CN1083075A - 线性肽 - Google Patents
线性肽 Download PDFInfo
- Publication number
- CN1083075A CN1083075A CN93107348A CN93107348A CN1083075A CN 1083075 A CN1083075 A CN 1083075A CN 93107348 A CN93107348 A CN 93107348A CN 93107348 A CN93107348 A CN 93107348A CN 1083075 A CN1083075 A CN 1083075A
- Authority
- CN
- China
- Prior art keywords
- leu
- gly
- asp
- val
- ala
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title abstract description 17
- 102000004196 processed proteins & peptides Human genes 0.000 title abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 20
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 4
- 230000037396 body weight Effects 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 208000007536 Thrombosis Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 208000010125 myocardial infarction Diseases 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 230000003203 everyday effect Effects 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 239000002253 acid Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- -1 CBZ carbobenzoxy-(Cbz) Chemical class 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000003999 initiator Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 238000003797 solvolysis reaction Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 238000011146 sterile filtration Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229940099259 vaseline Drugs 0.000 description 2
- 239000000273 veterinary drug Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OIXLLKLZKCBCPS-RZVRUWJTSA-N (2s)-2-azanyl-5-[bis(azanyl)methylideneamino]pentanoic acid Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.OC(=O)[C@@H](N)CCCNC(N)=N OIXLLKLZKCBCPS-RZVRUWJTSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000007079 Peptide Fragments Human genes 0.000 description 1
- 108010033276 Peptide Fragments Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000012928 buffer substance Substances 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 229940000351 hemocyte Drugs 0.000 description 1
- 210000003677 hemocyte Anatomy 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- YPGCWEMNNLXISK-UHFFFAOYSA-N hydratropic acid Chemical compound OC(=O)C(C)C1=CC=CC=C1 YPGCWEMNNLXISK-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/75—Fibrinogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Hematology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Diabetes (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及式Iα-In的新线性肽及其盐,它们
