吡啶基丙烯酰基甘氨酰基,等),被低级烷酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基(例如,乙酰基氨基吡啶基丙烯酰基甘氨酰基,丙酰基氨基吡啶基丙烯酰基甘氨酰基,等),被低级烯酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基(例如,丙烯酰基氨基吡啶基丙烯酰基甘氨酰基巴豆酰基氨基吡啶基丙烯酰基甘氨酰基,等),被杂环基(低级)烷酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基(例如,吡啶基乙酰基氨基吡啶基内烯酰基甘氨酰基,噻吩基乙酰基氨基吡啶基丙烯酰基甘氨酰基,等),被杂环基羰基氨基-杂环基(低级)烯酰基取代的氨基酸残基(例如,吡啶基羰基氨基吡啶其丙烯酸基甘氨酰基,呋喃基羰基氨基吡啶基丙烯酰基甘氨酰基,等),被低级烷酰基氨基(低级)烷酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基(例如,乙酰基氨基乙酰基氨基吡啶基丙烯酰基甘氨酰基,乙酰基氨基丙酰基氨基吡啶基丙烯酰基甘氨酰基,等),被低级烷氧基羰基(低级)烷酰基氨基-杂环基(低级)烯酰基取代的氨基酸残基(例如,乙氧基羰基乙酰基氨基吡啶基丙烯酰基甘氨酰基,乙氧基羰基丙酰基氨基吡啶基丙烯酰基甘氨酰基,等),被低级烷氧基(低级)烷酰基氨基杂环基(低级)烯酰基取代的氨基酸残基(例如,甲氧基乙酰基氨基吡啶基丙烯酰基甘氨酰基,甲氧基丙酰基氨基吡啶基丙烯酰基甘氨酰基,乙氧基丙酰基氨基吡啶基丙烯酰基甘氨酰基,等),被低级烷基脲基-杂环基(低级)烯酰基取代的氨基酸残基(例如,甲基脲基吡啶基丙烯酰基甘氨酰基,等),被羧基杂环基(低级)烯酰基取代的氨基酸残基(例如,羧基吡啶基丙烯酰基甘氨酰基,等),被低级烷氧基羰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,乙氧基羰基吡啶基丙烯酰基甘氨酰基,等),被低级烷基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,乙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,二甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,二乙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,异丙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,N-乙基-N-甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等),被低级烷氧基(低级)烷基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,甲氧基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,甲氧基乙基氨基甲酰基比啶基丙烯酰基甘氨酰基,甲氧基丙基氨基甲酰基比啶基丙烯酰基甘氨酰基,乙氧基乙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,二(甲氧基乙基)氨基甲酰基吡啶基丙烯酰基甘氨酰基,等),被羟基(低级)烷基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,羟基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,羟基乙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,二(羟基乙基)氨基甲酰基吡啶基丙烯酰基甘氨酰基,等),被杂环基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,吡啶基氨基甲酰基吡啶基丙烯酰基甘氨酰基,吗啉基氨基甲酰基吡啶基丙烯酰基甘氨酰基,噻吩基氨基甲酰基吡啶基丙烯酰基甘氨酰基,嘧啶基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等),被杂环基(低级)烷基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,吡啶基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,呋喃基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,噻吩基甲基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等),被杂环基羰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,吗啉代羰基吡啶基丙烯酰基甘氨酰基,吡咯烷基羰基吡啶基丙烯酰基甘氨酰基,哌啶基羰基吡啶基丙烯酰基甘氨酰基,等),被低级烯酰基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,乙烯基氨基甲酰基吡啶基丙烯酰基甘氨酰基,烯丙基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等),被低级炔基氨基甲酰基-杂环基(低级)烯酰基取代的氨基酸残基(例如,乙炔基氨基甲酰基吡啶基丙烯酰基甘氨酰基,丙炔基氨基甲酰基吡啶基丙烯酰基甘氨酰基,等),被杂环基硫代(低级)烷酰基取代的氨基酸残基(例如,吡啶基硫代乙酰基甘氨酰基,嘧啶基硫代乙酰基甘氨酰基,咪唑基硫代丙酰基甘氨酰基,等),被选择性取代的杂环基羰基取代的氨基酸残基(例如,吗啉代羰基甘氨酰基,吲哚基羰基甘氨酰基,4-甲基-1-哌嗪基羰基甘氨酰基,等),被环(低级)烷基羰基取代的氨基酸残基(例如,环丙基羰基甘氨酰基,环戊基羰基甘氨酰基,环己基羰基甘氨酰基,环己基羰基肌氨酰基,等),被低级烷氧基羰基取代的氨基酸残基(例如,甲氧基羰基甘氨酰基,叔丁氧基羰基甘氨酰基,叔丁氧基羰基肌氨酰基,叔丁氧基羰基丙氨酰基,等),被芳基氧基羰基取代的氨基酸残基(例如,苯氧基羰基甘氨酰基,等),被芳酰基(低级)烷酰基取代的氨基酸残基(例如,苯基草酰基甘氨酰基,苯甲酰基丙酰基甘氨酰基,等),被芳酰基取代的氨基酸残基(例如,苯甲酰基甘氨酰基,苯甲酰基肌氨酰基,萘甲酰基甘氨酰基,苯甲酰基丙氨酰基,等),被硝基-芳基氧基羰基取代的氨基酸残基(例如,硝基苯基氧基羰基甘氨酰基,等),被氨基甲酰基取代的氨基酸残基(例如,氨基甲酰基甘氨酰基,氨基甲酰基丙氨酰基,氨基甲酰基肌氨酰基,氨基甲酰基-β-丙氨酰基,等),被低级烷基氨基甲酰基取代的氨基酸残基(例如,甲基氨基甲酰基甘氨酰基,乙基氨基甲酰基甘氨酰基,丙基氨基甲酰基甘氨酰基,异丙基氨基甲酰基甘氨酰基,戊基氨基甲酰基甘氨酰基,甲基氨基甲酰基肌氨酰基,乙基氨基甲酰基丙氨酰基,异丙基氨基甲酰基-β-丙氨酰基,等),被低级烷氧基羰基(低级)烷基氨基甲酰基取代的氨基酸残基(例如,甲氧基羰基甲基氨基甲酰基甘氨酰基,乙氧基羰基甲基氨基甲酰基甘氨酰基,等),被低级烯基氨基甲酰基取代的氨基酸残基(例如,乙烯基氨基甲酰基甘氨酰基,烯丙基氨基甲酰基甘氨酰基,烯丙基氨基甲酰基肌氨酰基,等),被环(低级)烷基氨基甲酰基取代的氨基酸残基(例如,环丙基氨基甲酰基甘氨酰基,环己基氨基甲酰基甘氨酰基,环己基氨基甲酰基肌氨酰基,等),被芳基氨基甲酰基取代的氨基酸残基(例如,苯基氨基甲酰基甘氨酰基,萘基氨基甲酰基甘氨酰基,甲苯基氨基甲酰基甘氨酰基,乙基苯基氨基甲酰基甘氨酰基,苯基氨基甲酰基丙氨酰基,苯基氨基甲酰基肌氨酰基,等),被低级烷氧基-芳基氨基甲酰基取代的氨基酸残基(例如,甲氧基苯基氨基甲酰基甘氨酰基,乙氧基苯基氨基甲酰基甘氨酰基,甲氧基苯基氨基甲酰基丙氨酰基,等),被卤素(低级)烷基-芳基氨基甲酰基取代的氨基酸残基(例如,三氟甲基苯氨基甲酰基甘氨酰基,三氟甲基苯基氨基甲酰基丙氨酰基,三氟甲基苯基氨基甲酰基肌氨酰基,等),被卤代-芳基氨基甲酰基取代的氨基酸残基(例如,氯代苯基氨基甲酰基甘氨酰基,氯代苯基氨基甲酰基甘氨酰基,氟代苯基氨基甲酰基丙氨酰基,等),被低级烷酰基-芳基氨基甲酰基取代的氨基酸残基(例如,乙酰基苯基氨基甲酰基甘氨酰基,丙酰基苯基氨基甲酰基丙氨酰基,等),被羟基(低级)烷基-芳基氨基甲酰基取代的氨基酸残基(例如,羟基甲基苯基氨基甲酰基甘氨酰基,羟基乙基苯基氨基甲酰基甘氨酰基,羟基乙基苯基氨基甲酰基丙氨酰基,等),被杂环基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,吗啉代羰基苯基氨基甲酰基甘氨酰基,哌啶基羰基苯基氨基甲酰基甘氨酰基,硫代吗啉代羰基苯基氨基甲酰基丙氨酰基,哌嗪基羰基苯基氨基甲酰基甘氨酰基,吡咯烷基羰基苯基氨基甲酰基甘氨酰基,1、2、3、6-四氢吡啶基羰基苯基氨基甲酰基甘氨酰基,等),被羧基-芳基氨基甲酰基取代的氨基酸残基(例如,羧基苯基氨基甲酰基甘氨酰基,等),被低级烷氧基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,甲氧基羰基苯基氨基甲酰基甘氨酰基,乙氧基羰基苯基氨基甲酰基甘氨酰基,等),被氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被低级烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,丙基氨基甲酰基苯基氨基甲酰基甘氨酰基,二甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,二乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,N-乙基-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,N-异丙基-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被硝基-芳基氨基甲酰基取代的氨基酸残基(例如,硝基苯基氨基甲酰基甘氨酰基,等),被氰基-芳基氨基甲酰基取代的氨基酸残基(例如,氰基苯基氨基甲酰基甘氨酰基,等),被氨基-芳基氨基甲酰基取代的氨基酸残基(例如,氨基苯基氨基甲酰基甘氨酰基,等),被低级烷基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,甲基氨基苯基氨基甲酰基甘氨酰基,乙基氨基苯基氨基甲酰基甘氨酰基,二甲基氨基苯基氨基甲酰基甘氨酰基,等),被低级烷酰基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,乙酰基氨基苯基氨基甲酰基甘氨酰基,丙酰基氨基苯基氨基甲酰基甘氨酰基,等),被N-(低级烷酰基)-N-(低级烷基)氨基-芳基氨基甲酰基取代的氨基酸残基(例如,N-乙酰基-N-甲基氨基苯基氨基甲酰基甘氨酰基、N-丙酰基-N-甲基氨基苯基氨基甲酰基甘氨酰基,等),被低级烷氧基(低级)烷酰基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,甲氧基乙酰基氨基苯基氨基甲酰基甘氨酰基,甲氧基丙酰基氨基苯基氨基甲酰基甘氨酰基,等),被低级烷氧基羰基(低级)烷酰基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,乙氧基羰基乙酰基氨基苯基氨基甲酰基甘氨酰基,甲氧基羰基丙酰基氨基苯基氨基甲酰基甘氨酰基,等),被羧基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,羧基氨基苯基氨基甲酰基甘氨酰基,等),被低级烷氧基羰基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,乙氧基羰基氨基苯基氨基甲酰基甘氨酰基,等),被芳酰基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,苯甲酰基氨基苯基氨基甲酰基甘氨酰基,等),被杂环基羰基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,吡啶基羰基氨基苯基氨基甲酰基甘氨酰基,呋喃基羰基氨基苯基氨基甲酰基甘氨酰基,吗啉代羰基氨基苯基氨基甲酰基甘氨酰基,等),被杂环基(低级)烷酰基氨基-芳基氨基甲酰基取代的氨基酸残基(例如,吡啶基乙酰基氨基苯基氨基甲酰基甘氨酰基,噻吩基乙酰基氨基苯基氨基甲酰基甘氨酰基,等),被脲基-芳基氨基甲酰基取代的氨基酸残基(例如,脲基苯基氨基甲酰基甘氨酰基,等),被低级烷基脲基-芳基氨基甲酰基取代的氨基酸残基(例如,甲基脲基苯基氨基甲酰基甘氨酰基,乙基脲基苯基氨基甲酰基甘氨酰基,等),被羟基亚氨基(低级)烷基-芳基氨基甲酰基取代的氨基酸残基(例如,甲氧基亚氨基乙基苯基氨基甲酰基甘氨酰基,等),被低级烷基亚肼基(低级)烷基-芳基氨基甲酰基取代的氨基酸残基(例如,甲基亚肼基乙基苯基氨基甲酰基甘氨酰基,二甲基亚肼基乙基苯基氨基甲酰基甘氨酰基,等),被选择性取代的杂环基-芳基氨基甲酰基取代的氨基酸残基(例如,氧代吡咯烷基苯基氨基甲酰基甘氨酰基,氧代哌啶基苯基氨基甲酰基甘氨酰基,二氧代吡咯烷基苯基氨基甲酰基甘氨酰基,氧代噁唑烷基苯基氨基甲酰基甘氨酰基,吡咯基苯基氨基甲酰基甘氨酰基,等),被具有低级烷基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,甲基哌嗪基羰基苯基氨基甲酰基甘氨酰基,乙基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等),被具有芳基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,苯基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等),被具有一个杂环基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,吡啶基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等),被具有低级烷酰基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,乙酰基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等),被具有低级烷氧基羰基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,乙氧基羰基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等),被具有低级烷基氨基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,甲基氨基哌嗪基羰基苯基氨基甲酰基甘氨酰基,二甲基氨基哌啶基羰基苯基氨基甲酰基甘氨酰基,等),被具有低级烷基氨基甲酰基的杂环基羰基-芳基氨基甲酰基取代的氨基酸残基(例如,甲基氨基甲酰基哌嗪基羰基苯基氨基甲酰基甘氨酰基,等),被羟基(低级)烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,羟基甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,羟基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,二(羟基乙基)氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被N-[羟基(低级)烷基]-N-[低级烷基]氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,N-(羟基乙基-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被低级烷氧基(低级)烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,甲氧基甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,甲氧基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,乙氧基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,二(甲氧基乙基)氨基甲酰基苯基氨基甲酰基甘氨酰基,二(乙氧基乙基)氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被N-[低级烷氧基(低级)烷基]-N-(低级烷基)氨基甲酰基芳基氨基甲酰基取代的氨基酸残基(例如,N-(甲氧基甲基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,N-(甲氧基丙基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被低级烷基氨基(低级)烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,甲基氨基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,二甲基氨基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被N-[低级烷基氨基(低级)烷基]-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,N-(二甲基氨基乙基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,N-(二甲基氨基丙基)-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被杂环基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,吗啉基氨基甲酰基苯基氨基甲酰基甘氨酰基,噻吩基氨基甲酰基苯基氨基甲酰基甘氨酰基,吡啶基氨基甲酰基苯基氨基甲酰基甘氨酰基,嘧啶基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被N-(杂环基)-N-(低级烷基)氨基甲酰基芳基氨基甲酰基取代的氨基酸残基(例如,N-吡啶基-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被杂环基(低级)烷基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,吡啶基甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,吡啶基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,噻吩基甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被N-[杂环基(低级)烷基]-N-(低级烷基)氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,N-吡啶基甲基-N-甲基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被N-[杂环基(低级)烷氧基]-N-[低级烷氧基(低级)烷基]氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,N-吡啶基甲基-N-甲氧基乙基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被芳基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,苯基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被低级烷基氨基芳基氨基甲酰基-芳基氨基甲酰基取代的氨基酸残基(例如,二甲基氨基苯基氨基甲酰基苯基氨基甲酰基甘氨酰基,等),被芳硫基氨基甲酰基取代的氨基酸残基(例如,苯硫基氨基甲酰基甘氨酰基,萘硫基氨基甲酰基甘氨酰基,苯硫基氨基甲酰基丙氨酰基,苯硫基氨基甲酰基肌氨酰基,等),被芳(低级)烷基氨基甲酰基取代的氨基酸残基(例如,苄基氯基甲酰基甘氨酰基、苄基氨基甲酰基肌氨酰基,苄基氨基甲酰基丙氨酰基,等),被芳酰基氨基甲酰基取代的氨基酸残基(例如,苯甲酰基氨基甲酰基甘氨酰基,等),被杂环基氨基甲酰基取代的氨基酸残基(例如,吡啶基氨基甲酰基甘氨酰基,吡啶基氨基甲酰基丙氨酰基,吡啶基氨基甲酰基肌氨酰基,噻吩基氨基甲酰基甘氨酰基,吡唑基氨基甲酰基甘氨酰基,嘧啶基氨基甲酰基甘氨酰基,喹啉基氨基甲酰基甘氨酰基,异喹基氨基甲酰基甘氨酰基,等),被杂环基(低级)烷基氨基甲酰基取代的氨基酸残基(例如,吡啶基甲基氨基甲酰基甘氨酰基,吡啶基乙基氨基甲酰基甘氨酰基,噻吩基甲基氨基甲酰基甘氨酰基,等),被芳基氨基氨基甲酰基取代的氨基酸残基(例如,苯基氨基氨基甲酰基甘氨酰基,等),被芳(低级)烯基磺酰基取代的氨基酸残基(例如,苯乙烯基磺酰基甘氨酰基,肉桂酰基磺酰基甘氨酰基,等),被低级烷基磺酰基取代的氨基酸残基(例如,甲磺酰基甘氨酰基,乙磺酰基甘氨酰基,甲磺酰基肌氨酰基,甲磺酰基丙氨酰基,等),被苯二甲酰基取代的氨基酸残基(例如,苯二甲酰基甘氨酰基,苯二甲酰基丙氨酰基,苯二甲酰基-β-丙氨酰基,等),具有未被取代的氨基酸残基的氨基酸残基(例如,甘氨酰基甘氨酰基,丙氨酰基甘氨酰基,肌氨酰基甘氨酰基,脯氨酰基甘氨酰基,甘氨酰基肌氨酰基,脯氨酰基肌氨酰基,等),具有被取代的氨基酸残基的氨基酸残基如具有被低级烷基取代的氨基酸残基的氨基酸残基(例如,二甲基甘氨酰基甘氨酰基,二乙基甘氨酰基甘氨酰基,二甲基甘氨酰基肌氨酰基,乙基肌氨酰基甘氨酰基,异丙基肌氨酰基甘氨酰基,乙基甘氨酰基甘氨酰基,丙基甘氨酰基甘氨酰基,异丙基甘氯酰基甘氨酰基,乙基甘氨酰基丙氨酰基,二甲基甘氨酰基丙氨酰基,二甲基丙氨酰基甘氨酰基,二甲基-β-丙氨酰基甘氨酰基,等),具有被一个杂环基团取代的氨基酸残基的氨基酸残基(例如,吗啉基甘氨酰基甘氨酰基,哌啶基甘氨酰基甘氨酰基,吡啶基甘氨酰基甘氨酰基,哌啶基肌氨酰基甘氨酰基,等),具有被杂环基(低级)烷基取代的氨基酸残基的氨基酸残基(例如,吡啶基甲基甘氨酰基甘氨酰,咪唑基甲基甘氨酰基甘氨酰基,呋喃基甲基甘氨酰基甘氨酰基,噻恩基甲基肌氨酰基甘氨酰基,等),具有被环烷基取代的氨基酸残基的氨基酸残基(例如,环丙基甘氨酰基甘氨酰基,环丁基甘氨酰基甘氨酰基,环戊基甘氨酰基甘氨酰基,环已基甘氨酰基甘氨酰基,环庚基甘氨酰基甘氨酰基,环辛基甘氨酰基甘氨酰基,金刚烷基甘氨酰基甘氨酰基,环已基肌氨酰基甘氨酰基、环庚基肌氨酰基甘氨酰基,环已基甘氨酰基肌氨酰基、环已基甘氨酰基丙氨酰基,等),具有被芳基取代的氨基酸残基的氨基酸残基(例如,苯基甘氨酰基甘氨酰基,苯基肌氨酰基甘氨酰基,等),具有被低级烷酰基取代的氨基酸残基的氨基酸残基(例如,乙酰基甘氨酰基甘氨酰基,乙酰基脯氨酰基甘氨酰基,丙酰基甘氨酰基甘氨酰基,乙酰基丙氨酰基甘氨酰基,等),具有被低级烷氧基羰基取代的氨基酸残基的氨基酸残基(例如,叔丁氧基羰基甘氨酰基甘氨酰基,叔丁氧基羰基脯氨酰基甘氨酰基,等),具有被芳(低级)烷基取代的氨基酸残基的氨基酸残基(例如,苄基甘氨酰基甘氨酰基,等)和具有被苯二甲酰基取代的氨基酸残基的氨基酸残基(例如,苯二甲酰基甘氨酰基甘氨酰基,等),等},等];或如哌嗪的杂环基团,该基团可被如芳(低级)烷基[例如,苄基,苯乙基,等],低级烷氧基羰基(低级)烷基[例如,甲氧基羰基甲基,甲氧基羰基乙基,乙氧基羰基甲基,等]和/或氧取代;
R4和R5均是氢,或如氟、氯、溴和碘的卤素;Q是O或N-R9,其中R9是氢;或酰基如低级烷酰基[例如,甲酰基,乙酰基,丙酰基,丁酰基,等]和低级烷氧基羰基[例如,叔丁氧基羰基,等];A是低级亚烷基如亚甲基、亚乙基、甲基亚甲基和亚丙基。
适宜的“离去基团”可以是常规的离性残基如卤素[例如,氟、氯、溴和碘],芳烃磺酰氧基[例如,苯磺酰氧基,甲苯碘酰氧基,等],烷烃磺酰氧基[例如,甲磺酰氧基,乙磺酰氧基,等],等。
目的化合物[Ⅰ]的药学上可接受的盐是常规的无毒的盐和包括金属盐如碱金属盐(例如,钠盐、钾盐,等]和碱土金属盐[例如,钙盐,镁盐,等],铵盐,有机碱的盐[例如,三甲胺盐、三乙胺基盐、吡啶盐、皮考啉盐、二环己基胺盐、N,N’-二苄基亚乙基二胺盐,等],有机酸加合盐[例如,甲酸盐,乙酸盐,三氟乙酸盐,马来酸盐、酒石酸盐、草酸盐、甲磺酸盐、苯磺酸盐、甲苯磺酸盐,等],无机酸加合盐[例如,盐酸盐、氢溴酸盐、硫酸盐、磷酸盐,等],与氨基酸形成的盐[例如,精氨酸盐、天冬氨酸盐、谷氨酸盐,等],分子内盐等。
对于在方法2~4中的化合物[Ⅰa]到[Ⅰf]的盐来说,值得注意的是这些化合物包括在化合物[Ⅰ]的范围中,相应地,这些化合物的盐的适宜的实例参见那些作为目的化合物[Ⅰ]的例证。
下面详细解释目的化合物[Ⅰ]的制备方法。
方法1
目标化合物[Ⅰ]或它的盐可由将化合物[Ⅱ]或它的盐与化合(Ⅲ)或它的盐进行反应来制备。
化合物(Ⅱ)和(Ⅲ)的适宜的盐可以是与作为化合物[Ⅰ]的例证的那些相同的盐。
较好的是在有碱存在下实施反应,这些碱如碱金属(例如,锂、钠、钾,等],它们的氢氧化物或碳酸盐或碳酸氢盐[例如,氢氧化钠,碳酸钾,碳酸氢钾,等],碱金属烷氧化物[例如,甲醇钠、乙醇钠、叔丁醇钾,等],等。
该反应通常是在如四氢呋喃,二恶烷,N,N-二甲基甲酰胺,丙酮等常规溶剂中实施。
反应温度不很严格,该反应通常是在冷却至加热下进行实施的。
方法2
目标化合物[Ⅰb]或它的盐可通过将化合物[Ⅰa]或它的盐酰化来制备。
在酰化试剂存在下实施酰化反应。
适当的酰化剂是相应的羧酸或磺酸化合物,这些化合物用式R-OH表示,式中R是酰基,及其反应性衍生物,和相应的异氰酸酯或异硫代氟酸酯化合物。
作为适宜的所述的反应性衍生物,可述及的有酰卤,酸酐,活性酰胺和活性酯。适当的实例是酰卤如酰氯和酰溴,与不同酸混合的酸酐[例如,取代的磷酸如二烷基磷酸,硫酸,脂肪族羧酸,芳香族羧酸,等],对称酸酐,带有不同咪唑的活性酰胺,和活性酯如对硝基苯基酯和N-羟基琥珀酰亚胺酯。这类反应性衍生物的种类可根据所要引入的酰基的种类来进行选择。
通常在常规溶剂中实施反应,这些溶剂如二氯甲烷,三氯甲烷,吡啶,二恶烷,四氢呋喃,N,N-二甲基甲酰胺,等,当酰化剂是液体时也可用作溶剂,当羧酸或磺酸化合物以游离形式或盐形式被用作酰化剂时,较好的是在有常规的凝聚剂如N,N’-二环己基碳化二亚胺等存在下实施反应。
反应温度不很严格和可在冷却下、在室温下或在加热下实施该反应。
较好的是在有常规的无机碱存在下或在有常规的有机碱存在下实施此反应。
方法3
目的化合物[Ⅰd]或它的盐可将化合物[Ⅰc]或它的盐酰化来制备。
此反应可以用与方法2基本相同的方式来实施,因此该反应的反应模式和反应条件参看在方法2中所解释的那些。
方法4
目的化合物[Ⅰf]或它的盐可通过将化合物[Ⅰe]或其在羧基上的反应性衍生物或它们的盐与化合物[Ⅳ]或其在氨基上的反应性衍生物或它们的盐进行反应来制备。
化合物[Ⅰe]的羧基上的适宜的反应性衍生物可包括酰卤,酸酐,活性酰胺,活性酯,等。反应性衍生物的适当的实例可以是酰氯;酸性叠氮化物;与-种酸混合的酸酐,这种酸如二烷基磷酸,硫酸,脂族羧酸或芳香羧酸;对称酸酐;带有咪唑的活化酰胺;或活化的酯[例如,对-硝基苯基酯,等]。这些反应性衍生物可选择性地按照所用的化合物[Ⅰe]的种类从它们中选出。
化合物[Ⅳ]的氨基上的适宜的反应性衍生物可以是由通过化合物[Ⅳ]与甲硅烷基化合物如二(三甲基甲硅烷基)乙酰胺或单(三甲基甲硅烷基)乙酰胺,等反应形成的甲硅烷基衍生物。
化合物[Ⅳ]和它的反应性衍生物的适宜的盐可以参考作为化,合物[Ⅰ]的例证的有机或无机酸加合盐。
该反应可以与方法2基本相同的方式来实施,因此该反应的反应模式和反应条件参见在方法2中所解释的内容。
目的化合物[Ⅰ]和起始化合物也可通过下面述及的实施例和制备方法或与其类似的方法或常规的方式来制得。
用上述方法制得的化合物可用常规的方法如粉化,重结晶,色谱,重沉淀等进行分离和纯化。
值得注意的是化合物[Ⅰ]和其它化合物由于不对称碳原子和双键的存在,它们可以包括一种立体异构体和几何异构体,所有这些异构体或多种和它们的混合物均包括在本发明的范围之内。
作为缓激肽拮抗剂,目的化合物[Ⅰ]及其药物上可接受的盐具有很强的活性,可用于治疗和/或预防缓激肽或它的类似物介导的疾病如过敏症,炎症,自体免疫疾病,休克,疼痛等,尤其是用于在人体或动物体中预防和/或治疗气喘,咳嗽,支气管炎,鼻炎,鼻溢,阻塞性肺病[例如,肺气肿等],咳痰,肺炎,全身性炎性反应综合症(SIRS),脓毒性,休克,内毒性休克,过敏性休克,成人呼吸窘迫综合症,散播性血管内凝血疾病,关节炎,风湿病,骨关节炎,腰风湿病,炎症诱发性骨吸收,结膜炎,春季结膜炎,眼色素层炎,虹膜炎,虹膜睫状体炎,头痛,周期性偏头痛,牙痛,背痛,表皮痛,癌症疼痛,手术后疼痛,腱痛,损伤[例如,创伤,烧伤,等],皮疹,红斑,湿疹或皮炎[例如,接触性皮炎,特异反应性皮炎等],荨麻疹,疱疹,骚痒,牛皮癣,苔癣,炎性肠疾[例如,溃疡性结肠炎,克罗恩氏病等],腹泻,肝炎,胰腺炎,胃炎,食管炎,食物过敏症,溃疡,过敏性肠综合症,肾炎,心角痛,牙周炎,浮肿,遣传性血管神经性浮肿,脑水肿,低血压,血栓,心肌梗塞,脑血管痉挛,充血,血凝固,痛风,脑神经系统损伤,早产,动脉硬化,胃切除术后倾泻综合症,类癌瘤综合症,变质精液流动性,糖尿病性神经病,神经痛,在移植术中的移植物排斥,等。此外,已知缓激肽与如前列腺素、白细胞素,快速激肽,组胺,血栓丸等的介体的释放有关,因此,化合物(Ⅰ)被期望在预防和/或治疗这类介体介导的疾病中是有用的。
为了说明目的化合物(Ⅰ)的有用性,化合物(Ⅰ)的一些代表性化合物的药学上的试验数据如下所示。
3H-缓激肽受体的结合。
(ⅰ)试验方法:
(a)粗回肠膜的制备
将雄性Hartly品系豚鼠宰杀,除去回肠和在缓冲溶液(50mM三甲基氨基乙基磺酸(TES)、1mM1,10-菲绕啉PH=6.8)中均匀化,将组织匀浆离心化(1000×g,20分钟)以除去组织凝块和将上层清液离心(100,000×g、60分钟)以产生弹丸、将药丸在缓冲溶液(50mM TES,1mM 1,10-菲绕啉,140mg/l杆菌肽,1mM二硫苏糖醇,0.1%牛血清白肮,PH=6.8)中再悬浮和用玻璃-特氟隆匀化器进行均匀化以产生悬浮液,该悬浮液作为粗膜悬浮液述及。得到的膜悬浮液在使用前保存在-80℃下。
(b)3H-缓激肽结合在膜上
将冷冻的粗膜悬浮液融化,在结合分析中3H-运动徐缓素(0.06nM)和药物(1×10-6M)在502ll的膜悬浮液中于室温下培养60分钟最终体积为250ul。用在真空下直接过滤法从游离的
3H-缓激肽中分离出结合的受体和用5ml冰冷缓冲溶液(50mM Tris-HCl,pH=7.5)洗三次。非特定结合被定义为在0.1um缓激肽存在下的结合,用液体-闪烁计数器测定保留在冲洗过的过滤器上的放射性。(ⅱ)试验结果
测试化合物(实施例号) | 3H-缓激肽结合物的抑制%(浓度:1×10-6M) |
29-(36) | 98 |
34-(7) | 100 |
35-(3) | 99 |
41-(12) | 95 |
41-(53) | 99 |
41-(64) | 95 |
57 (盐酸盐) | 99 |
58-(11) (二盐酸盐) | 99 |
按照与在(英国药理学杂志)British Journal of pharma-cology,102,774-777(1991)中所述的相似方法测定化合物(Ⅰ)对缓激肽诱发的支气管压缩和角叉菜胶诱发的手足浮肿的效果。
为了治疗上的目的,可以药物组合物的形式使用本发明的化合物(Ⅰ)和它的药物上可接受的盐,该组合物含有一种所说的化合物,作为活性成分,与药物上可接受的载体如有机或无机的固体,半固体或液体赋形剂进行混合,赋形剂是适用于口服,非肠用如静脉内的,肌肉内的,皮下的或关节内的,外用如局部,enteral,直肠内的,阴道内的,吸入剂,眼的,鼻的或舌下服用的。药物组合物可以是胶囊、片剂、糖衣药丸、粒剂、栓剂、溶液、洗剂、悬浮液、乳液、软膏、凝胶、霜剂等。如果需要,在这些药物组合物中可以包括,辅剂,稳定剂,润湿剂或乳化剂,缓冲剂和其它常用的添加剂。
根据病人的年龄和症状化合物(Ⅰ)的剂量可以变化,对于预防和治疗上述疾病,大约0.1mg,1mg,10mg,50mg,100mg,250mg,500mg和1000mg的化合物(Ⅰ)的平均单一剂量可以是有效的。通常,每天可服用0,1mg/人体到大约1000mg/人体的量。
下面的制备和实施例说明了本发明。
制备Ⅰ
按照下述实施例5相似的方法制得2,6-二氯-3-(苯二甲酰亚氨基乙酰基)氨基甲苯。mp:245-246℃NMR(CDCl3,δ):2.48(3H,s),4.59(2H,s),7.27
(1H,d,J=9Hz),7.70-7.96(4H),8.00(1H,brs),
8.12(1H,d,J=9Hz)
制备2
按照下述实施例7相似的方法制得2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲基氨基〕-甲基
mp:193-194℃
NMR(CDCl3,δ):2.58(3H,s),3.21(3H,s),4.10
(2H,s),7.30(1H,d,J=9Hz),7.42(1H,d,
J=9Hz),7.65-7.91(4H)
制备3
将2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲基氨基〕甲基(303mg),N-溴丁二酰亚胺(150mg),2,2′-偶氮二-(2,4-二甲基-4-甲氧基戊腈)(30mg)和二氯甲烷(6ml)的混合物加热回流5小时。向其中加入N-溴丁二酰亚胺(75mg)并将混合物再加热回流3小时,反应混合物用饱和碳酸氢钠溶液洗两次并用盐水洗,用硫酸镁干燥和真空蒸发,剩余物从乙醚中结晶得到3-溴甲基-2,4-二氯-N-甲基-N-(苯二甲酰亚氨基乙酰基)苯胺(102mg)结晶。
mp:211℃(dec.)
NMR(CDCl3,δ):3.2 4(3H,s),4.09(2H,s),4.81
(2H,s),7.44(1H,d,J=9Hz),7.51(1H,d,
J=9Hz),7.68-7.91(4H)
制备4
邻甲氧基苯胺(15.11g),乙基丙酰基乙酸酯(17.69g)和乙酸(0.5ml)在苯(30ml)中的混合物回流除水24小时,减压除去溶剂,剩余物溶于甲苯(30ml)中,反应混合物再回流8小时,真空除去溶剂,剩余物用柱色谱(己烷-乙酸乙酯)纯化得到油状的3-(2-甲氧基苯胺基)-2-戊烯酸乙基酯(15.11g)。NMR(CDCl3,δ):1.06(3H,t,J=7Hz),1.30(3H,t,
J=7Hz),2.32(2H,q,J=7Hz),3.85(3H,s),4.18
(2H,q,J=7Hz),4.74(1H,s),6.83-6.98(2H),
7.06-7.20(2H),10.18(1H,brs)
制备5
向二苯醚(30ml)和二联苯(30g)的混合物中加入3-(2-甲氧基苯胺基)-2-戊烯酸乙基酯(15.1g),此时内部温度保持在230~235℃。混合物在235℃搅拌1小时,向反应混合物中加入己烷(150ml),真空过滤收集沉淀并用己烷洗,得到2-乙基-4-羟基-8-甲氧基喹啉(10.37g)结晶。
mp:190-192℃
NMR(CDCl3,δ):1.38(3H,t,J=7Hz),2.70(2H,q,
J=7Hz),4.00(3H,s),6.20(1H,d,J=1Hz),7.02
(1H,dd,J=9,1Hz),7.23(1H,t,J=9Hz),7.90
(1H,d,J=9Hz),8.52(1H,brs)
制备6
在冰浴中低于8℃下向2-乙基-4-羟基-8-甲氧基喹啉(9.96g)在磷酰氯(30ml)中的溶液加入N,N-二甲基苯胺(12.44ml)。10分钟后混合物在室温下搅拌1.5小时,真空除去溶剂,剩余物转移到二氯甲烷和饱和碳酸氢钠溶液中。有机层用盐水洗并用硫酸镁干燥。有机层用真空法蒸发,剩余物用柱色谱(己烷-乙酸乙酯)进行纯化并从己烷中重结晶,得到4-氯-2-乙基-8-甲氧基喹啉(8.90g)结晶。mp:80-81℃NMR(CDCl3,δ):1.40(3H,t,J=7Hz),3.08(2H,q,
J=7Hz),4.09(3H,s),7.10(1H,d,J=9Hz),
7.43-7.54(2H),7.78(1H,d,J=9Hz)
制备7
将4-氯-2-乙基-8-甲氧基喹啉(4.0g)在48%氢溴酸(80ml)中的溶液回流2天。用28%的氨水将混合物调整至PH12,用真空过滤法收集沉淀,用水和己烷洗,得到4-氯-2-乙基-8-羟基喹啉(3.13g)结晶。
mp:45-47℃
NMR(CDCl3,δ):1.40(3H,t,J=7Hz),2.98(2H,q,
J=7Hz),7.19(1H,d,J=9Hz),7.39-7.66(3H)
制备8
在冰水浴中搅拌下向哌嗪(3g)在二氯甲烷(30ml)中的溶液加入异氰酸甲基酯(2.16ml)。10分钟后混合物在室温下搅拌1小时。反应混合物在真空下蒸发,剩余物用乙腈(15ml)稀释并将结晶过滤出来。滤液真空蒸发,向剩余物中加入二甲苯和用真空法共沸除去溶剂,得到油状的N-甲基-1-哌嗪甲酰胺(2.43g)。NMR(CDCl3-CD3OD,δ):2.80(3H,s),2.83-2.93(4H),
3.32-3.44(4H)
制备9
在冰浴中搅拌二甲基胺(50%水溶液,3.6ml),滴加3-硝基苯甲酰氯(1.8g)在1,4-二噁烷(4ml)中的溶液,产生的混合物在室温下剧烈搅拌2.5小时,加入乙酸乙酯和用水,1N盐酸,1N氢氧化钠,水和饱和氯化钠溶液依次洗涤有机层并用无水硫酸镁干燥,过滤和浓缩后,剩余物从苯-正己烷中重结晶,得到N,N-二甲基-3-硝基苯甲酰胺(1.5g)的浅黄色棱晶。
mp:84.7-87.7℃
NMR(CDCl3,δ):3.00(3H,s),3.15(3H,s),7.61
(1H,t,J=7.5Hz),7.78(1H,d,J=7.5Hz),
8.22-8.35(2H,m)
制备10
在搅拌下向2-甲氧基乙基胺(0.9ml)在二氯甲烷(20ml)中的溶液加入三乙胺(2.1ml),混合物在冰冷却浴中冷却,向该混合物中滴加3-硝基苯甲酰氯(1.8g)在二氯甲烷(10ml)中的溶液,产生的混合物在同样温度下搅拌1.5小时。混合物用水和饱和氯化钠溶液洗,无水硫酸镁干燥,过滤后,真空除去溶剂,得到黄色油状的N-(2-甲氧基乙基)-3-硝基苯甲酰胺(2.7g)。NMR(CDCl3,δ):3.41(3H,s),3.53-3.63(2H,m),
3.63-3.76(2H,m),6.62(1H,brs),7.65(1H,
dt,J=8 and 0.5Hz),8.16(1H,dt,J=8,0.5Hz),
8.38(1H,dt,J=8,0.5Hz),8.61(1H,m)
制备11
在冰冷却浴中搅拌下向3-硝基苯甲酰氯(9.3g)在二乙醚(50ml)和饱和碳酸氢钠溶液(50ml)混合物中的两相溶液中加入3-氨基甲基吡啶(5.4g)。混合物在室温下剧烈搅拌30分钟。将反应混合物过滤,产生的固体用水洗。用二异丙醇-水将固体进-步固化产生3-硝基-N-(3-吡啶基甲基)苯甲酰胺(5.91g)浅黄色无定形固体。
NMR(CDCl3,δ):4.70(2H,d,J=5Hz),7.05(1H,br
s),7.30(1H,dd,J=7,5Hz),7.68(1H,t,
J=9Hz),7.76(1H,dt,J=8,0.5Hz),8.22(1H,d,
J=8Hz),8.39(1H,m),8.54(1H,dd,J=5,0.5Hz),
8.60(1H,d,J=0.5Hz),8.65(1H,t,J=0.5Hz)
制备12
按照与制备9至11中相类似的方法可制得下列化合物。
(1)N-甲基-3-硝基-N-(2-吡啶基)苯甲酰胺
mp:79-82℃
NMR(CDCl3,δ):3.61(3H,s),6.92(1H,d,J=9Hz),
7.10(1H,dd,J=7,5Hz),7.41(1H,dt,J=1,
7Hz),7.56(1H,dt,J=1,7Hz),7.67(1H,dt,
J=7,1Hz),8.11-8.21(2H),8.41(1H,dt,J=5,
1Hz)
(2)3-硝基-N-(4-吡啶基)苯甲酰胺
mp:>250℃
NMR(DMSO-d6,6):7.80(2H,d,J=6Hz),7.89(1H,t,
J=7Hz),8.38-8.58(4H),8.80(1H,t,J=1Hz)
(3)4-甲基-1-(3-硝基苯甲酰基)哌嗪
mp:97-98℃
NMR(CDCl3,δ):2.31-2.66(7H),3.38-3.97(4H),
7.62(1H,dt,J=8,1Hz),7.78(1H,dt,J=1,
8Hz),8.25-8.34(2H)
制备13
在冰冷却浴中向搅拌着的3-硝基-N-(3-吡啶基甲基)苯甲酰胺(2.00g)在四氢呋喃(40ml)中的溶液-次加入叔丁醇钾(9.17mg)。搅拌持续40分钟,然后加入碘甲烷(0.53ml)。反应混合物在0℃下搅拌1小时,然后在室温下搅拌5小时,向反应混合物中加入饱和碳酸氢钠溶液和用乙酸乙酯萃取混合物。有机层用水和饱和氯化钠溶液洗。用无水硫酸镁干燥和过滤后,真空除去溶剂,剩余物用快速色谱(甲醇-氯仿3%,V/V )进行纯化,产生黄色油状的3-硝基-N-甲基-N-(3-吡啶基甲基)-苯甲酰胺(1.8g)。NMR(CDCl3,δ):2.80-3.22(3H,m),4.40-4.93(2H,
m),7.30-7.42(1H,m),7.44-7.90(3H,m),
8.24-8.37(2H,m),8.40-8.75(2H,m)
制备14
按照与制备13相类似的方法可制得N-(2-甲氧基乙基)-N-甲基-3-硝基苯甲酰胺。NMR(CDCl3,δ):2.96-3.21(3H,m),3.25-3.90(7H,
m),7.60(1H,br t,J=8Hz),7.79(1H,br d,
J=8Hz),8.20-8.46(2H,m)
制备15
按照与实施例3相类似的方法可以从3-硝基-N,N-二甲基苯甲酰胺制得3-氨基-N,N-二甲基苯甲酰胺。
NMR(CDCl3,δ): 2.96(3H,br s),.3.09(3H,br s),
3.74(2H,br s),6.62-6.82(3H,m),7.08-7.22
(1H,m)
制备16
向搅拌着的N-(2-甲氧基乙基)-N-甲基-3-硝基苯甲酰胺(840mg)在乙酸乙酯(8ml)中的溶液加入二氧化铂(160mg),产生的非均相混合物在氢气气氛下搅拌8小时。过滤除去催化剂并真空浓缩滤液。剩余物用快速色谱以乙酸乙酯洗脱进行纯化,产生褐色粘稠油状物3-氨基-N-(2-甲氧基乙基)-N-甲基苯甲酰胺(761mg)。
NMR(CDCl3,δ):2.90-3.17(3H,m),3.18-3.96(9H,
m),6.56-6.83(3H,m),7.15(1H,t,J=9Hz)
制备17
按照与制备15或16相类似的方法可以制得下列化合物。
(1)3-氨基-N-甲基-N-(3-吡啶基甲基)苯甲酰胺
NMR(CDCl3,δ):2.87(3H,br s),3.75(l or 2H,br
s),4.41-4.88(2H,m),6.55-6.84(3H,m),
7.03-7.40(2H,m),7.42-7.84(1H,m),8.35-8.70
(2H,m)
(2)3-氨基-N-甲基-N-(2-吡啶基)苯甲酰胺NMR(CDCl3,δ):3.58(3H,s),3.66(2H,br s),
6.55-6.68(2H),6.79(1H,t,J=1Hz),6.81-7.09
(3H),7.48(1H,dt,J=7,1Hz),8.45(1H,d,
J=5Hz)
(3)3-氨基-N-(4-吡啶基)苯甲酰胺mp: 232-234℃NMR(DMSO-d6,δ):5.39(2H,br s),6.79(1H,br d,
J=8Hz),7.02-7.11(2H),7.19(1H,t,J=8Hz),
7.78(2H,d,J=7Hz),8.46(2H,d,J=7Hz)
(4)1-(3-氨基苯甲酰基)-4-甲基哌嗪mp:114-116℃NMR(CDCl3,δ):2.28-2.60(7H),3.38-3.90(6H),
6.68-6.79(3H),7.68(1H,t,J=8Hz)
制备18
在冰冷却浴中向搅拌着的3-氨基-N,N-二甲基苯甲酰胺(1.3g)在1,4-二噁烷(20ml)中的溶液依次加入1N氢氧化钠(23.4ml)和氯甲酸苯酯(1.5ml)。除去冰冷却浴并将反应混合物剧烈搅拌3小时,在这段时间内,进一步加入氯甲酸苯酯(0.7ml)。混合物用乙酸乙酯萃取和有机层用水和饱和氯化钠溶液洗。用无水硫酸镁干燥和过滤后,真空除去溶剂,剩余的油状物用快速色谱以乙酸乙酯-正己烷(2∶1,V/V)洗脱进行纯化,产生固体,此固体从苯-正己烷(5∶1,V/V)中重结晶产生3-(二甲基氨基甲酰基)苯基氨基甲酸苯酯(1.4g)无色粉末。
mp:151.2-153.0℃
NMR(CDCl3,δ):3.00(3H,s),3.10(3H,s),
7.09-7.46(6H,m),7.49-7.65(3H,m)
制备19
在冰冷却浴中向搅拌着的3-氨基苯甲酸乙酯(1g)和三乙胺(1.1ml)在二氯甲烷(10ml)中的混合物滴加氯甲酸苯酯(0.8ml)。除去冰浴并将产生的混合物在室温下搅拌5小时,混合物用二氯甲烷萃取并用水和饱和氯化钠洗。有机层用无水硫酸镁干燥,过滤和真空浓缩产生浅黄色固体。固体用快速色谱以乙酸乙酯-二氯甲烷(1∶9,V/V)洗脱进行纯化产生所需要的化合物。再加入二异丙基醚和产生的悬浮液在水浴(90℃)上加热,然后在搅拌下冷却至室温并过滤,产生3-(乙氧基羰基)苯基氨基甲酸苯酯(0.7g)的无色针晶。
mp:138℃
NMR(CDCl3,δ):1.39(3H,t,J=7.5Hz),4.38(2H,
q,J=7.5Hz),7.04-7.33(4H,m),7.3 4-7.51(3H,
m),7.73-7.88(2H,m),8.05(1H,t,J=0.5Hz)
制备20
按照与制备18或19中相类似的方法可以制得下列化合物。
(1)3-〔 N-(4-吡啶基)氨基甲酰基〕苯基氨基甲酸苯酯
mp:204-206℃
NMR(DMSO-d6,δ):5.39(1H,br s),6.71-6.82(2H),
7.02-7.33(4H),7.40-7.81(4H),8.09(1H,br s),
8.41-8.51(2H),9.32(1H,br s)
(2)3-(4-甲基-1-哌嗪基羰基)苯基氨基甲酸苯酯
mp:152-154℃
NMR(CDCl3,δ):2.27-2.56(7H),3.38-3.91(4H),
7.10-7.60(9H)
制备21
按照与制备19相类似的方法将3-氨基甲基吡啶与氯甲酸苄基酯反应制得3-吡啶基甲基氨基甲酸苄基酯。
mp:73.6-77.1℃
NMR(CDCl3,δ):4.40(2H,d,J=6Hz),5.64(2H,s),
5.60-5.77(1H,m),7.19-7.45(6H,m),7.65(1H,
d,J=7Hz),8.46-8.60(2H,m)
制备22
按照与制备13相类似的方法将3-吡啶基甲基氨基甲酸苄基酯与2-甲氧基乙基氯反应制得N-(2-甲氧基乙基)-N-(3-吡啶基甲基)氨基甲酸苄基酯。NMR(CDCl3,δ):3.25-3.30(3H,m),3.33-3.63(4H,
m),4.59(2H,br s),5.16(2H,br s),7,11-7.71
(7H,m),8.49(2H,br d,J=3Hz)
制备23
N-(2-甲氧基乙基)-N-(3-吡啶基甲基)氨基甲酸苄基酯(5.4 g)和10%固载于碳上的钯(1.0g)在乙醇(50ml)中的混合物在氢气气氛下搅拌9小时。过滤除去催化剂,滤液在与甲笨和乙醇共沸的条件下进行浓缩。剩余物溶于乙醇中,再加入乙醚,产生沉淀,用过滤法收集沉淀,产生N-(2-甲氧基乙基)-N-(3-吡啶基甲基)胺(1.3g)。mp:134-135℃NMR(CDCl3,δ):3.06(2H,t,J=5Hz),3.39(3H,s),
3.80(2H,t,J=5Hz),4.26(2H,s),7.36(1H,dd,
J=8and 5Hz),8.21(1H,br d,J=8Hz),8.60(1H,
d,J=5Hz),8.74(1H,br s)
制备24
在冰水浴中向4-氨基肉桂酸乙酯(300mg),三乙胺(167mg)和二氯甲烷(3ml)的混合物中加入丙酰氯(182mg)在二氯甲烷(1ml)中的溶液,混合物在同样温度下搅拌1小时。向反应混合物中加入4滴N,N-二甲基丙二胺,将反应混合物继续搅拌5分钟。反应混合物用水洗,硫酸镁干燥,真空蒸发。剩余物用二异丙基醚结晶,产生无色粉状的4-丙酰氨基肉桂酸乙酯(341mg)。mp:138℃NMR(CDCl3,δ):1.26(3H,t,J=8Hz),1.34(3H,t,
J=8Hz),2.42(2H,q,J=8Hz),4.26(2H,q,
J=8Hz),6.37(1H,d,J=16Hz),7.21(1H,br s),
7.49(2H,d,J=8Hz),7.58(2H,d,J=8Hz),7.68
(1H,d,J=16Hz)
制备25
在氮气氛下向于室温下的氢化钠(60%活性,31mg)在二甲基甲酰胺(1ml)中的悬浮液中加入4-丙酰氨基肉桂酸乙酯(160mg)在二甲基甲酰胺(2ml)中的溶液。混合物在同样温度下搅拌1小时,再向其中加入碘甲烷(111mg)在二甲基甲酰胺(2m1)中的溶液。反应混合物在同样温度下搅拌2小时,倒入水中,和用乙酸乙酯萃取。有机层用水洗,硫酸镁干燥和真空蒸发产生油状的4-(N-甲基丙酰氨基)肉桂酸乙酯(168mg)。NMR(CDCl3,δ):1.07(3H,t,J=8Hz),1.35(3H,t,
J=8Hz),2.13(2H,q,J=8Hz),3.27(3H,s),4.29
(2H,q,J=8Hz),6.44(1H,d,J=16Hz),7.21(2H,
d,J=8Hz),7.57(2H,d,J=8Hz),7.68(1H,d,
J=16Hz)
制备26
按照与制备25相似的方法制得4-(N-乙基乙酰氨基)肉桂酸乙酯。NMR(CDCl3,δ):1.13(3H,t,J=7.5Hz),1.35(3H,t,
J=7.5Hz),1.86(3H,br s),3.77(2H,q,
J=7.5Hz),4.29(2H,q,J=7.5Hz),6.45 (1H,d,
J=16Hz),7.19(2H,d,J=8Hz),7.58(2H,d,
J=8Hz),7.68(1H,d,J=16Hz)
制备27
在氮气氛下向于室温下的氢化钠(60%活性,125mg)在二甲基甲酰胺(2ml)中的悬浮液中加入4-羟基内桂酸乙酯(250mg),将混合物搅拌1小时。在同样温度下向混合物中加入2-吡啶甲基氯盐酸盐(256mg),静置16小时。将反应混合物倒入水中,用乙酸乙酯萃取。有机层用水洗,硫酸镁干燥和真空蒸发。剩余物从二异丙基醚中结晶,产生无色粉状4-(2-吡啶基甲氧基)肉桂酸乙酯(188mg)。mp:95℃NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),4.26(2H,q,
J=7.5Hz),5.22(2H,s),6.30(1H,d,J=16Hz),
7.00(2H,d,J=8Hz),7.20-7.30(1H,m),
7.42-7.56(3H,m),7.64(1H,d,J=16Hz),7.73
(1H,td,J=8,1Hz),8.61(1H,dif-dd,J=5Hz)
制备28
按照与制备27相类似的方法可制得下列化合物。
(1)4-〔2-(N,N-二甲基氨基)乙氧基〕肉桂酸乙酯NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),2.34(6H,
s),2.74(2H,t,J=6Hz),4.10(2H,t,J=6Hz),
4.26(2H,q,J=7.5Hz),6.30(1H,d,J=16Hz),
6.92(2H,d,J=8Hz),7.48(2H,d,J=8Hz),7.64
(1H,d,J=16Hz)
(2)4-(2-乙酰氧基乙氧基)肉桂酸乙酯
NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),2.11(3H,
S),4.19(2H,t,J=6Hz),4.25(2H,q,J=7.5Hz),
4.44(2H,t,J=6Hz),6.31(1H,d,J=16Hz),6.94
(2H,d,J=8Hz),7.49(2H,d,J=8Hz),7.64(1H,
d,J=16Hz)
制备29
在氮气氛下于室温向4-甲酰基苯甲酸(1.00g)在于四氢呋喃(15ml)中的悬浮液中加入(三苯基正亚磷基)乙酸甲酯(2.50g)。反应混合物在同样温度下搅拌1小时,倒入碳酸氢钠水溶液中,和用乙酸乙酯洗向水层中加入1N盐酸直至将该层调整至PH=2。水层用乙酸乙酯萃取。有机层用水洗,硫酸镁干燥和真空蒸发。剩余物从二异丙基醚中结晶,产生无色粉状的4-羧基肉桂酸甲酯(1.21g)。
mp:243℃
NMR(DMSO-d6,δ):3.74(3H,s),6.76(1H,d,
J=16Hz),7.73(1H,d,J=16Hz),7.85(2H,d,
J=8Hz),7.96(2H,d,J=8Hz)
制备30
在室温下向4-羧基肉桂酸甲酯(160mg)在二氯甲烷中的溶液中加入甲胺盐酸盐(58mg)和1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺(140mg),和将混合物搅拌2小时。向该悬浮液中加入1-羟基苯并三唑(137mg)和二甲基甲酰胺(2ml),将混合物在同样温度下搅拌14小时。将反应混合物倒入水中和用二氯甲烷萃取。有机层用碳酸氢钠水溶液和水洗,硫酸镁干燥,和真空蒸发。剩余物从二异丙基醚中结晶,产生无色粉状4-(甲基氨基甲酰基)肉桂酸甲酯(82mg)。
mp:210.5℃
NMR(DMSO-d7,δ):2.79(3H,d,J=5Hz),3.74(3H,
s),6.74(1H,d,J=16Hz),7.69(1H,d,J=16Hz),
7.80(2H,d,J=8Hz),7.87(2H,d,J=8Hz),8.51
(1H,q-like)
制备31
按照与制备30相类似的方法制得下列化合物。
(1)4-(N,N-二甲基氨基甲酰基)肉桂酸甲酯
mp:130℃
NMR(CDCl3,δ):3.00(3H,s),3.12(3H,s),3.83
(3H,s),6.49(1H,d,J=16Hz),7.45(2H,d,
J=8Hz),7.58(2H,d,J=8Hz),7.70(1H,d,
J=16Hz)
(2)4-〔N-(2-甲氧基乙基)氨基甲酰基〕肉桂酸甲酯mp:122-124℃NMR(CDCl3,δ):3.40(3H,s),3.53-3.72(4H),3.83
(3H,s),6.45-6.60(3H),7.58(2H,d,J=8Hz),
7.71(1H,d,J=15Hz),7.80(2H,d,J=8Hz)
(3)4-〔N,N-二(2-甲氧基乙基)氨基甲酰基〕肉桂酸甲酯
NMR(CDCl3,δ):3.21-3.86(17H),6.48(1H,d,
J=15Hz),7.44(1H,d,J=9Hz),7.57(1H,d,
J=9Hz),7.70(1H,d,J=15Hz)
制备32
