CN1312817A - 截尾海兔肽15衍生物 - Google Patents
截尾海兔肽15衍生物 Download PDFInfo
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- CN1312817A CN1312817A CN99809741A CN99809741A CN1312817A CN 1312817 A CN1312817 A CN 1312817A CN 99809741 A CN99809741 A CN 99809741A CN 99809741 A CN99809741 A CN 99809741A CN 1312817 A CN1312817 A CN 1312817A
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- Prior art keywords
- alkyl
- group
- aryl
- formula
- amino
- Prior art date
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- LQKSHSFQQRCAFW-CCVNJFHASA-N [(2s)-1-[(2s)-2-benzyl-3-methoxy-5-oxo-2h-pyrrol-1-yl]-3-methyl-1-oxobutan-2-yl] (2s)-1-[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxyl Chemical class C([C@@H]1N(C(=O)C=C1OC)C(=O)[C@@H](OC(=O)[C@H]1N(CCC1)C(=O)[C@H]1N(CCC1)C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C)C(C)C)C1=CC=CC=C1 LQKSHSFQQRCAFW-CCVNJFHASA-N 0.000 title description 2
- -1 alkylene alkyl ether Chemical class 0.000 claims abstract description 195
- 150000001875 compounds Chemical class 0.000 claims abstract description 76
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 73
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 72
- 239000002253 acid Substances 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 38
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 22
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 21
- 241000124008 Mammalia Species 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims description 83
- 125000004432 carbon atom Chemical group C* 0.000 claims description 54
- 125000001072 heteroaryl group Chemical group 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- 229910052731 fluorine Inorganic materials 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000001257 hydrogen Substances 0.000 claims description 31
- 239000011737 fluorine Substances 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 24
- 125000003368 amide group Chemical group 0.000 claims description 21
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 229940024606 amino acid Drugs 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 125000004122 cyclic group Chemical group 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 150000002475 indoles Chemical class 0.000 claims description 12
- 229950003188 isovaleryl diethylamide Drugs 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 10
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- 125000005161 aryl oxy carbonyl 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
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000005002 aryl methyl group Chemical group 0.000 claims description 6
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
- 125000004429 atom Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- YLFIGGHWWPSIEG-UHFFFAOYSA-N aminoxyl Chemical compound [O]N YLFIGGHWWPSIEG-UHFFFAOYSA-N 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000002015 acyclic group Chemical group 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 claims description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical class CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 claims description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 2
- NPDLYUOYAGBHFB-WDSKDSINSA-N Asn-Arg Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NPDLYUOYAGBHFB-WDSKDSINSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical class OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- OKJIRPAQVSHGFK-UHFFFAOYSA-N N-acetylglycine Chemical compound CC(=O)NCC(O)=O OKJIRPAQVSHGFK-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims description 2
- 229960005261 aspartic acid Drugs 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- GSERGAQIHKFDMG-UHFFFAOYSA-N cyclopentanamine;formic acid Chemical group OC=O.NC1CCCC1 GSERGAQIHKFDMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229940097043 glucuronic acid Drugs 0.000 claims description 2
- 229960002989 glutamic acid Drugs 0.000 claims description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims 20
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 20
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 20
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 12
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims 10
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims 10
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims 10
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims 10
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims 10
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims 10
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims 10
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 10
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims 10
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 10
- QZHPTGXQGDFGEN-UHFFFAOYSA-N chromene Chemical compound C1=CC=C2C=C[CH]OC2=C1 QZHPTGXQGDFGEN-UHFFFAOYSA-N 0.000 claims 10
- 150000002240 furans Chemical class 0.000 claims 10
- 150000002460 imidazoles Chemical class 0.000 claims 10
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims 10
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims 10
- 150000003217 pyrazoles Chemical class 0.000 claims 10
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims 10
- 150000003233 pyrroles Chemical class 0.000 claims 10
- 150000004867 thiadiazoles Chemical class 0.000 claims 10
- 229930192474 thiophene Natural products 0.000 claims 10
- 125000002114 valyl group Chemical group 0.000 claims 10
- 125000002877 alkyl aryl group Chemical group 0.000 claims 4
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims 1
- 125000005093 alkyl carbonyl alkyl group Chemical group 0.000 claims 1
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims 1
- 125000003710 aryl alkyl group Chemical group 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 1
- 125000001998 leucyl group Chemical group 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- 125000001382 thioacetal group Chemical group 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 46
- 239000000203 mixture Substances 0.000 abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
- 102000004196 processed proteins & peptides Human genes 0.000 abstract description 5
- 125000003275 alpha amino acid group Chemical group 0.000 abstract description 4
- 125000003277 amino group Chemical group 0.000 abstract description 4
- 239000003937 drug carrier Substances 0.000 abstract description 4
- 150000001280 alpha hydroxy acids Chemical group 0.000 abstract description 2
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical group NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 abstract description 2
- 125000005309 thioalkoxy group Chemical group 0.000 abstract description 2
- 125000005275 alkylenearyl group Chemical group 0.000 abstract 1
- 125000002344 aminooxy group Chemical group [H]N([H])O[*] 0.000 abstract 1
- 239000003966 growth inhibitor Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
- 239000000243 solution Substances 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 27
- 239000011347 resin Substances 0.000 description 27
- 229920005989 resin Polymers 0.000 description 27
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 21
- 230000008878 coupling Effects 0.000 description 18
- 238000010168 coupling process Methods 0.000 description 18
- 238000005859 coupling reaction Methods 0.000 description 18
- 241000237373 Aplysia sp. Species 0.000 description 17
- 150000001413 amino acids Chemical class 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 125000001153 fluoro group Chemical group F* 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical compound NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- AKCRVYNORCOYQT-YFKPBYRVSA-N N-methyl-L-valine Chemical compound CN[C@@H](C(C)C)C(O)=O AKCRVYNORCOYQT-YFKPBYRVSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 8
- 125000001624 naphthyl group Chemical group 0.000 description 8
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Abstract
本发明的化合物包括细胞生长抑制剂,它们是式(Ⅰ):A－B－D－E－F－G的肽及其酸盐,其中A、D和E是α－氨基酸残基,B是α－氨基酸残基或α－羟基酸残基,F是氨基苯甲酸残基或氨基环烷基甲酸残基,G是一价基团,例如氢原子、氨基、烷基、亚烷基烷基醚、亚烷基烷基硫醚、亚烷基醛、亚烷基酰胺、β－羟基氨基、肼基、烷氧基、硫代烷氧基、氨基氧基、肟基、亚烷基芳基、亚烷基酯、亚烷基亚砜或亚烷基砜。另一方面,本发明包括含有式(Ⅰ)化合物和可药用载体的药物组合物。本发明的另一个实施方案是在哺乳动物、例如人中治疗癌症的方法,该方法包括,以药物组合物的形式向哺乳动物施用有效量的式(Ⅰ)化合物。
Description
相关申请
本申请是1998年7月8日递交的序列号为09/112,249的接续申请并要求其优先权，其教导的内容全文引入本文作为参考。
发明背景
从印度洋海兔Dolabella auricularia中分离出了多种具有显著的细胞生长抑制剂活性的短肽(Bai等，《生化药理学》(Biochem.Pharmacology)40:1859-1864(1990)；Beckwith等，《国家癌症研究所杂志》(J.Natl.Cancer Inst.)85:483-488(1993)和其中引用的参考文献)。其中包括截尾海兔肽1-10(Dolastatins 1-10)(美国专利4,816,444，授权给Pettit等)和截尾海兔肽-15(Dolastatin-15)(欧洲专利申请号398558)。例如，截尾海兔肽15可以显著抑制国家癌症研究所的P388淋巴细胞白血病(PS系统)细胞系的生长，这是有效对抗各种类型的人类恶性肿瘤的有力的预示。
在Dolabella auricularia中存在极少量的各种截尾海兔肽(每100kg海兔中约含1mg)，因此难以纯化足够的量来进行评估和使用，于是人们开始尝试合成这些化合物(Roux等，《四面体》(Tetrahedron)50:5345-5360(1994)；Shioiri等，《四面体》(Tetrahedron)49:1913-24(1993)；Patino等，《四面体》(Tetrahedron)48:4115-4122(1992)和其中引用的参考文献)。但是，合成的截尾海兔肽15存在许多不足，包括在含水体系中的溶解度差以及需要昂贵的原料来合成。于是人们又开始合成和评估结构改性的截尾海兔肽15衍生物(参见，例如《生物有机药物化学通讯》(Bioorg.Med.Chem.Lett.)4:1947-50(1994)；WO 93 03054；JP-A-06234790)。
但是，仍需要具有截尾海兔肽15的生物学活性的水溶性良好并且能够有效而且经济地制备的合成化合物。
发明概述
本发明的化合物包括细胞生长抑制剂，它们是式Ⅰ的肽
A-B-D-E-F-G (Ⅰ)及其酸盐，其中A、D和E是α-氨基酸残基，B是α-氨基酸残基，F是氨基苯甲酸残基或氨基环烷基羧酸残基，G是一价基团，例如氢原子、氨基、烷基、亚烷基烷基醚、亚烷基烷基硫醚、亚烷基醛、亚烷基酰胺、β-羟基氨基、肼基、烷氧基、硫代烷氧基、氨基氧基、肟基(oximato)、亚烷基芳基、亚烷基酯、亚烷基亚砜或亚烷基砜。
另一方面，本发明包括含有式Ⅰ化合物和可药用载体的药物组合物。
本发明的另一个实施方案是在哺乳动物、例如人中治疗癌症的方法，该方法包括，以药物组合物的形式向哺乳动物施用有效量的式Ⅰ化合物。
本发明提供具有抗肿瘤活性并且代谢稳定性比截尾海兔肽15增加了的化合物。发明详述
本发明涉及具有抗肿瘤活性的肽。本发明还包括含有这些化合物的组合物以及通过向哺乳动物施用这些组合物而在哺乳动物、包括人中治疗癌症的方法。
本发明是基于如下发现，即，从海兔Dolabella auricularia分离的肽截尾海兔肽15是细胞生长的强效抑制剂。但是，该化合物在海兔中的含量非常少，因而难以分离，同时，该化合物的合成非常昂贵并且水溶性很差。但是，如文中所示，可以将截尾海兔肽15作为起点来开发克服了这些缺点并同时保留了抗肿瘤活性或者显示出比天然产物更强的抗肿瘤活性的化合物。申请人发现，对截尾海兔肽15的某些结构改变可以获得治疗肿瘤疾病的治疗潜力比截尾海兔肽-10和-15明显改进的化合物。截尾海兔肽-15衍生物甚至在多重抗药性的肿瘤体系中也显示出活性，并且在含水溶剂中显示出人意料的高溶解性。此外，本发明的化合物可以方便地合成，以下将进行详细描述。
对于本发明的目的而言，术语“一价基团”是指能够与第二个中性分子片段形成一个共价键的电中性的分子片段。一价基团包括氢原子；烷基，例如甲基、乙基和丙基；卤原子，例如氟、氯和溴原子；芳基，例如苯基和萘基；以及烷氧基，例如甲氧基和乙氧基。相邻的以σ键连接的原子上的两个一价基团还可以一起在相邻的原子之间形成π键。两个一价基团还可以通过多亚甲基单元连接在一起形成环状结构。例如，在单元-N(R)R’中，R和R’均是一价基团，并且可以和氮原子一起形成杂环。此外，连接在同一原子上的两个一价基团还可以一起形成二价基团，例如亚烷基如亚丙基或氧原子。
