CN108727468A - 环肽、包含其的医药或化妆品组成物及其制备方法 - Google Patents
环肽、包含其的医药或化妆品组成物及其制备方法 Download PDFInfo
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- CN108727468A CN108727468A CN201810178722.4A CN201810178722A CN108727468A CN 108727468 A CN108727468 A CN 108727468A CN 201810178722 A CN201810178722 A CN 201810178722A CN 108727468 A CN108727468 A CN 108727468A
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- alkyl
- group
- cyclic peptide
- alkyl group
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- 102000001189 Cyclic Peptides Human genes 0.000 title claims abstract description 36
- 108010069514 Cyclic Peptides Proteins 0.000 title claims abstract description 36
- 239000000203 mixture Substances 0.000 title claims abstract description 18
- 239000002537 cosmetic Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 title abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 230000008569 process Effects 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000003054 catalyst Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 230000007704 transition Effects 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 6
- 150000001255 actinides Chemical group 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052768 actinide Inorganic materials 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- FAQSSRBQWPBYQC-VGKOASNMSA-N dioxomolybdenum;(z)-4-hydroxypent-3-en-2-one Chemical compound O=[Mo]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FAQSSRBQWPBYQC-VGKOASNMSA-N 0.000 claims description 2
- ASLHVQCNFUOEEN-UHFFFAOYSA-N dioxomolybdenum;dihydrochloride Chemical compound Cl.Cl.O=[Mo]=O ASLHVQCNFUOEEN-UHFFFAOYSA-N 0.000 claims description 2
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 73
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 62
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 26
- 150000001408 amides Chemical class 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 108090000765 processed proteins & peptides Proteins 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- -1 4-methoxy-2, 3, 6-trimethylbenzenesulfonyl Chemical group 0.000 description 12
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- KSDTXRUIZMTBNV-INIZCTEOSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)butanedioic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)O)C(O)=O)C3=CC=CC=C3C2=C1 KSDTXRUIZMTBNV-INIZCTEOSA-N 0.000 description 11
- 239000007822 coupling agent Substances 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 102000004196 processed proteins & peptides Human genes 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 5
- 0 CCC=CC=[*@]=CC(*CC(CC(N[C@@](*C(O)=O)*(C)=O)=O)*C(C)=O)=C Chemical compound CCC=CC=[*@]=CC(*CC(CC(N[C@@](*C(O)=O)*(C)=O)=O)*C(C)=O)=C 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- BSSAGZFNNLCKNY-MHZLTWQESA-N (2S)-5-[[amino-[(4-methoxy-2,3,6-trimethylphenyl)sulfonylamino]methylidene]amino]-2-[[2-(9H-fluoren-9-ylmethoxycarbonylamino)acetyl]amino]pentanoic acid Chemical compound COc1cc(C)c(c(C)c1C)S(=O)(=O)N\C(N)=N\CCC[C@H](NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc12)C(O)=O BSSAGZFNNLCKNY-MHZLTWQESA-N 0.000 description 4
- 108010016626 Dipeptides Proteins 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 102000006495 integrins Human genes 0.000 description 4
- 108010044426 integrins Proteins 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- TUIAGKJNVWZBOW-UHFFFAOYSA-N [O-][N+](=O)c1cccc(c1C(=O)OC(=O)c1c(cccc1[N+]([O-])=O)[N+]([O-])=O)[N+]([O-])=O Chemical compound [O-][N+](=O)c1cccc(c1C(=O)OC(=O)c1c(cccc1[N+]([O-])=O)[N+]([O-])=O)[N+]([O-])=O TUIAGKJNVWZBOW-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 238000010549 co-Evaporation Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000000921 elemental analysis Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- NFLGAXVYCFJBMK-RKDXNWHRSA-N (+)-isomenthone Natural products CC(C)[C@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-RKDXNWHRSA-N 0.000 description 2
- NFLGAXVYCFJBMK-BDAKNGLRSA-N (-)-menthone Chemical compound CC(C)[C@@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-BDAKNGLRSA-N 0.000 description 2
- DVBUCBXGDWWXNY-SFHVURJKSA-N (2s)-5-(diaminomethylideneamino)-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C3=CC=CC=C3C2=C1 DVBUCBXGDWWXNY-SFHVURJKSA-N 0.000 description 2