按照与制备8相类似的方法通过将4-氨基肉桂酸乙酯与异氰酸甲酯反应制得4-(3-甲基脲基)肉桂酸乙酯。
mp:166℃
NMR(DMSO-d6,δ):1.25(3H,t,J=7.5Hz),2.64(3H,
d,J=5Hz),4.17(2H,q,J=7.5Hz),6.12(1H,q,
J=5Hz),6.43(1H,d,J=16Hz),7.45(2H,d,
J=8Hz),7.56(1H,d,J=16Hz),7.59(2H,d,
J=8Hz),8.81(1H,s)
制备33
在室温下向4-丙酰氨基肉桂酸乙酯(160mg)在乙醇(5ml)中的溶液加入1N氢氧化钠水溶液(1.5ml)。混合物在同样温度下搅拌14小时,然后在40℃搅拌2小时。向反应混合物中加入1N盐酸(1.5ml)和真空蒸发。剩余物用10%甲醇-二氯甲烷稀释,用水洗,硫酸镁干燥和真空蒸发。剩余物从二异丙基醚中结晶,产生无色粉状4-丙酰氨基肉桂酸(115mg)。mp:243℃NMR(DMSO-d6,δ):1.08(3H,t,J=8Hz),2.34(2H,q,
J=8Hz),6.39(1H,d,J=16Hz),7.51(1H,d,
J=16Hz),7,62(4H,s-like),10.07(1H,s)
制备34
按照与制备33相类似的方法制得下列化合物。
(1)4-(N-甲基丙酰氨基)肉桂酸mp:168℃NMR(DMSO-d6,δ):0.93(3H,t,J=8Hz),2.11(2H,
dif-q),3.16(3H,s),6.55(1H,d,J=16Hz),7.37
(2H,d,J=8Hz),7.61(1H,d,J=16Hz),7.76(2H,
d,J=8Hz)
(2)4-(N-乙基乙酰氨基)肉桂酸mp:203.5℃NMR(DMSO-d6,δ):1.01(3H,t,J=7.5Hz),1.78(3H,
br s),3.67(2H,q,J=7.5Hz),6.57(1H,d,
J=16Hz),7.33(2H,d,J=8Hz),7.62(1H,d,
J=16Hz),7.78(2H,d,J=8Hz)
(3)4-(2-吡啶基甲氧基)肉桂酸mp:208℃NMR(DMSO-d6,δ):5.23(2H,s),6.38(1H,d,
J=16Hz),7.06(2H,d,J=8Hz),7.35(1H,dd,J=8,
5Hz),7.51(1H,d,J=8Hz),7.53(1H,d,J=16Hz),
7.64(2H,d,J=8Hz),7.83(1H,td,J=8,1Hz),
8.58(1H,dif-dd,J=5Hz)
(4)4-〔2-(N,N-二甲基氨基)乙氧基〕肉桂酸
mp:187℃
NMR(DMSO-d6,δ):2.23(6H,s),2.66(2H,t,
J=6Hz),4.12(2H,t,J=6Hz),6.38(1H,d,
J=16Hz),6.97(2H,d,J=8Hz),7.51(1H,d,
J=16Hz),7.62(1H,d,J=8Hz)
(5)4-(2-羟基乙氧基)肉桂酸mp194℃NMR(DMSO-d6,δ):3.64-3.79(2H,br peak),4.02
(2H,t,J=6Hz),4.90(1H,br peak),6.37(1H,d,
J=16Hz),6.98(2H,d,J=8Hz),7.54(1H,d,
J=16Hz),7.63(2H,d,J=8Hz)
(6)4-(甲基氨基甲酰基)肉桂酸
mp:>250℃
NMR(DMSO-d6,δ):2.78(3H,d,J=5Hz),6.62(1H,d,
J=16Hz),7.61(1H,d,J=16Hz),7.77(2H,d,
J=8Hz),7.85(2H,d,J=8Hz),8.51(1H,q-like)
(7)4-(N,N-二甲基氨基甲酰基)肉桂酸
mp:82℃
NMR(DMSO-d6,δ):2.93(3H,s),2.97(3H,s),6.59
(1H,d,J=16Hz),7.43(2H,d,J=8Hz),7.61(1H,
d,J=16Hz),7.75(2H,d,J=8Hz)
(8)4-(3-甲基脲基)肉桂酸
mp:234℃
NMR(DMSO-d6,δ):2.64(3H,d,J=5Hz),6.12(1H,q,
J=5Hz),6.33(1H,d,J=16Hz),7.44(2H,d,
J=8Hz),7.51(1H,d,J=16Hz),7.55(2H,d,
J=8Hz),8.78(1H,s)
(9)4-〔N-(2-甲氧基乙基)氨基甲酰基〕肉桂酸
mp:207-209℃
NMR(DMSO-d6,δ):3.20-3.50(7H),6.63(1H,d,
J=15Hz),7.62(1H,d,J=15Hz),7.79(2H,d,
J=8Hz),7.89(2H,d,J=8Hz),8.61(1H,br s)
(10)4-〔N,N-二(2-甲氧基乙基)氨基甲酰基〕肉桂酸
NMR(CDCl3,δ):3.21-3.86(17H),6.48(1H,d,
J=15Hz),7.44(2H,d,J=9Hz),7.57(2H,d,
J=9Hz),7.70(1H,d,J=15Hz)
制备35
在氮气氛冰冷却下向4-氨基肉桂酸乙酯(150mg)和三乙胺(94mg)在二氯甲烷(3ml)中的溶液加入甲磺酰氯(0.08ml),并将混合物在室温下搅拌2小时。反应混合物倒入水中,并用二氯甲烷萃取二次,合并的有机层用水洗,硫酸镁干燥和浓缩,产生的剩余物包括4-甲磺酰基氨基肉桂酸乙酯和4-(N,N-二甲磺酰基氨基)肉桂酸乙酯。将剩余物溶于乙醇,再于40℃下加入1N氢氧化钠水溶液(1.5ml)。混合物在室温下搅拌2天,再加入1N盐酸(1.5ml)。混合物在真空下浓缩,将剩余物分配于10%甲醇-二氯甲烷和水之间。有机层用水洗,硫酸镁干燥和真空浓缩,剩余物用制备性薄层色谱(二氯甲烷-甲醇,10∶1,V/V)纯化,产生4-甲磺酰基氨基肉桂酸(49.3mg)。
mp:218℃
NMR(DMSO-d6,δ):3.05(3H,s),6.44(1H,d,
J=16Hz),7.21(2H,d,J=8Hz),7.53(1H,d,
J=16Hz),7.66(2H,d,J=8Hz)
制备36
在搅拌下于室温向N-甲基乙醇胺(600mg)在N,N-二甲基甲酰胺中的溶液加入咪唑(1.13g)和叔丁基二苯基甲硅烷基氯(2.20g)。8小时后,混合物用水(60ml)稀释和用乙酸乙酯(20ml)萃取两次。有机层用水洗三次和用盐水洗,用硫酸镁干燥,用真空法除去溶剂。剩余物用柱色谱以二氯甲烷-甲醇洗脱进行纯化,产生油状的N-(2-叔丁基二苯基甲硅烷氧基乙基)-N-甲基胺(780mg)。
NMR(CDCl3,δ):1.06(9H,s),2.43(3H,s),2.72
(2H,t,J=5Hz),3.78(2H,t,J=5Hz),7.32-7.49
(6H),7.61-7.71(4H)
制备37
将4-氯-8-(2,6-二氯-3-硝基苄氧基)-2-甲基喹啉(200mg)和N,N-二甲基甲酰胺(3ml)的混合物加热回流18小时。将反应混合物分配于乙酸乙酯和碳酸氢钠饱和水溶液中。有机层用水洗,硫酸镁干燥和真空蒸发。剩余物用制备性薄层色谱(二氯甲烷-甲醇)进行纯化,产生淡棕色粉状的8-羟基-2-甲基-4-二甲基氨基喹啉(26mg)。
NMR(CDCl3,δ):2.62(3H,s),3.03(6H,s),5.29
(1H,br s),6.63(1H,s),7.07(1H,d,J=8Hz),
7.28(1H,t,J=8Hz),7.46(1H,d,J=8Hz)
制备38
在氮气氛下于冰水浴中向搅拌着的3,4-二甲氧基苄醇(1.68g)在1,3-二甲基-2-咪唑啉酮(10ml)中的溶液分批加入氢化钠(油中含60%,400mg)。将混合物搅拌30分钟,然后再加入4-氯-8-羟基-2-甲基喹啉(770mg)。反应混合物在150℃搅拌3小时并冷却至室温,随后分配于乙酸乙酯和水中,有机层用水洗两次,硫酸镁干燥和真空蒸发。剩余物用乙醚洗,产生浅黄色粉状8-羟基-4-(3,4-二甲氧基苄氧基)-2-甲基喹啉(812mg)。mp:129-131℃NMR(CDCl3,δ):2.67(3H,s),3.91(6H,s),5.20
(2H,s),6.71(1H,s),6.91(1H,d,J=8Hz),7.02
(1H,s),7.06(1H,d,J=8Hz),7.12(1H,d,
J=8Hz),7.3 2(1H,t,J=8Hz),7.60(1H,d,J=8Hz)
制备39
将4-氯-8-羟基-2-甲基喹啉(9g),1,3-二甲基-2-咪唑啉酮(100ml)和28%的甲醇钠的甲醇溶液(135ml)的混合物在150℃搅拌4小时。反应混合物冷却至室温,随后分配于乙酸乙酯和水中。有机层用水洗、盐水洗,硫酸镁干燥和真空浓缩。剩余的结晶用正己烷洗,产生8-羟基-4-甲氧基-2-甲基喹啉(5.57g)。
mp:110.5-112℃
NMR(CDCl3,δ):2.67(3H,s),4.01(3H,s),6.63
(1H,s),7.11(1H,d,J=8Hz),7.31(1H,t,
J=8Hz),7.56(1H,d,J=8Hz)
制备40
按照与制备38或39相似的方法制得下列化合物。
(1)4-乙氧基-8-羟基-2-甲基喹啉mp:85-86℃NMR(CDCl3,δ):1.56(3H,t,J=6Hz),2.66(3H,s),
4.23(2H,q,J=6Hz),6.60(1H,s),7.10(1H,d,
J=8Hz),7.31(1H,t,J=8Hz),7.60(1H,d,J=8Hz)
(2)8-羟基-2-甲基-4-甲硫基喹啉mp:98-99℃NMR(CDCl3,δ):2.60(3H,s),2.70(3H,s),7.00
(1H,s),7.13(1H,d,J=8Hz),7.38(1H,t,
J=8Hz),7.50(1H,d,J=8Hz)
(3)8-羟基-4-(2-甲氧基乙氧基)-2-甲基喹啉NMR(CDCl3,δ):2.40(3H,s),3.52(3H,s),3.91
(2H,t,J=6Hz),4.32(2H,t,J=6Hz),6.64(1H,
s),7.12(1H,d,J=8Hz),7.32(1H,t,J=8Hz),
7.62(1H,d,J=8Hz)
(4)8-羟基-2-甲基-4-(2-二甲基氨基乙氧基)喹啉mp:94-96℃NMR(CDCl3δ):2.40(6H,s),2.67(3H,s),2.91
(2H,t,J=6Hz),4.29(2H,t,J=6Hz),6.63(1H,
s),7.12(1H,d,J=8Hz),7.31(1H,t,J=8Hz),
7.59(1H,d,J=8Hz)
制备41
按照与制备39相类似的方法将2-氯-8-羟基喹啉与甲醇钠反应制得8-羟基-2-甲氧基喹啉。mp:40-41℃NMR(CDCl3,δ):4.09(3H,s),6.94(1H,d,J=8Hz),
7.17(1H,dd,J=8,3Hz),7.20-7.36(2H),7.60
(1H,s),8.00(1H,d,J=8Hz)
实施例1
在冰水浴中向氢化钠(油中含40%,24mg)和N,N-二甲基甲酰胺(1ml)的混合物中加入8-羟基-2-甲基喹啉(80mg)。混合物在同样温度下搅拌30分钟,然后向其中加入2,6-二氯苄基溴(120mg)。反应混合物在室温下搅拌1小时。在冰水浴中向该混合物中加入水(0.5ml)。用真空过滤法收集沉淀并用水(3ml)洗,产生8-(2,6-二氯苄氧基)-2-甲基喹啉(117mg)白色粉末。NMR(CDCl3,δ):2.76(3H,s),5.62(2H,s),
7.18-7.47(7H),8.01(1H,d,J=8Hz)
实施例2
按照与实施例1相似的方法合成下列化合物。
(1)8-(2,6-二氯-3-硝基苄氧基)-2-甲基喹啉
NMR(CDCl3,δ):2.76(3H,s),5.70(2H,s),
7.21-7.57(5H),7.76(1H,d,J=8Hz),8.02(1H,
d,J=8Hz)
(2)4-氯-8-(2,6-二氯-3-硝基苄氧基)-2-甲基喹啉
NMR(CDCl3,δ):2.70(3H,s),5.67(2H,s),
7.23-7.92(6H)
(3)2-乙基-4-氯-8-〔2,6-二氯-3-〔N-甲基-N-(苯二甲酰亚氨基乙酰基)氨基〕苄氧基〕喹啉
mp:109-110℃
NMR(CDCl3,δ):1.40(3H,t,J=7Hz),3.00(2H,q,
J=7Hz),3.24(3H,s),4.04(2H,s),5.72(2H,
s),7.31-7.58(5H),7.69-7.91(5H)
(4)2-乙基-8-〔2,6-二氯-3-〔N-甲基-N-(苯二甲酰亚氨基乙酰基)氨基〕苄氧基.〕喹啉
mp:115-116℃
NMR(CDCl3,δ):1.40(3H,t,J=7Hz),3.01(2H,q,
J=7Hz),3.22(3H,s),4.04(2H,s),5.78(2H,
s),7.25-7.59(6H),7.70-7.91(4H),8.06(1H,d,
J=9Hz)
实施例3
向8-(2,6-二氯-3-硝基苄氧基)-2-甲基喹啉(1.0g),浓盐酸(5.2ml)和甲醇(5.2ml)的混合物中加入铁粉(666mg)。将混合物加热回流2小时和在冰水浴中搅拌1小时。用真空过滤法收集沉淀和用1N盐酸洗,水洗,产生8-(3-氨基-2,6-二氯苄氧基)-2-甲基喹啉二盐酸盐(635mg)淡棕色粉末。NMR(DMSO-d6,δ):2.93(3H,s),5.50(2H,s),6.98
(1H,d,J=8Hz),7.23(1H,d,J=8Hz),7.80-8.02
(4H),9.03(1H,d,J=8Hz)
实施例4
按照与实施例3相似的方法制得8-(3-氨基-2,6-二氯苄氧基)-4-氯-2-甲基喹啉二盐酸盐
NMR(DMSO-d6,δ):2.61(3H,s),5.30-5.45(2H),
6.80-7.26(2H),7.50-7.95(4H)
实施例5
在室温下向8-(3-氨基-2,6-二氯苄氧基)-2-甲基喹啉二盐酸盐(4.06g),4-二甲基氨基吡啶(120mg),N-甲基吡咯烷酮(30ml)和吡啶(10ml)的混合物中加入苯二甲酰亚氨基乙酰氯(3.35g)。混合物在50℃下搅拌1.5小时和在冰水浴中冷却。向混合物中加入水(40ml)和混合物在冰水浴中搅拌30分钟。用真空过滤收集沉淀和用水洗、乙酸乙酯洗,产生8-〔2,6-二氯-3-(苯二甲酰亚氨基乙酰基氨基)苄氧基〕-2-甲基喹啉(4.45g)淡黄色粉末。NMR(CDCl3,δ):2.86(3H,s),4.74(2H,s),5.51
(2H,s),7.20-7.50(5H),7.63-7.93(4H),8.03
(1H,d,J=8Hz),8.29(1H,d,J=8Hz)
实施例6
按照与实施例5相似的方法制得4-氯-8-〔2,6-二氯-3-(苯二甲酰亚氨基乙酰基氨基)苄氧基〕-2-甲基喹啉。
NMR(DMSO-d6,δ):2.60(3H,s),4.56(2H,s),5.48
(2H,s),7.48-8.02(10H)
实施例7
在冰水浴中向8-〔2,6-二氯-3-(苯二甲酰亚氨基乙酰基氨基)苄氧基〕-2-甲基喹啉(4.44g)和N,N-二甲基甲酰胺(44ml)的混合物中加入氢化钠(油中含60%,375mg)。在冰水浴中搅拌30分钟后,再加入碘甲烷(0.6ml)并将混合物在室温下搅拌1小时。在冰水浴中向该混合物中加入水(88ml)并将混合物在同样温度下搅拌1.5小时。用真空过滤收集沉淀和用水洗、甲醇洗,产生8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉(3.99g)黄色粉末。
NMR(CDCl3,δ):2.76(3H,s),3.23(3H,s),4.08
(2H,s),5.68(1H,d,J=12Hz),5.75(1H,d,
J=12Hz),7.24-7.59(6H),7.66-7.91(4H),8.03
(1H,d,J=8Hz)
实施例8
按照与实施例7相似的方法制得4-氯-8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉。
NMR(CDCl3,δ):2.72(3H,s),3.23(3H,s),4.06
(2H,s),5.66(1H,d,J=12Hz),5.73(1H,d,
J=12Hz),7.30-7.92(10H)
实施例9
将8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉(3.98g)、肼单水合物(0.72ml)和乙醇(40ml)的混合物加热回流1小时。真空过滤除去沉淀和将滤液真空蒸发。用二氯甲烷溶解剩余物和用真空过滤除去沉淀,将滤液真空蒸发,产生8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(2.99g)黄色无定形粉末。NMR(CDCl3,δ):2.76(3H,s),2.96(1H,d,J=16Hz),
3.10(1H,d,J=16Hz),3.21(3H,s),5.66(2H,
s),7.20-7.50(6H),8.02(1H,d,J=8Hz)
实施例10
按照与实施例9相似的方法制得下列化合物。
(1)8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-4-氯-2-甲基喹啉
NMR(CDCl3,δ):2.72(3H,s),2.96(1H,d,J=16Hz),
3.15(1H,d,J=16Hz),3.21(3H,s),5.63(2H
s),7.22-7.55(5H),7.88(1H,d,J=8Hz)
(2)8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-4-氯-2-乙基喹啉
mp:161-164℃
NMR(CDCl3,δ):1.40(3H,t,J=7Hz),2.89-3.09
(4H),3.20(3H,s),5.70(2H,s),7.19-7.52
(5H),7.88(1H,t,J=9Hz)
(3)8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-乙基喹啉
mp:125-128℃
NMR(CDCl3,δ):1.40(3H,t,J=7Hz),2.89-3.14
(4H),3.20(3H,s),5.71(2H,s),7.20-7.51
(6H),8.06(1H,d,J=9Hz)
实施例11
在冰水浴中向8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(100mg)在二氯甲烷(2ml)中的溶液中加入异氰酸乙酯(0.04ml)。混合物在相同温度下搅拌30分钟,然后真空蒸发。剩余物用制备性薄层色谱(乙酸乙酯-甲醇)进行纯化,产生8-〔2,6-二氯-3-〔N-(N′-乙基脲基乙酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉(115mg)白色无定形粉末。NMR(CDCl3,δ):1.02(3H,t,J=7Hz),2.69(3H,s),
3.10(2H,m),3.23(3H,s),3.82(2H,t,J=4Hz),
5.18(1H,m),5.52(1H,d,J=12Hz),5.68(1H,d,
J=12Hz),7.20-7.50(6H),8.04(1H,d,J=8Hz)
实施例12
在室温下向搅拌着的N,N′-羰基二咪唑(78.2mg)在1,4-二噁烷(1ml)中的溶液中加入3-乙酰氨基苯胺(72mg)在1,4-二噁烷(2ml)中的溶液并将该溶液在相同温度下搅拌21小时。在室温下再加入8-〔2,6-二氯-3-(N-甘氨酰-N-甲基氨基)苄氧基〕-2-甲基喹啉(150mg)和将产生的混合物在110℃加热6.5小时。再加入二甲基亚砜(0.5ml)并将产生的溶液在110℃搅拌5小时。冷却后,将混合物真空浓缩,剩余物用制备性薄层色谱(甲醇-氯仿,10%,V/V)进行纯化,产生8-〔2,6-二氯-3-〔N,〔N′-(3-乙酰氨基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉(75mg)浅黄色无定形固体。NMR(CDCl3,δ):1.99(3H,s),2.62(3H,s),3.16
(3H,s),3.79(1H,dd,J=20,4Hz),3.91(1H,dd,
J=20,5Hz),5.22(2H,s),6.07(1H,br t),
6.93-7.13(2H,m),7.16-7.37(5H,m),7.39-7.56
(3H,m),8.06(1H,d,J=9Hz),8.40(1H,br s),
9.00(1H,br s)
实施例13
在室温下向搅拌着的8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(100mg)和三乙胺(68μ1)在二氯甲烷(2ml)中的混合物加入氯甲酸4-硝基苯基酯(55mg)并将混合物在相同温度下搅拌2.5小时。将混合物用氯仿稀释并用饱和碳酸氢钠溶液洗。用硫酸镁干燥后,真空除去溶剂以产生黄色无定形固体,该固体包括8-〔2,6-二氯-3-〔N-甲基-N-(4-硝基苯氧基羰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉。将该固体溶于无水二噁烷(2ml)中和在室温下向该溶液加入3-氨基苯甲酸乙酯(45mg)。该混合物在100℃搅拌18小时。冷却和真空浓缩后,剩余物用快速色谱以乙酸乙酯-己烷(2∶1,然后4∶1,V/V)洗脱进行纯化,产生8-〔2,6-二氯-3-〔N-〔N′-(3-乙氧基羰基苯基)-脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉(107mg)无定形固体。NMR(CDCl3,δ):1.24(3H,t,J=7.5Hz),2.60(3H,
s),3.23(3H,s),3.81(1H,dd,J=17.5,5Hz),
4.24(2H,q,J=7.5Hz),4.3 4(1H,dd,J=17.5,and
7Hz),5.43(1H,d,J=10Hz),5.56(1H,dd,J=7
5Hz),5.62(1H,d,J=10Hz),7.12-7.37(5H,m)
7.41-7.54(3H,m),7.60(1H,dt,J=7.5,0.5Hz),
7.82(1H,t,J=0.5Hz),8.09(1H,d,J=7.5Hz),
8.55(1H,br s)
实施例14
按照与实施例11~13相似的方法制得下列化合物。
(1)8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.40(3H,s),2.62(3H,s),3.23
(3H,s),3.83(1H,dd,J=17,4Hz),4.37(1H,dd,
J=17,6Hz),5.47(1H,d,J=12Hz),5.60(1H,m),
5.65(1H,d,J=12Hz),7.17-7.58(9H),7.82(1H,
t,J=1Hz),8.10(1H,d,J=8Hz),8.71(1H,s)
(2)8-〔3-〔N-〔N ′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-4-氯-2-甲基喹啉NMR(CDCl3,δ):2.46(3H,s),2.62(3H,s),3.23
(3H,s),3.82(1H,dd,J=17,4Hz),4.26(1H,dd,
J=17,6Hz),5.49(1H,d,J=12Hz),5.56(1H,m),
5.65(1H,d,J=12Hz),7.17-7.64(9H),7.84(1H,
t,J=1Hz),7.90(1H,d,J=8Hz),8.32(1H,s)
(3)8-〔3-〔N-(N′-苯甲酰基脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:220-221℃NMR(CDCl3,δ):2.70(3H,s),3.26(3H,s),3.70
(1H,dd,J=16,4Hz),4.00(1H,dd,J=16,4Hz),
5.63(2H,s),7.20-7.60(9H),7.83(2H,d,
J=8Hz),8.01(1H,d,J=8Hz),8.87(1H,s),9.20
(1H,t like)
(4)8-〔2,6-二氯-3-〔N-〔N′-戊基脲基乙酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):0.80(3H,t,J=7.5Hz),1,05-1.60
(6H,m),2.70(3H,s),3.07(2H,m),3.25(3H,
s),3.80(2H,d,J=5Hz),5.03-5.28(2H,m),5.53
(1H,d,J=9Hz),5.67(1H,d,J=9Hz),7.16-7.56
(6H,m),8.03(1H,d,J=8Hz)
(5)8-〔2,6-二氯-3-〔N-〔N ′-〔3-(N-甲基-N-乙酰基氨基)-苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.81(3H,s),2.59(3H,s),3.13
(3H,s),3.23(3H,s),3.27(1H,dd,J=18,4Hz),
4.49(1H,dd,J=18,7Hz),5.42(1H,d,J=10Hz),
5.45(1H,m),5.63(1H,dd,J=10Hz),6.69(1H,
dt,J=6,1Hz),7.00-7.16(2H,m),7.17-7.42(5H.
m),7.43-7.56(2H,m),8.11(1H,d,J=8Hz),8.90
(1H,br s)
(6)8-〔2,6-二氯-3-〔N-〔N′-(3-二甲基氨基苯基)-脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.66(3H,s),2.82(6H,s),3.22
(3H,s),3.81(1H,dd,J=17,5Hz),4.05(1H,dd,
J=17,5Hz),5.51(1H,d,J=10Hz),5.61-5.70
(2H),6.89(1H,dd,J=9,1Hz),6.51(1H,d,
J=9Hz),6.74(1H,t,J=1Hz),7.05(1H,t,
J=9Hz),7.20-7.49(6H),7.56(1H,s),8.06(1H,
d,J=9Hz)
(7)8-〔2,6-二氯-3-〔N-〔N′-〔3-( N′-甲基脲基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.6 3(3H,s),2.71(3H,s),
3.19(3H,s),3.68(1H,d,J=17Hz),3.89(1H,d,
J=17Hz),5.51(2H,s),6.82(1H,d,J=7Hz),
6.96-7.50(9H),8.07(1H,d,J=9Hz)
(8)8-〔2,6-二氯-3-〔N-甲基-N-〔N ′-(3-硝基苯基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,6):2.60(3H,s),3.22(3H,s),3.81
(1H,dd,J=17,5Hz),4.43(1H,dd,J=17,8Hz),
5.42(1H,d,J=10Hz),5.56-5.69(2H),7.13-7.57
(8H),7.71(1H,dd,J=8,1Hz),8.12(1H,d,
J=8Hz),8.20(1H,t,J=1Hz),9.33(1H,br s)
(9)8-〔3-〔N-〔N′-(4-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.50(3H,s),2.59(3H,s),3.22
(3H,s),3.80(1H,dd,J=17,4Hz),4.42(1H,dd,
J=17,8Hz),5.45(1H,d,J=10Hz),5.56-5.69
(2H),7.20-7.40(6H),7.46-7.59(2H),7.73(2H,
d,J=9Hz),8.12(1H,d,J=9Hz),9.09(1H,s)
(10)8-〔2,6-二氯-3-〔N-甲基-N-(N′-苯基脲基乙酰基)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.62(3H,s),3.21(3H,s),3.80
(1H,dd,J=17,5Hz),4.20(1H,dd,J=17,6Hz),
5.48(1H,d,J=10Hz),5.56-5.69(2H),6.91(1H,
t,J=7Hz),7.10-7.37(8H),7.48(2H,d,J=5Hz),
8.09(1H,d,J=9Hz),8.12(1H,s)
(11)8-〔3-〔N-(N'-苄基脲基乙酰基)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.61(3H,s),3.17(3H,s),3.81
(2H,d,J=5Hz),4.19(1H,dd,J=17,5Hz),4.84
(1H,dd,J=17,5Hz),5.31(1H,br t,J=5Hz),
5.52(1H,d,J=9Hz),5.60-5.73(2H),7.10-7.52
(11H),8.01(1H,d,J=9Hz)
(12)8-〔2,6-二氯-3-〔N-〔N ′-(3-乙氧基羰基氨基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉mp:233-235℃NMR(CDCl3-CD3OD,δ):1.30(3H,t,J=7Hz),2.69
(3H,s),3.25(3H,s),3.64(1H,d,J=17Hz),
3.90(1H,d,J=17Hz),4.19(2H,q,J=7Hz),5.56
(2H,s),6.01(1/3H,t,J=5Hz),6.89(1H,d,
J=8Hz),7.06-7.56(9H),7.97(1/3H,br s),8.09
(1H,d,J=9Hz)
(13)8-〔2,6-二氯-3-〔N-〔N ′-(1-萘基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),3.17(3H,s),3.68
(1H,dd,J=17,5Hz),3.89(1H,dd,J=17,5Hz),
5.54(1H,d,J=10Hz),5.62(1H,d,J=10Hz),5.93
(1H,br t,J=5Hz),7.12-7.52(10H),7.70(2H,d,
J=9Hz),7.83(1H,d,J=9Hz),7.91-8.08(2H)
(14)8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-4-氯-2-乙基喹啉
NMR(CDCl3,δ):1.27(3H,t,J=7Hz),2.47(3H,s),
2.89(2H,q,J=7Hz),3.24(3H,s),3.82(1H,dd,
J=17,5Hz),4.12(1H,dd,J=17,6Hz),5.52(1H,
d,J=10Hz),5.61-5.7 2(2H),7.18-7.69(8H),
7.81-7.93(2H),8.19(1H,br s)
(15)8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基)-2,6-二氯苄氧基〕-2-乙基喹啉NMR(CDCl3,δ):1.21(3H,t,J=7Hz),2.40(3H,s),
2.90(2H,q,J=7Hz),3.22(3H,s),3.8 2(1H,dd,
J=17,5Hz),4.31(1H,dd,J=17,6Hz),5.50(1H,
d,J=10Hz),5.58(1H,m),5.69(1H,d,J=10Hz),
7.15-7.54(9H),7.82(1H,t,J=1Hz),8.12(1H,
d,J=9Hz),8.51(1H,s)
实施例15
在冰水浴中向8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(100mg)、三乙胺(50mg)和二氯甲烷(2.0ml)的混合物中加入庚酰氯(0.05ml)。混合物在同样温度下搅拌30分钟和用水洗。收集有机层,用硫酸镁干燥和真空蒸发。剩余物用制备性薄层色谱(二氯甲烷-甲醇)进行纯化,产生浅黄色油状的8-〔2,6-二氯-3-〔N-(庚酰基甘氨酰)-N-甲基氨基〕-苄氧基〕-2-甲基喹啉(130mg)。NMR(CDCl3,δ):0.88(3H,t,J=7Hz),1.20-1.40(4H),
1.53-1.80(4H),2.22(2H,t,J=7Hz),2.76(3H,
s),3.26(3H,s),3.50(1H,dd,J=17,4Hz),3.83
(1H,dd,J=17,6Hz),5.64(2H,s),6.41(1H,
t-like),7.22-7.52(6H),8.03(1H,d,J=8Hz)
实施例16
向8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(81mg〕,4-苯基丁酸(40mg)和二甲基甲酰胺(2ml)的混合物中加入1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(50mg)和1-羟基苯并三唑(41mg)。在室温下搅拌1小时后,将混合物倒入水中并用乙酸乙酯萃取。分出有机层,水洗,硫酸镁干燥和真空蒸发。剩余物用制备性薄层色谱(二氯甲烷-甲醇)进行纯化,产生8-〔2,6-二氯-3-〔N-甲基-N-(4-苯基丁酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉(105mg)无色玻璃体。NMR(CDCl3,δ):1.95(2H,m),2.23(2H,t,J=7Hz),
2.64(2H,t,J=7Hz),2.74(3H,s),3.23(3H,s),
3.48(1H,dd,J=18,4Hz),3.82(1H,dd,J=18,
4Hz),5.63(2H,s),6.39(1H,t-like),7.11-7.51
(11H),8.03(1H,d,J=8Hz)
实施例17
按照与实施例15或16相似的方法制得下列化合物。
(1)8-〔2,6-二氯-3-〔N-甲基-N-(苯基乙酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.20(3H,s),3.43
(1H,dd,J=17,4Hz),3.59(2H,s),3.80(1H,dd,
J=17,5Hz),5.63(2H,s),6.38(1H,t-like),
7.18-7.50(11H),8.01(1H,d,J=8Hz)
(2)8-〔2,6-二氯-3-〔N-甲基-N-(3-苯基丙酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.53(2H,t,J=7Hz),2.73(3H,s),
2.94(2H,t,J=7Hz),3.23(3H,s),3.46(1H,dd,
J=17,4Hz),3.80(1H,dd,J=17,5Hz),5.66(2H,
s),6.38(1H,t-like),7.12-7.52(11H),8.03
(1H,d,J=8Hz)
(3)8-〔2,6-二氯-3-〔N-甲基-N-(苯氧基乙酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.26(3H,s),3.58
(1H,dd,J=17,4Hz),3.90(1H,dd,J=17,5Hz),
4.50(2H,s),5.66(2H,s),6.89-7.08(3H),
7.20-7.58(9H),8.03(1H,d,J=8Hz)
(4)8-〔2,6-二氯-3-〔N-甲基-N-萘甲酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.75(3H,s),3.30(3H,s),3.77
(1H,dd,J=16,4Hz),4.08(1H,dd,J=16,5Hz),
5.68(2H,s),7.23-7.63(9H),7,82-7.98(4H),
8.03(1H,d,J=8Hz),8.33(1H,s)
(5)8-〔3-〔N-(肉桂酰甘氨酰)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.73(3H,s),3.26(3H,s),3.65
(1H,dd,J=17.5,4Hz),3.85(1H,dd,J=17.5,
5Hz),5.65(2H,s),6.48(1H,d,J=20Hz),6.65
(1H,br t),7.19-7.53(11H,m),7.57(1H,d,
J=20Hz),8.02(1H,d,J=8Hz)
(6)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-(2-噻吩基)-丙烯酰基甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.27(3H,s),3.63
(1H,dd,J=16,4Hz),3.94(1H,dd,J=16,5Hz),
5.64(2H,s),6.29(1H,d,J=15Hz),6.59(1H,
t-like),7.02(1H,dd,J=5,4Hz),7.16-7.54
(8H),
7.70(1H,d,J=15Hz),8.03(1H,d,J=8Hz)
(7)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-(3-噻吩基)-丙烯酰基甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.24(3H,s),3.63
(1H,dd,J=18,4Hz),3.95(1H,dd,J=18,5Hz),
5.63(2H,s),6.30(1H,d,J=15Hz),6.60(1H,
t-like),7.18-7.63(10H),8.02(1H,d,J=8Hz)
(8)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-(3-吡啶基)-丙烯酰基甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.72(3H,s),3.27(3H,s),3.67
(1H,dd,J=17,4Hz),3.95(1H,dd,J=17,5Hz),
5.65(2H,s),6.57(1H,d,J=15Hz),6.77(1H,
t-like),7.21-7.64(8H),7.80(1H,dt,J=8,
1Hz),8.03(1H,d,J=8Hz),8.57(1H,dd,J=5,
1Hz),8.72(1H,d,J=1Hz)
(9)8-〔2,6-二氯-3-〔N-甲基-N-(苯基乙二酰甘氨酰)氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.77(3H,s),3.29(3H,s),3.63
(1H,dd,J=17,4Hz),3.94(1H,dd,J=17,5Hz),
5.68(2H,s),7.21-7.68(9H),7.78(1H,t-like),
8.04(1H,d,J=8Hz),8.23-8.35(2H)
(10)8-〔2,6-二氯-3-〔N-甲基-N-(N-苯基甘氨酰甘氨酰)氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.66(3H,s),3.20(3H,s),3.61
(1H,dd,J=17,5Hz),3.73-3.86(2H),3.89(1H,
dd,J=17,5Hz),4.58(1H,t-like),5.62(2H,s),
6.58(2H,d,J=8Hz),6.78(1H,t,J=8Hz),
7.11-7.53(9H),8.02(1H,d,J=8Hz)
(11)8-〔2,6-二氯-3-〔N-甲基-N-(1-萘基乙酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),3.13(3H,s),3.35
(1H,dd,J=16,4Hz),3.74(1H,dd,J=16,5Hz),
4.03(2H,s),5.61(2H,s),6.29(1H,t-like),
7.16-7.59(10H),7.77-8.03(4H)
(12)8-〔2,6-二氯-3-〔N-甲基-N-(2-萘基乙酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.71(3H,s),3.17(3H,s),3.43
(1H,dd,J=16,4Hz),3.73(2H,s),3.81(1H,dd,
J=16,5Hz),5.62(2H,s),6.4l(1H,t-like),
7.14-7.55(9H),7.70-7.90(4H),8.00(1H,d,
J=8Hz)
(13)8-〔2,6-二氯-3-〔N-甲基-N-(苯氧基羰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.73(3H,s),3.26(3H,s),3.52
(1H,dd,J=17,4Hz),3.83(1H,dd,J=17,5Hz),
5.66(2H,s),5.90(1H,t-like),7.05-7.54
(11H),8.03(1H,d,J=8Hz)
(14)8-〔2,6-二氯-3-〔N-甲基-N-(2-硝基肉桂酰甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.74(3H,s),3.28(3H,s),3.67
(1H,dd,J=16,4Hz),3.95(1H,dd,J=16,5Hz),
5.65(2H,s),6.42(1H,d,J=15Hz),6.79(1H,
t-like),7.20-7.67(9H),7.92-8.08(3H)
(15)8-〔2,6-二氯-3-〔N-甲基-N-(3-硝基肉桂酰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.72(3H,s),3.28(3H,s),3.69
(1H,dd,J=16,4Hz),3.97(1H,dd,J=16,5Hz),
5.66(2H,s),6.63(1H,d,J=15Hz),6.80(1H,
t-like),7.22-7.57(7H),7.62(1H,d,J=15Hz),
7.79(1H,d,J=8Hz),8.04(1H,d,J=8Hz),8.20
(1H,d,J=8Hz),8.36(1H,t,J=1Hz)
(16)8-〔2,6-二氯-3-〔N-甲基-N-(4-硝基肉桂酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.73(3H,s),3.28(3H,s),3.70
(1H,dd,J=16,4Hz),3.97(1H,dd,J=16,5Hz),
5.66(2H,s),6.62(1H,d,J=15Hz),6.82(1H,
t-like),7.21-7.70(9H),8.03(1H,d,J=8Hz),
8.21(2H,d,J=8Hz)
(17)8-〔2,6-二氯-3-〔N-(2-甲氧基肉桂酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.27(3H,s),3.63
(1H,dd,J=16,4Hz),3.87(3H,s),3.96(1H,dd,
J=16,4Hz),5.65(2H,s),6.61(1H,d,J=15Hz),
6.62(1H,t-like),6.87-7.01(2H),7.21-7.55
(8H),7.81(1H,d,J=15Hz),8.03(1H,d,J=8Hz)
(18)8-〔2,6-二氯-3-〔N-(3-甲氧基肉桂酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.26(3H,s),3.66
(1H,dd,J=16,4Hz),3.81(3H,s),3.96(1H,dd,
J=16,4Hz),5.66(2H,s),6.48(1H,d,J=15Hz),
6.67(1H,t-like),6.90(1H,dd,J=8,2Hz),7.10
(1H,s),7.10(1H,d,J=8Hz),7.20-7.61(8H),
8.03(1H,d,J=8Hz)
(19)8-〔2,6-二氯-3-〔N-(4-甲氧基肉桂酰基甘氨酰基)-N-甲基氨基〕)苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.74(3H,s),3.27(3H,s),3.64
(1H,dd,J=16,4Hz),3.82(3H,s),3.96(1H,dd,
J=16,5Hz),5.66(2H,s),6.3 6(1H,d,J=15Hz),
6.60(1H,t-like),6.83-6.94(2H),7.18-7.60
(9H),8.04(1H,d,J=8Hz)
实施例18
在氮气氛下于室温将苯肼(54mg),N,N′-羰基二咪唑(81mg)和1,4-二噁烷(3ml)的混合物搅拌3天。向该混合物中加入8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(121mg)。混合物加热回流1小时。冷却至室温后,将混合物倒入水中和用二氯甲烷萃取。有机层用硫酸镁干燥和真空蒸发。剩余物用制备性薄层色谱(二氯甲烷-甲醇)进行纯化,产生8-〔2,6-二氯-3-〔N-甲基-N-(N′-苯胺基脲基乙酰基)氨基〕苄氧基〕-2-甲基喹啉(143mg)无定形粉末。
NMR(CDCl3,δ):2.60(3H,s),3.20(3H,s),3.72
(1H,dd,J=16,5Hz),3.88(1H,dd,J=16,5Hz),
5.62(2H,s),5.98(1H,s),6.34(1H,t-like),
6.46(1H,s),6.68-7.52(11H),8.00(1H,d,
J=8Hz)
实施例19
在冰水浴下向8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(81mg)和三乙胺(0.04ml)在二氯甲烷(2ml)中的溶液加入(E)-苯乙烯磺酰氯(48mg)在二氯甲烷(1ml)中的溶液。在冰冷却下搅拌30分钟后,将反应混合物分配到二氯甲烷和水中。有机层用硫酸镁干燥和真空蒸发。剩余物用制备性薄层色谱(二氯甲烷-甲醇)进行纯化,产生8-〔2,6-二氯-3-〔N-甲基-N-((E)-苯乙烯基磺酰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉(78mg)无定形粉末。
NMR(CDCl3,δ):2.73(3H,s),3.18(3H,s),3.38
(1H,dd,J=16,5Hz),3.54(1H,dd,J=16,5Hz),
5.35(1H,t like),5.60(2H,s),6.70(1H,d,
J=15Hz),7.11-7.52(12H),8.03(1H,d,J=8Hz)
实施例20
在室温下向8-〔2,6-二氯-3-〔N-〔N′-(3-乙氧基羰基苯基)脲基乙酰基〕-N-甲基氨基〕-苄氧基-2-甲基喹啉(97mg)在乙醇(1ml)中的溶液加入1N氢氧化钠溶液(0.179ml)。混合物在相同温度下搅拌3小时和在50℃下搅拌3小时。用1N的盐酸将反应混合物调整至PH=5和向其中加入水(1ml)。用真空过滤法收集沉淀和用水和乙腈洗涤沉淀,产生8-〔3-〔N-〔N ′-(3-羧基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(62mg)结晶。mp:240-241℃NMR(DMSO-d6,δ):2.63(3H,s),3.18(3H,s),3.43
(1H,dd,J=17,5Hz),3.69(1H,dd,J=17,5Hz),
5.49(1H,d,J=10Hz),5.58(1H,d,J=10Hz),
7.27-7.72(8H),7.30(2H,s),8.02(1H,s),8.29
(1H,br s),9.09(1H,s)
实施例21
向8-〔3-〔N-〔N′-(3-羧基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(130mg),吗啉(22μl)和N,N-二甲基甲酰胺(1.5ml)的混合物中加入1-乙基-3-(3-二甲基氨基丙基)碳化二亚胺盐酸盐(58mg)和1-羟基苯并三唑(41mg),混合物在室温下搅拌1小时。将反应混合物用甲醇和氯仿(1∶10,V/V)的混合物稀释,用饱和碳酸氢钠溶液洗和盐水洗,硫酸镁干燥和真空浓缩。剩余物用快速色谱(氯仿-甲醇)进行纯化,产生8-〔2,6-二氯-3-〔N-甲基-N-〔N′-3-(吗啉代羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉(137mg)无色无定形固体。
NMR(CDCl3,δ):2.60(3H,s),3.20(3H,s),
3.25-3.88(8H,m),3.78(1H,dd,J=17.5,5Hz),
4.27(1H,dd,J=17.5,7Hz),5.44(1H,d,
J=10Hz),5.51-5.66(1H,m),5.60(1H,d,
J=10Hz),6.95(1H,dt,J=7.5,0.5Hz),1.16(1H,
t,J=7.5Hz),7.18-7.37(6H,m),7.44-7.54(2H,
m),8.09(1H,d,J=8Hz),8.69(1H,br s)
实施例22
按照与实施例21相似的方法制得下列化合物。
(1)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-甲基-1-哌嗪基羰基)苯基〕脲基乙酰基〕氧基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.06-2.50(4H,m),2.23(3H,s),
2.61(3H,s),3.21(3H,s),3.23-3.81(4H,m),
3.76(1H,dd,J=17.5,5Hz),4.80(1H,dd,
J=17.5,7Hz),5.45(1H,d,J=10Hz),5.56(1H,
dd,J=7,5Hz),5.62(1H,d,J=10Hz),6.95(1H,
br d,J=7.5Hz),7.16(1H,t,J=7.5Hz),7.18-7.39
(6H,m),7.44-7.55(2H,m),8.09(1H,d,J=8Hz),
8.68(1H,br s)
(2)8-〔2,6-二氯-3-〔N-〔N′-〔3-(2-甲氧基乙基-氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.62(3H,s),3.20(3H,s),3.33
(3H,s),3.45-3.66(4H,m),3.83(1H,dd,
J=17.5,4Hz),4.11(1H,dd,J=17.5,6Hz),5.50
(1H,d,J=10Hz),5.65(1H,d,J=10Hz),5.82(1H,
br t,J=4Hz),6.70(1H,m),7.05-7.53(9H,m),
7.61(1H,br s),8.07(1H,d,J=9Hz),8.55(1H,
br s)
(3)8-〔2,6-二氯-3-〔N-〔 N′-〔3-〔N-〔2-(N,N-二甲基氨基)乙基〕-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.73-2.58(10H,m),2.60(3H,s),
2.79-3.10(3H,m),3.22(3H,s),3.58(1H,m),
3.78(1H,dd,J=17,5Hz),4.20(1H,m),5.47
(1H,d,J=10Hz),5.63(1H,d,J=10Hz),5.64(1H,
m),6.95(1H,d,J=6Hz),7.07-7.54(6H,m),7.99
(1H,d,J=8Hz),8.60(1H,m)
(4)8-〔2,6-二氯-3-〔N-〔N′-(3-甲基氨基甲酰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉mp:157-161℃(dec.)NMR(CDCl3,δ):2.62(3H,s),2.90(3H,d,J=5Hz),
3.20(3H,s),3.82(1H,dd,J=18,5Hz),4.00
(1H,dd,J=18,5Hz),5.52(1H,d,J=10Hz),5.64
(1H,d,J=10Hz),5.99(1H,br s),6.68(1H,br
s),7.07-7.51(9H),7.59(1H,br s),8.09(1H,
d,J=9Hz),8.56(1H,br s)
(5)8-〔3-〔N-〔N′-(3-二甲基氨基甲酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.61(3H,s),2.90(3H,br s),3.04
(3H,br s),3.22(3H,s),3.79(1H,dd,J=18,
5Hz),4.20(1H,dd,J=18,6Hz),5.48(1H,d,
J=10Hz),5.59-5.70(2H),6.95(1H,d,J=7Hz),
7.09-7.51(9H),8.09(1H,d,J=9Hz),8.59(1H,
s)
(6)8-〔2,6-二氯-3-〔N-〔N′-〔3-(3-吡啶基甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
mp:204-206℃
NMR(CDCl3-CD3OD,δ):2.66(3H,s),3.26(3H,s),
3.68(1H,d,J=17Hz),3.90(1H,d,J=17Hz),4.60
(2H,s),5.56(2H,s),7.20-7.56(10H),
7.72-7.82(2H),8.09(1H,d,J=9Hz),8.45(1.H,
dd,J=5,lHz),8.53(1H,d,J=1Hz)
(7)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-〔4-(4-吡啶基)-1-哌嗪基羰基〕苯基〕脲基乙酰基〕氨基〕苄氧基-2-甲基喹啉
NMR(CDCl3,δ):2.61(3H,s),3.08-3.91(12H),
4.28(1H,dd,J=17.6Hz),5.46(1H,d,J=10Hz),
5.58-5.70(2H),6.61(2H,br d,J=6Hz),6.99
(1H,d,J=7Hz),7.12-7.50(9H),8.08(1H,d,
J=9Hz),8.30(2H,br d,J=6Hz),8.81(1H,s)
(8)8-〔3-〔N-〔N′-〔3-(4-乙酰基-1-哌嗪基羰基)苯基〕脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR〔CDCl3,δ):2.10(3H,s),2.60(3H,s),3.21
(3H,s),3.23-3.87(9H),4.30(1H,dd,J=17,
6Hz),5.45(1H,d,J=10Hz),5.51-5.69(2H),6.94
(1H,d,J=8Hz),7.10-7.54(9H),8.10(1H,d,
J=9Hz),8.79(1H,br s)
(9)8-〔2,6-二氯-3-〔N-〔N′-〔3-(3-吡啶基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
mp:156-160℃(broad)
NMR(CDCl3,δ):2.68(3H,s),3.21(3H,s),
3.77-4.05(2H),5.41(1H,d,J=10Hz),5.57(1H,
d,J=10Hz),6.39(1H,br t,J=5Hz),6.96-7.52
(11H),8.03(1H,d,J=9Hz),8.32(1H,d,J=5Hz).
