DC-41-33, PRL-2903, -Drug Synthesis Database

【结构式】

【药物名称】DC-41-33, PRL-2903

【化学名称】(4-Fluoro)-L-phenylalanyl-D-cysteinyl-(3-pyridyl)-L-alanyl-D-tryptophyl-L-lysyl-(3-methyl)-L-valyl-L-cysteinyl-(2-naphthyl)-L-alaninamide cyclic (2-7)-disulfide

【CA登记号】209006-13-3

【分子式】C₅₉H₇₁FN₁₂O₈S₂

【分子量】1159.42572

【开发单位】Biomeasure (Originator), Tulane University (Originator)

【药理作用】PHARMACOLOGICAL TOOLS, Somatostatin SRIF1A (sst2) 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 4-methylbenzhydrylamine-functionalized resin using an automatic peptide synthesizer. Binding of N-Boc-3-(2-naphthyl)-L-alanine (I) to the resin was effected by double coupling, first with the 1,3-diisopropylcarbodiimide active ester, and then a second coupling with the TBTU ester to produce the amino acid-linked resin (II). Deblocking of the Boc group of (II) by treatment with trifluoroacetic acid provided resin (III). The following amino acids were then coupled and deprotected successively to (III) by the same procedure: N-Boc-S-(4-methylbenzyloxycarbonyl)-L-cysteine (IV), N-Boc-L-tert-leucine (VI), N(alpha)-Boc-N(epsilon)-(2-chlorobenzyloxycarbonyl)-L-lysine (VIII) and N-Boc-D-tryptophan (X) yielding the peptide resins (V), (VII), (IX) and (XI), respectively.

参考文献中间体

【1】 Rossowski, W.J.; Cheng, B.-L.; Jiang, N.-Y.; Coy, D.-H.; Examination of somatostatin involvement in the inhibitory action of GIP, GLP-1, amylin and adrenomedullin on gastric acid release using a new SRIF antagonist analogue. Br J Pharmacol 1998, 125, 1081.
【2】 Taylor, J.E.; Hocart, S.J.; Murphy, W.A.; Coy, D.H.; Jian, R.; Highly potent cyclic disulfide antagonists of somatostatin. J Med Chem 1999, 42, 11, 1863.
【3】 Murphy, W.; Coy, D.H.; Morgan, B. (Biomeasure Inc.; Tulane Educational Fund); Somatostatin antagonists. WO 9824807 .

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)	15061	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-naphthyl)propionic acid; N-T-BOC-L-3-(2-NAPHTHYL)ALANINE	58438-04-3	C₁₈H₂₁NO₄	详情	详情
(II)	31369	tert-butyl (1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethylcarbamate		C₁₈H₂₂N₂O₃	详情	详情
(III)	31370	(2S)-2-amino-3-(2-naphthyl)propanamide		C₁₃H₁₄N₂O	详情	详情
(IV)	31371	(2R)-2-[(tert-butoxycarbonyl)amino]-3-([[(4-methylbenzyl)oxy]carbonyl]sulfanyl)propionic acid		C₁₇H₂₃NO₆S	详情	详情
(V)	31372	S-((2R)-2-amino-3-[[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]-3-oxopropyl) O-(4-methylbenzyl) carbonothioate		C₂₅H₂₇N₃O₄S	详情	详情
(VI)	22251	(2S)-2-[(tert-butoxycarbonyl)amino]-3,3-dimethylbutyric acid;2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid;N-(tert-butoxycarbonyl)-3-methyl-L-valine	62965-35-9	C₁₁H₂₁NO₄	详情	详情
(VII)	31373	S-((2R)-2-[[(2S)-2-amino-3,3-dimethylbutanoyl]amino]-3-[[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]-3-oxopropyl) O-(4-methylbenzyl) carbonothioate		C₃₁H₃₈N₄O₅S	详情	详情
(VIII)	31374	(2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid		C₁₉H₂₇ClN₂O₆	详情	详情
(IX)	31375	S-[(2R,5S,8S)-8-amino-2-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-5-(tert-butyl)-16-(2-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-yl] O-(4-methylbenzyl) carbonothioate		C₄₅H₅₅ClN₆O₈S	详情	详情
(X)	16114	N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid	13139-14-5	C₁₆H₂₀N₂O₄	详情	详情
(XI)	31377	S-[(2R,5S,8S)-8-[[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-2-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-5-(tert-butyl)-16-(2-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-yl] O-(4-methylbenzyl) carbonothioate		C₅₆H₆₅ClN₈O₉S	详情	详情

