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【结 构 式】 
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【药物名称】Labradimil, Lobradimil, Receptor mediated permeabilizer, RMP-7, Cereport 【化学名称】Nalpha-[2(S)-[L-Arginyl-L-prolyl-[4(R)-hydroxy]-L-prolyl-glycyl-[3-(2-thienyl)]-L-alanyl-L-seryl-L-prolylamino]-3-(4-methoxyphenyl)propyl]-L-arginine 【CA登记号】159768-75-9 【 分 子 式 】C49H75N15O12S 【 分 子 量 】1098.3014 |
【开发单位】Alkermes (Originator), Alza (Codevelopment) 【药理作用】Absorption Promoters, Brain Cancer Therapy, DRUG DELIVERY, Oncolytic Drugs, Bradykinin B2 Agonists |
合成路线1
The reaction of N-(tert-butoxycarbonyl [Boc])-4-O-methyl-L-tyrosine (I) with N,O-dimethylhydroxylamine (II) by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding amide (III), which is reduced with LiAlH4 in ethyl ether yielding N-(tert-butoxycarbonyl)-4-O-methyl-L-tyrosinal (IV). The reductocondensation of (IV) with Nomega-tosyl-L-arginine (V) in methanol/acetic acid affords Nalpha-[2(S)-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propyl]-Nomega-tosyl-L-arginine (VI), which is then attached to a polyestyrene resin (Merrifield resin) by means of DCC and dimethylaminopyridine (DMAP) to give the starting peptide-resin complex (IX). This resin (IX) is introduced into a Beckman 990 peptide synthesizer and submitted to successive amino acid coupling cycles (deprotection with TFA and coupling with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [BOP]) in order to introduce successively Boc-L-proline (X), Boc-L-serine (XII), Boc-L-(2-thienyl)alanine (XIV), Boc-glycine (XVI), Boc-L-(4-benzyloxy)proline (XVIII), Boc-L-proline (X), and Boc-L-(Nomega-tosyl)arginine (XXI) yielding resins (XI), (XIII), (XV), (XVII), (XIX), (XX), and the final resin (XXII), successively. The final peptide (RMP-7) is liberated from the resin (XXII) and simultaneously deprotected by a treatment with anhydrous HF with a 10% anisole and purified by HPLC over a C18 reverse phase column using trifluoroacetic acid/acetonitrile with a 0-25% gradient. Tritiated RMP-7 is obtained by bromination of RMP-7 with Br2 in acetic acid giving a monobrominated compound (XXIII) (basically the 5-position of the thiophene ring of thienylalanine is brominated), which is then tritiated with 3H2 and Pd/C in water.
| 【1】 Graul, A.; Leeson, P.; Castañer, J.; RMP-7. Drugs Fut 1998, 23, 1, 32. |
| 【2】 Straub, J.A.; Musso, G.F.; Smart, J.L.; Lang, C.; Akiyama, A.; Bromination and subsequent catalytic tritiation of thienylalanine and 4-methyltyrosine residues in the bradykinin analog RMP-7. J Label Compd Radiopharm 1994, 34, 12, 1217-26. |
| 【3】 Malfroy-Camine, B.; Smart, J.L. (Alkermes, Inc.); Method for increasing blood-brain barrier permeability. WO 9116355 . |
| 【4】 Kozarich, J.W.; Musso, G.F.; Malfroy-Camine, B. (Alkermes, Inc.); Increasing blood-brain barrier permeability with permeabilizer peptides. WO 9218529 . |
| 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) | 16875 | (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(4-methoxyphenyl)propionic acid; N-t-BOC-O-Methyl-L-tyrosine | 53267-93-9 | C15H21NO5 | 详情 | 详情 |
| (II) | 13361 | (Methoxyamino)methane; N,O-Dimethylhydroxylamine | 1117-97-1 | C2H7NO | 详情 | 详情 |
| (III) | 16877 | tert-butyl N-[(1S)-1-(4-methoxybenzyl)-2-[methoxy(methyl)amino]-2-oxoethyl]carbamate | C17H26N2O5 | 详情 | 详情 | |
| (IV) | 16878 | tert-butyl N-[(1S)-1-formyl-2-(4-methoxyphenyl)ethyl]carbamate | C15H21NO4 | 详情 | 详情 | |
| (V) | 16879 | (2S)-2-amino-5-[[imino(methylamino)methyl]amino]pentanoic acid | C7H16N4O2 | 详情 | 详情 | |