- VCIVAWBKUQJNSX-UHFFFAOYSA-N 1-(9h-fluoren-9-ylmethoxycarbonylamino)cyclohexane-1-carboxylic acid Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)NC1(C(=O)O)CCCCC1 VCIVAWBKUQJNSX-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 description 2
- KSIPKXNIQOWMIC-UHFFFAOYSA-N 2-[[2-[(2-amino-4-methylsulfanylbutanoyl)amino]-3-hydroxybutanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound CSCCC(N)C(=O)NC(C(C)O)C(=O)NC(C(O)=O)CCCN=C(N)N KSIPKXNIQOWMIC-UHFFFAOYSA-N 0.000 description 2
- VGVHNLRUAMRIEW-UHFFFAOYSA-N 4-methylcyclohexan-1-one Chemical compound CC1CCC(=O)CC1 VGVHNLRUAMRIEW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- NFLGAXVYCFJBMK-UHFFFAOYSA-N Menthone Chemical compound CC(C)C1CCC(C)CC1=O NFLGAXVYCFJBMK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000000181 anti-adherent effect Effects 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- FPRSPUHXEPWUBZ-OAHLLOKOSA-N benzyl (2r)-2-amino-3-phenylpropanoate Chemical compound C([C@@H](N)C(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 FPRSPUHXEPWUBZ-OAHLLOKOSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229940091173 hydantoin Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229930007503 menthone Natural products 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
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- 229910052750 molybdenum Inorganic materials 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000001725 pyrenyl group Chemical group 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- JZKMIPDOAWBAHE-NVQRDWNXSA-N (2r,3r,4s,5r)-2-[6-[cyclohexyl(prop-2-enyl)amino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(N(CC=C)C3CCCCC3)=C2N=C1 JZKMIPDOAWBAHE-NVQRDWNXSA-N 0.000 description 1
- JYMVSZGJZRQOFY-UHFFFAOYSA-N (4-nitrobenzoyl) 4-nitrobenzoate Chemical compound C1=CC([N+](=O)[O-])=CC=C1C(=O)OC(=O)C1=CC=C([N+]([O-])=O)C=C1 JYMVSZGJZRQOFY-UHFFFAOYSA-N 0.000 description 1
- JFIJBPZIPDYERJ-RLBMWQAVSA-N (6S,9R)-9-methyl-6-propan-2-yl-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound C(C)(C)[C@@H]1CC[C@H](CC11C(NC(N1)=O)=O)C JFIJBPZIPDYERJ-RLBMWQAVSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 description 1
- PIINXYKJQGMIOZ-UHFFFAOYSA-N 1,2-dipyridin-2-ylethane-1,2-dione Chemical compound C=1C=CC=NC=1C(=O)C(=O)C1=CC=CC=N1 PIINXYKJQGMIOZ-UHFFFAOYSA-N 0.000 description 1
- WOXWUZCRWJWTRT-UHFFFAOYSA-N 1-amino-1-cyclohexanecarboxylic acid Chemical class OC(=O)C1(N)CCCCC1 WOXWUZCRWJWTRT-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
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- 240000008570 Digitaria exilis Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 235000010575 Pueraria lobata Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
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- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
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- JBCMPTHWXJGFJC-UHFFFAOYSA-N benzyl 1-aminocyclohexane-1-carboxylate Chemical compound C=1C=CC=CC=1COC(=O)C1(N)CCCCC1 JBCMPTHWXJGFJC-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
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- 230000002500 effect on skin Effects 0.000 description 1
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- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- MQWCXKGKQLNYQG-UHFFFAOYSA-N methyl cyclohexan-4-ol Natural products CC1CCC(O)CC1 MQWCXKGKQLNYQG-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 125000005287 vanadyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000037373 wrinkle formation Effects 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/08—Anti-ageing preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
本发明揭露一种下列式(I)或(I’)所表示的环肽: 其中,R1如说明书的定义。此外,也揭露包含其的医药或化妆品组合物及其制备方法。
Description
技术领域
本发明关于一环肽(cyclopeptide)、包含其的医药或化妆品组合物及 其制备方法。更具体地,本发明关于局部或化妆品皮肤护理的环肽、包含 其的医药或化妆品组成物及其制备方法。
背景技术
肽(peptide)已被广泛应用于各种领域,例如局部或化妆品皮肤护理。 在已知的肽中,发现具有精胺酸(R)-甘胺酸(G)-天门冬胺酸(D)构型 (arginine(R)-glycine(G)-aspartate(D)motif)的肽作为细胞辨识中常见的单 元。
已知包含RGD构型(motif)的肽可以结合于整合素(intergrin)RGD结合 位,且可通过模拟体内条件而涂布于组织工程中的合成支架以来增强细胞 的附着。
在制备含有RGD构型的肽的常规方法中,必须使用耦合剂来催化肽 的均相或固相合成。然而,耦合剂的使用量并不少,且耦合剂本身的成本 很高,因此,肽的生产成本不低,且所获得的肽并非全部可用。
因此,希望提供一种包含RGD构型的新肽,以及制备该肽的新方法; 因此,所获得的肽可广泛应用于各种领域。
发明内容
本发明的目的在于提供一种新的环肽及包含其的医药或化妆品组成 物。
本发明的RGD-和GRD-环肽分别由下列式(I)和(I’)所表示:
其中,
R1为
R2和R3各自独立为H或C1-6烷基;
X为O、S、CH2、或N-R4,其中,R4为H、C1-6烷基、(CH2CH2O)nH、 -C(=O)-C1-10烷基、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3。