8.39-8.50(2H),9.01(1H,d,J=1Hz),9.56(1H,
br s)
(10)8-〔2,6-二氯-3-〔N-〔N′-〔3-(2-吡啶基甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.62(3H,s),3.21(3H,s),3.81
(1H,dd,J=17,5Hz),4.11(1H,dd,J=17,6Hz),
4.70(2H,d,J=5Hz),5.50(1H,d,J=10Hz),5.65
(1H,d,J=10Hz),5.81(1H,br t,J=5Hz),
7.10-7.73(13H),8.06(1H,d,J=9Hz),8.50(1H,
d,J=5Hz),8.60(1H,s)
(11)8-〔2,6-二氯-3-〔N-〔N′-〔3-(4-吡啶基甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.61(3H,s),3.19(3H,s),3.81
(1H,dd,J=17,5Hz),4.03(1H,dd,J=17,6Hz),
4.52(2H,d,J=6Hz),5.51(1H,d,J=10Hz),5.61
(1H,d,J=10Hz),5.90(1H,br t,J=5Hz),
7.07-7.50(12H),7.58(1H,s),8.08(1H,d,
J=9Hz),8.50(2H,d,J=6Hz),8.60(1H,s)
(12)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(1-哌嗪基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.53-2.98(4H,m),2.62(3H,s),
3.14-3.86(5H,m),3.78(1H,dd,J=16,5Hz),
4.18(1H,dd,J=16,7Hz),5.25(1H,d,J=10Hz),
5.61(1H,d,J=10Hz),5.71(1H,br t,J=5Hz)
6.94(1H,br d,J=7.5Hz),7.08-7.40(6H,m),
7.15(1H,t,J=7.5Hz),7.48(2H,d,J=5Hz),8.08
(1H,d,J=9Hz),8.70(1H,br s)
(13)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-苯基-1-哌嗪基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.60(3H,s),2.64-4.11(8H,m),
3.21(3H,s),3.79(1H,dd,J=17,4Hz),4.30
(1H,dd,J=17,7Hz),5.44(1H,d,J=9Hz),5.57
(1H,m),5.61(1H,d,J=9Hz),6.81-7.05(4H,m),
7.11-7.53(1dH,m),8.03(1H,d,J=9Hz),8.71
(1H,br s)
(14)8-〔2,6-二氯-3-〔N-〔N′-〔3-(4-乙氧基羰基-1-哌嗪基羰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.28(3H,t,J=7.5Hz),2.60(3H,
s),3.10-4.16(8H,m),3.79(1H,dd,J=17.5,
7.5Hz),4.17(2H,q,J=7.5Hz),4.31(1H,dd,
J=17.5,7.5Hz),5.45(1H,d,J=9Hz),5.55(1H,
dd,J=7.5,5Hz),5.63(1H,d,J=9Hz),6.93(1H,
d,J=7Hz),7.10-7.39(6H,m),7.40-7.56(2H,m),
8.10(2H,m),8.7 3(1H,br s)
(15)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔2-(N,N-二甲基氨基)乙基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.40(6H,s),2.64(3H,s),2.70
(2H,t,J=7Hz),3.20(3H,s),3.37-3.69(3H,m),
3.80(1H,dd,J=16,4Hz),4.04(1H,dd,J=16,
and 6Hz),5.50(1H,d,J=10Hz),5.64(1H,d,
J=10Hz),5.87(1H,br t,J=5Hz),7.15(1H,t,
J=7.5Hz),7.20-7.50(8H,m),7.66(1H,br s),
8.06(1H,d,J=9Hz),8.64(1H,br s)
实施例23
在于冰-丙酮浴下向8-〔3-(N-甘氨酰-N-甲基氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(150mg),三乙胺(0.077ml)和二氯甲烷(1.5ml)的混合物中加入溴乙酰氯(0.034ml)。30分钟后,向混合物中加入N-甲基-N-环庚胺(236mg)。混合物在室温下搅拌3小时。反应混合物用碳酸氢钠水溶液洗,水洗和盐水洗。有机层用硫酸镁干燥和真空蒸发。剩余物用硅胶柱色谱(二氯甲烷-甲醇)进行纯化,产生无定形的8-〔3-〔N-〔(N-环庚基-N-甲基甘氨酰基)甘氨酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(151mg)。NMR(CDCl3,δ):1.29-1.96(12H),2.30(3H,s),2.58
(1H,m),2.75(3H,s),3.01(2H,s),3.26(3H,
s),3.50(1H,dd,J=18,4Hz),3.89(1H,dd,
J=18,5Hz),5.63(2H,s),7.19-7.52(6H),8.02
(1H,d,J=8Hz),8.13(1H,br t,J=5Hz)
实施例24
按照与实施例23相似的方法制得8-〔2,6-二氯-3-〔N-甲基-N-〔〔〔4-(4-吡啶基)-1-哌嗪基〕乙酰基〕甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉。NMR(CDCl3,δ):2.60-2.80(7H),3.10(2H,s),3.24
(3H,s),3.38-3.61(5H),3.91(1H,dd,J=18,
5Hz),5.65(2H,s),6.70(2H,d,J=6Hz),
7.22-7.55(6H),7.89(1H,br t,J=5Hz),8.03
(1H,d,J=8Hz),8.28(2H,d,J=6Hz)
实施例25
将8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(200mg),甲氧基胺盐酸盐(58.5mg)和吡啶(71μl)在乙醇(3ml)中的混合物在室温下搅拌1小时,然后在70℃搅拌2小时。冷却后,混合物用氯仿稀释和用碳酸氢钠饱和溶液洗。有机层用无水硫酸镁干燥和真空浓缩。剩余物从乙酸乙酯中结晶并过滤,产生8-〔2,6-二氯-3-〔N-〔N′-〔3-(1-甲氧基亚氨基乙基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉(161mg)无色粉末。mp:218-224℃NMR(DMSO-d6,δ):2.12(3H,s),2.60(3H,s),3.15
(3H,s),3.43(1H,dd,J=17.5,5Hz),3.66(1H,
dd,J=17.5,4Hz),3.89(3H,s),5.46(1H,d,
J=9Hz),5.53(1H,d,J=9Hz),6.37(1H,br t),
7.11-7.30(2H,m),7.32-7.60(5H,m),7.70(1H,
m),7.80(2H,s),8.20(1H,d,J=9Hz),8.92-9.08
(1H,m)
实施例26
按照与实施例25相似的方法制得8-〔2,6-二氯-3-〔N-〔N′-〔3-(1-羟基亚氨基乙基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.10(3H,s),2.64(3H,s),3.17
(3H,s),3.81(2H,br d,J=5Hz),5.45(1H,d,
J=10Hz),5.59(1H,d,J=10Hz),6.03(1H,brt,
J=5Hz),7.09-7.52(10H),8.03(1H,d,J=9Hz),
8.51(1H,s),9.23(1H,br s)
实施例27
将8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基.〕-2-甲基喹啉(200mg)和N,N-二甲基肼(35μl)在乙醇(2ml)中的混合物在50℃加热1小时,然后在90℃加热6小时。随后混合物在100℃加热15小时,在此期间向其中加入额外的N,N-二甲基肼(108μl)和乙酸(0.5ml)。将混合物真空浓缩,剩余物用乙酸乙酯稀释。有机相用饱和碳酸氢钠溶液洗和盐水洗,随后用无水硫酸镁干燥。将有机层真空浓缩,剩余物用快速色谱以乙酸乙酯洗脱进行纯化将所需要的部分浓缩和剩余物用乙醚粉末化并过滤,产生8-〔2,6-二氯-3-〔N-〔N′-〔3-(1-二甲基亚肼基乙基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉(50mg)无色粉末。mp:174.4-187.4℃NMR(CDCl3,δ):2.16(3H,s),2.50(6H,s),2.63
(3H,s),3.22(3H,s),3.82(1H,dd,J=16,4Hz),
4.20(1H,dd,J=16,6Hz),5.48(1H,d,J=18Hz),
5.62(1H,m),5.66(1H,d,J=18Hz),7.08-7.37
(6H,m),7.40-7.53(3H,m),7.57(1H,m),8.06
(1H,d,J=8Hz),8.18(1H,br s)
实施例28
向8-〔2,6-二氯-3-〔N-〔N′-乙基脲基乙酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉(111mg)在乙醇(3ml)中的溶液加入10%的氯化氢在甲醇(0.5ml)中的溶液。将混合物真空蒸发以产生浅黄色玻璃体,将其用乙醚洗,产生8-〔2,6-二氯-3-〔N-〔N′-乙基脲基乙酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐(112mg)浅黄色无定形粉末。NMR(DMSO-d6,δ):0.94(3H;t,J=7Hz),2.94(3H,
s),2.95(2H,q,J=7Hz),3.13(3H,s),3.39(1H,
d,J=16Hz),3.70(1H,d,J=16Hz),5.65(2H,s),
7.55-8.06(6H),9.05(1H,d,J=8Hz)
实施例29
按照与实施例28相似的方法制得下列化合物。
(1)8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐mp:168-170℃NMR(DMSO-d6,δ):2.51(3H,s),2.90(3H,s),3.17
(3H,s),3.52(1H,d,J=16Hz),3.76(1H,d,
J=16Hz),5.62(2H,s),6.56(1H,br s),
7.31-8.06(10H),8.90(1H,d like),9.32(1H,s)
(2)8-〔3-〔N-〔N′-(3-乙酰基笨基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-4-氯-2-甲基喹啉盐酸盐
NMR(DMSO-d6,δ):2.53(3H,s),2.68(3H,s),3.16
(3H,s),3.46(1H,d,J=16Hz),3.70(1H,d,
J=16Hz),5.52(1H,d,J=12Hz),5.61(1H,d,
J=12Hz),6.50(1H,br s),7.31-7.93(9H),8.00
(1H,t,J=1Hz),9.20(1H,s)
(3)8-〔2,6-二氯-3-〔N-(庚酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(DMSO-d6,δ):0.86(3H,t,J=7Hz),1.11-1.54
(8H),2.09(2H,t,J=7Hz),2.90(3H,s),3.11
(3H,s),3.40(1H,dd,J=16,4Hz),3.72(1H,dd,
J=16,6Hz),5.58(1H,d,J=12Hz),5.67(1H,d,
J=12Hz),7.50-8.10(6H),8.94(1H,d,J=8Hz)
(4)8-〔3-〔N-(肉桂酰基甘氨酰基)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD4∶1V/V,δ):3.09(3H,s),3.21
(3H,s),3.91(2H,s),5.59(1H,d,J=10Hz),
5.79(1H,d,J=10Hz),6.59(1H,d,J=20Hz),
7.28-7.66(6H,m),7.58(1H,d,J=20Hz),7.61
(1H,d,J=14Hz),7.72(1H,br d,J=6Hz),
7.81-8.03(3H,m),8.98(1H,d,J=6Hz)
(5)8-〔2,6-二氯-3-〔N-〔N′-(3-乙氧乙氧基羰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):1.37(3H,t,J=7Hz),3.01
(3H,s),3.31(3H,s),3.89(2H,br s),4.30
(2H,q,J=7Hz),5.61(1H,d,J=10Hz),5.82(1H,
d,J=10Hz),7.26-7.47(2H),7.58-8.00(7H),8.09
(1H,t,J=1Hz),8.96(1H,d,J=9Hz)
(6)8-〔2,6-二氯-3-〔N-(N′-戊基脲基乙酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐
NMR(DMSO-d6,δ):0.85(3H,t,J=7.5Hz),1.10-1.44
(6H,m),2.50(3H,s),3.11(3H,s),2.85-2.95
(2H,m),3.38(1H,d,J=17.5Hz),3.68(1H,d,
J=17.5Hz),5.61(2H,s),7.79(2H,br s),7.90
(3H,br s),7.98(1H,d,J=7.5Hz),9.01(1H,d,
J=8Hz)
(7)8-〔2,6-二氯-3-〔N,-〔N′-(3-乙酰氨基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD3∶1V/V,δ):2.07(3H,s),2.86
(3H,br s),3.29(3H,s),3.89(2H,s),5.58
(1H,br d,J=8Hz),5.79(1H,br d,J=8Hz),
6.91-7.23(3H,m),7.26-8.03(7H,m),8.90(1H,
br d,J=6Hz)
(8)8-〔2,6-二氯-3-〔N-〔N′-〔3-(N-甲基-N-乙酰基氨基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD3∶1V/V,δ):1.81(3H,s),3.04
(3H,br s),3.11(3H,s),3.27(3H,s),3.84
(1H,d,J=17Hz),3.96(1H,d,J=17Hz),5.59(1H,
d,J=8Hz),5.75(1H,d,J=8Hz),6.75(1H,m),
7.17-8.02(9H,m),8.91(1H,m)
(9)8-〔2,6-二氯-3-〔N-〔N,-〔3-(N,N-二甲基氨基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD,δ):3.08(3H,s),3.22(6H,s),
3.30(3H,s),3.81(2H,s),5.61(1H,d,
J=10Hz),5.80(1H,d,J=10Hz),7.25(1H,d,
J=7Hz),7.3 3-7.52(2H),7.60(1H,d,J=9Hz),
7.68(1H,d,J=9Hz),7.76-7.98(5H),8.96(1H,
d,J=9Hz)
(10)8-〔2,6-二氯-3-〔N-〔N′-〔3-(N,-甲基脲基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.75(3H,s),2.90(3H,s)
3.30(3H,s),3.80(1H,d,J=17Hz),3.92(1H,d,
J=17Hz),5.61(1H,d,J=10Hz),5.81(1H,d,
J=10Hz),6.80-7.00(3H),7.32(1H,s),7.56(1H,
d,J=9Hz),7.64(1H,d,J=9Hz),7.70-8.00(4H),
8.90(1H,d,J=9Hz)
(11)8-〔3-〔N-〔N'-(3-羧基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.00(3H,s),3.31(3H,s),
3.81(1H,d,J=18Hz),3.95(1H,d,J=18Hz),5.60
(1H,d,J=10Hz),5.82(1H,d,J=10Hz),7.23-7.40
(2H),7.56-8.02(7H),8.11(1H,s),8.94(1H,d,
J=9Hz)
(12)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(吗啉代羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕)-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD3∶1V/V,δ):2.93(3H,s),
3.20-3.44(8H,m),3.29(3H,s),3.80(1H,d,
J=17Hz),3.97(1H,d,J=17Hz),5.58(1H,d,
J=10Hz),5.79(1H,d,J=10Hz),6.91(1H,br d
J=7.5Hz),7.16-8.01(9H,m),8.89(1H,d,J=9Hz)
(13)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-甲基-1-哌嗪基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD3∶1V/V,δ):2.84-3.96(8H,m),
2.90(3H,s),2.98(3H,s),3.30(3H,s),3.84
(2H,br s),5.60(1H,d,J=10Hz),5.82(1H,d,
J=10Hz),7.01(1H,br d,J=6Hz),7.28(1H,t,
J=7.5Hz),7.36(1H,br t,J=7Hz),7.43-8.03(7H,
m),8.94(1H,d,J=9Hz)
(14)8-〔2,6-二氯-3-〔N-〔N′-〔3-(2-甲氧基乙基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD3∶1V/V,δ):2.92(3H,s),327
(3H,s),3.36(3H,s),3.44-3.60(4H,m),3.85
(1H,d,J=17Hz),3.96(1H,d,J=17Hz),5.58(1H,
d,J=9Hz),5.80(1H,d,J=9Hz),7.20(1H,t,
J=7Hz),7.30-7.50(2H,m),7.53-7.99(7H,m),
8.90(1H,d,J=9Hz)
(15)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-(2-二甲基氨基乙基)-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD3∶1V/V,δ):2.99(9H,br s),3.08
(3H,s),3.25(3H,s),3.30-3.54(4H,m),3.91
(2H,m),5.61(1H,d,J=10Hz),5.81(1H,d,
J=10Hz),7.08(1H,d,J=7Hz),7.28(1H,t,
J=8Hz),7.40-7.55(1H,m),7.59(1H,d,J=9Hz),
7.66(1H,d,J=9Hz),7.78(1H,d,J=7Hz),
7.82-8.02(4H,m),8.96(1H,d,J=9Hz)
(16)8-〔2,6-二氯-3-〔N-〔N′-(3-甲基氨基甲酰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):2.91(3H,s),3.00(3H,s),
3.31(3H,s),3.79(1H,d,J=18Hz),3.91(1H,d,
J=18Hz),5.60(1H,d,J=10Hz),5.82(1H,d,
J=10Hz),7.20-7.46(3H),7.60(1H,d,J=9Hz),
7.69(1H,d,J=9Hz),7.74-8.00(5H),8.95(1H,
d,J=9Hz)
(17)8-〔3-〔N-〔N′-(3-二甲基氨基甲酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):2.99(6H,s),3.06(3H,s),
3.30(3H,s),3.85(2H,s),5.60(1H,d,
J=10Hz),5.82(1H,d,J=10Hz),6.98(1H,d,
J=6Hz),7.20-7.38(2H),7.43-8.02(7H),8.94
(1H,d,J=8Hz)
(18)8-〔2,6-二氯-3-〔N-〔N′-〔3-(3-吡啶基甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD,δ):2.98(3H,s),3.30(3H,s),
3.86(2H,s),4.74(2H,s),5.60(1H,d,
J=10Hz),5.81(1H,d,J=10Hz),7.28(1H,d,
J=8Hz),7.48-8.09(10H),8.61-8.74(2H),
8.88-9.01(2H)
(19)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-〔4-(4-吡啶基)-1-哌嗪基羰基〕苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉三盐酸盐NMR(CDCl3-CD3OD,δ):2.99(3H,s),3.30(3H,s),
3.64-4.00(10H),5.62(1H,d,J=10Hz),5.82(1H,
d,J=10Hz),7.04(1H,d,J=7Hz),7.13(2H,br d,
J=7Hz),7.30(1H,t,J=8Hz),7.40-7.55(2H),
7.60(1H,d,J=9Hz),7.68(1H,d,J=9H2),7.78
(1H,d,J=7Hz),7.83-8.00(3H),8.16(2H,br d,
J=7Hz),8.95(1H,d,J=9Hz)
(20)8-〔3-〔N-〔N′-〔3-(4-乙酰基-1-哌嗪基羰基)苯基〕脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):2.14(3H,s),2.98(3H,s),
3.30(3H,s),3.35-3.90(10H),5.60(1H,d,
J=10Hz),5.81(1H,d,J=10Hz),6.99(1H,d,
J=7Hz),7.22-7.53(3H),7.60(1H,d,J=9Hz),
7.68(1H,d,J=9Hz),7.71-8.00(4H),8.93(1H,
d,J=9Hz)
(21)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-(3-硝基苯基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.10(3H,s),3.31(3H,s),
3.82(1H,d,J=17Hz),3.96(1H,d,J=17Hz),5.61
(1H,d,J=10Hz),5.83(1H,d,J=10Hz),7.33-7.48
(2H),7.61(1H,d,J=9Hz),7.19(1H,d,J=9Hz),
7.27-8.01(5H),8.61(1H,br s),8.99(1H,d,
J=9Hz)
(22)8-〔3-〔N-〔N′-(4-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐
mp:173-176℃
NMR(CDCl3-CD3OD,δ):2.58(3H,s),3.03(3H,s),
3.30(3H,s),3.79(1H,d,J=18Hz),3.90(1H,d,
J=18Hz),5.62(1H,d,J=10Hz),5.83(1H,d,
J=10Hz),7.45(1H,d,J=9Hz),7.60(1H,d,
J=9Hz),7.68(1H,d,J=9Hz),7.76-8.01(7H),
8.99(1H,d,J=9Hz)
(23)8-〔2,6-二氯-3-〔N-甲基-N-(N′-苯基脲基乙酰基)氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.91(3H,s),3.30(3H,s),
3.88(2H,s),5.61(1H,d,J=10Hz),5.84(1H,d,
J=10Hz),6.98(1H,t,J=6Hz),7.12-7.31(4H),
7.59(1H,d,J=9Hz),7.68(1H,d,J=9Hz),
7.74-8.00(4H),8.93(1H,d,J=9Hz)
(24)8-〔3-〔N-(N′-苄基脲基乙酰基)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.78(3H,s),3.29(3H,s),
3.84(2H,s),4.19(1H,d,J=16Hz),4.29(1H,d,
J=16Hz),5.59(1H,d,J=10Hz),5.82(1H,d,
J=10Hz),7.11-7.31(5H),7.58(1H,d,J=9Hz),
7.68(1H,d,J=9Hz),7.71-8.00(4H),8.92(1H,
d,J=9Hz)
(25)8-〔3-〔N-〔(N-环庚基-N-甲基甘氨酰基)甘氨酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD,δ):1.40-2.68(12H),2.86(3H,
s),3.23(6H,s),3.59(1H,m),3.70-4.13(4H),
5.59(1H,d,J=10Hz),5.71(1H,d,J=10Hz),
7.50-7.90(6H),8.75(1H,d,J=9Hz)
(26)8-〔2,6-二氯-3-〔N-甲基-N-〔〔4-(4-吡啶基)-1-哌嗪基〕乙酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉四盐酸盐
NMR(CDCl3-CD3OD,δ):3.10(3H,s),3.28(3H,s),
3.60-3.75(4H),3.81(2H,d,J=5Hz),4.00-4.30
(6H),5.68(1H,d,J=10Hz),5.79(1H,d,
J=10H2),7.28(2H,d,J=7Hz),7.58-8.00(6H),
8.20(2H,d,J=7Hz),8.95(1H,d,J=9Hz)
(27)8-〔2,6-二氯-3-〔N-〔N′-〔3-(3-吡啶基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.03(3H,s),3.30(3H,s),
3.89(2H,s),5.61(1H,d,J=10Hz),5.82(1H,d,
J=10Hz),7.38(1H,t,J=9Hz),7.46-8.11(10H),
8.51(1H,d,J=6Hz),8.94(1H,dd,J=9,1Hz),
9.00(1H,d,J=9Hz),9.61(1H,d,J=1Hz)
(28)8-〔2,6-二氯-3-〔N-〔N′-〔3-(2-吡啶基甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.00(3H,s),3.30(3H,s),
3.78(1H,d,J=17Hz),3.90(1H,d,J=17Hz),4.93
(2H,s),5.60(1H,d,J=10Hz),5.82(1H,d,
J=10Hz),7.31(1H,t,J=9Hz),7.50-8.01(10H),
8.10(1H,d,J=9Hz),8.52(1H,t,J=9Hz),8.72
(1H,d,J=6Hz),8.97(1H,d,J=9Hz)
(29)8-〔2,6-二氯-3-〔N-〔N′-〔3-(4-吡啶基甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD,δ):2.97(3H,s),3.30(3H,s),
3.86(2H,s),4.82(2H,s),5.60(1H,d,
J=10Hz),5.81(1H,d,J=10Hz),7.29(1H,t,
J=9Hz),7.50-8.00(9H),8.04(2H,d,J=6Hz),
8.71(2H,d,J=6Hz),8.94(1H,d,J=9Hz)
(30)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(1-哌嗪基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD3∶1V/V,δ):2.96(3H,s),
3.11-3.45(8H,m),3.29(3H,s),3.86(2H,s),
5.58(1H,d,J=10Hz),5.80(1H,d,J=10Hz),6.99
(1H,d,J=7Hz),7.18-8.01(9H,m),8.91(1H,d,
J=9Hz)
(31)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-苯基-1-哌嗪基羰基)苯基〕脲基乙酰基〕氧基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD3∶1V/V,δ):2.91(3H,s),3.23
(3H,s),3.26-3.40(4H,m),3.60(4H,br s),
3.72(2H,br s),5.52(1H,d,J=10Hz),5.76(1H,
d,J=10Hz),7.00(1H,br d,J=7Hz),7.15-7.37
(3H,m),7.39-7.95(11H,m),8.86(1H,d,J=9Hz)
(32)8-〔2,6-二氯-3-N-〔N′-〔3-(4-乙氧基羰基-1-哌嗪基羰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD3∶1V/V,δ):1.28(3H,t,
J=7.5Hz),2.92(3H,s),3.20-3.83(8H,m),3.95
(2H,s),4.16(2H,q,J=7.5Hz),5.59(1H,d,
J=9Hz),5.79(1H,d,J=9Hz),6.90(1H,d,
J=5Hz),7.22(1H,t,J=7.5Hz),7.40-7.74(6H,
m),7.75-7.98(3H,m),8.88(1H,d,J=9Hz)
(33)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔 2-(N,N-二甲基氨基)乙基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD3∶1V/V,δ):3.06(6H,s),3.08
(3H,s),3.30(3H,s),3.33-3.46(2H,m),3.79
(2H,brt,J=6Hz),3.81(1H,d,J=20Hz),3.89
(1H,d,J=20Hz),5.59(1H,d,J=10Hz),5.80(1H,
d,J=10Hz),7.28(1H,t,J=8Hz),7.45-8.00(9H,
m),8.94(1H,d,J=9Hz)
(34)8-〔2,6-二氯-3-〔N-〔N′-(3-乙氧基羰基氨基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基)-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):1.28(3H,t,J=7Hz),2,91
(3H,s),3,30(3H,s)3.89(2H,s),4.09(2H,q,
J=7Hz),5.60(1H,d,J=10Hz),5.81(1H,d,
J=10Hz),6.90-7.19(3H),7.39(1H,br s),7.58
(1H,d,J=9Hz),7.64(1H,d,J=9Hz),7.70-8.00
(4H),8.91(1H,d,J=9Hz)
(35)8-〔2,6-二氯-3-〔N-〔N′-(1-萘基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):2.50(3H,s),3.32(3H,s),
3.99(2H,s)5.62(1H,d,J=10Hz),5.80(1H,d,
J=10Hz),7.13(1H,t,J=9Hz),7.35-8.07(12H),
8.81(1H,d,J=9Hz)
(36)8-〔3-〔N-〔N ′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-4-氯-2-乙基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):1.35(3H,t,J=7Hz),2.52
(3H,s),3.19-3.46(5H),3.85(1H,d,J=17Hz),
3.99(1H,d,J=17Hz),5.60(1H,d,J=10Hz),5.84
(1H,d,J=10Hz),7.29-7.63(5H),7.85(1H,d,
J=8Hz),7.98-8.19(4H)
(37)8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-乙基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):1.39(3H,t,J=8Hz),2.54
(3H,s),3.22-3.44(5H),3.89(2Hs)5.60(1H,
d,J=10Hz),5.85(1H,d,J=10Hz),7.30-7.70
(5H),7.77-8.02(5H),9.00(1H,d,J=9Hz)
(38)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-(3-吡啶基)丙烯酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐
NMR(DMSO-d6,δ):2.90(3H,s),3.15(3H,s),3.60
(1H,dd,J=16,5Hz),3.92(1H,dd,J=16,5Hz),
5.64(2H,s)7.08(1H,d,J=15Hz),7.53(1H,d,
J=15Hz),7.77-8.00(7H),8.43-8.59(2H),8.77
(1H,d,J=8Hz),8.90-9.08(2H)
(39)8-〔2,6-二氯-3-〔N-甲基-N-(4-硝基肉桂酰基甘氨酰)氨基〕苄氧基〕-2-甲基喹啉盐酸盐
NMR(DMSO-d6,δ):2.89(3H,s),3.17(3H,s),
3.60(1H,dd,J=16,5Hz),3.90(1H,dd,J=16,
4Hz),5.62(2H,s),7.02(1H,d,J=15Hz),
7.50(1H,d,J=15Hz),7.65-7.97(9H),
8.26(1H,d,J=8Hz),8.52(1H,t like),
8.88(1H,br s)
实施例30
按照与实施例1相似的方法制得下列化合物。
(1)8-(2,6-二氯-3-硝基苄氧基)-2-甲基-4-二甲基氨基喹啉NMR(CDCl3,δ):2.59(3H,s),3.18(6H,s),5.52
(2H,s),6.61(1H,s),7.19-7.49(3H),7.67-7.78
(2H)
(2)8-(2,6-二氯-3-硝基苄氧基)-2,4-二甲基喹啉
mp:218-219℃
NMR(CDCl3,δ):2.66(3H,s),2.70(3H,s),5.70
(2H,s),7.15(1H,s),7.26(1H,d,J=8Hz),7.41
(1H,t,J=8Hz),7.52(1H,d,J=8Hz),7.65(1H,
d,J=8Hz),7.77(1H,d,J=8Hz)
(3)8-(2,6-二氯-3-硝基苄氧基)-4-(3,4-二甲氧基苄氧基)-2-甲基喹啉
mp:218-220℃
NMR(CDCl3,δ):2.70(3H,s),3.91(6H,s),5.18
(2H,s),5.68(2H,s),6.74(1H,s),6.92(1H,
d,J=8Hz),7.02(1H,s),7.06(1H,d,J=8Hz),
7.19-7.39(2H),7.50(1H,d,J=8Hz),7.76(1H,
d,J=8Hz),7.88(1H,d,J=8Hz)
(4)8-(2,6-二氯-3-硝基苄氧基)-4-甲氧基-2-甲基喹啉
NMR(CDCl3,δ):2.70(3H,s),4.02(3H,s),5.68
(2H,s),6.67(1H,s),7.25(1H,dd,J=8,1Hz),
7.34(1H,t,J=8Hz),7.50(1H,d,J=8Hz),7.75
(1H,d,J=8Hz),7.84(1H,dd,J=8,1Hz)
(5)8-(2,6-二氯-3-硝基苄氧基)-4-乙氧基-2-甲基喹啉
mp:212-213℃
NMR(CDCl3,δ):1.57(3H,t,J=6Hz),2.69(3H,s),
4.24(2H,q,J=6Hz),5.68(2H,s),6.62(1H,s),
7.23(1H,d,J=8Hz),7.34(1H,t,J=8Hz),7.50
(1H,d,J=8Hz),7.76(1H,d,J=8Hz),7.87(1H,
d,J=8Hz)
(6)8-(2,6-二氯-3-硝基苄氧基)-2-甲基-4-甲硫基喹啉
mp:225-226℃
NMR(CDCl3,δ):2.61(3H,s),2.72(3H,s),5.69
(2H,s),7.02(1H,s),7.26(1H,d,J=8Hz),7.40
(1H,t,J=8Hz),7.50(1H,d,J=8Hz),7.75(1H,
d,J=8Hz),7.76(1H,d,J=8Hz)
(7)8-(2,6-二氯-3-硝基苄氧基)-4-(2-甲氧基乙氧基)-2-甲基喹啉
mp:185-188℃
NMR(CDCl3,δ):2.69(3H,s),3.51(3H,s),3.90
(2H,t,J=6Hz),4.32(2H,t,J=6Hz),5.68(2H,
s),6.66(1H,s),7.24(1H,d,J=8Hz),7.34(1H,
t,J=8Hz),7.50(1H,d,J=8Hz),7.76(1H,d,
J=8Hz),7.89(1H,d,J=8Hz)
(8)8-(2,6-二氯-3-硝基苄氧基)-2-甲基-4-(2-二甲基氨基乙氧基)喹啉mp:144-146℃NMR(CDCl3,δ):2.41(6H,s),2.70(3H,s),2.90
(2H,t,J=6Hz),4.28(2H,t,J=6Hz),5.68(2H,
s),6.64(1H,s),7.23(1H,d,J=8Hz),7.33(1H,
t,J=8Hz),7.50(1H,d,J=8Hz),7.75(1H,d,
J=8Hz),7.85(1H,d,J=8Hz)
(9)2-氯-8-(2,6-二氯-3-硝基苄氧基)喹啉mp:198-199℃NMR(CDCl3,δ):5.66(2H,s),7.27-7.58(5H),
7.80(1H,d,J=8Hz),8.10(1H,d,J=8Hz)
(10)8-(2,6-二氯-3-硝基苄氧基)-2-甲氧基喹啉mp:137-138℃NMR(CDCl3,δ):4.10(3H,s),5.70(2H,s),6.95
(1H,d,J=8Hz),7.30(1H,d,J=5Hz),7.47(1H,
dd,J=8,5Hz),7.52(1H,d,J=8Hz),7.77(1H,d,
J=8Hz),8.00(1H,d,J=8Hz)
实施例31
将8-(2,6-二氯-3-硝基苄氧基)-4-(3,4-二甲氧基苄氧基)-2-甲基喹啉(106mg),2,3-二氯-5,6-二氰基-1,4-苯并醌(50mg)和二氯甲烷-水(18∶1,V/V,2.85ml)的混合物加热回流19小时。将反应混合物分配到二氯甲烷和饱和碳酸氢钠水溶液中。有机层用盐水洗,硫酸镁干燥和真空蒸发。剩余物用制备性薄层色谱(二氯甲烷-甲醇)进行纯化,然后用乙醇洗,产生淡棕色粉状8-(2,6-二氯-3-硝基苄氧基)-4-羟基-2-甲基喹啉(26mg)。
mp:255-258℃
NMR(DMSO-d6,δ):2.32(3H,s),5.47(2H,s),5.91
(1H,s),7.27(1H,t,J=8Hz),7.46(1H,d,
J=8Hz),7.69(1H,d,J=8Hz),7.90(1H,d,
J=8Hz),8.20(1H,d,J=8Hz)
实施例32
在室温下,向8-〔2,6-二氯-3-〔N-甲基-N-〔N ′-(3-硝基苯基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉(4.7g)在乙醇(47ml)中的悬浮液加入氯化锡(Ⅱ)(6.45g)。将混合物回流2小时。冷却后,用1N氢氧化钠溶液将混合物调整到pH=10。向该混合物中加入二氯甲烷(50ml)和用过滤法除去沉淀。滤液用二氯甲烷萃取两次。有机层用饱和碳酸氢钠溶液洗,水洗和盐水洗。用硫酸镁干燥后,真空除去溶剂。剩余物用柱色谱以二氯甲烷-甲醇洗脱进行纯化,产生无定形的8-〔3-〔N-〔N′-(3-氨基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(3.22g)。
NMR(CDCl3,δ):2.63(3H,s),3.20(3H,s),3.59
(2H,br s),3.79(1H,dd,J=17,5Hz),4.03(1H,
dd,J=17,6Hz),5.50(1H,d,J=10Hz),5.59-5.75
(2H),6.79(1H,dd,J=8,1Hz),6.48(1H,d,
J=8Hz),6.80(1H,t,J)=1Hz),6.91(1H,t,
J=8Hz),7.19-7.50(6H),7.82(1H,br s),8.06
(1H,d,J=9Hz)
实施例33
按照与实施例11~13相似的方法制得下列化合物。
(1)8-〔2,6-二氯-3-〔N-〔N′-(3-甲氧基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基)-2-甲基喹啉
NMR(CDCl3,δ):2.63(3H,s),3.21(3H,s),3.68
(3H,s),3.80(1H,dd,J=17,5Hz),4.20(1H,
dd,J=17,6Hz),5.49(1H,d,J=10Hz),5.57-5.70
(2H),6.50(1H,dd,J=8,1Hz),6.71(1H,d,
J=8Hz),6.94-7.09(2H),7.21-7.50(6H),8.08
(1H,d,J=9Hz),8.15(1H,br s)
(2)8-〔2,6-二氯-3-〔N-〔N′-(4-甲氧基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.64(3H,s),3.20(3H,s),
3.70-3.88(4H),4.07(1H,dd,J=17.5Hz),
5.42-5.57(2H),5.67(2H,d,J=10Hz),6.76(2H,
d,J=9Hz),7.10-7.50(8H),7.61(1H,br s),8.05
(1H,d,J=9Hz)
(3)8-〔2,6-二氯-3-〔N-〔N ′-(2-乙氧基羰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):1.40(3H,t,J=7Hz),2.75(3H,s),
3.25(3H,s),3.52(1H,dd,J=17,4Hz),3.89
(1H,dd,J=17,5Hz),4.35(2H,q,J=7Hz),
5.57-5.69(3H),6.95(1H,t,J=7Hz),7.20-7.52
(8H),7.93-8.06(2H),8.43(1H,d,J=9Hz)
(4)8-〔3-〔N-〔N′-(3-氰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.48(3H,s),3.21(3H,s),3.78
(1H,dd,J=17,5Hz),4.40(1H,dd,J=17,7Hz),
5.44(1H,d,J=10Hz),5.56(1H,dd,J=7,5Hz),
5.63(1H,d,J=10Hz),7.15(2H,d,J=5Hz),
7.20-7.44(5H,m),7.45-7.58(2H,m),7.64(1H,
br s),8.11(1H,d,J=9Hz),9.23(1H,br s)
(5)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-(2-吡啶基甲基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.70(3H,s),3.21(3H,s),3.68
(1H,dd,J=17,5Hz),3.85(1H,dd,J=17,5Hz),
4.42(2H,t,J=5Hz),5.48-5.61(2H),5.68(1H,
d,J=10Hz),6.02(1H,br t,J=5Hz),7.11(1H,t,
J=6Hz),7.20-7.50(7H),7.60(1H,dt,J=6,1Hz),
8.02(1H,d,J=9Hz),8.48(1H,d,J=5Hz)
(6)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-(2-吡啶基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,6):2.62(3H,s),3.26(3H,s),3.80
(1H,dd,J=17,5Hz),4.10(1H,dd,J=17,5Hz),
5.58(1H,d,J=10Hz),5.63(1H,d,J=10Hz),6.68
(1H,d,J=8Hz),6.86(1H,dd,J=7,6Hz),
7.20-7.56(7H),7.96-8.08(2H),8.26(1H,dd,
J=5,1Hz),9.80(1H,br t,J=5Hz)
(7)8-〔2,6-二氯-3-〔N-〔N′-(3-吡啶基甲基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.56(3H,s),3.20(3H,s),3.79
(1H,dd,J=17,4Hz),4.02(1H,dd,J=17,6Hz),
4.12(1H,dd,J=15,5Hz),4.33(1H,dd,J=15,
6Hz),5.28(1H,br t,J=5Hz),5.49(1H,d,
J=10Hz),5.70(1H,d,J=10Hz),6.24(1H,br t,
J=6Hz),7.08(1H,dd,J=8,5Hz),7.17-7.30(3H,
m),7.31(1H,d,J=9Hz),7.38-7.58(4H,m),8.01
(1H,d,J=8Hz),8.29-8.50(2H,m)
(8)8-〔3-〔N-〔N′-(3-氨基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.64(3H,s),3.20(3H,s),3.60
(2H,br s),3.80(1H,dd,J=17,5Hz),4.06(1H,
dd,J=17,6Hz),5.50(1H,d,J=10Hz),5.63(1H,
d,J=10Hz),5.64(1H,br s),6.29(1H,dd,J=8,
1Hz),6.46(1H,br s,J=8Hz),6.80(1H,t,
J=1Hz),6.91(1H,t,J=8Hz),7.17-7.55(7H,m),
7.84(1H,br s),8.05(1H,d,J=9Hz)
(9)8-〔2,6-二氯-3-〔N-〔N′-(4-吡啶基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.58(3H,s),3.20(3H,s),3.76
(1H,dd,J=17,5Hz),4.41(1H,dd,J=17,7Hz),
5.43(1H,d,J=10Hz),5.61(1H,d,J=10Hz),5.63
(1H,m),7.11(2H,dd,J=6,1Hz),7.19-7.40(4H,
m),7.43-7.60(2H,m),8.12(1H,d,J=9Hz),8.23
(2H,dd,J=6,0.5Hz),9.43(1H,br s)
(10)8-〔2,6-二氯-3-〔N-〔N ′-(4-吡啶基甲基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.59(3H,s),3.20(3H,s),3.80
(1H,dd,J=17,4Hz),4.01(1H,dd,J=17,6Hz),
4.10(1H,dd,J=16,6Hz),4.31(1H,dd,J=16,
6Hz),5.38(1H,br t,J=5Hz),5.50(1H,d,
J=10Hz),5.69(1H,d,J=10Hz),6.24(1H,br t,
J=6Hz),7.08(2H,d,J=6Hz),7.16-7.36(2H,m),
7.31(1H,d,J=8Hz),7.45(2H,d,J=4Hz),7.49
(1H,d,J=8Hz),8.01(1H,d,J=8Hz),8.40(2H,
d,J=5Hz)
(11)8-〔2,6-二氯-3-〔N-〔N′-(3-吡啶基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.58(3H,s),3.22(3H,s),3.80
(1H,dd,J=18,5Hz),4.51(1H,dd,J=18,8Hz),
5.41(1H,d,J=10Hz),5.50(1H,br t,J=4Hz),
5.63(1H,d,J=10Hz),7.09(1H,dd,J=8,5Hz),
7.18-7.39(4H,m),7.42-7.55(2H,m),7.90(1H,
dt,J=8,0.5Hz),8.04-8.16(2H,m),8.20(1H,d,
J=2Hz),9.15(1H,br s)
(12)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-(2-甲氧基乙基)-N-甲基-氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.61(3H,s),2.84-3.29(7H,m),
3.20(3H,s),3.28(1H,dd,J=17,5Hz),4.20
(1H,dd,J=7,17Hz),5.47(1H,d,J=10Hz),5.63
(1H,d,J=10Hz),5.64(1H,m),6.94(1H,d,
J=7Hz),7.13(1H,t,J=8Hz),7.15-7.56(8H,m),
8.09(1H,d,J=9Hz),8.60(1H,m)
(13)8-〔2,6-二氯-3-〔N-甲基-N-〔N ′-〔3-〔N-甲基-N-(3-吡啶基甲基)氨基甲酰基〕苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.59(3H,s),2.70-3.04(3H,m),
3.21(3H,s),3.79(1H,dd,J=16,4Hz),4.25
(1H,dd,J=16,6Hz),4.39-4.88(2H,m),5.46
(1H,d,J=10Hz),5.60(1H,d,J=10Hz),5.62(1H,
m),6.98(1H,br d,J=6Hz),7.08-7.76(10H,m),
8.10(1H,d,J=10Hz),8.30-8.79(3H,m)
(14)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-〔N-甲基-N-(2-吡啶基)氨基甲酰基〕苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.59(3H,s),3.21(3H,s),3.50
(3H,s),3.78(1H,dd,J=17,5Hz),4.19(1H,dd,
J=17,6Hz),5.48(1H,d,J=10Hz),5.56-5.69
(2H),6.77-7.02(4H),7.20-7.51(9H),8.09(1H,
d,J=8Hz),8.30(1H,dd,J=5,1Hz),8.39(1H,br
s)
(15)8-〔2,6-二氯-3-〔N-(N ′-乙基脲基乙酰基)-N-甲基氨基〕苄氧基-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):1.00(3H,t,J=7Hz),2.62(3H,s),
3.00-3.17(2H),3.21(3H,s),3.77(1H,dd,
J=17,5Hz),3.91(1H,dd,J=17,6Hz),4.02(3H,
s),5.69(1H,br s),5.85-5.02(2H),5.66(1H,
d,J=10Hz),6.67(1H,s),7.19-7.50(4H),7.80
(1H,dd,J=8,1Hz)
(16)8-〔2,6-二氯-3-〔N-〔N′-(3-二甲基氨基甲酰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):2.54(3H,s),2.88(3H,br s),3.00
(3H,br s),3.21(3H,s),3.79(1H,dd,J=17,
5Hz),4.05(3H,s),4.31(1H,dd,J=17,6Hz),
5.41(1H,d,J=10Hz),5.60(1H,d,J=10Hz),5.69
(1H,br s),6.68(1H,s),6.94(1H,d,J=8Hz),
7.07-7.39(6H),7.45(1H,t,J=8Hz),7.83(1H,
d,J=9Hz),8.89(1H,br s)
(17)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-吡啶基氨基甲酰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):2.61(3H,s),3.21(3H,s),
3.87-4.09(5H),5.41(1H,d,J=10Hz),5.51(1H,
d,J=10Hz),6.32(1H,br s),6.63(1H,s),
6.98-7.13(2H),7.20-7.50(5H),7.79-7.90(3H),
8.50(2H,d,J=6Hz),8.60(1H,br s),9.55(1H,
br s)
(18)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-3-(4-甲基-1-哌嗪基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉
NMR(CDCl3,δ):2.03-2.48(7H),2.52(3H,s),
3.15-3.87(8H),4.03(3H,s),4.45(1H,dd,
J=17,8Hz),5.40(1H,d,J=10Hz),5.49-5.62
(2H),6.67(1H,s),6.91(1H,d,J=7Hz),
7.10-7.50(9H),7.82(1H,d,J=8Hz),9.01(1H,
br s)
(19)8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):2.38(3H,s),2.55(3H,s),3.22
(3H,s),3.81(1H,dd,J=17,4Hz),4.05(3H,s),
4.49(1H,dd,J=17,7Hz),5.40(1H,d,J=10Hz),
5.51-5.68(2H),6.69(1H,s),7.12-7.52(8H),
7.79-7.89(2H),9.06(1H,br s)
(20)8-〔2,6-二氯-3-〔N-〔N′-(2-甲氧基苯基)脲基乙酰基〕-N-甲基氨基)苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.71(3H,s),3.24(3H,s),3.67
(3H,s),3.69(1H,dd,J=17,5Hz),3.86(1H,dd,
J=17,5Hz),5.58(1H,d,J=10Hz),5.65(1H,d,
J=10Hz),5.89(1H,br t,J=5Hz),6.72-6.84(1H,
m),6.85-7.00(2H,m),7.16(1H,br s),
7.20-7.51(6H,m),7.93-8.02(1H,m),8.02(1H,
d,J=10Hz)
实施例34
按照与实施例21相似的方法制得下列化合物。
(1)8-〔2,6-二氯-3-〔N-〔N′-〔3-(N-乙基-N-甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):0.96-1.20(3H),2.62(3H,s),
2.79-3.06(3H),3.13-3.30(4H),3.50(1H,m),
3.79(1H,dd,J=18,5Hz),4.19(1H,dd,J=18,
6Hz),5.48(1H,d,J=10Hz),5.59-5.72(2H),6.91
(1H,d,J=8Hz),7.09-7.53(9H),8.09(1H,d,
J=9Hz),8.59(1H,br s)
(2)8-〔2,6-二氯-3-〔N-〔N′-〔3-(N-异丙基-N-甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):0.99-1.19(6H),2.59-2.92(6H),3.21
(3H,s),3.79(1H,dd,J=18,5Hz),3.96(1H,m),
4.20(1H,dd,J=18,6Hz),5.48(1H,d,J=10Hz),
5.59-5.70(2H),6.90(1H,br d,J=7Hz),
7.10-7.51(9H),8.09(1H,d,J=9Hz),8.59(1H,
br s)
(3)8-〔2,6-二氯-3-〔N-〔N′-(3-二乙基氨基甲酰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):0.86-1.31(6H,m),2.61(3H,s),
3.04-3.63(4H,m),3.22(3H,s),3.80(1H,dd,
J=17,5Hz),4.20(1H,dd,J=17,7Hz),5.47(1H,
d,J=10Hz),5.63(1H,d,J=10Hz),5.65(1H,m),
6.90(1H,dt,J=7,0.5Hz),7.09-7.38(6H,m),
7.14(1H,t,J=8Hz),7.43-7.51(2H,m),8.09
(1H,d,J=9Hz),8.58(1H,br s)
(4)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(2-吡啶基氨基甲酰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.62(3H,s),3.22(3H,s),3.86
(1H,dd,J=17,5Hz),4.22(1H,dd,J=17,6Hz),
5.50(1H,d,J=10Hz),5.66(1H,d,J=10Hz),5.80
(1H,br t,J=6Hz),7.03(1H,dd,J=7,5Hz),
7.16-7.50(9H),7.71(1H,dt,J=8,1Hz),7.80
(1H,br s),8.09(1H,d,J=9Hz),8.25-8.33(2H),
8.68(1H,br s),8.71(1H,br s)
(5)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-吡啶基氨基甲酰基)苯基〕脲基乙酰基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.69(3H,s),3.23(3H,s),3.89
(1H,dd,J=17,5Hz),4.03(1H,dd,J=17,5Hz),
5.42(1H,d,J=10Hz),5.54(1H,d,J=10Hz),6.45
(1H,br t,J=5Hz),6.96(1H,br s),7.02(1H,t,
J=9Hz),7.20-7.56(9H),7.89(2H,d,J=6Hz),
8.06(1H,d,J=9Hz),8.44(1H,s),8.51(2H,d,
J=6Hz),9.61(1H,br s)
(6)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-〔N-甲基-N-(4-吡啶基)氨基甲酰基〕苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.50(3H,s),3.21(3H,s),3.40
(3H,s),3.73,(1H,dd,J=18,5Hz),4.33(1H,dd,
J=18,7Hz),5.39-5.50(2H),5.61(1H,d,
J=10Hz),6.80(2H,d,J=5Hz),6.90(1H,d,
J=7Hz),7.02(1H,t,J=8Hz),7.18-7.38(6H),
7.45-7.58(2H),8.10(1H,d,J=9Hz),8.31(2H,
br d,J=5Hz),8.61(1H,br s)
(7)8-〔2,6-二氯-3-〔N-甲基-〔N-〔N′-〔3-〔N-甲基-N-(3-吡啶基)氨基甲酰基〕苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.56(3H,s),3.21(3H,s),3.40
(3H,s),3.79(1H,dd,J=17,5Hz),4.25(1H,dd,
J=17,6Hz),5.41-5.69(3H),6.80(1H,d,J=7Hz),
6.99(1H,t,J=8Hz),7.04-7.54(10H),8.11(1H,
d,J=8Hz),8.22(1H,d,J=2Hz),8.31(1H,d,
J=5Hz),8.50(1H,br s)
(8)8-〔2,6-二氧-3-〔N-甲基-N-〔N′-〔3-(5-嘧啶基氨基甲酰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.63(3H,s),3.21(3H,s),
3.72-4.03(2H),5.49(1H,d,J=10Hz),5.59(1H,
d,J=10Hz),6.36(1H,br s),6.98-7.51(10H),
8.07(1H,d,J=9Hz),8.50(1H,br s),8.95(1H,
s),9.37(2H,s),9.85(1H,br s)
(9)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔3-(N,N-二甲基氨基)苯基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉
NMR(CDCl3,δ):2.70(3H,s),2.95(6H,s),3.22
(3H,s),3.83(1H,dd,J=17,5Hz),4.02(1H,dd,
J=17,6Hz),5.51(2H,s),6.79(1H,br t,
J=5Hz),6.55(1H,dt,J=7.1Hz),6.99-7.10(2H),
7.16-7.55(11H),8.06(1H,d,J=9Hz),8.32(1H,
s),9.04(1H,br s)
(10)8-〔2,6-二氯-3-〔N-〔N′-〔3-(4-乙基-1-哌嗪基羰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.08(3H,t,J=7Hz),2.13-2.48
(6H),2.60(3H,s),3.28-3.43(2H),3.61-3.85
(3H),4.39(1H,dd,J=18,8Hz),5.41-5.54(2H),
5.62(1H,d,J=10Hz),6.95(1H,d,J=8Hz),
7.11-7.39(7H),7.45-7.53(2H),8.10(1H,d,
J=9Hz),8.67(1H,br s)
(11)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔4-(甲基氨基甲酰基)-1-哌嗪基羰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.61(3H,s),2.80(3H,d,J=5Hz),
3.16-3.77(11H),3.80(1H,dd,J=17,5Hz),4.15
(1H,dd,J=17,6Hz),4.73(1H,br d,J=5Hz),
5.48(1H,d,J=10Hz),5.62(1H,d,J=10Hz),5.77
(1H,br t,J=5Hz),6.93(1H,d,J=7Hz),
7.10-7.52(9H),8.10(1H,d,J=9Hz),8.77(1H,
br s)
(12)8-〔2,6-二氯-3-〔N-〔N′-〔3-(4-二甲基氨基哌啶子基羰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):1.10-2.10(5H),2.29(6H,s),
2.39(1H,m),2.66(3H,s),2.92(1H,m),3.23
(3H,s),3.75(1H,d,J=17Hz),3.91(1H,d,
J=17Hz),4.70(1H,m),5.52(1H,d,J=10Hz),
5.60(1H,d,J=10Hz),6.94(1H,d,J=7Hz),
7.18-7.52(9H),8.07(1H,d,J=9Hz)
(13)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(1-吡咯烷基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.61-1.97(4H),2.62(3H,s),3.21
(3H,s),3.30(2H,t,J=6Hz),3.57(2H,t,
J=6Hz),3.80(1H,dd,J=18,5Hz),4.19(1H,dd,
J=18,6Hz),5.48(1H,d,J=10Hz),5.59-5.73
(2H),7.02-7.52(10H),8.09(1H,d,J=9Hz),8.62
(1H,br s)
(14)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(1,2,3,6-四氢吡啶-1-基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.95-2.31(2H,m),2.60(3H,s),
3.21(3H,s),3.32-3.52(1H,m),3.66-3.88(2H,
m),3.77(1H,dd,J=18,5Hz),4.02-4.23(1H,m),
4.17(1H,dd,J=18,6Hz),5.45(1H,d,J=10Hz),
5.56-5.88(3H,m),5.62(1H,d,J=10Hz),6.96
(1H,br d,J=6Hz),7.11-7.40(6H,m),7.16(1H,
t,J=8Hz),7.42-7.52(2H,m),8.08(1H,d,
J=10Hz),8.59(1H,br s)
(15)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-〔3-(二甲基氨基)丙基〕-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.60-1.92(2H),2.09-2.68(12H),
2.80-3.08(2H),3.13-3.31(4H),3.49(1H,m),
3.78(1H,dd,J=17,5Hz),4.09(1H,m),5.49
(1H,d,J=10Hz),5.62(1H,d,J=10Hz),5.73(1H,
br s),6.90(1H,d,J=7Hz),7.08-7.52(9H),8.08
(1H,d,J=9Hz),8.69(1H,br s)
(16)8-〔2,6-二氯-3-〔N-〔N ′-〔3-〔N-(3-甲氧基丙基)-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.53-2.04(4H,m),2.60(3H,s),
2.79-3.12(3H,m),3.14-3.64(8H,m),3.80(1H,
dd,J=17,5Hz),4.09-4.32(1H,m),5.48(1H,d,
J=10Hz),5.58-5.74(1H,m),5.54(1H,d,
J=10Hz),6.94(1H,br d,J=7Hz),7.14(1H,d,
J=8Hz),7.19-7.60(8H,m),8.09(1H,d,J=9Hz),
8.50-8.68(1H,m)
(17)8-〔3-〔N-〔N′-〔3-〔N,N-二(2-甲氧基乙基)氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.61(3H,s),3.12-3.87(18H),4.22
(1H,dd,J=18,6Hz),5.48(1H,d,J=10Hz),
5.53-5.70(2H),6.93(1H,d,J=7Hz),7.09-7.51
(9H),8.09(1H,d,J=9Hz),8.53(1H,br s)
(18)8-〔3-〔N-〔N′-〔3-〔N,N-二(2-乙氧基乙基)氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.00-1.28(6H,m),2.62(3H,s),
3.21(3H,s),3.23-3.80(12H,m),3.77(1H,dd,
J=17.5,5Hz),4.20(1H,dd,J=17.5,6Hz),5.46
(1H,d,J=10Hz),5.60(1H,br t,J=5Hz),5.64
(1H,d,J=10Hz),6.94(1H,br d,J=8Hz),7.14
(1H,t,J=7.5Hz),7.17-7.55(8H,m),8.08(1H,
d,J=8Hz),8.47(1H,br s)
(19)8-〔3-〔N-〔N′-〔3-〔N-〔2-(叔丁基二苯基甲硅烷基氧基)乙基〕-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.03(9H,br s),2.60(3H,s),2.98
(3H,br d,J=6Hz),3.21(3H,s),3.27-3.92(5H),
4.22(1H,m),5.45(1H,d,J=10Hz),5.56(1H,br
s),5.62(1H,d,J=10Hz),6.91(1H,br d,
J=7Hz),7.02-7.72(19H),8.07(1H,d,J=9Hz)
8.29(0.5H,br s),8.48(0.5H,br s)
(20)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-〔N-甲基-N-(2-吡啶基甲基)氨基甲酰基〕苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.59(3H,s),2.80-3.09(3H,m),
3.20(3H,s),3.78(1H,br d,J=17Hz),4.19(1H,