| (VI) | 16880 | (2S)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid | C22H37N5O5 | 详情 | 详情 | |
| (VII) | 16881 | (2S)-2-[benzyl[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoic acid | C29H43N5O5 | 详情 | 详情 | |
| (IX) | 16883 | methyl (2S)-2-[benzyl[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C30H45N5O5 | 详情 | 详情 | |
| (X) | 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 | |
| (XI) | 16885 | tert-butyl (2S)-2-[(3S,6S)-5-benzyl-11-imino-3-(4-methoxybenzyl)-6-(methoxycarbonyl)-2,5,10,12-tetraazatridec-1-anoyl]-1-pyrrolidinecarboxylate | C35H52N6O6 | 详情 | 详情 | |
| (XII) | 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 |
| (XIII) | 16887 | methyl (2S)-2-[benzyl[(2S)-2-[[((2S)-1-[(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]pyrrolidinyl)carbonyl]amino]-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C45H63N7O8 | 详情 | 详情 | |
| (XIV) | 16888 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine | 78452-55-8 | C12H17NO4S | 详情 | 详情 |
| (XV) | 16889 | methyl (2S)-2-[benzyl[(2S)-2-([[(2S)-1-((2S)-3-(benzyloxy)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propanoyl]amino]propanoyl)pyrrolidinyl]carbonyl]amino)-3-(4-methoxyphenyl)propyl]amino]-5-[[imino(methylamino)methyl]amino]pentanoate | C52H70N8O9S | 详情 | 详情 |
合成路线2
The reaction of N-(tert-butoxycarbonyl [Boc])-4-O-methyl-L-tyrosine (I) with N,O-dimethylhydroxylamine (II) by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding amide (III), which is reduced with LiAlH4 in ethyl ether yielding N-(tert-butoxycarbonyl)-4-O-methyl-L-tyrosinal (IV). The reductocondensation of (IV) with Nomega-tosyl-L-arginine (V) in methanol/acetic acid affords Nalpha-[2(S)-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propyl]-Nomega-tosyl-L-arginine (VI), which is then attached to a polyestyrene resin (Merrifield resin) by means of DCC and dimethylaminopyridine (DMAP) to give the starting peptide-resin complex (IX). This resin (IX) is introduced into a Beckman 990 peptide synthesizer and submitted to successive amino acid coupling cycles (deprotection with TFA and coupling with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [BOP]) in order to introduce successively Boc-L-proline (X), Boc-L-serine (XII), Boc-L-(2-thienyl)alanine (XIV), Boc-glycine (XVI), Boc-L-(4-benzyloxy)proline (XVIII), Boc-L-proline (X), and Boc-L-(Nomega-tosyl)arginine (XXI) yielding resins (XI), (XIII), (XV), (XVII), (XIX), (XX), and the final resin (XXII), successively. The final peptide (RMP-7) is liberated from the resin (XXII) and simultaneously deprotected by a treatment with anhydrous HF with a 10% anisole and purified by HPLC over a C18 reverse phase column using trifluoroacetic acid/acetonitrile with a 0-25% gradient.
| 【1】 Graul, A.; Leeson, P.; Castañer, J.; RMP-7. Drugs Fut 1998, 23, 1, 32. |
| 【2】 Straub, J.A.; Musso, G.F.; Smart, J.L.; Lang, C.; Akiyama, A.; Bromination and subsequent catalytic tritiation of thienylalanine and 4-methyltyrosine residues in the bradykinin analog RMP-7. J Label Compd Radiopharm 1994, 34, 12, 1217-26. |
| 【3】 Malfroy-Camine, B.; Smart, J.L. (Alkermes, Inc.); Method for increasing blood-brain barrier permeability. WO 9116355 . |
| 【4】 Kozarich, J.W.; Musso, G.F.; Malfroy-Camine, B. (Alkermes, Inc.); Increasing blood-brain barrier permeability with permeabilizer peptides. WO 9218529 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XX) | 16890 | tert-butyl (2S)-2-[[(2S,4R)-2-[(6S,9S)-9-([(2S)-2-[(3S,6S)-5-benzyl-11-imino-3-(4-methoxybenzyl)-6-(methoxycarbonyl)-2,5,10,12-tetraazatridec-1-anoyl]pyrrolidinyl]carbonyl)-4,7-dioxo-12-phenyl-6-(2-thienylmethyl)-11-oxa-2,5,8-triazadodec-1-anoyl]-4-(benzyloxy)pyrrolidinyl]carbonyl]-1-pyrrolidinecarboxylate | C71H93N11O13S | 详情 | 详情 | |