优选地,在本发明的环肽中,当X为CH2时R3为C1-6烷基。
本发明的医药或化妆品组成物包含:一赋形剂、铜(II)离子、或氧钒(II) 离子;以及上述本发明的环肽。
在本发明的环肽及医药或化妆品组成物中,X优选为O、S、CH2、或 N-R4,其中,R4为H、C1-6烷基、-C(=O)-C4-10烷基、(CH2CH2O)nH、或 C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3。
在本发明的环肽及医药或化妆品组成中,R1优选为或其中,R2为H或C1-6烷基,R3为C1-6烷基;以及R4为H、-C(=O)-C4-10烷基、或(CH2CH2O)nH。更优选地,当R1为时,R2为异丙基, R3为甲基;或当R1为时,R4为H、或-C(=O)-庚基。
在本发明的一优选态样中,本发明的环肽由下列式(I-1)至(I-5)和(I’-1) 至(I’-5)任一个所表示:
本发明的环肽包含精胺酸(R)-甘胺酸(G)-天门冬胺酸(D)的胺基酸,其 可以结合于整合素(intergrin)RGD结合位。当本发明的环肽结合于皮肤的 整合素RGD结合位时,可以恢复真皮层和表皮层的间的传递过程,且可 以刺激基底膜(basement membrane)重要蛋白质的产生。因此,可以达到改 善疤痕、伤口、发炎过程、老化、以及/或皱纹形成的目的。因此,本发明 的环肽和医药或化妆品组成物可以应用于局部或化妆品皮肤护理组成物。
优选地,在本发明的环肽中,本发明的环肽可为式(I-1)至(I-5)和(I’-1) 至(I’-5)任一化合物所表示。式(I’-5)的化合物代谢后的产物为ACHA(胺基 环己烷羧酸)衍生物,其为非天然胺基酸。然而,例如式(I’-3)的化合物的 产物为薄荷酮(menthone),其为天然分子。因此,相较于式(I′-5)的化合物, 优选为式(I’-1)至(I’-4)的化合物。
在本发明的医药或化妆品组成物中,用于本发明的适合的赋形剂可以 是任何用于本领域的赋形剂,例如黏合剂、防沾黏剂(anti-adhesive agent)、 分散剂、润滑剂。
除了本发明的上述环肽和医药或化妆品组成物外,本发明的另一目的 为提供一种用于制备本发明的环肽的新的生物兼容性催化方法。
本发明的方法包含下列步骤(A)至(D)。
在步骤(A)中,由商业来源或通过我们的催化方法制备,提供下列式 (II-1)或(II’-1)和(II-2)所表示的化合物。
Rc-NH-R1-COOH (II-2)
在此,Ra和Rb各自独立为烷基、环烷基、芳基、或杂芳基;
Rc和Rd各自独立为保护基;以及
R1为其中R2和R3各自独立为H或C1-6烷基;X为O、 S、CH2、或N-R4,其中,R4为H、C1-6烷基、(CH2CH2O)nH、-C(=O)-C1-10烷基、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3。
在步骤(B)中,进行式(II-1)或(II’-1)与(II-2)的化合物之间的反应,以分 别获得由下列式(II-3)和(II’-3)所表示的化合物,
在步骤(C)中,分别进行式(II-3)或(II’-3)的化合物与由下列式(II-4)或 (II’-4)所表示的化合物之间的反应,以分别获得由下列式(II-5)和(II’-5)所表 示的化合物。
其中,Rd和Re各自独立为保护基。
在步骤(D)中,将式(II-5)或(II’-5)的化合物与式(III)的催化剂进行环化 反应,以分别获得式(I)或(I’)所表示的化合物。
M(O)mL1 yL2 z (III)
其中,M一为金属,选自由IVB、VB、VIB、和锕系(actinide)族所组 成的群组;
L1和L2分别为配位基;
m和y为大于或等于1的整数;
z为大于或等于0的整数
在本发明的方法中,Rc和Rd可以为茀基甲氧基羰基(Fluorenylmethyloxycarbonyl,Fmoc);以及Re可以为MTr(4-甲氧基-2,3,6- 三甲基苯磺酰基)(4-methoxy-2,3,6-trimethylbenzenesulphonyl)。然而,本发 明并不局限于此。
在本发明的方法中,式(II-1)或(II′-1)与(II-2)的化合物的反应间,或式 (II-3)与(II-4)或(II’-3)与(II’-4)的化合物的反应间,可以用式(III)的催化剂或 耦合剂进行。
在本发明的方法中,当以式(III)的催化剂进行步骤(B)至(D)的反应时, 步骤(B)至(D)中使用的催化剂可以相同或不相同。
在式(III)的催化剂中,L1为一配位基,其优选为选自Cl、OTf、OTs、 NTf2、卤素、RC(O)CHC(O)R、OAc、OC(O)CF3、OEt、O-iPr、和丁基所 组成的群组,其中,R为烷基(优选地为C1-6烷基;更优选地为C1-3烷基)。 此外,L2也为一配位基,其优选为选自Cl、H2O、CH3OH、EtOH、THF、 CH3CN、和所组成的群组。
再者,在式(III)的催化剂中,M可以为一金属,选自由IVB、VB、 VIB、和锕系族所组成的群组。在一态样中,M为IVB族的过渡元素,m 为1且y为2;其中M可以是Ti、Zr、或Hf。在另一态样中,M为VB 族的过渡元素,m为1且y为2或3;其中M可以是V或Nb。在另一态 样中,M为VIB族的过渡元素,m为1且y为4,其中M可以是Mo、W、 或Cr。在另一态样中M为VIB族的过渡元素,m为2且y为2;其中M 为Mo、W、或Cr。在更另一态样中,M为选自锕系族,m为2且y为2; 其中M为U。式(III)的催化剂的具体例子为MoO2Cl2、V(O)OCl2、 V(O)(OAc)2、V(O)(O2CCF3)2、Ti(O)(acac)2、Zr(O)Cl2、Hf(O)Cl2、Nb(O)Cl2、 MoO2(acac)2、V(O)(OTs)2、V(O)(NTf2)2、或VO(OTf)2,但本发明并不局 限于此。
另外,在式(III)的催化剂中,z可以是大于或等于0的整数;且优选 地z为0。
用来制备环肽的常规方法中,使用3-5当量的耦合剂,例如羟基苯并 三唑(hydroxybenzotriazole,HOBt)、1-羟基-7-氮杂苯并三唑 (1-hydroxy-7-azabenzotriazole,HOAt)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲 基脲六氟磷酸盐(2-(1H-benzotriazol-1-y1)-1,1,3,3-tetramethyluronium hexafluorophosphate,HBTU)、和苯并三唑-1-基-氧基三吡咯烷基磷六氟磷 酸盐(benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, PyBOP)。因为这些耦合剂很贵,所获得的环肽不容易商业化并应用于各种 领域。
在本发明用于制备该环肽的方法中,式(III)的催化剂为水溶性的且用 于促进反应进行。因此,本发明的方法不需使用昂贵的耦合剂,因此,可 以以更便宜的方式生产环肽,且所获得的环肽可以应用于各种领域。
在本发明中,除非另有说明,化合物中存在的烷基、环烷基、芳基、 和杂芳基都包含取代和未取代基团。烷基、环烷基、芳基、和杂芳基上可 能的取代基包含但不限于烷基、烯基、卤素、烷氧基、酮、醇、硫醚、胺 甲酸酯(carbamate)、胺基、杂环基、或芳基;但烷基不能被烷基取代。
在本发明中,术语“卤素”包含F、Cl、Br、和I,且优选为Cl或I。 术语“烷基”是指直链或支链的烷基;优选为包含直链和支链C1-20烷基; 更优选为包含直链和支链C1-12烷基;最优选为包含直链和支链C1-6烷基。 烷基的具体例子包含但不局限于甲基、乙基、正丙基、异丙基、正丁基、 第二丁基、异丁基、叔丁基、戊基、新戊基、或己基。术语“烷氧基”是 指本发明中定义的烷基与氧原子耦合的基团;优选为包含直链和支链C1-20烷氧基;更优选为包含直链和支链C1-12烷氧基;最优选为包含直链和支链 C1-6烷氧基。烷氧基的具体例子包含但不局限于甲氧基、乙氧基、正丙氧 基、异丙氧基、正丁氧基、异丁氧基、第二丁氧基、叔丁氧基、戊氧基、 新戊氧基、或己氧基。术语“烯基”是指包含至少一个双键的直链或支链 的碳氢基团;优选为包含含有至少一个双键的直链和支链的碳氢C2-20基团; 更优选为包含含有至少一个双键的直链和支链的碳氢C2-12基团;最优选为 包含含有至少一个双键的直链和支链的碳氢C2-6基团。烯基的具体例子包 含但不限于乙烯基、丙烯基、烯丙基、或1,4-丁二烯。术语“芳基”是指 单价6-碳单环、10-碳双环、或14-碳三环的芳香环系统。芳基的具体例子 包含但不局限于苯基、萘基、芘基(pyrenyl)、蒽基(anthracenyl)、或菲基(phenanthryl);且该芳基优选为苯基。术语“杂环基”是指具有至少一杂 原子的5-8员单环、8-12员双环、或11-14员三环的杂芳基或杂环烷基, 其中该杂原子选自由O、S、和N所组成的群组。杂环基的具体例子包含 但不局限于吡啶基(pyridyl)、嘧啶基(pyrimidinyl)、呋喃基(furyl)、噻唑基 (thiazolyl)、咪唑基(imidazolyl)、或噻吩基(thienyl)。
从以下的详细描述中,本发明的其他目的、优点、和新颖特征将变得 更明显。
具体实施方式
本发明已经以例示性方式描述,且应当理解,所使用的术语是在描述 性质而不是限制性质。鉴于上述教导,本发明的许多修饰和变化是可能的。 因此,应当理解在所附的权利范围内,本发明可以以不同于具体描述的方 式实施。
本发明的一优选实施例的环肽可以由以下方法制备。
[流程I’]
[流程I]
[流程II’]
[流程II]
[流程III’]
[流程III]
在流程I’和II’中,也可以使用耦合剂,例如羟基苯并三唑(HOBt)、1- 羟基-7-氮杂苯并三唑(HOAt)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟 磷酸盐(HBTU)、和苯并三唑-1-基-氧基三吡咯烷基磷六氟磷酸盐(PyBOP)。
