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【结 构 式】 
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【药物名称】NPC-17731 【化学名称】D-Arginyl-L-arginyl-L-prolyl-L-(trans-4-hydroxy)prolyl-glycyl-L-phenylalanyl-L-seryl-D-(trans-4-propoxy)prolyl-L-[(2alpha,3abeta,7abeta)octahydroindol-2-ylcarbonyl]-L-arginine 【CA登记号】147267-10-5 【 分 子 式 】C59H95N19O14 【 分 子 量 】1294.5339 |
【开发单位】Scios (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiallergy/Antiasthmatic Drugs, Asthma Therapy, GASTROINTESTINAL DRUGS, Inflammatory Bowel Disease, Agents for, Non-Opioid Analgesics, RESPIRATORY DRUGS, Bradykinin B2 Antagonists, Non-Steroidal Antiinflammatory Drugs |
合成路线1
Double alkylation of N-Boc-D-trans-4-hydroxyproline with allyl bromide in the presence of NaH in DMF afforded (II), which was subsequently hydrolyzed to the acid (III) with NaOH in aqueous methanol. Hydrogenation of allylic double bond in the presence of Pd/C gave propyl ether (IV).
| 【1】 Kyle, D.J.; Hiner, R.N. (Scios Inc.); Bradykinin antagonist peptides. JP 1995504155; US 5385889 . |
| 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) | 19043 | (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid | C10H17NO5 | 详情 | 详情 | |
| (II) | 19044 | 2-allyl 1-(tert-butyl) (2R,4S)-4-(allyloxy)-1,2-pyrrolidinedicarboxylate | C16H25NO5 | 详情 | 详情 | |
| (III) | 19045 | (2R,4S)-4-(allyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C13H21NO5 | 详情 | 详情 | |
| (IV) | 19046 | (2R,4S)-1-(tert-butoxycarbonyl)-4-propoxy-2-pyrrolidinecarboxylic acid | C13H23NO5 | 详情 | 详情 |
合成路线2
In a solid phase synthesizer, an a-Boc-omega-Ts-Arg-phenylacetamidomethyl resin (V) was treated with trifluoroacetic acid (TFA) in anisole and dichloromethane in order to remove the Boc protecting group, and the resulting (VI) was coupled with Boc-octahydroindolecarboxylic acid (VII) in the presence of diisopropyl carbodiimide (DIPCDI) to give the dipeptide resin (VIII). This was submitted to successive coupling cycles (deprotection with TFA, and coupling with DIPCDI) to introduce sequentially the following amino acids: Boc-D-4-propoxyproline (IV), Boc-Ser(Bzl) (XIa) to yield the following resins: (IXa),(IXb) and (X), respectively.
| 【1】 Kyle, D.J.; Hiner, R.N. (Scios Inc.); Bradykinin antagonist peptides. JP 1995504155; US 5385889 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIa) | 16886 | (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine | 23680-31-1 | C15H21NO5 | 详情 | 详情 |
| (IXa) | 19051 | methyl (2S)-2-[[(2S,3aS,7aS)octahydro-1H-indol-2-ylcarbonyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C23H35N5O5S | 详情 | 详情 | |
| (IXb) | 19052 | methyl (2S)-2-[[((2S,3aS,7aS)-1-[[(2R,4S)-4-propoxypyrrolidinyl]carbonyl]octahydro-1H-indol-2-yl)carbonyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C31H48N6O7S | 详情 | 详情 | |
| (IV) | 19046 | (2R,4S)-1-(tert-butoxycarbonyl)-4-propoxy-2-pyrrolidinecarboxylic acid | C13H23NO5 | 详情 | 详情 | |
| (V) | 19047 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C19H30N4O6S | 详情 | 详情 | |
| (VI) | 19048 | methyl (2S)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C14H22N4O4S | 详情 | 详情 | |
| (VII) | 19049 | (2S,3aS,7aS)-1-(tert-butoxycarbonyl)octahydro-1H-indole-2-carboxylic acid | C14H23NO4 | 详情 | 详情 | |
| (VIII) | 19050 | tert-butyl (2S,3aS,7aS)-2-([[(1S)-4-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]-1-(methoxycarbonyl)butyl]amino]carbonyl)octahydro-1H-indole-1-carboxylate | C28H43N5O7S | 详情 | 详情 | |
| (X) | 19053 | methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-amino-3-(benzyloxy)propanoyl]-4-propoxypyrrolidinyl]carbonyl)octahydro-1H-indol-2-yl]carbonyl]amino)-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C41H59N7O9S | 详情 | 详情 |
合成路线3
Compound (X) was submitted to successive coupling cycles (deprotection with TFA, and coupling with DIPCDI) to introduce sequentially the following amino acids: (XIb), (XIII) and (XV) yielding the following resins: (XII),(XIV) and (XVI), respectively.