| (XXI) | 19064 | (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid | C18H28N4O6S | 详情 | 详情 | |
| (XXII) | 16892 | N(alpha)-[s(S)-[N(alpha)-tert-butoxycarbonyl-N(omega)-tosyl-arginyl-prolyl-[4(R)-benzyloxy]prolyl-glycyl-[3-(2-thienyl)]alanyl-)O-benzyl)seryl-propylamino]-1-(4-methoxyphenyl)propyl]-N(alpha)-benzyl-N(omega)-tosyl-arginine methyl ester | C84H111N15O16S2 | 详情 | 详情 |
合成路线3
The reaction of N-(tert-butoxycarbonyl [Boc])-4-O-methyl-L-tyrosine (I) with N,O-dimethylhydroxylamine (II) by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding amide (III), which is reduced with LiAlH4 in ethyl ether yielding N-(tert-butoxycarbonyl)-4-O-methyl-L-tyrosinal (IV). The reductocondensation of (IV) with Nomega-tosyl-L-arginine (V) in methanol/acetic acid affords Nalpha-[2(S)-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propyl]-Nomega-tosyl-L-arginine (VI), which is then attached to a polyestyrene resin (Merrifield resin) by means of DCC and dimethylaminopyridine (DMAP) to give the starting peptide-resin complex (IX). This resin (IX) is introduced into a Beckman 990 peptide synthesizer and submitted to successive amino acid coupling cycles (deprotection with TFA and coupling with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [BOP]) in order to introduce successively Boc-L-proline (X), Boc-L-serine (XII), Boc-L-(2-thienyl)alanine (XIV), Boc-glycine (XVI), Boc-L-(4-benzyloxy)proline (XVIII), Boc-L-proline (X), and Boc-L-(Nomega-tosyl)arginine (XXI) yielding resins (XI), (XIII), (XV), (XVII), (XIX), (XX), and the final resin (XXII), successively. The final peptide (RMP-7) is liberated from the resin (XXII) and simultaneously deprotected by a treatment with anhydrous HF with a 10% anisole and purified by HPLC over a C18 reverse phase column using trifluoroacetic acid/acetonitrile with a 0-25% gradient. Tritiated RMP-7 is obtained by bromination of RMP-7 with Br2 in acetic acid giving a monobrominated compound (XXIII) (basically the 5-position of the thiophene ring of thienylalanine is brominated), which is then tritiated with 3H2 and Pd/C in water.
| 【1】 Straub, J.A.; Musso, G.F.; Smart, J.L.; Lang, C.; Akiyama, A.; Bromination and subsequent catalytic tritiation of thienylalanine and 4-methyltyrosine residues in the bradykinin analog RMP-7. J Label Compd Radiopharm 1994, 34, 12, 1217-26. |
| 【2】 Graul, A.; Leeson, P.; Castañer, J.; RMP-7. Drugs Fut 1998, 23, 1, 32. |
| 【3】 Malfroy-Camine, B.; Smart, J.L. (Alkermes, Inc.); Method for increasing blood-brain barrier permeability. WO 9116355 . |
| 【4】 Kozarich, J.W.; Musso, G.F.; Malfroy-Camine, B. (Alkermes, Inc.); Increasing blood-brain barrier permeability with permeabilizer peptides. WO 9218529 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| RMP-7 | 41822 | C49H75N15O12S | 详情 | 详情 | ||
| (XXII) | 16892 | N(alpha)-[s(S)-[N(alpha)-tert-butoxycarbonyl-N(omega)-tosyl-arginyl-prolyl-[4(R)-benzyloxy]prolyl-glycyl-[3-(2-thienyl)]alanyl-)O-benzyl)seryl-propylamino]-1-(4-methoxyphenyl)propyl]-N(alpha)-benzyl-N(omega)-tosyl-arginine methyl ester | C84H111N15O16S2 | 详情 | 详情 | |
| (XXIII) | 16893 | (2S)-2-[[(2S)-2-([[(2S)-1-((2S)-2-[[(2S)-2-[(2-[[((2S,4R)-1-[[(2S)-1-((2S)-2-amino-5-[[amino(imino)methyl]amino]pentanoyl)pyrrolidinyl]carbonyl]-4-hydroxypyrrolidinyl)carbonyl]amino]acetyl)amino]-3-(5-bromo-2-thienyl)propanoyl]amino]-3-hydroxypropanoyl)pyrrolidinyl]carbonyl]amino)-3-(4-methoxyphenyl)propyl]amino]-5-[[amino(imino)methyl]amino]pentanoic acid | C49H74BrN15O12S | 详情 | 详情 |