在下文中,本发明提供用于制备本发明的环肽的实施例,但本发明并 不局限于此。
1-胺基-顺式-4-甲基环己烷羧酸
取4-甲基环己酮(45g,0.4mole)、氰化钾(30g,0.4mole)、和氯化铵(22.0g,0.4mole)溶于水(300mL)和乙醇(250mL),并保持在室温下6天,将深色溶 液以水(300mL)稀释并以氯化氢饱和,再经过2天后,1-胺基-顺式-4-甲基 环己腈盐酸盐(62.2g,88%)会结晶析出,将该盐酸盐(60g)与20%盐酸回流 12小时,将溶液蒸发至干,并将残余物用乙醇-乙醚(9:1)萃取(索氏(Soxhelt) 萃取器)8小时,移除溶剂后,将残余物以氨水碱化,得到1-胺基-顺式-4- 甲基环己烷羧酸(45.5g),针状物[用乙酸-水(1∶1)再结晶],m.p.356-360°(升 华),Rf0.69(元素分析:C8H15NO2实际值:C,61.6;H,9.7;N,8.4%;理论 值:C,61.1;H,9.6;N,8.9%)。
反式-2-异丙基-5-甲基环己烷-1-螺-5’-乙内酰脲 (trans-2-Isopropyl-5-methylcyclohexane-l-spiro-5′-hydantoin)
由天然的(-)-薄荷酮制备,产率37%,这种螺旋(spiran)形成的针状物(用 乙醇再结晶),m.p.228-231.5°(元素分析:实际值:C,63.0%;H,8.8%;N, 11.6%.)
1-胺基-反式-异丙基-5-甲基环己烷羧酸
将先前的乙内酰脲以60%硫酸水解成胺基酸,针状物[用水-乙酸(1∶1) 再结晶],m.p.330℃(元素分析:C11H21NO2实际值:C,66.0;H,10.5;N,6.8; 理论值C,66.3;H,10.6;N,7.0%)。
二肽Fmoc-Asp(OtBu)-D-Phe-OH的合成:
在N2气下于室温取Fmoc-Asp(OtBu)-OH(2.06g,5mmol,1.0当量)于 1,2-二氯乙烷(DCE,10mL),加入苯甲酸酐(114g,5.05mmol,1.01当量) 和MoO2Cl2(100mg,0.5mmol,10mol%),并通过TLC分析监测反应,反 应在室温下搅拌2小时,直到起始胺基酸完全消耗并冷却至0℃。在0℃ 下利用注射器(syringe)将溶于DCE(5mL)的D-苯丙胺酸苯甲基酯 (D-phenylalanine benzyl ester,1.275g,5.0mmol,1.0当量)加入上述溶液中, 接着加入胺碱(5.0mmol,1.0当量),将反应混合物在室温下搅拌30分钟后, 蒸发溶剂并将残余物以乙酸乙酯(100mL)溶解,以饱和水溶液 NaHCO3(30mL)、水(30mL)、食盐水(30mL)洗,并以Na2SO4干燥,待溶剂 蒸发后,残余物以硅胶快速层析法纯化,得到白色固体的 Fmoc-Asp(OtBu)-D-Phe-OBn(2.68g,产率81%)。TLC Rf=0.5(乙酸乙酯/ 己烷=1/5);1H NMR(400MHz,CDCl3):δ7.77(d,J=7.6,2H),7.57(q,J= 3.6,2H),7.41(t,J=7.6,2H),7.35-7.32(m,4H),7.30-7.27(m,4H),7.17(t,J =6.0,3H),7.02(t,J=6.4,3H),5.83(br,1H),5.13(q,J=12.0,2H),4.87(q,J =7.2,1H),4.58-4.49(m,1H),4.36(d,J=7.2,2H),4.20(t,J=7.2,1H),3.10 (dd,J=16.4,5.6,2H),1.43(s,9H);13C NMR(100MHz,CDCl3)δ170.8,170.0,156.0,143.8,143.6,141.3,135.5,135.0,129.2,128.6,128.5,127.7, 127.1,125.1,120.0,81.9,67.3,67.2,53.4,51.1,47.0,37.8,37.3,28.0;HRMS (ESI),C40H42N2NaO7理论值([M+Na]+):685.2889;实际值:685.2887。
在室温下取Fmoc-Asp(OtBu)-D-Phe-OBn(2.0g,3.0mmol,1当量)溶于 乙酸乙酯/甲醇(v/v=1/1,150mL),加入10%Pd/C(383mg,10mol%),反 应在氢气(气球)下搅拌1.5小时,接着以硅藻土过滤,以甲醇(30mL)、乙 酸乙酯(30mL)多次清洗硅藻土,并合并滤液以真空浓缩,得到白色固体的 二肽Fmoc-Asp(OtBu)-D-Phe-OH(1.699g,99%)。TLC Rf=0.23(乙酸乙酯/ 己烷=2/1)。
1H NMR(300MHz,CDCl3):δ7.75(d,J=7.5,2H),7.54(d,J=7.2,2H), 7.39(t,J=7.5,2H),7.29(d,J=7.2,2H),7.23-7.16(m,5H),7.06(d,J=7.5, 1H),6.12(d,J=8.7,1H),3.21(dd,J=9.6,6.3,1H),3.06(dd,J=9.6,6.6, 1H),2.72(dd,J=16.8,6.3,1H),2.57(dd,J=16.2,5.7,1H),1.43(s,9H);13C NMR(100MHz,CDCl3)δ171.4,170.8,170.0,156.0,143.7,143.6,141.2, 135.7,129.2,128.5,127.7,127.1,125.1,120.0,81.9,67.3,53.4,52.3,51.0, 47.0,37.9,37.4,29.7,28.0;HRMS(ESI),C33H36N2NaO7理论值([M+Na]+):595.2420;实际值:595.2423。
二肽Fmoc-Arg(Mtr)-Gly-OCH3的合成(通过EDC-HOBt耦合)
1H NMR(400MHz,CDCl3):δ7.72(d,J=7.6,2H),7.63-7.54(m,3H), 7.25(t,J=7.6,2H),7.24-7.22(m,1H),6.49(br,1H),6.40(br,1H),6.07(d,J =8.01H),4.32(q,J=6.8,3H),4.14(t,J=7.2,1H),4.02(dd,J=17.6,5.2, 1H),3.89(dd,J=17.6,5.2,1H),3.78(s,3H),3.66(s,3H),3.34-3.23(m,2H), 2.66(s,3H),2.60(s,3H),2.16(s,3H),2.05(s,3H),1.93(t,J=6.0,1H), 1.72-1.60(m,3H),1.27(t,J=6.8,1H);13C NMR(100MHz,CDCl3)172.8, 170.6,158.6,156.5,143.8,143.7,141.2,138.5,136.6,134.7,134.1,133.0, 129.1,127.7,125.1,124.9,124.3,120.3,120.0,111.7,67.1,60.4,55.4,52.3,47.0,41.0,40.2,31.9,30.0,29.7,25.1,24.0,21.0,18.3;HRMS(ESI), C34H41N5NaO8S理论值([M+Na]+):702.2573;实际值:702.2575。
实施例1
[流程I-3-5-Fmoc]
在室温下取Fmoc-Asp(OtBu)-D-Phe-OH(1.6g,2.8mmol,1.0当量)溶 于1,2-二氯乙烷(DCE,5mL),加入2,6-二硝基苯甲酸酐(2,6-dinitrobenzoic anhydride,974mg,2.82mmol,1.01当量)和MoO2Cl2(56mg,0.28mmol, 10mol%),并在N2气下逐渐加热至40℃,并以TLC分析监测反应。将反 应于40℃下搅拌2小时,直到起始胺基酸完全消耗并冷却至0℃。在0℃ 下利用注射器将溶于DCE(3mL)的1-胺基环己烷羧酸苯甲基酯(653mg, 2.8mmol)加入上述溶液中,接着加入胺(2.8mmol,1.0当量),反应混合物 在室温下搅拌12小时后,蒸发溶剂并将残余物以乙酸乙酯溶解,以饱和 水溶液NaHCO3(1mL)、水(1mL)、食盐水(1mL)洗,并以Na2SO4干燥,待 溶剂蒸发后,残余物以硅胶快速层析法纯化,得到白色固体的Fmoc-Asp(OtBu)-D-Phe-ACHA-OBn(1.69g,产率77%)。TLC Rf=0.26(乙 酸乙酯/己烷=1/5);1H NMR(400MHz,CDCl3):δ7.77(d,J=7.6,2H),7.57 (d,J=7.2,2H),7.41(t,J=7.6,2H),7.35-7.27(m,7H),7.24-7.16(m,5H), 6.95-7.89(br,1H),6.21(br,1H),5.72(br,1H),5.11(q,J=8.0,2H),4.63(q,J =7.6,1H),4.43-4.21(m,3H),4.23(t,J=7.2,1H),3.07(dd,J=16.4,6.4,1H), 2.98-2.92(m,1H),2.81(dd,J=16.2,4.8,1H),2.64-2.53(m,1H),1.85-1.79 (m,4H),1.64-1.49(m,3H),1.47(s,9H),1.26-1.20(m,4H);13C NMR(100MHz,CDCl3)δ173.5,170.8,170.5,169.6,143.6,141.3,136.0,129.4,128.7, 128.5,128.2,127.8,127.1,127.0,125.0,120.0,82.0,67.3,66.8,59.0,54.1, 51.4,47.1,37.3,32.3,32.1,28.0,24.9,21.2,18.3;HRMS(ESI), C46H51N3NaO8理论值([M+Na]+):796.3574;实际值:796.3580。