对于本发明的目的而言，术语“残基”是指从一个分子例如氨基酸或羟基酸上除去水分子(一个氧原子，两个氢原子)后剩余的分子片段。
对于本发明的目的而言，术语“正烷基”是指直链的烷基，例如正丙基(n-丙基，-CH2CH2CH3)。
本发明的化合物可以用式Ⅰ表示，
A-B-D-E-F-G (Ⅰ)其中A、D和E是α-氨基酸残基；B是α-氨基酸残基或α-羟基酸残基；F是氨基苯甲酸残基或氨基环烷基羧酸残基，例如氨基环丁烷羧酸残基、氨基环戊烷羧酸残基或氨基环己烷羧酸残基；G是一价基团。
式Ⅰ的肽通常由L-氨基酸组成，但它们也可含有一个或多个D-氨基酸。它们还可以以与生理相容性酸的盐的形式存在，所述的酸包括盐酸、柠檬酸、酒石酸、乳酸、磷酸、甲磺酸、乙酸、甲酸、马来酸、富马酸、苹果酸、琥珀酸、丙二酸、硫酸、L-谷氨酸、L-天冬氨酸、丙酮酸、粘酸、苯甲酸、葡糖醛酸、草酸、抗坏血酸和乙酰甘氨酸。
以下是对本发明的描述，包括对单个成分以及使用所要求保护的化合物之方法的详细描述。本发明的化合物A的描述
在一个实施方案中，A是式Ⅱa的氨基酸衍生物其中na是整数，优选0、1、2或3。Ra是一价基团，例如氢原子或C1-C3烷基，所述烷基可以是直链、支链或环状的，并且可以被一个或多个，优选1至约3个氟原子所取代；适宜的例子包括甲基、乙基、异丙基、2-氟乙基、2,2,2-三氟乙基、1-甲基-2-氟乙基、1-氟甲基-2-氟乙基或环丙基；优选甲基、乙基或异丙基。
在该实施方案中，R1 a是一价基团，例如氢原子或甲基、乙基、丙基或苯基。苯基可以是取代的；适宜的取代基包括一个或多个卤原子，优选氟、氯和溴、C1-C4-烷基、甲氧基、乙氧基、三氟甲基或硝基。
R2 a、R3 a、R4 a和R5 a彼此独立地是一价基团，例如氢原子或甲基。Ra和R1 a还可以合在一起形成亚丙基桥。
在另一个实施方案中，A是式Ⅲa的氨基酸衍生物，其中Ra具有式Ⅱa中所述的含义，R1 a是一价基团，例如氢原子或低级烷基，优选甲基、乙基或丙基。
在该实施方案中，R6 a是一价基团，例如氢原子、直链或支链的C1-C8-烷基，所述烷基可以被一个或多个卤素，优选氟原子所取代，或是C3-C8-环烷基或C3-C8-环烷基-C1-C4-烷基、C1-C4-氧烷基如甲氧基甲基、1-甲氧基乙基或1,1-二甲基羟基甲基、C2-C5链烯基，例如乙烯基或1-甲基乙烯基，或是取代或未取代的苯基。适宜的苯基取代基包括一个或多个卤原子、优选氟、氯或溴原子，以及烷基、甲氧基、乙氧基、三氟甲基、或硝基。R7 a是一价基团，优选甲基或乙基。
在另一个实施方案中，A是式Ⅳa的氨基酸残基，其中ma是整数，优选1或2。Ra和R7 a具有式Ⅲa中所述的Ra和R7 a的含义。
在另一个实施方案中，A是式Ⅴa的氨基酸残基，
其中Ra和R7 a具有式Ⅲa中所述的Ra和R7 a的含义。
在又一个实施方案中，A是式Ⅵa的取代的脯氨酸衍生物，
其中Ra和R1 a具有式Ⅱa中所述的Ra和R1 a的含义，Xa是一价基团，优选羟基、甲氧基或乙氧基或氟原子。
在另一个实施方案中，A是式Ⅶa的硫杂脯氨酰基衍生物，
其中Ra、R1 a、R2 a、R3 a、R4 a和R5 a具有式Ⅱa中所述的这些变量的含义。
在另一个实施方案中，A是式Ⅷa的1,3-二氢异吲哚衍生物，
其中Ra具有式Ⅱa中所述Ra的含义。
在另一个实施方案中，A是式Ⅸa的2-氮杂二环[2.2.1]庚烷-3-羧酸衍生物，
其中Za是单键或双键，Ra具有式Ⅱa中所述的该变量的含义。3-羰基取代基可以具有外型或内型的取向。B的描述
B是缬氨酰基、异亮氨酰基、别-异亮氨酰基、正缬氨酰基、2-叔丁基甘氨酰基或2-乙基甘氨酰基残基。B还可以是式Ⅱb的羧酸衍生物，
其中R1 b和R2 b分别是一价基团。R1 b优选是氢原子，R2 b是例如，环丙基、直链或支链的丁基，优选叔丁基、甲氧基甲基、1-甲氧基乙基或1-甲基乙烯基。此外，R1 b和R2 b合在一起还可以是亚异丙基。D的描述
D是N-烷基缬氨酰基、N-烷基-2-乙基甘氨酰基、N-烷基-2-叔丁基甘氨酰基、N-烷基-正亮氨酰基、N-烷基异亮氨酰基、N-烷基-别-异亮氨酰基或N-烷基-正缬氨酰基残基，其中的烷基优选甲基或乙基。
在另一个实施方案中，D是式Ⅱd的α-氨基羧酸衍生物，
其中Rd具有式Ⅲa中所述的Ra的含义，R1 d是一价基团，优选氢原子，R2是一价基团，例如环丙基、甲氧基甲基、1-甲氧基乙基或1-甲基乙烯基。此外，R1 d和R2 d合在一起还可以是亚异丙基。
或者，D可以是式Ⅲd的脯氨酸衍生物，
其中nd是整数，例如1或2,R3 d具有式Ⅲa中所述的R1 a的含义。Xd是一价基团，优选氢原子，并且当nd等于1时，还可以是羟基、甲氧基或乙氧基或氟原子。E的描述
E是脯氨酰基、噻唑烷基-4-羰基、高脯氨酰基或羟基脯氨酰基残基，或是式Ⅱe的环状α-氨基羧酸残基，
其中ne是整数，优选0、1或2。R1 e具有式Ⅲa中所述的R1 a的含义。R2 e和R3 e分别是一价基团，并且可以彼此独立地是氢原子或甲基。R4 e是一价基团，优选氢原子、羟基、甲氧基或乙氧基或氟原子。R5 e是一价基团，优选氢原子。当ne等于1时，R3 e和R4 e合在一起可以形成双键，或者R4 e和R5 e可以合在一起形成以双键连接的氧基。当ne等于1或2时，R1 e和R2 e可以合在一起形成双键。
在另一个实施方案中，E是式Ⅲe的2-或3-氨基-环戊烷羧酸残基，
其中Re是一价基团，例如甲基或乙基，R1 e具有式Ⅲa中所述的R1 a的含义。F的描述
在一个实施方案中，F是式Ⅱf的氨基苯甲酰基衍生物，其中Rf是氢原子或烷基，优选甲基、乙基或丙基。羰基可以位于苯环上相对于氮原子的1位(邻)、2位(间)或3位(对)。R1 f和R2 f彼此独立地是氢原子；卤原子，例如氟、氯、溴或碘原子；C1-C4-烷基；甲氧基、乙氧基、三氟甲基、硝基、氰基、氨基或二甲基氨基。此外，R1 f和R2 f还可以合在一起形成亚甲二氧基(dioxymethylene)。
在另一个实施方案中，F是式Ⅲf的氨基环烷基羧酸残基，其中Rf是一价基团，例如氢原子或低级烷基，优选甲基、乙基或丙基。af是整数，例如0、1或2。羰基位于环烷基环上相对于1位氮原子的2位或3位。产生立体异构的中心可以彼此独立地是R或S。对于5元环(af=1),R1,S2和S1,R2的组合称为顺-pentacin衍生物，而R1,R2和S1,S2组合称为反-pentacin衍生物。G的描述
在一个实施方案中，G是式Ⅱg的氨基或取代的氨基，
其中R1 l是一价基团，例如氢原子、直链或支链、饱和或不饱和的C1-C18-烷氧基、取代或未取代的芳氧基、取代或未取代的芳基-C1-C6-烷氧基或取代或未取代的芳氧基-C1-C6-烷氧基或杂芳基-C1-C6-烷氧基。芳基优选苯基或萘基。杂芳基是5-或6-元、优选含有氮、氧或硫的环系，例如咪唑基、异噁唑基、异噻唑基、噻唑基、噁唑基、吡唑基、噻吩基、呋喃基、吡咯基、1,2,4-或1,2,3-三唑基、吡嗪基、吲哚基、苯并呋喃基、苯并噻吩基、异吲哚基、吲唑基、喹啉基、哒嗪基、嘧啶基、苯并咪唑基、苯并吡喃基、苯并噻唑基、噁二唑基、噻二唑基或吡啶基。适宜的芳基或杂芳基取代基包括一个或多个卤原子，优选氟、溴或氯；C1-C4-烷基；甲氧基、乙氧基或三氟甲基、亚甲二氧基或硝基。
R2 l是一价基团，例如氢原子、直链或支链、饱和或不饱和的C1-C18-烷基、C3-C10-环烷基、取代或未取代的芳基，其中芳基优选苯基或萘基。适宜的芳基取代基包括一个或多个卤素，优选氟、氯或溴原子、C1-C4-烷基、甲氧基、乙氧基或三氟甲基、亚甲二氧基、硝基或氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基，其中的烷基还可以与氮原子合在一起形成5-或6-元杂环，或未取代或取代的杂芳基。杂芳基可以是5-或6-元、优选含有氮、氧或硫的环系，该环系可以与苯环稠合，例如，咪唑基、吡咯基、噻吩基、呋喃基、噻唑基、噁唑基、吡唑基、1,2,4-或1,2,3-三唑基、噁二唑基、噻二唑基、异噁唑基、异噻唑基、吡嗪基、哒嗪基、嘧啶基、吡啶基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噻唑基、苯并吡喃基、吲哚基、异吲哚基、吲唑基或喹啉基，优选的取代基是C1-C6-烷基、羟基或苯基。
R2 l还可以是式Ⅱl的结构，
其中al是整数，优选0、1、2、3、4或5。R3 l是一价基团，例如低级烷基，例如甲基、乙基、丙基或异丙基。R4 l是饱和或部分不饱和的含有3至约10个碳原子的碳环基团，或是取代或未取代的芳基或杂芳基，其中优选的芳基和杂芳基以及适宜的取代基如式Ⅱg中关于R2 l所述。
R2 l还可以是式Ⅲl的一价基团，
-(CH2)2-Wl-R5 l (Ⅲl)，其中W1是氧或硫原子或N-R6 l基团。R5 l是一价基团，例如氢原子、C1-C4-烷基C3-C7-环烷基或取代或未取代的芳基或芳基甲基，芳基及其优选的取代基具有式Ⅱg中关于R2 l所描述的含义。R6 l是一价基团，优选氢原子、C1-C4-烷基或C3-C7-环烷基、C1-C18-链烷酰基、苯甲酰基或取代或未取代的芳基或芳基甲基，芳基及其优选的取代基具有式Ⅱg中关于R2 l所描述的含义。
R2 l还可以是式Ⅳl的取代基，其中bl是整数，优选2、3或4。Zl是一价基团，例如甲酰基、氨基羰基或肼基羰基，或是环状或非环的缩醛(acetal)或硫缩醛(thioacetal)基团。
R2 l还可以是式Ⅴl的取代基，
其中bl是整数，优选2、3或4。R7 l是一价基团，例如式
-O(CH2CH2O)dl-CH3的乙二醇低聚物，其中dl是整数，优选约2至约4或约40至约90。
R2 l还可以是式Ⅵl的糖，其中R8 l是一价基团，例如氢原子、C1-C4-链烷酰基或烷基、苯甲酰基或苄基。
在另一个实施方案中，G是式Ⅲg的β-羟基胺，其中R9 l是一价基团例如氢原子、C1-C6-烷基或取代或未取代的芳基，芳基及其优选的取代基具有式Ⅱg中关于R2 l所描述的含义。R10 l是一价基团，优选氢原子、烷基如甲基或苯基。
本发明的另一亚类的化合物包括式Ⅰ的肽，其中G是式Ⅳg的肼基，其中R11 l和R12 l彼此独立地是一价基团，例如氢原子、直链或支链的C1-C8-烷基、C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基或取代或未取代的芳基、杂芳基、芳基-C1-C4-烷基或杂芳基-C1-C4-烷基，其中的芳基、杂芳基及其优选的取代基可以选自式Ⅱg中关于R2 l所列的选项。R11 l和R12 l还可以合在一起形成亚丙基或亚丁基桥。
另一亚类的本发明化合物包括式Ⅰ的肽，其中G是式-O-R13 l或-S-R13 l的一价基团，其中R13 l是一价基团，例如C3-C10-环烷基、直链或支链的C2-C16-链烯基甲基或C1-C16-烷基，其可以被1至约5个卤原子、优选氟原子所取代。
R13 l还可以是基团(CH2)el-R14 l，其中el是整数，优选1、2或3。R14 l是一价基团，优选饱和或部分不饱和的C3-C10-碳环。
R13 l还可以是基团
-[CH2-CH=C(CH3)-CH2]fl-H，其中fl是整数，优选1、2、3或4。
R13 l还可以是基团
-[CH2-CH2-O]gl-CH3，其中gl是整数，优选约2至约4，或约40至约90。
R13 l还可以是基团
-(CH2)hl-芳基或-(CH2)hl-杂芳基，其中芳基和杂芳基还可以是取代的，所述芳基、杂芳基及其优选的取代基可以选自式Ⅱg中关于R2 l所列的基团。hl是整数，优选0、1、2或3。
R13 l还可以是基团
-(CH2)bl-Wl-R5 l，其中bl、Wl和R5 l彼此独立地选自式Ⅲl中所述的选项。
另一亚类本发明的化合物包括式Ⅰ的肽，其中G是
-O-N(R15 l)(R16 l)，的氨基氧基，其中R15 l和R16 l分别是一价基团，并且可以彼此独立地是氢原子、直链或支链的C1-C8-烷基，所述烷基可以被卤原子、优选氟原子所取代、C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、取代或未取代的芳基或杂芳基或取代或未取代的芳基-C1-C4-烷基。芳基和杂芳基及其优选的取代基可以选自式Ⅱg中关于R2 l所列的选项。此外，R15 l和R16 l可以合在一起形成5-、6-或7-元杂环。
另一亚类本发明的化合物包括式Ⅰ的肽，其中G是式
-O-N=C(R15 l)(R16 l)，的肟基，其中R15 l和R16 l选自以上所列的选项，此外，它们还可以合在一起形成含有约3至约7个环原子的环系。该环系还可以与一个或多个芳族环稠合。特别优选的环系如下所示。
另一亚类本发明的化合物包括式Ⅰ的肽，其中G是氢原子、直链或支链的C1-C8-烷基，所述烷基可以被最多6个卤原子、优选氟原子所取代、C3-C8-环烷基或C3-C8-环烷基-C1-C4-烷基。
G还可以是式Ⅴg的芳基烷基、杂芳基烷基、芳基或杂芳基，
(CH2)ag-R17 l (Ⅴg)其中ag是整数，例如0、1或2。R17 l是取代或未取代的芳基或杂芳基。优选的芳基包括苯基和萘基。适宜的芳基取代基包括卤素，优选氟、溴或氯原子、C1-C4-烷基、甲氧基、乙氧基或三氟甲基、亚甲二氧基、硝基或氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C6-二烷基氨基，其中的烷基还可以与氮原子合在一起形成5-或6-元杂环。R17 l还可以是5-或6-元、优选含有氮、氧或硫的环系，所述环系可以与苯环稠合。适宜的杂芳基包括咪唑基、吡咯基、噻吩基、呋喃基、噻唑基、噁唑基、吡唑基、1,2,4-或1,2,3-三唑基、噁二唑基、噻二唑基、异噁唑基、异噻唑基、吡嗪基、哒嗪基、嘧啶基、吡啶基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噻唑基、苯并吡喃基、吲哚基、异吲哚基、吲唑基和喹啉基。优选的杂芳基取代基是C1-C6-烷基、羟基或苯基。
另一亚类本发明的化合物包括式Ⅰ的化合物，其中G是式Ⅵg的一价基团，
-(CH2)bg-(C=O)cg-OR18 l(Ⅵg)，其中bg是整数，优选0、1、2或3,cg是整数，优选0或1。 bg和cg不同时为0。R18 l是一价基团，例如氢原子、直链或支链的C1-C8-烷基，所述烷基可以被卤原子、优选氟原子所取代，特别是CF2部分，C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、取代或未取代的芳基、优选苯基或萘基。适宜的芳基取代基是卤素，优选氟、溴或氯原子、C1-C4-烷氧基、三氟甲基、硝基或氰基、亚甲二氧基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C6-二烷基氨基，其中的烷基还可以与氮原子合在一起形成5-或6-元杂环。
G还可以是式Ⅶg的一价基团，其中dg是整数，优选0、1、2或3,eg是整数，例如0或1。dg和eg不能同时为0。R19 l和R20 l彼此独立地是一价基团，例如氢原子、直链或支链的C1-C8-烷基，所述烷基可以进一步被卤原子、优选氟原子所取代，特别是CF2部分，C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、取代或未取代的芳基、优选苯基或萘基。适宜的芳基取代基包括一个或多个卤素，优选氟、溴或氯原子、C1-C4-烷氧基、三氟甲基、硝基或氰基、亚甲二氧基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C6-二烷基氨基，其中的烷基还可以与氮原子合在一起形成5-或6-元杂环。N(R19 l)R20 l还可以形成式N(CH2)fg的环系，其中fg是选自4、5或6的整数。
另一亚类本发明的化合物包括式Ⅰ的肽，其中G是式Ⅷg的一价基团，
(CH2)gg-S(O)hg-R21 l(Ⅷg)，其中gg是整数，例如1或2,hg是1或2。R21 l是一价基团，优选甲基、三氟甲基、乙基或苯基。
G还可以是式Ⅸg的烷基-或芳基羰基烷基
-(CH2)ig-(C=O)-R22 l (Ⅸg)其中R22 l是一价基团，例如氢原子、直链或支链的C1-C8-烷基，所述烷基可以被最多6个卤原子、优选氟原子所取代、特别是CF2部分、C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、取代或未取代的芳基、优选苯基或萘基。适宜的芳基取代基是卤素，优选氟、溴或氯原子、C1-C4-烷氧基、三氟甲基、硝基或氰基、亚甲二氧基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C6-二烷基氨基，其中的烷基还可以与氮原子合在一起形成5-或6-元杂环。合成方法
本发明的化合物可以通过已知的肽合成方法进行制备。因此，肽可以从单个的氨基酸顺序组装或通过连接适宜的小肽片段进行组装。在顺序组装中，肽链从C末端开始，每步一个氨基酸地逐步延长。在片段偶联中，可将不同长度片段连接在一起，所述片段则可以通过顺序组装从氨基酸制得或从更短的肽通过片段偶联制得。
在顺序组装以及片段偶联中，需要通过形成酰胺键将各单元连接，这可以通过各种酶方法和化学方法来完成。形成酰胺键的化学方法在肽化学的常规文献中有详细描述，包括Müller，《有机化学方法》(Methoden der organischen Chemi)第ⅩⅤ/2卷，1-364页，ThiemeVerlag,Stuttgart,Germany(1974)；Stewart和Young，《固相肽合成》(Solid Phase Peptide Synthesis),31-34和71-82页，PierceChemical Company,Rockford,IL(1984)；Bodanszky等，《肽合成》(Peptide Synthesis),85-128页，John Wiley & Sons,New York,(1976)。优选的方法包括叠氮化物法、对称和混合酸酐法、使用就地生成或预先形成的活泼酯、使用尿烷保护的氨基酸的N-羧基酸酐以及用偶联试剂如羧酸活化剂、特别是二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-乙氧基羰基-2-乙氧基-1,2-二氢喹啉(EEDQ)、新戊酰氯、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)、正丙烷膦酸酐(PPA)、N,N-二(2-氧代-噁唑烷基)亚氨基-磷酰氯(BOP-Cl)、溴-三-吡咯烷磷鎓六氟磷酸盐(PyBrop)、二苯基-磷酰叠氮(DPPA)、Castro试剂(BOP,PyBop)、O-苯并三唑基-N,N,N’,N’-四甲基脲盐(HBTU)、二乙基磷酰基氰化物(DEPCN)、2,5-二苯基-2,3-二氢-3-氧代-4-羟基-噻吩二氧化物(Steglich试剂；HOTDO)和1,1’-羰基-二咪唑(CDI)形成酰胺键。偶联试剂可以单独使用或与添加剂如N,N-二甲基-4-氨基吡啶(DMAP)、N-羟基苯并三唑(HOBt)、N-羟基苯并三嗪(HOOBt)、N-羟基琥珀酰亚胺(HOSu)或2-羟基吡啶结合使用。
虽然在酶催化的肽合成中通常不需要使用保护基，但在化学合成中则需要对两种试剂中不参与形成酰胺键的活泼基团进行可逆性地保护。在化学肽合成中优选三种常规的保护基技术：苄氧羰基(Z)、叔丁氧基羰基(Boc)和9-芴基甲氧基羰基(Fmoc)技术。上述情形是链延伸单元的α-氨基上的保护基。关于氨基酸保护基的详细论述可以参见Müller，《有机化学方法》(Methoden der organischen Chemie)第ⅩⅤ/1卷，20-906页，Thieme Verlag,Stuttgart(1974)。用于组装肽链的单元可以在溶液中、在悬浮液中或通过与Merrifield所述类似的方法进行反应(《美国化学会志》(J.Am.Chem.Soc.)85:2149(1963))。特别优选的方法是使用Z、Boc或Fmoc保护基技术进行顺序组装或片段偶联，在所述的Merrifield技术中，反应物之一被连接在不溶性的聚合物载体(以下也称为树脂)上。它一般适于用Boc或Fmoc保护基技术在聚合物载体上顺序组装肽，其中，延伸的肽链以C末端共价连接在不溶性的树脂颗粒上。该方法能够通过过滤除去反应物和副产物，而无需对中间体进行重结晶。
保护的氨基酸可以连接至任何适宜的聚合物上，所述聚合物必需在所用的溶剂中是不溶性的并且具有稳定的物理形式以便能够过滤。聚合物必需含有能够共价连接第一个保护的氨基酸的功能基。有多种聚合物均适用于该目的，包括纤维素、聚乙烯醇、聚甲基丙烯酸酯、磺化的聚苯乙烯、氯甲基化的苯乙烯/二乙烯基苯共聚物(Merrifield树脂)、4-甲基二苯甲基胺树脂树脂(MBHA-树脂)、苯基乙酰氨基甲基树脂(Pam-树脂)、对苄氧苄基-醇-树脂、二苯甲基-胺-树脂(BHA-树脂)、4-(羟甲基)-苯甲酰基-氧甲基-树脂、Breipohl等的树脂(《四面体通讯》(Tetrahedron Letters)28(1987)565；由BACHEM提供)、4-(2,4-二甲氧基苯基氨基甲基)苯氧基树脂(由Novabiochem提供)或邻-氯三苯甲基树脂(由Biohellas提供)。
用于肽合成的适宜溶剂包括在反应条件下呈惰性的任何溶剂，特别是水、N,N-二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、乙腈、二氯甲烷(DCM)、1,4-二氧六环、四氢呋喃(THF)、N-甲基-2-吡咯烷酮(NMP)以及这些溶剂的混合物。
在聚合物载体上的肽合成可以在氨基酸衍生物原料可溶解在其中的适宜的惰性有机溶剂中进行。此外，优选的溶剂还应具有树脂溶胀特性，包括DMF、DCM、NMP、乙腈、DMSO以及这些溶剂的混合物。合成后，将肽从聚合物载体上除去。文献中公开了对于各种类型的树脂完成该裂解的条件。最常用的裂解反应是酸或钯催化的反应，酸催化的裂解反应在例如液体的无水氟化氢中、无水三氟甲磺酸中、稀或浓的三氟乙酸中和乙酸/二氯甲烷/三氟乙醇混合物中进行。钯催化的裂解反应可以在THF或THF-DCM混合物中、在弱碱如吗啉的存在下完成。某些保护基也可以在该条件下裂解。
在进行某些衍生化反应之前，可能需要对肽进行部分脱保护。例如，在N-末端二烷基化的肽可以通过将适宜的N,N-二烷基氨基酸与溶液中或聚合物载体上的肽偶联进行制备，或者通过将与树脂结合的肽在DMF/1％乙酸中用NaCNBH3和适宜的醛进行还原烷基化来制备。
以下两个反应方案是对合成本发明化合物的更详细的描述。
反应方案Ⅰ
将四肽A-B-D-E-OH与氨基衍生物F-G用以上描述的肽偶联方法偶联得到最终的化合物A-B-D-E-F-G。
反应方案Ⅱ
将N-末端保护的四肽A’-B-D-E-OH与氨基衍生物F-G用以上描述的肽偶联方法偶联得到中间体化合物A’-B-D-E-F-G。然后，通过以上描述的常规方法除去N-保护基。然后将基团R7 A和RA通过以上描述的还原烷基化方法连接到氨基末端。
在合成所要求保护的化合物中所用的结构单元(反应方案Ⅰ和Ⅱ中所描述的F-G)可以按如下一般方法制备：a)氨基-苯基-酮的合成
如下合成方案描述了不能购买到的氨基苯基-酮的合成路线。反应方案Ⅲ.1