除具有其它性质外可抑制细胞粘连。
Description
本发明涉及有用的线性肽。欧洲专利申请0,406,428中公开了与此相似的但为环状的化合物。
本发明的目的是要提供具有有用性质,尤其是可用于制造药物的新化合物。
通过对本说明书及所附权利要求书进行研究,本领域熟练技术人员能够很容易地看出本发明的其它目的及其优点。
这些目的是通过提供式Ⅰa-Ⅰn的新线性肽及其盐而达到:
(Ⅰa) H-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ⅰb) H-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ⅰc) H-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ⅰd) H-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ⅰe) H-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ⅰf) H-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ⅰg) H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ⅰh) H-Gly-Asp-Gly-Arg-His-Asp-Leu-OH;
(Ⅰi) H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-OH;
(Ⅰj) H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-OH;
(Ⅰk) H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-OH;
(Ⅰl) H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;
(Ⅰm) Ac-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;
(Ⅰn) Ac-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;
其中Ac代表乙酰基。
现已发现式Ⅰa-Ⅰn化合物及其盐具有有用的性质。具体地说,它们是细胞粘连抑制剂,可用于抑制例如血细胞和肿瘤细胞的聚集。因此,该化合物为用于抑制动物细胞,例如哺乳动物的体细胞或癌细胞的粘连。
利用EP0,406,428,FEBS Lett.291,50-54(1991)或Smith,H.W.,Ruggeri、Ruggeri,Z.W.,Kuncki,J.J.Cheresh,D.A.,J.Biol.Chem.265,12267-12267-12271(1990)中所述的方法,可对以上抑制作用进行检测。
该化合物可用作人药或兽药中的药物活性成分,尤其是治疗和预防血栓形成、心肌梗塞、心绞痛、中风以及意味着癌症疾病的肿瘤。
在本上、下文中所出现的氨基酸残基的缩写代表如下氨基酸:
Ala 丙氨酸
Arg 精氨酸
Asp 天冬氨酸
Gly 甘氨酸
His 组氨酸
Leu 亮氨酸
Pro 脯氨酸
Tyr 酪氨酸
Val 缬氨酸
另外,以下各缩写符合分别代表:
Ac 乙酰基
BOC 叔丁氧羰基
CBZ 苄氧羰基
DCCI 二环己基碳化二亚胺
DMF 二甲基甲酰胺
EDCI N-乙基-N′-(3-二甲基氨基丙基)碳化二亚胺盐酸盐
FMOC 9-芴基甲氧羰基
Me 甲基
OMe 甲氧基
OEt 乙氧基
TFA 三氟乙酸
POA 苯氧乙酰基
对于本文中所提到的具体化合物,除非特别说明,则以上缩写所代表的氨基酸均为L-型。
本发明还涉及式Ⅰ线性肽的制备方法,其特征在于式Ⅰ线性肽是通过用溶剂分解剂或氢化剂处理而从其功能性衍生物中释放出来,或者其特征在于通过肽片段缩合将两个具有较小序列的肽结合在一起以产生一种式Ⅰ肽,和/或通过用酸处理将式Ⅰ化合物转化为其一种盐。
式Ⅰ化合物及用于制备式Ⅰ化合物的起始物可另外通过已知方法,如文献中所述的方法(如Houben-Weyl,Methoden der Organischen Chcmie,(Methods of Onganic chomistry)Georg-Thicme-Verlag,Stuttgart)制备。在本文中,也可使用这里没有更详细提到的各种不同方法。
根据需要,也可就地形成起始物,使它们不从反应混合物中分离出来,而是立即进一步反应,产生式Ⅰ化合物。
也可通过溶剂分解,尤其是水解,或通过氢化而使它们从其功能性衍生物中释放这一方法来获得式Ⅰ化合物。