在室温下取Fmoc-Asp(OtBu)-D-Phe-ACHA-OBn(1.5g,1.9mmol,1当 量)溶于乙酸乙酯/甲醇(v/v=1/1,100mL),加入10%Pd/C(242mg,10mol%), 反应在氢气气氛(气球)下搅拌2小时,接着以硅藻土过滤,以甲醇(20mL)、 乙酸乙酯(20mL)多次清洗硅藻土,并合并滤液以真空浓缩,得到白色固体 的二肽Fmoc-Asp(OtBu)-D-Phe-ACHA-OH(3-5-Fmoc)(1.31g,98%)。TLC Rf=0.24(EtOAc/Hex=2/1);1H NMR(400MHz,CDCl3):δ7.75(d,J=7.2,2H),7.73-7.72(m,6H),7.40-7.32(m,5H),7.31-7.21(m,6H),6.83(d,J= 16.0,1H),6.46(d,J=5.4,1H),6.03(br,1H),4.73(q,J=7.6,1H),4.48-4.42 (m,1H),4.41-4.12(m,4H),3.19-3.02(m,2H),2.84-2.68(m,2H),2.18-1.65 (m,4H),1.49(s,9H),1.63-1.24(m,6H);13C NMR(100MHz,CDCl3)δ176.6, 171.6,171.3,171.1,170.7,156.2,143.7,141.2,136.6,136.5,129.3,128.6, 127.7,127.1,126.9,125.1,120.0,81.7,67.5,59.4,54.7,52.1,51.6,47.0,38.0, 37.3,36.9,36.7,32.9,31.0,29.7,28.0,25.0,21.3,21.1;HRMS(ESI),C39H45N3NaO8理论值([M+Na]+):706.3104;实际值:706.3108。
[流程I’-1-3’-5-Fmoc]
步骤-A:取H-D-Phe-Asp(OtBu)-OMe.HCI(1-HCl)(48.7mg,0.126mmol, 1.01当量)溶于甲醇(1mL)并冷却至0℃,在室温下加入NaHCO3(1.5当量) 并搅拌0.5小时,蒸发甲醇后将残余物以四氢呋喃(2mL)溶解,以Na2SO4干燥并过滤,将移除溶剂并真空干燥,获得D-Phe-Asp(OtBu)-OMe(1)。
在干燥的50mL双颈圆底瓶中加入溶于无水二氯甲烷(1.0mL)的 MoO2Cl2(5.0mg,0.025mmol,20mol%),在环境温度下将Fmoc-1-胺基环 己烷-1-羧酸(2-5-Fmoc)(48.3mg,0.125mmol)加入上述溶液中,接着加入 苯甲酸酐(29mg,0.127mmol),并加热至40℃反应6小时后冷却至0℃。
在0℃下,将溶于DCM(0.5mL)的D-Phe-Asp(OtBu)-OMe(48.3mg, 0.125mmol)加入上述溶液中,并缓慢回到室温,在室温下搅拌2小时,之 后加入2,6-二甲吡啶(14μL),在室温下继续搅拌4小时,以水(2mL)终止反 应并分离有机层,水层以二氯甲烷(10mLx2)萃取,合并有机层以无水Na2SO4干燥并浓缩,粗产物以硅胶管柱层析法纯化(乙酸乙酯/己烷=2/3), 得到Fmoc-保护的三肽(3’-5-Fmoc)(58mg,67%)。
制备三肽(3’)的方法并不局限于上述步骤,例如可通过以下流程 I’-3’-5-Fmoc-B来制备Fmoc-保护的三肽(3’-5-Fmoc)。
[流程I’-3’-5-Fmoc-B]
步骤-B:在干燥的25mL双颈圆底瓶中加入溶于DCM(1mL/mmol)的 耦合剂(1当量),在0℃下以DIEA(3当量)搅拌处理5分钟,在0℃下加入 Fmoc-1-胺基环己烷-1-羧酸(2-5-Fmoc)(182.7mg,0.5mmol)反应10分钟, 并与H-D-Phe-Asp(OtBu)-OMe盐酸盐(1)(192.7mg,0.55mm0l)混合,10分 钟后移除冰浴,继续在室温下搅拌96小时。将混合物倒入乙酸乙酯(50x DCM的体积),并根据通常的处理方法处理该溶液,粗产物以硅胶管柱层 析法纯化,得到Fmoc-保护的三肽(3’-5-Fmoc),产率:68%。
管柱层析法纯化(乙酸乙酯/己烷=3∶7,Rf=0.2)1H NMR(400MHz, CDCl3)δ7.74(d,J=7.2Hz,2H),7.57(d,J=7.2Hz,2H),7.40-7.27(m,4H), 7.19-7.07(m,5H),6.63(d,J=8.0Hz,1H),5.11(s,1H),4.84(d,J=6.6Hz, 1H),4.74(d,J=5.4Hz,1H),4.41-4.32(m,2H),4.15(t,J=6.4Hz,1H),3.59 (s,3H),3.23(dd,J=14.0,6.9Hz,1H),3.04(dd,J=14.0,8.2Hz,1H), 2.76-2.63(m,2H),1.92-1.77(m,2H),1.60-1.47(m,5H),1.38(s,9H),1.27-1.18(m,3H);13C NMR(100MHz,CDCl3)δ173.8,171.2,170.6,169.2, 155.3,143.6,143.5,141.1,136.6,128.9,128.3,127.6,126.9,126.9,124.8, 124.8,119.8,119.8,81.3,66.7,59.3,53.5,52.1,48.7,47.0,37.2,37.0,32.4, 30.9,27.7,24.8,21.1,21.0;HRMS(ESI)C40H47N3O8理论值(M+Na+): 720.3255;实际值:720.3253。
[流程I’-3’-5]
在室温下,取Fmoc-保护的三肽(3’-5-Fmoc)(200mg,0.28mmol)溶液, 以溶于DCM(1mL)的20%哌啶处理1小时,通过与甲醇共蒸发后移除哌啶, 粗产物以真空干燥并以硅胶管柱层析法纯化,得到三肽(3’-5)。
产率:106.8/136.2=78%
管柱层析法纯化(乙酸乙酯/己烷=9∶1,Rf=0.2)1H NMR(400MHz, CDCl3)δ8.21(d,J=8.2Hz,1H,NH),7.21(t,J=6.8Hz,2H),7.16-7.14(m, 3H),7.05(d,J=8.4Hz,1H),4.76-4.72(m,1H),4.63-4.58(m,1H),3.66(s, 3H,OCH3),3.15(dd,J=14.0,6.2Hz,1H),3.00(dd,J=14.0,8.0Hz,1H), 2.81(dd,J=16.0,4.0Hz,1H),2.51(dd,J=16.0,4.0Hz,1H),1.97-1.72(m, 2H),1.58-1.51(m,4H),1.35(s,9H,C(CH3)3),1.36-1.28(m,2H),1.24-1.09 (m,2H);13C NMR(100MHz,CDCl3)δ178.3,170.9,170.8,169.9,136.8, 129.1,128.3,126.6,81.7,57.1,53.8,52.4,48.2,37.5,37.1,34.4,34.1,27.0, 25.0,21.0;HRMS(ESI)C25H37N3O6理论值(M+H+):476.2761;实际值: 476.2753。
实施例2
[流程I-3-1-Fmoc]
管柱层析法纯化(乙酸乙酯/己烷=3∶1,Rf=0.32);1H NMR(400MHz, CDCl3):δ7.74(d,J=7.4,2H),7.75-7.70(m,4H),7.38-7.30(m,2H), 7.31-7.217.19-7.14(m,5H),6.85(d,J=16.0,1H,NH),6.48(d,J=5.4,1H, NH),6.35(br,1H,NH),4.75(q,J=7.4,1H),4.52-4.45(m,1H),4.42-4.13 (m,3H),3.78-3.73(m,2H),3.37-3.33(m,2H),3.22-3.06(m,2H),2.85-2.67 (m,2H),2.38-2.23(m,2H),2.05-1.83(m,2H),1.49(s,9H),1.42(s,9H);HRMS(ESI),Calcd.for C43H52N4NaO10([M+Na]+):807.3581,found: 807.3577.
[流程I’-3’-1-Fmoc]
在干燥的25mL双颈圆底瓶中加入溶于DCM(1mL/mmol)的耦合剂(1 当量),在0℃下以DIEA(3当量)搅拌处理5分钟,在0℃下加入1-Boc-哌 啶-4-Fmoc-胺基-1-羧酸(2-1-Fmoc)(233.27mg,0.5mmol)反应10分钟,并 与H-D-Phe-Asp(OtBu)-OMe盐酸盐(1)(202.91mg,0.525mmol)混合,10分 钟后移除冰浴,继续在室温下搅拌96小时。将混合物倒入乙酸乙酯(50x DCM的体积),并根据通常的处理方法处理该溶液,粗产物以硅胶管柱层析法纯化,得到Fmoc-保护的三肽(3’-1-Fmoc)。
产率:259/399.17=65%
管柱层析法纯化(乙酸乙酯/己烷=3∶7,Rf=0.2)1H NMR(400MHz, CDCl3)δ7.75(d,J=7.6Hz,2H),7.56(t,J=5.2Hz,2H),7.39(dt,J=6.4, 2.4Hz,2H),7.32-7.27(m,2H),7.19(t,J=7.6Hz,2H),7.12(t,J=6.2Hz, 3H),6.68(d,J=7.6Hz,1H),4.79(s,1H),4.44(d,J=6.0Hz,1H),4.15(t,J =6.2Hz,1H),3.74-3.67(m,1H),3.63(s,3H),3.56(d,J=14.0Hz,1H),3.19 (br,1H),2.99(dd,J=14.0,8.2Hz,1H),2.89(br,1H),2.76(dd,J=16.0,6.0 Hz,1H),2.60(d,J=12.8Hz,1H),2.05-1.96(m,1H),1.77-1.53(m,6H),1.42 (s,9H),1.38(s,9H);13C NMR(100MHz,CDCl3)δ172.7,171.2,170.5,169.3, 155.3,154.3,143.5,143.4,141.1,136.5,128.9,128.3,127.6,126.9,126.9, 126.7,124.8,124.7,119.8,81.4,79.6,66.7,57.6,53.6,52.3,48.7,46.9,37.1, 28.2.27.8.
