MBX-36, SHU-9119, -Drug Synthesis Database

【结构式】

【药物名称】MBX-36, SHU-9119

【化学名称】N-Acetyl-L-norleucyl-L-aspartyl-L-histidyl-3-(2-naphthyl)-D-alanyl-L-arginyl-L-tryptophyl-L-lysinamide cyclic C-4.2-N-6.7-amide

【CA登记号】168482-23-3

【分子式】C₅₄H₇₁N₁₅O₉

【分子量】1074.26307

【开发单位】Oregon Health and Science University (Originator), University of Arizona (Originator)

【药理作用】METABOLIC DRUGS, Treatment of Eating Disorders, Treatment of Nutritional Disorders, Melanocortin MC1 Agonists, Melanocortin MC3 Antagonists, Melanocortin MC4 Antagonists, Melanocortin MC5 Agonists

合成路线1 合成路线2 合成路线3

合成路线1

The peptide was synthesized by a solid-phase method using a p-methylbenzhydrylamine resin to which N1-Boc-N6-Fmoc-L-lysine (I) was coupled giving (II). To this solid phase the following protected amino acids Nalpha-Boc-N1-formyl-L-tryptophan (III), Nalpha-Boc-Nomega-Tos-L-arginine (V), Nalpha-Boc-D-(2-naphthyl)alanine (VII), Nalpha-Boc-Npi-L-histidine (IX) and Nalpha-Boc-Ogamma-Fm-L-aspartic acid (XI) were sequentially coupled yielding resins (IV), (VI), (VIII), (X) and (XII).

参考文献中间体

【1】 Al-Obeidi, F.A.; Sharma, S.D.; de L. Castrucci, A.; Kesterson, R.A.; Lu, D.; Hadley, M.E.; Cone, R.D.; Hruby, V.J.; Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995, 38, 18, 3454.
【2】 Hadley, M.E.; Hruby, V.J.; Sharma, S.D. (University of Arizona); Peptides having potent antagonist and agonist bioactivities at melanocortin receptors. US 5731408 .

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)	25476	(2S)-2-[(tert-butoxycarbonyl)amino]-6-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid	84624-27-1	C₂₆H₃₂N₂O₆	详情	详情
(II)	25477	9H-fluoren-9-ylmethyl (5S)-6-amino-5-[(tert-butoxycarbonyl)amino]-6-oxohexylcarbamate		C₂₆H₃₃N₃O₅	详情	详情
(III)	25478	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1-formyl-1H-indol-3-yl)propionic acid		C₁₇H₂₀N₂O₅	详情	详情
(IV)	25479	9H-fluoren-9-ylmethyl (5S)-6-amino-5-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(1-formyl-1H-indol-3-yl)propanoyl]amino]-6-oxohexylcarbamate		C₃₈H₄₃N₅O₇	详情	详情
(V)	19064	(2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid		C₁₈H₂₈N₄O₆S	详情	详情
(VI)	25480	tert-butyl (1S,4S,7S)-7-(aminocarbonyl)-15-(9H-fluoren-9-yl)-4-[(1-formyl-1H-indol-3-yl)methyl]-1-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-2,5,13-trioxo-14-oxa-3,6,12-triazapentadec-1-ylcarbamate		C₅₁H₆₁N₉O₁₀S	详情	详情
(VII)	23498	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid		C₁₈H₂₁NO₄	详情	详情
(VIII)	25481	tert-butyl (1R,4S,7S,10S)-10-(aminocarbonyl)-18-(9H-fluoren-9-yl)-7-[(1-formyl-1H-indol-3-yl)methyl]-4-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-1-(2-naphthylmethyl)-2,5,8,16-tetraoxo-17-oxa-3,6,9,15-tetraazaoctadec-1-ylcarbamate		C₆₄H₇₂N₁₀O₁₁S	详情	详情
(IX)	25482	(2S)-3-[1-[(benzyloxy)methyl]-1H-imidazol-5-yl]-2-[(tert-butoxycarbonyl)amino]propionic acid	83468-83-1	C₁₉H₂₅N₃O₅	详情	详情
(X)	25483	9H-fluoren-9-ylmethyl (5S,8S,11S,14R,17S)-17-amino-5-(aminocarbonyl)-18-[1-[(benzyloxy)methyl]-1H-imidazol-5-yl]-8-[(1-formyl-1H-indol-3-yl)methyl]-11-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-14-(2-naphthylmethyl)-7,10,13,16-tetraoxo-6,9,12,15-tetraazaoctadec-1-ylcarbamate		C₇₃H₇₉N₁₃O₁₁S	详情	详情
(XI)	25484	(2S)-2-[(tert-butoxycarbonyl)amino]-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-4-oxobutyric acid		C₂₄H₂₅NO₈	详情	详情
(XII)	25485	N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide		C₉₇H₁₀₂N₁₄O₁₈S	详情	详情