用于溶剂分解或氢化的起始物最好含有适当保护的氨基和/或羟基,以代替一个或多个游离氨基和/或羟基,优选的是携带氨基保护基以取代氢原子与氮原子结合的起始物,如对应于式Ⅰ但含有NHR′基团(其中R′为氨基保护基,如BOC或CBZ)而不是NH2基团的物质。
另外,携带羟基保护基以取代羟基中的氢原子的起始物也是优选的,这类起始物如对应于式Ⅰ但羟基苯基被R″O-苯基(R″为羟基保护基)取代的物质。
起始物分子中可存在几个相同或不同的被保护氨基和/或羟基。如果所存在的保护基彼此互不相同,则在许多情况下它们可被分别除去。
术语“氨基保护基”是普遍熟知的,它涉及的是适用于保护(封阻)氨基免于化学反应而在分子中的其它位置所进行的所需化学反应完成后又易于除去的基团。这类基团的典型例子具体地有未取代或取代酰基、芳基、芳烷氧甲基或芳烷基。由于氨基保护基在所需反应(或反应序列)完成后被除去,因此其性质和大小并不重要;但优选具有1-20个,尤其是1-8个碳原子的基团。术语“酰基”在本发明方法中取其最宽含义。它包括得自脂族、芳脂族、芳族或杂环羧酸或磺酸的酰基,尤其是烷氧羰基、芳氧羰基以及芳烷氧羰基。这类酰基的例子有链烷酰基,如乙酰基、丙酰基或丁酰基;芳烷酰基,如苯基乙酰基;芳酰基,如苯甲酰基或甲苯甲酰基;芳氧烷酰基,如POA;烷氧羰基,如甲氧羰基、乙氧羰基、2,2,2-三氯乙氧羰基、BOC、2-碘乙氧羰基;芳烷氧羰基,如CBZ(“苄酯基”)、4-甲氧基苄氧羰基和FMOC。优选的氨基保护基是BOC以及CBZ、FMOC、苄基和乙酰基。
术语“羟基保护基”也是普遍熟知的,它涉及的是适用于保护羟基免受化学反应而在分子中其它位置所进行的所需化学反应完成后又易于除去的基团。这类基团的典型例子有上面提到的未取代或取代芳基、芳烷基或酰基,以及烷基。羟基保护基的性质和大小并不是关键,因为它们在所需化学反应或反应序列完成后被除去;优选具有1-20个,尤其是1-10个碳原子的基团。羟基保护基的例子特别有苄基、对-硝基苯甲酰基、叔丁基、对-甲苯磺酰基和乙酰基,尤其优选的是苄基、叔丁基和乙酰基。
用作起始物的式Ⅰ化合物的功能性衍生物可按合成氨基酸和肽的常规方法制备,这些方法包括所提到的经典著作和专利申请中所提到的方法,以及Merrificld固相法(B.F.Gysin和R.B.Merrificld,J.Am.Chem.Soc。94,3102 et seq(1972))。
根据所使用的保护基,可利用强酸,最好是TFA或高氯酸,但也可以是其它强无机酸(如盐酸或硫酸)或其它强有机羧酸(如三氯乙酸)或磺酸(如苯磺酸或对-甲苯磺酸),将式Ⅰ化合物从其功能性衍生物中释放出来。其它惰性溶剂的存在是可能的,但这一点并不总是必需的。这类惰性溶剂最好是有机溶剂,例如羧酸(如乙酸)、醚(如四氢呋喃和二噁烷)、酰胺(如DMF)、卤代烃(如二氯甲烷)和醇(如甲醇、乙醇或异丙醇),也可以是水。
另外,上述溶剂的混合物也是适用的。TFA最好在不加入其它溶剂的情况下过量使用;高氯酸可按乙酸与70%高氯酸之比为9∶1的混合物形式使用。用于裂解的反应温度优选约为0-50℃,更优选15-30℃(室温)。
BOC基团最好在15-30℃用40%TFA的二氯甲烷溶液或用3-5N盐酸的二噁烷溶液除去,FMOC基团最好于15-30℃用约5-20%二甲胺、二乙胺或哌啶的DMF溶液除去。
能够通过氢化除去的保护基(如CBZ或苄基)可在催化剂(如钯等贵金属催化剂,最好吸附于碳等载体上)存在下通过氢处理除去。在这种情况下合适的溶剂是上面所提到的溶剂,尤其是例如醇类(如甲醇或乙醇)或酰胺(如DMF)。氢化一般在温度为约0-100℃、压力为约1-200巴(优选20-30℃和1-10巴)的情况下进行,CBZ基团的氢化易在20-30℃在例如5-10%Pd-C的甲醇溶液中进行,或者利用甲酸铵(代替H2)在Pd-C的甲醇/DMF溶液中进行。
也可在合成肽的条件下通过缩合具有较小序列的肽来获得式Ⅰ化合物。在这种情况下,最好按合成肽的常规方法,如Houben-Weyl,loc cit volumc 15/Ⅱ,Pagelto806(1974)中所述的方法进行反应。
该反应最好在脱水剂存在的情况下于惰性溶剂中进行,该脱水剂的例子有碳化二亚胺类(如DCCI或EDCI)、丙烷膦酸酐(com-pare Anglw.Chem.92,129(1989))、二苯基磷酰叠氮化物或2-乙氧基-N-乙氧羰基-1,2-二氢喹啉,惰性溶剂的例子有卤代烃类(如二氯甲烷)、醚类(如四氢呋喃或二噁烷)、酰胺类(如DMF或二甲基乙酰胺)、腈类(如乙腈)或这些溶剂的混合物,反应温度为约-10至40℃,优选0-30℃。
可用酸将式Ⅰ碱转化成适当的酸加成盐。适用于碳反应的酸具体为产生生理上可接受的盐的酸。可使用的无机酸的例子有硫酸、硝酸、氢卤酸(如盐酸或氢溴酸)、磷酸(如正磷酸和氨基磺酸)、有机酸的例子有脂族酸、环脂族酸、芳脂族酸、芳族酸或杂环族一元或多元羧酸、磺酸或硫酸,如甲酸、乙酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、苯甲酸、水杨酸、2-或3-苯基丙酸、柠檬酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲烷磺酸、乙烷磺酸、乙烷二磺酸、2-羟基乙烷磺酸、苯磺酸、对-甲苯磺酸、萘-磺酸、萘二磺酸、十二烷基硫酸。与生理上不可接受的酸形成的盐(如苦味酸盐)可用于式Ⅰ化合物的分离和/或纯化。