[流程I’-3’-1]
在室温下,取Fmoc-保护的三肽(3’-1-Fmoc)(219mg,0.27mmol)溶液, 以溶于DCM(1mL)的20%哌啶处理3小时,通过与甲醇共蒸发后移除哌啶, 粗产物以真空干燥并以硅胶管柱层析法纯化,得到三肽(3’-1)。
产率:113/155.6=72%
管柱层析法纯化(乙酸乙酯/己烷=9∶1,Rf=0.2)1H NMR(400MHz, CDCl3)δ8.05(d,J=8.2Hz,1H,NH),7.26-7.14(m,5H),7.05(d,J=8.4Hz, 1H),4.76-4.72(m,1H),4.66-4.60(m,1H),3.88-3.76(m,2H,NH2),3.67(s, 3H,OCH3),3.16(dd,J=14.0,6.2Hz,1H),3.02-2.92(m,3H),2.82(dd,J= 17.0,4.4Hz,1H),2.52(dd,J=17.0,4.6Hz,1H),2.07-2.00(m,1H), 1.91-1.84(m,1H),1.58-1.38(m,1H),1.40(s,9H,C(CH3)3),1.36(s,9H, C(CH3)3),1.32-1.20(m,2H),1.11-1.06(m,1H);13C NMR(100MHz,CDCl3) δ176.7,170.9,170.6,169.9,154.4,136.6,129.1,128.4,126.7,81.7,79.4,55.3, 53.7,52.4,48.2,37.5,37.0,34.2,28.2,27.8;HRMS(ESI)C29H45N4O8理论值 (M++1):577.3232;实际值:577.3248。
实施例3
[流程II-5-5-Fmoc]
Fmoc-Asp(OtBu)-D-Phe-ACHA-Arg(Mtr)-Gly-OCH3的合成
在室温下取Fmoc-Asp(OtBu)-D-Phe-ACHA-OH(3-5-Fmoc)(698g, 1mmol,1.0当量)溶于1,2-二氯乙烷(DCE,5mL),加入2,6-二硝基苯甲酸 酐(348mg,1.01mmol,1.01当量)和VO(OTf)2(55mg,0.15mmol,15mol%), 在N2气下逐渐加热至40℃,并通过TLC分析监测反应。反应在40℃下搅 拌4小时,直到起始胺基酸完全消耗后冷却至0℃,在0℃下利用注射器 将溶于DCE(3mL)的NH2-Arg(Mtr)-Gly-OCH3(4)(457mg,1mmol)溶液加入 上述溶液中,接着加入碱(1.0mmol,1.0当量),将反应混合物在室温下搅 拌12小时,蒸发溶剂并将残余物以乙酸乙酯(100mL)溶解,以饱和水溶液 NaHCO3(20mL)、水(20mL)、食盐水(20mL)洗,并以Na2SO4干燥,待溶剂 蒸发后,残余物以硅胶快速层析法纯化,得到白色固体的 Fmoc-Asp(OtBu)-D-Phe-ACHA-Arg(Mtr)-Gly-OCH3(5-5-Fmoc)(612mg,产 率68%)。TLC Rf=0.50(EtOAc/Hexane=3/1);1H NMR(400MHz,CDCl3):δ 7.75(d,2H,J=7.20Hz),7.57(m,2H),7.39(t,2H,J=7.6Hz),7.30-7.18(m, 8H),6.60(br,1H),6.55(br,1H),4.67(br,1H),4.52-4.42(m,1H),4.37(q,1 H,J=6.40Hz),4.35-4.23(m,2H),4.19(t,1H,J=7.2Hz),4.14-4.04(m,1H), 3.81(s,3H,OCH3),3.69-3.61(m,1H),3.58(s,3H,CO2CH3),3.46-3.42(m, 1H),3.21-3.09(m,2H),3.03-2.92(m,1H),2.68(s,3H),2.59(s,3H), 2.25-2.11(m,2H),2.10(s,3H),2.04-1.83(m,4H),1.79-1.58(m,3H), 1.59-1.41(m,4H),1.39(s,9H,C(CH3)3),1.35-1.05(m,4H);13C NMR(100 MHz,CDCl3)δ175.4,172.9,172.6,172.0,171.2,170.5,156.7,143.6,141.2, 136.3,129.2,129.0,128.7,127.8,127.1,127.0,125.0,120.0,112.3,81.7,77.3,67.2,60.4,55.5,53.0.52.3,51.2,47.0,41.2,37.0,36.7,34.1,30.0,29.0,28.0, 24.9,24.3,21.3,20.9,18.3,12.0;HRMS(ESI),C58H74N8NaO13S理论值 ([M+Na]+):1145.4994;实际值:1145.4981。
[流程II’-5’-5-Fmoc]
在干燥的25mL双颈圆底瓶中加入溶于DCM(1mL/mmol)的耦合剂(1.5 当量),在0℃下以DIEA(4.0当量)搅拌处理5分钟,在0℃下加入 Fmoc-Gly-Arg(Mtr)-OH(4)(149.6mg,0.22mmol)反应20分钟,并与三肽(3’-5) (106.8mg,0.22mmol)混合,20分钟后移除冰浴,继续在室温下搅拌10天。 将粗产物真空干燥并以硅胶管柱层析法纯化,得到Fmoc-保护的肽(5’-5-Fmoc)。
产率:30%(PyBOP);65%(藉由MoO2Cl2/4-硝基苯甲酸酐)。
管柱层析法纯化(乙酸乙酯/甲醇=99.5∶0.5,Rf=0.6);1H NMR(400 MHz,CDCl3)δ7.76(d,J=8.0,1H,NH),7.70(d,J=8.2,2H),7.56(d,J=6.4, 1H,NH),7.51(d,J=7.2,2H),7.42(bd,1H,NH),7.38(d,J=8.0,2H), 7.36-7.16(m,2H),7.11-7.06(m,5H),6.86(d,J=7.6Hz,1H,NH),6.50(s, 1H),6.38(bs,2H),4.84(dd,J=14.0,6.6Hz,1H),4.67(dd,J=13.8,8.0Hz, 1H),4.45-4.27(m,2H),4.20-4.11(m,1H),3.90-3.89(m,1H),3.79(s,3H,OCH3),3.73-3.71(m,1H),3.65(s,3H,CO2CH3),3.54-3.46(m,1H),3.43-3.36 (m,2H),3.20-3.16(m,1H),3.05(dd,J=14.0,9.3Hz,1H),2.71(t,J=8.0Hz, 1H),2.71(m,1H),2.67(s,3H,CH3),2.61(s,3H,CH3),2.10(s,3H,CH3), 2.01-1.79(m,3H),1.76-1.51(m,2H),1.50-1.41(m,2H),1.39(s,9H, C(CH3)3),1.32-1.02(m,6H),0.94-0.82(m,2H);HRMS(ESI)C58H74N8O13S 理论值(M+H+):1122.5098;实际值:1122.5096。
实施例4
[流程II-5-1-Fmoc]
类似于[流程II-5-5-Fmoc]的步骤,得到产物的产率65%。管柱层析法 纯化(乙酸乙酯/甲醇=9.5∶0.5,Rf=0.40);1H NMR(400MHz,CDCl3):δ 7.76(d,2H,J=7.4Hz),7.59-7.56(m,2H),7.38(t,2H,J=7.6Hz), 7.28-7.15(m,8H),6.64(br,1H),6.58(br,1H),4.69(br,1H),4.55-4.45(m,1H),4.40(dd,1H,J=7.2,6.4Hz),4.38-4.24(m,2H),4.20(t,1H,J=7.2 Hz),4.16-4.08(m,2H),3.82(s,3H,OCH3),3.76-3.71(m,2H),3.66-3.62(m, 1H),3.56(s,3H,CO2CH3),3.44-3.40(m,1H),3.34-3.30(m,2H),3.18-3.12 (m,2H),3.01-2.93(m,1H),2.66(s,3H),2.57(s,3H),2.27-2.15(m,2H),2.09 (s,3H),2.25-2.04(m,4H),1.78-1.60(m,2H),1.56-1.52(m,2H),1.40(s,9H, C(CH3)3),1.36(s,9H,C(CH3)3);HRMS(ESI),calculated for C62H82N9O15S ([M+H]+):1224.5651,found:1224.5654.
