Venorphin, JVA-901, -Drug Synthesis Database

【结构式】

【药物名称】Venorphin, JVA-901

【化学名称】Acetyl-L-tyrosyl-L-lysyl-L-tryptophyl-L-tryptophyl-L-leucyl-L-arginyl-L-arginyl-D-alanyl-L-arginyl-L-prolyl-L-lysinamide

【CA登记号】

【分子式】C₇₇H₁₁₇N₂₅O₁₃

【分子量】1600.95074

【开发单位】University of Georgia (Originator), University of Maryland (Originator)

【药理作用】PHARMACOLOGICAL TOOLS, kappa-Opioid Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

The compound was prepared by solid-phase peptide synthesis on a poliethylene glycol amino resin. Coupling with N(alpha)-Fmoc-N(G)-Boc-lysine (I) using O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and N-methylmorpholine (NMM) afforded the protected lysine-linked resin (II), and subsequent Fmoc deprotection provided resin (III). This was submitted to further coupling and deprotection cycles with the N(alpha)-Fmoc-protected amino acids proline (IV), N(G)-(2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl)arginine (VI), D-alanine (VIII), N(G)-Pbf-arginine (VI), and again N(G)-Pbf-arginine (VI) yielding peptide resins (V), (VII), (IX), (X) and (XI).

参考文献中间体

【1】 Aldrich, J.V.; Murray, T.F.; Wan, Q.; A novel acetylated analogue of dynorphin A-(1-11) amide as a kappa-opioid receptor antagonist. J Med Chem 1999, 42, 16, 3011.

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)	18854	(2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid		C₂₆H₃₂N₂O₆	详情	详情
(II)	28723	9H-fluoren-9-ylmethyl (1S)-1-(aminocarbonyl)-5-[(tert-butoxycarbonyl)amino]pentylcarbamate		C₂₆H₃₃N₃O₅	详情	详情
(III)	34761	tert-butyl (5S)-5,6-diamino-6-oxohexylcarbamate		C₁₁H₂₃N₃O₃	详情	详情
(IV)	34762	(2S)-1-[(9H-fluoren-9-ylmethoxy)carbonyl]-2-pyrrolidinecarboxylic acid	71989-31-6	C₂₀H₁₉NO₄	详情	详情
(V)	34763	tert-butyl (5S)-6-amino-6-oxo-5-[[(2S)pyrrolidinylcarbonyl]amino]hexylcarbamate		C₁₆H₃₀N₄O₄	详情	详情
(VI)	34764	(2S)-5-[[[[(9H-fluoren-9-ylmethoxy)carbonyl]amino](imino)methyl]amino]-2-[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]pentanoic acid		C₃₄H₄₀N₄O₇S	详情	详情
(VII)	34765	tert-butyl (5S)-6-amino-5-[[((2S)-1-[(2S)-2-amino-5-[(imino[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]amino]-6-oxohexylcarbamate		C₃₅H₅₈N₈O₈S	详情	详情
(VIII)	19926	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid		C₁₈H₁₇NO₄	详情	详情
(IX)	34766	tert-butyl (5S)-6-amino-5-[[((2S)-1-[(2S)-2-[[(2R)-2-aminopropanoyl]amino]-5-[(imino[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]amino]-6-oxohexylcarbamate		C₃₈H₆₃N₉O₉S	详情	详情
(X)	34767	tert-butyl (5S)-6-amino-5-[[((2S)-1-[(2S)-2-[[(2R)-2-([(2S)-2-amino-5-[(imino[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]methyl)amino]pentanoyl]amino)propanoyl]amino]-5-[(imino[[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino]methyl)amino]pentanoyl]pyrrolidinyl)carbonyl]amino]-6-oxohexylcarbamate		C₅₇H₉₁N₁₃O₁₃S₂	详情	详情
(XI)	34768	tert-butyl (5S)-6-amino-5-({[(2S)-1-((2S,5R,8S,11S)-11-amino-16-imino-2,8-bis{3-[(imino{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}methyl)amino]propyl}-5-methyl-4,7,10-trioxo-16-{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}-3,6,9,15-tetraazahexadec-1-anoyl)pyrrolidinyl]carbonyl}amino)-6-oxohexylcarbamate		C₇₆H₁₁₉N₁₇O₁₇S₃	详情	详情

合成路线2

The coupling and deprotection cycles were continued with leucine (XII), N(in)-Boc-tryptophan (XIV), and again N(in)-Boc-tryptophan (XIV) affording peptide resins (XIII), (XV) and (XVI).