在反应方案Ⅲ.1中，合成从硝基苯甲醛开始。加入金属有机化合物如锂试剂或格氏试剂生成相应的醇(Fürstner等，《四面体》(Tetrahedron)52:7329-7344(1996)；Fürstner等，《四面体》(Tetrahedron)51,773-786(1995))。可以用已知的氧化剂如铬(Ⅵ)化合物(例如吡啶重铬酸盐/二氯甲烷，参见Fürstner等，文献出处同上)或Dess Martin试剂将这些醇氧化成酮。然后将硝基苯基酮通过在钯催化剂如钯碳的存在下氢化或用金属盐在酸的存在下(例如氯化锡(Ⅱ)和盐酸组合，Nunn等，《化学会志》(J.Chem.Soc.)1952:583-588)还原成相应的氨基-苯基-酮。反应方案Ⅲ.2
更直接的路线(参见反应方案Ⅲ.2)是将硝基苯甲酰氯与金属有机试剂如锂试剂或格氏试剂反应(Fürstner等，《四面体》(Tetrahedron)51,773-786(1995))。反应方案Ⅲ.32-氨基-苯基酮可以通过将相应的2-氟苯基-酮与叠氮化钠在极性溶剂如N,N-二甲基甲酰胺中反应然后将中间体苯并异噁唑还原制得(参见反应方案Ⅲ.3)。例如，N.Haider等描述了2-氨基苯基-(4-哒嗪基)-酮的合成，(《药物文献》(Arch.Pharm.)325:119-122(1992))。b)氨基-苯甲酰胺的合成
如下反应方案描述了不能购买到的氨基苯甲酰胺的合成路线。反应方案Ⅳ.1
在反应方案Ⅳ.1中，描述了从硝基苯甲酸或取代的硝基苯甲酸开始的步骤。用偶联试剂将这些酸与伯胺或仲胺(HNR1R2)偶联。优选的方法是使用偶联剂如羧酸活化剂，特别是二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-乙氧基羰基-2-乙氧基-1,2-二氢喹啉(EEDQ)、新戊酰氯、1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)、正丙烷膦酸酐(PPA)、N,N-二(2-氧代-噁唑烷基)亚氨基-磷酰氯(BOP-Cl)、溴-三-吡咯烷磷鎓六氟磷酸盐(PyBrop)、二苯基-磷酰叠氮(DPPA)、Castro试剂(BOP,PyBop)、O-苯并三唑基-N,N,N’,N’-四甲基脲盐(HBTU)、二乙基磷酰基氰化物(DEPCN)、2,5-二苯基-2,3-二氢-3-氧代-4-羟基-噻吩二氧化物(Steglich试剂；HOTDO)和1,1’-羰基-二咪唑(CDI)。偶联试剂可以单独使用或与添加剂如N,N-二甲基-4-氨基吡啶(DMAP)、N-羟基苯并三唑(HOBt)、N-羟基苯并三嗪(HOOBt)、氮杂苯并三唑、N-羟基琥珀酰亚胺(HOSu)或2-羟基吡啶一起结合使用。
可用相应的硝基苯甲酰氯代替酸。所述的酰氯可以购买到，或者可以从相应的酸和亚硫酰氯合成。胺与硝基苯甲酰氯在碱如吡啶的存在下反应，吡啶还可用作溶剂(N.S.Cho等，《杂环化学杂志》(J.Heterocycl.Chem.)33,1201-1206(1996))。然后将硝基苯甲酰胺用金属盐在盐酸的存在下还原或用承载在固体上的钯如钯/碳作为催化剂进行金属催化的氢化反应还原成相应的氨基苯甲酰胺。该路线描述于实施例1中。
另一种方法涉及将胺用三氟乙酸酐处理转变成三氟乙酰胺。将酰胺用碱如氢化钠或叔丁醇钾脱质子然后用相应的烷基卤化物如碘甲烷、碘乙烷或异丙基碘处理。三氟乙酰胺很容易在碱性醇溶液如碳酸钾/甲醇中裂解。反应方案Ⅳ.2
在反应方案Ⅳ.2中，合成氨基-苯甲酰胺的原料是N-保护的氨基苯甲酸。不同的氮保护基是相适应的，例如以上描述的Z-、Boc-或Fmoc-保护基。将N-保护的氨基-苯甲酸与以上关于硝基苯甲酸所描述的胺用上述的偶联条件进行偶联。在实施例2中对该路线进行了举例说明。反应方案Ⅳ.3
在反应方案Ⅳ.3中描述了制备2-氨基苯甲酰胺的路线。用胺使衣托酸酐(isatoic anhydride)(在氮上取代或未取代的)开环并释放出二氧化碳生成相应的2-氨基-苯甲酰胺，参见Clark等，《有机化学杂志》(J.Org.Chem.)9:55-64(1944)。c)氨基-环戊烷-或氨基环己烷-羧酰胺的合成
文献中描述了多种不同的合成外消旋形式或纯净对映体形式的顺-2-氨基-环戊基羧酸(cispentacin)的路线。采用分子内的硝酮-烯烃环加成，可以以多个合成步骤制得顺-2-(叔丁氧羰基氨基)环戊烷-1-羧酸(Konosu等，《化学药物通报》(Chem.Pharm.Bull.)41 1012(1993))。另一条合成对映体纯的顺-(1R,2S)-2-氨基-环戊基甲酸的路线是将手性的(S)-(-甲基苄基)苄基氨基锂与1-环戊烯-1-甲酸叔丁酯加成然后通过氢化除去苄基并用酸处理除去叔丁基(Davies等，《合成通讯》(Synlett)1993,461页)。相应的反式-差向异构体可以通过用碱例如叔丁醇钾异构化制得。通过在Michael加成中使用(R)-(-甲基苄基)苄基氨基锂可以制得(1S,2R)-2-氨基-环戊基甲酸和(1S,2S)-2-氨基-环戊基甲酸。该方法也可用于合成顺式-和反式-氨基环己烷-1-甲酸。
外消旋Boc-保护的顺-2-氨基环戊烷甲酸(Bernath等，《化学学报》(Acta Chim).74:479(1972)；Nativ等，Isr.J.Chem.10:55(1972))的拆分可以用(+)-和(-)-麻黄碱来高对映体过量的完成(Nteberg等，《四面体》(Tetrahedron)53:7975(1997))。在该文章中还描述了Boc-保护的反-2-氨基环戊烷甲酸甲酯的反式对映体的合成，该合成用反-(3R,4R)-二(甲氧基羰基)环戊酮或反-(3S,4S)-二(甲氧基羰基)-环戊酮作为原料。
Boc-保护的2-氨基环戊基甲酸的酰胺可以通过将酸与相应的胺用以上关于硝基苯甲酸与胺的偶联所描述的常规方法或按照D.Nteberg等在《四面体》(Tetrahedron)53:7975(1997)中的描述偶联制得。胺功能基的脱保护可以用Lewis酸，例如无机酸如盐酸在醚或二氧六环中或有机酸如三氟乙酸在二氯甲烷中来完成。所要求保护的化合物的使用方法
在另一个实施方案中，本发明包括在哺乳动物例如人中部分或完全抑制实体瘤(例如肺癌、乳腺癌、结肠癌、前列腺癌、膀胱癌、直肠癌或子宫内膜癌)或恶性血液疾病(例如白血病、淋巴瘤)的形成或对其进行治疗(例如，逆转或抑制进一步的发展)的方法，该方法包括，向哺乳动物施用治疗有效量的式Ⅰ化合物或式Ⅰ化合物的组合。该药物可单独使用或以含有药物以及可药用载体或稀释剂的药物组合物的形式使用。给药可以通过药物、优选肿瘤药物常用的任何方法来进行，包括口服和胃肠外的方法，例如皮下、静脉内、肌肉内和腹膜内、经鼻或直肠给药。可将化合物单独给药或以含有式Ⅰ化合物以及适于所需给药途径的可药用载体的药物组合物的形式给药。所述药物组合物可以是复方产品，即，它们还可以含有其它治疗活性成分。
用于向哺乳动物例如人给药的剂量应含有治疗有效量的本文所述的化合物。本文所用的“治疗有效量”是足以抑制(部分或完全)肿瘤或恶性血液疾病形成或逆转实体瘤或其它恶性肿瘤的发展或预防或减弱其进一步发展的量。对于具体的病症或治疗方法，剂量可以根据经验用已知的方法来确定，并取决于所用具体化合物的生物学活性；给药方式；使用者的年龄、健康状况和体重；症状的性质和程度；治疗的频率；其它治疗方法的给药情况；以及所需的效果等因素。典型的每日剂量为约5至约250mg/kg体重口服给药和约1至约100mg/kg体重胃肠外给药。
本发明的化合物可以以常规的固体或液体药物形式给药，例如未包衣或(薄膜)包衣的片剂、胶囊、散剂、颗粒剂、栓剂或溶液剂。这些药物形式以常规的方式生产。为此，可将活性成分用常规的药物助剂如片剂粘合剂、填充剂、防腐剂、片剂崩解剂、流动调节剂、增塑剂、湿润剂、分散剂、乳化剂、溶剂、缓释组合物、抗氧剂和/或抛射剂气体进行加工(参见H.Sücker等：Pharmazeutische Technologie,Thieme-Verlag,Stuttgart,1978)。由此得到的给药形式通常含有约1至约90％(重量)活性成分。
以下实施例旨在说明本发明，不应将其看作是对本发明的限定。
实施例
生成蛋白质的氨基酸在实施例中用已知的三字母代码缩写。使用的其它缩写是：TFA=三氟乙酸，Ac=酸，DCM=二氯甲烷，DMSO=二甲亚砜，Bu=丁基，Et=乙基，Me=甲基，Bn=苄基。若无另外说明，在所列举的化合物中，所有生成蛋白质的氨基酸均是L-氨基酸。一般原料和方法
本发明的化合物通过经典的溶液合成法用以上讨论的标准的Z-和Boc-方法合成，或者通过标准的固相合成法在APPLIED BIOSYSTEMS提供的431A型合成仪上合成。该仪器对Boc和Fmoc保护基技术使用不同的合成循环，以下将对其进行描述。用于Boc保护基技术的合成循环1．30％三氟乙酸/DCM 1×3分钟2．50％三氟乙酸/DCM 1×1分钟3．DCM洗涤 5×1分钟4．5％二异丙基乙基胺/DCM 1×1分钟5．5％二异丙基乙基胺/NMP 1×1分钟6．NMP洗涤 5×1分钟7．加入预先活化的保护的氨基酸(用1当量DCC和1
当量HOBt在NMP/DCM中活化)；
肽偶联(第1部分) 1×30分钟8．向反应混合物中加入DMSO直至其中含有20％
DMSO(体积)9．肽偶联(第2部分) 1×16分钟10．向反应混合物中加入3.8当量二异丙基乙基胺11．肽偶联(第3部分) 1×7分钟12．DCM洗涤 3×1分钟13．如果转化不完全，重复偶联(返回至第5步)14．10％乙酸酐，5％二异丙基乙基胺/DCM 1×2分钟15．10％酸酐/DCM 1×4分钟16．DCM洗涤 4×1分钟17．返回至第1步。
使用BOP-Cl和PyBrop作为将氨基酸偶联到N-甲基氨基酸上的试剂。反应时间相应地增加。在溶液合成中，分别使用Boc-保护的氨基酸NCAs(N-叔丁氧羰基-氨基酸-N-羧基-酸酐)或Z-保护的氨基酸NCAs(N-苄氧羰基-氨基酸-N-羧基-酸酐)对于该类型的偶联最为优选。Fmoc保护基技术的合成循环1．DMF洗涤 1×1分钟2．20％哌啶/DMF 1×4分钟3．20％哌啶/DMF 1×16分钟4．DMF洗涤 5×1分钟5．加入预先活化的保护的氨基酸(用1当量TBTU
和1.5当量DIPEA在DMF中活化)；
肽偶联 1×61分钟6．DMF洗涤 3×1分钟7．如果转化不完全，重复偶联(返回至5.)8．10％乙酸酐/DMF 1×8分钟9．DMF洗涤 3×1分钟10．返回至2．
使用BOP-Cl和PyBrop作为将氨基酸偶联到N-甲基氨基酸上的试剂。反应时间相应的增加。N末端的还原烷基化
将按照以上描述制备的肽-树脂在N末端脱保护，然后与3倍摩尔过量的醛或酮在DMF/1％乙酸中反应，向其中加入3当量NaCNBH3。反应结束后(Kaiser试验为阴性)，将树脂用水、异丙醇、DMF和二氯甲烷洗涤数次。肽-树脂的处理
将通过Boc保护基技术制得的肽-树脂减压干燥，然后转移至TEFLON HF仪器(由PENINSULA提供)的反应容器内。然后加入清除剂，通常为茴香醚(1mL/g树脂)，在含色氨酸肽的情况下，还需加入硫醇(0.5mL/g树脂)，优选乙二硫醇，以除去吲哚的甲酰基。然后在液氮浴中在氟化氢(10mL/g树脂)中缩合。将混合物升温至0℃并在该温度下搅拌45分钟。然后减压汽提出氟化氢，将残余物用乙酸乙酯洗涤以除去任何残余的清除剂。将肽用30％乙酸萃取然后过滤，将滤液冷冻干燥。
将由Fmoc保护基方法形成的肽-树脂减压干燥，然后进行如下裂解方法之一，其取决于氨基酸的组成(Wade,Tregear,Howard FloreyFmoc Workshop Manual,Melbourne 1985)。将肽-树脂在适宜的TFA混合物中的悬浮液室温搅拌一定的时间，然后滤出树脂并用TFA和DCM洗涤。将滤液和洗涤液浓缩，加入乙醚使肽析出沉淀。在冰浴中冷却后，滤出沉淀，用30％乙酸处理然后冷冻干燥。
当使用邻氯三苯甲基-树脂(由Biohellas提供)时，将肽-树脂在乙酸/三氟乙醇/二氯甲烷混合物(1∶1∶3)中的悬浮液室温搅拌1小时。然后将悬浮液抽滤并将肽-树脂用裂解溶液充分洗涤。将合并的滤液真空浓缩并用水处理。通过过滤或离心分离出析出的固体，用乙醚洗涤然后减压干燥。肽的纯化和鉴定
纯化通过凝胶色谱(SEPHADEX G-10,G-15/10％HOAc,SEPHADEXLH20/MeOH)来进行，随后进行或不进行中压色谱(固定相：HD-SILC-18,20-45m,100埃；流动相：用A=0.1％TFA/MeOH,B=0.1％TFA/H2O梯度洗脱)。所得到的产品的纯度通过分析HPLC(固定相：1002.1mmVYDAC C-18,51,300埃；流动相：CH3CN/H2O梯度洗脱，用0.1％TFA,40％C缓冲)确定。
将多肽通过氨基酸分析和快原子轰击质谱进行鉴定。实施例1(2)-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)2(化合物Ⅰ-78)的合成
Me2Val-Val-MeVal-Pro-OH和Z-Val-Val-MeVal-Pro-OH通过专利申请DE 4415998和DE 19527575中公开的方法制备，其内容引入本文作为参考。a)N,N-二甲基-2-硝基苯甲酰胺的合成
0℃下，向2.0g 2-硝基苯甲酸和0.98g氯化二甲基铵的二氯甲烷溶液中加入2.29g 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐、1.62g N-羟基-苯并三唑和6.05g N-甲基-吗啉。将形成的混合物室温搅拌过夜。然后将反应混合物依次用饱和的碳酸氢钠、5％柠檬酸水溶液和盐水洗涤。将有机相用硫酸钠干燥。过滤并真空蒸除溶剂后得到N,N-二甲基-2-硝基苯甲酰胺(2.13g)。1H-NMR(DMSO,270 MHz)d=2.7(s,3H),3.0(s,3H),7.5(d,1H),7.7(dd,1H),7.85(dd,1H),8.15(d,1H)ppmb)N,N-二甲基-2-氨基苯甲酰胺的合成
将钯/碳(0.54g,10％重量Pd)加入到2.1g N,N-二甲基-2-硝基苯甲酰胺的150 mL甲醇溶液中。将形成的悬浮液在室温下常压氢化3小时。滤除催化剂后，真空蒸除溶剂得到N,N-二甲基-2-氨基苯甲酰胺(1.8g)。1H-NMR(DMSO,270 MHz)d=2.9(s,6H),5.1(s,2H),6.5(dd,1H),6.65(d,1H),7.95(d,1H),7.0(dd,1H)ppmc)(2)-(Z-Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)2的合成
于0℃下向2.0g Z-Val-Val-MeVal-Pro-OH和0.53g N,N-二甲基-2-氨基-苯甲酰胺的二氯甲烷溶液中加入1.66g溴-三吡咯烷磷鎓六氟磷酸盐(PyBrop)和0.77g N-乙基二异丙基胺。将混合物室温搅拌过夜，然后依次用饱和的碳酸氢钠、5％柠檬酸水溶液和盐水洗涤。将有机相用硫酸钠干燥。过滤后，真空蒸除溶剂。将残余物通过硅胶色谱纯化(1∶3二氯甲烷∶乙酸乙酯)得到(2)-(Z-Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)2(1.8g)。FAB-MS707.0(M+H+d)d)2-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)2的合成
将钯/碳(58mg,10％重量Pd)加入到1.8g 2-(Z-Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)2的150mL甲醇溶液中。将形成的悬浮液在室温下常压氢化3小时，然后加入1.5mL甲醛水溶液(37重量％甲醛)和341mg钯碳。将混合物在室温下常压氢化过夜。用硅藻土过滤后，真空蒸除溶剂得到1.30g 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)2。FAB-MS:601.0(M+H+)1H-NMR(DMSO,270 MHz)d=0.7(s,6H),0.8-1.0(m,12H),1.75(m,1H),1.8-2.2(m,6H),2.2(s,6H),2.6(d,1H),2.8(s,3H),2.9(s,3H),3.05(s,3H),3.55,3.7(m,2H),4.4(m,1H),4.5(m,1H),5.0(d,1H),7.2(dd,1H),7.25(d,1H),7.4,dd,1H),7.6(dd,1H),8.0(d,1H),9.6(s,1H)实施例2(2)-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)(OCH3)(化合物Ⅰ-60)的合成a)N,O-二甲基-(2-N-叔丁氧羰基-氨基)苯甲酰羟胺(benzohydroxylamide)的合成
0℃下，向1.5g 2-N-叔丁氧羰基邻氨基苯甲酸和0.68g N,O-二甲基羟基胺盐酸盐的二氯甲烷溶液中加入1.33g 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐、0.94g N-羟基苯并三唑和3.20g N-甲基吗啉。将混合物室温搅拌过夜。将反应混合物依次用饱和碳酸氢钠水溶液、5％柠檬酸水溶液和盐水洗涤。将有机相用硫酸钠干燥。过滤然后真空蒸除溶剂。快速色谱(硅胶，庚烷∶乙酸乙酯10∶1)得到N,O-二甲基-(2-N-叔丁氧羰基-氨基)苯甲酰羟胺(1.18g)。1H-NMR(CDCl3,270MHz)d=1.5(s,9H),3.4(s,3H),3.6(s,3H),7.0(dd,1H),7.2-7.4(m,2H),8.1(d,1H),8.4(s,1H)b)N,O-二甲基-(2-氨基)苯甲酰羟胺盐酸盐的合成
0℃下，向0.5g N,O-二甲基-(2-N-叔丁氧羰基-氨基)苯甲酰羟胺的15mL二氯甲烷溶液中加入17mL氯化氢的乙醚溶液，然后将形成的溶液搅拌2小时。蒸除溶剂得到0.41g N,O-二甲基-(2-氨基)苯甲酰羟胺盐酸盐。1H-NMR(CDCl3,270MHz)d=3.4(s,3H),3.6(s,3H),7.3(dd,1H),7.5(dd,2H),7.6(d,1H),7.9(d,1H)c)(2)-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)(OCH3)的合成
0℃下，向0.892g Me2Val-Val-MeVal-Pro-OH和0.234g三乙胺的10mL二氯甲烷溶液中加入0.218g甲酸酯。将形成的混合物搅拌2小时，然后加入0.41g N,O-二甲基-(2-氨基)苯甲酰羟胺盐酸盐和0.234g三乙胺并将混合物室温搅拌过夜。将反应混合物依次用饱和碳酸氢钠溶液和盐水洗涤。将有机相用硫酸钠干燥。过滤后真空蒸除溶剂。将残余物通过色谱(用1％三乙胺处理的硅胶，溶剂：二氯甲烷/3％异丙醇)纯化得到0.28g(2)-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CON(CH3)(OCH3)。FAB-MS:617.5(M+H+)1H-NMR(DMSO,270MHz)d=0.7(S,6H),0.8-1.0(m,12H),1.7(m,1H),1.8-2.2(m,6H),2.2(s,6H),2.6(d,1H),3.0(s,3H),3.2(s,3H),3.5(s,3H),3.5,3.7(m,2H),4.4(m,1H),4.5(m,1H),5.0(d,1H),7.2(dd,1H),7.3-7.5(m,2H),7.6(dd,1H),8.0(d,1H),9.65(s,1H)实施例3 Me2-Val-Val-MeVal-Pro-[顺-2-氨基环戊烷甲酸]-NHBn(化合物Ⅶ-2)的合成a)外消旋环戊烷-顺-1,2-二甲酸酐的合成
将8.4g(44.3mmol)市售的环戊烷-反-1,2-二甲酸在75ml乙酸酐中回流20小时，然后蒸发并将得到的残余物在库格尔若蒸馏器(“Kugelrohr-apparatus”)中于1.0毫巴下蒸馏。收集沸点为165℃的馏份得到5.8g油状产物。13C-NMR(400MHz；DMSO-d6)d(ppm):25.3(C-4),30.6(C-3,5),45.7(C-1,2),175.6(C-6,7).b)外消旋顺-2-氨基甲酰基环戊烷甲酸的合成
将1.1g(7.85mmol)环戊烷-顺-1,2-二甲酸酐加入到8ml氨水溶液中并搅拌至离析物溶解。然后蒸除过量的氨，将剩余的溶液冷却至0℃并用浓盐酸酸化。滤出形成的沉淀，用冷水洗涤然后干燥，得到0.7g顺-2-氨基甲酰基环戊烷甲酸，熔点132-133℃(lit.:126-128℃)。c)外消旋顺-2-氨基环戊烷甲酸的合成
于0℃搅拌下，将0.41g(2.6mmol)Br2加入到0.48g(12mmol)NaOH的水溶液(1.8mL)中。将混合物再次冷却，然后加入0.34g(2.16mmol)顺-2-氨基甲酰基环戊烷甲酸。搅拌约10分钟后，再次加入溶于1.35ml水的0.35g(8.65mmol)NaOH，然后将整个混合物升温至75℃约5分钟。将混合物再次冷却，加入浓盐酸进行中和，用乙酸酸化然后蒸发至干。将得到的残余物用蒸馏过的乙醇萃取5次，然后将合并的乙醇馏份蒸发得到1.1g白色固体。
将该残余物通过在Dowex 50离子交换树脂柱上过滤进行纯化。因此，将柱子用固体的水溶液洗涤，然后将通过处理固体洗脱的产物溶于水并将吸附的柱子用稀氨水洗涤。将水蒸发后，将剩余的粗产物用丙酮重结晶得到0.14g纯净的顺-2-氨基环戊烷甲酸，熔点200-202℃。d)外消旋顺-2-叔丁氧羰基氨基环戊烷甲酰苄胺的合成
向1.5g(11.6mmol)顺-2-氨基环戊烷甲酸在乙腈/水3∶1混合物中的溶液中加入3.3g(15.1mmol)二碳酸二叔丁酯、0.5g(12.2mmol)NaOH的12ml水溶液和0.1g(0.82mmol)DMAP。将混合物室温搅拌约3天，然后用水稀释，用乙酸乙酯萃取。将合并的有机相用饱和氯化钠水溶液洗涤，用硫酸镁干燥然后蒸发至于得到1.3g油状Boc-保护的化合物。将粗产物和0.65g(6.1mmol)苄胺在THF/DMF 10∶1混合物中的溶液冷却至-10℃，然后依次加入0.9g(5.86mmol)HOBT、1.12g(5.86mmol)EDC×HCl和3ml NMM。将混合物于-10℃搅拌2小时，于0℃搅拌3小时，然后升温至室温。蒸发至干后，将剩余的残余物溶于乙酸乙酯，用5％柠檬酸水溶液、碳酸氢钠和氯化钠洗涤，然后用硫酸镁干燥。蒸发得到1.3g油状的顺-2-叔丁氧羰基氨基环戊烷甲酰苄胺。HPLC(梯度2):Rt10.5分钟(柱：Machery & Nagel Nucleosil C18 PPN,100×2.1,5m/100A，乙腈/H2O+0.1％TFA；流速：0.2ml/分钟；温度：40℃)。
1H-NMR(270MHz；DMSO-d6)d(ppm):1.35(s,9H),1.35-1.95
(m,6H),2.82(m,1H),4.03(m,1H),4.25(m,2H),6.35(d,
NH),7.1-7.35(m,5H),8.3(m,1H).e)外消旋顺-2-氨基环戊烷甲酰苄胺盐酸盐的合成
向0.7g(2.2mmol)顺-2-叔丁氧羰基氨基环戊烷甲酰苄胺的30ml二氯甲烷溶液中加入25ml饱和氯化氢的乙醚溶液；然后将混合物室温搅拌2小时。蒸发至干然后与甲苯共同蒸发得到0.6g脱保护的胺的盐酸盐。f)Me2Val-Val-MeVal-Pro-[顺-2-氨基环戊烷甲酸]-NHBn(化合物Ⅶ-2)的合成