[流程II’-5’-1-Fmoc]
类似于[流程II’-5’-5-Fmoc]的步骤,得到产物的产率72%。管柱层析 法纯化(乙酸乙酯/甲醇=9.5∶0.5,Rf=0.4);1H NMR(400MHz,CDCl3)δ 7.62(d,J=8.2,1H,NH),7.60(d,J=8.0,2H),7.53(d,J=6.4,1H),7.45(d,J =7.2,2H),7.30(bd,1H,NH),7.36(d,J=8.0,2H),7.34-7.18(m,6H), 7.18-7.10(m,5H),6.74(d,J=7.6Hz,1H,NH),6.40(s,1H),6.25(bs,2H), 4.81(dd,J=13.8,6.8Hz,1H),4.70(dd,J=13.8,8.0Hz,1H),4.52-4.31(m,3H),4.18-4.08(m,1H),3.95-3.86(m,2H),3.77(s,3H,OCH3),3.73-3.71(m, 1H),3.62(s,3H,OCH3),3.68-3.60(m,2H),3.57-3.46(m,1H),3.48-3.36(m, 2H),3.18-3.12(m,1H),3.08(t,J=8.0Hz,1H),2.71(dd,J=14.0,9.3Hz, 1H),2.73-2.67(m,1H),2.63(s,3H,CH3),2.55(s,3H,CH3),2.11(s,3H, CH3),2.11-1.83(m,6H),1.76-1.61(m,8H),1.55-1.45(m,6H),1.36(s,9H, C(CH3)3),1.36-1.06(m,8H),0.92-0.84(m,2H);HRMS(ESI)C62H82N9O15S理论值(M++H):1224.5651;实际值:1224.5662。
实施例5
[流程III-6-5]
在Fmoc去保护和环化后
1H NMR(400MHz,CDCl3):δ8.00(s,1H,C=NH),7.88(bs,1H,NH), 7.75(bs,1H,NH),7.64(bs,1H,NH),7.42-7.13(m,6H),7.01(br,1H,NH), 6.52(br,1H,MTR-H),6.27(br,2H,NH),4.79-4.71(m,1H),4.62-4.51(m, 1H),4.31-4.22(m,1H),4.09-4.02(m,2H),3.81(s,3H,OCH3),3.61-3.56(m, 1H),3.54-3.25(m,2H,CH2-quanidine),3.21-3.09(m,1H),3.03-2.87(m,2H), 2.69(s,3H,CH3),2.59(s,3H,CH3),2.59-2.47(m,1H),2.11(s,3H,CH3),2.01-1.68(m,5H),1.59-1.52(m,4H),1.52-1.38(m,4H),1.52(s,9H, C(CH3)3),0.86(quin,2H,J=7.8Hz);HRMS(ESI),calculated for C42H61N8O10S([M+H]+):869.4231,found:869.4201;TLC:Rf0.42 (EtOAc/MeOH,3/1).
在同时MTR和t-Boc去保护后。
化合物6-5的数据:1H NMR(400MHz,CDCl3)δ10.02(bs,2H, G-NH2 +),8.25(bs,1H,G-NH),7.83(bd,J=8.2,1H,amide NH),7.75(d,J= 8.0,1H,amide NH),7.71(d,J=8.4,1H,amide NH),7.62(t,J=8.0,1H,amide NH),7.36(d,J=8.2,1H,amide NH),7.22-7.11(m,5H,Ph),4.72(dd,J= 15.8,7.8,1H),4.55(bt,1H),4.36(bs,2H),4.20(dd,J=16.0,7.2,1H),3.36(t, J=14.8Hz,2H),3.25-3.12(m,4H),2.64(dd,J=7.6,16.0Hz,1H),2.57(dd, J=16.0,10.4,1H),1.84-1.72(m,4H),1.58-1.50(m,4H),1.48-1.38(m,4H); HRMS(ESI)C28H41N8O7理论值(M++H):601.3093;实际值:601.3094;HPLC分析:(C18,250×4.6mm,0.5(mL/min),λ=254nm).a:1%三氟乙酸溶 于水/乙腈(95∶5),30分钟;b:1%三氟乙酸溶于水/乙腈(5∶95),31-60分钟; tR:36.71、46.17分钟。
[流程III’-6’-5]
在室温下取Fmoc-保护的肽(5’-5-Fmoc)(40.5mg,0.036mmol)溶液,以 溶于DCM(1mL)的20%哌啶处理1小时,通过与甲醇共蒸发移除哌啶后, 将粗产物真空干燥并以硅胶管柱层析法纯化,产生的产物以在回流甲苯中 的VOOCl2、V(O)(acac)2、或Ti(O)(acac)2(10mol%)处理18小时,形成分 子内的酰胺键。将产生的粗混合物冷却至环境温度并浓缩,粗残余物以三 氟乙酸(5mL)和水(1mL)溶解,接着以硫代苯甲醚(thioanisole,1mL)处理,混合物以二异丙基醚(5mL)诱导沉淀后,将固体以二异丙基醚清洗并真空 干燥,以获得环肽(6’-5)。环五肽(cyclic pentapeptide)进一步以逆相C-18 管柱的HPLC纯化(梯度:95/5至80/20,水/乙腈),得到纯化合物6’-5(18mg, 产率69%)。
在Fmoc去保护和环化后:
1H NMR(400MHz,CDCl3)δ7.68and 7.28(m,2H,imine and amide), 7.22-7.12(m,5H,Ph group),6.50(s,1H,amide),6.33(br,2H,amide),4.80 (dd,J=6.0,6.9Hz,1H),4.59-4.55(m,1H),4.45-4.36(m,1H),3.80(s,3H, OCH3-Ph),3.33-3.15(m,3H),2.79(t,J=8.4Hz,1H),2.65(s,3H,CH3-Ph), 2.59(s,3H,CH3-Ph),2.31(t,J=10.4Hz,1H),2.08(s,3H,CH3-Ph),2.03-1.95(m,4H),1.64-1.41(m,5H),1.36(s,9H,tBu),1.30-1.27(m,2H),1.25-1.22(m,4H);Rf0.5(EtOAc/MeOH,9/1);HRMS(ESI)C42H61N8O10S理 论值(M++H):869.4231;实际值:869.4233。
在同时MTr和tert-Boc去保护后:
化合物6’-5的数据:1H NMR(400MHz,CDCl3)δ10.12(bs,2H, G-NH2 +),8.22(bs,1H,G-NH),7.79(bd,J=8.4,1H,amide NH),7.72(d,J= 8.2,1H,amide NH),7.68(d,J=8.2,1H,amide NH),7.58(t,J=8.0,1H,amide NH),7.41(d,J=8.2,1H,amide NH),7.24-7.13(m,5H,Ph),4.68(dd,J= 13.2,6.8,1H),4.45(bt,1H),4.30(bs,2H),4.22(dd,J=16.0,7.2,1H),3.30(t, J=14.0Hz,2H),3.18-3.00(m,4H),2.68(dd,J=7.6,16.0Hz,1H),2.55(dd, J=16.0,10.4,1H),1.78-1.01(m,10H);HRMS(ESI)C28H41N8O7理论值 (M++H):601.3098;实际值:601.3090;HPLC分析:(C18,250×4.6mm,0.5 (mL/min),λ=254nm).a:1%三氟乙酸溶于水/乙腈(90∶10),30分钟;b: 1%三氟乙酸溶于水/乙腈(10∶90),31-60分钟;tR:34.6、42.6分钟。
[流程III-6-2]
在Fmoc去保护和环化后:
1H NMR(400MHz,CDCl3):δ7.98(s,1H,C=NH),7.86(bs,1H, NH),7.62(bs,1H,NH),7.38-7.11(m,6H),7.00(br,1H),6.58(br,1H,NH), 6.30(br,1H,NH),4.80-4.74(m,1H),4.65-4.57(m,1H),4.34-4.26(m,1H), 4.10-4.07(m,2H),3.71-3.67(m,2H),3.60-3.54(m,4H),3.52-3.31(m,2H, CH2-quanidine),3.48(s,3H,OCH3),3.18-3.09(m,1H),3.05-2.91(m,2H), 2.69(s,3H,CH3),2.59(s,3H,CH3),2.11(s,3H,CH3),2.21-1.78(m,5H), 1.63-1.57(m,2H),1.55(s,9H,C(CH3)3),1.53-1.43(m,2H),1.50(s,9H, C(CH3)3);HRMS(ESI),calculated for C46H68N9O12S([M+H]+):970.4708, found:970.4715;TLC:Rf0.33(EtOAc/MeOH,3/1).