参考文献中间体

【1】 Aldrich, J.V.; Murray, T.F.; Wan, Q.; A novel acetylated analogue of dynorphin A-(1-11) amide as a kappa-opioid receptor antagonist. J Med Chem 1999, 42, 16, 3011.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	34768	tert-butyl (5S)-6-amino-5-({[(2S)-1-((2S,5R,8S,11S)-11-amino-16-imino-2,8-bis{3-[(imino{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}methyl)amino]propyl}-5-methyl-4,7,10-trioxo-16-{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}-3,6,9,15-tetraazahexadec-1-anoyl)pyrrolidinyl]carbonyl}amino)-6-oxohexylcarbamate	C₇₆H₁₁₉N₁₇O₁₇S₃	详情	详情
(XII)	19934	(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid	C₂₁H₂₃NO₄	详情	详情
(XII)	34769	tert-butyl (5S)-6-amino-5-({[(2S)-1-((2S,5R,8S,11S,14S)-14-amino-2,8,11-tris{3-[(imino{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}methyl)amino]propyl}-5,16-dimethyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaheptadec-1-anoyl)pyrrolidinyl]carbonyl}amino)-6-oxohexylcarbamate	C₈₂H₁₃₀N₁₈O₁₈S₃	详情	详情
(XIV)	34770	(2S)-2-[(tert-butoxycarbonyl)[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)propionic acid	C₃₁H₃₀N₂O₆	详情	详情
(XV)	34771	tert-butyl 3-((2S,5S,8S,11S,14R,17S)-2-amino-17-({(2S)-2-[({(1S)-1-(aminocarbonyl)-5-[(tert-butoxycarbonyl)amino]pentyl}amino)carbonyl]pyrrolidinyl}carbonyl)-22-imino-8,11-bis{3-[(imino{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}methyl)amino]propyl}-5-isobutyl-14-methyl-3,6,9,12,15-pentaoxo-22-{[(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)sulfonyl]amino}-4,7,10,13,16,21-hexaazadocos-1-yl)-1H-indole-1-carboxylate	C₉₈H₁₄₈N₂₀O₂₁S₃	详情	详情
(XVI)	34772		C₁₁₄H₁₆₆N₂₂O₂₄S₃	详情	详情

合成路线3

Further coupling and deprotection cycles with N(epsilon)-Boc-lysine (I), and O-tert-butyl-tyrosine (XVIII), yielded the peptide resins (XVII) and (XIX), respectively. Then, acetylation of the free amino group of peptide resin (XIX) with Ac2O, and final deprotection and cleavage from the resin by means of moist trifluoroacetic acid, phenol and triisopropylsilane furnished the title peptide amide.

参考文献中间体

【1】 Aldrich, J.V.; Murray, T.F.; Wan, Q.; A novel acetylated analogue of dynorphin A-(1-11) amide as a kappa-opioid receptor antagonist. J Med Chem 1999, 42, 16, 3011.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	23540	Phenol	108-95-2	C₆H₆O	详情	详情
(I)	18854	(2S)-6-[(tert-butoxycarbonyl)amino]-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]hexanoic acid		C₂₆H₃₂N₂O₆	详情	详情
(XVI)	34772			C₁₁₄H₁₆₆N₂₂O₂₄S₃	详情	详情
(XVII)	34773			C₁₂₅H₁₈₆N₂₄O₂₇S₃	详情	详情
(XVIII)	34774	(2S)-2-[tert-butyl[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid		C₂₈H₂₉NO₅	详情	详情
(XIX)	34775			C₁₃₈H₂₀₃N₂₅O₂₉S₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)