合成路线2

The coupling sequences were continued with Nalpha-Boc-L-norleucine (XIII) to afford resin (XIV). Elimination of the Fmoc and OFm protecting groups of (XIV) was performed with piperidine in NMP allowing the formation of the lactam ring by cyclization with BOP and DIEA in NMP providing the macrocyclic lactam (XV).

参考文献中间体

【1】 Al-Obeidi, F.A.; Sharma, S.D.; de L. Castrucci, A.; Kesterson, R.A.; Lu, D.; Hadley, M.E.; Cone, R.D.; Hruby, V.J.; Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995, 38, 18, 3454.
【2】 Hadley, M.E.; Hruby, V.J.; Sharma, S.D. (University of Arizona); Peptides having potent antagonist and agonist bioactivities at melanocortin receptors. US 5731408 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XII)	25485	N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide	C₉₇H₁₀₂N₁₄O₁₈S	详情	详情
(XIII)	20398	(2S)-2-[(tert-butoxycarbonyl)amino]hexanoic acid	C₁₁H₂₁NO₄	详情	详情
(XIV)	25486	N-(Tert-butoxycarbonyl)-D-norleucyl-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide; N-(Tert-butoxycarbonyl)-D-norleucyl-[4-O-(9-fluorenylmethoxycarbonyl)]-L-aspartyl-[N-tau-(benzyloxymethyl)]-D-histidyl-D-2-naphthylalanyl-(N-omega-tosyl)-L-arginyl-(N-1-formyl)-D-tryptophyl-[N-6-(9-fluorenylmethoxycarbonyl)]-L-leucinamide	C₁₀₃H₁₁₃N₁₅O₁₉S	详情	详情
(XV)	25487	tert-butyl (1S)-1-([[(3S,6S,9R,12S,15S,23S)-23-(aminocarbonyl)-12-([1-[(benzyloxy)methyl]-1H-imidazol-5-yl]methyl)-3-[(1-formyl-1H-indol-3-yl)methyl]-6-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(2-naphthylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaazacyclotricosan-15-yl]amino]carbonyl)pentylcarbamate	C₇₃H₉₁N₁₅O₁₄S	详情	详情

合成路线3

Elimination of the Boc protecting group of (XV) with trifluoroacetic acid followed by acetylation of the free amino group with acetic anhydride yielded resin (XVI) with a terminal acetyl group. Finally, this resin was treated with FH, anisole and dithioethane to complete the deprotection process and elimnate the solid phase resin affornig the target macrocyclic peptide.

参考文献中间体

【1】 Al-Obeidi, F.A.; Sharma, S.D.; de L. Castrucci, A.; Kesterson, R.A.; Lu, D.; Hadley, M.E.; Cone, R.D.; Hruby, V.J.; Cyclic lactam alpha-melanotropin analogues of Ac-Nle4-cyclo[Asp5, D-Phe7,Lys10] alpha-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. J Med Chem 1995, 38, 18, 3454.
【2】 Hadley, M.E.; Hruby, V.J.; Sharma, S.D. (University of Arizona); Peptides having potent antagonist and agonist bioactivities at melanocortin receptors. US 5731408 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	25487	tert-butyl (1S)-1-([[(3S,6S,9R,12S,15S,23S)-23-(aminocarbonyl)-12-([1-[(benzyloxy)methyl]-1H-imidazol-5-yl]methyl)-3-[(1-formyl-1H-indol-3-yl)methyl]-6-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(2-naphthylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaazacyclotricosan-15-yl]amino]carbonyl)pentylcarbamate		C₇₃H₉₁N₁₅O₁₄S	详情	详情
(XVI)	25488	(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-(acetamido)hexanoyl]amino]-12-([1-[(benzyloxy)methyl]-1H-imidazol-5-yl]methyl)-3-[(1-formyl-1H-indol-3-yl)methyl]-6-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-9-(2-naphthylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaazacyclotricosane-23-carboxamide		C₇₀H₈₅N₁₅O₁₃S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)