于-10℃下，向0.86g(1.9mmol)四肽Me2Val-Val-MeVal-Pro-OH和0.56g(2.2mmol)氨基环戊烷甲酰苄胺盐酸盐的30ml THF/DMF 5∶1溶液中依次加入0.29g(1.9mmol)HOBT；0.37g(1.9mmol)EDC×HCl和1.2ml NMM。将混合物于-10℃继续搅拌1小时，然后于0℃搅拌1-2小时，然后升温至室温。蒸发后，将残余物用乙酸乙酯稀释，用氯化钠水溶液洗涤，用硫酸镁干燥然后再次蒸发。将剩余的粗产物(1.2g)通过快速硅胶色谱(二氯甲烷/甲醇)纯化得到0.37gMe2Val-Val-MeVal-Pro-[顺-2-氨基环戊烷甲酸]-NHBn。FAB-MS:655(M+H+)。
以下化合物可以按照反应方案Ⅰ-Ⅲ的描述并根据以上实施例进行制备。
表1A是Me2Val,B是Val,D是MeVal,E是Pro,F是式ⅡF，以及基团-C(=O)-G在相对于氮原子的2位，G是式Ⅱg或Ⅲg或Ⅳg No. RF R1 F R2 F -C(=O)-GⅠ-1 H H H -NH-CH3Ⅰ-2 H H H -NH-CH2-C6H5Ⅰ-3 H H H -NH-异C3H7Ⅰ-4 H H H -NH-C6H5Ⅰ-5 H H H 1,3-噻唑-2-基-酰胺Ⅰ-6 H 4-OCH3 5-OCH3 -NH-CH3Ⅰ-7 H 3- 环C5H9 H -NH-CH3Ⅰ-8 H H H -NH-C2H5Ⅰ-9 H H H -NH-nC3H7Ⅰ-10 H H H -NH-nC4H9Ⅰ-11 H H H -NH-叔C4H9Ⅰ-12 H H H -NH-环C3H5Ⅰ-13 H H H -NH-环C4H7Ⅰ-14 H H H -NH-环C5H9Ⅰ-15 H H H -NH-环C6H11Ⅰ-16 H H H -NH-环C7H12Ⅰ-17 H H H -NH-CH2-O-CH3Ⅰ-18 H H H -NH-CH2-CH2-O-CH3Ⅰ-19 H H H -NH-1-金刚烷基Ⅰ-20 H H H -NH-(4-HO-C6H5)Ⅰ-21 H H H -NH-(2-CF3-C6H4)Ⅰ-22 H H H -NH-(3-CF3-C6H4)Ⅰ-23 H H H -NH-(4-CF3-C6H4)Ⅰ-24 H H H -NH-(2-OCH3-C6H4)Ⅰ-25 H H H -NH-(3-OCH3-C6H4)Ⅰ-26 H H H -NH-(4-OCH3-C6H4)Ⅰ-27 H H H -NH-(2-SCH3-C6H4)Ⅰ-28 H H H -NH-(3-SCH3-C6H4)Ⅰ-29 H H H -NH-(4-SCH3-C6H4)Ⅰ-30 H H H -NH-(2-N(CH3)2-C6H4)Ⅰ-31 H H H -NH-(3-N(CH3)2-C6H4)Ⅰ-32 H H H -NH-(4-N(CH3)2-C6H4)Ⅰ-33 H H H -NH-(4-CN-C6H4)Ⅰ-34 H H H -NH-(4-Cl-C6H4)Ⅰ-35 H H H -NH-(4-Br-C6H4)Ⅰ-36 H H H -NH-(4-F-C6H4)Ⅰ-37 H H H -NH-(4-CH3-C6H4)Ⅰ-38 H H H -NH-(2-NO2-C6H4)Ⅰ-39 H H H -NH-(3-NO2-C6H4)Ⅰ-40 H H H -NH-(4-NO2-C6H4]Ⅰ-41 H H H -NH-(2,4-OCH3-C6H3)Ⅰ-42 H H H -NH-(3,4-OCH3-C6H3)Ⅰ-43 H H H -NH-(3,4,5-OCH3-C6H2)Ⅰ-44 H H H -NH-(3,4-CH2OCH2-C6H3)Ⅰ-45 H H H -NH-(2,3-CH2OCH2-C6H3)Ⅰ-46 H H H -NH-2-吡啶基Ⅰ-47 H H H -NH-2-呋喃基Ⅰ-48 H H H -NH-2-噻吩基Ⅰ-49 H H H -NH-3-吡啶基Ⅰ-50 H H H -NH-3-呋喃基Ⅰ-51 H H H -NH-3-噻吩基Ⅰ-52 H H H -NH-4-吡啶基Ⅰ-53 H H H -NH-2-噁唑基Ⅰ-54 H H H -NH-3-异噁唑基Ⅰ-55 H H H -NH-4-异噁唑基Ⅰ-56 H H H -NH-5-异噁唑基Ⅰ-57 H H H -NH-2R-(丁-2-基)Ⅰ-58 H H H -NH-2S-(丁-2-基)Ⅰ-59 H H H -NH-O-CH3Ⅰ-60 H H H -N(CH3)(OCH3)Ⅰ-61 H H H -N(-(CH2)3-O-)Ⅰ-62 H H H -NH-O-CH2-C6H5Ⅰ-63 H H H -N(CH3)(O-CH2-C6H5)Ⅰ-64 H H H -N(-(CH2)2-CH(C6H5)-O-)Ⅰ-65 H H H -NH-O-C2H5Ⅰ-66 H H H -N(C2H5)(OC2H5)Ⅰ-67 H H H -N(CH3)(OC2H5)Ⅰ-68 H H H -NH-O-异C3H7Ⅰ-69 H H H -N(CH3)(O-异C3H7)Ⅰ-70 H H H -NH-O-nC3H7Ⅰ-71 H H H -N(CH3)(O-nC3H7)Ⅰ-72 H H H -NH-O-nC4H9Ⅰ-73 H H H -N(CH3)(O-nC4H9)Ⅰ-74 H H H -NH-O-叔C4H9Ⅰ-75 H H H -N(CH3)(O-叔C4H9)Ⅰ-76 H H H -NH-O-C6H5Ⅰ-77 H H H -N(CH3)(O-C6H5)Ⅰ-78 H H H -N(CH3)2Ⅰ-79 H H H -N(CH2-C6H5)2Ⅰ-80 H H H -N(C2H5)2Ⅰ-81 H H H -N(异C3H7)2Ⅰ-82 H H H -N(nC3H7)2Ⅰ-83 H H H -N(nC4H9)2Ⅰ-84 H H H -N(C6H5)2Ⅰ-85 H H H -NH-CH2-CH2-OHⅠ-86 H H H -NH-(CH2)3-OHⅠ-87 H H H -NH(-(CH3)2CH(C6H5)OH)Ⅰ-88 H H H -NH-(CH2)4-OHⅠ-89 H H H -NH(-CH(CH3)-CH2-OH)Ⅰ-90 H H H -NH(-CH2-CH(CH3)-OH)Ⅰ-91 H H H -NH(CH(CH3)(CH2)2OH)Ⅰ-92 H H H -NH(-(CH2)2CH(CH3)OH)Ⅰ-93 H 4-CH3 H -NH-CH3Ⅰ-94 H 4-CH3 H -NH-CH2-C6H5Ⅰ-95 H 4-CH3 H -NH-异C3H7Ⅰ-96 H 4-CH3 H -NH-C6H5Ⅰ-97 H 4-CH3 H -NH-C2H5Ⅰ-98 H 4-CH3 H -NH-nC3H7Ⅰ-99 H 4-CH3 H -NH-nC4H9Ⅰ-100 H 4-CH3 H -NH-叔C4H9Ⅰ-101 H 4-CH3 H -NH-环C3H5Ⅰ-102 H 4-CH3 H -NH-环C4H7Ⅰ-103 H 4-CH3 H -NH-环C5H9Ⅰ-104 H 4-CH3 H -NH-环C6H11Ⅰ-105 H 4-CH3 H -NH-1-金刚烷基Ⅰ-106 H 4-CH3 H -NH-2R-(丁-2-基)Ⅰ-107 H 4-CH3 H -NH-2S-(丁-2-基)Ⅰ-108 H 4-CH3 H -NH-O-CH3Ⅰ-109 H 4-CH3 H -N(CH3)(OCH3)Ⅰ-110 H 4-CH3 H -N(-(CH2)3-O-)Ⅰ-111 H 4-CH3 H -N(CH3)2Ⅰ-112 H 4-CH3 H -N(CH2-C6H5)2Ⅰ-113 H 4-CH3 H -N(C2H5)2Ⅰ-114 H 4-CH3 H -N(异C3H7)2Ⅰ-115 H 4-CH3 H -N(nC3H7)2Ⅰ-116 H 4-CH3 H -N(nC4H9)2Ⅰ-117 H 4-CH3 H -N(C6H5)2Ⅰ-118 H 5-CH3 H -NH-CH3Ⅰ-119 H 5-CH3 H -NH-CH2-C6H5Ⅰ-120 H 5-CH3 H -NH-异C3H7Ⅰ-121 H 5-CH3 H -NH-C6H5Ⅰ-122 H 5-CH3 H -NH-C2H5Ⅰ-123 H 5-CH3 H -NH-nC3H7Ⅰ-124 H 5-CH3 H -NH-nC4H9Ⅰ-125 H 5-CH3 H -NH-叔C4H9Ⅰ-126 H 5-CH3 H -NH-环C3H5Ⅰ-127 H 5-CH3 H -NH-环C4H7Ⅰ-128 H 5-CH3 H -NH-环C5H9Ⅰ-129 H 5-CH3 H -NH-环C6H11Ⅰ-130 H 5-CH3 H -NH-1-金刚烷基Ⅰ-131 H 5-CH3 H -NH-2R-(丁-2-基)Ⅰ-132 H 5-CH3 H -NH-2S-(丁-2-基)Ⅰ-133 H 5-CH3 H -NH-O-CH3Ⅰ-134 H 5-CH3 H -N(CH3)(OCH3)Ⅰ-135 H 5-CH3 H -N(-(CH2)3-O-)Ⅰ-136 H 5-CH3 H -N(CH3)2Ⅰ-137 H 5-CH3 H -N(CH2-C6H5)2Ⅰ-138 H 5-CH3 H -N(C2H5)2Ⅰ-139 H 5-CH3 H -N(异C3H7)2Ⅰ-140 H 5-CH3 H -N(nC3H7)2Ⅰ-141 H 5-CH3 H -N(nC4H9)2Ⅰ-142 H 5-CH3 H -N(C6H5)2Ⅰ-143 CH3 H H -NH-CH3Ⅰ-144 CH3 H H -NH-CH2-C6H5Ⅰ-145 CH3 H H -NH-异C3H7Ⅰ-146 CH3 H H -NH-C6H5Ⅰ-147 CH3 H H -NH-C2H5Ⅰ-148 CH3 H H -NH-nC3H7Ⅰ-149 CH3 H H -NH-nC4H9Ⅰ-150 CH3 H H -NH-叔C4H9Ⅰ-151 CH3 H H -NH-环C3H5Ⅰ-152 CH3 H H -NH-环C4H7Ⅰ-153 CH3 H H -NH-环C5H9Ⅰ-154 CH3 H H -NH-环C6H11Ⅰ-155 CH3 H H -NH-1-金刚烷基Ⅰ-156 CH3 H H -NH-2R-(丁-2-基)Ⅰ-157 CH3 H H -NH-2S-(丁-2-基)Ⅰ-158 CH3 H H -NH-O-CH3Ⅰ-159 CH3 H H -N(CH3)(OCH3)Ⅰ-160 CH3 H H -N(-(CH2)3-O-)Ⅰ-161 CH3 H H -N(CH3)2Ⅰ-162 CH3 H H -N(CH2-C6H5)2Ⅰ-163 CH3 H H -N(C2H5)2Ⅰ-164 CH3 H H -N(异C3H7)2Ⅰ-165 CH3 H H -N(nC3H7)2Ⅰ-166 CH3 H H -N(nC4H9)2Ⅰ-167 CH3 H H -N(C6H5)2Ⅰ-168 H 4-OCH3 H -NH-CH3Ⅰ-169 H 4-OCH3 H -NH-CH2-C6H5Ⅰ-170 H 4-OCH3 H -NH-异C3H7Ⅰ-171 H 4-OCH3 H -NH-C6H5Ⅰ-172 H 4-OCH3 H -NH-C2H5Ⅰ-173 H 4-OCH3 H -NH-nC3H7Ⅰ-174 H 4-OCH3 H -NH-nC4H9Ⅰ-175 H 4-OCH3 H -NH-叔C4H9Ⅰ-176 H 4-OCH3 H -NH-环C3H5Ⅰ-177 H 4-OCH3 H -NH-环C4H7Ⅰ-178 H 4-OCH3 H -NH-环C5H9Ⅰ-179 H 4-OCH3 H -NH-环CH6H11Ⅰ-180 H 4-OCH3 H -NH-1-金刚烷基Ⅰ-181 H 4-OCH3 H -NH-2R-(丁-2-基)Ⅰ-182 H 4-OCH3 H -NH-2S-(丁-2-基)Ⅰ-183 H 4-OCH3 H -NH-O-CH3Ⅰ-184 H 4-OCH3 H -N(CH3)(OCH3)Ⅰ-185 H 4-OCH3 H -N(-(CH2)3-O-)Ⅰ-186 H 4-OCH3 H -N(CH3)2Ⅰ-187 H 4-OCH3 H -N(CH2-C6H5)2Ⅰ-188 H 4-OCH3 H -N(C2H5)2Ⅰ-189 H 4-OCH3 H -N(异C3H7)2Ⅰ-190 H 4-OCH3 H -N(nC3H7)2Ⅰ-191 H 4-OCH3 H -N(nC4H9)2Ⅰ-192 H 4-CH3 H -N(C6H5)2Ⅰ-193 H 5-OCH3 H -NH-CH3Ⅰ-194 H 5-OCH3 H -NH-CH2-C6H5Ⅰ-195 H 5-OCH3 H -NH-异C3H7Ⅰ-196 H 5-OCH3 H -NH-C6H5Ⅰ-197 H 5-OCH3 H -NH-C2H5Ⅰ-198 H 5-OCH3 H -NH-nC3H7Ⅰ-199 H 5-OCH3 H -NH-nC4H9Ⅰ-200 H 5-OCH3 H -NH-叔C4H9Ⅰ-201 H 5-OCH3 H -NH-环C3H5Ⅰ-202 H 5-OCH3 H -NH-环C4H7Ⅰ-203 H 5-OCH3 H -NH-环C5H9Ⅰ-204 H 5-OCH3 H -NH-环C6H11Ⅰ-205 H 5-OCH3 H -NH-1-金刚烷基Ⅰ-206 H 5-OCH3 H -NH-2R-(丁-2-基)Ⅰ-207 H 5-OCH3 H -NH-2S-(丁-2-基)Ⅰ-208 H 5-OCH3 H -NH-O-CH3Ⅰ-209 H 5-OCH3 H -N(CH3)(OCH3)Ⅰ-210 H 5-OCH3 H -N(-(CH2)3-O-)Ⅰ-211 H 5-OCH3 H -N(CH3)2Ⅰ-212 H 5-OCH3 H -N(CH2-C6H5)2Ⅰ-213 H 5-OCH3 H -N(C2H5)2Ⅰ-214 H 5-OCH3 H -N(异C3H7)2Ⅰ-215 H 5-OCH3 H -N(nC3H7)2Ⅰ-216 H 5-OCH3 H -N(nC4H9)2Ⅰ-217 H 5-OCH3 H -N(C6H5)2
表2A是Me2Val,B是Val,D是MeVal,E是Pro,F是式Ⅱf，基团-C(O)-G在相对于氮原子的3位，以及G是式Ⅱg、Ⅲg或ⅣgNo. RF R1 F R2 F -GⅡ-1 H H H -NH-CH3Ⅱ-2 H H H -NH-CH2-C6H5Ⅱ-3 H H H -NH-isoC3H7Ⅱ-4 H H H -NH-C6H5Ⅱ-5 H H H 1,3-噻唑-2-基-酰胺Ⅱ-6 H 4-OCH3 5-OCH3 -NH-CH3Ⅱ-7 H 4-环-C5H9 H -NH-CH3Ⅱ-8 H H H -NH-C2H5Ⅱ-9 H H H -NH-nC3H7Ⅱ-10 H H H -NH-nC4H9Ⅱ-11 H H H -NH-叔C4H9Ⅱ-12 H H H -NH-环C3H5Ⅱ-13 H H H -NH-环C4H7Ⅱ-14 H H H -NH-环C5H9Ⅱ-15 H H H -NH-环C6H11Ⅱ-16 H H H -NH-环C7H12Ⅱ-17 H H H -NH-CH2-O-CH3Ⅱ-18 H H H -NH-CH2-CH2-O-CH3Ⅱ-19 H H H -NH-1-金刚烷基Ⅱ-20 H H H -NH-(4-HO-C6H5)Ⅱ-21 H H H -NH-(2-CF3-C6H4)Ⅱ-22 H H H -NH-(3-CF3-C6H4)Ⅱ-23 H H H -NH-(4-CF3-C6H4)Ⅱ-24 H H H -NH-(2-OCH3-C6H4)Ⅱ-25 H H H -NH-(3-OCH3-C6H4)Ⅱ-26 H H H -NH-(4-OCH3-C6H4)Ⅱ-27 H H H -NH-(2-SCH3-C6H4)Ⅱ-28 H H H -NH-(3-SCH3-C6H4)Ⅱ-29 H H H -NH-(4-SCH3-C6H4)Ⅱ-30 H H H -NH-(2-N(CH3)2-C6H4)Ⅱ-31 H H H -NH-(3-N(CH3)2-C6H4)Ⅱ-32 H H H -NH-(4-N(CH3)2-C6H4)Ⅱ-33 H H H -NH-(4-CN-C6H4)Ⅱ-34 H H H -NH-(4-Cl-C6H4)Ⅱ-35 H H H -NH-(4-Br-C6H4)Ⅱ-36 H H H -NH-(4-F-C6H4]Ⅱ-37 H H H -NH-(4-CH3-C6H4)Ⅱ-38 H H H -NH-(2-NO2-C6H4)Ⅱ-39 H H H -NH-(3-NO2-C6H4)Ⅱ-40 H H H -NH-(4-NO2-C6H4]Ⅱ-41 H H H -NH-(2,4-OCH3-C6H3)Ⅱ-42 H H H -NH-(3,4-OCH3-C6H3)Ⅱ-43 H H H -NH-(3,4,5-OCH3-C6H2)Ⅱ-44 H H H -NH-(3,4-CH2OCH2-C6H3)Ⅱ-45 H H H -NH-(2,3-CH2OCH2-C6H3)Ⅱ-46 H H H -NH-2-吡啶基Ⅱ-47 H H H -NH-2-呋喃基Ⅱ-48 H H H -NH-2-噻吩基Ⅱ-49 H H H -NH-3-吡啶基Ⅱ-50 H H H -NH-3-呋喃基Ⅱ-51 H H H -NH-3-噻吩基Ⅱ-52 H H H -NH-4-吡啶基Ⅱ-53 H H H -NH-2-噁唑基Ⅱ-54 H H H -NH-3-异噁唑基Ⅱ-55 H H H -NH-4-异噁唑基Ⅱ-56 H H H -NG-5-异噁唑基Ⅱ-57 H H H -NH-2R-(丁-2-基)Ⅱ-58 H H H -NH-2S-(丁-2-基)Ⅱ-59 H H H -NH-O-CH3Ⅱ-60 H H H -N(CH3)(OCH3)Ⅱ-61 H H H -N(-(CH2)3-O-)Ⅱ-62 H H H -NH-O-CH2-C6H5Ⅱ-63 H H H -N(CH3)(O-CH2-C6H5)Ⅱ-64 H H H -N(-(CH2)2-CH(C6H5)-O-)Ⅱ-65 H H H -NH-O-C2H5Ⅱ-66 H H H -N(C2H5)(OC2H5)Ⅱ-67 H H H -N(CH3)(OC2H5)Ⅱ-68 H H H -NH-O-异C3H7Ⅱ-69 H H H -N(CH3)(O-异C3H7)Ⅱ-70 H H H -NH-O-nC3H7Ⅱ-71 H H H -N(CH3)(O-nC3H7)Ⅱ-72 H H H -NH-O-nC4H9Ⅱ-73 H H H -N(CH3)(O-nC4H9)Ⅱ-74 H H H -NH-O-叔C4H9Ⅱ-75 H H H -N(CH3)(O-叔C4H9)Ⅱ-76 H H H -NH-O-C6H5Ⅱ-77 H H H -N(CH3)(O-C6H5)Ⅱ-78 H H H -N(CH3)2Ⅱ-79 H H H -N(CH2-C6H5)2Ⅱ-80 H H H -N(C2H5)2Ⅱ-81 H H H -N(异C3H7)2Ⅱ-82 H H H -N(nC3H7)2Ⅱ-83 H H H -N(nC4H9)2Ⅱ-84 H H H -N(C6H5)2Ⅱ-85 H H H -NH-CH2-CH2-OHⅡ-86 H H H -NH-(CH2)3-OHⅡ-87 H H H -NH(-(CH2)2-CH(C6H5)-OH)Ⅱ-88 H H H -NH-(CH2)4-OHⅡ-89 H H H -NH(-CH(CH3)-CH2-OH)Ⅱ-90 H H H -NH(-CH2-CH(CH3)-OH)Ⅱ-91 H H H -NH(-CH(CH3)-(CH2)2-OH)Ⅱ-92 H H H -NH(-(CH2)2-CH(CH3)-OH)Ⅱ-93 H 4-CH3 H -NH-CH3Ⅱ-94 H 4-CH3 H -NH-CH2-C6H5Ⅱ-95 H 4-CH3 H -NH-异C3H7Ⅱ-96 H 4-CH3 H -NH-C6H5Ⅱ-97 H 4-CH3 H -NH-C2H5Ⅱ-98 H 4-CH3 H -NH-nC3H7Ⅱ-99 H 4-CH3 H -NH-nC4H9Ⅱ-100 H 4-CH3 H -NH-叔C4H9Ⅱ-101 H 4-CH3 H -NH-环C3H5Ⅱ-102 H 4-CH3 H -NH-环C4H7Ⅱ-103 H 4-CH3 H -NH-环C5H9Ⅱ-104 H 4-CH3 H -NH-环C6H11Ⅱ-105 H 4-CH3 H -NH-1-金刚烷基Ⅱ-106 H 4-CH3 H -NH-2R-(丁-2-基)Ⅱ-107 H 4-CH3 H -NH-2S-(丁-2-基)Ⅱ-108 H 4-CH3 H -NH-O-CH3Ⅱ-109 H 4-CH3 H -N(CH3)(OCH3)Ⅱ-110 H 4-CH3 H -N(-(CH2)3-O-)Ⅱ-111 H 4-CH3 H -N(CH3)2Ⅱ-112 H 4-CH3 H -N(CH2-C6H5)2Ⅱ-113 H 4-CH3 H -N(C2H5)2Ⅱ-114 H 4-CH3 H -N(异C3H7)2Ⅱ-115 H 4-CH3 H -N(nC3H7)2Ⅱ-116 H 4-CH3 H -N(nC4H9)2Ⅱ-117 H 4-CH3 H -N(C6H5)2Ⅱ-118 H 5-CH3 H -NH-CH3Ⅱ-119 H 5-CH3 H -NH-CH2-C6H5Ⅱ-120 H 5-CH3 H -NH-异C3H7Ⅱ-121 H 5-CH3 H -NH-C6H5Ⅱ-122 H 5-CH3 H -NH-C2H5Ⅱ-123 H 5-CH3 H -NH-nC3H7Ⅱ-124 H 5-CH3 H -NH-nC4H9Ⅱ-125 H 5-CH3 H -NH-叔C4H9Ⅱ-126 H 5-CH3 H -NH-环C3H5Ⅱ-127 H 5-CH3 H -NH-环C4H7Ⅱ-128 H 5-CH3 H -NH-环C5H9Ⅱ-129 H 5-CH3 H -NH-环C6H11Ⅱ-130 H 5-CH3 H -NH-1-金刚烷基Ⅱ-131 H 5-CH3 H -NH-2R-(丁-2-基))Ⅱ-132 H 5-CH3 H -NH-2S-(丁-2-基)Ⅱ-133 H 5-CH3 H -NH-O-CH3Ⅱ-134 H 5-CH3 H -N(CH3)(OCH3)Ⅱ-135 H 5-CH3 H -N(-(CH2)3-O-)Ⅱ-136 H 5-CH3 H -N(CH3)2Ⅱ-137 H 5-CH3 H -N(CH2-C6H5)2Ⅱ-138 H 5-CH3 H -N(C2H5)2Ⅱ-139 H 5-CH3 H -N(异C3H7)2Ⅱ-140 H 5-CH3 H -N(nC3H7)2Ⅱ-141 H 5-CH3 H -N(nC4H9)2Ⅱ-142 H 5-CH3 H -N(C6H5)2Ⅱ-143 CH3 H H -NH-CH3Ⅱ-144 CH3 H H -NH-CH2-C6H5Ⅱ-145 CH3 H H -NH-异C3H7Ⅱ-146 CH3 H H -NH-C6H5Ⅱ-147 CH3 H H -NH-C2H5Ⅱ-148 CH3 H H -NH-nC3H7Ⅱ-149 CH3 H H -NH-nC4H9Ⅱ-150 CH3 H H -NH-叔C4H9Ⅱ-151 CH3 H H -NH-环C3H5Ⅱ-152 CH3 H H -NH-环C4H7Ⅱ-153 CH3 H H -NH-环C5H9Ⅱ-154 CH3 H H -NH-环C6H11Ⅱ-155 CH3 H H -NH-1-金刚烷基Ⅱ-156 CH3 H H -NH-2R-(丁-2-基)Ⅱ-157 CH3 H H -NH-2S-(丁-2-基)Ⅱ-158 CH3 H H -NH-O-CH3Ⅱ-159 CH3 H H -N(CH3)(OCH3)Ⅱ-160 CH3 H H -N(-(CH2)3-O-)Ⅱ-161 CH3 H H -N(CH3)2Ⅱ-162 CH3 H H -N(CH2-C6H5)2Ⅱ-163 CH3 H H -N(C2H5)2Ⅱ-164 CH3 H H -N(异C3H7)2Ⅱ-165 CH3 H H -N(nC3H7)2Ⅱ-166 CH3 H H -N(nC4H9)2Ⅱ-167 CH3 H H -N(C6H5)2Ⅱ-168 H 4-OCH3 H -NH-CH3Ⅱ-169 H 4-OCH3 H -NH-CH2-C6H5Ⅱ-170 H 4-OCH3 H -NH-异C3H7Ⅱ-171 H 4-OCH3 H -NH-C6H5Ⅱ-172 H 4-OCH3 H -NH-C2H5Ⅱ-173 H 4-OCH3 H -NH-nC3H7Ⅱ-174 H 4-OCH3 H -NH-nC4H9Ⅱ-175 H 4-OCH3 H -NH-叔C4H9Ⅱ-176 H 4-OCH3 H -NH-环C3H5Ⅱ-177 H 4-OCH3 H -NH-环C4H7Ⅱ-178 H 4-OCH3 H -NH-环C5H9Ⅱ-179 H 4-OCH3 H -NH-环C6H11Ⅱ-180 H 4-OCH3 H -NH-1-金刚烷基Ⅱ-181 H 4-OCH3 H -NH-2R-(丁-2-基)Ⅱ-182 H 4-OCH3 H -NH-2S-(丁-2-基)Ⅱ-183 H 4-OCH3 H -NH-O-CH3Ⅱ-184 H 4-OCH3 H -N(CH3)(OCH3)Ⅱ-185 H 4-OCH3 H -N(-(CH2)3-O-)Ⅱ-186 H 4-OCH3 H -N(CH3)2Ⅱ-187 H 4-OCH3 H -N(CH2-C6H5)2Ⅱ-188 H 4-OCH3 H -N(C2H5)2Ⅱ-189 H 4-OCH3 H -N(异C3H7)2Ⅱ-190 H 4-OCH3 H -N(nC3H7)2Ⅱ-191 H 4-OCH3 H -N(nC4H9)2Ⅱ-192 H 4-OCH3 H -N(C6H5)2Ⅱ-193 H 5-OCH3 H -NH-CH3Ⅱ-194 H 5-OCH3 H -NH-CH2-C6H5Ⅱ-195 H 5-OCH3 H -NH-异C3H7Ⅱ-196 H 5-OCH3 H -NH-C6H5Ⅱ-197 H 5-OCH3 H -NH-C2H5Ⅱ-198 H 5-OCH3 H -NH-nC3H7Ⅱ-199 H 5-OCH3 H -NH-nC4H9Ⅱ-200 H 5-OCH3 H -NH-叔 C4H9Ⅱ-201 H 5-OCH3 H -NH-环C3H5Ⅱ-202 H 5-OCH3 H -NH-环C4H7Ⅱ-203 H 5-OCH3 H -NH-环C5H9Ⅱ-204 H 5-OCH3 H -NH-环C6H11Ⅱ-205 H 5-OCH3 H -NH-1-金刚烷基Ⅱ-206 H 5-OCH3 H -NH-2R-(丁-2-基)Ⅱ-207 H 5-OCH3 H -NH-2S-(丁-2-基)Ⅱ-208 H 5-OCH3 H -NH-O-CH3Ⅱ-209 H 5-OCH3 H -N(CH3)(OCH3)Ⅱ-210 H 5-OCH3 H -N(-(CH2)3-O-)Ⅱ-211 H 5-OCH3 H -N(CH3)2Ⅱ-212 H 5-OCH3 H -N(CH2-C6H5)2Ⅱ-213 H 5-OCH3 H -N(C2H5)2Ⅱ-214 H 5-OCH3 H -N(异C3H7)2Ⅱ-215 H 5-OCH3 H -N(nC3H7)2Ⅱ-216 H 5-OCH3 H -N(nC4H9)2Ⅱ-217 H 5-OCH3 H -N(C6H5)2