| 【1】 Kyle, D.J.; Hiner, R.N. (Scios Inc.); Bradykinin antagonist peptides. JP 1995504155; US 5385889 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIb) | 12874 | (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine | 13734-34-4 | C14H19NO4 | 详情 | 详情 |
| (X) | 19053 | methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-amino-3-(benzyloxy)propanoyl]-4-propoxypyrrolidinyl]carbonyl)octahydro-1H-indol-2-yl]carbonyl]amino)-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C41H59N7O9S | 详情 | 详情 | |
| (XII) | 19056 | methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-(benzyloxy)propanoyl]-4-propoxypyrrolidinyl]carbonyl)octahydro-1H-indol-2-yl]carbonyl]amino)-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentano | C50H68N8O10S | 详情 | 详情 | |
| (XIII) | 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 |
| (XIV) | 19058 | methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-([(2S)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino)-3-(benzyloxy)propanoyl]-4-propoxypyrrolidinyl]carbonyl)octahydro-1H-indol-2-yl]carbonyl]amino)-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C52H71N9O11S | 详情 | 详情 | |
| (XV) | 19059 | (2R,4S)-4-(benzyloxy)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | 54631-81-1 | C17H23NO5 | 详情 | 详情 |
| (XVI) | 19060 | methyl (2S)-2-[([(2S,3aS,7aS)-1-[((2R,4S)-1-[(2S)-3-(benzyloxy)-2-[((2S)-2-[[2-([[(2S,4R)-4-(benzyloxy)pyrrolidinyl]carbonyl]amino)acetyl]amino]-3-phenylpropanoyl)amino]propanoyl]-4-propoxypyrrolidinyl)carbonyl]octahydro-1H-indol-2-yl]carbonyl)amino | C64H84N10O13S | 详情 | 详情 |
合成路线4
Compound (XVIII) was submitted to successive coupling cycles (deprotection with TFA, and coupling with DIPCDI) to introduce sequentially the following amino acids: (XVII) and (XX) yielding the following resins: (XIX) and (XXI), respectively.
| 【1】 Kyle, D.J.; Hiner, R.N. (Scios Inc.); Bradykinin antagonist peptides. JP 1995504155; US 5385889 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVII) | 19061 | (2R)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid; (2R)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-D-proline | C10H17NO4 | 详情 | 详情 | |
| (XVIII) | 19060 | methyl (2S)-2-[([(2S,3aS,7aS)-1-[((2R,4S)-1-[(2S)-3-(benzyloxy)-2-[((2S)-2-[[2-([[(2S,4R)-4-(benzyloxy)pyrrolidinyl]carbonyl]amino)acetyl]amino]-3-phenylpropanoyl)amino]propanoyl]-4-propoxypyrrolidinyl)carbonyl]octahydro-1H-indol-2-yl]carbonyl)amino | C64H84N10O13S | 详情 | 详情 | |
| (XIX) | 19063 | methyl (2S)-2-[[((2S,3aS,7aS)-1-[[(2R,4S)-1-((2S)-3-(benzyloxy)-2-[[(2S)-2-([2-[([(2S,4R)-4-(benzyloxy)-1-[(2S)pyrrolidinylcarbonyl]pyrrolidinyl]carbonyl)amino]acetyl]amino)-3-phenylpropanoyl]amino]propanoyl)-4-propoxypyrrolidinyl]carbonyl]octahydro-1H-indol-2-yl)carbonyl]amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoate | C69H91N11O14S | 详情 | 详情 | |
| (XX) | 19064 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (XXI) | 19065 | methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-[((2S)-2-[[2-([[(2S,4R)-1-[((2S)-1-[(2S)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]-4-(benzyloxy)pyrrolidinyl]carbonyl]amino)acetyl]amino]-3-phe | C82H109N15O17S2 | 详情 | 详情 |
合成路线5
Compound (XVIII) was submitted to a coupling cycle (deprotection with TFA, and coupling with DIPCDI) to introduce the following amino acid (XXII) yielding the resin (XXIII). The final peptide was liberated from the resin (XXIII) and simultaneously deprotected by treatment with anhydrous HF containing a 10% anisole, and was purified by HPLC over a C18 reverse phase column, using as eluent acetonitrile-water containing a 0.1% of TFA.
| 【1】 Kyle, D.J.; Hiner, R.N. (Scios Inc.); Bradykinin antagonist peptides. JP 1995504155; US 5385889 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 19065 | methyl (2S)-2-([[(2S,3aS,7aS)-1-([(2R,4S)-1-[(2S)-2-[((2S)-2-[[2-([[(2S,4R)-1-[((2S)-1-[(2S)-2-amino-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]-4-(benzyloxy)pyrrolidinyl]carbonyl]amino)acetyl]amino]-3-phe | C82H109N15O17S2 | 详情 | 详情 | |
| (XXII) | 19064 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (XXIII) | 19067 | N-alpha-(tert-Butoxycarbonyl)-N-omega-tosyl-D-arginyl-(N-omega-tosyl)-L-arginyl-L-prolyl-(4(R)-benzyloxy)-L-prolyl-glycyl-L-phenylalanyl-(3-O-benzyl)-L-seryl-(4(R)-benzyloxy)-D-prolyl-(2S,3aS,7aS)-perhydroindol-2-ylcarbonyl-(N-omega-tosyl)-L-arginine methyl ester | C100H135N19O22S3 | 详情 | 详情 |