dd,J=17 and 6Hz),4.49-4.89(2H,m),5.45(1H,
d,J=10Hz),5.53-5.71(2H,m),6.92-7.70(13H,
m),8.09(1H,d,J=9Hz),8.51(1H,d,J=4Hz),
8.60(1H,m)
(21)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔 N-(2-甲氧基乙基)-N-(3-吡啶基甲基)氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.59(3H,s),3.04-3.70(7H,m),
3.20(3H,s),3.28(1H,dd,J=16,5Hz),
4.30(1H,dd,J=16,6Hz),4.51-4.88(2H,m),
5.44(1H,d,J=10Hz),5.49-5.69(3H,m),
6.95(1H,br d,J=6Hz),7.05-7.77(11H,m),
8.08(1H,d,J=8Hz),8.30-8.74(3H,m)
实施例35
按照与实施例15或16相似的方法制得下列化合物。
(1)8-〔2,6-二氯-3-〔N-甲基-N-(3-苯基丙酰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.75(3H,s),3.26(3H,s),
3.60(1H,dd,J=18,4Hz),3.90(1H,dd,J=18,
4Hz),5.65(2H,s),6.95(1H,br s),7.20-7.61
(11H,m),8.04(1H,d,J=8Hz)
(2)8-〔2,6-二氯-3-〔N-(4-甲酰基肉桂酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.28(3H,s),
3.69(1H,dd,J=18,4Hz),3.96(1H,dd,J=18,
4Hz),5.65(2H,s),6.61(1H,d,J=16Hz),
6.75(1H,br s),7.20-7.71(9H,m),
7.88(2H,d,J=8Hz),8.06(1H,d,J=8Hz),
10.01(1H,s)
(3)8-〔3-〔N-(4-氨基肉桂酰基甘氨酰基)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.25(3H,s),3.62
(1H,dd,J=18,4Hz),3.94(1H,dd,J=18,5Hz),
5.65(2H,s),6.28(1H,d,J=15Hz),6.52(1H,
t-like),6.63(2H,d,J=8Hz),7.18-7.54(9H),
8.03(1H,d,J=8Hz)
(4)8-〔2,6-二氯-3-〔N-甲基-N-((E)-2-甲基-3-苯基丙烯酰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.11(3H,s),2.74(3H,s),
3.26(3H,s),3.61(1H,dd,J=16Hz,5Hz),3.93
(1H,dd,J=16,5Hz),5.63(2H,s),6.87(1H,
t-like),7.20-7.54(12H,m),8.02(1H,d,J=8Hz)
(5)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-(4-吡啶基)丙烯酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉mp:111-114.5℃NMR(CDCl3,δ):2.73(3H,s),3.28(3H,s),3.72
(1H,dd,J=16,5Hz),3.95(1H,dd,J=16,5Hz),
5.63(2H,s),6.65(1H,d,J=16Hz),6.87(1H,
t-like),7.21-7.40(5H,m),7.40-7.57(4H,m),
8.03(1H,d,J=8Hz),8.60(2H,d,J=6Hz)
(6)8-〔2,6-二氯-3-〔N-〔4-(N,N-二甲基氨基)肉桂酰基甘氨酰〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.00(6H,s),3.25
(3H,s),3.60(1H,dd,J=16,5Hz),3.93(1H,dd,
J=16,5Hz),5.62(2H,s),6.25(1H,d,J=16Hz),
6.47(1H,t-like),6.56-6.77(2H,m),7.14-7.60
(9H,m),8.03(1H,d,J=8Hz)
(7)8-〔3-〔N-(4-氯肉桂酰基甘氨酰基)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.26(3H,s),3.64
(1H,dd,J=17,3Hz),3.94(1H,dd,J=17,3Hz),
5.64(1H,s),6.45(1H,d,J=16Hz),6.65(1H,
t-like),7.20-7.60(11H,m),8.03(1H,d,J=8Hz)
(8)8-〔2,6-二氯-3-〔N-甲基-N-(4-甲基肉桂酰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.36(3H,s),2.75(3H,s),3.26
(3H,s),3.63(1H,dd,J=4,17Hz),3.94(1H,dd,
J=4,17Hz),5.64(2H,s),6.42(1H,d,J=16Hz),
6.58(1H,t-like),7.16(2H,d,J=8Hz),
7.20-7.50(8H,m),7.53(1H,d,J=16Hz),8.02
(1H,d,J=8Hz)
(9)8-〔3-〔N-〔4-(乙酰氨基)肉桂酰基甘氨酰基)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.10(3H,s),2.68(3H,s),3.23
(3H,s),3.61(1H,dd,J=16,5Hz),3.87(1H,dd,
J=16,5Hz),5.60(2H,s),6.38(1H,d,J=16Hz),
6.62(1H,t-like),7.15-7.65(11H,m),8.05(1H,
d,J=8Hz),8.44(1H,s)
(10)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(N-甲基乙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.90(3H,s),2.75(3H,s),3.28
(6H,s),3.66(1H,dd,J=17,3Hz),3.95(1H,dd,
J=17,3Hz),5.66(2H,s),6.49(1H,d,J=16Hz),
6.67(1H,t-like),7.13-7.65(11H,m),8.03(1H,
d,J=8Hz)
(11)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(丙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.21(3H,t,J=8Hz),2.35(2H,q,
J=8Hz),2.70(3H,s),3.25(3H,s),3.62(1H,
dd,J=4,17Hz),3.90(1H,dd,J=4,17Hz),5.60
(2H,s),6.40(1H,d,J=16Hz),6.61(1H,
t-like),7.13-7.61(11H,m),7.86(1H,s),8.04
(1H,d,J=8Hz)
(12)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(N-甲基丙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.06(3H,t,J=8Hz),2.13(2H,
dif-q),2.74(3H,s),3.18-3.29(6H,m),3.65
(1H,dd,J=17,4Hz),3.95(1H,dd,J=17,4Hz),
5.66(2H,s),6.48(1H,d,J=16Hz),6.67(1H,
t-like),7.07-7.64(11H,m),8.03(1H,d,J=8Hz)
(13)8-〔2,6-二氯-3-〔N-〔4-(N-乙基乙酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.10(3H,t,J=7.5Hz),1.84(3H,
s),2.74(3H,s),3.28(3H,s),3.65(1H,dd,
J=17,4Hz),3.74(2H,q,J=7.5Hz),3.95(1H,dd,
J=17,4Hz),5.65(2H,s),6.48(1H,d,J=16Hz),
6.67(1H,t-like),7.15(2H,d,J=8Hz),
7.20-7.65(9H,m),8.03(1H,d,J=8Hz)
(14)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(2-吡啶基甲氧基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.27(3H,s),3.63
(1H,dd,J=17,3Hz),3.94(1H,dd,J=17,3Hz),
5.23(2H,s),5.65(2H,s),6.35(1H,d,
J=16Hz),6.56(1H,t-like),6.98(2H,d,J=8Hz),
7.18-7.59(11H,m),7.73(1H,td,J=8,1Hz),
8.02(1H,d,J=8Hz),8.62(1H,dif-dd,J=5Hz)
(15)8-〔2,6-二氯-3-〔N-〔4-〔2-(N,N-二甲基氨基)乙氧基〕肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.35(6H,s),2.67-2.81(5H,m),
3.27(3H,s),3.62(1H,dd,J=16,4Hz),3.95
(1H,dd,J=16,4Hz),4.10(2H,t,J=6Hz),5.68
(2H,s),6.35(1H,d,J=16Hz),6.55(1H,
t-like),6.92(2H,d,J=8Hz),7.20-7.45(3H,m),
7.45-7.58(6H,m),8.02(1H,d,J=8Hz)
(16)8-〔2,6-二氯-3-〔N-〔4-(2-羟基乙氧基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.01(1H,t-like),2.73(3H,s),
3.27(3H,s),3.63(1H,dd,J=18,4Hz),
3.86-4.04(3H,m),4.11(2H,t,J=5Hz),5.65
(2H,s),6.35(1H,d,J=16Hz),6.58(1H,
t-like),6.90(2H,d,J=8Hz),7.21-7.48(3H,m),
7.48-7.60(6H,m),8.03(1H,d,J=8Hz)
(17)8-〔2,6-二氯-3-〔 N-甲基-N-〔4-(甲基氨基甲酰基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.00(3H,d,J=5Hz),
3.26(3H,s),3.64(1H,dd,J=4,17Hz),3.93
(1H,dd,J=4,17Hz),5.66(2H,s),6.28(1H,
q-like),6.53(1H,d,J=16Hz),6.69(1H,
t-like),7.18-7.64(9H,m),7.75(2H,d,J=8Hz),
8.03(1H,d,J=8Hz)
(18)8-〔2,6-二氯-3-〔N-〔4-(二甲基氨基甲酰基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),2.99(3H,s),3.12
(3H,s),3.28(3H,s),3.65(1H,dd,J=17,4Hz),
3.95(1H,dd,J=17,4Hz),5.64(2H,s),6.52
(1H,d,J=16Hz),6.68(1H,t-like),7.20-7.66
(11H,m),8.05(1H,d,J=8Hz)
(19)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(3-甲基脲基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.63(3H,s),2.71(3H,d,J=5Hz),
3.14(3H,s),3.62(1H,dd,J=17,4Hz),3.80
(1H,dd,J=17,4Hz),5.32(1H,q-like),5.55
(2H,s),6.32(1H,d,J=16Hz),6.70(1H,
t-like),7.18-7.38(8H,m),7.38-7.55(3H,m),
8.02-8.14(2H,m)
(20)8-〔2,6-二氯-3-〔N-〔4-(甲磺酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.04(3H,s),3.28
(3H,s),3.66(1H,dd,J=18,4Hz),3.95(1H,dd,
J=18,4Hz),5.65(2H,s),6.41(1H,d,J=16Hz),
6.64(1H,t-like),6.78(1H,br s),7.13-7.59
(11H,m),8.02(1H,d,J=8Hz)
(21)8-〔2,6-二氯-3-〔N-甲基-N-(丁酰基甘氨酰基)氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):0.93(3H,t,J=7Hz),1.54-1.80
(2H),2.20(2H,t,J=7Hz),2.71(3H,s),3.22
(3H,s),3.49(1H,dd,J=17,4Hz),3.82(1H,dd,
J=17,5Hz),4.01(3H,s),5.60(2H,s),6.41
(1H,br s),6.65(1H,s),7.19-7.51(4H),7.81
(1H,dd,J=8,1Hz)
(22)8-〔2,6-二氯-3-〔N-(庚酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):0.81-0.99(3H),1.20-1.40(6H),
1.52-1.80(2H),2.21(2H,t,J=7Hz),2.70(3H,
s),3.25(3H,s),3.48(1H,dd,J=17,4Hz),3.83
(1H,dd,J=17,5Hz),4.01(3H,s),5.61(2H,s),
6.40(1H,br s),6.67(1H,s),7.20-7.41(3H),
7.49(1H,d,J=9Hz),7.81(1H,dd,J=8,1Hz)
(23)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-(3-吡啶基)丙烯酰基甘氨酰基〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):2.69(3H,s),3.28(3H,s),3.66
(1H,dd,J=17,4Hz),3.89-4.04(4H),5.61(2H,
s),6.57(1H,d,J=15Hz),6.65(1H,s),6.75
(1H,m),7.20-7.62(4H),7.74-7.88(2H),8.57
(1H,dd,J=5,1Hz),8.71(1H,d,J=1Hz)
(24)8-〔2,6-二氯-3-〔N-〔4-(二甲基氨基甲酰基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):2.69(3H,s),2.99(3H,br s),3.11
(3H,br s),3.29(3H,s),3.67(1H,dd,J=17,
4Hz),3.78-4.08(4H),5.61(2H,s),6.51(1H,d,
J=15Hz),6.67(1H,s),6.72(1H,br s),
7.20-7.63(8H),7.82(1H,dd,J=8,1Hz)
(25)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(N-甲基乙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):1.91(3H,br s),2.70(3H,s),3.28
(6H,s),3.68(1H,dd,J=17,4Hz),3.89-4.06
(4H),5.62(2H,s),6.49(1H,d,J=15Hz),6.67
(1H,s),6.73(1H,br s),7.12-7.62(9H),7.82
(1H,d,J=8Hz)
(26)8-〔2,6-二氯-3-〔N-〔4-〔N-(2-甲氧基乙基)氨基甲酰基〕肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.28(3H,s),3.39
(3H,s),3.51-3.76(5H),3.96(1H,dd,J=18,
5Hz),5.64(2H,s),6.49-6.62(2H),6.75(1H,br
t,J=4Hz),7.21-7.66(9H),7.78(2H,d,J=8Hz),
8.03(1H,d,J=8Hz)
(27)8-〔3-〔N-〔4-〔N,N-二(2-甲氧基乙基)氨基甲酰基〕肉桂酰基甘氨酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.20-3.84(18H),3.96
(1H,dd,J=18,5Hz),5.63(2H,s),6.50(1H,d,
J=15Hz),6.69(1H,br t,J=4Hz),7.20-7.63
(11H),8.02(1H,d,J=8Hz)
实施例36
按照与实施例16相似的方法将8-〔2,6-二氯-3-〔N-(4-氨基肉桂酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉与甲氧基乙酸反应制得8-〔2,6-二氯-3-〔N-〔4-(甲氧基乙酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.26(3H,s),3.51
(3H,s),3.65(1H,dd,J=18,4Hz),3.86-4.07
(3H,m),5.65(2H,s),6.43(1H,d,J=16Hz),
6.61(1H,br peak),7.22-7.40(3H,m),7.40-7.66
(8H,m),8.03(1H,d,J=8Hz),8.35(1H,s)
实施例37
按照与实施例36相似的方法制得下列化合物。
(1)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(3-吡啶基乙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.64(3H,s),3.21(3H,s),
3.51-3.70(3H,m),3.88(1H,dd,J=18,4Hz),
5.60(2H,s),6.38(1H,d,J=16Hz),6.62(1H,
t-like),7.16-7.74(13H,m),8.07(1H,d,
J=8Hz),8.36(1H,s),8.47-8.60(2H,m)
(2)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(异烟酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.62(3H,s),3.19(3H,s),3.60
(1H,dd,J=18,4Hz),3.88(1H,dd,J=18,4Hz),
5.60(2H,s),6.41(1H,d,J=16Hz),6.65(1H,
t-like),7.18-7.60(9H,m),7.64-7.80(4H,m),
8.05(1H,d,J=8Hz),8.68(2H,d,J=5Hz),8.93
(1H,s)
(3)8-〔3-〔N-〔4-(苯甲酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),3.25(3H,s),3.63
(1H,dd,J=4,18Hz),3.93(1H,dd,J=4,18Hz),
5.64(2H,s),6.43(1H,d,J=16Hz),6.63(1H,
t-like),7.14-7.36(4H,m),7.3 6-7.62(9H,m),
7.69(2H,d,J=8Hz),7.89(2H,d,J=8Hz),
7.98-8.14(2H,m)
(4)8-〔3-〔N-〔4-(4-溴丁酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.18(3H,t,J=6Hz),2.55(3H,t,
J=6Hz),2.75(3H,s),3.26(3H,s),3.46-3.72
(4H,m),3.94(1H,dd,J=18,4Hz),5.63(2H,s),
6.40(1H,d,J=16Hz),6.63(1H,br peak),
7.18-7.37(4H,m),7.37-7.62(7H,m),7.68(1H,
s),8.06(1H,d,J=8Hz)
实施例38
在室温下,向8-〔3〔N-〔N′-〔3-〔N-〔2-(叔丁基二苯基甲硅烷基氧基)乙基〕-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(256mg)在四氢呋喃(2.5ml)中的溶液加入1M氟化四丁基铵在四氢呋喃(0.6ml)中的溶液。将反应混合物搅拌2小时。混合物分配到二氯甲烷和水中。有机层用水洗和盐水洗,硫酸镁干燥和真空蒸发。剩余物用柱色谱以二氯甲烷-甲醇洗脱进行纯化,产生无定形的8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-(2-羟基乙基)-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉(148mg)。NMR(CDCl3,δ):2.65(3H,s),2.91-3.14(3H),3.21
(3H,s),3.32-4.09(7H),5.50(1H,d,J=10Hz),
5.63(1H,d,J=10Hz),5.90(1H,br t,J=5Hz),
6.92-7.51(10H),8.09(1H,d,J=9Hz),8.72(1H,
br s)
实施例39
在室温下,向搅拌着的8-〔3-〔N-〔4-(溴丁酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(50mg)在N,N-二甲基甲酰胺中的溶液加入碳酸钾(30mg)和产生的混合物在相同温度下搅拌16小时。将反应混合物倒入水中并用乙酸乙酯萃取。有机层用水洗和盐水洗,和用无水硫酸镁干燥。过滤后,真空除去溶剂,剩余物用制备性薄层色谱(甲醇-乙酸乙酯=1:12,V/V)进行纯化,产生8-〔2,6-二氯-3-〔N-甲基-N-〔4-(2-氧代-1-吡咯烷基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉(33.4mg)无定形固体。NMR(CDCl3,δ):2.18(2H,quint.,J=7.5Hz),2.64
(2H,t,J=7.5Hz),2.74(3H,s),3.27(3H,s),
3.63(1H,dd,J=18,4Hz),3.80-4.04(3H,m),
5.65(2H,s),6.44(1H,d,J=16Hz),6.60(1H,
t-like),7.15-7.56(9H,m),7.56-7.70(2H,m),
8.02(1H,d,J=8Hz)
实施例40
(1)8-(3-氨基-2,6-二氯苄氧基)-4-甲氧基-2-甲基喹啉是按照与实施例32相似的方法从8-(2,6-二氯-3-硝基苄氧基)-4-甲氧基-2-甲基喹啉制得的。mp:>250℃NMR(DMSO-d6,δ):2.58(3H,s),4.00(3H,s),5.31
(2H,s),5.68(2H,br s),6.90(1H,d,J=8Hz),
7.23(1H,d,J=8Hz),7.31-7.46(2H),7.68(1H,
dd,J=8,2Hz)
(2)按照与实施例5相似的方法制得8-〔2,6-二氯-3-(苯二甲酰亚氨基乙酰基氨基)苄氧基〕-4-甲氧基-2-甲基喹啉mp:184-185℃NMR(CDCl3,δ):2.62(3H,s),4.27(3H,s),
4.78-5.02(2H),5.10-5.79(2H),6.60(1H,br d,
J=9Hz),7.19-7.38(2H),7.58(1H,t,J=9Hz),
7.70-7.99(7H)
(3)按照与实施例7相似的方法制得8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲基氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉mp:209-210℃NMR(CDCl3,δ):2.70(3H,s),3.22(3H,s),3.99
(3H,s),4.02(2H,s),5.65(1H,d,J=10Hz),
5.72(1H,d,J=10Hz),6.63(1H,s),7.21-7.40
(2H),7.46(1H,d,J=9Hz),7.53(1H,d,J=9Hz),
7.68-7.91(5H)
(4)按照与实施例9相似的方法制得8-〔3-(N-甘氨酰基-N-甲基氨基)-2,6-二氯苄氧基〕-4-甲氧基-2-甲基喹啉。NMR(CDCl3,δ):2.70(3H,s),2.95(1H,d,J=17Hz),
3.10(1H,d,J=17Hz),3.21(3H,s),4.01(3H,
s),5.62(2H,s),7.18-7.29(2H),7.33(1H,t,
J=8Hz),7.46(1H,d,J=9Hz),7.32(1H,d,J=8Hz)
实施例41
按照与实施例28相似的方法制得下列化合物。
(1)8-〔2,6-二氯-3-〔N-(2-甲氧基肉桂酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(DMSO-d6,δ):2.88(3H,s),3.15(3H,s),3.60
(1H,dd,J=16,5Hz),3.85(3H,s),3.86(1H,dd,
J=16,4Hz),5.62(2H,s),6.80(1H,d,J=15Hz),
6.91-7.11(2H),7.38(1H,t,J=8Hz),7.46-7.98
(8H),8.34(1H,t-like),8.9 2(1H,d-like)
(2)8-〔2,6-二氯-3-〔N-(3-甲氧基肉桂酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(DMSO-d6,δ):2.86(3H,s),3.13(3H,s),3.58
(1H,dd,J=16,6Hz),3.78(3H,s),3.90(1H,dd,
J=16,5Hz),5.63(2H,s),6.83(1H,d,J=15Hz),
6.98(1H,dd,J=8,3Hz),7.09-7.20(2H),
7.28-7.42(2H),7.70-7.97(6H),8.32(1H,
t-like),8.90(1H,d-like)
(3)8-〔2,6-二氯-3-〔N-( 4-甲氧基肉桂酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(DMSO-d6,δ):2.91(3H,s),3.16(3H,s),3.59
(1H,dd,J=16,5Hz),3.79(3H,s),3.89(1H,dd,
J=16,6Hz),5.63(2H,s),6.66(1H,d,J=15Hz),
6.99(2H,d,J=8Hz),7.34(1H,d,J=15Hz),7.52
(2H,d,J=8Hz),7.74-7.99(6H),8.24(1H,
t-like),8.96(1H,d-like)
(4)8-〔2,6-二氯-3-〔N-〔N ′-(2-甲氧基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基盐酸盐NMR(CDCl3-CD3OD,3:1 V/V,δ):2.93(3H,s),3.30
(3H,s),3.86(5H,s),5.60(1H,d,J=10Hz),
5.83(1H,d,J=10Hz),6.74(1H,dt,J=7,0.5Hz),
6.82-7.02(2H,m),7.57(1H,d,J=9Hz),7.65
(1H,d,J=9Hz),7.70-7.80(2H,m),7.81-8.01
(3H,m),8.95(1H,d,J=10Hz)
(5)8-〔2,6-二氯-3-〔N-〔N′-(3-甲氧基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.94(3H,s),3.30(3H,s),
3.70(3H,s),3.88(2H,s),5.60(1H,d,
J=10Hz),5.82(1H,d,J=10Hz),6.50(1H,dd,
J=8,1Hz),6.80(1H,dd,J=8,1Hz),6.98(1H,t,
J=1Hz),7.09(1H,t,J=7Hz),7.58(1H,d,
J=9Hz),7.66(1H,d,J=9Hz),7.76(1H,d,
J=7Hz),7.81-8.00(3H),8.93(1H,d,J=9Hz)
(6)8-〔2,6-二氯-3-〔N-〔N′-(4-甲氧基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.86(3H,s),3.29(3H,s),
3.71(3H,s),3.82(1H,d,J=16Hz),3.96(1H,d,
J=16Hz),5.60(1H,d,J=10Hz),5.82(1H,d,
J=10Hz),6.68(2H,d,J=10Hz),7.14(2H,d,
J=10Hz),7.58(1H,d,J=9Hz),7.63(1H,d,
J=9Hz),7.70-8.00(4H),8.90(1H,d,J=9Hz)
(7)8-〔2,6-二氯-3-〔N-〔N′-(2-乙氧基羰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):1.41(3H,t,J=7Hz),
2.99(3H,s),3.31(3H,s),3.79(1H,d,
J=17Hz),3.89(1H,d,J=17Hz),4.39(2H,q,
J=7Hz),5.61(1H,d,J=10Hz),5.81(1H,d,
J=10Hz),7.01(1H,t,J=8Hz),7.40(1H,dt,
J=9,1Hz),7.57(1H,d,J=9Hz),7.66(1H,d,
J=9Hz),7.77(1H,dd,J=8,1Hz),7.84-8.05(4H),
8.13(1H,d,J=9Hz),8.98(1H,J=9Hz)
(8)8-〔3-〔N-〔N′-(3-氰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,3:1 V/V,δ):3.06(3H,s),3.30
(3H,s),3.83(1H,d,J=17Hz),3.92(1H,d,
J=17Hz),5.60(1H,d,J=10Hz),5.83(1H,d,
J=10Hz),7.18-7.30(1H,m),7.31-7.41(2H,m),
7.59(1H,d,J=8Hz),7.65(1H,d,J=8Hz),7.77
(1H,br d,J=7Hz),7.82-8.04(4H,m),8.95(1H,
d,J=9Hz)
(9)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-(2-吡啶基甲基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3,δ):3.01(3H,s),3.28(3H,s),3.73
(2H,s),4.76(2H,br s),5.62(1H,d,J=10Hz),
5.79(1H,d,J=10Hz),7.58(1H,d,J=9Hz),7.67
(1H,d,J=9Hz),7.75(1H,dd,J=6,1Hz),
7.81-8.10(5H),8.54(1H,dt,J=7,1Hz),8.71
(1H,br d,J=6Hz),8.95(1H,d,J=9Hz)
(10))8-〔2,6-二氯-3-〔N-甲基-N-〔N′-(2-吡啶基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.10(1H,s),3.12(2H,s),
3.29(3H,s),3.76(0.8H,d,J=17Hz),3.92
(0.8H,d,J=17Hz),4.31(0.2H,d,J=17Hz),4.51
(0.2H,d,J=17Hz),5.50(0.3H,d,J=10Hz),5.68
(0.7H,d,J=10Hz),5.76(0.7H,d,J=10Hz),5.89
(0.3H,d,J=10Hz),7.30-7.49(8H),8.20(1H,br
d,J=7Hz),8.30(1H,br t,J=7Hz),8.92(1H,d,
J=9Hz)
(11)8-〔2,6-二氯-3-〔N-〔N′-(3-吡啶基甲基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,3:1 V/V,δ):3.01(3H,s),3.27
(3H,s),3.75(2H,s),4.50(2H,s),5.60(1H,
d,J=10Hz),5.77(1H,d,J=10Hz),7.55(1H,d,
J=9Hz),7.64(1H,d,J=9Hz),7.73(1H,d,
J=7Hz),7.80-8.11(4H,m),8.58(1H,br d,
J=7Hz),8.70(1H,d,J=6Hz),8.76(1H,br s),
8.93(1H,d,J=8Hz)
(12)8-〔3-〔N-〔N ′-(3-氨基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,3:1 V/V,δ):3.05(3H,s),3.29
(3H,s),3.83(2H,s),5.60(1H,d,J=10Hz),
5.81(1H,d,J=10Hz),6.98(1H,br d,J=9Hz),
7.27(1H,t,J=8Hz),7.31-7.54(2H,m),7.59
(1H,d,J=9Hz),7.65(1H,d,J=9Hz),7.75(1H,
d,J=8Hz),7.80-8.04(2H,m),8.93(1H,d,
J=8Hz)
(13)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-(4-吡啶基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):3.08(1H,s),3.12
(2H,s),3.28(2H,s),3.42(1H,s),3.80
(0.67H,d,J=15Hz),3.90(0.67H,d,J=15Hz),
4.29(0.33H,d,J=17Hz),4.46(0.33H,d,
J=17Hz),5.49(0.33H,d,J=9Hz),5.65(0.67H,d,
J=10Hz),5.75(0.67H,d,J=10Hz),5.89(0.33H,
d,J=9Hz),7.41-8.04(8H,m),8.35(0.67H,d,
J=7Hz),8.48(1.33H,d,J=7Hz),8.89(0.33H,d,
J=9Hz),9.05(0.67H,d,J=9Hz)
(14)8-〔2,6-二氯-3-〔N-〔N′-(4-吡啶基甲基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):2.93(3H,s),3.27
(3H,s),3.74(2H,s),4.58(2H,s),5.60(1H,
d,J=10Hz),5.78(1H,d,J=10Hz),7.57(1H,d,
J=9Hz),7.66(1H,d,J=9Hz),7.76(1H,d,
J=7Hz),7.80-8.10(5H,m),8.65-8.8l(2H,m),
8.95(1H,d,J=9Hz)
(15)8-〔2,6-二氯-3-〔N-〔N′-(3-吡啶基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):3.08(0.6H,s),3.18
(2.4H,s),3.29(2.4H,s),3.41(0.6H,s),3.36
(1.6H,s),4.28(0.2H,d,J=17Hz),4.41(0.2H,
d,J=17Hz),5.46(0.2H,d,J=10Hz),5.60(0.8H,
d,J=10Hz),5.78(0.8H,d,J=10Hz),5.90(0.2H,
d,J=10Hz),7.44-8.07(7H,m),8.23-8.44(1.8H,
m),8.53(0.2H,br d),8.91(0.2H,d,J=10Hz),
8.93(0.8H,d,J=10Hz),9.25(0.8H,br s),9.35
(0.2H,d,J=0.5Hz)
(16)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-(2-甲氧基乙基)-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):2.88-3.18(6H,m),
3.21-3.55(8H,m),3.64(2H,br s),3.86(2H,br
s),5.59(1H,d,J=10Hz),5.83(1H,d,J=10Hz),
6.96(1H,br d,J=6Hz),7.19-7.38(2H,m),
7.46-8.04(7H,m),8.94(1H,d,J=9Hz)
(17)8-[2,6-二氯-3-[N-甲基-N-[N′-[3-[N-甲基-N-(3-吡啶基甲基)氨基甲酰基]苯基]脲基乙酰基]氨基]苄氧基]-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD,3∶1V/V,δ):2.94(3H,s),3.09(3H,s),3.29(3H,s),3.82(1H,d,J=14HZ),3.91(1H,d,J=14HZ),4.88(2H,br,s),5.62(1H,d,J=10HZ),5.80(1H,d,J=10HZ),7.02(1H,brd,J=6HZ),7.27(1H,t,J=7HZ),7.35-8.22(10H,m),8.54-8.70(1H,m),8.81(1H,d,J=10Hz),8.88-9.10(2H,m)
(18)8-[2,6-二氯-3-[N-甲基-N-[N′-[3-[N-甲基-N-(2-吡啶基)氨基甲酰基]苯基]脲基乙酰基]氨基]苄氧基]-2-甲基喹啉二盐酸盐
NMR(CDCl3-CD3OD,δ):3∶02(3H,s),3.29(3H,s),3.59(3H,s),3.83(2H,s),5.60(1H,d,J=10HZ),5.81(1H,d,J=10HZ),6.91(1H,d,J=7HZ),7.14(1H,t,J=8HZ),7.28-7.70(6H),7.75(1H,d,J=7HZ),7.81-8.07(4H),8.53(1H,d,J=6HZ),8.93(1H,d,J=9Hz)
(19)8-[2,6-二氯-3-[N-[N′-[3-[N-乙基-N-甲基-氨基甲酰基)苯基]脲基乙酰基]-N-甲基氨基]苄氧基]-2-甲基喹啉盐酸盐
NMR(CDCl3-CD3OD,δ):1.05-1.22(3H),2.82-3.09(6H),3.19-3.50(5H),3.78-4.12(2H),5.09(1H,
d,J=10Hz),5.80(1H,d,J=10Hz),6.91(1H,d,
J=7Hz),7.17-8.00(9H),8.90(1H,d,J=9Hz)
(20)8-〔2,6-二氯-3-〔N-〔N′-〔3-(N-异丙基-N-甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):1.00(6H,br d,J=6Hz),
2.59-2.91(6H),3.18(3H,s),3.64-4.00(3H),
5.47(1H,d,J=10Hz),5.69(1H,d,J=10Hz),6.77
(1H,d,J=7Hz),7.03-7.30(3H),7.43-7.86(6H),
8.78(1H,d,J=9Hz)
(21)8-〔2,6-二氯-3-〔N-〔N′-(3-二乙基氨基甲酰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):1.14(6H,br q,
J=9Hz),2.90(3H,s),3.11-3.61(4H,m),3.30
(3H,s),3.83(1H,d,J=14Hz),3.96(1H,d,
J=14Hz),5.58(1H,d,J=10Hz),5.79(1H,d,
J=10Hz),6.90(1H,m),7.16-7.35(2H,m),
7.38-7.77(4H,m),7.79-8.01(3H,m),8.90(1H,
d,J=9Hz)
(22)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(2-吡啶基氨基甲酰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.04(3H,s),3.30(3H,s),
3.81(1H,d,J=16Hz),3.93(1H,d,J=16Hz),5.60
(1H,d,J=10Hz),5.81(1H,d,J=10Hz),7.32-8.12
(11H),8.41(2H,br d,J=5Hz),8.53(1H,br d,
J=6Hz),8.96(1H,d,J=9Hz)
(23)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-吡啶基氨基甲酰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.01(3H,s),3.30(3H,s),
3.90(2H,s),5.61(1H,d,J=10Hz),5.81(1H,d,
J=10Hz),7.38(1H,t,J=9Hz),7.57-8.08(9H),
8.48(2H,d,J=7Hz),8.57(2H,d,J=7Hz),8.96
(1H,d,J=9Hz)
(24)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-〔N-甲基-N-(4-吡啶基)氨基甲酰基〕苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.02(3H,s),3.30(3H,s),
3.60(3H,s),3.86(2H,s),5.62(1H,d,
J=10Hz),5.81(1H,d,J=10Hz),7.10(1H,d,
J=8Hz),7.31(1H,t,J=8Hz),7.49(1H,m),7.60
(1H,d,J=8Hz),7.67(1H,d,J=8Hz),7.71-8.00
(7H),8.58(2H,d,J=6Hz),8.99(1H,d,J=9Hz)
(25)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(5-嘧啶基氨基甲酰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):2.98(3H,s),3.29(3H,s),
3.32-4.13(2H),5.59(1H,d,J=10Hz),5.78(1H,
d,J=10Hz),7.30(1H,t,J=8Hz),7.49(1H,d,
J=9Hz),7.58-8.04(9H),8.92(1H,d,J=9Hz),
9.10(1H,br s),9.52(1H,br s)
(26)8-〔2,6-二氯-3-〔N-〔N ′-〔3-〔3-(N,N-二甲基氨基)苯基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.00(3H,s),3.29(6H,s),
3.31(3H,s),3.90(2H,s),5.60(1H,d,
J=10Hz),5.81(1H,d,J=10Hz),7.31(1H,t,
J=8Hz),7.40-7.98(12H),8.24(1H,br s),8.91
(1H,d,J=9Hz)
(27)8-〔2,6-二氯-3-〔N-〔N′-〔3-(4-乙基-1-哌嗪基羰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):1.46(3H,t,J=7Hz),
2.89-4.09(18H),5.59(1H,d,J=10Hz),5.81(1H,
d,J=10Hz),6.99(1H,d,J=7Hz),7.23(1H,t,
J=7Hz),7.31-7.62(4H),7.72(1H,d,J=7Hz),
7.79-8.00(3H),8.90(1H,d,J=9Hz)
(28)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔4-(甲基氨基甲酰基)-1-哌嗪基羰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.78(3H,s),2.99(3H,s),
3.26-3.79(11H),3.85(2H,s),5.61(1H,d,
J=10Hz),5.82(1H,d,J=10Hz),6.98(1H,d,
J=7Hz),7.22-7.53(3H),7.60(1H,d,J=9Hz),
7.69(1H,d,J=9Hz),7.79(1H,d,J=7Hz),
7.81-8.01(3H),8.96(1H,d,J=9Hz)
(29)8-〔2,6-二氯-3-〔N-〔N′-〔3-(4-二甲基氨基哌啶子基羰基)苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):1.67-1.91(2H),2.02-2.48
(2H),2.74-3.14(10H),3.29(3H,s),3.49(1H,
m),3.80-4.02(3H),4.78(1H,m),5.59(1H,d,
J=10Hz),5.82(1H,d,J=10Hz),6.99(1H,d,
J=7Hz),7.25(1H,t,J=7Hz),7.33-7.49(2H),
7.58(1H,d,J=9Hz),7.66(1H,d,J=9Hz),7.77
(1H,d,J=7Hz),7.81-8.00(3H),8.92(1H,d,
J=9Hz)
(30)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(1-吡咯烷基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):1.81-2.08(4H),2.98(3H,s),
3.30(3H,s),3.33-3.60(4H),3.87(2H,s),5.60
(1H,d,J=10Hz),5.81(1H,d,J=10Hz),7.06(1H,
d,J=7Hz),7.20-7.39(2H),7.51-7.61(2H),7.66
(1H,d,J=9Hz),7.74(1H,d,J=7Hz),7.81-8.00
(3H),8.92(1H,d,J=9Hz)
(31)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(1,2,3,6-四氢吡啶-1-基-羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):2.18-2.32(2H,m),
2.85-3.05(3H,m),3.29(3H,m),3.38-4.30(6H,
m),5.56(1H,d,J=10Hz),5.68-5.98(2H,m),
5.81(1H,d,J=10Hz),6.88-7.02(1H,m),
7.19-7.38(2H,m),7.43-8.00(7H,m),8.90(1H,
d,J=9Hz)
(32)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-〔3-(二甲基氨基)丙基〕-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):2.07-2.30(2H),2.80-3.42
(17H),3.50-4.01(4H),5.60(1H,br d,J=10Hz),
5.79(1H,br d,J=10Hz),6.96(1H,d,J=8Hz),
7.10-7.49(3H),7.56(1H,d,J=9Hz),7.62(1H,
d,J=9Hz),7.71(1H,d,J=7Hz),7.80-8.00(3H),
8.90(1H,m)
(33)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-(3-甲氧基丙基)-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,3:1 V/V,δ):1.66-2.02(2H,m),
2.94(3H,s),3.00(3H,s),3.13-3.66(10H,m),
3.85(2H,s),5.59(1H,d,J=8Hz),5.82(1H,d,
J=8Hz),6.92(1H,d,J=5Hz),7.15-8.06(9H,m),
8.92(1H,br s)
(34)8-〔3-〔N-〔N′-〔3-〔N,N-二(2-甲氧基乙基)氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.98(3H,s),3.21-3.97
(19H),5.61(1H,d,J=10Hz),5.85(1H,d,
J=10Hz),6.99(1H,m),7.21-7.34(2H),7.47(1H,
br s),7.60(1H,d,J=9Hz),7.69(1H,d,J=9Hz),
7.74-8.00(4H),8.95(1H,d,J=9Hz)
(35)8-〔3-〔N-〔N′-〔3-〔N,N-二(2-乙氧基乙基)氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):1.05-1.34(6H,m),
2.93(3H,s),3.23-3.78(12H,m),3.29(3H,s),
3.83(2H,s),5.59(1H,d,J=10Hz),5.80(1H,d,
J=10Hz),6.98(1H,d,J=7Hz),7.18-7.35(2H,m),
7.39-7.52(1H,m),7.60(1H,d,J=8Hz),7.68
(1H,d,J=8Hz),7.76(1H,d,J=7Hz),7.80-8.00
(3H,m),8.91(1H,d,J=9Hz)
(36)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-(2-羟基乙基)-N-甲基氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.95-3.13(6H),3.31(3H,s),
3.58-3.90(6H),5.61(1H,d,J=10Hz),5.85(1H,
d,J=10Hz),7.00(1H,m),7.21-7.35(2H),7.49
(1H,m),7.60(1H,d,J=9Hz),7.69(1H,d,
J=9Hz),7.76-7.99(4H),8.95(1H,d,J=9Hz)
(37)8-〔2,6-二氯-3-〔N-甲基-〔N-〔N′-〔3-〔N-甲基-N-(2-吡啶基甲基)氨基甲酰基〕苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):2.98(3H,s),3.20
(3H,br s),3.30(3H,s),3.86(2H,s),5.10
(2H,s),5.60(1H,d,J=10Hz),5.80(1H,d,
J=10Hz),7.01-7.17(1H,m),7.20-7.36(1H,m),
7.37-7.50(1H,m),7.52-7.69(2H,m),7.76(1H,
d,J=7Hz),7.80-8.15(6H,m),8.50-8.68(1H,m),
8.81(1H,br d,J=5Hz),8.95(1H,br d,J=9Hz)
(38)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔N-(2-甲氧基乙基)-N-(3-吡啶基甲基)氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):2.93(3H,s),3.23
(3H,s),3.29(3H,s),3.36-3.71(4H,m),3.80
(1H,d,J=16Hz),3.91(1H,d,J=16Hz),4.30-5.02
(2H,m),5.60(1H,d,J=10Hz),5.80(1H,d,
J=10Hz),6.95-7.10(1H,m),7,25(1H,br t,
J=8Hz),7.34-8.14(9H,m),8.44-9.06(4H,m)
(39)8-〔2,6-二氯-3-〔N-甲基-N-(3-苯基丙酰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.14(3H,s),3.31(3H,s),
3.89(2H,s),5.65(1H,d,J=10Hz),5.74(1H,d,
J=10Hz),7.29-7.76(8H,m),7.76-7.98(3H,m),
8.90(1H,dif-d)
(40)8-〔2,6-二氯-3-〔N-(4-甲酰基肉桂酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐及其水合物NMR(CDCl3-CD3OD,δ):3.16(15/8H,s),3.18(9/8H),
3.32(3H,s),3.80-4.10(2H,m),5.40(5/8H,s),
5.61(1H,d,J=10Hz),5.72(3/8H,d,J=10Hz),
5.75(5/8H,d,J=10Hz),6.57(5/8H,d,J=16Hz),
6.75-(3/8H,d,J=16Hz),7.38-7.73(7H,m),
7.73-7.96(4H,m),8.88(3/8H,d,J=8Hz),8,91
(5/8H,d,J=8Hz),10.00(3/5H,s)
(41)8-〔3-〔N-(4-氨基肉桂酰基甘氨酰基)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.04(3H,s),3.23(3H,s),
3.80(1H,d,J=17Hz),3.98(1H,d,J=17Hz),5.51
(1H,d,J=10Hz),5.68(1H,d,J=10Hz),6.51(1H,
d,J=16Hz),7.19-7.28(1H,m),7.28-7.56(6H,
m),7.60(1H,d,J=7.5Hz),7.68-7.92(3H,m),
8.86(1H,d,J=8Hz)
(42)8-〔2,6-二氯-3-〔N-甲基-N-((E)-2-甲基-3-苯基丙烯酰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.11(3H,s),3.16(3H,s),
3.36(3H,s),3.88(2H,s),5.61(1H,d,
J=10Hz),5.74(1H,d,J=10Hz),7.25-7.44(5H,
m),7.44-7.72(3H,m),7.76-7.98(3H,m),8.93
(1H,d,J=8Hz)
(43)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-(4-吡啶基)丙烯酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,3∶1,δ):3.90(1H,d,J=15Hz),
4.20(1H,d,J=15Hz),5.58(1H,d,J=10Hz),5.71
(1H,d,J=10Hz),7.30(1H,d,J=16Hz),7.44-7.71
(4H,m),7.71-7.97(3H,m),8.19(2H,d,J=6Hz),
8.77(2H,d,J=6Hz),8.88(1H,d,J=8Hz)
(44)8-〔2,6-二氯-3-〔N-〔4-(N,N-二甲基氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.01(3H,s),3.83(1H,d,
J=17.5Hz),3.97(1H,d,J=17.5Hz),5.67(1H,d,
J=11Hz),5.80(1H,d,J=11Hz),6.68(1H,d,
J=16Hz),7.33-8.00(11H,m),9.00(1H,d,J=8Hz)
(45)8-〔3-〔N-(4-氯肉桂酰基甘氨酰基)-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,3∶1,δ):3.26(3H,s),3.81(1H,
d,J=17Hz),3.93(1H,d,J=17Hz),5.57(1H,d,
J=10Hz),5.68(1H,d,J=10Hz),6.51(1H,d,
J=16Hz),7.25(2H,d,J=8Hz),7.33-7.67(6H,m),
7.71-7.91(3H,m),8.85(1H,d,J=8Hz)
(46)8-〔2,6-二氯-3-〔N-甲基-N-(4-甲基肉桂酰基甘氨酰基)氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.37(3H,s),3.14(3H,s),
3.31(3H,s),3.86(1H,d,J=17Hz),3.96(1H,d,
J=17Hz),5.60(1H,d,J=10Hz),5.73(1H,d,
J=10Hz),6.51(1H,d,J=16Hz),7.16(2H,d,
J=8Hz),7.35-7.71(6H,m),7.78-7.98(3H,m),
8.93(1H,d,J=8Hz)
(47)8-〔3-〔N-〔4-(乙酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕-2,6-乙氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.15(3H,s),3.07(3H,s),
3.28(3H,s),3.87(1H,d,J=16Hz),4.03(1H,d,
J=16Hz),5.58(1H,d,J=10Hz),5.74(1H,d,
J=10Hz),6.44(1H,d,J=16Hz),7.27-7.42(2H,
m),7.42-7.71(6H,m),7.79-7.97(3H,m),8.92
(1H,d,J=8Hz)
(48)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(N-甲基乙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):1.89(3H,s),3.12(3H,s),
3.27(3H,s),3.30(3H,s),5.61(1H,d,
J=10Hz),5.77(1H,d,J=10Hz),6.62(1H,d,
J=16Hz),7.23(1H,d,J=8Hz),7.41-7.77(6H,m),
7.77-8.05(3H,m),8.95(1H,d,J=8Hz)
(49)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(丙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):1.17(3H,t,J=8Hz),2.37
(3H,t,J=8Hz),3.03(3H,s),3.81(1H,d,
J=17Hz),3.97(1H,d,J=17Hz),5.52(1H,d,
J=9Hz),5.69(1H,d,J=9Hz),6.40(1H,d,
J=16Hz),7.20-7.39(3H,m),7.39-7.69(5H,
m),7.69-7.95(3H,m),8.75-8.97(1H,dif-d)
(50)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(N-甲基丙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):0.98(3H,t,J=8Hz),
1.93-2.14(2H,dif-q),3.03(3H,s),3.17(3H,
s),3.23(3H,s),3.72-3.95(2H,m),5.52(1H,
d,J=10Hz),5.66(1H,d,J=10Hz),6.52(1H,d,
J=16Hz),7.12(2H,d,J=8Hz),7.33-7.65(6H,m),
7.70-7.90(3H,m),8.86(1H,d,J=8Hz)
(51)8-〔2,6-二氯-3-〔N-〔4-(N-乙基乙酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):1.16(3H,t,J=7.5Hz),1.89
(3H,s),3.17(3H,s),3.36(3H,s),3.91(1H,
d,J=17Hz),4.03(1H,d,J=17Hz),5.67(1H,d,
J=10Hz),5.82(1H,d,J=10Hz),6.68(1H,d,
J=16Hz),7.23(2H,d,J=8Hz),7.49-7.80(6H,m),
7.83-8.06(3H,m),9.00(1H,d,J=8Hz)
(52)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(2-吡啶基甲氧基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.04(3H,s),3.83(1H,d,
J=16Hz),3.98(1H,d,J=16Hz),5.45-5.76(4H,
m),6.42(1H,d,J=16Hz),7.01(2H,d,J=8Hz),
7.21-7.67(6H,m),7.70-7.99(4H,m),8.16(1H,
d,J=8Hz),8.50(1H,d,J=8Hz),8.77-8.99(2H,
m)
(53)8-〔2,6-二氯-3-〔N-〔4-〔2-(N,N-二甲基氨基)乙氧基〕肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):2.94(6H,s),3.13(3H,s),
3.30(3H,s),3.55(2H,br peak),3.87(1H,d,
J=16Hz),4.02(1H,d,J=16Hz),4.47(2H,br
peak),5.58(1H,d,J=10Hz),5.73(1H,d,
J=10Hz),6.46(1H,d,J=16Hz),6.91(2H,d,
J=8Hz),7.32-7.74(6H,m),7.74-8.00(3H,m),
8.95(1H,d,J=8Hz)
(54)8-〔2,6-二氯-3-〔N-〔4-(2-羟基乙氧基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.10(3H,s),3.33(3H,s),
3.85-4.00(4H,m),4.11(2H,t,J=5Hz),5.61
(1H,d,J=10Hz),5.78(1H,d,J=10Hz),6.44(1H,
d,J=16Hz),6.93(2H,d,J=8Hz),7.38-7.77(6H,
m),7.77-8.03(3H,m),8.97(1H,d,J=8Hz)
(55)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.98(3H,s),3.10(3H,s),
3.31(3H,s),3.89(1H,d,J=17Hz),4.05(1H,d,
J=17Hz),5.59(1H,d,J=10Hz),5.75(1H,d,
J=10Hz),6.65(1H,d,J=16Hz),7.37-7.73(6H,
m),7.73-8.00(5H,m),8.92(1H,d,J=8Hz)
(56)8-〔2,6-二氯-3-〔N-〔4-(二甲基氨基甲酰基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.01(3H,s),3.10(6H,s),
3.31(3H,s),3.84-4.05(2H,m),5.60(1H,d,
J=10Hz),5.77(1H,d,J=10Hz),6.64(1H,d,
J=16Hz),7.34-7.59(3H,m),7.59-7.75(5H,m),
7.81-8.02(3H,m),8.95(1H,d,J=8Hz)
(57)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(3-甲基脲基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.72(3H,s),2.96(3H,s),
3.24(3H,s),3.91(2H,s),5.55(1H,d,
J=10Hz),5.68(1H,d,J=10Hz),6.26(1H,d,
J=16Hz),7.11-7.22(3H,m),7.34(2H,d,J=8Hz),
7.41-7.55(2H,m),7.60(1H,d,J=7.5Hz),
7.71-7.90(3H,m),8.87(1H,d,J=8Hz)
(58)8-〔2,6-二氯-3-〔N-〔4-(甲磺酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.94(3H,s),3.08(3H,s),
3.25(3H,s),3.84(1H,d,J=17.5Hz),4.00(1H,
d,J=17.5Hz),5.54(1H,d,J=10Hz),5.68(1H,d,
J=10Hz),6.45(1H,d,J=16Hz),7.16(2H,d,
J=8Hz),7.21-7.42(3H,m),7.42-7.65(3H,m),
7.70-7.91(3H,m),8.85(1H,d,J=8Hz)
(59)8-〔2,6-二氯-3-〔N-〔4-(甲氧基乙酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.09(3H,s),3.52(3H,s),
3.92(2H,d,J=12.5Hz),4.03(2H,s),5.60(1H,
d,J=10Hz),5.76(1H,d,J=10Hz),7.38-7.74(8H,
m),7.80-7.98(3H,m),8.94(1H,d,J=8Hz)
(60)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(3-吡啶基乙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.08(3H,s),3.30(3H,s),
3.95(2H,s),4.10(2H,s),5.58(1H,d,
J=10Hz),5.77(1H,d,J=10Hz),6.48(1H,d,
J=16Hz),7.28-7.44(3H,m),7.44-7.75(5H,m),
7.80-8.03(4H,m),8.66-8.79(2H,m),8.96(1H,
d,J=8Hz),9.03(1H,dif-d)
(61)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(异烟酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):3.10(3H,s),3.30(3H,s),
3.96(2H,d,J=2.5Hz),5.60(1H,d,J=10Hz),
5.78(1H,d,J=10Hz),6.54(1H,d,J=16Hz),
7.28-7.41(1H,m),7.41-7.78(5H,m),7.78-8.02
(5H,m),8.62(2H,d,J=5Hz),8.86-9.04(3H,m)
(62)8-〔3-〔N-〔4-(苯甲酰氨基)肉桂酰基甘氨酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.11(3H,s),3.98(1H,d,
J=17.5Hz),4.05(1H,d,J=17.5Hz),5.60(1H,d,
J=10Hz),5.75(1H,d,J=10Hz),7.36-7.63(8H,
m),7.63-7.80(3H,m),7.80-8.01(5H,m),8.94
(1H,d,J=8Hz)
(63)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(2-氧代-1-吡咯烷基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,3∶1 V/V,δ):2.14(3H,quint,
J=7.5Hz),2.59(2H,t,J=7.5Hz),3.10(3H,s),
3.25(3H,s),3.76-4.03(4H,m),5.56(1H,d,
J=10Hz),5.69(1H,d,J=10Hz),6.48(1H,d,
J=16Hz),7.34-7.69(8H,m),7.70-7.91(3H,m),
8.88-(1H,d,J=8Hz)
(64)8-〔2,6-二氯-3-〔N-(N′-乙基脲基乙酰基)-N-甲基氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):0.93(3H,t,J=7Hz),2.80
(3H,s),2.96(2H,q,J=7Hz),3.11(3H,s),3.64
(2H,s),4.20(3H,s),5.36(1H,d,J=10Hz),
5.59(1H,d,J=10Hz),7.11(1H,s),7.38(1H,d,
J=9Hz),7.42-7.52(2H),7.64(1H,t,J=8Hz),
7.83(1H,d,J=8Hz)
(65)8-〔2,6-二氯-3-〔N-甲基-N-(丁酰基甘氨酰基)氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):0.94(3H,t,J=7Hz),
1-51-1.72(2H),2.21(2H,t,J=7Hz),2.93(3H,
s),3.30(3H,s),3.78(2H,s),4.38(3H,s),
5.58(1H,d,J=10Hz),5.77(1H,d,J=10Hz),7.31
(1H,s),7.56(1H,d,J=9Hz),7.61-7.72(2H),
7.81(1H,t,J=8Hz),8.01(1H,d,J=8Hz)
(66)8-〔2,6-二氯-3-〔N-庚酰基甘氨酰基)-N-甲基氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):0.80-0.95(3H),1.20-1.40
(6H),1.49-1.68(2H),2.22(2H,t,J=7Hz),2.94
(3H,s),3.30(3H,s),3.69(1H,d,J=17Hz),
3.80(1H,d,J=17Hz),4.37(3H,s),5.56(1H,d
J=10Hz),5.74(1H,d,J=10Hz),7.31(1H,s),
7.52(1H,d,J=8Hz),7.66(2H,d,J=8Hz),7.80
(1H,t,J=8Hz),8.00(1H,d,J=8Hz)
(67)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-(3-吡啶基)丙烯酰基甘氨酰基〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):2.99(3H,s),3.31(3H,s),
3.89(1H,d,J=17Hz),4.03(1H,d,J=17Hz),5.60