通过将式Ⅰ新化合物及其生理上可接受的盐与至少一种赋形剂或助剂(根据需要还可包括一种或多种其它活性化合物)一起配制成适当的剂量形式可制备出药物制剂。由此获得的制剂可用作人用或兽用药物。合适的赋形物质是适用于肠道(如口腔或直肠)、非肠道或局部(如皮肤)给药或以吸入喷雾形式给药且不与新化合物反应的物质。如水、低级醇、植物油、苄醇、聚乙二醇、三乙酸甘油酯和其它脂肪酸甘油酯、白明胶、大豆卵磷脂、碳水化合物(如乳糖或淀粉)、硬脂酸镁、滑石、纤维素和凡士林。片剂、包衣片剂、胶囊、糖浆、液体剂或滴剂可用于口服给药,尤其适用的是薄膜片剂和具有耐胃液涂层或胶囊壳的胶囊剂。栓剂可用于直肠给药,溶液剂(尤其是油溶液或水溶液)、悬浮剂、乳剂或植入物可用于非肠道给药。溶液(如可用作眼滴剂的溶液)、悬浮、乳液、油膏、软膏或敷布可用于表皮给药。所使用的雾剂中含有溶于或悬浮于推进剂气体混合物(如含氧氟烃或基经济、无害替代物)的活性化合物,以作为吸入喷雾给药。该活性化合物最好以粉碎形式使用,其中还可存在一种或多种其它生理上耐受的溶剂(如乙醇)。吸入溶液可借助常规吸入器给药。可将新化合物冷冻干燥,且新获得的冻干物可用于例如生产注射制剂。该制剂能被灭菌并可含有辅助剂,如防腐剂、稳定剂和/或润湿剂、乳化剂、影响渗透压的盐、缓冲物质、着色剂和/或调味剂。根据需要,该制剂也可含有一种或多种其它活性化合物,如一种或多种维生素。
本发明的物质一般按与其它已知市售肽类似的方式给药,尤其是按照与US-A-4,472,305中所述化合物类似的方式给药,其剂量优选每剂量单位约0.05-500mg,更优选0.5-100mg。日剂量最好为0.01-2mg/kg体重。但是,对每一特定患者来说,具体剂量取决于许多不同因素,如所使用具体化合物的活性、患者年龄、体重、总的健康状况、性别、成本、给药时间及途径、排泄途径、药物组合以及所要治疗疾病的严重程度。优选非肠道途径给药。
无需进一步详细说明,相信本领域熟练技术人员根据前面的说明就能够最大限度的利用本发明。因此,以下优选的具体实施方案仅在于说明而不是以任何方式限定本发明。
在本文中,除非特别说明,所有温度均指摄氏温度,所有份和百分数均指重量。
以上和以下提到的所有专利申请、专利及其它出版物均作为参考文献加到说明书中。
以下面的实施例中,“常规处理”意指:根据需要加入水,中和混合物,用乙醚或二氯甲烷萃取,分离掉有机相,于硫酸钠上干燥,过滤和蒸发后,其残余物通过硅胶层析和/或结晶纯化。RT为在LuhrosorbRRP Select B(250-4.7μm)柱上进行HPLC的保留时间(分),除非特别说明;洗脱剂:α=0.3%TFA的水溶液,b=异丙醇(梯度:0-80vol.%)。
通过快速原子轰击测定出化合物的分子质量(FAB;M+:分子离子峰)。
实施例1
将2.0g BOC-Leu-Leu-Val-OH〔可通过例如合成肽的改性Merrificld技术获得〕溶于150m二氯甲烷和20ml DMF的混合物中,并冷却至0℃。在搅拌下依次向其中加入0.5g DCCI、0.3g HOBt、0.23ml N-甲基吗啉和1当量H-Gly-Ala-Pro-Leu-Tyr-OMe,并将混合物于0℃搅拌24小时,于25℃搅拌12小时,然后浓缩溶液,并且混合床离子交换剂处理以将其从盐中游离出来,过滤后蒸发溶液,并纯化残余物,从而得到BOC-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OMe。
按照类似方法可得到以下肽:
BOC-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OMe;
BOC-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OMe;
BOC-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OMe;
BOC-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OMe;
BOC-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OMe;
BOC-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OMe;
BOC-Gly-Asp-Gly-Arg-His-Asp-Leu-OMe;
BOC-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-OMe;
BOC-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-OMe;
BOC-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-OMe;
BOC-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OMe;
BOC-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OMe;
BOC-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OMe.
