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【结 构 式】 
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【药物名称】PMX-53, AcF-(OPdChaWR) 【化学名称】(3S,9S,12S,15R,18S)-3-(N-Acetyl-L-phenylalanylamino)-15-(cyclohexylmethyl)-9-(3-guanidinopropyl)-12-(1H-indol-3-ylmethyl)--1,7,10,13,16-pentaazabicyclo[16.3.0]heneicosane-2,8,11,14,17-pentaone 【CA登记号】219639-70-0 【 分 子 式 】C47H65N11O7 【 分 子 量 】896.1116 |
【开发单位】Promics (Originator), University of Queensland (Originator) 【药理作用】Antiarthritic Drugs, Antipsoriatics, Atopic Dermatitis, Agents for, DERMATOLOGIC DRUGS, RENAL-UROLOGIC DRUGS, Rheumatoid Arthritis, Treatment of, Topical Antiinflammatory Agents, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Treatment of Renal Diseases, C5a Antagonists |
合成路线1
The compound was prepared by solid-phase peptide synthesis on a PAM-resin. Starting from a N(alpha)-Boc-N(gamma)-Tos-L-arginine resin (I), cleavage of the Boc protecting group by means of trifluoroacetic acid provided Arg(Tos)-resin (II). Coupling of (II) with N(alpha)-Boc-L-tryptophan (III) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and diisopropylethylamine, followed by acid cleavage of the Boc group gave dipeptide resin (IV). This was in turn coupled and deprotected with the following amino acids N-Boc-D-cyclohexylalanine (V), N--Boc-L-proline (VII) and N(alpha)-Boc-N(delta)-Tos-L-ornithine (IX) to furnish the peptide resins (VI), (VIII), (X) and (XII), respectively.
| 【1】 Wong, A.K.; Finch, A.M.; Pierens, G.K.; Craik, D.J.; Taylor, S.M.; Fairlie, D.P.; Small molecular probes for G-protein-coupled C5a receptors: Conformationally constrained antagonists derived from the C terminus of the human plasma protein C5a. J Med Chem 1998, 41, 18, 3417. |
| 【2】 Wong, A.K.; Fairlie, D.P.; Finch, A.M.; Wadi, S.K.; Craik, D.J.; Taylor, S.M.; Paczkowski, N.J.; Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a. J Med Chem 1999, 42, 11, 1965. |
| 【3】 Fairlie, D.; Wong, A.; Finch, A.M.; Taylor, S.M. (University of Queensland); Cyclic agonists and antagonists of C5a receptors and G protein-coupled receptors. EP 1017713; WO 9900406 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 19064 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (II) | 34498 | (2S)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C13H20N4O4S | 详情 | 详情 | |
| (III) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (IV) | 34499 | (2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C24H30N6O5S | 详情 | 详情 | |
| (V) | 29348 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid | C14H25NO4 | 详情 | 详情 | |
| (VI) | 34500 | (2S)-2-[[(2S)-2-[[(2R)-2-amino-3-cyclohexylpropanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C33H45N7O6S | 详情 | 详情 | |
| (VII) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (VIII) | 34505 | (2S)-2-[[(2S)-2-[((2R)-3-cyclohexyl-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoyl)amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C38H52N8O7S | 详情 | 详情 | |
| (IX) | 34501 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(4-methylphenyl)sulfonyl]amino]pentanoic acid | C17H26N2O6S | 详情 | 详情 | |
| (X) | 34502 | C50H68N10O10S2 | 详情 | 详情 |
合成路线2
The resin (X) was coupled with N-Boc-L-phenylalanine (XI) affording resin (XII). The acetylation of the free amino group, side-chain deprotection and cleavage from the resin (XII) employing liquid HF and p-cresol yielded the linear dipeptide (XIII). This was finally cyclized with benzotriazol-1-yloxytris (dimethylamino)phosphonium hexafluorophosphate (BOP) to produce the title cyclic peptide.
| 【1】 Wong, A.K.; Finch, A.M.; Pierens, G.K.; Craik, D.J.; Taylor, S.M.; Fairlie, D.P.; Small molecular probes for G-protein-coupled C5a receptors: Conformationally constrained antagonists derived from the C terminus of the human plasma protein C5a. J Med Chem 1998, 41, 18, 3417. |
| 【2】 Wong, A.K.; Fairlie, D.P.; Finch, A.M.; Wadi, S.K.; Craik, D.J.; Taylor, S.M.; Paczkowski, N.J.; Low-molecular-weight peptidic and cyclic antagonists of the receptor for the complement factor C5a. J Med Chem 1999, 42, 11, 1965. |
| 【3】 Fairlie, D.; Wong, A.; Finch, A.M.; Taylor, S.M. (University of Queensland); Cyclic agonists and antagonists of C5a receptors and G protein-coupled receptors. EP 1017713; WO 9900406 . |