(1H,d,J=10Hz),5.78(1H,d,J=10Hz),7.10(1H,
d,J=15Hz),7.40(1H,s),7.59-7.89(5H),
7.98-8.14(2H),8.71-8.83(2H),9.16(1H,br s)
(68)8-〔2,6-二氯-3-〔N-〔4-(二甲基氨基甲酰基)肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.98(3H,s),3.02(3H,br
s),3.13(3H,br s),3.31(3H,s),3.93(2H,s),
4.34(2H,s),5.59(1H,d,J=10Hz),5.77(1H,d,
J=10Hz),6.68(1H,d,J=15Hz),7.32(1H,s),
7.40-7.73(8H),7.82(1H,t,J=8Hz),8.01(1H,
d,J=8Hz)
(69)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(N-甲基乙酰氨基)肉桂酰基甘氨酰基〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):1.91(3H,s),2.98(3H,s),
3.23-3.33(6H),3.89(1H,d,J=17Hz),4.00(1H,
d,J=17Hz),4.36(3H,s),5.60(1H,d,J=10Hz),
5.79(1H,d,J=10Hz),6.65(1H,d,J=15Hz),
7.21-7.37(3H),7.44-7.77(6H),7.82(1H,t,
J=8Hz),8.02(1H,d,J=8Hz)
(70)8-〔2,6-二氯-3-〔N-〔N′-(3-二甲基氨基甲酰基苯基)脲基乙酰基〕-N-甲基氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.83(3H,s),2.98(3H,br
s),3.02(3H,br s),3.29(3H,s),3.87(2H,s),
4.33(3H,s).5.52(1H.d,J=10Hz),5.78(1H,d,
J=10Hz),6.95(1H,d,J=7Hz),7.20-7.32(3H),
7.49(1H,s),7.52-7.70(3H),7.80(1H,t,
J=8Hz),8.00(1H,d,J=8Hz)
(71)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-吡啶基)氨基甲酰基苯基〕脲基乙酰基〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):2.88(3H,s),3.30(3H,s),
3.81(1H,d,J=17Hz),3.93(1H,d,J=17Hz),4.30
(3H,s),5.57(1H,d,J=10Hz),5.79(1H,d,
J=10Hz),7.25-7.48(2H),7.54-7.71(6H),7.80
(1H,t,J=8Hz),7.93-8.04(2H),8.45-8.61(4H)
(72)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-甲基-1-哌嗪基羰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):2.90(3H,s),2.92(3H,s),
3.03-3.95(13H),4.36(3H,s),5.56(1H,d,
J=10Hz),5.80(1H,d,J=10Hz),7.06(1H,m),
7.27-7.77(7H),7.82(1H,t,J=8Hz),8.00(1H,
d,J=8Hz)
(73)8-〔3-〔N-〔N′-(3-乙酰基苯基)脲基乙酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-4-甲氧基-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):2.59(3H,s),2.95(3H,s),
3.31(3H,s),3.80(1H,d,J=17Hz),3.92(1H,d,
J=17Hz),4.34(3H,s),5.56(1H,d,J=10Hz),
5.79(1H,d,J=10Hz),7.29(1H,s),7.32-7.48
(2H),7.53-7.73(4H),7.81(1H,t,J=8Hz),8.01
(1H,d,J=8Hz),8.09(1H,br s)
(74)8-〔2,6-二氯-3-〔 N-〔4-〔N-(2-甲氧基乙基)氨基甲酰基〕肉桂酰基甘氨酰基〕-N-甲基氨基〕苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.10(3H,s),3.31(3H,s),
3.41(3H,s),3.61(4H,s),3.95(2H,s),5.61
(1H,d,J=10Hz),5.80(1H,d,J=10Hz),6.69(1H,
d,J=15Hz),7.40-8.01(11H),8.99(1H,d,J=9Hz)
(75)8-〔3-〔N-〔4-〔N,N-二(2-甲氧基乙基)氨基甲酰基〕肉桂酰基甘氨酰基〕-N-甲基氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉盐酸盐NMR(CDCl3-CD3OD,δ):3.09(3H,s),3.22-3.85
(17H),3.95(2H,s),5.63(1H,d,J=10Hz),5.82
(1H,d,J=10Hz),6.68(1H,d,J=15Hz),7.40-7.71
(8H),7.80(1H,d,J=7Hz),7.87-8.02(3H),9.00
(1H,d,J=8Hz)
制备42
(1)按照与制备18相似的方法将2-乙氧基乙基胺与氯甲酸苄基酯反应制得2-乙氧基乙基氨基甲酸苄基酯。NMR(CDCl3,δ):1.15(3H,t,J=7.5Hz),3.38(2H,q,
J=6Hz),3.42-3.53(4H,m),5.10(3H,s-like),
7.27-7.43(5H,m)
(2)按照与制备13相似的方法将2-乙氧基乙基氨基甲酸苄基酯与碘甲烷反应制得N-(2-乙氧基乙基)-N-甲基氨基甲酸苄基酯。NMR(CDCl3,δ):1.10-1.24(3H,m),3.00(3H,s),
3.35-3.62(6H,m),5.13(2H,s),7.24-7.44(5H,
m)
(3)按照与制备23相似的方法制得N-(2-乙氧基乙基)-N-甲基胺盐酸盐。NMR(CD3OD,δ):1.14-1.30(3H,m),2.70(3H,s),
3.12-3.23(2H,m),3.50-3.63(2H,m),3.63-3.73
(2H,m)
制备43
(1)在冰水浴中向4-氨基肉桂酸乙酯(3.00g)在二氯甲烷(21ml)中的溶液加入二碳酸二叔丁基酯(3.77g)和三乙胺(318mg)并将混合物在0℃搅拌1小时,在室温下搅拌3小时和加热回流12小时。将反应混合物倒入水中和用二氯甲烷萃取。过滤出沉淀。分离出有机层,用水洗和盐水洗,硫酸镁干燥和真空蒸发。剩余物在硅胶上以氯仿洗脱进行色谱纯化和从乙酸乙酯和正己烷的混合物中重结晶,产生4-(叔丁氧羰基氨基)肉桂酸乙酯(2.38g)结晶。mp:104.6-108.6℃NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),4.52(9H,
s),4.25(2H,q,J=7.5Hz),6.33(1H,d,J=16Hz),
6.57(1H,br s),7.38(2H,d,J=8Hz),7.46(2H,
d,J=8Hz),7.62(1H,d,J=16Hz)
(2)在冰水浴中于氮气氛下向氢化钠(60%矿物油中的分散液,165mg)在N,N-二甲基甲酰胺(1ml)中的悬浮液滴加4-(叔-丁氧羰基氨基)肉桂酸乙酯(1.00g)在N,N-二甲基甲酰胺(5ml)中的溶液和在同样条件下搅拌1小时。向混合物中加入2-溴乙基甲基醚(602mg),在同样条件下搅拌1小时和在室温下搅拌20小时。将反应混合物倒入水中和用乙酸乙酯萃取。将有机层分出,用水洗和盐水洗,硫酸镁干燥和真空蒸发。剩余物在硅胶上用正己烷和乙酸乙酯(4∶1)的混合物洗脱进行色谱纯化,产生油状的4-〔N-叔丁氧羰基-N-(2-甲氧基乙基)氨基〕肉桂酸乙酯(935mg)。NMR(CDCl3,δ):1.34(1H,t,J=7.5Hz),1.45(9H,
s),3.33(3H,s),3.54(2H,t,J=6Hz),3.80(2H,
t,J=6Hz),4.26(2H,q,J=7.5Hz),6.39(1H,d,
J=16Hz),7.29(2H,d,J=8Hz),7.48(2H,d,
J=8Hz),7.65(1H,d,d=16Hz)
(3)在冰水浴中向4-〔N-叔丁氧羰基-N-(2-甲氧基乙基)氨基〕肉桂酸乙酯(932mg)中加入三氟乙酸(3ml)和在同样温度下搅拌15分钟。减压蒸发出溶剂。剩余物分配于乙酸乙酯和碳酸氢钠水溶液中。用水洗和盐水洗有机层,硫酸镁干燥和真空蒸发。剩余物在硅胶上用正己烷和乙酸乙酯(3∶1)的混合物洗脱进行色谱纯化和从正己烷和乙酸乙酯的混合物中重结晶,产生4-(2-甲氧基乙基氨基)肉桂酸乙酯(470mg)结晶。mp:49.9-53.4℃NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),3.32(2H,q-
like,J=6Hz),3.40(3H,s),3.60(2H,t,J=6Hz),
4.24(2H,q,J=7.5Hz),4.35(1H,t-like),6.21
(1H,d,J=16Hz),6.60(2H,d,J=8Hz),7.38(2H,
d,J=8Hz),7.60(1H,d,J=16Hz)
(4)按照与制备24相似的方法将4-(2-甲氧基乙基氨基)肉桂酸乙酯与异烟酰氯盐酸盐反应制得4-〔N-(2-甲氧基乙基)-N-(异烟酰基)氨基〕肉桂酸乙酯。mp:98.4-102.3℃NMR(CDCl3,δ):1.31(3H,t,J=7.5Hz),3.35(3H,
s),3.65(2H,t,J=6Hz),4.08(2H,t,J=6Hz),
4.25(2H,q,J=7.5Hz),6.36(1H,d,J=16Hz),
7.06-7.20(4H,m),7.40(2H,d,J=8Hz),7.57
(1H,d,J=16Hz),8.47(2H,d,J=6Hz)
制备44
在室温下向(E)-3-(6-乙酰基氨基吡啶-3-基)丙烯酸(460mg)在乙醇(5.4ml)中的悬浮液加入1N氢氧化钠(5.4ml),混合物在50℃下搅拌3小时。将反应混合物调整到PH=7,用过滤法收集产生的沉淀和干燥,产生(E)-(6-氨基吡啶-3-基)丙烯酸(295mg)。mp:243.6-246.4℃NMR(DMSO-d6,δ):6.21(1H,d,J=15Hz),6.45(1H,
d,J=8Hz),6.52(2H,s),7.42(1H,d,J=15Hz),
7.75(1H,d,J=8Hz),8.11(1H,s)
制备45
(1)按照与制备36相似的方法将2,6-二氯-3-硝基苄醇与叔丁基二苯基甲硅烷基氯反应制得1-(叔丁基二苯基甲硅烷氧基甲基)-2,6-二氯-3-硝基苯。NMR(CDCl3,δ):1.05(9H,s),4.96(2H,s),7.27-
7.51(7H,m),7.58-7.81(5H,m)
(2)在60~70℃下,向搅拌着的1-(叔丁基二苯基甲硅烷氧基甲基)-2,6-二氯-3-硝基苯(433mg),三氯化铁六水合物(17.5mg)和活性炭(17.5mg)在甲醇(2.78ml)和水(0.69ml)混合溶剂中的混合物滴加肼单水合物(0.135ml)。加完后,将混合物回流半小时。将混合物冷却并过滤。真空浓缩滤液。剩余物用二氯甲烷萃取和将有机相用无水硫酸镁干燥。过滤后,真空浓缩滤液和产生的剩余物用正己烷洗,产生3-氨基-1-(叔丁基二苯基甲硅烷氧基甲基)-2,6-二氯苯(348mg)白色固体。NMR(CDCl3,δ):1.05(9H,s),4.07(2H,br s),4.87
(2H,s),6.66(1H,d,J=9Hz),7.08(1H,d,
J=9Hz),7.30-7.50(6H,m),7.70-7.84(4H,m)
(3)按照与实施例5相似的方法制得1-(叔丁基二苯基甲硅烷氧基甲基)-2,6-二氯-3-苯二甲酰亚氨基乙酰基氨基)苯。mp:198.1℃NMR(CDCl3,δ):1.04(9H,s),4.57(2H,s),4.90
(2H,s),7.25-7.50(7H,m),7.55-7.83(6H,m),
7.85-8.07(2H,m),8.00(1H,br s),8.25(1H,d,
J=8Hz)
(4)按照与实施例7相似的方法制得1-(叔丁基二苯基甲硅烷氧基甲基)-2,6-二氯-3-〔N-甲基-N-苯二甲酰亚氧基乙酰基)氨基〕苯。mp:167-172℃NMR(CDCl3,δ):1.06(9H,s),3.20(3H,s),4.04
(2H,s),4.98(2H,s),7.31-7.51(9H,m),7.65-
7.79(6H,m),7.80-7.92(2H,m)
(5)按照与实施例38相似的方法制得2,6-二氯-1-羟甲基-3-〔N-甲基-N-(苯二甲酰亚氨基乙酰基)氨基〕苯。mp:236.2-240.8℃NMR(CDCl3,δ):2.24(1H,t,J=7Hz),3.21(3H,s),
4.09(2H,s),5.04(2H,d,J=7Hz),7.43(1H,d,
J=8Hz),7.48(1H,d,J=8Hz),7.67-7.75(2H,m),
7.80-7.88(2H,m)
(6)在-20℃下,向2,6-二氯-1-羟甲基-3-〔N-甲基-N-(苯二甲酰亚氨基乙酰基)氨基〕苯(399mg)和三乙胺(0.17ml)在二氯甲烷(8ml)中的混合物加入甲磺酰氯(0.086ml),并将混合物搅拌1小时。将混合物用碳酸氢钠溶液洗和盐水洗,硫酸镁干燥和真空浓缩,产生2,6-二氯-1-甲基磺酰氧基甲基-3-〔N-甲基-N-(苯二甲酰亚氨基乙酰基)氨基〕苯(561mg)。NMR(CDCl3,δ):3.15(3H,s),3.24(3H,s),4.09
(2H,s),5.48(2H,s),7.56(2H,s),7.67-7.78
(2H,m),7.80-7.93(2H,m)
制备46
在60℃下,向2,3-二氨基苯酚(2.93g)在2M乙酸水溶液(47ml)和4M乙酸钠水溶液(29ml)中的悬浮液加入40%丙酮醛水溶液(3.79ml)。反应混合物在60℃下搅拌40分钟。冷却后用饱和碳酸氢钠将反应混合物调整到PH=8和用二氯甲烷(50ml)萃取两次。有机层用饱和碳酸氢钠洗,水洗和盐水洗。用无水硫酸镁干燥后,真空蒸发溶液。剩余物用快速柱色谱(硅胶450)mg)以正己烷/乙酸乙酯(5/1,V/V)洗脱进行纯化,产生8-羟基-2-甲基喹喔啉(弱极性产物)晶体和用正己烷/乙酸乙酯(3/1,V/V)洗脱进行纯化,产生8-羟基-3-甲基喹喔啉(强极性产物)晶体。前者用正己烷洗,产生浅黄色结晶(1.27g)。后者用异丙醚洗,产生浅黄色结晶(1.30g)。
8-羟基-2-甲基喹喔啉mp:83-84℃NMR(CDCl3,δ):2.78(3H,s),7.21(1H,m),7.60
(2H,d,J=5Hz),7.84(1H,s),8.79(1H,5)
8-羟基-3-甲基喹喔啉mp:104-105℃NMR(CDCl3,δ):2.80(3H,s),7.18(1H,d,
J=7.5Hz),7.55(1H,d,J=7.5Hz),7.67(1H,t,
J=7.5Hz),7.79(1H,s),8.60(1H,s)
制备47
(1)按照与制备16相似的方法从3-硝基-N-(2-甲氧基乙基)苯甲酰胺制得3-氨基-N-(2-甲氧基乙基)苯甲酰胺。NMR(CDCl3,δ):3.39(3H,s),3.56(2H,d,J=5Hz),
3.62(2H,d,J=5Hz),6.48(1H,br s),6.79(1H,
d,J=7.5Hz),7.06(1H,d,J=7.5Hz),7.10-7.27
(3H)
(2)按照与制备18相似的方法制得3-〔(2-甲氧基乙基)氨基甲酰基〕苯基氨基甲酸苯基酯。mp:142.1-150.3℃NMR(CDCl3,δ):3.38(3H,s),3.52(2H,d,J=5Hz),
3.62-3.72(2H),6.59(1H,br s),7.16-7.29(3H),
7.37-7.50(4H),7.65(1H,br s),7.80(1H,br d,
J=7.5Hz),7.95(1H,s)
制备48
(1)在3-15℃下用20分钟向2-氨基-3-甲氧基苯甲酸(10.3g),4-二甲基氨基吡啶(0.65g)和三乙胺(34.3ml)在N,N-二甲基甲酰胺(60ml)中的溶液加入乙酰氯(10.5ml)。然后将反应混合物加热至90℃。3小时后,用10分钟向反应混合物中分批加入碳酸铵(17.7g)。将反应混合物在同样温度下搅拌1小时。将混合物冷却,向其中加入水(300ml)。过滤收集沉淀,水洗和乙腈洗,产生8-甲氧基-2-甲基-4-氧代-3,4-二氢喹唑啉(9.24g)无色结晶。mp:261-262℃NMR(CDCl3,δ):2.32(3H,s),3.88(3H,s),7.30
(1H,d,J=7.5Hz),7.38(1H,t,J=7.5Hz),7.61
(1H,d,J=7.5Hz)
(2)按照与制备6相似的方法制得4-氯-8-甲氧基-2-甲基喹唑啉mp:101-102℃NMR(CDCl3,δ):2.91(3H,s),4.09(3H,s),7.27
(1H,d,J=7.5Hz),7.58(1H,t,J=7.5Hz),7.80
(1H,d,J=7.5Hz)
(3)4-氯-8-甲氧基-2-甲基喹唑啉(5.12g),10%固载于碳上的钯(5.12mg)和三乙胺(3.72g)在乙酸乙酯(51ml)中的混合物在氢气气氛下搅拌3小时。过滤除去催化剂,并将滤液浓缩。剩余物溶解在二氯甲烷中,溶液用饱和碳酸氢钠溶液洗,水洗和盐水洗,硫酸镁干燥,和浓缩。剩余物用硅胶柱色谱(二氯甲烷-甲醇)进行纯化,产生8-甲氧基-2-甲基喹唑啉(3.07g)。mp:131-132℃NMR(CDCl3,δ):2.95(3H,s),4.09(3H,s),7.21
(1H,d,J=7.5Hz),7.48(1H,d,J=7.5Hz),7.52
(1H,t,J=7.5Hz),9.30(1H,s)
(4)在3-5℃下,向8-甲氧基-2-甲基喹唑啉(1.50g)在二氯甲烷(10ml)中的溶液加入1M三溴化硼在二氯甲烷(12.9ml)中的溶液。10分钟后,将反应混合物在室温下搅拌2天。用饱和碳酸氢钠将混合物调至PH=7,和用二氯甲烷萃取两次。有机层用无水硫酸镁干燥,过滤和真空蒸发。剩余物从正己烷中结晶,产生8-羟基-2-甲基喹唑啉(1.22g)无色晶体。
mp:135-137℃
NMR(CDCl3,δ):2.89(3H,s),7.32(1H,d,
J=7.5Hz),7.41(1H,d,J=7.5Hz),7.49(1H,t,
J=7.5Hz),9.30(1H,s)
制备49
(1)按照与制备48-(1)相似的方法从2-氨基-3-羟基苯甲酸,乙酰氯和碳酸铵中制得8-羟基-2-甲基-4-氧代-3,4-二氢喹唑啉。
mp:258℃
NMR(DMSO-d6,δ):2.36(3H,s),3.35(1H,br,s),
7.13(1H,dd,J=8,2Hz),7.25(1H,t,J=8Hz),
7.49(1H,dd,J=8,2Hz)
(2)按照与实施例1相似的方法制得8-(2,6-二氯-3-硝基苄氧基)-2-甲基-4-氧代-3,4-二氢喹唑啉。mp:270-290℃(dec.)NMR(DMSO-d6,δ):2.30(3H,s),5.44(2H,s),7.40
(1H,t,J=8Hz),7.52(1H,dd,J=8,2Hz),7.73
(1H,dd,J=8,2Hz),7.89(1H,d,J=9Hz),8.19
(1H,d,J=9Hz)
制备50
将2-乙酰基氨基-5-甲酰基吡啶(241mg)和丙二酸(168mg)在吡啶(0.12ml)和乙醇(0.36ml)中的混合物回流2小时。将混合物冷却后,过滤收集沉淀,用乙酸乙酯洗,产生(E)-3-(6-乙酰基氨基-3-吡啶基)丙烯酸(248mg)无色粉末。mp:291-292℃NMR(DMSO-d6,δ):2.10(3H,s),6.55(1H,d,
J=16Hz),7.58(1H,d,J=16Hz),8.07-8.21(2H),
8.59(1H,br s)
制备51
按照与制备50相似的方法,自5-甲酰-2-吡啶羧酸乙酯制得(E)-3-(6-乙氧羰基-3-吡啶基)丙烯酸。mp:201-202℃NMR(DMSO-d6,δ):1.33(3H,t,J=7Hz),4.36(2H,q,
J=7Hz),6.80(1H,d,J=16Hz),7.69(1H,d,
J=16Hz),8.07(1H,d,J=9Hz),8.33(1H,dd,J=9,
2Hz),9.00(1H,d,J=2Hz)
制备52
(1)按照与制备30相似的方法,通过使4-甲酰苯甲酸与盐酸甲胺反应,得到4-(甲基氨基甲酰基)苯甲醛。mp:160.3-161℃NMR(DMSO-d6,δ):2.81(3H,d,J=5.5Hz),7.97(2H,
d,J=9.0Hz),8.02(2H,d,J=9.0Hz),8.67(1H,
m),10.06(1H,s)
(2)按照与制备50相似的方法,通过使4-(甲基氨基甲酰基)苯甲醛与丙二酸反应,得到4-(甲基氨基甲酰基)肉桂酸。mp:272.7℃NMR(DMSO-d6,δ):2.78(3H,d,J=5Hz),3.34(1H,br
s),6.62(1H,d,J=16Hz),7.61(1H,d,J=16Hz),
7.77(2H,d,J=8Hz),7.85(2H,d,J=8Hz),8.51
(1H,q-like)
制备53
(1)在冰浴冷却下,向2-(2-羟乙基)苯邻二甲酰亚胺(10.0g)和三乙胺(0.729ml)于1,4-二噁烷(50ml)的悬浮液中,加入异氰酸甲酯(4.63ml),混合物在环境温度下搅拌4天。真空除去溶剂,残余物用甲醇重结晶,得到2-邻苯二甲酰亚氨基乙基甲基氨基甲酸酯(10.13g)。mp:142.3-145.0℃NMR(CDCl3,δ):2.73(3H,d,J=4.5Hz),3.95(2H,t,
J=7.5Hz),4.30(2H,t,J=7.5Hz),4.60(1H,br
s),7.67-7.77(2H,m),7.80-7.90(2H,m)
(2)按照与实例9相似的方法,得到2-氨基乙基甲基氨基甲酸酯。NMR(CDCl3,δ):3.30(3H,d,J=6Hz),3.40(2H,t,
J=7.5Hz),4.06(2H,t,J=7.5Hz),4.74(2H,br s)
制备54
按照与制备18相似的方法,通过使4-氨基苯甲酸乙酯与氯甲酸苯酯反应,得到4-乙氧羰基苯基氨基甲酸苯酯。mp:155.6-161.7℃NMR(CDCl3,δ):1.38(3H,t,J=7.5Hz),4.37(2H,q,
J=7.5Hz),7.00-7.27(4H,m),7.27-7.45(2H,m),
7.51(2H,d,J=8Hz),8.02(2H,d,J=8Hz)
制备55
按照与制备13相似的方法,得到下述化合物。
(1)4-〔N-(3-吡啶基甲基)乙酰氨基〕肉桂酸乙酯(自4-乙酰氨基肉桂酸乙酯和3-吡啶基甲基氯盐酸盐)NMR(CDCl3,δ):1.34(3H,t,J=7Hz),1.92(3H,s),
4.29(2H,q,J=7Hz),4.90(2H,s),6.41(1H,d,
J=15Hz),7.02(2H,d,J=7Hz),7.24(1H,m),7.51
(2H,d,J=7Hz),7.60-7.70(2H),8.38(1H,br s),
8.51(1H,d,J=3Hz)
(2)4-〔N-(叔丁氧羰基甲基)乙酰氨基肉桂酸乙酯(自4-乙酰氨基肉桂酸乙酯和溴乙酸叔丁酯)NMR(CDCl3,δ):1.36(3H,t,J=7Hz),1.47(9H,s),
1.94(3H,s),4.21-4.32(4H),6.45(1H,d,
J=16Hz),7.35(2H,d,J=8Hz),7.58(2H,d,
J=8Hz),7.68(1H,d,J=16Hz)
(3)4-〔N-(2-吡啶基甲基)乙酰氨基〕肉桂酸乙酯(自4-乙酰氨基肉桂酸乙酯和2-吡啶基甲基氯盐酸盐)NMR(CDCl3,δ):1.31(3H,t,J=7.5Hz),1.96(3H,
s),4.25(2H,q,J=7.5Hz),5.01(2H,s),6.39
(1H,d,J=16Hz),7.06-7.23(3H,m),7.36(1H,d,
J=7.5Hz),7.49(2H,d,J=7.5Hz),7.55-7.70(2H,
m),8.49(1H,d,J=5Hz)
(4)4-〔N-(4-吡啶基甲基)乙酰氨基〕肉桂酸乙酯(自4-乙酰氨基肉桂酸乙酯和4-吡啶基甲基氯盐酸盐)NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),1.95(3H,
s),4.28(2H,q,J=7.5Hz),4.90(3H,s),6.43
(1H,d,J=16Hz),7.07(2H,d,J=8Hz),7.14(2H,
d,J=7Hz),7.51(2H,d,J=8Hz),7.65(1H,d,
J=16Hz),8.53(2H,d,J=7Hz)
(5)4-〔N-(2-甲氧乙基)乙酰氨基〕肉桂酸乙酯(自4-乙酰氨基肉桂酸乙酯和2-甲氧乙基溴)NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),1.85(3H,
s),3.30(3H,s),3.52(2H,t,J=6Hz),3.88(2H,
t,J=6Hz),4.28(2H,q,J=7.5Hz),6.44.(1H,d,
J=16Hz),7.25(2H,d,J=8Hz),7.56(2H,d,
J=8Hz),7.68(1H,d,J=16Hz)
(6)4-〔N-甲氧基乙酰基-N-(3-吡啶基甲基)氨基〕肉桂酸乙酯(自4-甲氧乙酰氨基)肉桂酸乙酯和3-吡啶基甲基氯盐酸盐)NMR(CDCl3,δ):1.32(3H,t,J=7.5Hz),3.35(3H,
s),3.81(2H,s),4.27(2H,q,J=7.5Hz),4.91
(2H,s),6.42(1H,d,J=16Hz),7.01(2H,d,
J=8Hz),7.18-7.28(1H,m),7.50(2H,d,J=8Hz),
7.57-7.72(2H,m),8.35(1H,d,J=2Hz),8.52
(1H,dd,J=6,2Hz)
制备56
(1)按照与制备18相似的方法,通过使4-氨基肉桂酸乙酯与氯甲酸苯酯反应,得到4-(苯氧羰基氨基)肉桂酸乙酯。mp:136-138℃NMR(CDCl3,δ):1.33(3H,t,J=7Hz),4.27(2H,q,
J=7Hz),6.39(1H,d,J=15Hz),7.09(1H,br s),
7.15-7.58(9H),7.65(1H,d,J=15Hz)
(2)将4-(苯氧羰基氨基)-肉桂酸乙酯(500mg),3-氨基吡啶(154mg)和三乙胺(325mg)的N,N-二甲基甲酰胺(5ml)溶液在80℃搅拌2小时。加水,过滤收集得到的沉淀,得到4-〔3-(3-吡啶基)脲基〕-肉桂酸乙酯(307mg),为无色粉末。mp:188-189℃NMR(DMSO-d6,δ):1.26(3H,t,J=7Hz),4.19(2H,q,
J=7Hz),6.50(1H,d,J=15Hz),7.34(1H,dd,J=9,
5Hz),7.46-7.72(5H),7.96(1H,dt,J=9,1Hz),
8.21(1H,dd,J=9,1Hz),8.62(1H,d,J=1Hz),
8.98(1H,br s),9.10(1H,m)
制备57
按照与制备24相似的方法,得到下述化合物。
(1)4-(吗啉代羰基氨基)肉桂酸乙酯
mp:170-173℃
NMR(CDCl3,δ):1.33(3H,t,J=7Hz),3.43-3.56
(4H),3.70-3.81(4H),4.28(2H,q,J=7Hz),6.35
(1H,d,J=15Hz),6.49(1H,br s),7.40(2H,d,
J=9Hz),7.48(2H,d,J=9Hz),7.63(1H,d,
J=15Hz)
(2)4-(4-溴丁酰氨基)肉桂酸乙酯mp:119-124℃NMR(CDCl3,δ):1.32(3H,t,J=7.5Hz),2.21(2H,
quint,J=6Hz),2.59(2H,t,J=6Hz),3.66(2H,t,
J=6Hz),4.25(2H,q,J=7.5Hz),6.34(1H,d,
J=16Hz),7.47(2H,d,J=8Hz),7.55(2H,d,
J=8Hz),7.61(1H,d,J=16Hz)
(3)4-〔(2-吡啶基)乙酰氨基〕肉桂酸乙酯mp:127℃NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),3.88(2H,
s),4.25(2H,q,J=7.5Hz),6.35(1H,d,J=16Hz),
7.20-7.35(2H,m),7.49(2H,d,J=8Hz),7.54-
7.80(4H,m),8.63(1H,d,J=5Hz),10.18(1H,s)
(4)4-〔(4-吡啶基)乙酰氨基〕肉桂酸乙酯mp:188℃NMR(CDCl3,δ):1.34(3H,t,J=7.5Hz),3.73(2H,
s),4.25(2H,q,J=7.5Hz),6.37(1H,d,J=16Hz),
7.20-7.35(2H,m),7.40(1H,s),7.43-7.55(4H,
m),7.52(1H,d,J=16Hz),8.62(2H,d,J=6Hz)
制备58
向搅拌中的4-羧基肉桂酸甲酯(400mg)的亚硫酰氯(1.4ml)悬浮液中加入一滴N,N-二甲基甲酰胺。混合物回流20分钟。真空除去溶剂。向残余物中加入甲苯(2ml),真空蒸发混合物两次。将残余物溶于二氯甲烷(4ml),冰-水浴下加入4-氨基吡啶(201mg)和三乙胺(0.81ml)。10分钟后,在环境温度下搅拌混合物。3小时后,向混合物中加水,混合物用二氯甲烷-甲醇(5∶1,V/V)萃取。有机层用饱和碳酸氢钠溶液,水和盐水洗涤,用无水硫酸镁干燥。真空蒸除溶剂,残余物用乙酸乙酯结晶,得到4-〔N-(4-吡啶基)氨基甲酰基〕肉桂酸甲酯(555mg),为无色粉末。mp:209-211℃NMR(DMSO-d6,δ):3.76(3H,s),6.82(1H,d,
J=15Hz),7.69-7.83(3H),7.92(2H,d,J=9Hz),
8.01(2H,d,J=9Hz),8.50(2H,d,J=7Hz)
制备59
按照与制备30或58相似的方法,得到下述化合物。
(1)4-(乙基氨基甲酰基)肉桂酸乙酯
mp:132-134.5℃
(2)4-(4-甲基-1-哌嗪基羰基)肉桂酸甲酯
mp:88-90℃
制备60
按照与制备33相似的方法,得到下述化合物。
(1)4-〔N-(4-吡啶基)氨基甲酰基〕肉桂酸mp:>250℃NMR(DMSO-d6,δ):6.69(1H,d,J=16Hz),7.52-8.08
(7H),8.49(2H,d,J=6Hz)
(2)4-〔N-(3-吡啶基甲基)乙酰氨基〕肉桂酸mp:184-186℃NMR(DMSO-d6,δ):1.90(3H,s),4.91(2H,s),6.52
(1H,d,J=15Hz),7.21-7.39(3H),7.50-7.79(4H),
8.39(1H,d,J=2Hz),8.43(1H,dd,J=5,2Hz)(3)4-〔3-(3-吡啶基)脲基〕肉桂酸mp:219-221℃NMR(DMSO-d6,δ):6.40(1H,d,J=15Hz),7.37(1H,
dd,J=9,5Hz),7.47-7.70(5H),7.98(1H,dt,
J=9,1Hz),8.21(1H,br d,J=5Hz),8.62(1H,d,
J=1Hz),9.03(1H,s),9.16(1H,s)(4)4-(吗啉代羰基氨基)肉桂酸mp:219-221℃(5)4-(乙基氨基甲酰基)肉桂酸mp:256-261℃(6)4-(4-甲基-1-哌嗪基羰基)肉桂酸NMR(DMSO-d6,δ):2.12-2.58(7H),2.92-3.87(4H,
overlapped with H2O),6.60(1H,d,J=16Hz),7.41
(2H,d,J=8Hz),7.62(1H,d,J=16Hz),7.78(2H,
d,J=8Hz)(7)4-(N-乙酰基-N-叔丁氧羰基甲基氨基)肉桂酸mp:177-178℃NMR(CDCl3,δ):1.48(9H,s),1.98(3H,s),4.28
(2H,s),6.48(1H,d,J=16Hz),7.39(2H,d,
J=8Hz),7.60(2H,d,J=8Hz),7.79(1H,d,
J=16Hz)(8)4-〔(2-吡啶基)乙酰氨基〕肉桂酸mp:215℃NMR(DMSO-d6,δ):3.90(2H,s),6.40(1H,d,
J=16Hz),7.34(1H,dd,J=5,8Hz),7.38-7.72(6H,
m),7.84(1H,td,J=8,1Hz),8.54(1H,d,J=5Hz)
(9)4-〔(4-吡啶基)乙酰氨基〕肉桂酸mp:>250℃NMR(DMSO-d6,δ):3.75(2H,s),6.42(1H,d,
J=16Hz),7.35(2H,d,J=5Hz),7.52(1H,d,
J=16Hz),7.65(4H,s-like),8.51(2H,d,J=5Hz)
(10)4-〔N-(2-吡啶基甲基)乙酰氨基〕肉桂酸NMR(DMSO-d6,δ):1.90(3H,s),4.97(2H,s),6.51
(1H,d,J=16Hz),7.24(1H,dd,J=5,7.5Hz),
7.29-7.45(3H,m),7.55(1H,d,J=16Hz),7.61-
7.80(3H,m),8.1-8.50(1H,m)(11)4-〔N-(4-吡啶基甲基)乙酰氨基〕肉桂酸NMR(CDCl3,δ):2.00(3H,s),4.91(2H,s),6.45
(1H,d,J=16Hz),7.09(2H,d,J=8Hz),7.20(2H,
d,J=6Hz),8.54(2H,d,J=8Hz),7.70(1H,d,
J=16Hz),8.55(2H,d,J=6Hz)(12)4-〔N-(甲氧基乙基)乙酰氨基〕肉桂酸mp:102-106℃NMR(CDCl3,δ):1.88(3H,s),3.30(3H,s),3.53
(2H,t,J=6Hz),5.89(2H,t,J=6Hz),6.45(1H,
d,J=16Hz),7.28(2H,d,J=8Hz),7.60(2H,d,
J=8Hz),7.77(1H,d,J=16Hz)(13)4-〔N-(2-甲氧乙基)-N-(异烟酰基)氨基〕肉桂酸NMR(CDCl3,δ):3.33(3H,s),3.66(2H,t,J=5Hz),
4.10(2H,t,J=5Hz),6.37(1H,d,J=16Hz),7.15
(2H,d,J=8Hz),7.20(2H,d,J=6Hz),7.40(2H,
d,J=8Hz),7.62(1H,d,J=16Hz),8.50(2H,d,
J=6Hz)
(14)4-〔N-甲氧乙酰基-N-(3-吡啶基甲基)氨基肉桂酸mp:160℃NMR(DMSO-d6,δ):3.20(3H,s),3.87(2H,s),4.91
(2H,s),6.54(1H,d,J=16Hz),7.27(8H,d),
7.27-7.38(1H,m),7.56(1H,d,J=16Hz),7.62
(1H,dd-like,J=8Hz),7.70(2H,d,J=8Hz),8.37
(1H,d,J=2Hz),8.43(1H,d,J=6Hz)
(15)4-(2-氧代-1-吡咯烷基)肉桂酸mp:>250℃NMR(DMSO-d6,δ):2.06(2H,quint,J=8Hz),3.86
(2H,t,J=8Hz),6.46(1H,d,J=16Hz),7.55(1H,
d,J=16Hz),7.65-7.76(4H,m)
制备61
在冰-水浴下,向N,N-双(2-甲氧乙基)胺(2.40g)和三乙胺(2.27g)的二氯甲烷(30ml)溶液中加入3-硝基苯甲酰氯(2.78g)。混合物在环境温度下搅拌1小时,用饱和氢氧化钠溶液,水和盐水洗涤,用无水硫酸镁干燥,真空除去溶剂。残余物用柱色谱提纯,二氯甲烷-甲醇洗脱,得到N,N-双(2-甲氧乙基)-3-硝基苯甲酰胺(4.12g),为油状物。NMR(CDCl3,δ):3.22-3.88(14H),7.59(1H,t,
J=8Hz),7.80(1H,dt,J=8,1Hz),8.26(1H,dt,
J=8,1Hz),8.39(1H,t,J=1Hz)
制备62
在环境温度下,N,N-双(2-甲氧乙基)-3-硝基苯甲酰胺(4.11g)和钯/炭(411mg)在乙酸乙酯(41ml)中的混合物在1个大气压氢压下氢化1小时。滤除催化剂,用乙酸乙酯洗涤,并真空除去挥发物。残余物用柱色谱提纯,二氯甲烷-甲醇洗脱,得到3-氨基-N,N-双(2-甲氧乙基)苯甲酰胺(3.62g),为油状物。NMR(CDCl3,δ):3.19-3.86(16H),6.62-6.79(3H),
7.16(1H,dt,J=8,1Hz)
制备63
在冰冷却浴下,向搅拌中的3-氨基-N,N-双(2-甲氧乙基)苯甲酰胺(1.01g)的1,4-二噁烷(10ml)溶液中相继加入1N氢氧化钠溶液(5.2ml)和氯甲酸苯酯(0.55ml)。撤掉冰浴,强烈搅拌反应混合物1小时,其间再次加入氯甲酸苯酯(0.25ml)。混合物用二氯甲烷萃取,有机相用水洗涤两次和用盐水洗涤,用无水硫酸镁干燥,真空蒸发。残余物用二异丙醚结晶,得到3-〔N,N-双(2-甲氧乙基)氨基甲酰基〕苯基氨基甲酸苯酯(1.30g),为无色粉末。mp:116-118℃NMR(CDCl3,δ):3.19-3.82(14H),7.10-7.57(10H)
制备64
在环境温度下,向搅拌中的4-(4-溴丁酰氧基)肉桂酸乙酯(420mg)的N,N-二甲基甲酰胺(5ml)溶液中加入碳酸铂(552mg),混合物在50℃保温3小时。用乙酸乙酯稀释反应混合物,用水和盐水洗涤,有机相用无水硫酸镁干燥,真空浓缩。残余物用快速柱色谱提纯,氯仿洗脱,得到4-(2-氧代-1-吡咯烷基)肉桂酸乙酯(281mg),为暗黄色固体。mp:134℃NMR(CDCl3,δ):1.34(3H,t,J=7.7Hz),2.19(2H,
quint,J=7.7Hz),2.63(2H,t,J=7.7Hz),3.88
(2H,t,J=7.7Hz),4.26(2H,q,J=7.7Hz),6.38
(1H,d,J=16Hz),7.53(2H,d,J=8Hz),7.64(1H,
d,J=16Hz),7.68(2H,d,J=8Hz)
实施例42
根据与实施例1相似的方法,得到8-(2,6-二氯-3-硝基苄氧基)-3-甲基喹啉。NMR(CDCl3,δ):2.50(3H,s),5.58(2H,s),7.18
(1H,dd,J=8,1Hz),7.36-7.57(3H),7.78(1H,d,
J=8Hz),7.90(1H,d,J=1Hz),8.79(1H,d,J=1Hz)
实施例43
在冰浴冷却下,向8-羟基-2-甲基喹啉(17.8g)的N,N-二甲基甲酰胺(89ml)溶液中加入氢化钠(40%油液,4.48g),常温下搅拌混合物40分钟。冰浴冷却下加入2,6-二氯-1-甲磺酰氧基-3-〔N-甲基-N-(苯二甲酰亚氨基乙酰基)氨基〕苯(56.1g)的N,N-二甲基甲酰胺(200ml)溶液,常温下搅拌混合物70分钟。滴加水(290ml),过滤收集沉淀,得到8-〔2,6-二氯-3-〔N-甲基-N-(苯二甲酰亚氨基乙酰基)氨基〕苄氧基〕-2-甲基喹啉(57.07g)。
mp:204℃.
实施例44
根据与实施例43相似的方法,得到下列化合物:
(1)8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲氨基〕苄氧基〕-3-甲基喹喔啉mp:238.8-240℃NMR(CDCl3,δ):2.78(3H,s),3.25(3H,s),4.12
(2H,s),5.59(1H,d,J=10Hz),5.63(1H,d,
J=10Hz),7.25-7.31(1H,overlapped with CDCl3),
7.51(1H,d,J=9Hz),7.56(1H,d,J=9Hz),7.67
7.77(4H),7.82-7.89(2H),8.74(1H,s)
(2)8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲氨基〕苄氧基〕-2-甲基喹喔啉mp:218-220℃NMR(CDCl3,δ):2.78(3H,s),3.24(3H,s),4.10
(2H,s),5.63(1H,d,J=10Hz),5.71(1H,d,
J=10Hz),7.33(1H,br d,J=7.5Hz),7.50(1H,d,
J=8Hz),7.54(1H,d,J=8Hz),7.63(1H,t,
J=7.5Hz),7.69-7.78(3H),7.82-7.90(2H),
8.73(1H,s)
(3)8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲氨基〕苄氧基〕噌啉mp:221.4-222℃NMR(CDCl3,δ):3.27(3H,s),4.12(2H,s),5.71
(2H,s),7.36(1H,d,J=7.5Hz),7.48(1H,d,
J=7.5Hz),7.52(1H,d,J=8Hz),7.58(1H,d,
J=8Hz),7.69-7.78(3H),7.81-7.90(3H),9.35
(1H,d,J=6Hz)
(4)8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲氨基〕苄氧基〕-2-甲基喹唑啉mp:237.5-238℃NMR(CDCl3,δ):2.90(3H,s),3.24(3H,s),4.10
(2H,s),5.66(1H,d,J=10Hz),5.72(1H,d,
J=10Hz),7.43-7.60(5H),7.70-7.75(2H),7.82-
7.89(2H),9.30(1H,s)
(5)5,7-二溴-8-〔2,6-二氯-3-〔N-(苯二甲酰亚氨基乙酰基)-N-甲氨基〕苄氧基〕-2-甲基喹啉mp:204-207℃NMR(CDCl3,δ):2.79(3H,s),3.17(3H,s),3.87
(1H,d,J=16.5Hz),3.98(1H,d,J=16.5Hz),5.92
(1H,d,J=11.5Hz),6.00(1H,d,J=11.5Hz),7.38
(1H,d,J=8.5Hz),7.44(1H,d,J=8.5Hz),7.51
(1H,d,J=8.5Hz),7.67-7.77(2H,m),7.81-7.91
(3H,m),8.30(1H,d,J=8.5Hz)
实施例45
根据与实施例7相似的方法,使8-〔2,6-二氯-3-(苯二甲酰亚氨基乙酰基)-苄氧基〕-2-甲基喹啉与苄基溴反应,得到8-〔3-〔N-苄基-N-(苯二甲酰亚氨基乙酰基)氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉。NMR(CDCl3,δ):2.75(3H,s),3.98-4.06(2H),4.09
(1H,d,J=17Hz),5.62(1H,d,J=14Hz),5.68(1H,
d,J=10Hz),5.73(1H,d,J=10Hz),6.92(1H,d,
J=8Hz),7.16-7.35(8H),7.40(1H,t,J=7.5Hz),
7.47(1H,d,J=7.5Hz),7.70-7.78(2H),7.85-7.91
(2H),8.02(1H,d,J=7.5Hz)
实施例46
根据与实施例9相似的方法,得到下列化合物:
(1)8-〔3-(N-甘氨酰-N-甲氨基)-2,6-二氯苄氧基〕-3-甲基喹喔啉NMR(CDCl3,δ):2.77(3H,s),2.98-3.32(5H),5.57
(2H,s),7.21-7.30(2H),7.48(1H,d,J=8Hz),
7.67-7.75(2H),8.74(1H,s)
(2)8-〔3-(N-甘氨酰-N-甲氨基)-2,6-二氯苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.79(3H,s),3.00(1H,d,J=17Hz),
3.11(1H,d,J=17Hz),3.22(3H,s),5.62(2H,
s),7.23-7.33(2H),7.49(1H,d,J=8Hz),7.64
(1H,d,J=7.5Hz),7.6 3(1H,br d,J=7.5Hz),8.75
(1H,s)
(3)8-〔3-(N-甘氨酰-N-甲氨基)-2,6-二氯苄氧基〕噌啉NMR(CDCl3,δ):3.02(1H,d,J=17Hz),3.13(1H,d,
J=17Hz),3.24(3H,s),5.65(1H,d,J=10Hz),
5.70(1H,d,J=10Hz),7.28-7.36(2H),7.42-7.51
(2H),7.71(1H,t,J=7.5Hz),7.82(1H,d,
J=7.5Hz),9.36(1H,d,J=6Hz)
(4)8-〔3-(N-甘氨酰-N-甲氨基)-2,6-二氯苄氧基〕-2-甲基喹唑啉NMR(CDCl3,δ):2.90(3H,s),3.00(1H,d,J=16Hz),
3.11(1H,d,J=16Hz),3.22(3H,s),5.62(2H,
s),7.28(1H,d,J=8Hz),7.40-7.59(4H),9.31
(1H,s)
(5)8-〔3-(N-甘氨酰-N-苄氧基)-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.75(3H,s),2.99(1H,d,J=17Hz),
3.08(1H,d,J=17Hz),3.94(1,d,J=14Hz),3.60-
3.72(3H),6.69(1H,d,J=7.5Hz),7.15-7.33
(8H),7.39(1H,t,J=7.5Hz),7.48(1H,d,
J=7.5Hz),8.03(1H,br d,J=7.5Hz)
(6)8-〔3-(N-甘氨酰-N-甲氨基)-2,6-二氯苄氧基〕-5,7-二溴-2-甲基喹啉NMR(CDCl3,δ):2.78(3H,s),2.84(1H,d,
J=16.5Hz),3.03(1H,d,J=16.5Hz),3.16(3H,s),
5.90(2H,s),7.22(1H,d,J=8.5Hz),7.41(1H,
d,J=8.5Hz),7.43(1H,d,J=8.5Hz),7.85(1H,
s),8.34(1H,d,J=8.5Hz)
实施例47
(1)根据与实施例7相似的方法,使8-〔2,6-二氯-3-(苯二甲酰亚氨基乙酰基氨基)苄氧基〕-2-甲基喹啉与溴乙酸乙酯反应,得到8-〔2,6-二氯-3-〔N-乙氧羰基甲基-N-苯二甲酰亚氨基乙酰基)氨基〕苄氧基〕-2-甲基喹啉。mp:211-213℃NMR(CDCl3,δ):1.28(3H,t,J=7.5Hz),2.73(3H,
s),3.68(1H,d,J=17Hz),4.03(1H,d,J=17Hz),
4.13-4.30(3H),5.00(1H,d,J=17Hz),5.65(1H,
d,J=10Hz),5.70(1H,d,J=10Hz),7.23-7.31
(2H),7.36-7.49(3H),7.69-7.75(2H),7.81-7.91
(3H),8.01(1H,d,J=8Hz)
(2)在常温下,向8-〔2,6-二氯-3-〔N-乙氧羰基甲基-N-(苯二甲酰亚氨基乙酰基)氨基〕苄氧基〕-2-甲基喹啉(527mg)的二氯甲烷(5.3ml)溶液中加入30%甲胺的甲醇(2ml)溶液。搅拌24小时后,真空蒸发反应混合物。残余物用柱色谱提纯(硅胶50ml),用二氯甲烷/甲醇(20/1,V/V)洗脱,经异丙醚结晶,得到8-〔2,6-二氯-3-(2,5-二氧哌嗪-1-基)苄氧基〕-2-甲基喹啉(187mg),为无色晶体。mp:211-213℃NMR(CDCl3,δ):2.74(3H,s),4.09-4.21(3H),4.40
(1H,d,J=17Hz),5.62(2H,s),6.38(1H,br s),
7.21-7.51(6H),8.01(1H,d,J=8Hz)
(3)根据与实施例7相似的方法,使8-〔2,6-二氯-3-(2,5-二氧哌嗪-1-基)苄氧基〕-2-甲基喹啉与苄基溴反应,得到8-〔3-(4-苄基-2,5-二氧哌嗪-1-基)-2,6-二氯苄氧基〕-2-甲基喹啉。NMR(CDCl3,δ):2.75(3H,s),4.01(1H,d,
J=17Hz),4.10(1H,d,J=17Hz),4.21(1H,d,
J=17Hz),4.48(1H,d,J=17Hz),4.63(1H,d,
J=15Hz),4.72(1H,d,J=15Hz),5.62(2H,s),
7.20-7.52(11H),8.02(1H,d,J=8Hz)
(4)根据与实施例7相似的方法,使8-〔2,6-二氟-3-(2,5-二氧哌嗪-1-基)苄氧基〕-2-甲基喹啉与溴乙酸乙酯反应,得到8-〔2,6-二氯-3-(4-乙氧羰基甲基-2,5-二氧哌嗪-1-基)苄氧基〕-2-甲基喹啉。NMR(CDCl3,δ):1.31(3H,t,J=7.5Hz),2.74(3H,
s),4.11-4.36(7H),4.48(1H,d,J=17Hz),5.61
(2H,s),7.21-7.32(3H),7.36-7.51(3H),8.02
(1H,d,J=8Hz)
实施例48
根据与制备6相似的方法,由8-〔2,6-二氯-3-硝基苄氧基)-2-甲基-4-氧代-3,4-二氢喹唑啉,得到4-氯-8-(2,6-二氯-3-硝基苄氧基)-2-甲基喹唑啉。mp:192.8-194.3℃NMR(CDCl3,δ):2.86(3H,s),5.66(2H,s),7.44-
7.65(3H,m),7.80(1H,d,J=9Hz),7.91(1H,dd,
J=8,0.5Hz)
实施例49
在常温下,搅拌8-〔2,6-二氯-3-〔N-甘氨酰-N-甲氨基)苄氧基〕-2-甲基喹啉(100mg),乙酸酐(35ml),吡啶(60μl)和二氯甲烷(2ml)的混合物3小时,浓缩反应混合物。残余物用制备性薄层色谱提纯(乙酸乙酯/甲醇),得到8-〔3-〔N-(乙酰基甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(138mg)。NMR(CDCl3,δ):2.00(3H,s),2.74(3H,s),3.24
(3H,s),3.50(1H,dd,J=17,4Hz),3.80(1H,dd,
J=17,5Hz),5.63(2H,s),6.33(1H,br s),7.21-
7.34(2H,m),7.37-7.52(4H,m),8.01(1H,d,
J=7.5Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.98(3H,s),3.01(3H,s),
3.28(3H,s),3.75(1H,d,J=15Hz),3.80(1H,d,
J=15Hz),5.65(1H,d,J=9Hz),5.80(1H,d,
J=9Hz),7.60(1H,d,J=8Hz),7.70(1H,d,
J=8Hz),7.83(1H,d,J=8Hz),7.86-8.02(3H,m),
9.00(1H,d,J=8Hz)
实施例50
根据与实施例49相似的方法,得到下列化合物:
(1)8-〔3-〔N-(乙酰基甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-3-甲基喹喔啉NMR(CDCl3,δ):2.01(3H,s),2.78(3H,s),3.25
(3H,s),3.53(1H,dd,J=17,4Hz),3.80(1H,dd,
J=17,5Hz),5.54(2H,s),6.42(1H,br s),7.26
(1H,overlapped with CDCl3),7.31(1H,d,
J=8Hz),7.49(1H,d,J=8Hz),7.66-7.78(2H),
8.23(1H,s)
(2)8-〔3-〔N-(乙酰基甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.01(3H,s),2.78(3H,s),3.24
(3H,s),3.52(1H,dd,J=17,4Hz),3.80(1H,dd,
J=17,4Hz),5.60(2H,s),6.42(1H,br s),7.30
(1H,d,J=9Hz),7.50(1H,d,J=7.5Hz),7.65(1H,
t,J=7.5Hz),7.77(1H,br d,J=7.5Hz),8.72(1H,
s)
(3)8-〔3-〔N-(乙酰基甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕噌啉NMR(CDCl3,δ):2.01(3H,s),3.28(3H,s),3.54
(1H,dd,J=17,4Hz),3.80(1H,dd,J=17,5Hz),
5.63(1H,d,J=10Hz),5.69(1H,d,J=10Hz),6.45
(1H,br s),7.30-7.38(2H),7.42-7.52(2H),7.73
(1H,t,J=7.5Hz),7.82(1H,d,J=7.5Hz),9.34
(1H,d,J=6Hz)
(4)8-〔3-〔N-(乙酰基甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹唑啉NMR(CDCl3,δ):2.01(3H,s),2.90(3H,s),3.26
(3H,s),3.51(1H,dd,J=17,4Hz),3.80(1H,dd,
J=17,4Hz),5.62(2H,s),6.43(1H,br s),7.30
(1H,d,J=7.5Hz),7.31-7.59(4H),9.30(1H,s)
(5)8-〔3-〔N-(乙酰基甘氨酰)-N-苄氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMH(CDCl3,δ):2.02(3H,s),2.77(3H,s),3.51
(1H,dd,J=17,4Hz),3.79(1H,dd,J=17,5Hz),
3.98(1H,d,J=14Hz),5.60-5.72(3H),6.47(1H,
br s),6.71(1H,d,J=8Hz),7.15-7.33(8H),7.40
(1H,t,J=7.5Hz),7.48(1H,d,J=7.5Hz),8.03
(1H,d,J=7.5Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.01(3H,s),3.08(3H,s),
3.68-3.80(2H,overlapped with H2O),4.24(1H,
d,J=14Hz),5.53(1H,d,J=14Hz),5.59(1H,d,
J=10Hz),5.73(1H,d,J=10Hz),6.99(1H,d,
J=7.5Hz),7.21-7.34(5H),7.43(1H,d,J=7.5Hz),
7.70(1H,d,J=7.5Hz),7.82-7.98(3H),8.96(1H,
d,J=7.5Hz)
(6)8-〔3-〔N-(乙酰基甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-5,7-二溴-2-甲基喹啉mp:179-183.5℃NMR(CDCl3,δ):2.01(3H,s),2.81(3H,s),3.20
(3H,s),3.41(1H,dd,J=16.5,3.0Hz),3.78(1H,
dd,J=16.5,3.0Hz),5.87(1H,d,J=10.5Hz),5.93
(1H,d,J=10.5Hz),6.38(1H,br t),7.25(1H,d,
J=8.5Hz),7.41(1H,d,J=8.5Hz),7.44(1H,d,
J=8.5Hz),7.86(1H,s),8.34(1H,d,J=8.5Hz)
其盐酸盐mp:93-96.5℃NMR(CDCl3-CD3OD,δ):2.01(3H,s),2.96(3H,s),
3.20(3H,s),3.42(1H,d,J=16.5Hz),3.80(1H,
d,J=16.5Hz),5.88(2H,s),7.31(1H,d,
J=8.5Hz),7.46(1H,d,J=8.5Hz),7.54(1H,d,
J=8.5Hz),7.97(1H,s),8.52(1H,d,J=8.5Hz)
实施例51
根据与实施例11和13相似的方法,得到下列化合物:
(1)8-〔2,6-二氯-3-〔N-〔N′-(4-乙氧羰基苯基)-脲基乙酰基〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.32(3H,t,J=7.5Hz),2.55(3H,
s),3.21(3H,s),3.77(1H,dd,J=4.5,18Hz),
4.30(2H,q,J=7.5Hz),4.45(1H,dd,J=7.5,
18Hz),5.43(1H,d,J=10Hz),5.55(1H,dd,
J=4.5,7.5Hz),5.62(1H,d,J=10Hz),7.20-7.35
(6H,m),7.44-7.55(2H,m),7.80(2H,d,J=8Hz),
8.10(1H,d,J=8Hz),8.99(1H,s)
(2)8-〔3-〔N-〔N′-(3-〔N,N-二(2-甲氧乙基)氨基甲酰基〕-苯基〕脲基乙酰基〕-N-甲氨基〕-2,6-二氯苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):2.53(3H,s),3.12-3.85(18H),4.03
(3H,s),4.39(1H,dd,J=18,7Hz),5.40(1H,d,
J=10Hz),5.50-5.67(2H),6.68(1H,s),6.91(1H,
d,J=8Hz),7.08-7.50(7H),7.82(1H,d,J=8Hz),
8.85(1H,br s)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.87(3H,s),3.20-3.81
(18H),3.89(1H,d,J=17Hz),4.32(3H,s),5.54
(1H,d,J=10Hz),5.80(1H,d,J=10Hz),6.99(1H,
m),7.20-7.38(2H),7.41-7.52(2H),7.58(1H,d,
J=9Hz),7.62-7.72(2H),7.81(1H,t,J=8Hz),
8.00(1H,d,J=8Hz)
(3)8-〔2,6-二氯-3-〔N-〔N ′-(3-二甲基氨基甲酰基)-苯基〕脲基乙酰基〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.71(3H,s),2.94(3H,br s),3.09
(3H,br s),3.23(3H,s),3.78(1H,dd,J=17,
5Hz),3.84(1H,dd,J=17,5Hz),5.56(1H,d,
J=10Hz),5.62(1H,d,J=10Hz),5.82(1H,br t,
J=5Hz),6.99(1H,d,J=7.5Hz),7.10(1H,t,
J=7.5Hz),7.29-7.38(4H),7.43(1H,d,J=8Hz),
7.68(1H,t,J=7.5Hz),7.78(1H,d,J=7.5Hz),
7.89(1H,br s),8.76(1H,s)
(4)8-〔2,6-二氯-3-〔N-〔N′-〔3-〔(2-甲氧乙基)氨基甲酰基〕苯基〕脲基乙酰基〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.71(3H,s),3.23(3H,br s),3.37
(3H,s),3.49-3.66(4H),3.79(1H,dd,J=17,
5Hz),3.89(1H,dd,J=17,5Hz),5.56(1H,d,
J=10Hz),5.64(1H,d,J=10Hz),5.92(1H,br t,
J=5Hz),6.80(1H,br t,J=5Hz),7.18-7.58(7H),
7.68(1H,t,J=8Hz),7.78(1H,d,J=8Hz),7.83
(1H,br s),8.73(1H,s)
实施例52
根据与实施例15或16相似的方法,得到下列化合物:
(1)8-〔2,6-二氯-3-〔N-〔4-(甲氧羰基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.27(3H,s),3.64
(1H,dd,J=18,4Hz),3.87-4.00(4H,m),5.60-
5.70(2H,m),6.57(1H,d,J=16Hz),6.75(1H,t-
like),7.24-7.63(11H,m),7.99-8.05(1H,m)
(2)8-(2,6-二氯-3-〔N-甲基-N-〔4-(4-甲基-1-哌嗪羰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.26-2.57(7H),2.74(3H,s),3.29
(3H,s),3.36-3.89(9H),3.96(1H,dd,J=18,
5Hz),5.65(2H,s),6.51(1H,d,J=16Hz),6.70
(1H,br t,J=4Hz),7.21-7.63(11H),8.03(1H,d,
J=8Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):2.90(3H,s),2.99-3.21(5H),
3.28-3.88(9H),3.94(2H,s),5.62(1H,d,
J=10Hz),5.81(1H,d,J=10Hz),6.70(1H,d,
J=16Hz),7.40-7.70(7H),7.89(1H,d,J=7Hz),
7.87-8.01(3H),9.00(H,d,J=9Hz)
(3)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(4-吡啶基)-氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.69(3H,s),3.28(3H,s),
3.58-3.73(1H,overlapped with H2O),4.02(1H,
d,J=18Hz),5.09(2H,s),6.62(1H,d,J=16Hz),
7.21-7.62(9H),7.76(2H,d,J=7Hz),7.89(2H,
d,J=8Hz),8.10(1H,d,J=8Hz),8.43(1H,d,
J=7Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.10(3H,s),3.32(3H,s),
3.91(1H,d,J=17Hz),4.03(1H,d,J=17Hz),5.63
(1H,d,J=10Hz),5.82(1H,d,J=10Hz),6.78(1H,
d,J=15Hz),7.51-8.02(9H),8.16(2H,d,J=8Hz),
8.58(4H,s),9.00(1H,d,J=8Hz)
(4)8-〔3-〔N-〔4-(乙酰基-N-叔丁氧羰基甲氨基)肉桂酰甘氨基〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.48(9H,s),1.94(3H,s),2.73
(3H,s),3.29(3H,s),3.69(1H,dd,J=18,4Hz),
3.98(1H,dd,J=18,5Hz),4.26(2H,s),5.65
(2H,s),6.49(1H,d,J=15Hz),6.70(1H,br t,
J=4Hz),7.22-7.63(11H),8.03(1H,d,J=8Hz)
(5)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔N-(3-吡啶基甲基)乙酰氨基)肉桂酰甘氨基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.91(3H,s),2.73(3H,s),3.28
(3H,s),3.68(1H,dd,J=18,4Hz),3.98(1H,dd,
J=18,5Hz),4.89(2H,s),5.65(2H,s),6.48
(1H,d,J=16Hz),6.70(1H,br t,J=4Hz),6.99
(2H,d,J=8Hz),7.19-7.69(11H),8.03(1H,d,
J=8Hz),8.38(1H,d,J=2Hz),8.51(1H,dd,J=5,
2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):1.99(3H,s),3.09(3H,s),
3.31(3H,s),3.93(2H,br s),5.10(2H,s),
5.62(1H,d,J=10Hz),5.81(1H,d,J=10Hz),6.68
(1H,d,J=16Hz),7.21(1H,d,J=9Hz),7.49-7.70
(5H),7.78(1H,br d,J=8Hz),7.85-8.11(4H),
8.52(1H,br d,J=8Hz),8.72-8.82(2H),9.00
(1H,d,J=9Hz)
(6)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔N′-(3-吡啶基)脲基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.70(3H,s),3.22(3H,s),
3.63(1H,br d,J=18Hz),3.93(1H,br d,
J=18Hz),5.59(2H,s),6.40(1H,d,J=15Hz),
7.08(0.7H,m),7.20-7.58(12H),8.09(1H,d,
J=15Hz),8.13-8.32(3H)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.09(3H,s),3.31(3H,s),
3.96(2H,s),5.60(1H,d,J=10Hz),5.81(1H,d,
J=10Hz),6.49(1H,d,J=15Hz),7.36-7.68(7H),
7.77(1H,br d,J=8Hz),7.84-8.00(4H),8.31
(1H,br d,J=5Hz),8.62(1H,br d,J=9Hz),8.99
(1H,d,J=9Hz),9.33(1H,d,J=2Hz)
(7)8-〔2,6-二氧-3-〔N-甲基-N-〔4-(吗啉代羰基氨基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.71(3H,s),3.23(3H,s),3.41-
3.60(5H),3.64-3.77(4H),3.92(1H,dd,J=17,
5Hz),5.62(2H s),6.39(1H,d,J=15Hz),6.59
(1H,br t,J=4Hz),6.73(1H,br s),7.22-7.58
(11H),8.03(1H,d,J=9Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.09(3H,s),3.30(3H,s),
3.50-3.60(4H),3.70-3.80(4H),3.95(2H,s),
5.61(1H,d,J=10Hz),5.81(1H,d,J=10Hz),6.48
(1H,d,J=15Hz),7.37-7.53(5H),7.59(1H,d,
J=9Hz),7.67(1H,d,J=9Hz),7.79(1H,d,
J=7Hz),7.85-8.00(3H),8.99(1H,d,J=9Hz)
(8)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(2-吡啶基)-乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.71(3H,s),3.26(3H,s),3.64
(1H,dd,J=4,18Hz),3.81-4.02(3H,m),5.60
(2H,s),6.39(1H,d,J=16Hz),6.63(1H,t-
like),7.16-7.34(5H,m),7.34-7.63(8H,m),
7.70(1H,td,J=8Hz,1Hz),8.03(1H,d,J=8Hz),
8.63(1H,dd,J=5Hz,1Hz),10.13(1H,s)
其二盐酸盐NMR(CDCl3-CD3OD):3.09(3H,s),3.29(3H,s),3.92
(2H,s),4.36-4.47(2H,m),5.60(1H,d,
J=10Hz),5.76(1H,d,J=10Hz),6.48(1H,d,
J=16Hz),7.26-7.48(3H,m),7.48-7.74(5H,m),
7.80-7.99(4H,m),8.18(1H,d,J=8Hz),8.50
(1H,td,J=8,1Hz),8.75(1H,d,J=6Hz),8.97
(1H,d,J=8Hz)
(9)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(4-吡啶基)乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.60(3H,s),3.22(3H,s),3.53-
3.70(3H,m),3.88(1H,dd,J=18,4Hz),5.61
(2H,s),6.38(1H,d,J=16Hz),6.63(1H,t-
like),7.10-7.62(13H,m),8.06(1H,d,J=8Hz),
8.45(1H,s),8.53(2H,d,J=6Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.09(3H,s),3.30(3H,s),
3.90(1H,d,J=16Hz),4.01(1H,d,J=16Hz),5.56
(1H,d,J=10Hz),5.75(1H,d,J=10Hz),6.43(1H,
d,J=16Hz),7.23-7.41(3H,m),7.49-7.61(2H,
m),7.61-7.75(3H,m),7.75-7.97(3H,m),8.20
(2H,d,J=6Hz),8.70(2H,d,J=6Hz),8.94(1H,
d,J=8Hz)
(10)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔 N-(2-吡啶基甲基)乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.96(3H,s),2.73(3H,s),3.26
(3H,s),3.64(1H,dd,J=4.16Hz),3.94(1H,dd,
J=4,16Hz),5.02(2H,s),5.64(2H,s-like),
6.43(1H,d,J=16Hz),6.64(1H,t-like),7.10-
7.20(3H,m),7.20-7.59(10H,m),7.65(1H,t,
J=7.5Hz),8.03(1H,d,J=8Hz),8.50(1H,d,
J=5Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):2.03(3H,s),3.14(3H,s),
3.30(3H,s),3.88(1H,d,J=16Hz),4.12(1H,d,
J=16Hz),5.43(2H,s),5.58(1H,d,J=10Hz),
5.71(1H,d,J=10Hz),6.63(1H,d,J=16Hz),
7.24-7.33(1H,m),7.39(1H,d,J=16Hz),7.50-
7.59(4H,m),7.64(1H,d,J=7.5Hz),7.75-8.01
(6H,m),8.43(1H,t,J=7.5Hz),8.73(1H,d,
J=6Hz),8.89(1H,d,J=8Hz)
(11)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔N-(4-吡啶基甲基)乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.95(3H,s),2.74(3H,s),3.26
(3H,s),3.64(1H,dd,J=4,16Hz),3.94(1H,dd,
J=4,16Hz),4.88(2H,s),5.65(2H,s),6.45
(1H,d,J=16Hz),6.65(1H,t-like),7.03(2H,d,
J=7.5Hz),7.14(2H,d,J=5Hz),7.21-7.33(3H.