实施例2
将1.8g BOC-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OMe溶于60ml甲醇中,并向其中加入1.5ml2N氢氧化钠溶液,将混合物于20℃搅拌3小时。蒸发后将残余物加入水中,用稀盐酸酸化至pH3,并用乙酸乙酯萃取。萃取物在Na2SO4上干燥,再次蒸发后得到BOC-Leu-Val-Gly-Ala-Pro-Ieu-Tyr-OH,将其与20ml 2N盐酸的二烷溶液一起于20℃搅拌2小时。接着,蒸发混合物,残余物通过HPLC纯化,得到H-Leu-Leu-Val-Gly-Ala-Pro-Ieu-Tyr-OH,M+846。
按照类似方式,得到以下肽:
H-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;M+961;
H-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;M+1098;
H-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;M+1252;
H-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;M+1309;
H-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;M+1425;
H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;M+1482;
H-Gly-Asp-Gly-Arg-His-Asp-Leu-OH;M+769;
H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-OH;M+882;
H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-OH;M+1038;
H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-OH;M+1109;
H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;M+1319;
H-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;M+935;
H-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;M+1146.
实施例3
将2.7g H-His-Asp-Ieu-Leu-Val-Gly-Ala-Pro-Leu-OH溶于200ml DMF水溶液中。在搅拌下向其中滴加1.0g乙酰氯的10ml二氯甲烷溶液。将溶液搅拌10分钟后浓缩。过滤出所产生的Ac-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH,M+976。
实施例4
按与实施例3相似的方法得到Ac-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH(M+1189)。
以下实施例涉及含有式Ⅰ化合物或其酸加成盐的药物配方。
实施例A:片剂
按常规方法将1kg H-Gly-Asp-Gly-Arg-His-Asp-Leu-OH、10kg乳糖、6kg微结晶纤维素、6kg马铃薯淀粉、1kg聚乙烯吡咯烷酮、0.8g滑石和0.1kg硬脂酸镁挤压成片剂,每片含10mg活性化合物。
实施例B:包衣片剂
按实施例A挤压片剂,然后按常规方法包衣一层蔗糖、马铃薯淀粉、滑石、黄蓍糖和着色物质。
实施例C:胶囊
按常规方式向硬明胶胶囊中填入1kg H-Glg-Asp-Gly-Arg-His-Asp-Leu-OH,使得每粒胶囊含有5mg活性物质。
实施例D:安瓿
将1kg H-Gly-Asp-Gly-Arg-His-Asp-Leu-OH的30l1,2-丙二醇溶液进行无菌过滤,注入安瓿中后在无菌条件下冷冻干燥,并无菌封口。每安瓿含2mg活性化合物。
实施例E:软膏
在无菌条件下将5000mg H-Gly-Asp-Gly-Arg-His-Asp-Leu-OH与99.5g矿脂混合。
实施例F:注射小瓶
将100g H-Gly-Asp-Gly-Arg-His-Asp-Leu-OH和5g磷酸氢二钠溶于3l双蒸馏水中,用2N盐酸调节pH至6.5,无菌过滤后注入注射小瓶,并在无菌条件下冷冻干燥。按无菌方法封瓶。每一注射小瓶含有5mg活性化合物。
按类似方式可制备出含有其它式Ⅰ活性化合物之一和/或其生理上可接受的酸加成盐的药物配方。
通过改变概括描述或具体描述的反应物和/或操作条件,可重复上述实施例。
从上面的叙述中本领域普通技术人员能够很容易地确定本发明的主要特征。且在不背离其精神和范围的情况下可对本发明作出各种改动和改进,以使其适应各种用途和条件。
Claims (10)
1、式Ia-In的化合物或其盐
(Ia)H-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ib)H-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ic)H-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Id)H-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ie)H-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(If)H-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ig)H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-Tyr-OH;