表3A是Me2Val,B是Val,D是MeVal,E是Pro,F是式Ⅱf，取代基-(C=O)-G在相对于氮原子的4位，G是式Ⅱg、Ⅲg或Ⅳg
No. RF R1 F R2 F -G
Ⅲ-1 H H H -NH-CH3Ⅲ-2 H H H -NH-CH2-C6H5Ⅲ-3 H H H -NH-异C3H7Ⅲ-4 H H H -NH-C6H5Ⅲ-5 H H H 1,3-噻唑-2-基-酰胺Ⅲ-6 H 3-OCH3 5-OCH3 -NH-CH3Ⅲ-7 H 3-环-C5H9 H -NH-CH3Ⅲ-8 H H H -NH-C2H5Ⅲ-9 H H H -NH-nC3H7Ⅲ-10 H H H -NH-nC4H9Ⅲ-11 H H H -NH-叔 C4H9Ⅲ-12 H H H -NH-环 C3H5Ⅲ-13 H H H -NH-环 C4H7Ⅲ-14 H H H -NH-环 C5H9Ⅲ-15 H H H -NH-环 C6H11Ⅲ-16 H H H -NH-环 C7H12Ⅲ-17 H H H -NH-CH2-O-CH3Ⅲ-18 H H H -NH-CH2-CH2-O-CH3Ⅲ-19 H H H -NH-1-金刚烷基Ⅲ-20 H H H -NH-(4-HO-C6H5)Ⅲ-21 H H H -NH-(2-CF3-C6H4)Ⅲ-22 H H H -NH-(3-CF3-C6H4)Ⅲ-23 H H H -NH-(4-CF3-C6H4)Ⅲ-24 H H H -NH-(2-OCH3-C6H4)Ⅲ-25 H H H -NH-(3-OCH3-C6H4)Ⅲ-26 H H H -NH-(4-OCH3-C6H4)Ⅲ-27 H H H -NH-(2-SCH3-C6H4)Ⅲ-28 H H H -NH-(3-SCH3-C6H4)Ⅲ-29 H H H -NH-(4-SCH3-C6H4)Ⅲ-30 H H H -NH-(2-N(CH3)2-C6H4)Ⅲ-31 H H H -NH-(3-N(CH3)2-C6H4)Ⅲ-32 H H H -NH-(4-N(CH3)2-C6H4)Ⅲ-33 H H H -NH-(4-CN-C6H4)Ⅲ-34 H H H -NH-(4-Cl-C6H4)Ⅲ-35 H H H -NH-(4-Br-C6H4)Ⅲ-36 H H H -NH-(4-F-C6H4)Ⅲ-37 H H H -NH-(4-CH3-C6H4)Ⅲ-38 H H H -NH-(2-NO2-C6H4)Ⅲ-39 H H H -NH-(3-NO2-C6H4)Ⅲ-40 H H H -NH-(4-NO2-C6H4)Ⅲ-41 H H H -NH-(2,4-OCH3-C6H3)Ⅲ-42 H H H -NH-(3,4-OCH3-C6H3)Ⅲ-43 H H H -NH-(3,4,5-OCH3-C6H2)Ⅲ-44 H H H -NH-(3,4-CH2OCH2-C6H3)Ⅲ-45 H H H -NH-(2,3-CH2OCH2-C6H3)Ⅲ-46 H H H -NH-2-吡啶基Ⅲ-47 H H H -NH-2-呋喃基Ⅲ-48 H H H -NH-2-噻吩基Ⅲ-49 H H H -NH-3-吡啶基Ⅲ-50 H H H -NH-3-呋喃基Ⅲ-51 H H H -NH-3-噻吩基Ⅲ-52 H H H -NH-4-吡啶基Ⅲ-53 H H H -NH-2-噁唑基Ⅲ-54 H H H -NH-3-异噁唑基Ⅲ-55 H H H -NH-4-异噁唑基Ⅲ-56 H H H -NH-5-异噁唑基Ⅲ-57 H H H -NH-2R-(丁-2-基)Ⅲ-58 H H H -NH-2S-(丁-2-基)Ⅲ-59 H H H -NH-O-CH3Ⅲ-60 H H H -N(CH3)(OCH3)Ⅲ-61 H H H -N(-(CH2)3-O-)Ⅲ-62 H H H -NH-O-CH2-C6H5Ⅲ-63 H H H -N(CH3)(O-CH2-C6H5)Ⅲ-64 H H H -N(-(CH2)2-CH(C6H5)-O-)Ⅲ-65 H H H -NH-O-C2H5Ⅲ-66 H H H -N(C2H5)(OC2H5)Ⅲ-67 H H H -N(CH3)(OC2H5)Ⅲ-68 H H H -NH-O-异C3H7Ⅲ-69 H H H -N(CH3)(O-异C3H7)Ⅲ-70 H H H -NH-O-nC3H7Ⅲ-71 H H H -N(CH3)(O-nC3H7)Ⅲ-72 H H H -NH-O-nC4H9Ⅲ-73 H H H -N(CH3)(O-nC4H9)Ⅲ-74 H H H -NH-O-tertC4H9Ⅲ-75 H H H -N(CH3)(O-叔C4H9)Ⅲ-76 H H H -NH-O-C6H5Ⅲ-77 H H H -N(CH3)(O-C6H5)Ⅲ-78 H H H -N(CH3)2Ⅲ-79 H H H -N(CH2-C6H5)2Ⅲ-80 H H H -N(C2H5)2Ⅲ-81 H H H -N(异C3H7)2Ⅲ-82 H H H -N(nC3H7)2Ⅲ-83 H H H -N(nC4H9)2Ⅲ-84 H H H -N(C6H5)2Ⅲ-85 H H H -NH-CH2-CH2-OHⅢ-86 H H H -NH-(CH2)3-OHⅢ-87 H H H -NH(-(CH2)2-CH(C6H5)-OH)Ⅲ-88 H H H -NH-(CH2)4-OHⅢ-89 H H H -NH(-CH(CH3)-CH2-OH)Ⅲ-90 H H H -NH(-CH2-CH(CH3)-OH)Ⅲ-91 H H H -NH(-CH(CH3)-(CH2)2-OH)Ⅲ-92 H H H -NH(-(CH2)2-CH(CH3)-OH)Ⅲ-93 H 2-CH3 H -NH-CH3Ⅲ-94 H 2-CH3 H -NH-CH2-C6H5Ⅲ-95 H 2-CH3 H -NH-异C3H7Ⅲ-96 H 2-CH3 H -NH-C6H5Ⅲ-97 H 2-CH3 H -NH-C2H5Ⅲ-98 H 2-CH3 H -NH-nC3H7Ⅲ-99 H 2-CH3 H -NH-nC4H9Ⅲ-100 H 2-CH3 H -NH-叔C4H9Ⅲ-101 H 2-CH3 H -NH-环C3H5Ⅲ-102 H 2-CH3 H -NH-环C4H7Ⅲ-103 H 2-CH3 H -NH-环C5H9Ⅲ-104 H 2-CH3 H -NH-环C6H11Ⅲ-105 H 2-CH3 H -NH-1-金刚烷基Ⅲ-106 H 2-CH3 H -NH-2R-(丁-2-基)Ⅲ-107 H 2-CH3 H -NH-2S-(丁-2-基)Ⅲ-108 H 2-CH3 H -NH-O-CH3Ⅲ-109 H 2-CH3 H -N(CH3)(OCH3)Ⅲ-110 H 2-CH3 H -N(-(CH2)3-O-)Ⅲ-111 H 2-CH3 H -N(CH3)2Ⅲ-112 H 2-CH3 H -N(CH2-C6H5)2Ⅲ-113 H 2-CH3 H -N(C2H5)2Ⅲ-114 H 2-CH3 H -N(异C3H7)2Ⅲ-115 H 2-CH3 H -N(nC3H7)2Ⅲ-116 H 2-CH3 H -N(nC4H9)2Ⅲ-117 H 2-CH3 H -N(C6H5)2Ⅲ-118 H 3-CH3 H -NH-CH3Ⅲ-119 H 3-CH3 H -NH-CH2-C6H5Ⅲ-120 H 3-CH3 H -NH-异C3H7Ⅲ-121 H 3-CH3 H -NH-C6H5Ⅲ-122 H 3-CH3 H -NH-C2H5Ⅲ-123 H 3-CH3 H -NH-nC3H7Ⅲ-124 H 3-CH3 H -NH-nC4H9Ⅲ-125 H 3-CH3 H -NH-叔C4H9Ⅲ-126 H 3-CH3 H -NH-环C3H5Ⅲ-127 H 3-CH3 H -NH-环C4H7Ⅲ-128 H 3-CH3 H -NH-环C5H9Ⅲ-129 H 3-CH3 H -NH-环C6H11Ⅲ-130 H 3-CH3 H -NH-1-金刚烷基Ⅲ-131 H 3-CH3 H -NH-2R(丁-2-基)Ⅲ-132 H 3-CH3 H -NH-2S(丁-2-基)Ⅲ-133 H 3-CH3 H -NH-O-CH3Ⅲ-134 H 3-CH3 H -N(CH3)(OCH3)Ⅲ-135 H 3-CH3 H -N(-(CH2)3-O-)Ⅲ-136 H 3-CH3 H -N(CH3)2Ⅲ-137 H 3-CH3 H -N(CH2-C6H5)2Ⅲ-138 H 3-CH3 H -N(C2H5)2Ⅲ-139 H 3-CH3 H -N(异C3H7)2Ⅲ-140 H 3-CH3 H -N(nC3H7)2Ⅲ-141 H 3-CH3 H -N(nC4H9)2Ⅲ-142 H 3-CH3 H -N(C6H5)2Ⅲ-143 CH3 H H -NH-CH3Ⅲ-144 CH3 H H -NH-CH2-C6H5Ⅲ-145 CH3 H H -NH-异C3H7Ⅲ-146 CH3 H H -NH-C6H5Ⅲ-147 CH3 H H -NH-C2H5Ⅲ-148 CH3 H H -NH-nC3H7Ⅲ-149 CH3 H H -NH-nC4H9Ⅲ-150 CH3 H H -NH-叔C4H9Ⅲ-151 CH3 H H -NH-环C3H5Ⅲ-152 CH3 H H -NH-环C4H7Ⅲ-153 CH3 H H -NH-环C5H9Ⅲ-154 CH3 H H -NH-环C6H11Ⅲ-155 CH3 H H -NH-1-金刚烷基Ⅲ-156 CH3 H H -NH-2R-(丁-2-基)Ⅲ-157 CH3 H H -NH-2S-(丁-2-基)Ⅲ-158 CH3 H H -NH-O-CH3Ⅲ-159 CH3 H H -N(CH3)(OCH3)Ⅲ-160 CH3 H H -N(-(CH2)3-O-)Ⅲ-161 CH3 H H -N(CH3)2Ⅲ-162 CH3 H H -N(CH2-C6H5)2Ⅲ-163 CH3 H H -N(C2H5)2Ⅲ-164 CH3 H H -N(异C3H7)2Ⅲ-165 CH3 H H -N(nC3H7)2Ⅲ-166 CH3 H H -N(nC4H9)2Ⅲ-167 CH3 H H -N(C6H5)2Ⅲ-168 H 2-OCH3 H -NH-CH3Ⅲ-169 H 2-OCH3 H -NH-CH2-C6H5Ⅲ-170 H 2-OCH3 H -NH-异C3H7Ⅲ-171 H 2-OCH3 H -NH-C6H5Ⅲ-172 H 2-OCH3 H -NH-C2H5Ⅲ-173 H 2-OCH3 H -NH-nC3H7Ⅲ-174 H 2-OCH3 H -NH-nC4H9Ⅲ-175 H 2-OCH3 H -NH-叔C4H9Ⅲ-176 H 2-OCH3 H -NH-环C3H5Ⅲ-177 H 2-OCH3 H -NH-环C4H7Ⅲ-178 H 2-OCH3 H -NH-环C5H9Ⅲ-179 H 2-OCH3 H -NH-环C6H11Ⅲ-180 H 2-OCH3 H -NH-1-金刚烷基Ⅲ-181 H 2-OCH3 H -NH-2R-(丁-2-基)Ⅲ-182 H 2-OCH3 H -NH-2S-(丁-2-基)Ⅲ-183 H 2-OCH3 H -NH-O-CH3Ⅲ-184 H 2-OCH3 H -N(CH3)(OCH3)Ⅲ-185 H 2-OCH3 H -N(-(CH2)3-O-)Ⅲ-186 H 2-OCH3 H -N(CH3)2Ⅲ-187 H 2-OCH3 H -N(CH2-C6H5)2Ⅲ-188 H 2-OCH3 H -N(C2H5)2Ⅲ-189 H 2-OCH3 H -N(异C3H7)2Ⅲ-190 H 2-OCH3 H -N(nC3H7)2Ⅲ-191 H 2-OCH3 H -N(nC4H9)2Ⅲ-192 H 2-OCH3 H -N(C6H5)2Ⅲ-193 H 3-OCH3 H -NH-CH3Ⅲ-194 H 3-OCH3 H -NH-CH2-C6H5Ⅲ-195 H 3-OCH3 H -NH-异C3H7Ⅲ-196 H 3-OCH3 H -NH-C6H5Ⅲ-197 H 3-OCH3 H -NH-C2H5Ⅲ-198 H 3-OCH3 H -NH-nC3H7Ⅲ-199 H 3-OCH3 H -NH-nC4H9Ⅲ-200 H 3-OCH3 H -NH-叔C4H9Ⅲ-201 H 3-OCH3 H -NH-环C3H5Ⅲ-202 H 3-OCH3 H -NH-环C4H7Ⅲ-203 H 3-OCH3 H -NH-环C5H9Ⅲ-204 H 3-OCH3 H -NH-环C6H11Ⅲ-205 H 3-OCH3 H -NH-1-金刚烷基Ⅲ-206 H 3-OCH3 H -NH-2R-(丁-2-基)Ⅲ-207 H 3-OCH3 H -NH-2S-(丁-2-基)Ⅲ-208 H 3-OCH3 H -NH-O-CH3Ⅲ-209 H 3-OCH3 H -N(CH3)(OCH3)Ⅲ-210 H 3-OCH3 H -N(-(CH2)3-O-)Ⅲ-211 H 3-OCH3 H -N(CH3)2Ⅲ-212 H 3-OCH3 H -N(CH2-C6H5)2Ⅲ-213 H 3-OCH3 H -N(C2H5)2Ⅲ-214 H 3-OCH3 H -N(异C3H7)2Ⅲ-215 H 3-OCH3 H -N(nC3H7)2Ⅲ-216 H 3-OCH3 H -N(nC4H9)2Ⅲ-217 H 3-OCH3 H -N(C6H5)2
表4A是Me2Val,B是Val,D是MeVal,E是Pro,F是式Ⅱf，取代基-(C=O)-G在相对于氮原子的2位，G是式Ⅴg、Ⅵg、Ⅶg、Ⅷg或Ⅸg。No. RF R1 F R2 F -GⅣ-1 H H H -CH3Ⅳ-2 H H H -C2H5Ⅳ-3 H H H -nC3H7Ⅳ-4 H H H -异C3H7Ⅳ-5 H H H -nC4H9Ⅳ-6 H H H -叔C4H9Ⅳ-7 H H H -环C3H5Ⅳ-8 H H H -环C4H7Ⅳ-9 H H H -环C5H9Ⅳ-10 H H H -环C6H11Ⅳ-11 H H H -环C7H12Ⅳ-12 H H H -CH2-O-CH3Ⅳ-13 H H H -CH2-CH2-O-CH3Ⅳ-14 H H H -CH2-C6H5Ⅳ-15 H H H -C6H5Ⅳ-16 H H H -(4-HO-C6H5)Ⅳ-17 H H H -(2-CF3-C6H4)Ⅳ-18 H H H -(3-CF3-C6H4)Ⅳ-19 H H H -(4-CF3-C6H4)Ⅳ-20 H H H -(2-OCH3-C6H4)Ⅳ-21 H H H -(3-OCH3-C6H4)Ⅳ-22 H H H -(4-OCH3-C6H4)Ⅳ-23 H H H -(2-SCH3-C6H4)Ⅳ-24 H H H -(3-SCH3-C6H4)Ⅳ-25 H H H -(4-SCH3-C6H4)Ⅳ-26 H H H -(2-N(CH3)2-C6H4)Ⅳ-27 H H H -(3-N(CH3)2-C6H4)Ⅳ-28 H H H -(4-N(CH3)2-C6H4)Ⅳ-29 H H H -(4-CN-C6H4)Ⅳ-30 H H H -(4-Cl-C6H4)Ⅳ-31 H H H -(4-Br-C6H4]Ⅳ-32 H H H -(4-F-C6H4]Ⅳ-33 H H H -(4-CH3-C6H4)Ⅳ-34 H H H -(2-NO2-C6H4)Ⅳ-35 H H H -(3-NO2-C6H4)Ⅳ-36 H H H -(4-NO2-C6H4]Ⅳ-37 H H H -(2,4-OCH3-C6H3)Ⅳ-38 H H H -(3,4-OCH3-C6H3)Ⅳ-39 H H H -(3,4,5-OCH3-C6H2)Ⅳ-40 H H H -(3,4-CH2OCH2-C6H3)Ⅳ-41 H H H -(2,3-CH2OCH2-C6H3)Ⅳ-42 H H H -2-吡啶基Ⅳ-43 H H H -2-呋喃基Ⅳ-44 H H H -2-噻吩基Ⅳ-45 H H H -3-吡啶基Ⅳ-46 H H H -3-呋喃基Ⅳ-47 H H H -3-噻唑基Ⅳ-48 H H H -4-吡啶基Ⅳ-49 H H H -2-噻吩基Ⅳ-50 H H H -2-噁唑基Ⅳ-51 H H H -3-异噁唑基Ⅳ-52 H H H -4-异噁唑基Ⅳ-53 H H H -5-异噁唑基Ⅳ-54 H H H -CF3Ⅳ-5S H H H -C2F5Ⅳ-56 H H H -CH3Ⅳ-57 H H H -C2H5Ⅳ-58 H H H -nC3H7Ⅳ-59 H H H -叔C4H9Ⅳ-60 H H H -CH2-C6H5Ⅳ-61 H H H -C6H5Ⅳ-62 H H H -CH2-COOCH3Ⅳ-63 H H H -CH2-COOC2H5Ⅳ-64 H H H -CF2-COOCH3Ⅳ-65 H H H -CF2-COOC2H5Ⅳ-66 H H H -CH2-CONH2Ⅳ-67 H H H -CH2-CONHCH3Ⅳ-68 H H H -CH2-CON(CH3)2Ⅳ-69 H H H -CH2-CONH-CH2-C6H5Ⅳ-70 H H H -CH2-CONH-C6H5Ⅳ-71 H H H -CH2-CONH(CH2-C6H5)2Ⅳ-72 H H H -CH2-CON(-CH2-CH2-CH2-CH2-)Ⅳ-73 H H H -CH2-CON(-CH2-CH2-CH2-CH2-CH2)Ⅳ-74 H H H -CH2-CH2-COOCH3Ⅳ-75 H H H -CH2-CH2-COOC2H5Ⅳ-76 H H H -CH2-CH2-CONH2Ⅳ-77 H H H -CH2-CH2-CONHCH3Ⅳ-78 H H H -CH2-CH2-CON(CH3)2Ⅳ-79 H H H -CH2-CH2-CONH-CH2-C6H5Ⅳ-80 H H H -CH2-CH2-CONH-C6H5Ⅳ-81 H H H -CH2-CH2-CONH(CH2-C6H5)2Ⅳ-82 H H H -CH2-CH2-CON(-CH2-CH2-CH2-CH2-)Ⅳ-83 H H H -CH2-CH2-CON(-CH2-(CH2)3-CH2)Ⅳ-84 H H H -CH2-COCH3Ⅳ-85 H H H -CH2-CH2-COCH3Ⅳ-86 H H H -CH2-COC2H5Ⅳ-87 H H H -CH2-CH2-COC2H5Ⅳ-88 H H H -CH2-CO-C6H5Ⅳ-89 H H H -CH2-CH2-CO-C6H5Ⅳ-90 H H H -CH2-CO-CH2-C6H5Ⅳ-91 H H H -CH2-CH2-CO-CH2-C6H5Ⅳ-92 H H H -CH2-SOC6H5Ⅳ-93 H H H -CH2-SOCH3Ⅳ-94 H H H -CH2-SO(4-CH3-C6H4)Ⅳ-95 H H H -CH2-SO2C6H5Ⅳ-96 H H H -CH2-SO2CH3Ⅳ-97 H H H -CH2-SO2(4-CH3-C6H4)Ⅳ-98 H H H -CH2-CH2-SOC6H5Ⅳ-99 H H H -CH2-CH2-SOCH3Ⅳ-100 H H H -CH2-CH2-SO(4-CH3-C6H4)Ⅳ-101 H H H -CH2-CH2-SO2C6H5Ⅳ-102 H H H -CH2-CH2-SO2CH3Ⅳ-103 H H H -CH2-CH2-SOx(4-CH3-C6H4)Ⅳ-104 CH3 H H -CH3Ⅳ-105 CH3 H H -C2H5Ⅳ-106 CH3 H H -nC3H7Ⅳ-107 CH3 H H -异C3H7Ⅳ-108 CH3 H H -nC4H9Ⅳ-109 CH3 H H -叔C4H9Ⅳ-110 CH3 H H -环C3H5Ⅳ-111 CH3 H H -环C4H7Ⅳ-112 CH3 H H -环C5H9Ⅳ-113 CH3 H H -环C6H11Ⅳ-114 CH3 H H -环C7H12Ⅳ-115 CH3 H H -CH2-O-CH3Ⅳ-116 CH3 H H -CH2-CH2-O-CH3Ⅳ-117 CH3 H H -CH2-C6H5Ⅳ-118 CH3 H H -C6H5Ⅳ-119 CH3 H H -(4-HO-C6H5)Ⅳ-120 CH3 H H -(2-CF3-C6H4)Ⅳ-121 CH3 H H -(3-CF3-C6H4)Ⅳ-122 CH3 H H -(4-CF3-C6H4)Ⅳ-123 CH3 H H -(2-OCH3-C6H4)Ⅳ-124 CH3 H H -(3-OCH3-C6H4)Ⅳ-125 CH3 H H -(4-OCH3-C6H4)Ⅳ-126 CH3 H H -(2-SCH3-C6H4)Ⅳ-127 CH3 H H -(3-SCH3-C6H4)Ⅳ-128 CH3 H H -(4-SCH2-C6H4)Ⅳ-129 CH3 H H -(2-N(CH3)2-C6H4)Ⅳ-130 CH3 H H -(3-N(CH3)2-C6H4)Ⅳ-131 CH3 H H -(4-N(CH3)2-C6H4)Ⅳ-132 CH3 H H -(4-CN-C6H4)Ⅳ-133 CH3 H H -(4-Cl-C6H4)Ⅳ-134 CH3 H H -(4-Br-C6H4)Ⅳ-135 CH3 H H -(4-F-C6H4)Ⅳ-136 CH3 H H -(4-CH3-C6H4)Ⅳ-137 CH3 H H -(2-NO2-C6H4)Ⅳ-138 CH3 H H -(3-NO2-C6H4)Ⅳ-139 CH3 H H -(4-NO2-C6H4)Ⅳ-140 CH3 H H -(2,4-OCH3-C6H3)Ⅳ-141 CH3 H H -(3,4-OCH3-C6H3)Ⅳ-142 CH3 H H -(3,4,5-OCH3-C6H2)Ⅳ-143 CH3 H H -(3,4-CH2OCH2-C6H3)Ⅳ-144 CH3 H H -(2,3-CH2OCH2-C6H3)Ⅳ-145 CH3 H H -2-吡啶基Ⅳ-146 CH3 H H -2-呋喃基Ⅳ-147 CH3 H H -2-噻吩基Ⅳ-148 CH3 H H -3-吡啶基Ⅳ-149 CH3 H H -3-呋喃基Ⅳ-150 CH3 H H -3-噻吩基Ⅳ-151 CH3 H H -4-吡啶基Ⅳ-152 CH3 H H -2-噻唑基Ⅳ-153 CH3 H H -2-噁唑基Ⅳ-154 CH3 H H -3-异噁唑基Ⅳ-155 CH3 H H -4-异噁唑基Ⅳ-156 CH3 H H -5-异噁唑基Ⅳ-157 CH3 H H -CF3Ⅳ-158 CH3 H H -C2F5Ⅳ-159 CH3 H H -CH3Ⅳ-160 CH3 H H -C2H5Ⅳ-161 CH3 H H -nC3H7Ⅳ-162 CH3 H H -tertC4H9Ⅳ-163 CH3 H H -CH2-C6H5Ⅳ-164 CH3 H H -C6H5Ⅳ-165 CH3 H H -CH2-COOCH3Ⅳ-166 CH3 H H -CH2-COOC2H5Ⅳ-167 CH3 H H -CF2-COOCH3Ⅳ-168 CH3 H H -CF2-COOC2H5Ⅳ-169 CH3 H H -CH2-CONH2Ⅳ-170 CH3 H H -CH2-CONHCH3Ⅳ-171 CH3 H H -CH2-CON(CH3)2Ⅳ-172 CH3 H H -CH2-CONH-CH2-C6H5Ⅳ-173 CH3 H H -CH2-CONH-C6H5Ⅳ-174 CH3 H H -CH2-CONH(CH2-C6H5)2Ⅳ-175 CH3 H H -CH2-CON(-CH2-CH2-CH2-CH2-)Ⅳ-176 CH3 H H -CH2-CON (-CH2-CH2-CH2-CH2-CH2)Ⅳ-177 CH3 H H -CH2-CH2-COOCH3Ⅳ-178 CH3 H H -CH2-CH2-COOC2H5Ⅳ-179 CH3 H H -CH2-CH2-CONH2Ⅳ-180 CH3 H H -CH2-CH2-CONHCH3Ⅳ-181 CH3 H H -CH2-CH2-CON(CH3)2Ⅳ-182 CH3 H H -CH2-CH2-CONH-CH2-C6H5Ⅳ-183 CH3 H H -CH2-CH2-CONH-C6H5Ⅳ-184 CH3 H H -CH2-CH2-CONH(CH2-C6H5)2Ⅳ-185 CH3 H H -CH2-CH2-CON(-CH2-CH2-CH2-CH2-)Ⅳ-186 CH3 H H -CH2-CH2-CON(-CH2-(CH2)3-CH2)Ⅳ-187 CH3 H H -CH2-COCH3Ⅳ-188 CH3 H H -CH2-CH2-COCH3Ⅳ-189 CH3 H H -CH2-COC2H5Ⅳ-190 CH3 H H -CH2-CH2-COC2H5Ⅳ-191 CH3 H H -CH2-CO-C6H5Ⅳ-192 CH3 H H -CH2-CH2-CO-C6H5Ⅳ-193 CH3 H H -CH2-CO-CH2-C6H5Ⅳ-194 CH3 H H -CH2-CH2-CO-CH2-C6H5Ⅳ-195 CH3 H H -CH2-SOC6H5Ⅳ-196 CH3 H H -CH2-SOCH3Ⅳ-197 CH3 H H -CH2-SO(4-CH3-C6H4)Ⅳ-198 CH3 H H -CH2-SO2C6H5Ⅳ-199 CH3 H H -CH2-SO2CH3Ⅳ-200 CH3 H H -CH2-SO2(4-CH3-C6H4)Ⅳ-201 CH3 H H -CH2-CH2-SOC6H5Ⅳ-202 CH3 H H -CH2-CH2-SOCH3Ⅳ-203 CH3 H H -CH2-CH2-SO(4-CH3-C6H4)Ⅳ-204 CH3 H H -CH2-CH2-SO2C6H5Ⅳ-205 CH3 H H -CH2-CH2-SO2CH3Ⅳ-206 CH3 H H -CH2-CH2-SO2(4-CH3-C6H4)
表5A是Me2Val,B是Val,D是MeVal,E是Pro,F是式Ⅱf，取代基-(C=O)-G在相对于氮原子的3位，G是式Ⅴg、Ⅵg、Ⅶg、Ⅷg或Ⅸg。No. RF R1 F R2 F -GⅤ-1 H H H -CH3Ⅴ-2 H H H -C2H5Ⅴ-3 H H H -nC3H7Ⅴ-4 H H H -异C3H7Ⅴ-5 H H H -nC4H9Ⅴ-6 H H H -叔C4H9Ⅴ-7 H H H -环C3H5Ⅴ-8 H H H -环C4H7Ⅴ-9 H H H -环C5H9Ⅴ-10 H H H -环C6H11Ⅴ-11 H H H -环C7H12Ⅴ-12 H H H -CH2-O-CH3Ⅴ-13 H H H -CH2-CH2-O-CH3Ⅴ-14 H H H -CH2-C6H5Ⅴ-15 H H H -C6H5Ⅴ-16 H H H -(4-HO-C6H5)Ⅴ-17 H H H -(2-CF3-C6H4)Ⅴ-18 H H H -(3-CF3-C6H4)Ⅴ-19 H H H -(4-CF3-C6H4)Ⅴ-20 H H H -(2-OCH3-C6H4)Ⅴ-21 H H H -(3-OCH3-C6H4)Ⅴ-22 H H H -(4-OCH3-C6H4)Ⅴ-23 H H H -(2-SCH3-C6H4)Ⅴ-24 H H H -(3-SCH3-C6H4)Ⅴ-25 H H H -(4-SCH3-C6H4)Ⅴ-26 H H H -(2-N(CH3)2-C6H4)Ⅴ-27 H H H -(3-N(CH3)2-C6H4)Ⅴ-28 H H H -(4-N(CH3)2-C6H4)Ⅴ-29 H H H -(4-CN-C6H4)Ⅴ-3O H H H -(4-Cl-C6H4)Ⅴ-31 H H H -(4-Br-C6H4)Ⅴ-32 H H H -(4-F-C6H4)Ⅴ-33 H H H -(4-CH3-C6H4)Ⅴ-34 H H H -(2-NO2-C6H4)Ⅴ-35 H H H -(3-NO2-C6H4)Ⅴ-36 H H H -(4-NO2-C6H4)Ⅴ-37 H H H -(2,4-OCH3-C6H3)Ⅴ-38 H H H -(3,4-OCH3-C6H3)Ⅴ-39 H H H -(3,4,5-OCH3-C6H2)Ⅴ-40 H H H -(3,4-CH2OCH2-C6H3)Ⅴ-41 H H H -(2,3-CH2OCH2-C6H3)Ⅴ-42 H H H -2-吡啶基Ⅴ-43 H H H -2-呋喃基Ⅴ-44 H H H -2-噻吩基Ⅴ-45 H H H -3-吡啶基Ⅴ-46 H H H -3-呋喃基Ⅴ-47 H H H -3-噻吩基Ⅴ-48 H H H -4-吡啶基Ⅴ-49 H H H -2-噻唑基Ⅴ-50 H H H -2-噁唑基Ⅴ-51 H H H -3-异噁唑基Ⅴ-52 H H H -4-异噁唑基Ⅴ-53 H H H -5-异噁唑基Ⅴ-54 H H H -CF3Ⅴ-55 H H H -C2F5Ⅴ-56 H H H -CH3Ⅴ-57 H H H -C2H5Ⅴ-58 H H H -nC3H7Ⅴ-59 H H H -tertC4H9Ⅴ-60 H H H -CH2-C6H5Ⅴ-61 H H H -C6H5Ⅴ-62 H H H -CH2-COOCH3Ⅴ-63 H H H -CH2-COOC2H5Ⅴ-64 H H H -CF2-COOCH3Ⅴ-65 H H H -CF2-COOC2H5Ⅴ-66 H H H -CH2-CONH2Ⅴ-67 H H H -CH2-CONHCH3Ⅴ-68 H H H -CH2-CON(CH3)2Ⅴ-69 H H H -CH2-CONH-CH2-C6H5Ⅴ-70 H H H -CH2-CONH-C6H5Ⅴ-71 H H H -CH2-CONH(CH2-C6H5)2Ⅴ-72 H H H -CH2-CON(-CH2-CH2-CH2-CH2-)Ⅴ-73 H H H -CH2-CON(-CH2-CH2-CH2-CH2-CH2)Ⅴ-74 H H H -CH2-CH2-COOCH3Ⅴ-75 H H H -CH2-CH2-COOC2H5Ⅴ-76 H H H -CH2-CH2-CONH2Ⅴ-77 H H H -CH2-CH2-CONHCH3Ⅴ-78 H H H -CH2-CH2-CON(CH3)2Ⅴ-79 H H H -CH2-CH2-CONH-CH2-C6H5Ⅴ-80 H H H -CH2-CH2-CONH-C6H5Ⅴ-81 H H H -CH2-CH2-CONH(CH2-C6H5)2Ⅴ-82 H H H -CH2-CH2-CON(-CH2-CH2-CH2-CH2-)Ⅴ-83 H H H -CH2-CH2-CON(-CH2-(CH2)3-CH2)Ⅴ-84 H H H -CH2-COCH3Ⅴ-85 H H H -CH2-CH2-COCH3Ⅴ-86 H H H -CH2-COC2H5Ⅴ-87 H H H -CH2-CH2-COC2H5Ⅴ-88 H H H -CH2-CO-C6H5Ⅴ-89 H H H -CH2-CH2-CO-C6H5Ⅴ-90 H H H -CH2-CO-CH2-C6H5Ⅴ-91 H H H -CH2-CH2-CO-CH2-C6H5Ⅴ-92 H H H -CH2-SOC6H5Ⅴ-93 H H H -CH2-SOCH3Ⅴ-94 H H H -CH2-SO(4-CH3-C6H4)Ⅴ-95 H H H -CH2-SO2C6H5Ⅴ-96 H H H -CH2-SO2CH3Ⅴ-97 H H H -CH2-SO2(4-CH3-C6H4)Ⅴ-98 H H H -CH2-CH2-SOC6H5Ⅴ-99 H H H -CH2-CH2-SOCH3Ⅴ-100 H H H -CH2-CH2-SO(4-CH3-C6H4)Ⅴ-101 H H H -CH2-CH2-SO2C6H5Ⅴ-102 H H H -CH2-CH2-SO2CH3Ⅴ-103 H H H -CH2-CH2-SO2(4-CH3-C6H4)Ⅴ-104 CH3 H H -CH3Ⅴ-105 CH3 H H -C2H5Ⅴ-106 CH3 H H -nC3H7Ⅴ-107 CH3 H H -异C3H7Ⅴ-108 CH3 H H -nC4H9Ⅴ-109 CH3 H H -叔C4H9Ⅴ-110 CH3 H H -环C3H5Ⅴ-111 CH3 H H -环C4H7Ⅴ-112 CH3 H H -环C5H9Ⅴ-113 CH3 H H -环C6H11Ⅴ-114 CH3 H H -环C7H12Ⅴ-115 CH3 H H -CH2-O-CH3Ⅴ-116 CH3 H H -CH2-CH2-O-CH3Ⅴ-117 CH3 H H -CH2-C6H5Ⅴ-118 CH3 H H -C6H5Ⅴ-119 CH3 H H -(4-HO-C6H5)Ⅴ-120 CH3 H H -(2-CF3-C6H4)Ⅴ-121 CH3 H H -(3-CF3-C6H4)Ⅴ-122 CH3 H H -(4-CF3-C6H4)Ⅴ-123 CH3 H H -(2-OCH3-C6H4)Ⅴ-124 CH3 H H -(3-OCH3-C6H4)Ⅴ-125 CH3 H H -(4-OCH3-C6H4)Ⅴ-126 CH3 H H -(2-SCH3-C6H4)Ⅴ-127 CH3 H H -(3-SCH3-C6H4)Ⅴ-128 CH3 H H -(4-SCH3-C6H4)Ⅴ-129 CH3 H H -(2-N(CH3)2-C6H4)Ⅴ-130 CH3 H H -(3-N(CH3)2-C6H4)Ⅴ-131 CH3 H H -(4-N(CH3)2-C6H4)Ⅴ-132 CH3 H H -(4-CN-C6H4)Ⅴ-133 CH3 H H -(4-Cl-C6H4)Ⅴ-134 CH3 H H -(4-Br-C6H4)Ⅴ-135 CH3 H H -(4-F-C6H4)Ⅴ-136 CH3 H H -(4-CH3-C6H4)Ⅴ-137 CH3 H H -(2-NO2-C6H4)Ⅴ-138 CH3 H H -(3-NO2-C6H4)Ⅴ-139 CH3 H H -(4-NO2-C6H4)Ⅴ-140 CH3 H H -(2,4-OCH3-C6H3)Ⅴ-141 CH3 H H -(3,4-OCH3-C6H3)Ⅴ-142 CH3 H H -(3,4,5-OCH3-C6H2)Ⅴ-143 CH3 H H -(3,4-CH2OCH2-C6H3)Ⅴ-144 CH3 H H -(2,3-CH2OCH2-C6H3)Ⅴ-145 CH3 H H -2-吡啶基Ⅴ-146 CH3 H H -2-呋喃基Ⅴ-147 CH3 H H -2-噻吩基Ⅴ-148 CH3 H H -3-吡啶基Ⅴ-149 CH3 H H -3-呋喃基Ⅴ-150 CH3 H H -3-噻吩基Ⅴ-151 CH3 H H -4-吡啶基Ⅴ-152 CH3 H H -2-噻唑基Ⅴ-153 CH3 H H -2-噁唑基Ⅴ-154 CH3 H H -3-异噁唑基Ⅴ-155 CH3 H H -4-异噁唑基Ⅴ-156 CH3 H H -5-异噁唑基Ⅴ-157 CH3 H H -CF3Ⅴ-158 CH3 H H -C2F5Ⅴ-159 CH3 H H -CH3Ⅴ-160 CH3 H H -C2H5Ⅴ-161 CH3 H H -nC3H7Ⅴ-162 CH3 H H -tertC4H9Ⅴ-163 CH3 H H -CH2-C6H5Ⅴ-164 CH3 H H -C6H5Ⅴ-165 CH3 H H -CH2-COOCH3Ⅴ-166 CH3 H H -CH2-COOC2H5Ⅴ-167 CH3 H H -CF2-COOCH3Ⅴ-168 CH3 H H -CF2-COOC2H5Ⅴ-169 CH3 H H -CH2-CONH2Ⅴ-170 CH3 H H -CH2-CONHCH3Ⅴ-171 CH3 H H -CH2-CON(CH3)2Ⅴ-172 CH3 H H -CH2-CONH-CH2-C6H5Ⅴ-173 CH3 H H -CH2-CONH-C6H5Ⅴ-174 CH3 H H -CH2-CONH(CH2-C6H5)2Ⅴ-175 CH3 H H -CH2-CON(-CH2-CH2-CH2-CH2-)Ⅴ-176 CH3 H H -CH2-CON(-CH2-CH2-CH2-CH2-CH2)Ⅴ-177 CH3 H H -CH2-CH2-COOCH3Ⅴ-178 CH3 H H -CH2-CH2-COOC2H5Ⅴ-179 CH3 H H -CH2-CH2-CONH2Ⅴ-180 CH3 H H -CH2-CH2-CONHCH3Ⅴ-181 CH3 H H -CH2-CH2-CON(CH3)2Ⅴ-182 CH3 H H -CH2-CH2-CONH-CH2-C6H5Ⅴ-183 CH3 H H -CH2-CH2-CONH-C6H5Ⅴ-184 CH3 H H -CH2-CH2-CONH(CH2-C6H5)2Ⅴ-185 CH3 H H -CH2-CH2-CON(-CH2-CH2-CH2-CH2-)Ⅴ-186 CH3 H H -CH2-CH2-CON(-CH2-(CH2)3-CH2)Ⅴ-187 CH3 H H -CH2-COCH3Ⅴ-188 CH3 H H -CH2-CH2-COCH3Ⅴ-189 CH3 H H -CH2-COC2H5Ⅴ-190 CH3 H H -CH2-CH2-COC2H5Ⅴ-191 CH3 H H -CH2-CO-C6H5Ⅴ-192 CH3 H H -CH2-CH2-CO-C6H5Ⅴ-193 CH3 H H -CH2-CO-CH2-C6H5Ⅴ-194 CH3 H H -CH2-CH2-CO-CH2-C6H5Ⅴ-195 CH3 H H -CH2- SOC6H5Ⅴ-196 CH3 H H -CH2-SOCH3Ⅴ-197 CH3 H H -CH2-SO(4-CH3-C6H4)Ⅴ-198 CH3 H H -CH2-SO2C6H5Ⅴ-199 CH3 H H -CH2-SO2CH3Ⅴ-200 CH3 H H -CH2-SO2(4-CH3-C6H4)Ⅴ-201 CH3 H H -CH2-CH2-SOC6H5Ⅴ-202 CH3 H H -CH2-CH2-SOCH3Ⅴ-203 CH3 H H -CH2-CH2-SO(4-CH3-C6H4)Ⅴ-204 CH3 H H -CH2-CH2-SO2C6H5Ⅴ-205 CH3 H H -CH2-CH2-SO2CH3Ⅴ-206 CH3 H H -CH2-CH2-SO2(4-CH3-C6H4)
表6A是Me2Val,B是Val,D是MeVal,E是Pro,F是式Ⅱf，取代基-(C=O)-G在相对于氮原子的4位，G是式Ⅴg、Ⅵg、Ⅶg、Ⅷg或Ⅸg。No. RF R1 F R2 F -GⅥ-1 H H H -CH3Ⅵ-2 H H H -C2H5Ⅵ-3 H H H -nC3H7Ⅵ-4 H H H -异C3H7Ⅵ-5 H H H -nC4H9Ⅵ-6 H H H -叔C4H9Ⅵ-7 H H H -环C3H5Ⅵ-8 H H H -环C4H7Ⅵ-9 H H H -环C5H9Ⅵ-10 H H H -环C6H11Ⅵ-11 H H H -环C7H12Ⅵ-12 H H H -CH2-O-CH3Ⅵ-13 H H H -CH2-CH2-O-CH3Ⅵ-14 H H H -CH2-C6H5Ⅵ-15 H H H -C6H5Ⅵ-16 H H H -(4-HO-C6H5)Ⅵ-17 H H H -(2-CF3-C6H4)Ⅵ-18 H H H -(3-CF3-C6H4)Ⅵ-19 H H H -(4-CF3-C6H4)Ⅵ-20 H H H -(2-OCH3-C6H4)Ⅵ-21 H H H -(3-OCH3-C6H4)Ⅵ-22 H H H -(4-OCH3-C6H4)Ⅵ-23 H H H -(2-SCH3-C6H4)Ⅵ-24 H H H -(3-SCH3-C6H4)Ⅵ-25 H H H -(4-SCH3-C6H4)Ⅵ-26 H H H -(2-N(CH3)2-C6H4)Ⅵ-27 H H H -(3-N(CH3)2-C6H4)Ⅵ-28 H H H -(4-N(CH3)2-C6H4)Ⅵ-29 H H H -(4-CN-C6H4)Ⅵ-30 H H H -(4-Cl-C6H4)Ⅵ-31 H H H -(4-Br-C6H4]Ⅵ-32 H H H -(4-F-C6H4]Ⅵ-33 H H H -(4-CH3-C6H4)Ⅵ-34 H H H -(2-NO2-C6H4)Ⅵ-35 H H H -(3-NO2-C6H4)Ⅵ-36 H H H -(4-NO2-C6H4]Ⅵ-37 H H H -(2,4-OCH3-C6H3)Ⅵ-38 H H H -(3,4-OCH3-C6H3)Ⅵ-39 H H H -(3,4,5-OCH3-C6H2)Ⅵ-40 H H H -(3,4-CH2OCH2-C6H3)Ⅵ-41 H H H -(2,3-CH2OCH2-C6H3)Ⅵ-42 H H H -2-吡啶基Ⅵ-43 H H H -2-呋喃基Ⅵ-44 H H H -2-噻吩基Ⅵ-45 H H H -3-吡啶基Ⅵ-46 H H H -3-呋喃基Ⅵ-47 H H H -3-噻吩基Ⅵ-48 H H H -4-吡啶基Ⅵ-49 H H H -2-噁唑基Ⅵ-50 H H H -2-噁唑基Ⅵ-51 H H H -3-异噁唑基Ⅵ-52 H H H -4-异噁唑基Ⅵ-53 H H H -5-异噁唑基Ⅵ-54 H H H -CF3Ⅵ-55 H H H -C2F5Ⅵ-56 H H H -CH3Ⅵ-57 H H H -C2H5Ⅵ-58 H H H -nC3H7Ⅵ-59 H H H -tertC4H9Ⅵ-60 H H H -CH2-C6H5Ⅵ-61 H H H -C6H5Ⅵ-62 H H H -CH2-COOCH3Ⅵ-63 H H H -CH2-COOC2H5Ⅵ-64 H H H -CF2-COOCH3Ⅵ-65 H H H -CF2-COOC2H5Ⅵ-66 H H H -CH2-CONH2Ⅵ-67 H H H -CH2-CONHCH3Ⅵ-68 H H H -CH2-CON(CH3)2Ⅵ-69 H H H -CH2-CONH-CH2-C6H5Ⅵ-70 H H H -CH2-CONH-C6H5Ⅵ-71 H H H -CH2-CONH(CH2-C6H5)2Ⅵ-72 H H H -CH2-CON(-CH2-CH2-CH2-CH2-)Ⅵ-73 H H H -CH2-CON(-CH2-CH2-CH2-CH2-CH2)Ⅵ-74 H H H -CH2-CH2-COOCH3Ⅵ-75 H H H -CH2-CH2-COOC2H5Ⅵ-76 H H H -CH2-CH2-CONH2Ⅵ-77 H H H -CH2-CH2-CONHCH3Ⅵ-78 H H H -CH2-CH2-CON(CH3)2Ⅵ-79 H H H -CH2-CH2-CONH-CH2-C6H5Ⅵ-80 H H H -CH2-CH2-CONH-C6H5Ⅵ-81 H H H -CH2-CH2-CONH(CH2-C6H5)2Ⅵ-82 H H H -CH2-CH2-CON(-CH2-CH2-CH2-CH2-)Ⅵ-83 H H H -CH2-CH2-CON(-CH2-(CH2)3-CH2)Ⅵ-84 H H H -CH2-COCH3Ⅵ-85 H H H -CH2-CH2-COCH3Ⅵ-86 H H H -CH2-COC2H5Ⅵ-87 H H H -CH2-CH2-COC2H5Ⅵ-88 H H H -CH2-CO-C6H5Ⅵ-89 H H H -CH2-CH2-CO-C6H5Ⅵ-90 H H H -CH2-CO-CH2-C6H5Ⅵ-91 H H H -CH2-CH2-CO-CH2-C6H5Ⅵ-92 H H H -CH2-SOC6H5Ⅵ-93 H H H -CH2-SOCH3Ⅵ-94 H H H -CH2-SO(4-CH3-C6H4)Ⅵ-95 H H H -CH2-SO2C6H5Ⅵ-96 H H H -CH2-SO2CH3Ⅵ-97 H H H -CH2-SO2(4-CH3-C6H4)Ⅵ-98 H H H -CH2-CH2-SOC6H5Ⅵ-99 H H H -CH2-CH2-SOCH3Ⅵ-100 H H H -CH2-CH2-SO(4-CH3-C6H4)Ⅵ-101 H H H -CH2-CH2-SO2C6H5Ⅵ-102 H H H -CH2-CH2-SO2CH3Ⅵ-103 H H H -CH2-CH2-SO2(4-CH3-C6H4)Ⅵ-104 CH3 H H -CH3Ⅵ-105 CH3 H H -C2H5Ⅵ-106 CH3 H H -nC3H7Ⅵ-107 CH3 H H -异C3H7Ⅵ-108 CH3 H H -nC4H9Ⅵ-109 CH3 H H -叔C4H9Ⅵ-110 CH3 H H -环C3H5Ⅵ-111 CH3 H H -环C4H7Ⅵ-112 CH3 H H -环C5H9Ⅵ-113 CH3 H H -环C6H11Ⅵ-114 CH3 H H -环C7H12Ⅵ-115 CH3 H H -CH2-O-CH3Ⅵ-116 CH3 H H -CH2-CH2-O-CH3Ⅵ-117 CH3 H H -CH2-C6H5Ⅵ-118 CH3 H