在同时MTr和tert-Boc去保护后:
化合物6-2的数据:1H NMR(400MHz,CDCl3):9.40(bs,2H,G-NH2 +), 8.55(bs,1H,G-NH),7.63(bd,J=8.2,1H,amide NH),7.69(d,J=8.0,1H, amide NH),7.63(d,J=8.4,1H,amide NH),7.55(t,J=8.0,1H,amide NH), 7.38(d,J=8.2,1H,amide NH),7.24-7.14(m,5H,Ph),6.81(bs,2H,G-NH2), 4.82(dd,J=15.8,7.8,1H),4.70(bt,1H),4.40(bs,2H),4.15(dd,J=16.0,7.2, 1H),3.40(t,J=14.8Hz,2H),3.22-3.12(m,4H),2.97-2.88(m,2H),2.81-2.72 (dd,J=7.6,16.0Hz,1H),2.68-2.62(m,2H),2.60(dd,J=16.0,10.4,1H),2.24-2.06(m,3H),1.84-1.77(m,4H),1.54-1.48(m,2H);HRMS(ESI)calcd for C27H40N9O7(M++H):602.3045;found:602.3041;HPLC analysis:(C18, 250×4.6mm,0.5(mL/min),λ=254nm).a.1%TFA in H2O/ACN(90∶10)30 min;b.1%TFAin H2O/ACN(5:95)31-60min;tR42.5,51.2min.
[流程III’-6’-2]
在Fmoc、MTR、和t-Boc去保护后:
化合物6’-2的数据:1H NMR(400MHz,CDCl3)δ9.68(bs,2H,G-NH2 +), 8.09(bs,1H,G-NH),7.68(bd,J=8.4,1H,amide NH),7.64(d,J=8.2,1H, amide NH),7.60(d,J=8.2,1H,amide NH),7.50(t,J=8.0,1H,amide NH), 7.45(d,J=8.2,1H,amide NH),7.27-7.16(m,5H,Ph),4.65(dd,J=15.8, 7.6,1H),4.72(bt,1H),4.27(bs,2H),4.15(dd,J=15.8,7.4,1H),3.32(t,J= 15.2Hz,2H),3.24-3.15(m,4H),2.80-2.65(m,4H),2.64(dd,J=7.6,16.0Hz, 1H),2.58(dd,J=16.0,10.4,1H),2.14-2.06(m,2H),2.05(bs,1H,NH), 1.89-1.82(m,2H),1.78-1.72(m,4H),1.67-1.48(m,2H);HRMS(ESI) C27H40N9O7理论值(M++H):602.3045;实际值:602.3049;HPLC分析:(C18, 250×4.6mm,0.5(mL/min),λ=254nm).a:1%三氟乙酸溶于水/乙腈(90∶10), 30分钟;b:1%三氟乙酸溶于水/乙腈(5∶95),31-60分钟;tR:41.8、50.4 分钟。
虽然已经以优选实施例说明了本发明,但应当理解的是,可以在不脱 离权利要求书所要求保护的本发明的精神及范围下,进行其他可能的修饰 或改变。
Claims (20)
1.一种环肽,由下列式(I)或(I’)所表示:
其中,
R1为
R2和R3各自独立为H、或C1-6烷基;
X为O、S、CH2、或N-R4,其中,R4为H、C1-6烷基、(CH2CH2O)nH、-C(=O)-C1-10烷基、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3;以及
当X为CH2时,R3为C1-6烷基。
2.如权利要求1所述的环肽,其中,X为O、CH2、S或N-R4,其中R4为H、C1-6烷基、-C(=O)-C4-10烷基、(CH2CH2O)nH、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中,n=1-3。
3.如权利要求1所述的环肽,其中,R1为其中,R2为H、或C1-6烷基,R3为C1-6烷基;以及R4为H、-C(=O)-C4-10烷基、或(CH2CH2O)nH。
4.如权利要求3所述的环肽,其中,R2为H。
5.如权利要求3所述的环肽,其中,R4为H、或-C(=O)-庚基。
6.如权利要求1所述的环肽,其中,该环肽可由下列式(I-1)至(I-5)和(I’-1)至(I’-5)任一个所表示:
7.一种医药或化妆品组成物,包含:
一赋形剂、Cu(II)离子、或VO(II)离子;以及
一环肽,由下列式(I)或(I’)所表示:
其中,
R1为
R2和R3各自独立为H、或C1-6烷基;
X为O、S、CH2、或N-R4,其中,R4为H、C1-6烷基、(CH2CH2O)nH、-C(=O)-C1-10烷基、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3;以及
当X为CH2时,R3为C1-6烷基。
8.一种环肽的制备方法,包含下列步骤:
提供由下列式(II-1)或(II’-1)与(II-2)所表示的化合物:
Rc-NH-R1-COOH (II-2)
其中,Ra和Rb各自独立为烷基、环烷基、芳基、或杂芳基;
Rc和Rd各自独立为保护基;以及
R1为其中,R2和R3各自独立为H或C1-6烷基;X为O、S、CH2、或N-R4,其中,R4为H、C1-6烷基、(CH2CH2O)nH、-C(=O)-C1-10烷基、或C(=O)(C2H4)2C(=O)O(C2H4O)nH,其中n=1-3;
进行式(II-1)或(II’-1)与(II-2)的化合物之间的反应,分别获得由下列式(II-3)和(II’-3)所表示的化合物:
分别进行式(II-3)或(II′-3)的化合物与由下列式(II-4)或(II’-4)所表示的化合物之间的反应,以分别获得下列式(II-5)和(II’-5)所表示的化合物:
Rd和Re各自独立为保护基;以及
将式(II-5)或(II’-5)的化合物与式(III)的催化剂进行环化反应,以分别获得一由下列式(I)或(I’)所表示的化合物:
M(O)mL1 yL2 z (III)
其中,M为一金属,选自由IVB、VB、VIB、和锕系族所组成的群组;
L1和L2分别为一配位基;
m和y为大于或等于1的整数;以及
z为大于或等于0的整数。
9.如权利要求8所述的方法,其中L1为选自Cl、OTf、OTs、NTf2、卤素、RC(O)CHC(O)R、OAc、OC(O)CF3、OEt、O-iPr、和丁基所组成的群组,其中,R为烷基。
10.如权利要求8所述的方法,其中,L2为选自Cl、H2O、CH3OH、EtOH、THF、CH3CN、和所组成的群组。
11.如权利要求8所述的方法,其中,Rc和Rd为茀基甲氧基羰基,且Re为2,3,6,-三甲基-4-甲氧基苯磺酰基。
12.如权利要求8所述的方法,其中,以该式(III)的催化剂进行式(II-1)或(II’-1)与(II-2)化合物之间的反应,或以式(III)的该催化剂进行式(II-3)与(II-4)或式(II’-3)与(II’-4)化合物之间的反应。
13.如权利要求8所述的方法,其中,M为IVB族过渡元素,m为1且y为2。
14.如权利要求8所述的方法,其中,M为VB族过渡元素,m为1且y为2或3。
15.如权利要求8所述的方法,其中,M为VIB族过渡元素,m为1且y为4。
16.如权利要求8所述的方法,其中,M为VIB族过渡元素,m为2且y为2。
17.如权利要求8所述的方法,其中,M为选自锕系族,m为2且y为2。
18.如权利要求8所述的方法,其中,该式(III)的催化剂为MoO2Cl2、V(O)OCl2、V(O)(OAc)2、V(O)(O2CCF3)2、Ti(O)(acac)2、Zr(O)Cl2、Hf(O)Cl2、Nb(O)Cl2、MoO2(acac)2、V(O)(OTs)2、VO(OTf)2、或V(O)(NTf2)2。
19.如权利要求8所述的方法,其中,z为0。
20.如权利要求8所述的方法,其中,该式(I)或(I’)的化合物为下列式(I-1)至(I-5)和(I’-1)至(I’-5)任一种:
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CN113121647A (zh) * | 2020-01-16 | 2021-07-16 | 陈建添 | 环肽及其制备方法 |
CN114634554A (zh) * | 2022-04-09 | 2022-06-17 | 浙江湃肽生物股份有限公司 | 一种抗皱环六肽化合物及其制备方法 |
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TWI747138B (zh) * | 2020-01-16 | 2021-11-21 | 國立清華大學 | 環胜肽及其製備方法 |
CN117462440B (zh) * | 2023-12-26 | 2024-09-13 | 杭州湃肽生化科技有限公司 | 功能性环肽及其制备方法及应用 |
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CN114634554A (zh) * | 2022-04-09 | 2022-06-17 | 浙江湃肽生物股份有限公司 | 一种抗皱环六肽化合物及其制备方法 |
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