m),7.33-7.59(6H,m),8.03(1H,d,J=8Hz),8.52
(2H,d,J=5Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):2.01(3H,s),3.16(3H,s),
3.29(3H,s),3.88(1H,d,J=16Hz),4.06(1H,d,
J=16Hz),5.10(2H,s),5.60(1H,d,J=10Hz),
5.71(1H,d,J=10Hz),6.65(1H,d,J=16Hz),7.15
(2H,d,J=7.5Hz),7.45(1H,d,J=16Hz),7.50-
7.70(5H,m),7.79(1H,d,J=7.5Hz),7.82-7.95
(4H,m),8.79(2H,d,J=6Hz),8.86(1H,d,
J=7.5Hz)
(12)8-〔2,6-二氯-3-〔N-〔3-(甲氧羰基)-肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.27(3H,s),3.65
(1H,dd,J=4,16Hz),3.85-4.01(4H,m),5.65
(2H,s),6.55(1H,d,J=16Hz),6.68(1H,t-
like),7.20-7.36(3H,m),7.36-7.54(4H,m),
7.54-7.70(2H,m),7.95-8.06(2H,m),8.20(1H,
s-like)
(13)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(N-甲基丙酰氨基)肉桂酰甘氨酰〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):1.08(3H,t,J=7Hz),2.02-2.21
(2H),2.70(3H,s),3.28(6H,s),3.67(1H,dd,
J=17,4Hz),3.89-4.06(4H),5.62(2H,s),6.49
(1H,d,J=15Hz),6.64(1H,s),6.71(1H,br s),
7.11-7.63(9H),7.82(1H,d,J=9Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.08(3H,t,J=7Hz),2.03-
2.26(2H),2.99(3H,s),3.28(3H,s),3.31(3H,
s),3.82-4.06(2H,overlapped with H2O),4.37
(3H,s),5.55(1H,d,J=10Hz),5.72(1H,d,
J=10Hz),6.60(1H,d,J=15Hz),7.21(1H,d,
J=9Hz),7.30-7.70(7H),7.80(1H,t,J=9Hz),
8.00(1H,d,J=9Hz)
(14)8-〔2,6-二氯-3-〔N-〔4-(甲磺酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):2.69(3H,s),3.03(3H,s),3.28
(3H,s),3.63(1H,dd,J=17,4Hz),3.88-4.09
(4H),5.62(2H,s),6.40(1H,d,J=15Hz),6.62-
6.77(2H),7.14-7.60(10H),7.82(1H,d,J=9Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.95(3H,s),3.02(3H,s),
3.30(3H,s),3.89(1H,d,J=16Hz),4.00(1H,d,
J=16Hz),4.35(3H,s),5.59(1H,d,J=10Hz),
5.79(1H,d,J=10Hz),6.54(1H,d,J=15Hz),
7.21-7.34(3H),7.39-7.74(6H),7.81(1H,t,
J=9Hz),8.01(1H,d,J=9Hz)
(15)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(3-甲基脲基)肉桂酰甘氨酰〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.63(3H,s),2.79(3H,s),
3.22(3H,s),3.62(1H,d,J=17Hz),3.83-4.10
(4H),5.53(2H,s),6.41(1H,d,J=16Hz),6.71
(1H,s),7.18-7.60(9H),7.81(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.81(3H,s),2.93(3H,s),
3.31(3H,s),3.94(2H,s),4.34(3H,s),5.56
(1H,d,J=10Hz),5.78(1H,d,J=10Hz),6.41(1H,
d,J=15Hz),7.25-7.72(9H),7.81(1H,t,J=9Hz),
8.01(1H,d,J=9Hz)
(16)8-〔3-〔N-(4-氰基肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.27(3H,s),3.68
(1H,dd,J=18,4Hz),3.95(1H,dd,J=18,5Hz),
5.65(2H,s),6.57(1H,d,J=15Hz),6.79(1H,br
t,J=5Hz),7.21-7.69(11H,m),8.03(1H,d,
J=9Hz)
(17)8-〔2,6-二氯-3-〔N-〔4-〔N-(2-甲氧乙基)-乙酰氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.85(3H,s),2.73(3H,s),3.26
(3H,s),3.30(3H,s),3.51(2H,t,J=6Hz),3.65
(1H,-dd,J=4,16Hz),3.86(2H,t,J=6Hz),3.95
(1H,dd,J=4,16Hz),5.65(2H,s-like),6.48
(1H,d,J=16Hz),6.66(1H,t-like),7.17-7.35
(5H,m),7.35-7.62(6H,m),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.85(3H,s),3.20-3.33(9H,
m),3.47(2H,t,J=6Hz),3.84(2H,t,J=6Hz),
3.92(1H,d,J=16Hz),4.03(1H,d,J=16Hz),5.64
(2H,s),6.61(1H,d,J=16Hz),7.16(2H,d,
J=8Hz),7.43-7.92(9H,m),8.75(1H,d,J=8Hz)
(18)8-〔2,6-二氯-3-〔N-〔4-〔N-(二甲氧乙基)-N-(异烟酰基)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.25(3H,s),3.35
(3H,s),3.58-3.70(3H,m),3.93(1H,dd,J=4,
16Hz),4.07(2H,t,J=6Hz),5.64(2H,s-like),
6.40(1H,d,J=16Hz),6.64(1H,br),7.10(2H,
d,J=8Hz),7,15(2H,d,J=6Hz),7.22-7.53(9H,
m),8.03(1H,d,J=8Hz),8.47(2H,d,J=6Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.14(3H,s),3.26(3H,s),
3.36(3H,s),3.62(2H,t-like),3.86(1H,d,
J=16Hz),4.03-4.17(3H,m),5.56(1H,d,
J=10Hz),5.70(1H,d,J=10Hz),6.61(1H,d,
J=16Hz),7.13(2H,d,J=8Hz),7.33(1H,d,
J=16Hz),7.45(2H,d,J=8Hz),7.50-7.59(2H,m),
7.63(1H,d,J=8Hz),7.71-7.93(5H,m),8.69
(2H,d,J=6Hz),8.83(1H,d,J=8Hz)
(19)8-〔2,6-二氯-3-〔N-〔(E)-3-(6-乙氧羰基吡啶-3-基)丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.45(3H,t,J=7.5Hz ),2.72(3H,
s),3.27(3H,s),3.70(1H,dd,J=18,4Hz),3.94
(1H,dd,J=18,4Hz),4.49(2H,q,J=7.5Hz),
5.59-5.70(2H,m),6.66(1H,d,J=16Hz),6.80
(1H,t-like),7.22-7.35(3H,m),7.37-7.53(3H,
m),7.60(1H,d,J=16Hz),7.88-7.94(1H,m),
8.02(1H,d,J=8Hz),8.12(1H,d,J=8Hz),8.81-
8.86(1H,m)
(20)8-〔3-〔N-〔(E)-3-(6-氨基吡啶-3-基)丙烯酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.27(3H,s),3.65
(1H,dd,J=17,4Hz),3.94(1H,dd,J=17,5Hz),
4.75(2H,s),5.64(2H,s),5.84(1H,d,
J=10Hz),6.30(1H,d,J=15Hz),6.48(1H,d,
J=8.5Hz),6.62(1H,br t,J=4Hz),7.23-7.35
(3H),7.39-7.52(4H),7.60(1H,dd,J=8.5,
1.5Hz),8.02(1H,d,J=8.5Hz),8.16(1H,d,
J=1.5Hz)
(21)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.78(3H,s),3.02(3H,d,J=5Hz),
3.28(3H,s),3.69(1H,dd,J=17,4Hz),3.93
(1H,dd,J=17,5Hz),5.57(2H,s),6.18(1H,br
d,J=5Hz),6.52(1H,d,J=15Hz),6.68(1H,br t,
J=4Hz),7.27(1H,overlapped with CDCl3),7.35
(1H,d,J=9Hz),7.49-7.79(8H),8,73(1H,s)
(22)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.77(3H,s),3.02(3H,d,J=5Hz),
3.28(3H,s),3.67(1H,dd,J=17,4Hz),3.94
(1H,dd,J=17,4Hz),5.62(2H,s),6.20(1H,br
d,J=5Hz),6.53(1H,d,J=16Hz),6.69(1H,br t,
J=4Hz),7.29-7.38(2H),7.49-7.80(8H),8.74
(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.89(3H,s),2.98(3H,s),
3.29(3H,s),3.19(1H,d,J=17Hz),4.00(1H,d,
J=17Hz),5.65(2H,s),6.62(1H,d,J=15Hz),
7.44-7.63(6H),7.75-7.91(4H),8.92(1H,s)
(23)8-〔2,6-二氯-3-〔N-〔4-(二甲基氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉mp:109-116℃NMR(CDCl3,δ):2.77(3H,s),2.98(3H,s),3.11
(3H,s),3.27(3H,s),3.67(1H,dd,J=16.5,
3.0Hz),3.95(1H,dd,J=16.5,3.0Hz),5.62(2H,
s),6.51(1H,d,J=15.0Hz),6.68(1H,br t,
J=3.0Hz),7.28-7.36(2H,m),7.42(2H,d,
J=8.5Hz),7.48-7.70(5H,m),7.76(1H,d,
J=8.5Hz),8.74(1H,s)
(24)8-〔2,6-二氯-3-〔N-〔4-(乙基氨基甲酰基)-肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉mp:199-202℃NMR(CDCl3,δ):1.26(3H,t,J=7.5Hz),2.77(3H,
s),3.27(3H,s),3.51(2H,m),3.66(1H,dd,
J=16.5,3.0Hz),3.95(1H,dd,J=16.5,3.0Hz),
5.63(2H,s),6.15(1H,br t,J=7.5Hz),6.53
(1H,d,J=16.0Hz),6.68(1H,br t,J=3.0Hz),
7.28-7.36(2H,m),7.48-7.79(8H,m),8.73(1H,
s)
(25)8-〔2,6-二氯-3-〔N-〔4-(甲氧羰基)-肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.77(3H,s),3.27(3H,s),3.65
(1H,dd,J=16.5,2.5Hz),3.90(3H,s),3.94(1H,
dd,J=16.5,2.5Hz),5.62(2H,s),6.56(1H,d,
J=15.0Hz),6.69(1H,br t,J=2.5Hz),7.28-7.38
(2H,m),7.47-7.79(6H,m),7.98-8.06(2H,m),
8.73(1H,s)
(26)8-〔3-N-〔4-(乙酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.15(3H,s),2.76(3H,s),3.26
(3H,s),3.64(1H,dd,J=17,4Hz),3.92(1H,dd,
J=17,5Hz),5.61(2H,s),6.39(1H,d,J=15Hz),
6.61(1H,br t,J=4Hz),7.28-7.35(2H),7.40-
7.58(6H),7.62-7.71(2H),7.78(1H,d,J=8Hz),
8.74(1H,s)
(27)8-〔2,6-二氯-3-〔N-〔4-(甲氧乙酰氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.78(3H,s),3.28(3H,s),3.51
(3H,s),3.65(1H,dd,J=17,4Hz),3.94(1H,dd,
J=17,5Hz),4.02(2H,s),5.62(2H,s),6.41
(1H,d,J=15Hz),6.59(1H,br t,J=4Hz),7.29-
7.37(2H),7.44-7.70(7H),7.78(1H,d,J=8Hz),
8.32(1H,br s),8.72(1H,s)
(28)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(2-氧代吡咯烷-1-基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹喔啉NMR(CDCl3,δ):2.12-2.25(2H),2.63(2H,t,
J=7.5Hz,),2.78(3H,s),3.28(3H,s),3.65(1H,
dd,J=17,4Hz),3.85-4.00(3H),5.62(2H,s),
6.43(1H,d,J=15Hz),6.59(1H,br t,J=4Hz),
7.29-7.38(2H),7.48-7.70(7H),7.78(1H,d,
J=8Hz),8.73(1H,s)
(29) 8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)-肉桂酰甘氨酰〕氨基〕苄氧基〕噌啉NMR(CDCl3,δ):3.02(3H,d,J=5Hz),3.29(3H,s),
3.70(1H,dd,J=17,4Hz),3.93(1H,dd,J=17,
5Hz),5.64(1H,d,J=10Hz),5.70(1H,d,
J=10Hz),6.20(1H,br d,J=5Hz),6.53(1H,d,
J=15Hz),6.71(1H,br t,J=4Hz),7.31-7.39(2H),
7.45-7.62(5H),7.70-7.78(3H),7.82(1H,d,
J=7.5Hz),9.34(1H,d,J=6Hz)
(30)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)-肉桂酰甘氨酰〕氨基)苄氧基〕-2-甲基喹唑啉NMR(CDCl3,δ):2.90(3H,s),3.02(3H,d,J=5Hz),
3.28(3H,s),3.67(1H,dd,J=18,4Hz),3.93
(1H,dd,J=18,4Hz),5.63(2H,s),6.20(1H,br
d,J=5Hz),6.52(1H,d,J=16Hz),6.68(1H,br t,
J=4Hz),7.33(1H,d,J=7.5Hz),7.41-7.62(7H),
7.77(2H,d,J=8Hz),9.31(1H,s)
(31)8-〔3-〔N-苄基-N-〔4-(甲基氨基甲酰基)-肉桂酰甘氨酰〕氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.02(3H,d,J=5Hz),
3.67(1H,dd,J=17,5Hz),3.92(1H,dd,J=17,
5Hz),4.00(1H,d,J=14Hz),5.60-5.71(3H),6.19
(1H,m),6.53(1H,d,J=16Hz),6.69-6.79(2H),
6.69-6.79(2H),7.18-7.62(13H),7.75(2H,d,
J=7.5Hz),8.03(1H,d,J=7.5Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.98(3H,s),3.10(3H,s),
3.98(2H,br s),4.30(1H,d,J=14Hz),5.51(1H,
d,J=14Hz),5.59(1H,d,J=10Hz),5.75(1H,d,
J=10Hz),6.68(1H,d,J=15Hz),7.04(1H,d,
J=7.5Hz),7.21-7.33(5H),7.41(1H,d,J=7.5Hz),
7.48(1H,d,J=15Hz),7.57(2H,d,J=7.5Hz),
7.69(1H,d,J=7.5Hz),7.79-7.99(5H),8.95(1H,
d,J=7.5Hz)
(32)5,7-二溴-8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉mp:134-139℃NMR(CDCl3,δ):2.81(3H,s),3.03(3H,d,
J=5.5Hz),3.23(3H,s),3.56(1H,dd,J=16.5,
5.5Hz),3.92(1H,dd,J=16.5,5.5Hz),5.88(1H,
d,J=11.5Hz),5.95(1H,d,J=11.5Hz),6.17(1H,
br q,J=5.5Hz),6.52(1H,d,J=16.0Hz),6.64
(1H,br t,J=5.5Hz),7.30(1H,d,J=8.5Hz),7.40
(1H,d,J=8.5Hz),7.47(1H,d,J=8.5Hz),7.54
(2H,d,J=8.5Hz),7.60(1H,d,J=16.0Hz),7.76
(2H,d,J=8.5Hz),7.87(1H,s),8.33(1H,d,
J=8.5Hz)
其盐酸盐mp:121-126℃NMR(CDCl3-CD3OD):2.93-3.07(6H,m),3.21(3H,s),
3.59-(1H,d,J=16.5Hz),3.96(1H,d,J=16.5Hz),
5.88(2H,s),6.60(1H,d,J=16.0Hz),7.37(1H,
d,J=8.5Hz),7.44-7.64(6H,m),7.70-7.80(3H,
m),8.01(1H,s),8.61(1H,d,J=8.5Hz)
(33)8-〔2,6-二氯-3-〔N-〔4-〔N-甲氧乙酰基-N-(3-吡啶基甲基)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.75(3H,s),3.27(3H,s),3.35
(3H,s),3.66(1H,dd,J=4,16Hz),3.79(2H,s),
3.95(1H,dd,J=4,16Hz),4.49(2H,s),5.65
(2H,s-like),6.46(1H,d,J=16Hz),6.66(1H,
t-like),6.8(2H,d,J=8Hz),7.20-7.35(4H,m),
7.37-7.58(6H,m),7.66(1H,dd-like,J=8Hz),
8.03(1H,d,J=8Hz),8.35(1H,d,J=2Hz),8.51
(1H,dd,J=6,2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.15(3H,s),3.28(3H,s),
3.33(3H,s),3.85(2H,s),3.89(1H,d,
J=16Hz),4.10(1H,d,J=16Hz),5.06(2H,s),
5.59(1H,d,J=10Hz),5.71(1H,d,J=10Hz),6.67
(1H,d,J=16Hz),7.10(2H,d,J=8Hz),7.43(1H,
d,J=16Hz),7.51-7.67(5H,m),7.79(1H,d,
J=8Hz),7.83-8.00(3H,m),8.53(1H,d,J=8Hz),
8.70(1H,s-like),8.78(1H,d,J=6Hz),8.85
(1H,d,J=8Hz)
(34)8-〔3-〔N-〔(E)-3-(6-乙酰氨基吡啶-3-基)丙烯酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:133-139℃NMR(CDCl3,δ):2.22(3H,s),2.74(3H,s),3.27
(3H,s),3.67(1H,dd,J=16.5,5.5Hz),3.96(1H,
dd,J=16.5,5.5Hz),5.62(1H,d,J=11.0Hz),5.67
(1H,d,J=11.0Hz),6.46(1H,d,J=16.0Hz),6.73
(1H,br t,J=5.5Hz),7.21-7.33(3H,m),7.38-
7.51(3H,m),7.52(1H,d,J=16.0Hz),7.82(1H,
dd,J=8.5,1.5Hz),8.03(1H,d,J=8.5Hz),8.13-
8.25(2H,m),8.33(1H,d,J=1.5Hz)
其二盐酸盐mp:153.5-158℃NMR(DMSO-d6,δ):2.12(3H,s),2.94(3H,s),3.16
(3H,s),3.59(1H,dd,J=16.5,5.5Hz),3.90(1H,
dd,J=16.5,5.5Hz),5.63(1H,d,J=10.5Hz),5.67
(1H,d,J=10.5Hz),6.81(1H,d,J=16.0Hz),7.37
(1H,d,J=16.0Hz),7.79-8.06(6H,m),8.10(1H,
d,J=8.5Hz),8.30-8.40(1H,m),8.49(1H,d,
J=1.0Hz),9.03(1H,d,J=8.5Hz)
实施例53
根据与实施例20相似的方法,得到下列化合物:
(1)8-〔3-〔N-(羧基肉桂酰甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:237.8-240.9℃NMR(DMSO-d6,δ):2.61(3H,s),3.15(3H,s),3.51
(1H,dd,J=4,18Hz),3.81(1H,dd,J=4,18Hz),
5.48(1H,d,J=10Hz),5.54(1H,d,J=10Hz),6.90
(1H,d,J=16Hz),7.32-7.60(5H,m),7.64-7.75
(2H,m),7.75-7.85(2H,m),7.96(2H,d,J=8Hz),
8.21(1H,d,J=8Hz),8.35-8.44(1H,m)
(2)8-〔3-〔N-(3-羧基肉桂酰甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:161℃NMR(CDCl3-CD3OD,δ):2.70(3H,s),3.26(3H,s),
3.65(1H,d,J=16Hz),4.00(1H,d,J=16Hz),5.58
(2H,s),6.60(1H,d,J=16Hz),7.20-7.68(9H,
m),8.00(1H,d,J=7,5Hz),8.06(1H,d,J=8Hz),
8.20(1H,s-like)
(3)8-〔3-〔N-〔N ′-(4-羧基苯基)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:186-235℃NMR(CDCl3-CD3OD,δ):2.70(3H,s),3.25(3H,s),
3.85(1H,d,J=16Hz),3.93(1H,d,J=16Hz),5.52
(1H,d,J=10Hz),5.60(1H,d,J=10Hz),7.25-7.60
(8H,m),7.86(2H,d,J=7.5Hz),8.13-8.23(1H,
m)
(4)8-〔3-〔N-〔(E)-3-(6-羧基吡啶-3-基)丙烯酰甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(DMSO-d6,δ):2.58(3H,s),3.13(3H,s),3.50
(1H,dd,J=4,16Hz),3.80(1H,dd,J=4,16Hz),
5.46(1H,d,J=10Hz),5.53(1H,d,J=10Hz),6.95
(1H,d,J=16Hz),7.30-7.57(5H,m),7.78(2H,
s-like),8.02(1H,d,J=8Hz),8.10(1H,d,
J=7.5Hz),8.20(1H,d,J=8Hz),8.45(1H,t-
like),8.85(1H,s-like)
(5)8-〔3-〔N-(4-羧基肉桂酰甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹喔啉
NMR(CDCl3,δ):2.77(3H,s),3.26(3H,s),3.62
(1H,dd,J=16.5,2.5Hz),3.99(1H,dd,J=16.5,
2.5Hz),5.60(2H,s),6.51(1H,d,J=15.0Hz),
6.97(1H,br s),7.24-7.80(8H,m),7.93-8.07
(2H,m),8.76(1H,s)
实施例54
向8-〔3-〔N-(4-羧基肉桂酰甘氨酰)-N-甲氨基)-2,6-二氯苄氧基〕-2-甲基喹啉(100mg),乙胺化氢氯(16.9mg)和N,N-二甲基甲酰胺(2ml)的混合物中加入1-乙基-3-(3-二甲氨基丙基)碳化二亚胺(32.2mg)和1-羟基苯并三唑(30.4mg),室温下搅拌混合物6小时。将混合物倾入水中,用乙酸乙酯萃取。有机相用水,饱和碳酸氢钠溶液和盐水洗涤,硫酸镁干燥和真空浓缩。残余物用制备性薄层色谱提纯(二氯甲烷/甲醇),得到8-〔2,6-二氯-3-〔N-〔4-(乙基氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉(91mg)。NMR(CDCl3,δ):1.26(3H,t,J=7.5Hz),2.72(3H,
s),3.29(3H,s),3.50(2H,quint,J=7.5Hz),
3.68(1H,dd,J=4,18Hz),3.96(1H,dd,J=4,
18Hz),5.58-5.70(2H,m),6.15(1H,t-like),
6.54(1H,d,J=16Hz),6.73(1H,t-like),7.21-
7.35(2H,m),7.35-7.62(7H,m),7.75(2H,d,
J=8Hz),8.04(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.23(3H,t,J=7.5Hz),3.13
(3H,s),3.30(3H,s),3.47(2H,q,J=7.5Hz),
3.90(1H,d,J=16Hz),4.10(1H,d,J=16Hz),5.60
(1H,d,J=10Hz),5.70(1H,d,J=10Hz),6.65(1H,
d,J=16Hz),7.42(1H,d,J=16Hz),7.48-7.58(4H,
m),7.63(1H,d,J=7.5Hz),7.70-7.84(3H,m),
7.84-7.93(2H,m),8.87(1H,d,J=8Hz)
实施例55
根据与实施例21或54相似的方法,得到下列化合物:
(1)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)-肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,6):2.73(3H,s),3.00(3H,d,J=5Hz),
3.26(3H,s),3.64(1H,dd,J=4,17Hz),3.93
(1H,dd,J=4,17Hz),5.66(2H,s),6.28(1H,
q-like),6.53(1H,d,J=16Hz),6.69(1H,t-
like),7.18-7.64(9H,m),7.75(2H,d,J=8Hz),
8.03(1H,d,J=8Hz)
其甲磺酸盐mp:174.1-182.3℃NMR(DMSO-d6,δ):2.29(3H,s),2.78(3H,d,
J=5Hz),2.85(3H,br s),3,15(3H,s),3.58(1H,
dd,J=17,4Hz),3.88(1H,dd,J=17,5Hz),5.58
(1H,d,J=10Hz),5.64(1H,d,J=10Hz),6.88(1H,
d,J=15Hz),7.41(1H,d,J=15Hz),7.63(2H,d,
J=8Hz),7.73-7.90(7H),8.34(1H,br t,J=5Hz),
8.49(1H,br d,J=5Hz),8.83(1H,br s)
其马来酸盐NMR(DMSO-d6,δ):2.64(3H,s),2.77(3H,d,
J=6Hz),3.14(3H,s),3.51(1H,d,J=17 and
6Hz),3.81(1H,dd,J=17,5Hz),5.49(1H,d,
J=9Hz),5.54(1H,d,J=9Hz),6.22(2H,s),6.86
(1H,d,J=15Hz),7.35-7.70(7H,m),7.72-7.90
(4H,m),8.23-8.40(2H,m),8.42-8.54(1H,m)
(2)8-〔3-〔N-(4-氨基甲酰基肉桂酰甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.27(3H,s),3.68
(1H,dd,J=4,18Hz),3.95(1H,dd,J=4,18Hz),
5.57-5.69(2H,m),6.54(1H,d,J=16Hz),6.77
(1H,t-like),7.22-7.35(2H,m),7.38-7.63(7H,
m),7.80(2H,d,J=8Hz),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.13(3H,s),3,30(3H,s),
3.90(1H,d,J=16Hz),4.07(1H,d,J=16Hz),5.59
(1H,d,J=10Hz),5.71(1H,d,J=10Hz),6.67(1H,
d,J=16Hz),7.44(1H,d,J=16Hz),7.49-7.69(5H,
m),7.77-7.95(5H,m),8.89(1H,d,J=8Hz)
(3)8-〔2,6-二氯-3-〔N-〔4-(N-乙基-N-甲基氨基甲酰基)-肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.06-1.29(3H,m),2.73(3H,s),
2.94(3/2H,br s),3.06(3/2H,br s),3.26(3H,
s),3.45-3.73(3H,m),3.95(1H,dd,J=4,18Hz),
5.64(2H,s),6.50(1H,d,J=16Hz),6.68(1H,t-
like),7.20-7.61(11H,m),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.10-1.33(3H,m),2.93-3.12
(6H,m),3.50-3.66(2H,m),3.90(1H,d,
J=16Hz),3.99(1H,d,J=16Hz),5.65(1H,d,
J=10Hz),5.8 3(1H,d,J=10Hz),6.70(1H,d,
J=16Hz),7.35-7.73(7H,m),7.76-8.01(4H,m),
9.01-(1H,d,J=8Hz)
(4)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(1-吡咯烷基羰基)-肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.83-2.03(4H,m),2.74(3H,s),
3.28(3H,s),3.43(2H,t,J=7Hz),3.60-3.74
(3H,m),3.95(1H,dd,J=4,18Hz),7.22-7.61
(11H,m),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.80-2.05(4H,m),3.15(3H,
s),3.30(3H,s),3.30-3.72(4H,m),3.88(1H,
d,J=16Hz),4.03(1H,d,J=16Hz),5.61(1H,d,
J=10Hz),5.71(1H,d,J=10Hz),6.64(1H,d,
J=16Hz),7.40-7.70(8H,m),7.73-7.96(3H,m),
8.89(1H,d,J=8Hz)
(5)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(吗啉代羰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.75(3H,s),3.27(3H,s),3.55-
3.85(9H,m),3.94(1H,dd,J=4,18Hz),5.60-
5.70(2H,m),6.51(1H,d,J=16Hz),6.66(1H,t-
like),7.21-7.34(2H,m),7.37-7.61(9H,m),
8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.20(3H,s),3.31(3H,s),
3.56-3.84(8H,m),3.90(1H,d,J=16Hz),4.03
(1H,d,J=16Hz),5.53(1H,d,J=10Hz),5.70(1H,
d,J=10Hz),7.33-7.63(8H,m),7.73-7.93(3H,
m),8.85(1H,d,J=8Hz)
(6)8-〔2,6-二氯-3-〔N-〔4-(3-甲氧丙基氨基甲酰基)-肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.81-1.96(2H,m),2.74(3H,s),
3.27(3H,s),3.40(3H,s),3.51-3.71(5H,m),
3.88-4.00(1H,m),5.65(2H,s),6.53(1H,d,
J=16Hz),6.60-6.70(1H,m),6.90-7.00(1H,m),
7.20-7.63(9H,m),7.74(2H,d,J=8Hz),8.03
(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.90(2H,quint,J=7Hz),3.16
(3H,s),3.29(3H,s),3.55(4H,q-like),3.90
(1H,d,J=16Hz),4.08(1H,d,J=16Hz),5.61(1H,
d,J=10Hz),5.70(1H,d,J=10Hz),6.66(1H,d,
J=16Hz),7.41-7,93(11H,m),8.85(1H,d,J=8Hz)
(7)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(3-吡啶基甲基)氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.69(3H,s),3.27(3H,s),3.67
(1H,dd,J=4,18Hz),3.93(1H,dd,J=4,18Hz),
4.64(2H,d,J=6Hz),5.63(2H,s),6.54(1H,d,
J=16Hz),6.66-6.77(1H,m),7.19-7.33(5H,m),
7.38-7.63(6H,m),7.63-7.82(3H,m),8.03(1H,
d,J=8.4Hz),8.51-8.59(2H,m)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.09(3H,s),3.28(3H,s),
3.90(1H,d,J=16Hz),4.09(1H,d,J=16Hz),4.77
(2H,s),5.58(1H,d,J=10Hz),5.72(1H,d,
J=10Hz),6.63(1H,d,J=16Hz),7.39(1H,d,
J=16Hz),7.48(2H,d,J=7.5Hz),7.56(2H,s-
like),7.65(1H,d,J=7.5Hz),7.77-7.97(6H,m),
8.65(2H,d,J=6Hz),8.89(1H,d,J=8Hz),8.95
(1H,s)
(8)8-〔2,6-二氯-3-〔N-〔4-〔-(2-甲氧乙基)-N-甲基氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),2.99-3.15(3H,m),
3.27(3H,s),3.32-3.48(2H,m),3.59-3.75(3H,
m),3.95(1H,dd,J=4,18Hz),5.65(2H,s),6.50
(1H,d,J=16Hz),6.66(1H,t-like),7.20-7.61
(11H,m),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.00-3.13(3H,m),3.15(3H,
s),3.30(3H,s),3.36-3.50(2H,m),3.64-3.76
(2H,m),3.88(1H,d,J=16Hz),3.99(1H,d,
J=16Hz),5.61(1H,d,J=10Hz),5.72(1H,d,
J=10Hz),6.62(1H,d,J=16Hz),7.39(2H,d,
J=7.5Hz),7.43-7.68(6H,m),7.77-7.93(3H,m),
8.89(1H,d,J=8Hz)
(9)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(正丙基氨基甲酰基)-肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):0.92(3H,t,J=7.5Hz),1.55-1.70
(2H,m),2.73(3H,s),3.27(3H,s),3.43(2H,
q,J=7.5Hz),3.66(1H,dd,J=4,16Hz),3.95(1H,
dd,J=4,16Hz),5.66(2H,s),6.13(1H,t-like),
6.55(1H,d,J=16Hz),6.69(1H,t-like),7.23-
7.35(3H,m), 7.38-7.63(6H,m),7.75(2H,d,
J=7.5Hz),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):0.98(3H,t,J=7.5Hz),1.57-
1.73(2H,m),3.16(3H,s),3.29(3H,s),3.34-
3.45(2H,m),3.89(1H,d,J=16Hz),4.11(1H,d,
J=16Hz),5.60(1H,d,J=10Hz),5.69(1H,d,
J=10Hz),6.65(1H,d,J=16Hz),7.37-7.65(6H,
m),7.65-7.92(5H,m),8.84(1H,d,J=8Hz)
(10)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(3-吡啶基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.69(3H,s),3.23(3H,s),3.65
(1H,dd,J=4,16Hz),3.93(1H,dd,J=4,16Hz),
5.64(2H,s),6.55(1H,d,J=16Hz),6.73(1H,t-
like),7.23-7.39(4H,m),7.39-7.51(3H,m),
7.51-7.65(3H,m),7.92(2H,d,J=7.5Hz),8.05
(1H,d,J=8Hz),8.32(1H,d,J=8Hz),8.39(1H,
d,J=6Hz),8.45(1H,s),8.72(1H,s-like)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.13(3H,s),3.30(3H,s),
3.91(1H,d,J=16Hz),4.15(1H,d,J=16Hz),5.59
(1H,d,J=10Hz),5.74(1H,d,J=10Hz),6.66(1H,
d,J=16Hz),7.32(1H,d,J=16Hz),7.48(2H,d,
J=7.5Hz),7.53-7.70(3H,m),7.78-7.98(4H,m),
8.07(2H,d,J=7.5Hz),8.47(6H,d),8.90(1H,
d,J=7.5Hz),9.25(1H,d,J=7.5Hz),9.63(1H,s-
like)
(11)8-〔2,6-二氯-3-〔N-〔4-(2-羟乙基氨基甲酰基)肉桂酰甘氨酰)-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),3.26(3H,s),3.53-
3.63(2H,m),3.65-3.82(3H,m),3.97(1H,dd,
J=4,16Hz),5.60(1H,d,J=10Hz),5.67(1H,d,
J=10Hz),6.51(1H,d,J=16Hz),6.75(1H,t-
like),6.93(1H,t-like),7.20-7.37(3H,m),
7.37-7.56(6H,m),7.75(2H,d,J=8Hz),8.03
(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.10(3H,s),3.28(3H,s),
3.57(2H,t,J=6Hz),3.79(2H,t,J=6Hz),3.90
(1H,d,J=16Hz),4.11(1H,d,J=16Hz),5.59(1H,
d,J=10Hz),5.70(1H,d,J=10Hz),6.60(1H,d,
J=16Hz),7.35(1H,d,J=16Hz),7.43(2H,d,
J=8Hz),7.49-7.58(2H,m),7.63(1H,d,J=8Hz),
7.75-7.93(5H,m),8.87(1H,d,J=8Hz)
(12)8-〔2,6-二氯-3-〔N-〔4-(2-乙氧乙基氨基甲酰基)-肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.20(3H,t,J=7.5Hz),2.73(3H,
s),3.25(3H,s),3.47-3.71(7H,m),3.95(1H,
dd,J=4,16Hz),5.60-5,70(2H,m),6.49-6.60
(2H,m),6.67(1H,t-like), 7.22-7.33(3H,m),
7.33-7.64(6H,m),7.76(2H,d,J=7.5Hz),8.03
(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.23(3H,t,J=7.5Hz),3.15
(3H,s),3.30(3H,s),3.57(2H,q),3.63(4H,
s-like),3.90(1H,d,J=16Hz),4.05(1H,d,
J=16Hz),5.62(1H,d,J=10Hz),5.72(1H,d,
J=10Hz),6.66(1H,d,J=16Hz),7.43-7.69(6H,
m),7.73-7.94(5H,m),8.49(1H,d,J=8Hz)
(13)8-〔3-〔N-〔4-〔N,N-二(2-乙氧乙基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.11-1.25(6H,m),2.73(3H,s),
3.26(3H,s),3.30-3.80(13H,m),3.95(1H,dd,
J=4,16Hz),5.60-5.70(2H,m),6.49(1H,d,
J=16Hz),6.64(1H,t-like),7.23-7.33(3H,m),
7.33-7.63(8H,m),8.01(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.00-1.30(6H,m),3.01(3H,
s),3.17-3.82(15H,m),3.89(2H,s),5.61(1H,
d,J=10Hz),5.77(1H,d,J=10Hz),6.63(1H,d,
J=16Hz),7.35-7.71(6H,m),7.71-8.01(5H,m),
8.96(1H,d,J=8Hz)
(14)8-〔2,6-二氯-3-〔N-〔4-〔2-(二甲氨基)-乙基氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.30(6H,s),2.55(2H,t,J=6Hz),
2.73(3H,s),3.28(3H,s),3.54(2H,q,J=6Hz),
3.67(1H,dd,J=4,16Hz),3.95(1H,dd,J=4,
16Hz),5.65(2H,s-like),6.53(1H,d,J=16Hz),
6.69(1H,t-like),6.95(1H,t-like),7.22-7.35
(3H,m),7.35-7.63(6H,m),7.80(2H,d,
J=7.5Hz),8.02(1H,d,J=8Hz)
其二盐酸盐NMR(CD3OD,δ):2.92-3.03(9H,m),3.35-3.47(2H,
m),3.72-3.91(3H,m),4.01(1H,d,J=16Hz),
5.71(1H,d,J=10Hz),5.81(1H,d,J=10Hz),6.80
(1H,d,J=16Hz),7.55(1H,d,J=16Hz),7.62-7.75
(4H,m),7.86-8.00(6H,m),9.03(1H,d,J=8Hz)
(15)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(2-吡啶基甲基)氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.27(3H,s),3.66
(1H,dd,J=3,16Hz),3.95(1H,dd,J=4,16Hz),
4.75(2H,d,J=5Hz),5.63(2H,s-like),6.54
(1H,d,J=16Hz),6.70-6.77(1H,m),7.18-7.36
(5H,m),7.36-7.75(8H,m),7.87(2H,d,
J=7.5Hz),8.03(1H,d,J=8Hz),8.08(1H,d,
J=5Hz)
其二盐酸盐NMR(CD3OD,δ):3.00(3H,s),3.27(3H,s),3.84
(1H,d,J=16Hz),4.00(1H,d,J=16Hz),4.91(2H
s),5.73(1H,d,J=10Hz),5.82(1H,d,J=10Hz),
6.81(1H,d,J=16Hz),7.55(1H,d,J=16Hz),
7.63-7.76(4H,m),7.90-8.05(7H,m),8.09(1H,
d,J=7.5Hz),8.61(1H,t,J=7.5Hz),8.79(1H,d
J=7.5Hz),9.04(1H,d,J=7.5Hz)
(16)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(4-吡啶基甲基)氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),3.24(3H,s),3.66
(1H,dd,J=3,16Hz),3.93(1H,dd,J=4,16Hz),
4.65(2H,d,J=6Hz),5.64(2H,s-like),6.54
(1H,d,J=16Hz),6.66-6.75(1H,m),7.19-7.34
(6H,m),7.34-7.51(3H,m),7.51-7.63(3H,m),
7.81(2H,d,J=8Hz),8.01(1H,d,J=8Hz),8.50-
8.60(2H,m)
其二盐酸盐NMR(CD3OD,δ):3.01(3H,s),3.85(1H,d,J=16Hz),
4.01(1H,d,J=16Hz),5.73(1H,d,J=10Hz),5.82
(1H,d,J=10Hz),6.80(1H,d,J=16Hz),7.54(1H,
d,J=16Hz),7.63-7.75(4H,m),7.87-7.99(6H,
m),8.06(2H,d,J=6Hz),8.80(2H,d,J=6Hz),
9.04(1H,d,J=7.5Hz)
(17)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(1,2,3,6-四氢吡啶-1-基羰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.10-2.33(2H,m),2.73(3H,s),
3.26(3H,s),3.37-3.53(1H,m),3.65(1H,dd,
J=4,16Hz),3.75-4.00(3H,m),4.12-4.26(1H,
m),5.64(2H,s),5.67-5.94(2H,m),6.50(1H,
d,J=16Hz),6.68(1H,t-like),7.20-7.35(2H,
m),7.35-7.63(9H,m),8.02(1H,d,J=8Hz)
其盐酸盐NMR(CD3OD,δ):2.15-2.31(2H,m),3.00(3H,s),
3.27(3H,s),3.34-3.56(2H,m),3.81-4.06(3H,
m),4.17(1H,s-like),5.54-5.96(4H,m),6.76
(1H,d,J=16Hz),7.41-7.74(7H,m),7.88-7.99
(4H,m),9.03(1H,d,J=8Hz)
(18)8-〔2,6-二氯-3-〔N-甲基-N-〔4-哌啶子基羰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.43-1.73(6H,m),2.73(3H,s),
3.26(3H,s),3.29-3.43(2H,m),3.60-3.75(3H,
m),3.95(1H,dd,J=4,16Hz),5.66(2H,s-like),
6.50(1H,d,J=16Hz),6.66(1H,t-like),7.20-
7.61(11H,m),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CD3OD,δ):1.48-1.60(2H,m),1.60-1.78(4H,
m),3.00(3H,s),3.33-3.45(2H,m),3.64-3.76
(2H,m),3.85(1H,d,J=16Hz),4.01(1H,d,
J=16Hz),5.70(1H,d,J=10Hz),5.82(1H,d,
J=10Hz),6.74(1H,d,J=16Hz),7.40(2H,d,
J=8Hz),7.50(1H,d,J=16Hz),7.64(2H,d,
J=8Hz),7.72(2H,s-like),7.87-7.99(4H,m),
9.03(1H,d,J=8Hz)
(19)8-〔2,6-二氯-3-〔N-〔4-〔(2-呋喃基甲基)氨基用酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.71(3H,s),3.26(3H,s),3.65
(1H,dd,J=4,16Hz),3.94(1H,dd,J=4,16Hz),
4.14(2H,d,J=5Hz),5.64(2H,s-like),6.26-
6.30(1H,m),6.30-6.35(1H,m),6.45-6.58(2H,
m),6.69(1H,t-like),7.23-7.33(4H,m),7.33-
7.61(6H,m),7.78(2H,d,J=8Hz),8.03(1H,d,
J=8Hz)
其盐酸盐NMR(CD3OD,δ):3.00(3H,s),3.85(1H,d,J=16Hz),
4.00(1H,d,J=16Hz),4.56(2H,s),5.70(1H,d,
J=10Hz),5.81(1H,d,J=10Hz),6.26-6.32(1H,
m),6.32-6.39(1H,m),6.75(1H,d,J=16Hz),
7.43(1H,d,J=2Hz),7.51(1H,d,J=16Hz),7.57-
7.77(4H,m),7.77-8.02(6H,m),8.02(1H,d,
J=8Hz)
(20)8-〔3-〔N-〔4-(烯丙基氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.25(3H,s),3.65
(1H,dd,J=4,16Hz),3.94(1H,dd,J=4,16Hz),
4.09(2H,t-like),5.20(1H,d,J=11Hz),5.26
(1H,d,J=18Hz),5.65(2H,s),5.85-6.02(1H,
m),6.20(1H,t-like),6.53(1H,d,J=16Hz),
6.69(1H,t-like),7.22-7.33(3H,m),7.33-7.63
(6H,m),7.77(2H,d,J=7.5Hz),8.03(1H,d,
J=8Hz)
其盐酸盐NMR(CD3OD,δ):2.99(3H,s),3.85(1H,d,J=16Hz),
3.91-4.05(3H,m),5.14(1H,d,J=11Hz),5.23
(1H,d,J=18Hz),5.71(1H,d,J=10Hz),5.82(1H,
d,J=10Hz),5.85-6.02(1H,m),6.76(1H,d,
J=16Hz),7.47-7.75(5H,m),7.80-8.00(6H,m),
9.03(1H,d,J=8Hz)
(21)8-〔2,6-二氯-3-〔N-甲基-N-4-(2-丙炔基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.27(1H,s),2.72(3H,s),3.25
(3H,s),3.66(1H,dd,J=4,16Hz),3.93(1H,dd,
J=4,16Hz),4.25(2H,t-like),5.60-5.69(2H,
m),6.40(1H,t-like),6.55(1H,d,J=16Hz),
6.70(1H,t-like)7.23-7.34(3H,m),7.37-7.63
(6H,m),7.78(2H,d,J=8Hz),8.03(1H,d,
J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.28(1H,t-like),3.15(3H,
s),3.29(3H,s),3.90(1H,d,J=16Hz),4.12
(1H,d,J=16Hz),4.21(2H,d-like),5.60(1H,d,
J=10Hz),5.70(1H,d,J=10Hz),6.67(1H,d,
J=16Hz),7.36-7.65(6H,m),7.70-7.92(5H,m),
8.85(1H,d,J=7.5Hz)
(22)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(2-噻吩基甲基)氨基甲酰基〕-肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.27(3H,s),3.65
(1H,dd,J=4,16Hz),3.94(1H,dd,J=4,16Hz),
4.83(2H,d,J=6Hz),5.66(2H,s-like),6.46-
6.58(2H,m),6.70(1H,t-like),6.98(1H,t,
J=5Hz),7.00-7.06(1H,m),7.20-7.34(4H,m),
7.34-7.62(6H,m),7.79(2H,d,J=8Hz),8.03
(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.13(3H,s),3.28(3H,s),
3.89(1H,d,J=16Hz),4.09(1H,d,J=16Hz),4.77
(2H,s),5.59(1H,d,J=10Hz),5.69(1H,d,
J=10Hz),6.66(1H,d,J=16Hz),6.96(1H,t,
J=5Hz),7.06(1H,d-like),7.23(1H,d,J=5Hz),
7.43(1H,d,J=16Hz),7.48-7.57(4H,m),7.63
(1H,d,J=7.5Hz),7.71-7.82(3H,m),7.82-7.92
(2H,m),8.84(1H,d,J=8Hz)
(23)8-〔2,6-二氯-3-〔N-甲基-N-〔3-(甲基氨基甲酰基)-肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),2.99(3H,d-like),
3.25(3H,s),3.66(1H,dif.-dd,J=16Hz),3.95
(1H,dif.-dd,J=16Hz),5.65(2H,s),6.45-6.60
(2H,m),6.81-6.90(1H,m),7.21-7.69(9H,m),
7.75-(1H,d,J=8Hz),7.87(1H,s-like),8.04
(1H,d,J=7.5Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.00(3H,s),3.19(3H,s),
3.28(3H,s),3.86(1H,d,J=16Hz),4.28(1H,d,
J=16Hz),5.55(1H,d,J=10Hz),5.72(1H,d,
J=10Hz),6.72(1H,d,J=16Hz),7.32-7.48(3H,
m),7.48-7.69(3H,m),7.73-7.96(4H,m),8.18
(1H,s-like)8.87(8H,d)
(24)8-〔3-N-〔N′-(3-氨基甲酰基苯基)脲基乙酰基〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),3.28(3H,s),3.65
(1H,d,J=17Hz),3.90(1H,d,J=17Hz),5.59(2H,
s),7.21-7.61(9H),7.81(1H,br s),8.10(1H,
d,J=9Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.94(3H,s),3.29(3H,s),
3.80-4.10(2H,overlapped with H2O),5.59(1H,
d,J=10Hz),5.79(1H,d,J=10Hz),7.20(1H,t,
J=8Hz),7.31-7.98(9H),8.89(1H,d,J=9Hz)
(25)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-(3-丙基氨基甲酰基苯基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):0.86(3H,t,J=7.5Hz),1.42-1.55
(2H,m),2.56(3H,s),3.18(3H,s),3.21-3.35
(2H,m),3.80(1H,dd,J=4,16Hz),4.16(1H,dd,
J=7,16Hz),5.45(1H,d,J=9Hz),5.61(1H,d,
J=9Hz),5.64-5.72(1H,m),6.29(1H,t-like),
7.10(1H,t,J=7.5Hz),7.17-7.40(6H,m),7.42-
7.49(2H,m),7.54-7.59(1H,m),8.05(1H,d,
J=8Hz),8.44(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):0.92(3H,t,J=7.5Hz),1.50-
1.64(2H,m),2.81(3H,s),3.15-3.29(5H,m),
3.851(1H,d,J=16Hz),4.28(1H,d,J=16Hz),5.59
(1H,d,J=10Hz),5.71(1H,d,J=10Hz),7.02(1H,
t,J=7.5Hz),7.26-7.39(2H,m),7.51(1H,d,
J=7.5Hz),7.55-7.65(3H,m),7.65-7.78(2H,m),
7.78(1H,t,J=7.5Hz),8.75(1H,d,J=7.5Hz)
(26)8-〔2,6-二氯-3-〔N-〔N′-〔3-(2-羟乙基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.67(3H,s),3.23(3H,s),3.47-
3.56(2H,m),3.69-3.82(3H,m),3.83-3.93(2H,
m),5.56(1H,d,J=10Hz),5.65(1H,d,J=10Hz),
6.04-6.16(1H,m),7.06-7.17(2H,m),7.17-7.54
(9H,m),8.05(1H,d,J=8Hz),8.03(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.25(3H,s),3.42-3.51(2H,
m),3.72(2H,t,J=6Hz),3.88(1H,d,J=16Hz),
4.19(1H,d,J=16Hz),5.58(1H,d,J=10Hz),5.74
(1H,d,J=10Hz),7.04(1H,t,J=7.5Hz),7.28-
7.44(3H,m),7.48-7.82(5H,m),7.87(1H,t,
J=7.5Hz),8.79(1H,d,J=8Hz)
(27)8-〔2,6-二氯-3-〔N-〔N′-〔3-(2-乙氧乙基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.20(3H,t,J=7.5Hz),2.61(3H,
s),3.24(3H,s),3.43-3.62(6H,m),3.81(1H,
dd,J=4,16Hz),4.25(1H,dd,J=7.5,16Hz),5.47
(1H,d,J=10Hz),5.58-5.70(2H,m),6.60(1H,br
s),7.17(1H,t,J=7.5Hz),7.21-7.38(6H,m),
7.41-7.50(2H,m),7.64-7.70(1H,m),8.08(1H,
d,J=7.5Hz),8.48(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.19(3H,t,J=7.5Hz),2.84
(3H,s),3.26(3H,s),3.30-3.61(6H,m),3.85
(1H,d,J=16Hz),4.26(1H,d,J=16Hz),5.58(1H,
d,J=10Hz),5.73(1H,d,J=10Hz),7.09(1H,t,
J=7.5Hz),7.25-7.33(1H,m),7.39(1H,d,
J=7.5Hz),7.53(1H,d,J=8Hz),7.57-7.70(3H,
m),7.70-7.80(2H,m),7.87(1H,t,J=8Hz),8.78
(1H,d,J=8Hz)
(28)8-〔2,6-二氯-3-〔N-〔N′-〔4-(二甲基氨基甲酰基)苯基〕脲基乙酰基〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.59(3H,s),3.01(6H,br s),3.22
(3H,s),3.78(1H,dd,J=4,16Hz),4.37(1H,dd,
J=7.5,16Hz),5.42(1H,d,J=10Hz),5.47-5.55
(1H,m),5.62(1H,d,J=10Hz),7.16-7.37(8H,
m),7.44-7.54(2H,m),8.10(1H,d,J=8Hz),7.71
(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.92(3H,s),3.25(3H,s),
3.85(1H,d,J=16Hz),4.13(1H,d,J=16Hz),5.60
(1H,d,J=10Hz),5.75(1H,d,J=10Hz),7.19(2H,
d,J=8Hz),7.28-7.42(2H,m),7.48-7.70(3H,m),
7.70-7.95(3H,m),8.83(1H,d,J=8Hz)
(29)8-〔3-〔N-〔N′-(3-乙基氨基甲酰基苯基)脲基乙酰基〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.16(3H,t,J=7.5Hz),2.63(3H,
s),3.20(3H,s),3.38(2H,dq,J=7.5,5Hz),
3.81(1H,dd,J=17,5Hz),4.00(1H,dd,J=17,
6Hz),5.51(1H,d,J=9Hz),5.63(1H,d,J=9Hz),
5.95(1H,br t,J=5Hz),6.57(1H,br t,J=5Hz),
7.13(1H,t,J=8Hz),7.20-7.41(6H,m),7.45
(2H,d,J=5Hz),7.55(1H,br s),8.06(1H,d,
J=9Hz),8.48(1H,br s)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.22(3H,t,J=7.5Hz),2.97
(3H,s),3.30(3H,s),3.40(2H,q,J=7.5Hz),
3.86(2H,s),5.60(1H,d,J=9Hz),5.82(1H,d,
J=9Hz),7.24(1H,t,J=8Hz),7.30-7.46(2H,m),
7.58(1H,d,J=7Hz),7.65(1H,d,J=7Hz),7.70-
7.81(2H,m),7.81-8.01(3H,m),8.91(1H,d,
J=8Hz)
(30)8-〔2,6-二氯-3-〔N-〔4-〔N-(2-乙氧乙基)-N-〔甲基氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.11-1.26(3H,m),2.74(3H,s),
3.03(1.5H,br s),3.10(1.5H,br s),3.28(3H,
s),3.33-3.60(4H,m),3.60-3.75(3H,m),3.96
(1H,dd,J=4,16Hz),5.65(2H,s-like),6.50
(1H,d,J=16Hz),6.65(1H,t-like),7.22-7.35
(3H,m),7.35-7.46(3H,m),7.48(1H,d,
J=16Hz),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.13-1.27(3H,m),3.03
(1.5H,br s),3.10(1.5H,br s),3.20(3H,s),
3.30(3H,s),3.36-3.58(4H,m),3.71(2H,br),
3.90(1H,d,J=16Hz),4.03(1H,d,J=16Hz),5.63
(1H,d,J=10Hz),5.70(1H,d,J=10Hz),6.62(1H,
d,J=16Hz),7.36(2H,d,J=8Hz),7.40-7.57(5H,
m),7.61(1H,d,J=8Hz),7.76(1H,d,J=8Hz),
7.80-7.90(2H,m),8.81(1H,d,J=8Hz)
(31)8-〔2,6-二氯-3-〔N-〔4-〔N-甲基-N-(2-吡啶基甲基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.00(1.5H,br s),
3.09(1.5H,br s),3.65(1H,br d,J=16Hz),3.94
(1H,br d,J=16Hz),4.60(1H,s),4.87(1H,s),
5.64(1H,s-like),6.41-6.59(1H,m),6.59-6.76
(1H,m),7.14-7.36(5H,m),7.36-7.65(8H,m),
7.71(1H,td,J=8,2Hz),8.03(1H,d,J=8Hz),
8.57(1H,d,J=6Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.18(3H,s),3.25(3H,s),
3.29(3H,s),3.90(1H,d,J=16Hz),4.06(1H,d,
J=16Hz),5.20(2H,s),5.61(1H,d,J=10Hz),
5.70(1H,d,J=10Hz),6.67(1H,d,J=16Hz),
7.41-7.59(7H,m),7.63(1H,d,J=8Hz),7.79
(1H,d,J=8Hz),7.83-7.93(3H,m),8.01-8.11
(1H,m),8.40-8.52(1H,m),8.81(1H,d,J=6Hz),
8.85(1H,d,J=8Hz)
(32)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(2-甲基烯丙基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.80(3H,s),2.71(3H,s),3.25
(3H,s),3.65(1H,dd,J=4,16Hz),3.94(1H,dd,
J=4,16Hz),4.02(2H,d,J=6Hz),4.85-4.93(2H,
m),5.60-5.70(2H,m),6.21(1H,t-like),6.54
(1H,d,J=16Hz),6.69(1H,t-like),7.22-7.36
(3H,m),7.36-7.65(6H,m),7.79(2H,d,J=8Hz),
8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.78(3H,s),3.14(3H,s),
3.29(3H,s),3.89(1H,d,J=16Hz),3.99(2H,
s),4.10(1H,d,J=16Hz),4.90(2H,d-like),
5.60(1H,d,J=10Hz),5.70(1H,d,J=10Hz),6.66
(1H,d,J=16Hz),7.45(1H,d,J=16Hz),7.49-7.67
(5H,m),7.67-7.94(5H,m),8.86(1H,d,J=8Hz)
(33)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(甲基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.04(3H,d,J=6Hz),
3.28(3H,s),3.61-3.75(1H,m),3.95(1H,dd,
J=4,16Hz),5.64(2H,s),6.64(1H,d,J=16Hz),
6.76(1H,br),7.21-7.37(3H,m),7.37-7.54(3H,
m),7.60(1H,d,J=16Hz),7.88-8.09(3H,m),
8.19(1H,d,J=8Hz),8.62(1H,d-like)
其二盐酸盐NMR(CDCl3=CD3OD,δ):3.00(3H,s),3.13(3H,s),
3.25(3H,s),3.85(1H,d,J=16Hz),4.21(1H,d,
J=16Hz),5.53(1H,d,J=10Hz),5.64(1H,d,
J=10Hz),6.85(1H,d,J=16Hz),7.41-7.62(4H,
m),7.73(1H,d,J=8Hz),7.78-7.88(2H,m),8.33
(2H,s-like),8.80(1H,d,J=8Hz),9.00(1H,br
s)
(34)8-〔2,6-二氯-3-〔N-〔(E)-3-〔6-二甲基氨基甲酰基)-吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.09(3H,s),3.14
(3H,s),3.28(3H,s),3.68(1H,dd,J=4,16Hz),
3.95(1H,dd,J=4,16Hz),5.60-5.71(2H,m),
6.60(1H,d,J=16Hz),6.75(1H,t-like),7.23-
7.35(3H,m),7.35-7.68(5H,m),7.89(1H,dd,
J=8,2Hz),8.03(1H,d,J=8Hz),8.66(1H,
d-like)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.06(3H,s),3.08-3.16(6H,
m),3.26(3H,s),3.85(1H,d,J=16Hz),4.35
(1H,d,J=16Hz),5.51(1H,d,J=10Hz),5.65(1H,
d,J=10Hz),6.97(1H,d,J=16Hz),6.44(1H,d,
J=16Hz),7.50-7.66(3H,m),7.73(1H,d,J=8Hz),
7.78-7.91(3H,m),8.70(1H,br d,J=8Hz),8.79
(1H,d,J=8Hz),9.04(1H,br s)
(35)8-〔2,6-二氯-3-〔N-〔(E)-3-〔6-(乙基氨基甲酰基)-吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉NMR(CDCl3,δ):1.28(3H,t,J=7.5Hz),2.74(3H,s),
3.28(3H,s),3.52(2H,quint,J=7.5Hz),3.70
(1H,dd,J=4,16Hz),3.95(1H,dd,J=4,16Hz),
5.65(2H,s),6.63(1H,d,J=16Hz),6.77(1H,
br),7.20-7.36(3H,m),7.36-7.54(3H,m),7.61
(1H,d,J=16Hz),7.88-8.00(2H,m),8.04(1H,d,
J=8Hz),8.18(1H,d,J=8Hz),8.62(1H,br)
其二盐酸盐NMR(CDCl3-CD3OD,δ):1.29(3H,t,J=7.5Hz),3.18
(3H,s),3.30(3H,s),3.50(2H,q,J=7.5Hz),
3.90(1H,d,J=16Hz),4.07(1H,d,J=16Hz),5.60
(1H,d,J=10Hz),5.20(1H,d,J=10Hz), 6.81(1H,
d,J=16Hz),7.49-7.60(3H,m),7.64(1H,d,
J=8Hz),7.79(1H,d,J=8Hz),7.83-7.93(2H,m),
8.09(1H,d,J=8Hz),8.17(1H,d,J=8Hz),8.74
(1H,br s),8.86(1H,d,J=8Hz)
(36)8-〔2,6-二氯-3-〔N-〔(E)-3-〔6-(N-乙基-N-甲基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.17(3/2H,t,J=7.5Hz),1.25
(3/2H,t,J=7.5Hz),2.73(3H,s),3.03(3/2H,
s),3.10(3/2H,s),3.27(3H,s),3.41(1H,q,
J=7.5Hz),3.60(1H,q,J=7.5Hz),3.69(1H,dd,
J=4,16Hz),3.95(1H,dd,J=4,16Hz),5.60-5.67
(2H,m),6.58(1H,d,J=16Hz),6.73(1H,br),
7.19-7.35(3H,m),7.35-7.65(5H,m),7.88(1H,
d,J=8Hz),8.03(1H,d,J=8Hz),8.66(1H,br s)
其二盐酸盐NMR(CDCl3-CD3OD,δ):1.22(1.5H,t,J=7.5Hz),1.27
(1.5H,t,J=7.5Hz),3.05(1.5H,s),3.11(1.5H,
s),3.15(3H,s),3.29(3H,s),3.33-3.46(1H,
m),3.60(1H,q,J=7.5Hz),3.87(1H,d,J=16Hz),
4.32(0.5H,d,J=16Hz),4.39(0.5H,d,J=16Hz),
5.01-5.10(1H,m),5.69(1H,d,J=10Hz),6.94
(0.5H,d,J=16Hz),7.00(0.5H,d,J=16Hz),7.50
(1H,d,J=16Hz),7.55-7.69(3H,m),7.78(1H,d,
J=8Hz),7.81-7.95(3H,m),8.56(0.5H,br),8.75
(0.5H,br),8.82(1H,d,J=8Hz),9.00(0.5H,br
s),9.09(0.5H,br s)
(37)8-〔3-〔N-〔(E)-3-〔6-(烯丙基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.28(3H,s),3.70
(1H,dd,J=4,16Hz),3.95(1H,dd,J=4,16Hz),
4.10(2H,t-like),5.18(1H,d,J=11Hz),5.26
(1H,d,J=18Hz),5.59-5.70(2H,m),5.86-6.03
(1H,m),6.63(1H,d,J=16Hz),6.75(1H,
t-like),7.20-7.34(3H,m),7.36-7.52(3H,m),
7.60(1H,d,J=16Hz),7.93(1H,dd,J=2,8Hz),
8.03(1H,d,J=8Hz),8.07(1H,t-like),8.18
(1H,d,J=8Hz),8.63(1H,d,J=2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.13(3H,s),3.25(3H,s),
3.86(1H,d,J=16Hz),4.06(2H,d-like),4.23
(1H,d,J=16Hz),5.17(1H,d,J=11Hz),5.26(1H,
d,J=18Hz),5.55(1H,d,J=10Hz),5.64(1H,d,
J=10Hz),5.82-6.00(1H,m),6.88(1H,d,
J=16Hz),7.43-7.63(4H,m),7.73(1H,d,J=8Hz),
7.78-7.89(2H,m),8.2 -8.41(2H,m),8.78(1H,
d,J=8Hz),8.97(1H,br s)
(38)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(2-丙炔基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.27(1H,t-like),2.73(3H,s),
3.26(3H,s),3.70(1H,dd,J=4,16Hz),3.95
(1H,dd,J=4,16Hz),4.23-4.30(2H,m),5.65
(2H,s-like),6.13(1H,d,J=16Hz),6.77(1H,
t-like),7.20-7.35(3H,m),7.35-7.53(3H,m),
7.60(1H,d,J=16Hz),7.94(1H,dd,J=2,8Hz),
8.03(1H,d,J=8Hz),8.16(1H,d,J=8Hz),8.62
(1H,d,J=2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):2.27(1H,t-like),3.17(3H,
s),3.27(3H,s),3.88(1H,d,J=16Hz),4.18-
4.32(3H,m),5.55(1H,d,J=10Hz),5.64(1H,d,
J=10Hz),6.90(1H,d,J=16Hz),7.41-7.63(4H,
m),7.73(1H,d,J=8Hz),7.78-7.88(2H,m),8.30
(1H,d,J=8Hz),8.37(1H,d,J=8Hz),8.79(1H,
d,J=8Hz),9.00(1H,br s)
(39)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(1-吡咯烷基羰基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉二盐酸盐NMR(CDCl3-CD3OD,δ):1.93-2.05(4H,m),3.13(3H,
s),3.30(3H,s),3.63-3.75(4H,m),3.86(1H,
d,J=16Hz),4.40(1H,d,J=16Hz),5.53(1H,d,
J=10Hz),5.70(1H,d,J=10Hz),6.99(1H,d,
J=16Hz),7.49(1H,d,J=16Hz),7.55-7.70(3H,
m),7.77(1H,d,J=8Hz),7.81-7.93(2H,m),
8.06-8.15(1H,m),8.74-8.87(2H,m),9.20(1H,
br s)
(40)8-〔2,6-二氯-3-〔N-〔(E)-3-〔6-(2-甲氧乙基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.26(3H,s),3.40
(3H,s),3.57(2H,t,J=6Hz),3.66(2H,t,
J=6Hz),3.70(1H,dd,J=4,16Hz),3.95(1H,dd,
J=4,16Hz),5.63(1H,d,J=10Hz),5.67(1H,d,
J=10Hz),6.63(1H,d,J=16Hz),6.76(1H,
t-like),7.22-7.35(3H,m),7.37-7.53(3H,m),
7.60(1H,d,J=16Hz),7.93(1H,dd,J=2,8Hz),
8.03(1H,d,J=8Hz),8.16(1H,d,J=8Hz),8.26
(1H,t-like),8.63(1H,d,J=2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.17(3H,s),3.30(3H,s),
3.40(3H,s),3.57-3.63(2H,m),3.63-3.70(2H,
m),3.89(1H,d,J=16Hz),4.24(1H,d,J=16Hz),
5.58(1H,d,J=10Hz),5.68(1H,d,J=10Hz),6.90
(1H,d,J=16Hz),7.45-7.67(4H,m),7.77(1H,d,
J=8Hz),7.81-7.92(2H,m),8.26-8.43(2H,m),
8.83(1H,d,J=8Hz),8.99(1H,br s)
(41)8-〔2,6-二氯-3-〔N-〔(E)-3-〔6-(2-乙氧乙基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.23(3H,t,J=7.5Hz),2.73(3H,
s),3.27(3H,s),3.55(2H,q,J=7.5Hz),3.57-
3.75(5H,m),3.94(1H,dd,J=4,16Hz),5.62
(1H,d,J=10Hz),5.67(1H,d,J=10Hz),6.61(1H,
d,J=16Hz),6.75(1H,t-like),7.23-7.35(3H,
m),7.35-7.53(3H,m),7.60(1H,d,J=16Hz),
7.93(1H,dd,J=2,8Hz),8.03(1H,d,J=8Hz),
8.16(1H,d,J=8Hz),8.29(1H,t-like),8.63
(1H,d,J=2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,5):1.21(3H,t,J=7.5Hz),3.17
(3H,s),3.30(3H,s),3.55(2H,q,J=7.5Hz),
3.60-3.70(4H,m),3.86(1H,d,J=16Hz),4.30
(1H,d,J=16Hz),5.57(1H,d,J=10Hz),5.67(1H,
d,J=10Hz),6.93(1H,d,J=16Hz),7.50(1H,d,
J=16Hz),7.56-7.64(3H,m),7.78(1H,d,J=8Hz),
7.82-7.92(2H,m),8.36(1H,d,J=8Hz),8.47
(1H,d,J=8Hz),8.83(1H,d,J=8Hz),9.07(1H,
br s)
(42)8-〔3-〔N-〔(E)-3-〔6-〔N,N ′-二(2-甲氧乙基)氨基甲酰基〕吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.23(3H,s),3.27
(3H,s),3.38(3H,s),3.54(2H,t,J=6Hz),
3.61-3.83(7H,m),3.94(1H,dd,J=4,16Hz),
5.65(1H,d,J=10Hz),5.68(1H,d,J=10Hz),6.60
(1H,d,J=16Hz),6.72(1H,t-like),7.24-7.36
(3H,m),7.36-7.70(5H,m),7.88(1H,dd,J=2,
8Hz),8.03(1H,d,J=8Hz),8,65(1H,d,J=2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.13(3H,s),3.21-3.80(17H,
m),3.85(1H,d,J=16Hz),4.51(1H,d,J=16Hz),
5.50(1H,d,J=10Hz),5.67(1H,d,J=10Hz),7.05
(1H,d,J=16Hz),7.47(1H,d,J=16Hz),7.53-7.64
(2H,m),7.70(1H,d,J=8Hz),7.76(1H,d,
J=8Hz),7.84(1H,d,J=8Hz),7.89(1H,d,
J=8Hz),8.00-8.06(1H,m),8.81(1H,d,J=8Hz),
8.87-8.96(1H,m),9.29(1H,br s)
(43)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(吗啉代羰基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.25(3H,s),3.63-
3.74(5H,m),3.80(4H,s-like),3.95(1H,dd,
J=4,16Hz),5.63(1H,d,J=10Hz),5.68(1H,d,
J=10Hz),6.60(1H,d,J=16Hz),6.73(1H,
t-like),7.23-7.35(3H,m),7.35-7.53(3H,m),
7.59(1H,d,J=16Hz),7.71(1H,d,J=8Hz),7.91
(1H,dd,J=2,8Hz),8.03(1H,d,J=8Hz),8.66
(1H,d,J=2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.15(3H,s),3.29(3H,s),
3.61(2H,br),3.73(2H,br),3.82(4H,br),
3.90(1H,d,J=16Hz),4.27(1H,d,J=16Hz),5.67
(1H,d,J=10Hz),5.70(1H,d,J=10Hz),6.93(1H,
d,J=16Hz),7.49(1H,d,J=16Hz),7.53-7.65(3H,
m),7.76(1H,d,J=8Hz),7.80-7.92(3H,m),
8.47-8.57(1H,m),8.82(1H,d,J=8Hz),8.94
(1H,br)
(44)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-〔(2-吡啶基甲基)氨基甲酰基〕吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.27(3H,s),3.70
(1H,dd,J=4,16Hz),3.95(1H,dd,J=4,16Hz),
4.80(2H,d,J=6Hz),5.65(2H,s),6.63(1H,d,
J=16Hz),6.76(1H,t-like),7.17-7.38(5H,m),
7.37-7.54(3H,m),7.61(1H,d,J=16Hz),7.67
(1H,td,J=8,2Hz),7.95(1H,d,J=8Hz),8.03
(1H,d,J=8Hz),8.20(1H,d,J=8Hz),8.61(1H,
d,J=6Hz),8.67(1H,s-like),8.90(1H,t-like)
其三盐酸盐NMR(CDCl3-CD3OD,δ):3.19(3H,s),3.30(3H,s),
3.90(1H,d,J=16Hz),4.17(1H,d,J=16Hz),5.13
(2H,s),5.60(1H,d,J=10Hz),5.70(1H,d,
J=10Hz),6.90(1H,d,J=16Hz),7,45-7.70(4H,
m),7.77-7.98(4H,m),8.12(1H,d,J=8Hz),
8.16-8.30(2H,m),8.43(1H,t,J=8Hz),8.77
(1H,d,J=6Hz),8.81-8.93(2H,m)
(45)8-〔2,6-二氯-3-〔N-甲基-N-〔4-吗啉代羰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹喔啉mp:118-130℃NMR(CDCl3,δ):2.78(3H,s),3.28(3H,s),3.37-
3.55(2H,m),3.67(1H,dd,J=16.5,3.0Hz),
3.59-3.88(6H,m),3.96(1H,dd,J=16.5,3.0Hz),
5.62(2H,s),6.52(1H,d,J=15.0Hz),6.66(1H,
t,J=3.0Hz),7.29-7.38(2H,m),7.42(2H,d,
J=8.5Hz),7.49-7.70(5H,m),7.77(1H,d,
J=8.5Hz),8.73(1H,s)
(46)8-〔2,6-二氯-3-〔N-〔4-〔(2-吡啶基甲基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉mp:111-124℃NMR(CDCl3,δ):2.78(3H,s),3.28(3H,s),3.67
(1H,dd,J=16.5,3.0Hz),3.96(1H,dd,J=16.5,
3.0Hz),4.77(2H,d,J=3.0Hz),5.62(2H,s),
6.53(1H,d,J=16.0Hz),6.72(1H,t,J=3.0Hz),
7.20-7.38(4H,m),7.49-7.71(7H,m),7.75(1H.
