【药物名称】Labradimil, Lobradimil, Receptor mediated permeabilizer, RMP-7, Cereport
化学结构式(Chemical Structure):
参考文献No.25961
标题:Increasing blood-brain barrier permeability with permeabilizer peptides
作者:Kozarich, J.W.; Musso, G.F.; Malfroy-Camine, B. (Alkermes, Inc.)
来源:WO 9218529
合成路线图解说明:

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.

合成路线图解说明:

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.

合成路线图解说明:

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.

参考文献No.26412
标题:Method for increasing blood-brain barrier permeability
作者:Malfroy-Camine, B.; Smart, J.L. (Alkermes, Inc.)
来源:WO 9116355
合成路线图解说明:

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.

合成路线图解说明:

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.

合成路线图解说明:

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.

参考文献No.286921
标题:Bromination and subsequent catalytic tritiation of thienylalanine and 4-methyltyrosine residues in the bradykinin analog RMP-7
作者:Straub, J.A.; Musso, G.F.; Smart, J.L.; Lang, C.; Akiyama, A.
来源:J Label Compd Radiopharm 1994,34(12),1217-26
合成路线图解说明:

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.

合成路线图解说明:

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.

合成路线图解说明:

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.

参考文献No.441593
标题:RMP-7
作者:Graul, A.; Leeson, P.; Casta馿r, J.
来源:Drugs Fut 1998,23(1),32
合成路线图解说明:

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.

合成路线图解说明:

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.

合成路线图解说明:

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.

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