H -C6H5Ⅵ-119 CH3 H H -(4-HO-C6H5)Ⅵ-120 CH3 H H -(2-CF3-C6H4)Ⅵ-121 CH3 H H -(3-CF3-C6H4)Ⅵ-122 CH3 H H -(4-CF3-C6H4)Ⅵ-123 CH3 H H -(2-OCH3-C6H4)Ⅵ-124 CH3 H H -(3-OCH3-C6H4)Ⅵ-125 CH3 H H -(4-OCH3-C6H4)Ⅵ-126 CH3 H H -(2-SCH3-C6H4)Ⅵ-127 CH3 H H -(3-SCH3-C6H4)Ⅵ-128 CH3 H H -(4-SCH3-C6H4)Ⅵ-129 CH3 H H -(2-N(CH3)2-C6H4)Ⅵ-130 CH3 H H -(3-N(CH3)2-C6H4)Ⅵ-131 CH3 H H -(4-N(CH3)2-C6H4)Ⅵ-132 CH3 H H -(4-CN-C6H4)Ⅵ-133 CH3 H H -(4-Cl-C6H4)Ⅵ-134 CH3 H H -(4-Br-C6H4)Ⅵ-135 CH3 H H -(4-F-C6H4)Ⅵ-136 CH3 H H -(4-CH3-C6H4)Ⅵ-137 CH3 H H -(2-NO2-C6H4)Ⅵ-138 CH3 H H -(3-NO2-C6H4)Ⅵ-139 CH3 H H -(4-NO2-C6H4)Ⅵ-140 CH3 H H -(2,4-OCH3-C6H3)Ⅵ-141 CH3 H H -(3,4-OCH3-C6H3)Ⅵ-142 CH3 H H -(3,4,5-OCH3-C6H2)Ⅵ-143 CH3 H H -(3,4-CH2OCH2-C6H3)Ⅵ-144 CH3 H H -(2,3-CH2OCH2-C6H3)Ⅵ-145 CH3 H H -2-吡啶基Ⅵ-146 CH3 H H -2-呋喃基Ⅵ-147 CH3 H H -2-噻吩基Ⅵ-148 CH3 H H -3-吡啶基Ⅵ-149 CH3 H H -3-呋喃基Ⅵ-150 CH3 H H -3-噻吩基Ⅵ-151 CH3 H H -4-吡啶基Ⅵ-152 CH3 H H -2-噻唑基Ⅵ-153 CH3 H H -2-噁唑基Ⅵ-154 CH3 H H -3-异噁唑基Ⅵ-155 CH3 H H -4-异噁唑基Ⅵ-156 CH3 H H -5-异噁唑基Ⅵ-157 CH3 H H -CF3Ⅵ-158 CH3 H H -C2F5Ⅵ-159 CH3 H H -CH3Ⅵ-160 CH3 H H -C2H5Ⅵ-161 CH3 H H -nC3H7Ⅵ-162 CH3 H H -叔C4H9Ⅵ-163 CH3 H H -CH2-C6H5Ⅵ-164 CH3 H H -C6H5Ⅵ-165 CH3 H H -CH2-COOCH3Ⅵ-166 CH3 H H -CH2-COOC2H5Ⅵ-167 CH3 H H -CF2-COOCH3Ⅵ-168 CH3 H H -CF2-COOC2H5Ⅵ-169 CH3 H H -CH2-CONH2Ⅵ-170 CH3 H H -CH2-CONHCH3Ⅵ-171 CH3 H H -CH2-CON(CH3)2Ⅵ-172 CH3 H H -CH2-CONH-CH2-C6H5Ⅵ-173 CH3 H H -CH2-CONH-C6H5Ⅵ-174 CH3 H H -CH2-CONH(CH2-C6H5)2Ⅵ-175 CH3 H H -CH2-CON(-CH2-CH2-CH2-CH2-)Ⅵ-176 CH3 H H -CH2-CON(-CH2-CH2-CH2-CH2-CH2)Ⅵ-177 CH3 H H -CH2-CH2-COOCH3Ⅵ-178 CH3 H H -CH2-CH2-COOC2H5Ⅵ-179 CH3 H H -CH2-CH2-CONH2Ⅵ-180 CH3 H H -CH2-CH2-CONHCH3Ⅵ-181 CH3 H H -CH2-CH2-CON(CH3)2Ⅵ-182 CH3 H H -CH2-CH2-CONH-CH2-C6H5Ⅵ-183 CH3 H H -CH2-CH2-CONH-C6H5Ⅵ-184 CH3 H H -CH2-CH2-CONH(CH2-C6H5)2Ⅵ-185 CH3 H H -CH2-CH2-CON(-CH2-CH2-CH2-CH2-)Ⅵ-186 CH3 H H -CH2-CH2-CON(-CH2-(CH2)3-CH2)Ⅵ-187 CH3 H H -CH2-COCH3Ⅵ-188 CH3 H H -CH2-CH2-COCH3Ⅵ-189 CH3 H H -CH2-COC2H5Ⅵ-190 CH3 H H -CH2-CH2-COC2H5Ⅵ-191 CH3 H H -CH2-CO-C6H5Ⅵ-192 CH3 H H -CH2-CH2-CO-C6H5Ⅵ-193 CH3 H H -CH2-CO-CH2-C6H5Ⅵ-194 CH3 H H -CH2-CH2-CO-CH2-C6H5Ⅵ-195 CH3 H H -CH2-SOC6H5Ⅵ-196 CH3 H H -CH2-SOCH3Ⅵ-197 CH3 H H -CH2-SO(4-CH3-C6H4)Ⅵ-198 CH3 H H -CH2-SO2C6H5Ⅵ-199 CH3 H H -CH2-SO2CH3Ⅵ-200 CH3 H H -CH2-SO2(4-CH3-C6H4)Ⅵ-201 CH3 H H -CH2-CH2-SOC6H5Ⅵ-202 CH3 H H -CH2-CH2-SOCH3Ⅵ-203 CH3 H H -CH2-CH2-SO(4-CH3-C6H4)Ⅵ-204 CH3 H H -CH2-CH2-SO2C6H5Ⅵ-205 CH3 H H -CH2-CH2-SO2CH3Ⅵ-206 CH3 H H -CH2-CH2-SO2(4-CH3-C6H4)
表7A是Me2Val,B是Val,D是MeVal,E是Pro,F是式Ⅲf，取代基-(C=O)-G在相对于氮原子的2位，af是1,G是式Ⅱg或Ⅲg。该化合物是非对映体的混合物，在F中的构型为R,S(顺)或S,R(顺)。No. Rf -GⅦ-1 H -NH-CH3Ⅶ-2 H -NH-CH2-C6H5Ⅶ-3 H -NH-异C3H7Ⅶ-4 H -NH-C6H5Ⅶ-5 H 1,3-噻唑-2-基-酰胺Ⅶ-6 H -NH-CH3Ⅶ-7 H -NH-CH3Ⅶ-8 H -NH-C2H5Ⅶ-9 H -NH-nC3H7Ⅶ-10 H -NH-nC4H9Ⅶ-11 H -NH-叔C4H9Ⅶ-12 H -NH-环C3H5Ⅶ-13 H -NH-环C4H7Ⅶ-14 H -NH-环C5H9Ⅶ-15 H -NH-环C6H11Ⅶ-16 H -NH-环C7H12Ⅶ-17 H -NH-CH2-O-CH3Ⅶ-18 H -NH-CH2-CH2-O-CH3Ⅶ-19 H -NH-1-金刚烷基Ⅶ-20 H -NH-(4-HO-C6H5)Ⅶ-21 H -NH-(2-CF3-C6H4)Ⅶ-22 H -NH-(3-CF3-C6H4)Ⅶ-23 H -NH-(4-CF3-C6H4)Ⅶ-24 H -NH-(2-OCH3-C6H4)Ⅶ-25 H -NH-(3-OCH3-C6H4)Ⅶ-26 H -NH-(4-OCH3-C6H4)Ⅶ-27 H -NH-(2-SCH3-C6H4)Ⅶ-28 H -NH-(3-SCH3-C6H4)Ⅶ-29 H -NH-(4-SCH3-C6H4)Ⅶ-30 H -NH-(2-N(CH3)2-C6H4)Ⅶ-31 H -NH-(3-N(CH3)2-C6H4)Ⅶ-32 H -NH-(4-N(CH3)2-C6H4)Ⅶ-33 H -NH-(4-CN-C6H4)Ⅶ-34 H -NH-(4-Cl-C6H4)Ⅶ-35 H -NH-(4-Br-C6H4)Ⅶ-36 H -NH-(4-F-C6H4]Ⅶ-37 H -NH-(4-CH3-C6H4)Ⅶ-38 H -NH-(2-NO2-C6H4)Ⅶ-39 H -NH-(3-NO2-C6H4)Ⅶ-40 H -NH-(4-NO2-C6H4)Ⅶ-41 H -NH-(2,4-OCH3-C6H3)Ⅶ-42 H -NH-(3,4-OCH3-C6H3)Ⅶ-43 H -NH-(3,4,5-OCH3-C6H2)Ⅶ-44 H -NH-(3,4-CH2OCH2-C6H3)Ⅶ-45 H -NH-(2,3-CH2OCH2-C6H3)Ⅶ-46 H -NH-2-吡啶基Ⅶ-47 H -NH-2-呋喃基Ⅶ-48 H -NH-2-噻吩基Ⅶ-49 H -NH-3-吡啶基Ⅶ-50 H -NH-3-呋喃基Ⅶ-51 H -NH-3-噻吩基Ⅶ-52 H -NH-4-吡啶基Ⅶ-53 H -NH-2-噁唑基Ⅶ-54 H -NH-3-异噁唑基Ⅶ-55 H -NH-4-异噁唑基Ⅶ-56 H -NH-5-异噁唑基Ⅶ-57 H -NH-2R-(丁-2-基)Ⅶ-58 H -NH-2S-(丁-2-基)Ⅶ-59 H -NH-O-CH3Ⅶ-60 H -N(CH3)(OCH3)Ⅶ-61 H -N(-(CH2)3-O-)Ⅶ-62 H -NH-O-CH2-C6H5Ⅶ-63 H -N(CH3)(O-CH2-C6H5)Ⅶ-64 H -N(-(CH2)2-CH(C6H5)-O-)Ⅶ-65 H -NH-O-C2H5Ⅶ-66 H -N(C2H5)(OC2H5)Ⅶ-67 H -N(CH3)(OC2H5)Ⅶ-68 H -NH-O-异C3H7Ⅶ-69 H -N(CH3)(O-异C3H7)Ⅶ-70 H -NH-O-nC3H7Ⅶ-71 H -N(CH3)(O-nC3H7)Ⅶ-72 H -NH-O-nC4H9Ⅶ-73 H -N(CH3)(O-nC4H9)Ⅶ-74 H -NH-O-叔C4H9Ⅶ-75 H -N(CH3)(O-叔C4H9)Ⅶ-76 H -NH-O-C6H5Ⅶ-77 H -N(CH3)(O-C6H5)Ⅶ-78 H -N(CH3)2Ⅶ-79 H -N(CH2-C6H5)2Ⅶ-80 H -N(C2H5)2Ⅶ-81 H -N(异C3H7)2Ⅶ-82 H -N(nC3H7)2Ⅶ-83 H -N(nC4H9)2Ⅶ-84 H -N(C6H5)2Ⅶ-85 H -NH-CH2-CH2-OHⅦ-86 H -NH-(CH2)3-OHⅦ-87 H -NH(-(CH2)2-CH(C6H5)-OH)Ⅶ-88 H -NH-(CH2)4-OHⅦ-89 H -NH(-CH(CH3)-CH2-OH)Ⅶ-90 H -NH(-CH2-CH(CH3)-OH)Ⅶ-91 H -NH(-CH(CH3)-(CH2)2-OH)Ⅶ-92 H -NH(-(CH2)2-CH(CH3)-OH)Ⅶ-93 CH3 -NH-CH3Ⅶ-94 CH3 -NH-CH2-C6H5Ⅶ-95 CH3 -NH-异C3H7Ⅶ-96 CH3 -NH-C6H5Ⅶ-97 CH3 -NH-C2H5Ⅶ-98 CH3 -NH-nC3H7Ⅶ-99 CH3 -NH-nC4H9Ⅶ-100 CH3 -NH-叔C4H9Ⅶ-101 CH3 -NH-环C3H5Ⅶ-102 CH3 -NH-环C4H7Ⅶ-103 CH3 -NH-环C5H9Ⅶ-104 CH3 -NH-环C6H11Ⅶ-105 CH3 -NH-1-金刚烷基Ⅶ-106 CH3 -NH-2R-(丁-2-基)Ⅶ-107 CH3 -NH-2S-(丁-2-基)Ⅶ-108 CH3 -NH-O-CH3Ⅶ-109 CH3 -N(CH3)(OCH3)Ⅶ-110 CH3 -N(-(CH2)3-O-)Ⅶ-111 CH3 -N(CH3)2Ⅶ-112 CH3 -N(CH2-C6H5)2Ⅶ-113 CH3 -N(C2H5)2Ⅶ-114 CH3 -N(异C3H7)2Ⅶ-115 CH3 -N(nC3H7)2Ⅶ-116 CH3 -N(nC4H9)2Ⅶ-117 CH3 -N(C6H5)2
表8A是Me2Val,B是Val,D是MeVal,E是Pro,F是式Ⅲf，取代基-(C=O)-G在相对于氮原子的2位，以及af是1,G是式Ⅱg或Ⅲg。该化合物是非对映体的混合物，在F中的构型为R,R(反)或S,S(反)。No. Rf -GⅧ-1 H -NH-CH3Ⅷ-2 H -NH-CH2-C6H5Ⅷ-3 H -NH-异C3H7Ⅷ-4 H -NH-C6H5Ⅷ-5 H 1,3-噻唑-2-基-酰胺Ⅷ-6 H -NH-CH3Ⅷ-7 H -NH-CH3Ⅷ-8 H -NH-C2H5Ⅷ-9 H -NH-nC3H7Ⅷ-10 H -NH-nC4H9Ⅷ-11 H -NH-叔C4H9Ⅷ-12 H -NH-环C3H5Ⅷ-13 H -NH-环C4H7Ⅷ-14 H -NH-环C5H9Ⅷ-15 H -NH-环C6H11Ⅷ-16 H -NH-环C7H12Ⅷ-17 H -NH-CH2-O-CH3Ⅷ-18 H -NH-CH2-CH2-O-CH3Ⅷ-19 H -NH-1-金刚烷基Ⅷ-20 H -NH-(4-HO-C6H5)Ⅷ-21 H -NH-(2-CF3-C6H4)Ⅷ-22 H -NH-(3-CF3-C6H4)Ⅷ-23 H -NH-(4-CF3-C6H4)Ⅷ-24 H -NH-(2-OCH3-C6H4)Ⅷ-25 H -NH-(3-OCH3-C6H4)Ⅷ-26 H -NH-(4-OCH3-C6H4)Ⅷ-27 H -NH-(2-SCH3-C6H4)Ⅷ-28 H -NH-(3-SCH3-C6H4)Ⅷ-29 H -NH-(4-SCH3-C6H4)Ⅷ-30 H -NH-(2-N(CH3)2-C6H4)Ⅷ-31 H -NH-(3-N(CH3)2-C6H4)Ⅷ-32 H -NH-(4-N(CH3)2-C6H4)Ⅷ-33 H -NH-(4-CN-C6H4)Ⅷ-34 H -NH-(4-Cl-C6H4)Ⅷ-35 H -NH-(4-Br-C6H4)Ⅷ-36 H -NH-(4-F-C6H4)Ⅷ-37 H -NH-(4-CH3-C6H4)Ⅷ-38 H -NH-(2-NO2-C6H4)Ⅷ-39 H -NH-(3-NO2-C6H4)Ⅷ-40 H -NH-(4-NO2-C6H4)Ⅷ-41 H -NH-(2,4-OCH3-C6H3)Ⅷ-42 H -NH-(3,4-OCH3-C6H3)Ⅷ-43 H -NH-(3,4,5-OCH3-C6H2)Ⅷ-44 H -NH-(3,4-CH2OCH2-C6H3)Ⅷ-45 H -NH-(2,3-CH2OCH2-C6H3)Ⅷ-46 H -NH-2-吡啶基Ⅷ-47 H -NH-2-呋喃基Ⅷ-48 H -NH-2-噻吩基Ⅷ-49 H -NH-3-吡啶基Ⅷ-50 H -NH-3-呋喃基Ⅷ-51 H -NH-3-噻吩基Ⅷ-52 H -NH-4-吡啶基Ⅷ-53 H -NH-2-噁唑基Ⅷ-54 H -NH-3-异噁唑基Ⅷ-55 H -NH-4-异噁唑基Ⅷ-56 H -NH-5-异噁唑基Ⅷ-57 H -NH-2R-(丁-2-基)Ⅷ-58 H -NH-2S-(丁-2-基)Ⅷ-59 H -NH-O-CH3Ⅷ-60 H -N(CH3)(OCH3)Ⅷ-61 H -N(-(CH2)3-O-)Ⅷ-62 H -NH-O-CH2-C6H5Ⅷ-63 H -N(CH3)(O-CH2-C6H5)Ⅷ-64 H -N(-(CH2)2-CH(C6H5)-O-)Ⅷ-65 H -NH-O-C2H5Ⅷ-66 H -N(C2H5)(OC2H5)Ⅷ-67 H -N(CH3)(OC2H5)Ⅷ-68 H -NH-O-异C3H7Ⅷ-69 H -N(CH3)(O-异C3H7)Ⅷ-70 H -NH-O-nC3H7Ⅷ-71 H -N(CH3)(O-nC3H7)Ⅷ-72 H -NH-O-nC4H9Ⅷ-73 H -N(CH3)(O-nC4H9)Ⅷ-74 H -NH-O-叔C4H9Ⅷ-75 H -N(CH3)(O-叔C4H9)Ⅷ-76 H -NH-O-C6H5Ⅷ-77 H -N(CH3)(O-C6H5)Ⅷ-78 H -N(CH3)2Ⅷ-79 H -N(CH2-C6H5)2Ⅷ-80 H -N(C2H5)2Ⅷ-81 H -N(异C3H7)2Ⅷ-82 H -N(nC3H7)2Ⅷ-83 H -N(nC4H9)2Ⅷ-84 H -N(C6H5)2Ⅷ-85 H -NH-CH2-CH2-OHⅧ-86 H -NH-(CH2)3-OHⅧ-87 H -NH(-(CH2)2-CH(C6H5)-OH)Ⅷ-88 H -NH-(CH2)4-OHⅧ-89 H -NH(-CH(CH3)-CH2-OH)Ⅷ-90 H -NH(-CH2-CH(CH3)-OH)Ⅷ-91 H -NH(-CH(CH3)-(CH2)2-OH)Ⅷ-92 H -NH(-(CH2)2-CH(CH3)-OH)Ⅷ-93 CH3 -NH-CH3Ⅷ-94 CH3 -NH-CH2-C6H5Ⅷ-95 CH3 -NH-异C3H7Ⅷ-96 CH3 -NH-C6H5Ⅷ-97 CH3 -NH-C2H5Ⅷ-98 CH3 -NH-nC3H7Ⅷ-99 CH3 -NH-nC4H9Ⅷ-100 CH3 -NH-叔C4H9Ⅷ-101 CH3 -NH-环C3H5Ⅷ-102 CH3 -NH-环C4H7Ⅷ-103 CH3 -NH-环C5H9Ⅷ-104 CH3 -NH-环C6H11Ⅷ-105 CH3 -NH-1-金刚烷基Ⅷ-106 CH3 -NH-2R-(丁-2-基)Ⅷ-107 CH3 -NH-2S-(丁-2-基)Ⅷ-108 CH3 -NH-O-CH3Ⅷ-109 CH3 -N(CH3)(OCH3)Ⅷ-110 CH3 -N(-(CH2)3-O-)Ⅷ-111 CH3 -N(CH3)2Ⅷ-112 CH3 -N(CH2-C6H5)2Ⅷ-113 CH3 -N(C2H5)2Ⅷ-114 CH3 -N(异C3H7)2Ⅷ-115 CH3 -N(nC3H7)2Ⅷ-116 CH3 -N(nC4H9)2Ⅷ-117 CH3 -N(C6H5)2
选择的实施例的质谱数据Ⅰ-1 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4C(O)NHCH3
FAB-MS:588(M+H+)Ⅰ-2 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4C(O)NHCH2C6H5
FAB-MS:664(M+H+)Ⅰ-3 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4C(O)NHCH(CH3)2
FAB-MS:616(M+H+)Ⅰ-4 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4C(O)NHC6H5
FAB-MS:650 (M+H+)Ⅰ-5 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4C(O)NH(噻唑-2-基)
FAB-MS:657(M+H+)Ⅰ-6 2(Me2Val-Val-MeVal-ProNH)-4,5-bis(甲氧基)C6H2C(O)NHCH3
FAB-MS:649(M+H+)Ⅰ-7 2-(Me2ValVal-MeVal-ProNH)-3-环戊基-C6H3C(O)NHCH3
FAB-MS:656(M+H+)Ⅰ-64 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CO-N(-(CH2)2-CH(C6H5)O-)
(非对映体混合物)FAB-MS:706(M+H+)Ⅰ-79 2-(Me2Val-Val-MeVal-pro-NH)-C6H4-CO-N(CH2C6H5)2
FAB-MS:754(M+H+)Ⅰ-86 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CO-NH(-(CH2)3-OH)
FAB-MS:632(M+H+)Ⅰ-87 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4C(O)NH((CH2)2CH(C6H5)OH)
FAB-MS:708(M+H+)Ⅰ-143 2-(Me2Val-Val-MeVal-pro-N(CH3))-C6H4-CONHCH3
FAB-MS:601(M+H+)Ⅱ-1 3-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CO-NHCH3
FAB-MS:588(M+H+)Ⅱ-2 3-(Me2Val-Val-MeVal-pro-NH)-C6H4-CO-NH CH2C6H5
FAB-MS:664(M+H+)Ⅳ-1 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CO-CH3
FAB-MS:609(M+H+)Ⅳ-15 2-(Me2Val-Val-MeVal-Pro-NH)-C6H4-CO-C6H5
FAB-MS:635(M+H+)生物学活性评估体外方法
用常规方法测定对粘着细胞系的毒性，例如微量培养四唑氮试验(MTT)。该试验的详细描述参见Alley,M.c．等，《癌症研究》(cancerResearch)48:589-601,1988。用指数生长的肿瘤细胞如HT-29结肠癌或LX-1肺癌的培养物制备微滴定板培养物。将细胞以5000-20,000细胞/孔接种在96孔平板上(在150mL培养液中)，然后于37℃生长过夜。以10-4M至10-10M的10倍稀释液加入试验化合物。然后将细胞保温48小时。为了测定各孔中活细胞的数量，加入MTT染料(50mL 3mg/mL3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物的盐水溶液)。将该混合物于37℃保温5小时，然后向各孔中加入50mL 25％SDS,pH2。保温过夜后，用ELISA读数器测定各孔在550nM下的吸收值。用式％T/C(％活细胞处理/对照)计算平行测定孔的数据的平均值±SD。将给出50％生长抑制的T/C的试验化合物浓度称为IC50。化合物编号 IC50(mol/l)Ⅰ-1 4×10-7Ⅰ-2 ＞10-6Ⅰ-3 5×10-7Ⅰ-4 4×10-7Ⅰ-5 1.5×10-7Ⅰ-6 2×10-7Ⅰ-7 4×10-7Ⅰ-60 4×10-7Ⅰ-64 2.5×10-7Ⅰ-86 6×10-7Ⅰ-87 2×10-7Ⅱ-1 ＞10-6Ⅱ-2 ＞10-6Ⅳ-1 ＞10-6Ⅳ-15 7×10-8Ⅶ-2 ＞10-6体内方法
还可以在各种临床前的试验中测试本发明的化合物的体内活性，这是临床应用的指标。该试验用本领域熟知的移植了肿瘤组织、优选来自人的肿瘤组织(“异种移植”)的裸鼠进行。在向带有异种移植物的小鼠给药试验化合物后评估该化合物的抗肿瘤效力。
更具体地讲，将在无胸腺裸鼠中生长的人肿瘤移植到新的动物内，移植时使用约50mg大小的肿瘤块。将移植的当天指定为第0天。6至10天后，将小鼠用试验化合物通过静脉内或腹膜内注射进行处理，每一剂量下每组5-10只小鼠。每天给药化合物，共给药5天、10天或15天，给药剂量为10-100mg/kg体重。每周两次测定肿瘤的直径的体重。用通过游标卡尺测得的直径和下式计算肿瘤的质量：
(长×宽2)/2=肿瘤重量的mg数计算各治疗组的平均肿瘤重量，确定各组相对于未处理的对照肿瘤的T/C值。
本发明的新化合物在上述试验体系中显示出良好的体外活性。等同形式
虽然参照优选的实施方案对本发明进行了具体的说明和描述，但本领域技术人员应当理解，可以在形式和细节上进行各种改变而不背离所附权利要求所定义的本发明的实质和范围。本领域技术人员将会理解或仅仅通过常规的实验就能够确定文中具体描述的具体实施方案的多种等同形式。所述等同形式均包括在本发明的范围内。
Claims (21)
1．下式化合物或其与可药用酸形成的盐
A-B-D-E-F-G，其中A是式Ⅱa的脯氨酸衍生物
其中na是0-3；Ra是氢或未取代的或被氟取代的直链、支链或环状的C1-C3烷基；R1 a是氢、C1-C3烷基、苯基或取代的苯基；或者Ra和R1 a合在一起形成亚丙基桥；R2 a、R3 a、R4 a和R5 a彼此独立地是氢或烷基；或
式Ⅲa的α-氨基酸衍生物，