t,J=8.5Hz),7.89(2H,d,J=8.5Hz),8.57(1H,d,
J=4.5Hz),8.73(1H,s)
(47)8-〔3-〔N-〔4-(烯丙基氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹喔啉mp:117-123℃NMR(CDCl3,δ):2.76(3H,s),3.27(3H,s),3.65
(1H,dd,J=16.5,3.0Hz),3.94(1H,dd,J=16.5,
3.0Hz),4.09(2H,m),5.19(1H,d,J=11.5Hz),
5.27(1H,d,J=16.5Hz),5.62(2H,s),5.86-6.00
(1H,m),6.25(1H,t,J=7.0Hz),6.53(1H,d,
J=15.0Hz),6.70(1H,t,J=3.0Hz),7.29-7.36(2H,
m),7.48-7.82(8H,m),8.73(1H,s)
(48)8-〔2,6-二氯-3-〔N-〔4-(2-乙氧乙基氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉mp:97-111℃NMR(CDCl3,δ):1.23(3H,t,J=7.0Hz),2.77(3H,
s),3.27(3H,s),3.54(2H,q,J=7.0Hz),3.57-
3.71(5H,m),3.94(1H,dd,J=16.5,3.0Hz),5.63
(2H,s),6.53(1H,d,J=15.0Hz),6.58(1H,t,
J=6.0Hz),6.69(1H,t,J=3.0Hz),7.29-7.37(2H,
m),7.49-7.82(8H,m),8.74(1H,s)
(49)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(苯基氨基甲酰基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.69(3H,s),3.24(3H,s),3.88
(1H,dd,J=17,4Hz),4.02(1H,dd,J=17,5Hz),
5.51(2H,s),6.35(1H,br s),7.00-7.51(13H),
7.88(2H,d,J=8Hz),8.06(1H,d,J=8Hz),8.39
(1H,s),9.17(1H,br s)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.84(3H,s),3.25(3H,s),
3.87(1H,br d,J=17Hz),4.31(1H,br d,
J=17Hz),5.59(1H,d,J=10Hz),5.68(1H,d,
J=10Hz),7.05-7.13(2H),7.28-7.71(11H),7.76-
7.86(2H),8.70(1H,d,J=8Hz)
(50)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(苯基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.69(3H,s),3.24(3H,s),3.65
(1H,dd,J=17,4Hz),3.92(1H,dd,J=17,5Hz),
5.63(2H,s),6.53(1H,d,J=15Hz),6.76(1H,br
t,J=4Hz),7.13(1H,t,J=8Hz),7.23-7.61(11H),
7.67(2H,d,J=8Hz),7.88(2H,d,J=8Hz),8.03
(1H,d,J=8Hz),8.18(1H,br s)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.12(3H,s),3.29(3H,s),
3.89(1H,d,J=17Hz),4.13(1H,d,J=17Hz),5.59
(1H,d,J=10Hz),5.70(1H,d,J=10Hz),6.69(1H,
d.J=15Hz),7.15(1H,t,J=8Hz),7.32-7.40(2H),
7.42(1H,d,J=15Hz),7.62(1H,d,J=8Hz),7.70-
7.92(8H),8.85(1H,d,J=8Hz)
(51)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔2-(甲基氨基甲酰基氧基)乙基氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),2.80(3H,d,J=6Hz),
3.27(3H,s),3.61-3.77(2H,m),3.66(1H,d,
J=17,4Hz),3.94(1H,d,J=17,5Hz),
4.25-4.37(2H,m),5.61(1H,d,J=9Hz),5.66
(1H,d,J=9Hz),6.5 3(1H,d,J=16Hz),6.71(1H,
br t,J=6Hz),7.01(1H,m),7.22-7.35(3H,m),
7.38-7.64(6H,m),7.74-7.85(2H,m),8.02(1H,
d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.74(3H,s),3.10(3H,s),
3.30(3H,s),3.66(2H,br t,J=7Hz),3.91(1H,
d,J=17Hz),4.02(1H,d,J=17Hz),4.26(2H,br
t,J=7Hz),5.60(1H,d,J=9Hz),5.76(1H,d,
J=9Hz),6.66(1H,d,J=15Hz),7.45(1H,d,
J=15Hz),7.50-7.74(5H,m),7.77-8.00(5H,m),
8.94(1H,d,J=9Hz)
(52)8-〔2,6-二氯-3-〔N-4-〔(乙氧羰基甲基氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.31(3H,t,J=7.5Hz),2.74(3H,
s),3.27(3H,s),3.64(1H,dd,J=4,16Hz),3.95
(1H,dd,J=4,16Hz),4.15-4.33(4H,m),5.60-
5.71(2H,m),6.55(1H,d,J=16Hz),6.65-6.77
(2H,m),7.17-7.35(3H,m),7.35-7.65(6H,m),
7.80(2H,d,J=8Hz),8.03(1H,d,J=8Hz)
(53)8-〔2,6-二氯-3-〔N-〔4-〔N-(甲氧羰基甲基)-N-甲基氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.05(2H,s),3.10
(1H,s),3.26(3H,s),3.64(1H,dd,J=4,16Hz),
3.70-3.83(3H,m),3.86-4.02(1.7H,m),4.27
(1.3H,br s),5.60-5.71(2H,m),6.50(1H,br d,
J=16Hz),6.65(1H,br),7.17-7.33(3H,m),
7.33-7.63(8H,m),8.02(1H,d,J=8Hz)
(54)8-〔2,6-二氯-3-〔N-〔4-〔(2-甲氧羰基乙基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.65(2H,t,J=6Hz),2.73(3H,s),
3.25(3H,s),3.58-3.77(6H,m),3.94(1H,dd,
J=4,16Hz),5.90-5.70(2H,m),6.52(1H,d,
J=16Hz),6.63-6.70(1H,m),6.85(1H,t-like),
7.20-7.35(3H,m),7.35-7.62(6H,m),7.75(2H,
d,J=8Hz),8.01(1H,d,J=8Hz)
(55)8-〔2,6-二氯-3-〔N-〔4-〔((R)-1-甲氧羰基乙基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.52(3H,d,J=7.5Hz),2.72(3H,
s),3.25(3H,s),3.65(1H,dt,J=16,4Hz),3.80
(3H,s),3.95(1H,dt,J=16,4Hz),4.80(1H,
quint,J=7.5Hz),5.59-5.70(2H,m),6.54(1H,
dd,J=4,16Hz),6.64-6.81(2H,m),7.20-7.35
(3H,m),7.35-7.65(6H,m),7.80(2H,d,J=8Hz),
8.03(1H,d,J=8Hz),[α]D 20:-22.7°(C=20mg/2ml,CDCl3)
(56)8-〔2,6-二氯-3-〔N-〔4-〔((R)-1-甲氧羰基-2-苯乙基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.16-3.37(5H,m),
3.65(1H,dd,J=4,16Hz),3.78(3H,s),3.94
(1H,dd,J=4,16Hz),5.09(1H,q,J=7.5Hz),
5.60-5.71(2H,m),6.49-6.60(2H,m),6.63-6.72
(1H,m),7.12(2H,d,J=8Hz),7.20-7.36(6H,m),
7.36-7.63(6H,m),7.70(2H,d,J=8Hz),8.02
(1H,d,J=8Hz)[α]D 20:+49.5°(C=20mg/2ml,MeOH)
(57)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(4-吡啶基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.28(3H,s),3.71
(1H,dd,J=17,4Hz),3.97(1H,dd,J=17,5Hz),
5.66(2H,s),6.69(1H,d,J=15Hz),6.83(1H,br
t,J=4Hz),7.21-7.36(4H),7.39-7.52(3H),7.62
(1H,d,J=15Hz),7.71(1H,d,J=6Hz),7.98-8.07
(2H),8.27(1H,d,J=7.5Hz),8.58(2H,d,
J=6Hz),8.69(1H,d,J=2Hz)
其三盐酸盐NMR(CDCl3-CD3OD,δ):3.20(3H,s),3.30(3H,s),
3.92(1H,d,J=17Hz),4.26(1H,d,J=17Hz),5.60
(1H,d,J=10Hz),5.71(1H,d,J=10Hz),6.98(1H,
d,J=15Hz),7.49-7.69(4H),7.79(1H,d,
J=7.5Hz),7.85-7.93(2H),8.17(1H,br d,
J=7.5Hz),8.33(1H,br d,J=7.5Hz),8.46(2H,d,
J=6Hz),8.67(2H,d,J=6Hz),8.87(1H,d,
J=7.5Hz),8.99(1H,br s)
(58)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(3-吡啶基甲基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.71(3H,s),3.27(3H,s),3.69
(1H,dd,J=17,4Hz),3.93(1H,dd,J=17,5Hz),
4.69(2H,d,J=5Hz),5.65(2H,s),6.62(1H,d,
J=15Hz),6.79(1H,br t,J=4Hz),7.20-7.33(4H),
7.37-7.52(4H),7.59(1H,d,J=15Hz),7.71(1H,
br d,J=7.5Hz),7.95(1H,dd,J=7.5,2Hz),8.02
(1H,d,J=7.5Hz),8.20(1H,d,J=7.5Hz),8.37
(1H,br t,J=5Hz),8.53(1H,d,J=2Hz),8.62
(2H,dd,J=7.5,2Hz)
其三盐酸盐NMR(CDCl3-CD3OD,δ):3.13(3H,s),3.29(3H,s),
3.90(1H,d,J=17Hz),4.28(1H,d,J=17Hz),4.88
(2H,br s),5.56(1H,d,J=10Hz),5.72(1H,d,
J=10Hz),7.04(1H,br d,J=15Hz),7.46-7.69
(4H),7.81(1H,d,J=7.5Hz),7.87-8.02(3H),
8.56(1H,br d,J=7.5Hz),8.69-8.81(3H),8.89
(1H,br d,J=7.5Hz),8.99(1H,br s),9.33(1H,
br s)
(59)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(4-吡啶基甲基氨基甲酰基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.28(3H,s),3.70
(1H,dd,J=17,4Hz),3.96(1H,dd,J=17,5Hz),
4.69(2H,d,J=5Hz),5.66(2H,s),6.64(1H,d,
J=15Hz),6.79(1H,br t,J=4Hz),7.23-7.33(5H),
7.38-7.52(3H),7.61(1H,d,J=15Hz),7.98(1H,
dd,J=7.5,2Hz),8.02(1H,d,J=7.5Hz),8.20
(1H,d,J=7.5Hz),8.42(1H,br t,J=5Hz),8.57
(2H,d,J=6Hz),8.62(1H,d,J=2Hz)
其三盐酸盐NMR(CDCl3-CD3OD,δ):3.15(3H,br s),3.29(3H,
s),3.90(1H,d,J=17Hz),4.30(1H,d,J=17Hz),
4.92(2H,br s),5.56(1H,d,J=10Hz),5.72(1H,
d,J=10Hz),7.07(1H,br s),7.45-7.68(4H),
7.60(1H,d,J=7.5Hz),7.85-7.98(2H),8.03-8.12
(2H),8.58(1H,br s),8.70-8.91(4H),9.40(1H,
br s)
(60)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(2-吡啶基)氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.71(3H,s),3.26(3H,s),3.67
(1H,dd,J=4,16Hz),3.95(1H,dd,J=4,16Hz),
5.64(2H,s-like),6.58(1H,d,J=16Hz),
6.86(1H,t-like),7.08(1H,dd,J=5,8Hz),
7.18-7.35(4H,m),7.35-7.52(3H,m),7.52-7.67
(3H,-m),7.76(1H,ddd,J=8,8,2Hz),7.91(2H,
d,J=8Hz),8.03(1H,d,J=8Hz),8.29(1H,dd,
J=2,5Hz),8.38(1H,d,J=8Hz),8.75(1H,s)
(61)8-〔2,6-二氯-3-〔N甲基-N-〔4-〔(5-四唑基)氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.69(3H,s),3.27(3H,s),
3.51-3.78(1H,m),4.01(1H,d,J=17Hz),5.58
(2H,s),6.67(1H,d,J=15Hz),7.20-7.80(8H,
m),7.90-8.20(4H,m)
其盐酸盐NMR(CDCl3-CD3OD,6):3.11(3H,br s),3.32(3H,s),
3.92(1H,d,J=17Hz),4.00(1H,d,J=17Hz),5.63
(1H,d,J=9Hz),5.80(1H,d,J=9Hz),6.77(1H,
d,J=15Hz),7.44-8.15(11H,m),8.98(1H,m)
实施例56
根据与实施例15相似的方法,使8-〔3-〔N-(4-氨基肉桂酰甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉与乙氧羰基乙酰氯反应,得到8-〔2,6-二氯-3-〔N-〔4-(乙氧羰基乙酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉。NMR(CDCl3,δ):1.33(3H,t,J=7.5Hz),2.73(3H,
s),3.25(3H,s),3.46(2H,s),3.63(1H,dd,
J=4,18Hz),3.93(1H,dd,J=4,18Hz),4.25(2H,
q,J=7.5Hz),5.63(2H,s),6.40(1H,d,J=16Hz),
6.60-(1H,t-like),7.20-7.34(3H,m),7.34-7.53
(6H,m),7.53-7.62(2H,m),8.02(1H,d,J=8Hz),
9.46(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.31(3H,t,J=7.5Hz),3.07
(3H,s),3.27(3H,s),3.51(2H,s),3.87(1H,
d,J=10Hz),4.01(1H,d,J=10Hz),4.25(2H,q,
J=7.5Hz),5.60(1H,d,J=10Hz),5.20(1H,d,
J=10Hz),6.47(1H,d,J=16Hz),7.32-7.43(3H,
m),7.49-7.65(5H,m),7.71-7.90(3H,m),
8.76-8.88(1H,m)
实施例57
根据与实施例56相似的方法,使8-〔3-N-〔N′-(3-氨基苯基)脲基乙酰基〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉与丙酰氯反应,得到8-〔2,6-二氯-3-〔N-甲基- N-〔N′-(3-丙酰氨基苯基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉。NMR(CDCl3,δ):1.13(3H,t,J=7.5Hz),2.27(2H,q,
J=7.5Hz),2.60(3H,s),3.18(3H,s),3.78-3.90
(1H,m),3.93-4.06(1H,m),5.50(1H,d,
J=10Hz),5.60(1H,d,J=10Hz),5.75-7.85(1H,
m),6.78-6.88(1H,m),7.04(1H,t,J=7.5Hz),
7.21-7.50(8H,m),7.91(1H,br s),8.07(1H,d,
J=8Hz),8.26(1H,br s)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.11(3H,t,J=7.5Hz),2.29
(2H,q,J=7.5Hz),2.73(3H,s),3.25(3H,s),
3.84(1H,d,J=16Hz),4.24(1H,d,J=16Hz),5.58
(1H,d,J=10Hz),5.7 3(1H,d,J=10Hz),6.78(1H,
t,J=8Hz),6.90(1H,d,J=7.5Hz),7.14(1H,
s-like),7.36(1H,d,J=7.5Hz),7.50(1H,d,
J=8Hz),7.54-7.65(2H,m),7.65-7.80(2H,m),
7.86(1H,t,J=8Hz),8.76(1H,d,J=8Hz)
实施例58
根据与实施例36,56或57相似的方法,得到下列化合物:
(1)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔2-(1-甲基-1H-吡咯-2-基)乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ).2.74(3H,s),3.27(3H,s),3.55
(3H,s),3.64(1H,dd,J=4,16Hz),3.71(2H,s),
3.94(1H,dd,J=4,16Hz),5.65(2H,s-like),
6.11-6.29(2H,m),6.40(1H,d,J=16Hz),6.10
(1H,t-like),6.64-6.70(1H,m),7.23-7.33(3H,
m),7,37-7.55(9H,m),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.13(3H,s),3.30(3H,s),
3.59(3H,s),3.74(2H,s),3.88(1H,d,
J=16Hz),4.00(1H,d,J=16Hz),5.59(1H,d,
J=10Hz),5.70(1H,d,J=10Hz),6.47(1H,d,
J=16Hz),7.32-7.63(10H,m),7.75-7.90(4H,m),
8.86-(1H,d,J=8Hz)
(2)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(3-噻吩基羰基)氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.67(3H,s),3.21(3H,s),3.62
(1H,dd,J=4,16Hz),3.90(1H,dd,J=4,16Hz),
5.62(2H,s),6.40(1H,d,J=16Hz),6.60(1H,
t-like),7.20-7.56(11H,m),7.65(2H,d,
J=8Hz),8.00-8.09(2H,m),8.35(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.08(3H,s),3.29(3H,s),
3.91(1H,d,J=17Hz),4.06(1H,d,J=17Hz),5.59
(1H,d,J=10Hz),5.74(1H,d,J=10Hz),6.49(1H,
d,J=16Hz),7.30-7.97(13H,m),8.25(1H,d,
J=2Hz),8.92(1H,d,J=8Hz)
(3)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(2-噻吩基羰基)氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.60(3H,s),3.19(3H,s),
3.60(1H,d,J=16Hz),3.90(1H,d,J=16Hz),5.53
(2H,s),6.40(1H,d,J=16Hz),7.01(1H,t-like,
J=4.5Hz),7.19-7.41(6H,m),7.41-7.55(4H,m),
7.64(2H,d,J=8Hz),7.80(1H,d,J=4.5Hz),8.06
(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.10(3H,s),3.30(3H,s),
3.83-4.18(2H,m),5.59(1H,d,J=10Hz),5.71
(1H,d,J=10Hz),6.49(1H,d,J=16Hz),7.11-7.18
(1H,m),7.25-7.46(3H,m),7.46-7.98(10H,m),
8.90(1H,d,J=7.5Hz)
(4)8-〔2,6-二氯-3-〔N-〔4-〔(2-呋喃基羰基)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.26(3H,s),3.65
(1H,dd,J=4,16Hz),3.94(1H,dd,J=4,16Hz),
5.64(2H,s),6.43(1H,d,J=16Hz),6.54-6.58
(1H,m),6.61(1H,t-like),7.20-7.34(4H,m),
7.37-7.60(7H,m),7.68(2H,d,J=8Hz),8.03
(1H,d,J=8Hz),8.20(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.16(3H,s),3.30(3H,s),
3.90(1H,d,J=16Hz),4.05(1H,d,J=16Hz),5.61
(1H,d,J=10Hz),5.72(1H,d,J=10Hz),6.48-6.61
(2H,m),7.24-7.37(1H,m),7.37-7.50(3H,m),
7.50-7.60(3H,m),7.60-7.70(3H,m),7.76-7.94
(3H,m),8.89(1H,d,J=8Hz)
(5)8-〔 2,6-二氯-3-〔N-〔4-〔(3-呋喃基羰基)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.63(3H,s),3.20(3H,s),
3.60(1H,d,J=16Hz),3.93(1H,d,J=16Hz),5.55
(2H,s),6.40(1H,d,J=16Hz),6.85(1H,
d-like),7.20-7.50(10H,m),7.63(2H,d,
J=8Hz),8.06(1H,d,J=8Hz),8.13(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.09(3H,s),3.29(3H,s),
3.90(1H,d,J=16Hz),4.08(1H,d,J=16Hz),5.58
(1H,d,J=10Hz),5.71(1H,d,J=10Hz),6.46(1H,
d,J=16Hz),6.95(1H,s-like),7.49(2H,d,
J=7.5Hz),7.45-7.48(1H,m),7.55(1H,s-like),
7.60-7.75(4H,m),7.75-7.93(4H,m),8.25(1H,
s-like),8.90(1H,d,J=8Hz)
(6)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(3-噻吩基)乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.70(3H,s),3.25(3H,s),
3.63(1H,dd-like,J=16Hz),3.76(2H,s),3.93
(1H,dd,J=4,16Hz),5.65(2H,s),6.40(1H,d,
J=16Hz),6.55-6.64(1H,m),7.03-7.09(1H,m),
7.16-7.34(4H,m),7.34-7.57(10H,m),8.04(1H,
d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.07(3H,s),3.27(3H,s),
3.76(2H,s),3.90(1H,d,J=16Hz),4.04(1H,d,
J=16Hz),5.58(1H,d,J=10Hz),5.70(1H,d,
J=10Hz),6.45(1H,d,J=16Hz),7.13(1H,d,
J=5Hz),7.21-7.70(9H,m),7.70-7.92(4H,m),
8.88(1H,d,J=8Hz)
(7)8-〔3-〔N-(4-丙烯酰氨基肉桂酰甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.66(3H,s),3.23(3H,s),3.62
(1H,dd,J=4,16Hz),3.89(1H,dd,J=4,16Hz),
5.70(1H,d,J=10Hz),6.23(1H,d,J=16Hz),
6.35-6.45(2H,m),6.62(1H,t-1ike),7.21-7.56
(9H,m),7.61(2H,d,J=8Hz),8.05(1H,d,
J=8Hz),8.30(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.08(3H,s),3.30(3H,s),
3.91(1H,d,J=16Hz),4.07(1H,d,J=16Hz),5.57
(1H,d,J=10Hz),5.65-5.80(2H,m),6.35-6.55
(2H,m),7.24-7.35(4H,m),7.53(2H,s-like),
7.58-7.70(3H,m),7.75-7.91(3H,m),8.90(1H,
d,J=8Hz)
(8)8-〔2,6-二氯-3-〔N-甲基-N-(4-三氟乙酰氨基肉桂酰甘氨酰)氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.60(3H,s),3.17(3H,s),3.58
(1H,dd,J=4,16Hz),3.83(1H,dd,J=4,16Hz),
5.54(2H,s-like),6.41(1H,d,J=16Hz),6.79
(1H,t-like),7.14(1H,d,J=8Hz),7.20-7.33
(3H,m),7.33-7.55(5H,m),7.71(2H,d,J=8Hz),
8.07(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):3.15(3H,s),3.30(3H,s),
3.90(1H,d,J=16Hz),4.12(1H,d,J=16Hz),5.60
(1H,d,J=10Hz),5.70(1H,d,J=10Hz),6.56(1H,
d,J=16Hz),7.31-7.50(3H,m),7.55(2H,
s-like),7.58-7.66(3H,m),7.77-7.94(3H,m),
8.87(1H,d,J=8Hz)
(9)8-〔2,6-二氯-3-〔N-〔4-(乙氧羰基氨基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.30(3H,t,J=7.5Hz),2.72(3H,
s),3.25(3H,s),3.63(1H,dd,J=4,18Hz),3.93
(1H,dd,J=4,18Hz),4.23(2H,q,J=7.5Hz),5.63
(2H,s),6.39(1H,d,J=16Hz),6.61(1H,
t-like),6.79(1H,s),7.20-7.59(11H,m),8.02
(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD):1.27(3H,t,J=7.5Hz),3.07(3H,
s),3.26(3H,s),3.83(1H,d,J=16Hz),3.95
(1H,d,J=16Hz),4.18(2H,q,J=7.5Hz),5.54
(1H,d,J=10Hz),5.69(1H,d,J=10Hz),6.40(1H,
d,J=16Hz),7.29-7.45(5H,m),7.45-7.65(3H,
m),7.70-7.91(3H,m),8.86(1H,d,J=8Hz)
(10)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(烟酰氨基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.56(3H,s),3.16(3H,s),3.60
(1H,dd,J=4,17.5Hz),3.88(1H,dd,J=4,
17.5Hz),5.55(2H,s),6.38(1H,d,J=16Hz),
6.72(1H,t-like),7.10-7.35(5H,m),7.35-7.60
(5H,m),7.70(2H,d,J=8Hz),8.05(1H,d,
J=8Hz),8.24(1H,dif.-dd,J=8Hz),8.66(1H,d,
J=5Hz),9.11(1H,d,J=1Hz),9.29(1H,s)
其二盐酸盐NMR(DMSO-d6,δ):2.91(3H,s),3.15(3H,s),3.90
(1H,dd,J=4,17Hz),5.91(1H,d,J=10Hz),5.67
(1H,d,J=10Hz),6.75(1H,d,J=16Hz),7.38(1H,
d,J=16Hz),7.59(2H,d,J=8Hz),7.74(1H,dd,
J=5,8Hz),7.79-7.99(7H,m),8.31(1H,t,
J=5Hz),8.51(1H,d,J=8Hz),8.86(1H,d,
J=5Hz),8.98(1H,dif.-d),9.23(1H,s-like)
(11)8-〔2,6-二氯-3-〔N-甲基-N-〔4-(2-吡啶甲酰氨基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.74(3H,s),3.26(3H,s),3.65
(1H,dd,J=4,18Hz),3.96(1H,dd,J=4,18Hz),
5.65-(2H,s),6.45(1H,d,J=16Hz),6.60(1H,
t-like),7.21-7.40(3H,m),7.40-7.65(7H,m),
7.81(2H,d,J=8Hz),7.93(1H,td,J=8Hz,1Hz),
8.03(1H,d,J=8Hz),8.30(1H,d,J=8Hz),8.63
(1H,d,J=5Hz),10.13(1H,s)
其二盐酸盐NMR(CMSO-d6,δ):2.90(3H,s),3.15(3H,s),3.90
(1H,dd,J=4,18Hz),5.60(1H,d,J=10Hz),5.66
(1H,d,J=10Hz),6.74(1H,d,J=16Hz),7.38(1H,
d,J=16Hz),7.58(2H,d,J=8Hz),7.66-7.75(1H,
m),7.78-8.04(8H,m),8.09(1H,t,J=7.5Hz),
8.19(1H,d,J=7.5Hz),8.30(1H,t,J=5Hz),8.76
(1H,d,J=5Hz),8.90(1H,br)
(12)8-〔2,6-二氯-3-〔N-(4-异丁酰氨基肉桂酰甘氨酰)-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.24(6H,d,J=7.5Hz),2.50(1H,m,
J=7.5Hz),2.73(3H,s),3.27(3H,s),3.64(1H,
dd,J=18,4Hz),3.94(1H,dd,J=18,4Hz),5.63
(1H,d,J=10Hz),5.64(1H,d,J=10Hz),6.41(1H,
d,J=15Hz),6.60(1H,t-like),7.23-7.36(2H,
m),7.36-7.60(9H,m),8.03(1H,d,J=8Hz)
其盐酸盐NMR(DMSO-d6,δ):1.09(6H,d,J=7.5Hz),2.60(1H,
m),2.85(3H,s),3.13(3H,s),3.86(1H,dd,
J=4,17Hz),5.51-5.78(2H,m),6.66(1H,d,
J=16Hz),7.31(1H,d,J=16Hz),7.49(2H,d,
J=8Hz),7.66(2H,d,J=8Hz),7.73-7.93(6H,m),
8.25(1H,t,J=5Hz)
(13)8-〔3-〔N-〔4-(乙酰基甘氨酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.94(3H,s),2.66(3H,s),3.20
(3H,s),3.60(1H,dd,J=4,18Hz),3.80-4.04
(3H,m),5.55(2H,s),6.37(1H,d,J=16Hz),
7.10-7.60(11H,m),8.03(1H,d,J=8Hz)
其盐酸盐NMR(DMSO-d6,δ):1.87(3H,s),2.87(3H,s),3.11
(3H,s),3.80-3.91(3H,m),5.55-5.68(2H,m),
6.66(1H,d,J=16Hz),7.31(1H,d,J=16Hz),7.50
(2H,d,J=8Hz),7.64(2H,d,J=8Hz),7.75-7.97
(5H,m),8.19-8.32(2H,m)
(14)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(二甲氨基)乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.35(6H,s),2.70(3H,s),3.07
(2H,s),3.25(3H,s),3.63(1H,dd,J=4,18Hz),
3.90(1H,dd,J=4,18Hz),5.60(2H,s),6.41
(1H,d,J=16Hz),6.69(1H,t-like),7.20-7.35
(3H,m),7.36-7.49(5H,m),7.52(1H,d,
J=16Hz),7.60(2H,d,J=8Hz),8.04(1H,d,
J=8Hz),9.22(1H,s)
其二盐酸盐NMR(DMSO-d6,δ):2.76-2.93(9H,m),3.12(3H,s),
3.86(1H,dif.-dd,J=16Hz),4.11-4.21(2H,m),
5.52-5.63(2H,m),6.70(1H,d,J=16Hz),7.35
(1H,d,J=16Hz),7.55(2H,d,J=8Hz),7.66(2H,
d,J=8Hz),7.70-7.94(6H,m),8.25-8.34(1H,m)
(15)8-〔2,6-二氯-3-〔N-〔4-(3-甲氧丙酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.57(2H,t,J=6Hz),2.68(3H,s),
3.24(3H,s),3.40(3H,s),3.54-3.75(3H,m),
3.90(1H,dd,J=17.5,4Hz),5.60(2H,s),6.69
(1H,t-like),7.17-7.33(3H,m),7.33-7.48(5H,
m),7.48-7.60(3H,m),8.03(1H,d,J=8Hz),8.89
(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.63(2H,t,J=6Hz),3.09
(3H,s),3.30(3H,s),3.40(3H,s),3.74(2H,
t,J=6Hz),3.93(2H,s),5.59(1H,d,J=10Hz),
5.77(1H,d,J=10Hz),6.46(1H,d,J=16Hz),
7.28-7.40(1H,m),7.43(2H,d,J=8Hz),7.48-
7.76(5H,m),7.80-7.99(3H,m),8.95(1H,d,
J=8Hz)
(16)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(2-噻吩基)乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),3.24(3H,s),3.62
(1H,dd,J=4,16Hz),3.85-3.97(3H,m),5.58-
5.68(2H,m),6.38(1H,d,J=16Hz),6.59(1H,t-
like),6.93-7.00(1H,m),7.00-7.05(1H,m),
7.22-7.32(2H,m),7.36-7.54(8H,m),7.74(1H,
s),8.03(1H,d,J=8Hz)
其盐酸盐NMR(CD3OD,δ):2.99(3H,s),3.76-3.94(3H,m),
4.00(1H,d,J=16Hz),5.70(1H,d,J=10Hz),5.80
(1H,d,J=10Hz),6.60(1H,d,J=16Hz),6.92-7.07
(2H,m),7.23-7.35(1H,m),7.35-7.80(7H,m),
7.80-8.04(4H,m),9.02(1H,d,J=8Hz)
(17)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(4-吡啶基乙酰氨基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.51(3H,s),3.13(3H,s),3.53
(2H,s),3.85(1H,br s),5.51(2H,s),5.59
(1H,br s),6.88-7.38(8H,m),7.38-7.56(4H,
m),8.07(1H,d,J=8Hz),8.40-8.50(3H,m)
其二盐酸盐NMR(CDCl3-CD3OD,δ):2.78(3H,s),3.21(3H,s),
3.80-(1H,d,J=16Hz),3.98(1H,d,J=16Hz),4.07
(2H,s),5.53(1,d,J=10Hz),5.67(1H,d,
J=10Hz),6.74-6.86(2H,m),7.29-7.38(1H,m),
7.43-7.53(3H,m),7.66-7.89(3H,m),8.04(2H,
d,J=6Hz),8.60(2H,d,J=6Hz),8.79(1H,d,
J=8Hz)
(18)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-〔3-(异烟酰氨基)苯基〕脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3-CD3OD,δ):2.64(3H,s),3.22(3H,s),
3.77-3.95(2H,m),5.53(1H,d,J=10Hz),5.60
(1H,d,J=10Hz),5.88-5.96(1H,m),6.78-6.86
(1H,m),7.15(1H,t,J=7.5Hz),7.21-7.50(6H,
m),7.55-7.66(2H,m),7.71-7.80(2H,m),8.07
(1H,d,J=8Hz),8.70(2H,d,J=6Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):2.92(3H,s),3.24(3H,s),
3.85(1H,d,J=16Hz),4.05(1H,d,J=16Hz),5.56
(1H,d,J=10Hz),5.71(1H,d,J=10Hz),6.90-7.07
(2H,m),7.38-7.67(5H,m),7.67-7.89(3H,m),
8.42-8.60(2H,m),8.75-8.99(3H,m)
(19)8-〔2,6-二氯-3-〔N-甲基-N-〔N′-(3-甲氧乙酰氨基苯基)脲基乙酰基〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.60(3H,s),3.23(3H,s),3.46
(3H,s),3.80(1H,dd,J=4,16Hz),3.96(2H,s),
4.27(1H,dd,J=7.5,16Hz),5.48(1H,d,
J=10Hz),5.54(1H,t-like),5.66(1H,d,
J=10Hz),6.70(1H,d,J=8Hz),7.05(1H,t,
J=7.5Hz),7.22-7.38(4H,m),7.38-7.50(3H,m),
7.58(1H,t-like),8.08(1H,d,J=8Hz),8.19
(1H,s),8.28(1H,s)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.78(3H,s),3.25(3H,s),
3.41(3H,s),3.63(1H,d,J=16Hz),3.73-3.91
(2H,m),4.32(1H,d,J=16Hz),5.60(1H,d,
J=10Hz),5.74(1H,d,J=10Hz),6.97(2H,d,
J=5Hz),7.20-7.27(1H,m),7.31(1H,s-like),
7.50(1H,d,J=8Hz),7.58-7.65(2H,m),7.65-
7.80(2H,m),7.86(1H,t,J=7.5Hz),8.77(1H,
d,J=8Hz)
(20)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(丙酰氨基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.26(3H,t,J=7.5Hz),2.45(2H,q,
J=7.5Hz),2.72(3H,s),3.28(3H,s),3.68(1H,
dd,J=17,4Hz),3.94(1H,dd,J=17,5Hz),5.62
(1H,d,J=10Hz),5.68(1H,d,J=10Hz),6.48(1H,
d,J=15Hz),6.69(1H,br t,J=4Hz),7.21-7.32
(3H),7.39-7.57(4H),7.82(1H,dd,J=7.5,2Hz),
7.99(1H,br s),8.02(1H,d,J=7.5Hz),8.21
(1H,d,J=7.5Hz),8.34(1H,d,J=2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):1.27(3H,t,J=7.5Hz),2.78
(2H,q,J=7.5Hz),3.22(3H,s),3.28(3H,s),
3.93(1H,d,J=17Hz),4.27(1H,d,J=17Hz),5.59
(1H,d,J=10Hz),5.64(1H,d,J=10Hz),6.95(1H,
d,J=15Hz),7.52(2H,s),7.57-7.70(2H),7.85-
8.12(5H),8.97-9.02(2H)
(21)8-〔3-〔N-〔(E)-3-〔6-(丙烯酰氨基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.72(3H,s),3.28(3H,s),3.68
(1H,dd,J=17,4Hz),3.94(1H,dd,J=17,5Hz),
5.62(1H,d,J=10Hz),5.68(1H,d,J=10Hz),5.84
(1H,d,J=10Hz),6.29(1H,dd,J=15,10Hz),6.49
(1H,d,J=15Hz),6.70(1H,br t,J=4Hz),7.22-
7.58(7H),7.87(1H,dd,J=7.5,2Hz),8.02(1H,
d,J=7.5Hz),8.21(1H,br s),8.30(1H,d,
J=7.5Hz),8.38(1H,d,J=2Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):3.21(3H,s),3.26(3H,s),
3.92(1H,d,J=17Hz),4.32(1H,d,J=17Hz),5.58
(1H,d,J=10Hz),5.63(1H,d,J=10Hz),5.84(1H,
dd,J=10,2Hz),6.70-6.78(2H),6.94(1H,d,
J=15Hz),7.48-7.64(4H),7.80-7.94(3H),8.10
(1H,br d,J=7.5Hz),8.31(1H,br d,J=7.5Hz),
8.92(1H,d,J=7.5Hz),8.99(1H,br s)
(22)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(异烟酰氨基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.28(3H,s),3.69
(1H,dd,J=17,4Hz),3.95(1H,dd,J=17,5Hz),
5.66(2H,s),6.52(1H,d,J=15Hz),6.72(1H,br
s),7.24-7.34(3H),7.39-7.52(3H),7.57(1H,d,
J=15Hz),7.77(2H,d,J=6Hz),7.92(1H,dd,
J=7.5,2Hz),8.03(1H,d,J=7.5Hz),8.42(1H,d,
J=2Hz),8.71(1H,s),8.84(2H,d,J=6Hz)
其三盐酸盐NMR(CDCl3-CD3OD,δ):3.18(3H,s),3.29(3H,s),
3.92(1H,d,J=17Hz),4.24(1H,d,J=17Hz),5.57
(1H,d,J=10Hz),5.73(1H,d,J=10Hz),7.06(1H,
br d,J=15Hz),7.47(1H,d,J=15Hz),7.56-7.69
(3H),7.81(1H,d,J=7.5Hz),7.90(1H,t,
J=7.5Hz),7.98(1H,d,J=7.5Hz),8.67(2H,s),
8.89(1H,d,J=7.5Hz),8.91-8.99(2H),9.05-9.14
(3H)
(23)8-〔2,6-二氯-3-〔N-〔(E)-3-〔6-(乙氧羰基乙酰氨基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.32(3H,t,J=7.5Hz),2.73(3H,
s),3.28(3H,s),3.50(2H,s),3.68(1H,dd,
J=17,4Hz),3.95(1H,dd,J=17,5Hz),4.28(2H,
q,J=7.5Hz),5.62(1H,d,J=10Hz),5.69(1H,d,
J=10Hz),6.49(1H,d,J=15Hz),6.69(1H,br s),
7.22-7.33(3H),7.39-7.49(3H),7.52(1H,d,
J=15Hz),7.82(1H,dd,J=7.5,2Hz),8.02(1H,d,
J=7.5Hz),8.18(1H,br d,J=7.5Hz),8.40(1H,d,
J=2Hz),9.59(1H,s)
其二盐酸盐NMR(CDCl3-CD3OD,δ):1.30(3H,t,J=7.5Hz),3.21
(3H,br s),3.28(3H,s),3.79(1H,d,J=8Hz),
3.91(1H,d,J=17Hz),4.18-4.28(3H),4.32(1H,
d,J=17Hz),5.59(1H,d,J=10Hz),5.64(1H,d,
J=10Hz),6.96(1H,br d,J=15Hz),7.42-7.64
(4H),7.79-7.93(3H),8.05(1H,m),8.35(1H,
m),8.88-8.96(2H)
(24)8-〔3-〔N-〔N′-〔3-(苯甲酰氨基)苯基〕脲基乙酰基〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.60(3H,s),3.15(3H,s),3.81
(1H,dd,J=17,5Hz),3.99(1H,br dd,J=17,
5Hz),-5.49(1H,d,J=10Hz),5.60(1H,d,
J=10Hz),5.85(1H,br s),6.82(1H,br d,
J=8Hz),7.09(1H,t,J=8Hz),7.23-7.59(10H),
7.62(1H,br s),7.83(2H,d,J=8Hz),8.06(1H,
d,J=8Hz),8.30-8.41(2H)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.66(3H,br s),3.26(3H,
s),3.85(1H,br d,J=17Hz),4.36(1H,br d,
J=17Hz),5.59(1H,d,J=10Hz),5.71(1H,d,
J=10Hz),6.91(1H,t,J=8Hz),6.99(1H,br d,
J=8Hz),7.37(1H,br s),7.39-7.58(6H),7.62
(1H,d,J=8Hz),7.68(2H,d,J=8Hz),7.72-7.82
(3H),8.71(1H,d,J=8Hz)
(25)8-〔3-〔N-〔4-(环己烷甲酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.18-1.99(10H),2.20(1H,m),2.72
(3H,s),3.26(3H,s),3.64(1H,dd,J=17,4Hz),
3.93(1H,dd,J=17,5Hz),5.61(1H,d,J=10Hz),
5.67(1H,d,J=10Hz),6.39(1H,d,J=15Hz),6.61
(1H,br t,J=4Hz),7.22-7.59(12H),8.02(1H,d,
J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.20-1.98(10H),2.38(1H,
m),3.12(3H,br s),3.29(3H,s),3.91(1H,br
d,J=17Hz),4.10(1H,br d,J=17Hz),5.59(1H,
d,J=10Hz),5.69(1H,d,J=10Hz),6.48(1H,d,
J=15Hz),7.26-7.38(3H),7.50-7.65(5H),7.77-
7.90(3H),8.90(1H,d,J=8Hz)
(26)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(4-甲基-5-噁唑基羰基)氨基〕乙酰氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉mp:141-148℃NMR(CDCl3,δ):2.58(3H,s),2.70(3H,s),3.24
(3H,s),3.63(1H,dd,J=16.5,4.5Hz),3.93(1H,
dd,J=16.5,4.5Hz),5.61(1H,d,J=11.0Hz),5.66
(1H,d,J=11.0Hz),6.43(1H,d,J=15.0Hz),6.62
(1H,br t,J=4.5Hz),7.23-7.32(3H,m),7.37-
7.54(5H,m),7.54(1H,d,J=15.0Hz),7.65(2H,
d,J=8.5Hz),7.77(1H,s),8.03(1H,d,
J=8.5Hz),8.16(1H,s)
其二盐酸盐mp:160.5-164.5℃NMR(CDCl3-CD3OD,δ):2.57(3H,s),3.11(3H,s),
3.30(3H,s),3.89(1H,d,J=16.0Hz),4.04(1H,
d,J=16.0Hz),5.60(1H,d,J=9.0Hz),5.73(1H,
d,J=9.0Hz),6.53(1H,d,J=16.0Hz),7.41(1H,
d,J=16.0Hz),7.47(2H,d,J=8.5Hz),7.55(2H,
s),7.63-7.72(3H,m),7.79-7.95(3H,m),7.97
(1H,s),8.93(1H,d,J=8.5Hz)
(27)8-〔2,6-二氟-3-〔N-甲基-N-〔4-〔(2-甲基-4-噁唑基羰基)氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.52(3H,s),2.73(3H,s),3.26
(3H,s),3.63(1H,dd,J=17,4Hz),3.94(1H,dd,
J=17,5Hz),5.62(1H,d,J=10Hz),5.68(1H,d,
J=10Hz),6.42(1H,d,J=15Hz),6.60(1H,br t,
J=4Hz),7.23-7.33(3H),7.39-7.59(6H),7.69
(2H,d,J=8Hz),8.02(1H,d,J=8Hz),8.18(1H,
s),8.73(1H,s)
其二盐酸盐NMR(CDCl3-CD3OD,δ):2.54(3H,s),3.16(3H,s),
3.31(3H,s),3.90(1H,d,J=17Hz),4.01(1H,d,
J=17Hz),5.61(1H,d,J=10Hz),5.72(1H,d,
J=10Hz),6.53(1H,d,J=15Hz),7.41-7.51(3H),
7.54(1H,d,J=8Hz),7.59(1H,d,J=8Hz),7.63-
7.71(3H),7.79-7.93(3H),8.25(1H,s),8.91
(1H,d,J=8Hz)
(28)8-〔2,6-二氯-3-〔N-〔4-〔(3,5-二甲基-4-异噁唑基羰基)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.50(3H,s),2.69(3H,s),2.74
(3H,s),3.28(3H,s),3.67(1H,dd,J=17,4Hz),
3.94(1H,dd,J=17,5Hz),5.63(1H,d,J=10Hz),
5.68(1H,d,J=10Hz),6.44(1H,d,J=15Hz),6.65
(1H,br t,J=4Hz),7.23-7.61(12H),8.04(1H,d,
J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.47(3H,s),2.64(3H,s),
3.17(3H,br s),3.30(3H,s),3.91(1H,d,
J=17Hz),4.10(1H,d,J=17Hz),5.60(1H,d,
J=10Hz),5.71(1H,d,J=10Hz),6.52(1H,d,
J=15Hz),7.34-7.48(3H),7.53(2H,s),7.62(3H,
d,J=8Hz),7.79(1H,d,J=8Hz),7.83-7.91(2H),
8.88(1H,d,J=8Hz)
(29)8-〔3-〔N-〔4-〔(N-叔丁氧羰基-L-脯氨酰)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.49(9H,br s),1.83-2.03(4H),
2.70(3H,s),3.26(3H,s),3.29-3.69(3H),3.93
(1H,dt,J=17,5Hz),4.46(1H,m),5.63(2H,s),
6.39(1H,d,J=15Hz),6.62(1H,m),7.20-7.57
(12H),8.02(1H,d,J-8Hz)
(30)8-〔2,6-二氯-3-〔N-〔4-〔(1-乙基哌啶-4-羰基)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.11-1.22(3H),1.62-2.10(9H),
2.72(3H,s),3.04-3.17(2H),3.27(3H,s),3.64
(1H,dd,J=17,4Hz),3.94(1H,dd,J=17,5Hz),
5.65(2H,br s),6.40(1H,d,J=15Hz),6.61(1H,
m),7.21-7.61(12H),8.03(1H,d,J=8Hz)
其二盐酸盐NMR(CDCl3-CD3OD,δ):1.42(3H,t,J=7.5Hz),2.10-
2.47(4H),2.98-3.19(8H),3.28(3H,s),3.49-
3.59(2H),3.92(1H,d,J=17Hz),4.08(1H,d,
J=17Hz),5.58(1H,d,J=10Hz),5.71(1H,d,
J=10Hz),6.43(1H,d,J=15Hz),7.24(2H,d,
J=8Hz),7.38(1H,m),7.52-7.69(5H),7.80-7.95
(3H),8.95(1H,d,J=8Hz)
(31)8-〔2,6-二氯-3-〔N-〔(E)-3-〔 6-(甲氧乙酰氨基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.73(3H,s),3.26(3H,s),3.51
(3H,s),3.67(1H,dd,J=16.5,5.5Hz),3.93(1H,
dd,J=16.5,5.5Hz),4.03(2H,s),5.63(1H,d,
J=11.0Hz),5.68(1H,d,J=11.0Hz),6.49(1H,d,
J=16.0Hz),6.67(1H,br t,J=5.5Hz),7.22-7.35
(3H,m),7.38-7.53(3H,m),7.53(1H,d,
J=16.0Hz),7.85(1H,dd,J=8.5,1.5Hz),8.03
(1H,d,J=8.5Hz),8.25(1H,d,J=8.5Hz),8.40
(1H,d,J=1.5Hz),8.93(1H,s)
其二盐酸盐mp:142-146℃NMR(DMSO-d6,δ):2.91(3H,s),3.13(3H,s),3.36
(3H,s),3.59(1H,dd,J=16.0,5.5Hz),3.90(1H,
dd,J=16.0,5.5Hz),4.09(2H,s),5.62(1H,d,
J=10.5Hz),5.67(1H,d,J=10.5Hz),6.81(1H,d,
J=16.0Hz),7.38(1H,d,J=16.0Hz),7.77-8.07
(6H,m),8.11(1H,d,J=8.5Hz),8.30-8.40(1H.