(Ih)H-Gly-Asp-Gly-Arg-His-Asp-Leu-OH;
(Ii)H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-OH;
(Ij)H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-OH;
(Ik)H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-OH;
(Il)H-Gly-Asp-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;
(Im)Ac-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;
(In)Ac-Gly-Arg-His-Asp-Leu-Leu-Val-Gly-Ala-Pro-Leu-OH;
其中Ac代表乙酰基。
2、一种药物组合物,它含有抑制细胞粘连有效量的权利要求1化合物以及可作药用的载体。
3、根据权利要求2的药物组合物,其中所说化合物的量为0.05-500mg。
4、根据权利要求2的药物组合物,其中所说化合物的量为0.5-100mg。
5、一种治疗或预防血栓形成、心肌梗塞、心绞痛、中风以及肿瘤的方法,它包括给患者服用权利要求1化合物。
6、一种抑制动物细胞粘连的方法,它包括服用权利要求1化合物。
7、根据权利要求6的方法,其中所说细胞为动物的体细胞。
8、根据权利要求6的方法,其中所说细胞为哺乳动物的癌细胞。
9、根据权利要求5的方法,其中所说化合物按每日剂量为0.1-2mg/kg体重给药。
10、根据权利要求6的方法,其中所说化合物按每日剂量为0.1-2mg/kg体重给药。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US90038592A | 1992-06-18 | 1992-06-18 | |
US900,385 | 1992-06-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1083075A true CN1083075A (zh) | 1994-03-02 |
Family
ID=25412429
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN93107348A Pending CN1083075A (zh) | 1992-06-18 | 1993-06-18 | 线性肽 |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0576898A2 (zh) |
JP (1) | JPH0665290A (zh) |
KR (1) | KR940005667A (zh) |
CN (1) | CN1083075A (zh) |
AU (1) | AU4125193A (zh) |
CA (1) | CA2098535A1 (zh) |
CZ (1) | CZ118593A3 (zh) |
HU (1) | HUT66469A (zh) |
MX (1) | MX9303638A (zh) |
NO (1) | NO932237L (zh) |
PL (1) | PL299367A1 (zh) |
SK (1) | SK57693A3 (zh) |
ZA (1) | ZA934353B (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5753230A (en) | 1994-03-18 | 1998-05-19 | The Scripps Research Institute | Methods and compositions useful for inhibition of angiogenesis |
US5780426A (en) * | 1995-06-07 | 1998-07-14 | Ixsys, Incorporated | Fivemer cyclic peptide inhibitors of diseases involving αv β3 |
US5767071A (en) * | 1995-06-07 | 1998-06-16 | Ixsys Incorporated | Sevenmer cyclic peptide inhibitors of diseases involving αv β3 |
SK163598A3 (en) | 1996-05-31 | 1999-06-11 | Scripps Research Inst | Methods and compositions useful for inhibition of angiogenesis |
US6849712B1 (en) | 1998-01-22 | 2005-02-01 | Regents Of The University Of Minnesota | Peptides with β1 integrin subunit dependent cell adhesion modulating activity |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5196511A (en) * | 1989-12-01 | 1993-03-23 | The Scripps Research Institute | Peptides and antibodies that inhibit integrin-ligand binding |
-
1993
- 1993-06-08 SK SK576-93A patent/SK57693A3/sk unknown