其中Ra是氢或未取代的或被氟取代的C1-C3烷基；R1 a是氢或C1-C4烷基；R6 a是烷基、取代的烷基、链烯基、苯基或取代的苯基；或者R1 a是烷基而R6 a是C1-C6烷基、环烷基甲基、苄基或取代的苄基；R7 a是氢或烷基；或
式Ⅳa的α-氨基酸衍生物，其中ma是1或2；R7 a是氢或烷基；Ra是氢、未取代或氟取代的烷基；或式Ⅴa的α-氨基酸衍生物，
其中R7 a是氢或烷基，Ra是氢、未取代的或被氟取代的烷基；或Ⅵa的α-氨基酸，
其中Ra是氢、未取代的或被氟取代的烷基；R1 a是氢、烷基、苯基或取代的苯基；或者Ra和R1 a合在一起形成亚丙基桥；Xa是羟基、烷氧基或氟；或
式Ⅶa的α-氨基酸，
其中Ra是氢、未取代的或被氟取代的烷基；R1 a是氢、烷基、苯基或取代的苯基；或者Ra和R1 a合在一起形成亚丙基桥；R2 a、R3 a、R4 a和R5 a彼此独立地是氢或烷基；或
式Ⅷa的α-氨基酸残基，
其中Ra是氢、未取代的或被氟取代的烷基；或式Ⅸa的2-氮杂二环[2.2.1]庚烷-3-羧酸衍生物，
其中的3-羰基部分处于内型或外型的位置，Za是单键或双键，Ra是氢、未取代的或被氟取代的烷基；或
式Ⅹa的α-氨基酸残基，
其中na是1、2或3,R7 a是氢或烷基，Ra是氢、未取代的烷基或被氟取代的烷基；
B是缬氨酰基、异亮氨酰基、别-异亮氨酰基、正缬氨酰基、2-叔丁基甘氨酰基或2-乙基甘氨酰基残基；或
式Ⅱb的α-氨基酸残基，
其中R1 b是氢，和R2 b是烷基或链烯基；或者R1 b和R2 b合在一起形成异亚丙基；
D是N-烷基缬氨酰基、N-烷基-2-乙基甘氨酰基、N-烷基-2-叔丁基甘氨酰基、N-烷基-正亮氨酰基、N-烷基异亮氨酰基、N-烷基-别-异亮氨酰基或N-烷基-正缬氨酰基残基；或
式Ⅱd的α-氨基羧酸残基，
其中Rd是氢、未取代的或被氟取代的烷基；R1 d是氢；R2 d是烷基、取代的烷基或链烯基；或者R1 d和R2 d合在一起是异亚丙基；或
式Ⅲd的α-氨基酸残基，
其中nd是1或2；R3 d是氢、烷基或被氟取代的烷基；Xd是氢；或者nd是1并且Xd是氟、羟基、甲氧基或乙氧基；
E是脯氨酰基、噻唑烷基-4-羰基、高脯氨酰基或羟基脯氨酰基残基，或是式Ⅱe的α-氨基酸残基，
其中ne是0、1或2,R1 e是氢、未取代的或被氟取代的烷基；R2 e和R3 e彼此独立地是氢或烷基；R4 e是氢、羟基或烷氧基；R5 e是氢或氟；或者ne是1并且R3 e和R4 e合在一起形成双键；或者ne是1并且R4 e和R5 e合在一起形成双键连接的氧二价基团；或者ne是1或2并且R1 e和R2 e合在一起形成双键；或
Ⅲe的氨基环戊烷甲酸残基，
其中Re是烷基，R1 e是氢、未取代的或被氟取代的烷基；F是式Ⅱf的氨基苯甲酰基衍生物，
其中Rf是氢原子或烷基；羰基位于氮原子的邻、间或对位；R1 f和R2 f彼此独立地是氢原子；卤原子；C1-C4-烷基；甲氧基、乙氧基、三氟甲基、硝基、氰基、氨基或二甲基氨基；或者R1 f和R2 f可以合在一起形成亚甲二氧基；或者
F是式Ⅲf的氨基环烷基甲酸残基，
其中Rf是氢或烷基；af是0、1或2；羰基位于环烷基环上相对于氮原子的2位或3位；
G是取代或未取代的氨基、肼基、氨基氧基、肟基、芳烷基、杂芳基烷基、芳基、杂芳基、烷氧基羰基烷基、芳氧基羰基烷基、烷氧基羰基、芳氧基羰基、氨基羰基烷基、氨基羰基、烷基羰基烷基、烷基羰基、芳基羰基烷基、芳基羰基、烷基亚磺酰基烷基、烷基亚磺酰基、芳基亚磺酰基烷基、芳基亚磺酰基、烷基磺酰基烷基、烷基磺酰基、芳基磺酰基烷基或芳基磺酰基。
2．权利要求1的化合物，其中的可药用酸是盐酸、柠檬酸、酒石酸、乳酸、磷酸、甲磺酸、乙酸、甲酸、马来酸、富马酸、苹果酸、琥珀酸、丙二酸、硫酸、L-谷氨酸、L-天冬氨酸、丙酮酸、粘酸、苯甲酸、葡糖醛酸、草酸、抗坏血酸和乙酰甘氨酸。
3．权利要求1的化合物，其中G是式Ⅱg的一价基团，
其中
R1 l是氢原子、直链或支链、饱和或不饱和的C1-C18-烷氧基、取代或未取代的芳氧基、取代或未取代的芳基-C1-C6-烷氧基、取代或未取代的芳氧基-C1-C6-烷氧基，其中的芳基取代基包括一个或多个卤原子或一个或多个C1-C4-烷基、甲氧基、乙氧基、三氟甲基、硝基或亚甲二氧基；或杂芳基-C1-C6-烷氧基，其中的杂芳基衍生自咪唑、异噁唑、异噻唑、噻唑、噁唑、吡唑、噻吩、呋喃、吡咯、1,2,4-或1,2,3-三唑、吡嗪、吲哚、苯并呋喃、苯并噻吩、吲哚、异吲哚、吲唑、喹啉、哒嗪、嘧啶、苯并咪唑、苯并吡喃、苯并噻唑、噁二唑、噻二唑或吡啶；
R2 l是氢原子、直链或支链的C1-C18-烷基、直链的C1-C18-链烯基、C3-C10-环烷基、芳基或取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷基、烷氧基、亚甲二氧基、三氟甲基或硝基；或杂芳基或取代的杂芳基，其中的杂芳基衍生自咪唑、异噁唑、异噻唑、噻唑、噁唑、吡唑、噻吩、呋喃、吡咯、1,2,4-或1,2,3-三唑、吡嗪、吲哚、苯并呋喃、苯并噻吩、异吲哚、吲唑、喹啉、哒嗪、嘧啶、苯并咪唑、苯并吡喃、苯并噻唑、噁二唑、噻二唑或吡啶，并且杂芳基的取代基包括一个或多个C1-C6-烷基、羟基或苯基；或式Ⅱl的一价基团，
其中al是0、1、2、3、4或5；R3 l是甲基、乙基、正丙基或异丙基；R4 l是饱和或部分不饱和的含有3至10个碳原子的碳环体系、芳基或取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、亚甲二氧基、三氟甲基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；或取代或未取代的杂芳基，其中的杂芳基衍生自咪唑、吡咯、噻吩、呋喃、噻唑、噁唑、吡唑、1,2,4-或1,2,3-三唑、噁二唑、噻二唑、异噁唑、异噻唑、吡嗪、哒嗪、嘧啶、吡啶、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并吡喃、吲哚、异吲哚、吲唑或喹啉，并且杂芳基取代基包括一个或多个C1-C6-烷基、羟基或苯基；或
式Ⅲl的一价基团，
-(CH2)2-W1-R5 l (Ⅲl)，
其中W1是N-R6 l基团、氧原子或硫原子，R5 l和R6 l彼此独立地是氢原子或C1-C4-烷基、C3-C7-环烷基、芳基、芳基甲基或取代的芳基或芳基甲基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、亚甲二氧基、三氟甲基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；或者R6 l是C1-C18-链烷酰基或苯甲酰基；或式Ⅳl的一价基团，
其中bl是2、3或4,Z1是甲酰基、氨基羰基、肼基羰基，环状缩醛、环状的硫缩醛、非环的缩醛或非环的硫缩醛基团；或
式Ⅴl的一价基团，
其中bl是2、3或4；R7 l是式-O(CH2-CH2-O)dl-CH3的聚乙二醇基团；其中dl是约2至约4，或是约40至约90；或
式Ⅵl的一价基团，
其中R8 l是氢原子、C1-C4链烷酰基、C1-C4烷基、苯甲酰基或苄基。
4．权利要求1的化合物，其中G是式Ⅲg的β-羟基氨基基团，
其中R9 l是氢原子、C1-C6-烷基、芳基或取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；R10 l是氢原子、甲基或苯基。
5．权利要求1的化合物，其中G是式Ⅳg的肼基，
其中R11 l是氢原子，R12 l是氢原子、直链或支链的C1-C8-烷基、C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、芳基-C1-C4-烷基、芳基、取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；或杂芳基、杂芳基-C1-C4-烷基或取代的杂芳基，其中的杂芳基衍生自咪唑、吡咯、噻吩、呋喃、噻唑、噁唑、吡唑、1,2,4-或1,2,3-三唑、噁二唑、噻二唑、异噁唑、异噻唑、吡嗪、哒嗪、嘧啶、吡啶、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并吡喃、吲哚、异吲哚、吲唑或喹啉，并且杂芳基取代基包括一个或多个C1-C6-烷基、羟基或苯基。
6．权利要求1的化合物，其中G是式-O-R13 l或-S-R13 l的一价基团，R13 l是C3-C10-环烷基、直链或支链的C2-C16-链烯基甲基、C1-C16-烷基或卤素取代的C1-C16-烷基；R13 l是式-(CH2)el-R14 l的一价基团，el是1、2或3,R14 l是饱和或部分不饱和的C3-C10-碳环基团；R13 l是式-[CH2-CH=C(CH3)-CH2]fl-H的一价基团，fl是1、2、3或4；R13 l是式-[CH2-CH2-O]gl-CH3的一价基团，gl是约2至约4，或约40至约90；R13 l是式-(CH2)hl-X的一价基团，hl是0、1、2或3；X是芳基或取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；或者X是杂芳基或取代的杂芳基，其中的杂芳基衍生自咪唑、吡咯、噻吩、呋喃、噻唑、噁唑、吡唑、1,2,4-或1,2,3-三唑、噁二唑、噻二唑、异噁唑、异噻唑、吡嗪、哒嗪、嘧啶、吡啶、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并吡喃、吲哚、异吲哚、吲唑或喹啉，并且杂芳基取代基包括一个或多个C1-C6-烷基、羟基或苯基；R13 l是式-(CH2)bl-W1-R5 l的一价基团，bl是2、3或4,Wl是氧原子、硫原子或NR6 l基团；R5 l是含有约3至约10个碳原子的饱和碳环体系、含有约3至约10个碳原子的部分不饱和的碳环体系、芳基或取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；杂芳基或取代的杂芳基，其中的杂芳基衍生自咪唑、吡咯、噻吩、呋喃、噻唑、噁唑、吡唑、1,2,4-或1,2,3-三唑、噁二唑、噻二唑、异噁唑、异噻唑、吡嗪、哒嗪、嘧啶、吡啶、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并吡喃、吲哚、异吲哚、吲唑或喹啉，并且杂芳基取代基包括一个或多个C1-C6-烷基、羟基或苯基；R6 l是氢原子、C1-C4烷基、C3-C7环烷基、C1-C18链烷酰基、苯甲酰基、芳基甲基、芳基或取代的芳基或芳基甲基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基。
7．权利要求1的化合物，其中G是式-O-N(R16 l)(R15 l)的氨基氧基，其中R15 l和R16 l彼此独立地是氢原子、直链或支链的C1-C8-烷基、卤素取代的直链或支链的C1-C8-烷基、C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、芳基-C1-C4-烷基、芳基或取代的芳基-C1-C4-烷基或芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；杂芳基或取代的杂芳基，其中的杂芳基衍生自咪唑、吡咯、噻吩、呋喃、噻唑、噁唑、吡唑、1,2,4-或1,2,3-三唑、噁二唑、噻二唑、异噁唑、异噻唑、吡嗪、哒嗪、嘧啶、吡啶、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并吡喃、吲哚、异吲哚、吲唑或喹啉，并且杂芳基取代基包括一个或多个C1-C6-烷基、羟基或苯基；或者
R15 l和R16 l与氮原子合在一起形成含有5、6或7个原子的杂环结构。
8．权利要求1的化合物，其中G是式-O-N=C(R15 l)(R16 l)的肟基基团，其中R15 l和R16 l彼此独立地是氢原子、直链或支链的C1-C8-烷基、卤素取代的直链或支链的C1-C8-烷基、C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、芳基-C1-C4-烷基、芳基或取代的芳基-C1-C4-烷基或芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；杂芳基或取代的杂芳基，其中的杂芳基衍生自咪唑、吡咯、噻吩、呋喃、噻唑、噁唑、吡唑、1,2,4-或1,2,3-三唑、噁二唑、噻二唑、异噁唑、异噻唑、吡嗪、哒嗪、嘧啶、吡啶、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并吡喃、吲哚、异吲哚、吲唑或喹啉，并且杂芳基取代基包括一个或多个C1-C6-烷基、羟基或苯基；或者
R15 l和R16 l与碳原子合在一起形成环系、与芳族环系稠合的环系或选自如下的环系：
9．权利要求1的化合物，其中G是氢原子、直链或支链的C1-C8-烷基、卤素取代的直链或支链的C1-C8-烷基、C3-C8-环烷基或C3-C8-环烷基-C1-C4-烷基。
10．权利要求1的化合物，其中G是式Ⅴg的一价基团，
其中ag是0、1或2,R17 l是芳基或取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；或杂芳基或取代的杂芳基，其中的杂芳基衍生自咪唑、吡咯、噻吩、呋喃、噻唑、噁唑、吡唑、1,2,4-或1,2,3-三唑、噁二唑、噻二唑、异噁唑、异噻唑、吡嗪、哒嗪、嘧啶、吡啶、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并吡喃、吲哚、异吲哚、吲唑或喹啉，并且杂芳基取代基包括一个或多个C1-C6-烷基、羟基或苯基。
11．权利要求1的化合物，其中G是式Ⅵg的一价基团，
其中bg是0、1、2或3；cg是0或1；R18 l是氢原子、直链或支链的C1-C8-烷基、卤素取代的直链或支链的C1-C8-烷基、C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、芳基或取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基。
12．权利要求1的化合物，其中G是式Ⅶg的一价基团，
其中dg是0、1、2或3；eg是0或1；R19 l和R20 l彼此独立地是氢原子、直链或支链的C1-C8-烷基、卤素取代的C1-C8-烷基、C3-C8-环烷基、C3-C8-环烷基-C1-C4-烷基、芳基或取代的芳基，其中的芳基取代基包括一个或多个卤原子或一个或多个烷氧基、三氟甲基、亚甲二氧基、硝基、氰基、C1-C7-烷氧基羰基、C1-C7-烷基磺酰基、氨基或C1-C7-二烷基氨基；杂芳基或取代的杂芳基，其中的杂芳基衍生自咪唑、吡咯、噻吩、呋喃、噻唑、噁唑、吡唑、1,2,4-或1,2,3-三唑、噁二唑、噻二唑、异噁唑、异噻唑、吡嗪、哒嗪、嘧啶、吡啶、苯并呋喃、苯并噻吩、苯并咪唑、苯并噻唑、苯并吡喃、吲哚、异吲哚、吲唑或喹啉，并且杂芳基取代基包括一个或多个C1-C6-烷基、羟基或苯基；或者R19 l、R20 l和氮原子形成含有6个或更少碳原子的环系。
13．权利要求1的化合物，其中G是式Ⅷg的亚烷基亚砜或亚烷基砜，
其中gg是1或2,hg是1或2,R21 l是甲基、三氟甲基、乙基或苯基。
14．下式化合物：
A-B-D-E-F-G
其中A是N,N-二甲基缬氨酰基，B是叔-亮氨酰基，D是N-甲基缬氨酰基，E是脯氨酰基，F是氨基苯甲酸残基或氨基环烷基甲酸残基，G是一价基团。
15．下式化合物：
A-B-D-E-F-G
其中A是N,N-二甲基缬氨酰基，B是缬氨酰基，D是N-甲基-叔亮氨酰基，E是脯氨酰基，F是氨基苯甲酸残基或氨基环烷基甲酸残基，G是一价基团。
16．下式化合物：
A-B-D-E-F-G
其中A是N-甲基-d-脯氨酰基，B是缬氨酰基，D是N-甲基缬氨酰基，E是脯氨酰基，F是氨基苯甲酸残基或氨基环烷基甲酸残基，G是一价基团。
17．下式的化合物：
A-B-D-E-F-G
其中A是N-甲基高脯氨酰基，B是缬氨酰基，D是N-甲基缬氨酰基，E是脯氨酰基，F是氨基苯甲酸残基或氨基环烷基甲酸残基，以及G是一价基团。
18．式Me2Val-Val-MeVal-Pro-F-G的化合物，其中F是式Ⅱf以及Rf是氢原子或甲基，R1 f和R2 f各是氢原子、烷基或烷氧基，以及G是氨基、N-取代的氨基、肼基、烷基、环烷基、芳基、或烷基芳基、亚烷基酯、亚烷基酰胺、亚烷基亚砜或亚烷基砜基团或式-O-R13 l或-S-R13 l的一价基团，以及R13 l是烷基、芳基或烷基芳基。
19．式Me2Val-Val-MeVal-Pro-F-G的化合物，其中F是式Ⅲf，以及Rf是氢原子或甲基，af是1或2，以及G是氨基、N-取代的氨基、肼基、烷基、环烷基、芳基或烷基芳基、亚烷基酯、亚烷基酰胺、亚烷基亚砜或亚烷基砜基团或式-O-R13 l或-S-R13 l的一价基团，以及R13 l是烷基、芳基或烷基芳基。
20．在哺乳动物中治疗癌症的方法，该方法包括将治疗有效量的权利要求1的化合物对所述哺乳动物给药。
21．权利要求45的方法，其中所述哺乳动物是人。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/112,249 US5985837A (en) | 1998-07-08 | 1998-07-08 | Dolastatin 15 derivatives |
| US09/112,249 | 1998-07-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1312817A true CN1312817A (zh) | 2001-09-12 |
Family
ID=22342878
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99809741A Pending CN1312817A (zh) | 1998-07-08 | 1999-06-23 | 截尾海兔肽15衍生物 |
Country Status (14)
| Country | Link |
|---|---|
| US (2) | US5985837A (zh) |
| EP (1) | EP1093460A1 (zh) |
| JP (1) | JP2002520335A (zh) |
| KR (1) | KR20010053428A (zh) |
| CN (1) | CN1312817A (zh) |
| AU (1) | AU4708199A (zh) |
| BR (1) | BR9911932A (zh) |
| CA (1) | CA2332641A1 (zh) |
| HK (1) | HK1041007A1 (zh) |
| HU (1) | HUP0103560A3 (zh) |
| IL (1) | IL140578A0 (zh) |
| NO (1) | NO20010046L (zh) |
| WO (1) | WO2000002906A1 (zh) |
| ZA (1) | ZA200100169B (zh) |
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-
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- 1998-07-08 US US09/112,249 patent/US5985837A/en not_active Expired - Fee Related
-
1999
- 1999-06-23 KR KR1020017000268A patent/KR20010053428A/ko not_active Application Discontinuation
- 1999-06-23 CN CN99809741A patent/CN1312817A/zh active Pending
- 1999-06-23 BR BR9911932-3A patent/BR9911932A/pt not_active IP Right Cessation
- 1999-06-23 CA CA002332641A patent/CA2332641A1/en not_active Abandoned
- 1999-06-23 WO PCT/US1999/014099 patent/WO2000002906A1/en not_active Application Discontinuation
- 1999-06-23 HU HU0103560A patent/HUP0103560A3/hu unknown
- 1999-06-23 AU AU47081/99A patent/AU4708199A/en not_active Abandoned
- 1999-06-23 IL IL14057899A patent/IL140578A0/xx unknown
- 1999-06-23 JP JP2000559135A patent/JP2002520335A/ja not_active Withdrawn
- 1999-06-23 EP EP99930569A patent/EP1093460A1/en not_active Withdrawn
-
2001
- 2001-01-04 NO NO20010046A patent/NO20010046L/no not_active Application Discontinuation
- 2001-01-08 ZA ZA200100169A patent/ZA200100169B/en unknown
- 2001-01-08 US US09/756,593 patent/US20010018422A1/en not_active Abandoned
-
2002
- 2002-03-12 HK HK02101870.1A patent/HK1041007A1/zh unknown
Also Published As
| Publication number | Publication date |
|---|---|
| US20010018422A1 (en) | 2001-08-30 |
| IL140578A0 (en) | 2002-02-10 |
| CA2332641A1 (en) | 2000-01-20 |
| JP2002520335A (ja) | 2002-07-09 |
| WO2000002906A1 (en) | 2000-01-20 |
| ZA200100169B (en) | 2002-01-08 |
| EP1093460A1 (en) | 2001-04-25 |
| BR9911932A (pt) | 2001-10-16 |
| HUP0103560A3 (en) | 2002-05-28 |
| US5985837A (en) | 1999-11-16 |
| HUP0103560A2 (hu) | 2002-02-28 |
| NO20010046D0 (no) | 2001-01-04 |
| AU4708199A (en) | 2000-02-01 |
| HK1041007A1 (zh) | 2002-06-28 |
| NO20010046L (no) | 2001-03-02 |
| KR20010053428A (ko) | 2001-06-25 |
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