m),8.50(1H,s),8.99(1H,m)
(32)8-〔3-〔N-〔(E)-3-〔6-(乙酰甘氨酰氨基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:128-136.5℃NMR(CDCl3,δ):2.07(3H,s),2.73(3H,s),3.27
(3H,s),3.67(1H,dd,J=16.0,4.5Hz),3.99(1H,
dd,J=16.0,4.5Hz),4.03(2H,d,J=6.0Hz),5.64
(2H,s),6.45(1H,d,J=16.0Hz),6.83-6.96(2H,
m),7.22-7.67(7H,m),7.78(1H,dd,J=8.5,
1.5Hz),8.02(1H,d,J=8.5Hz),8.09-8.24(1H,
m),8.35(1H,d,J=1.5Hz),9.04(1H,s)
其二盐酸盐mp:150-157℃NMR(CDCl3-CD3OD,δ):2.10(3H,s),3.15(3H,s),
3.28(3H,s),3.89(1H,d,J=16.0Hz),4.10-4.31
(1H,m),4.19(2H,s),5.57(1H,d,J=8.5Hz),
5.70(1H,d,J=8.5Hz),6.83(1H,m),7.44-7.68
(4H,m),7.71-7.98(3H,m),8.10(1H,m),8.38
(1H,m),8.70(1H,m),8.88(1H,m)
(33)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(1-甲基-1H-咪唑-2-羰基)氨基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉mp:106.5-115℃NMR(CDCl3,δ):2.73(3H,s),3.26(3H,s),3.64
(1H,dd,J=16.5,4.5Hz),3.94(1H,dd,J=16.5,
4.5Hz),4.12(3H,s),5.63(1H,d,J=11.0Hz),
5.68(1H,d,J=11.0Hz),6.43(1H,d,J=16.0Hz),
6.63(1H,br t,J=4.5Hz),7.03(1H,s),7.07
(1H,s),7.23-7.34(3H,m),7.39-7.54(5H,m),
7.54(1H,d,J=16.0Hz),7.67(2H,d,J=8.5Hz),
8.02(1H,s),9.32(1H,s)
其二盐酸盐mp:132.5-140℃NMR(CDCl3-CD3OD,δ):3.12(3H,s),3.29(3H,s),
3.90(1H,d,J=16.0Hz),3.99(1H,d,J=16.0Hz),
4.29(3H,s),5.61(1H,d,J=8.5Hz),5.73(1H,
d,J=8.5Hz),6.54(1H,d,J=16.0Hz),7.39-7.50
(3H,m),7.52-7.62(4H,m),7.69(1H,d,
J=8.5Hz),7.82-8.00(5H,m),8.97(1H,d,
J=8.5Hz)
(34)8-〔2,6-二氯-3-〔N-〔(E)-3-〔6-(2-呋喃甲酰氨基)吡啶-3-基〕丙烯酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉mp:208-212℃NMR(CDCl3,δ):2.73(3H,s),3.27(3H,s), 3.67
(1H,dd,J=16.5,5.5Hz),3.96(1H,dd,J=16.5,
5.5Hz),5.63(1H,d,J=10.5Hz),5.68(1H,d,
J=10.5Hz),6.51(1H,d,J=16.0Hz),6.57-6.61
(1H,m),6.68(1H,br t,J=5.5Hz),7.23-7.34
(4H,m),7.39-7.58(5H,m),7.88(1H,dd,J=8.5,
1.5Hz),8.03(1H,d,J=8.5Hz),8.33(1H,d,
J=8.5Hz),8.41(1H,d,J=1.5Hz),8.80(1H,s)
其二盐酸盐mp:154.5-158℃NMR(CDCl3-CD3OD,δ):3.19(3H,s),3.28(3H,s),
3.90(1H,d,J=16.0Hz),4.29(1H,d,J=16.0Hz),
5.57(1H,d,J=9.0Hz),5.69(1H,d,J=9.0Hz),
6.63(1H,m),6.89(1H,d,J=16.0Hz),7.42(1H,
d,J=16.0Hz),7.52-7.64(3H,m),7.72(1H,s),
7.77-7.95(4H,m),8.42-8.58(2H,m),8.72(1H,
br s),8.87(1H,d,J=8.5Hz)
(35)8-〔2,6-二氯-3-〔N-甲基-N-〔(E)-3-〔6-(4-吡啶基乙酰氨基)吡啶-3-基〕丙烯酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉mp:126.5-132℃NMR(CDCl3,δ):2.72(3H,s),3.26(3H,s),3.65
(1H,dd,J=16.5,5.5Hz),3.75(2H,s),3.95(1H,
dd,J=16.5,5.5Hz),5.62(1H,d,J=10.5Hz),5.68
(1H,d,J=10.5Hz),6.47(1H,d,J=16.0Hz),6.77
(1H,br t,J=5.5Hz),7.21-7.33(5H,m),7.39-
7.49(3H,m),7.51(1H,d,J=16.0Hz),7.82(1H,
dd,J=8.5,1.5Hz),8.03(1H,d,J=8.5Hz),8.19
(1H,d,J=8.5Hz),8.28(1H,s),8.33(1H,d,
J=1.5Hz),8.57-8.65(2H,m)
其三盐酸盐mp:156-158℃NMR(CDCl3-CD3OD,δ):2.80-3.24(2H,m),3.13(3H,
s),3.28(3H,s),3.89(1H,d,J=16.5Hz),4.19
(1H,d,J=16.5Hz),5.55(1H,d,J=9.0Hz),5.72
(1H,d,J=9.0Hz),6.90(1H,d,J=16.5Hz),7.40
(1H,d,J=16.5Hz),7.53-7.69(3H,m),7.79-8.07
(4H,m),8.17-8.28(2H,m),8.39(1H,m),8.76-
8.94(4H,m)
(36)8-〔3-〔N-〔4-(1-金刚烷基乙酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:147-154℃NMR(CDCl3,δ):1.56-1.77(12H,m),1.92-2.01(3H,
m),2.07(2H,s),2.73(3H,s),3.25(3H,s),
3.63(1H,dd,J=16.5,5.5Hz),3.93(1H,dd,
J=16.5,5.5Hz),5.62(1H,d,J=11.5Hz),5.66
(1H,d,J=11.5Hz),6.40(1H,d,J=16.0Hz),6.60-
6.68(1H,m),7.21-7.35(5H,m),7.39-7.59(7H,
m),8.04(1H,d,J=8.5Hz)
(37)8-〔3-〔N-〔4-〔(1-乙酰基哌啶-4-基)羰基氨基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:146.5-153℃NMR(CDCl3,δ):1.62-1.91(4H,m),2.07(3H,s),
2.24-2.50(2H,m),2.69(3H,s),2.85-2.97(1H,
m),3.20(3H,s),3.61(1H,dd,J=16.5,5.5Hz),
3.77-3.87(1H,m),3.90(1H,dd,J=16.5,5.5Hz),
4.47-4.58(1H,m),5.58(1H,d,J=11.5Hz),5.62
(1H,d,J=11.5Hz),6.40(1H,d,J=16.0Hz),6.69
(1H,br t,J=5.5Hz),7.18-7.62(11H,m),8.05
(1H,d,J=8.5Hz),8.23(1H,s)
其盐酸盐mp:155-16l℃NMR(CDCl3-CD3OD,δ):1.63-1.84(2H,m),1.88-2.03
(2H,m),2.14(3H,s),2.71-3.33(3H,m),3.08
(3H,s),3.29(3H,s),3.82-3.98(1H,m),3.91
(1H,d,J=16.0Hz),4.06(1H,d,J=16.0Hz),4.49-
4.61(1H,m),5.59(1H,d,J=9.0Hz),5.73(1H,
d,J=9.0Hz),6.43(1H,d,J=16.0Hz),7.26-7.38
(3H,m),7.55(2H,s),7.60-7.71(3H,m),7.79-
7.95(3H,m),8.92(1H,d,J=8.5Hz)
(38)8-〔3-〔N-〔4-(环丙基羰基氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉mp:129-133℃NMR(CDCl3,δ):0.69-0.82(2H,m),0.97-1.08(2H,
m),1.46-1.57(1H,m),2.69(3H,s),3.21(3H,
s),3.61(1H,dd,J=16.5,5.5Hz),3.88(1H,dd,
J=16.5,5.5Hz),5.60(2H,s),6.38(1H,d,
J=16.0Hz),6.61(1H,br t,J=5.5Hz),7.19-7.49
(9H,m),7.54(2H,d,J=8.5Hz),8.06(1H,d,
J=8.5Hz),8.71(1H,br s)
其盐酸盐mp:160-165℃NMR(CDCl3-CD3OD,δ):0.79-0.87(2H,m),0.97-1.04
(2H,m),1.81-1.93(1H,m),3.08(3H,s),3.28
(3H,s),3.90(1H,d,J=16.5Hz),4.08(1H,d,
J=16.5Hz),5.58(1H,d,J=9.0Hz),5.70(1H,d,
J=9.0Hz),6.42(1H,d,J=16.0Hz),7.23-7.34(3H,
m),7.50-7.67(5H,m),7.78-7.92(3H,m),8.91
(1H,d,J=8.5Hz)
实施例59
根据与实施例20相似的方法,由8-〔3-N-〔4-〔(乙氧羰基甲基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉得到8-〔3-〔N-〔4-〔(羧甲基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉。NMR(DMSO-d6,δ):2.63(3H,s),3.15(3H,s),3.53
(1H,d,J=16Hz),3.82(1H,d,J=16Hz),3.92(2H,
d,J=6Hz),5.44-5.60(2H,m),6.90(1H,d,
J=16Hz),7.35-7.63(4H,m),7.63-7.73(2H,m),
7.79(2H,s-like),7.90(2H,d,J=8Hz),8.30-
8.41(1H,m),8.85-8.94(1H,m)
实施例60
根据与实施例59相似的方法,得到下列化合物:
(1)8-〔3-〔N-〔4-(N-羧甲基-N-甲基氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(DMSO-d6,δ):2.60(3H,s),2.95(1.8H,s),
2.97(1.2H,s),3.15(3H,s),3.51(1H,dd-like,
J=16Hz),3.81(1H,dd,J=16,4Hz),3.93(0.8H,
s),4.14(1.2H,s),5.46(1H,d,J=11Hz),5.53
(1H,d,J=11Hz),6.83(1H,d,J=16Hz),7.29-7.57
(7H,m),7.57-7.70(2H,m),7.85(2H,s-like),
8.20(1H,d,J=8Hz),8.26-8.40(1H,m)
(2)8-〔3-〔N-〔4-(2-羧乙基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉
NMR(DMSO-d6,δ): 2.70(3H,br s),3.15(3H,s),
3.27-3.60(5H,m),3.84(1H,dd,J=4,16Hz),
5.56-5.61(2H,m),6.88(1H,d,J=16Hz),7.43
(1H,d,J=16Hz),7.49-7.73(5H,m),7.80(2H,
s-like),7.85(2H,d,J=8Hz),8.29-8.43(2H,m),
8.59(1H,t-like)
(3)8-〔3-〔N-〔(R)-1-羧乙基)氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.40(3H,d,J=7.5Hz),2.63(3H,
s),3.16(3H,s),3.53(1H,dd-like,J=16Hz),
3.83(1H,dd-like,J=16Hz),4.41(1H,quint,
J=7.5Hz),5.43-5.60(2H,m),6.90(1H,d,
J=16Hz),7.31-7.61(5H,m),7.61-7.71(2H,m),
7.80(2H,s-like),7.92(2H,d,J=8Hz),8.16-
8.43(2H,m),8.71(1H,d,J=7.5Hz)
[α]D 20:-6.70(C=20mg/2ml,MeOH)
(4)8-〔3-〔N-〔4-〔((R)-1-羧基-2-苯乙基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氟苄氧基〕-2-甲基喹啉NMR(DMSO-d6,δ):2.65(3H,s),3.00-3.26(5H,m),
3.53(1H,dd-like,J=16Hz),3.83(1H,dd-like,
J=16Hz),4.56-4.69(1H,m),5.45-5.60(2H,m),
6.87(1H,d,J=16Hz),7.13-7.21(1H,m),7.21-
7.35(4H,m),7.35-7.75(7H,m),7.75-7.88(4H,
m),8.26-8.42(2H,m),8.77(1H,d,J=7.5Hz)[α]D 20:+38.5°(C=20mg/2ml,MeOH)
实施例61
根据与实施例54相似的方法,使8-〔3-N-〔4-〔(羧甲基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉与盐酸甲胺反应,得到8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔(甲基氨基甲酰基甲基)氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉。NMR(CDCl3,δ):2.73(3H,s),2.85(3H,d,J=5Hz),
3.27(3H,s),3.64(1H,dd-like,J=16Hz),3.96
(1H,dd,J=16,4Hz),4.09(2H,d,J=5Hz),5.58-
5.71(2H,m),6.19-6.29(1H,m),6.55(1H,d,
J=16Hz),6.80-6.88(1H,m),7.15-7.37(3H,m),
7.37-7.62(6H,m),7.80(2H,d,J=8Hz),8.03
(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.79(3H,s),3.13(3H,s),
3.30(3H,s),3.89(1H,d,J=16Hz),4.05(2H,
s),4.07(1H,d,J=16Hz),5.61(1H,d,J=10Hz),
5.70(1H,d,J=10Hz),6.63(1H,d,J=16Hz),7.40
(1H,d,J=16Hz),7.50(2H,d,J=8Hz),7.50(2H,
s-like),7.64(1H,d,J=8Hz),7.75-7.93(5H,m),
8.38(1H,d,J=8Hz)
实施例62
根据与实施例61相似的方法,得到下列化合物:
(1)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔N-(甲基氨基甲酰基甲基)-N-甲基氨基甲酰基〕肉桂酰甘-氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.70(3H,s),2.85(3H,d,J=5Hz),
3.10(3H,s),3.26(3H,s),3.65(1H,dd,J=4,
16Hz),3.83-4.03(1.5H,m),4.03-4.13(1.5H,m),
5.60-5.72(2H,m),6.43-6.60(2H,m),6.70(1H,
br s),7.22-7.36(3H,m),7.36-7.65(8H,m),
8.03(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.82(3H,br s),3.09(3H,
s),3.29(3H,s),3.82-4.20(4H,m),5.60(1H,
d,J=10Hz),5.73(1H,d,J=10Hz),6.54-6.71(1H,
m),7.36-7.63(7H,m),7.66(1H,d,J=8Hz),
7.79-7.98(3H,m),8.90(1H,d,J=8Hz)
(2)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔〔2-(甲基氨基甲酰基)乙基〕氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.50(2H,t,J=6Hz),2.73(3H,s),
2.83(3H,d,J=5Hz),3.27(3H,s),3.65(1H,dd,
J=4,16Hz),3.73(2H,q,J=6Hz),3.95(1H,dd,
J=4,16Hz),5.60-5.76(3H,m),6.54(1H,d,
J=16Hz),6.70(1H,t-like),7.23-7.36(3H,m),
7.36-7.63(6H,m),7.78(2H,d,J=8Hz),8.03
(1H,d,J=8Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.70(2H,t,J=7Hz),2.73
(3H,s),3.15(3H,s),3.30(3H,s),3.68(2H,
t,J=7Hz),3.90(1H,d,J=16Hz),4.06(1H,d,
J=16Hz),5.60(1H,d,J=10Hz),5.60(1H,d,
J=10Hz),6.65(1H,d,J=16Hz),7.45(1H,d,
J=16Hz),7.49-7.57(4H,m),7.63(1H,d,J=8Hz),
7.77-7.93(5H,m),8.88(1H,d,J=8Hz)
(3)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔〔(R)-1-(甲基氨基甲酰基)乙基〕氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):1.47(3H,d,J=7.5Hz),2.73(3H,
s),2.85(3H,d,J=5Hz),3.65(1H,dt,J=16,
4Hz),3.95(1H,dt,J=16,4Hz),4.65(1H,quint,
J=7.5Hz),5.58-5.70(2H,m),6.19(1H,br),6.55
(1H,dd-like,J=16Hz),6.68-6.80(1H,m),6.87
(1H,t-like),7.20-7.37(3H,m),7.37-7.64(6H,
m),7.79(2H,d,J=8Hz),8.03(1H,d,J=8Hz)[α]D 20:-6.2°(C=20mg/2ml,CHCl3)
其盐酸盐NMR(CDCl3-CD3OD,δ):1.45(3H,d,J=7.5Hz),2.81
(3H,s),3.14(3H,s),3.30(3H,s),3.90(1H,
d,J=16Hz),4.04(1H,d,J=16Hz),4.61(1H,q,
J=7.5Hz),5.60(1H,d,J=10Hz),5.73(1H,d,
J=10Hz),6.66(1H,d,J=16Hz),7.47(1H,d,
J=16Hz),7.50-7.69(5H,m),7.79-7.95(5H,m),
8.90(1H,d,J=8Hz)[α]D 25:-13.0°(C=20mg/2mg,MeOH)
(4)8-〔2,6-二氯-3-〔N-甲基-N-〔4-〔〔(R)-1-(甲基氨基甲酰基)-2-苯乙基〕氨基甲酰基〕肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉NMR(CDCl3,δ):2.68-2.77(6H,m),3.09(1H,dd,
J=7.5,13Hz),3.20-3.35(4H,m),3.67(1H,dt,
J=16,4Hz),3.96(1H,dt,J=16,4Hz),4.78(1H,
q,J=7.5Hz),5.60-5.78(3H,m),6.55(1H,
dd-like,J=16Hz),6.73-6.84(1H,m),6.94(1H,
t-like),7.20-7.38(3H,m),7.38-7.63(6H,m),
7.72(2H,d,J=8Hz),8.03(1H,d,J=8Hz)[α]D 20:-0.5°(C=20mg/2ml,CHCl3)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.73(3H,s),3.09-3.21(5H,
m),3.30(3H,s),3.89(1H,d,J=16Hz),4.03
(1H,d,J=16Hz),4.77(1H,t,J=7.5Hz),5.60
(1H,d,J=10Hz),5.70(1H,d,J=10Hz),6.65(1H,
d,J=16Hz),7.18-7.33(4H,m),7.0-7.93(12H,
m),8.88(1H,d,J=8Hz)[α]D 25:+13.3°(C=20mg/2ml,MeOH)
实施例63
在冰-水浴冷却下,向8-叔丁氧羰基氨基-2-甲基喹啉(258mg)的N,N-二甲基甲酰胺(3ml)溶液中加入氢化钠(44mg),混合物在相同温度下搅拌20分钟。在冰-水浴冷却下,向反应混合物中加入2,6-二氯-3-硝基苄基甲磺酸酯(300mg),混合物在相同温度下搅拌80分钟,然后在环境温度下搅拌15分钟。反应混合物用乙酸乙酯和水分开。有机层用硫酸镁干燥,真空浓缩。残余物经快速色谱提纯,二氯甲烷洗脱,用正己烷结晶,得到8-〔N-叔丁氧羰基-N-(2,6-二氯-3-硝基苄基)氨基〕-2-甲基喹啉(352mg)。mp:130-131℃NMR(CDCl3,δ):1.21(6H,s),1.60(3H,s),2.72
(3H,s),5.20(1H,d,J=15Hz),5.67(1H,d,
J=15Hz),6.91(1H,d,J=8Hz),7.11-7.31(3H),
7.53(1H,d,J=8Hz),7.65(1H,d,J=8Hz),8.00
(1H,d,J=8Hz)
实施例64
室温下用4M氯化氢-乙酸乙酯(2ml)处理8-〔 N-叔丁氧羰基-N-(2,6-二氯-3-硝基苄基)氨基〕-2-甲基喹啉(100mg)40分钟。真空过滤收集沉淀,用乙酸乙酯洗涤,得到8-〔(2,6-二氯-3-硝基苄基)氨基〕-2-甲基喹啉二盐酸盐(88mg),为暗黄色晶体。mp:230-232℃NMR(DMSO-d6,δ):2.80(3H,s),4.76(2H,s),7.10
(1H,d,J=8Hz),7.31(1H,d,J=8Hz),7.48-7.69
(2H),7.84(1H,d,J=8Hz),8.10(1H,d,J=8Hz),
8.52(1H,d,J=8Hz)
实施例65
室温下向8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉(149.7mg)的乙醇(1.5ml)悬浮液中加入1M硫酸-乙醇溶液(253.1μl),将混合物在90℃加温,然后在室温下搅拌1小时。真空除去溶剂,得到8-〔(2,6-二氯-3-〔N-甲基-N-〔4-(甲基氯基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉的硫酸盐(144.5mg)。mp:219-226℃NMR(DMSO-d6,δ):2.77(3H,d,J=4.5Hz),2.86(3H,
s),3.14(3H,s),3.58(1H,dd,J=4.5,16.5Hz),
3.89(1H,dd,J=4.5,16.5Hz),5.59(1H,d,
J=11.5Hz),5.64(1H,d,J=11.5Hz),6.87(1H,d,
J=16Hz),7.40(1H,d,J=16Hz),7.63(2H,d,
J=8.5Hz),7.73-7.93(8H,m),8.33(1H,t,
J=4.5Hz),8.47(1H,q,J=4.5Hz),8.87(1H,br s)
实施例66
室温下向8-〔2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉(225mg)的乙醇(2.3ml)悬浮液中加入1N硫酸-乙醇溶液(0.38ml),将混合物在90℃加温,然后在室温下搅拌1小时。过滤收集沉淀,将残余物溶于二氯甲烷-甲醇(10∶1)。真空除去溶剂,得到8-〔(2,6-二氯-3-〔N-甲基-N-〔4-(甲基氨基甲酰基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉的1/2硫酸盐(210mg)。NMR(DMSO-d6,δ):2.63-2.84(6H,m),3.15(3H,s),
3.55(1H,dd,J=4,16Hz),3.85(1H,dd,J=5,
16Hz),5.47-5.65(2H,m),6.86(1H,d,J=16Hz),
7.41(1H,d,J=16Hz),7.48-7.90(11H,m),8.33
(1H,t-like),8.48(1H,q-like)
实施例67
室温下向8-〔3-〔N-〔4-(N-乙酰基-N-叔丁氧羰基甲氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(143mg)的二氯甲烷(1.4ml)溶液中加入三氟乙酸(0.05ml),在相同温度下搅拌混合物。1小时后,向溶液中加入三氟乙酸(1ml)。5小时后,真空除去溶剂,得到8-〔3-〔N-〔4-(N-乙酰基-N-羧甲基氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(124mg),为非晶固体。NMR(CDCl3-CD3OD,δ):1.98(3H,s),3.04(3H,s),
3.31(3H,s),3.91(2H,s),4.21-4.50(2H,
overlapped with H2O),5.62(1H,d,J=10Hz),5.80
(1H,d,J=10Hz),6.63(1H,d,J=16Hz),7.32-8.00
(11H),8.91(1H,d,J=8Hz)
实施例68
室温下向8-〔3-〔N-〔4-(N-乙酰基-N-羧甲基氨基)肉桂酰甘氨基〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(120mg)的乙醇(1ml)溶液中加入0.1N氢氧化钠水溶液(1.85ml),在相同温度下搅拌混合。3分钟后,真空除去溶剂。将残余物溶于乙醇和水的混合物(1∶2V/V,1ml)中,过滤。滤液经冻干,得到8-〔3-〔N-〔4-(N-乙酰基-N-羧甲基氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(124mg),为非晶固体。NMR(CDCl3-CD3OD,δ):1.95(3H,s),2.99(3H,s),
3.30(3H,s),3.82(1H,d,J=17Hz),3.97(1H,d,
J=17Hz),4.33(2H,s),5.61(1H,d,J=10Hz),
5.77(1H,d,J=10Hz),6.61(1H,d,J=16Hz),
7.30-7.90(11H),8.75(1H,d,J=8Hz)
实施例69
根据与实施例23相似的方法,由8-〔3-(N-甘氨酰-N-甲氨基)-2,6-二氯苄氧基〕-4-甲氧基-2-甲基喹啉,溴乙酰氯和1-(4-吡啶基)哌嗪,得到8-〔2,6-二氯-3-〔N-甲基-N-〔〔2-〔4-(4-吡啶基)-1-哌嗪基〕乙酰基〕甘氨酰〕氨基〕苄氧基〕-4-甲氧基-2-甲基喹啉。NMR(CDCl3,δ):2.60-2.79(7H),3.09(2H,s),3.23
(3H,s),3.30-3.61(5H),3.90(1H,dd,J=18,
5Hz),4.01(3H,s),5.62(2H,s),6.60-6.72
(3H),7.20-7.42(3H),7.50(1H,d,J=8Hz),7.78-
7.94(2H),8.29(2H,d,J=7Hz)
其四盐酸盐NMR(CDCl3-CD3OD,δ):3.01(3H,s),3.27(3H,s),
3.08-4.24(12H),4.35(3H,s),5.57(1H,d,
J=10Hz),5.72(1H,d,J=10Hz),7.19-7.40(3H),
7.52-7.69(3H),7.79(1H,t,J=8Hz),7.99(1H,
d,J=8Hz),8.20(2H,br d,J=7Hz)
实施例70
8-〔3-〔N-(4-氰基肉桂酰甘氨酰)-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉(76mg)和叠氮化三甲锡(109mg)在二甲苯(1ml)中的混合物在125℃加热20小时。冷却后,向反应混合物中加入甲醇-氯仿(1∶4V/V,10ml)和硅胶(296mg)。得到的悬浮液在室温下搅拌1小时。滤除硅胶,真空浓缩滤液。残余物用制备性薄层色谱提纯,用甲醇-氨仿(1∶6)洗脱,得到8-〔2,6-二氯-3-〔N-甲基-N-〔4-(5-四唑基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹啉(40mg),为暗黄色玻璃体。mp:196-208℃NMR(CDCl3-CD3OD,δ):2.70(3H,s),3.26(3H,s),
3.68(1H,d,J=18Hz),4.01(1H,d,J=18Hz),5.58
(2H,s),6.60(1H,d,J=15Hz),7.20-7.69(10H,
m),8.00(1H,d,J=9Hz),8.10(1H,d,J=10Hz)
实施例71
室温下用4M氯化氢-乙酸乙酯(2ml)处理8-〔2,6-二氯-3-〔N-〔4-〔(N-叔丁氧羰基-L-脯氨酰)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉(170mg)30分钟。浓缩反应混合物,得到8-〔(2,6-二氯-3-〔N-〔4-(L-脯氨酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹啉二盐酸盐(152mg)。NMR(CDCl3-CD3OD,δ):2.05-2.19(4H),3.12(3H,br
s),3.29(3H,s),3.44-3.53(2H),3.91(1H,d,
J=17Hz),4.06(1H,d,J=17Hz),4.68(1H,m),
5.59(1H,d,J=10Hz),5.70(1H,d,J=10Hz),6.49
(1H,d,J=15Hz),7.25-7.38(3H),7.50-7.59(4H),
7.64-(1H,br d,J=7.5Hz),7.78-7.96(3H),8.95
(1H,d,J=8Hz)
实施例72
根据与实施例49相似的方法,使8-〔(2,6-二氯-3-〔N-〔4-(L-脯氨酰氨基)肉桂酰甘氨酰〕-N-甲氧基〕苄氧基〕-2-甲基喹啉二盐酸盐与乙酸酐反应,得到8-〔3-〔N-〔4-〔(N-乙酰基-L-脯氨酰)氨基〕肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹啉。NMR(CDCl3,δ):1.74-2.25(6H),2.60(1H,m),2.72
(3H,s),3.25(3H,s),3.35-3.70(3H),3.93(1H,
m),4.78(1H,t,J=5Hz),5.63(2H,s),6.38(1H,
dd,J=15,7.5Hz),6.60(0.3H,br t,J=4Hz),6.78
(0.3H,br t,J=4Hz),7.12-7.57(10H),8.02(1H,
d,J=8Hz),9.93(1H,br d,J=5Hz)
其盐酸盐NMR(CDCl3-CD3OD,δ):2.00-2.27(6H),2.40(1H,m),
3.15(3H,br s),3.30(3H,s),3.53(1H,m),3.69
(1H,m),3.91(1H,br d,J=17Hz),4.04(1H,br d,
J=17Hz),4.77(1H,m),5.61(1H,d,J=10Hz),5.69
(1H,d,J=10Hz),6.48(1H,d,J=15Hz),.7.29-7.68
(8H),7.78-7.91(3H),8.90(1H,br d,J=8Hz)
实施例73
根据与实施例28相似的方法,得到下列化合物:
(1)8-〔(2,6-二氯-3-〔N-〔4-〔(2-吡啶基甲基)氨基甲酰基〕肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉二盐酸盐mp:181-186℃NMR(CDCl3-CD3OD,δ):2.85(3H,s),3.27(3H,s),
3.67(1H,d,J=17.5Hz),3.98(1H,d,
J=17.5Hz),4.99(2H,s),5.63(2H,s),6.63(1H,
d,J=16.0Hz),7.43(1H,d,J=8.5Hz),7.48(1H,
d,J=8.5Hz),7.52-7.63(4H,m),7.80(1H,t,
J=8.5Hz),7.34-7.93(2H,m),7.98(2H,d,
J=8.5Hz),8.15(1H,d,J=8.5Hz),8.45(1H,t,
J=8.5Hz),8.72(1H,d,J=6.0Hz),8.85(1H,s)
(2)8-〔(2,6-二氯-3-〔N-〔4-(二甲基氨基甲酰基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉盐酸盐mp:173-180℃NMR(CDCl3-CD3OD,δ):2.90(3H,s),2.99(3H,br
s),3.11(3H,br s),3.28(3H,s),3.69(1H,d,
J=17.5Hz),3.98(1H,d,J=17.5Hz),5.63(2H,s),
6.58(1H,d,J=15.0Hz),7.37-7.49(4H,m),7.51-
7.62(4H,m),7.85(1H,t,J=8.5Hz),7.93(1H,
d,J=8.5Hz),8.90(1H,s)
(3)8-〔3-〔N-〔4-乙酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕-2,6-二氯苄氧基〕-2-甲基喹喔啉盐酸盐NMR(CDCl3-CD3OD,δ):2.17(3H,s),2.91(3H,s),
3.29(3H,s),3.69(1H,d,J=17Hz),3.98(1H,d,
J=17Hz),5.62(2H,s),6.43(1H,d,J=15Hz),
7.40-7.59(8H),7.87(1H,br t,J=8Hz),7.95
(1H,br d,J=8Hz),8.90(1H,s)
(4)8-〔(2,6-二氯-3-〔N-〔4-(甲氧乙酰氨基)肉桂酰甘氨酰〕-N-甲氨基〕苄氧基〕-2-甲基喹喔啉盐酸盐NMR(CDCl3-CD3OD,δ):2.92(3H,br s),3.28(3H,
s),3.51(3H,s),3.69(1H,d,J=17Hz),3.96
(1H,d,J=17Hz),4.02(2H,s),5.63(2H,s),
6.47(1H,d,J=15Hz),7.41-7.62(8H),7.87(1H,
br t,J=8Hz),7.99(1H,br d,J=8Hz),8.90(1H,
s)
(5)8-〔(2,6-二氯-3-〔N-甲基-N-〔4-(2-氧代吡咯烷-1-基)肉桂酰甘氨酰〕氨基〕苄氧基〕-2-甲基喹喔啉盐酸盐NMR(CDCl3-CD3OD,δ):2.13-2.25(2H),2.59-2.72
(2H,overlapped with H2O),2.91(3H,br s),3.29
(3H,s),3.69(1H,d,J=17Hz),3.89(2H,t,
J=7Hz),3.96(1H,d,J=17Hz),5.63(2H,s),6.48
(1H,d,J=15Hz),7.41-7.38(2H),7.85(1H,br t,
J=8Hz),7.98(1H,br d,J=8Hz),8.90(1H,s)
Claims (10)
式中X1是N或CR6,
X2是N或CR7
X3是N或CR8
R1是氢或卤素,
R2是卤素,
其中
R10是氢或低级烷基,
R11是甘氨酰或被取代基取代的甘氨酰,取代基选自低级烷基、烷酰基、卤低级烷酰基、苯基低级烷酰基、萘基低级烷酰基、苯甲酰基、萘甲酰基、吡啶基哌嗪基低级烷酰基、低级链烯酰基、甲苯基低级链烯酰基、苯基低级链烯酰基、低级烷氧-苯基低级链烯酰基、低级亚烷基二氧基-苯基低级链烯酰基、硝基-苯基低级链烯酰基、氰基-苯基低级链烯酰基、卤-苯基低级链烯酰基、羟基-苯基低级链烯酰基、羟基低级烷氧-苯基低级链烯酰基、氨基低级烷氧-苯基低级链烯酰基、低级烷氨基低级烷氧-苯基低级链烯酰基、吡啶基低级烷氧-苯基低级链烯酰基、四唑基-苯基低级链烯酰基、氧代吡咯烷基-苯基低级链烯酰基、氨基-苯基低级链烯酰基、低级烷氨基-苯基低级链烯酰基、低级烷酰氨基-苯基低级链烯酰基、N-低级烷酰基-N-低级烷基氨基-苯基低级链烯酰基、环烷基低级烷酰氨基-苯基低级链烯酰基、环烷基羰基氨基-苯基低级链烯酰基、低级链烯酰氨基-苯基低级链烯酰基、低级烷氧羰基氨基-苯基低级链烯酰基、羟基低级烷酰氨基-苯基低级链烯酰基、低级烷氧低级烷酰氨基-苯基低级链烯酰基、卤低级烷酰氨基-苯基低级链烯酰基、氨基低级烷酰氨基-苯基低级链烯酰基、低级烷氨基低级烷酰氨基-苯基低级链烯酰基、低级烷酰氨基低级烷酰氨基-苯基低级链烯酰基、羧基低级烷酰氨基-苯基低级链烯酰基、低级烷氧羰基低级烷酰氨基-苯基低级链烯酰基、低级烷氧羰基低级链烯酰氨基-苯基低级链烯酰基、卤低级烷氧羰基氨基-苯基低级链烯酰基、吡啶基低级烷酰氨基-苯基低级链烯酰基、噻吩基低级烷酰氨基-苯基低级链烯酰基、甲基吡咯基低级烷酰氨基-苯基低级链烯酰基、苯甲酰氨基-苯基低级链烯酰基、吡啶基羰基氨基-苯基低级链烯酰基、吗啉代羰基氨基-苯基低级链烯酰基、呋喃基羰基氨基-苯基低级链烯酰基、噻吩基羰基氨基-苯基低级链烯酰基、噁唑基羰基氨基-苯基低级链烯酰基、甲基噁唑基羰基氨基-苯基低级链烯酰基、二甲基异噁唑基羰基氨基-苯基低级链烯酰基、咪唑基羰基氨基-苯基低级链烯酰基、甲基咪唑基羰基氨基-苯基低级链烯酰基、哌啶基羰基氨基-苯基低级链烯酰基、乙基哌啶基羰基氨基-苯基低级链烯酰基、乙酰哌啶基羰基氨基-苯基低级链烯酰基、吡咯烷基羰基氨基-苯基低级链烯酰基、乙酰吡咯烷基羰基氨基-苯基低级链烯酰基、叔丁氧羰基吡咯烷基羰基氨基-苯基低级链烯酰基、低级烷磺酰氨基-苯基低级链烯酰基、N-(低级烷氧低级烷酰)-N低级烷基氨基-苯基低级链烯酰基、N-(低级烷酰)-N(低级烷氧羰基低级烷基)氨基-苯基低级链烯酰基、N-(低级烷酰)-N-(吡啶基低级烷基)氨基-苯基低级链烯酰基、N-低级烷酰-N-(低级烷氧低级烷基)氨基-苯基低级链烯酰基、N-低级烷酰-N-(羧基低级烷基)氨基-苯基低级锭烯酰基、N-(低级烷氧低级烷酰)-N-(吡啶基低级烷基)氨基-苯基低级链烯酰基、N-(吡啶基羰基)-N-(低级烷氧低级烷基)氨基-苯基低级链烯酰基、脲基-苯基低级链烯酰基、低级烷基脲基-苯基低级链烯酰基、吡啶基脲基-苯基低级链烯酰基、低级烷酰-苯基低级链烯酰基、羧基-苯基低级链烯酰基、低级烷氧羰基-苯基低级链烯酰基、氨基甲酰基-苯基低级链烯酰基、低级烷基氨基甲酰基-苯基低级链烯酰基、羟基低级烷基氨基甲酰基-苯基低级链烯酰基、N-(羟基低级烷基)氨基甲酰基-苯基低级链烯酰基、N-(羟基低级烷基)-N-低级烷基氨基甲酰基-苯基低级链烯酰基、低级烷氧低级烷基氨基甲酰基-苯基低级链烯酰基、N-(低级烷基低级烷基)-N-低级烷基氨基甲酰基-苯基低级链烯酰基、吡啶基低级烷基氨基甲酰基-苯基低级链烯酰基、呋喃基低级烷基氨基甲酰基-苯基低级链烯酰基、噻吩基低级烷基氨基甲酰基-苯基低级链烯酰基、N-(吡啶基低级烷基)-N-低级烷基氨基甲酰基-苯基低级链烯酰基、吡啶基氨基甲酰基-苯基低级链烯酰基、四唑基氨基甲酰基-苯基低级链烯酰基、吗啉代羰基-苯基低级链烯酰基、吡咯烷基羰基-苯基低级链烯酰基、哌啶基羰基-苯基低级链烯酰基、甲基哌嗪基羰基-苯基低级链烯酰基、低级链烯基氨基甲酰基-苯基低级链烯酰基、低级炔基氨基甲酰基-苯基低级链烯酰基、氨基低级烷基氨基甲酰基-苯基低级链烯酰基、低级烷氨基低级烷基氨基甲酰基-苯基低级链烯酰基、低级烷基氨基甲酰氧基低级烷基氨基甲酰基-苯基低级链烯酰基、低级烷基氨基甲酰低级烷基氨基甲酰-苯基低级链烯酰基、低级烷氧羰基低级烷基氨基甲酰-苯基低级链烯酰基、羧基低级烷基氨基甲酰-苯基低级链烯酰基、(低级烷基氨基甲酰-苯基低级烷基)氨基甲酰基-苯基低级链烯酰基、(低级烷氧羰基-苯基低级烷基)氨基甲酰基-苯基低级链烯酰基、羧基-苯基低级烷基)氨基甲酰基-苯基低级链烯酰基、N-(低级烷基氨基甲酰基低级烷基)-N-低级烷基氨基甲酰基-苯基低级链烯酰基、N-(低级烷氧羰基低级烷基)-N-低级烷基氨基甲酰基-苯基低级链烯酰基、N-(羧基低级烷基)-N-低级烷基氨基甲酰基-苯基低级链烯酰基、苯基氨基甲酰基-苯基低级链烯酰基、苯基低级炔酰基、吡啶基低级链烯酰基、吡啶基硫代低级烷酰基、氨基-吡啶基低级链烯酰基、低级烷氨基-吡啶基低级链烯酰基、低级烷酰氨基-吡啶基低级链烯酰基、低级链烯酰氨基-吡啶基低级链烯酰基、吡啶基低级烷酰氨基-吡啶基低级链烯酰基、吡啶基羰基氨基-吡啶基低级链烯酰基、呋喃基羰基氨基-吡啶基低级链烯酰基、低级烷酰氨基低级烷酰氨基-吡啶基低级链烯酰基、低级烷氧羰基低级烷酰氨基-吡啶基低级链烯酰基、低级烷氧羰基低级烷酰氨基-吡啶基低级链烯酰基、低级烷氧低级烷酰氨基-吡啶基低级链烯酰基、低级烷基脲基-吡啶基低级链烯酰基、羧基-吡啶基低级链烯酰基、低级烷氧羰基-吡啶基低级链烯酰基、低级烷基氨基甲酰基-吡啶基低级链烯酰基、低级烷氧低级烷基氨基甲酰基-吡啶基低级链烯酰基、羟基低级烷基氨基甲酰基-吡啶基低级链烯酰基、吡啶基氨基甲酰基-吡啶基低级链烯酰基、吡啶基低级烷基氨基甲酰基-吗啉代低级链烯酰基、吡咯烷基羰基-吡啶基低级链烯酰基、吗啉代羰基-吡啶基低级链烯酰基、低级链烯基氨基甲酰基-吡啶基低级链烯酰基、低级炔基氨基甲酰基-吡啶基低级链烯酰基、环低级烷基羰基、低级烷氧羰基、苯氧基羰基、苯甲酰低级烷酰基、硝基-苯氧基羰基、氨基甲酰基、低级烷基氨基甲酰基、低级烷氧羰基低级烷基氨基甲酰基、低级链烯基氨基甲酰基、环低级烷基氨基甲酰基、苯基氨基甲酰基、萘基氨基甲酰基、低级烷氧-苯基氨基甲酰基、卤低级烷基-苯基氨基甲酰基、卤-苯基氨基甲酰基、低级烷酰-苯基氨基甲酰基、羟基低级烷基-苯基氨基甲酰基、吗啉代羰基-苯基氨基甲酰基、哌啶基羰基-苯基氨基甲酰基、硫代吗啉代羰基-苯基氨基甲酰基、哌嗪基羰基-苯基氨基甲酰基、吡咯烷基羰基-苯基氨基甲酰基、1,2,3,6-四氢吡啶基羰基-苯基氨基甲酰基、羧基-苯基氨基甲酰基、低级烷氧羰基-苯基氨基甲酰基、氨基甲酰基-苯基氨基甲酰基、低级烷基氨基甲酰基-苯基氨基甲酰基、硝基-苯基氨基甲酰基、氰基-苯基氨基甲酰基、氨基-苯基氨基甲酰基、低级烷基氨基-苯基氨基甲酰基、低级烷酰氨基-苯基氨基甲酰基、N-低级烷酰-N-低级烷基氨基-苯基氨基甲酰基、低级烷氧低级烷酰氨基-苯基氨基甲酰基、低级烷氧羰基低级烷酰氨基-苯基氨基甲酰基、羧基氨基-苯基氨基甲酰基、低级烷氧羰基氨基-苯基氨基甲酰基、苯甲酰氨基-苯基氨基甲酰基、吡啶基羰基氨基-苯基氨基甲酰基、吡啶基低级烷酰氨基-苯基氨基甲酰基、脲基-苯基氨基甲酰基、低级烷基脲基-苯基氨基甲酰基、羟基亚氨基低级烷基-苯基氨基甲酰基、低级烷氧亚氨基低级烷基-苯基氨基甲酰基、低级烷基亚肼基低级烷基-苯基氨基甲酰基、氧代吡咯烷基苯基氨基甲酰基、氧代哌啶并苯基氨基甲酰基、二氧代吡咯烷基苯基氨基甲酰基、氧代噁唑烷基苯基氨基甲酰基、甲基哌嗪基羰基苯基氨基甲酰基、乙基哌嗪基羰基苯基氨基甲酰基、苯基哌嗪基羰基苯基氨基甲酰基、吡啶基哌嗪基羰基苯基氨基甲酰基、乙酰哌嗪基羰基苯基氨基甲酰基、乙氧羰基哌嗪基羰基苯基氨基甲酰基、甲基氨基哌嗪基羰基苯基氨基甲酰基、二甲基氨基哌嗪基羰基苯基氨基甲酰基、甲基氨基甲酰基哌嗪基羰基苯基氨基甲酰基、羟基低级烷基氨基甲酰基-笨基氨基甲酰基、N-(羟基低级烷基)-N-低级烷基氨基甲酰基-苯基氨基甲酰基、低级烷氧低级烷基氨基甲酰基-苯基氨基甲酰基、N-(低级烷氧低级烷基)-N-低级烷基氨基甲酰基-苯基氨基甲酰基、低级烷氨基低级烷基氨基甲酰基-苯基氨基甲酰基、N-(低级烷氨基低级烷基)-N-低级烷基氨基甲酰基-苯基氨基甲酰基、吡啶基氨基甲酰基-苯基氨基甲酰基、嘧啶基氨基甲酰基-苯基氨基甲酰基、吗啉基氨基甲酰基-苯基氨基甲酰基、噻吩基氨基甲酰基-苯基氨基甲酰基、N-吡啶基-N-低级烷基氨基甲酰基-苯基氨基甲酰基、吡啶基低级烷基氨基甲酰基-苯基氨基甲酰基、N-(吡啶基低级烷基)-N-低级烷基氨基甲酰基-苯基氨基甲酰基、N-(吡啶基低级烷基)-N-(低级烷氧低级烷基)氨基甲酰基-苯基氨基甲酰基、苯基氨基甲酰基-苯基氨基甲酰基、低级烷氨基苯基氨基甲酰基-苯基氨基甲酰基、苯硫基氨基甲酰基、苯基低级烷基氨基甲酰基、苯甲酰基氨基甲酰基、吡啶基氨基甲酰基、吡啶基低级烷基氨基甲酰基、苯基氨基氨基甲酰基、苯基低级链烯基磺酰基、低级烷基磺酰基、邻苯二甲酰基,甘氨酰、被环烷基取代的甘氨酰、被苯基取代的甘氨酰、和被邻苯二甲酰基取代的甘氨酰;或R3是可被氧、苯基低级烷基或低级烷氧羰基低级烷基取代的哌嗪基,
R4和R5各自为氢或卤素,
R6和R8各自为氢、卤素、低级烷基、羟基、低级烷硫基、可被低级烷基取代的氨基、可被羟基、低级烷氧基、氨基、低级烷基氨基或可被低级烷氧基取代的苯基取代的低级烷氧基,
R7是氢或低级烷基,
A是低级亚烷基,和
Q是O或N-R9,其中R9是氢,条件是当X1是C-R6,其中R6是氢时,R3不是氢。
3.权利要求2的化合物,其中X1是C-R6,其中R6是低级烷基,A是亚甲基。
5.权利要求4的化合物,该化合物是8-(2,6-二氯-3-(N-(4-二甲基氨基甲酰基肉桂酰甘氨酰)-N-甲氨基)苯甲酰氧基)-2-甲基喹啉或其酸加成盐。
6.权利要求4的化合物,该化合物是8-(2,6二氯-3-(N-甲基-N-(4-甲基氨基甲酰基-肉桂酰甘氨酰)氨基)苄氧基)-2-甲基喹啉或其酸加成盐。
7.权利要求4的化合物,该化合物是8-(3-(N-(E-3-6-乙酰氨基吡啶-3-基丙烯酰甘氨酰)-N甲氨基)-2,6-二氯苄氧基)2-甲基喹啉或其酸加成盐。
式中R1,R2,R3,R4,R5,X1,X2,X3,Q和A各自如权利要求1所定义,
所述方法包括:
a)使下式的化合物或其盐:
式中X是离去基团,R1、R2、R3和A各自如权利要求1所定义,得到下式的化合物或其盐:
式中R1、R2、R3、R4、R5、X1、X2、X3、Q和A各自如权利要求1所定义,或
式中R1、R2、R4、R5、R10、R11、X1、X2、X3、Q和A各自如权利要求1所定义,或
式中Rb11是被低级烷基氨基甲酰基-苯基低级链烯酰基取代的甘氨酰、被低级烷酰氨基-苯基低级链烯酰基取代的甘氨酰、被低级烷基氨基甲酰基-吡啶基低级链烯酰基取代的甘氨酰或被低级烷酰氨基-吡啶基低级链烯酰基取代的甘氨酰,R1、R2、R4、R5、R10、X1、X2、X3、Q和A各自如权利要求1所定义,或
式中AA是甘氨酰,Y是NH或低级亚烷基,Z是CH或N,R1、R2、R4、R5、R10、X1、X2、X3、Q和A各自如权利要求1所定义,与下式的化合物或其氨基位反应性衍生物或其盐反应;
式中R12是氢,低级烷基、低级烷氧低级烷基、低级烷氨基低级烷基、吡啶基低级烷基、呋喃基低级烷基、噻吩基低级烷基、吡啶基、嘧啶基、四唑基、低级链烯基、低级炔基、低级烷基氨基甲酰氧基低级烷基、低级烷氧羰基低级烷基、羧基低级烷基、低级烷基氨基甲酰基低级烷基、低级烷氧羰基-苯基低级烷基,羧基-苯基低级烷基,低级烷基氨基甲酰基-苯基低级烷基,被保护的或非保护的羟基低级烷基,或可被低级烷氨基取代的苯基;
R13是氢,低级烷基、低级烷氧低级烷基、或被保护的或非保护的羟基低级烷基,或
R12和R13与相连的氮原子一起形成吗啉代、硫代吗啉代、吡咯烷-1-基、哌啶基、1,2,3,6-四氢吡啶-1-基或哌嗪-1-基,其各自可被选自低级烷基、低级烷氨基、苯基、吡啶基、低级烷酰基、低级烷氧羰基和低级烷基氨基甲酰基的取代基取代,得到下式的化合物或其盐:
式中AA、Y、Z、R12和R13各自如上所定义,R1、R2、R4、R5、R10、X1、X2、X3、和Q各自如权利要求1所定义。
9.一种药物组合物,含有作为活性成分的权利要求1所述的化合物和与之组合使用的、药物上可接受的基本无毒性的载体或赋形剂。
10.权利要求1所述的化合物的用途,该用途是制备用于预防和/或治疗缓激肽及其相关疾病的药物组合物。
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Application Number | Priority Date | Filing Date | Title |
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GB939308804A GB9308804D0 (en) | 1993-04-28 | 1993-04-28 | New hetrocyclic compounds |
GB9308804.5 | 1993-04-28 | ||
GB939318929A GB9318929D0 (en) | 1993-09-13 | 1993-09-13 | New heterocyclic compounds |
GB9318929.8 | 1993-09-13 |
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CN1097417A CN1097417A (zh) | 1995-01-18 |
CN1043344C true CN1043344C (zh) | 1999-05-12 |
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EP (1) | EP0622361B1 (zh) |
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CN (1) | CN1043344C (zh) |
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AU (1) | AU680870B2 (zh) |
CA (1) | CA2122236C (zh) |
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DK (1) | DK0622361T3 (zh) |
ES (1) | ES2161231T3 (zh) |
HU (1) | HU223140B1 (zh) |
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- 1994-04-26 ES ES94106486T patent/ES2161231T3/es not_active Expired - Lifetime
- 1994-04-26 KR KR1019940008888A patent/KR100329469B1/ko not_active IP Right Cessation
- 1994-04-26 CA CA002122236A patent/CA2122236C/en not_active Expired - Fee Related
- 1994-04-26 JP JP08889794A patent/JP3346437B2/ja not_active Expired - Fee Related
- 1994-04-26 DK DK94106486T patent/DK0622361T3/da active
- 1994-04-26 PT PT94106486T patent/PT622361E/pt unknown
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Also Published As
Publication number | Publication date |
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PT622361E (pt) | 2002-03-28 |
CA2122236C (en) | 2007-02-13 |
DE69428476T2 (de) | 2002-05-08 |
US5563162A (en) | 1996-10-08 |
PH30752A (en) | 1997-10-17 |
EP0622361B1 (en) | 2001-10-04 |
EP0622361A1 (en) | 1994-11-02 |
AU680870B2 (en) | 1997-08-14 |
CA2122236A1 (en) | 1994-10-29 |
US5922711A (en) | 1999-07-13 |
HUT70493A (en) | 1995-10-30 |
ATE206412T1 (de) | 2001-10-15 |
US6169095B1 (en) | 2001-01-02 |
CN1097417A (zh) | 1995-01-18 |
RU2135478C1 (ru) | 1999-08-27 |
DK0622361T3 (da) | 2001-12-03 |
KR100329469B1 (ko) | 2003-01-09 |
ES2161231T3 (es) | 2001-12-01 |
DE69428476D1 (de) | 2001-11-08 |
AU6052594A (en) | 1994-11-03 |
IL109395A (en) | 1998-09-24 |
JP3346437B2 (ja) | 2002-11-18 |
HU9401221D0 (en) | 1994-08-29 |
IL109395A0 (en) | 1994-07-31 |
HU223140B1 (hu) | 2004-03-29 |
JPH072780A (ja) | 1995-01-06 |
US5708173A (en) | 1998-01-13 |
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