- 1993-06-15 EP EP93109532A patent/EP0576898A2/en not_active Withdrawn
- 1993-06-15 AU AU41251/93A patent/AU4125193A/en not_active Abandoned
- 1993-06-16 CA CA002098535A patent/CA2098535A1/en not_active Abandoned
- 1993-06-17 MX MX9303638A patent/MX9303638A/es unknown
- 1993-06-17 HU HU9301768A patent/HUT66469A/hu unknown
- 1993-06-17 CZ CZ931185A patent/CZ118593A3/cs unknown
- 1993-06-17 NO NO932237A patent/NO932237L/no unknown
- 1993-06-17 KR KR1019930011106A patent/KR940005667A/ko not_active Application Discontinuation
- 1993-06-17 ZA ZA934353A patent/ZA934353B/xx unknown
- 1993-06-17 PL PL29936793A patent/PL299367A1/xx unknown
- 1993-06-18 JP JP5147794A patent/JPH0665290A/ja active Pending
- 1993-06-18 CN CN93107348A patent/CN1083075A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
HUT66469A (en) | 1994-11-28 |
KR940005667A (ko) | 1994-03-22 |
ZA934353B (en) | 1994-01-13 |
NO932237D0 (no) | 1993-06-17 |
MX9303638A (es) | 1994-05-31 |
CA2098535A1 (en) | 1993-12-19 |
HU9301768D0 (en) | 1993-09-28 |
EP0576898A3 (zh) | 1994-04-13 |
AU4125193A (en) | 1993-12-23 |
CZ118593A3 (en) | 1994-02-16 |
NO932237L (no) | 1993-12-20 |
SK57693A3 (en) | 1994-07-06 |
EP0576898A2 (en) | 1994-01-05 |
PL299367A1 (en) | 1994-02-21 |
JPH0665290A (ja) | 1994-03-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
FI75563C (fi) | Foerfarande foer framstaellning av nya, terapeutiskt anvaendbara 2,5-diketopiperazinderivat. | |
JP3509029B2 (ja) | 生物活性環化ポリペプチド | |
CN1161374C (zh) | 环肽 | |
CN1309633A (zh) | 作为整合素抑制剂的二酰基肼衍生物 | |
CN1111640A (zh) | 脂肽衍生物,它们的制备方法及用途 | |
KR101904808B1 (ko) | 데가렐릭스 및 이의 중간 화합물의 제조 방법 | |
PT98023B (pt) | Processo para a preparacao de novos polipeptidos | |
CN1238781A (zh) | 七肽催产素类似物 | |
CN1264388A (zh) | 多拉司他汀15衍生物 | |
CN1140171A (zh) | 苯并呋喃类 | |
CN108395471B (zh) | 抑制MERS-CoV感染的多肽 | |
IE913831A1 (en) | Cyclopeptides | |
CN1335853A (zh) | 整联蛋白αvβb的抑制剂 | |
CN1126759C (zh) | 含d-2-烷基色氨酸、能促进生长激素释放的寡肽化合物 | |
US9850285B2 (en) | Process for preparing eptifibatide | |
CN88103015A (zh) | 环状抗凝血剂肽 | |
CN1329610A (zh) | 用作整联蛋白抑制剂的苯并吡喃酮和苯并二氢吡喃酮衍生物 | |
CN1083075A (zh) | 线性肽 | |
CN1158622A (zh) | 含d-2-烷基色氨酸的能促进生长激素释放的多肽化合物 | |
CN1261895A (zh) | 具有拮抗作用的环氮杂肽 | |
CN1447799A (zh) | 联苯衍生物及其作为整联蛋白抑制剂的应用 | |
CN1200947C (zh) | 制备环(Asp-Dphe-NMeVal-Arg-Gly)的方法 | |
CN1127514C (zh) | 抗癌的肽类 | |
JP2011503215A (ja) | 新規の免疫調節ペプチド、その組成物およびその使用 | |
CN1247543A (zh) | 环肽衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C01 | Deemed withdrawal of patent application (patent law 1993) | ||
WD01 | Invention patent application deemed withdrawn after publication |