合成路线2

The coupling and deprotection cycles was continued with N-Boc-L-(3-pyridyl)alanine (XII), N-Boc-S-(4-methylbenzyloxy-carbonyl)-D-cysteine (IV), and N-Boc-L-4-fluorophenylalanine (XV), yielding the peptide resins (XIII), (XIV) and (XVI), respectively.

参考文献中间体

【1】 Taylor, J.E.; Hocart, S.J.; Murphy, W.A.; Coy, D.H.; Jian, R.; Highly potent cyclic disulfide antagonists of somatostatin. J Med Chem 1999, 42, 11, 1863.
【2】 Rossowski, W.J.; Cheng, B.-L.; Jiang, N.-Y.; Coy, D.-H.; Examination of somatostatin involvement in the inhibitory action of GIP, GLP-1, amylin and adrenomedullin on gastric acid release using a new SRIF antagonist analogue. Br J Pharmacol 1998, 125, 1081.
【3】 Murphy, W.; Coy, D.H.; Morgan, B. (Biomeasure Inc.; Tulane Educational Fund); Somatostatin antagonists. WO 9824807 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(IV)	31371	(2R)-2-[(tert-butoxycarbonyl)amino]-3-([[(4-methylbenzyl)oxy]carbonyl]sulfanyl)propionic acid	C₁₇H₂₃NO₆S	详情	详情
(XI)	31377	S-[(2R,5S,8S)-8-[[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-2-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-5-(tert-butyl)-16-(2-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-1-yl] O-(4-methylbenzyl) carbonothioate	C₅₆H₆₅ClN₈O₉S	详情	详情
(XII)	34944	(2S)-2-[(tert-butoxycarbonyl)(3-pyridinyl)amino]propionic acid	C₁₃H₁₈N₂O₄	详情	详情
(XIII)	31376	S-[(2R,5S,8S)-2-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-8-[[(2R)-2-[[(2S)-2-amino-3-(3-pyridinyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-(tert-butyl)-16-(2-chlorophenyl)-4,7,14-trioxo-15-oxa-3,6,13-triazahexadec-	C₆₄H₇₃ClN₁₀O₁₀S	详情	详情
(XIV)	31379	S-[(2R,5S,8S,11R,14S,17S)-17-amino-2-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-5-(tert-butyl)-8-[4-([[(2-chlorobenzyl)oxy]carbonyl]amino)butyl]-11-(1H-indol-3-ylmethyl)-22-(4-methylphenyl)-4,7,10,13,16,20-hexaoxo-14-(3-pyridiny	C₇₆H₈₆ClN₁₁O₁₃S₂	详情	详情
(XV)	25929	(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-fluorophenyl)propionic acid	C₁₄H₁₈FNO₄	详情	详情
(XVI)	34945		C₉₀H₁₀₂ClFN₁₂O₁₆S₂	详情	详情

合成路线3

Cleavage of the resin support of (XVI) with simultaneous side-chain deprotection using anhydrous HF in the presence of the scavengers anisole and dithiothreitol gave the peptide amide (XVII). This was finally cyclized to the title disulfide by oxidation with iodine in AcOH.

参考文献中间体

【1】 Taylor, J.E.; Hocart, S.J.; Murphy, W.A.; Coy, D.H.; Jian, R.; Highly potent cyclic disulfide antagonists of somatostatin. J Med Chem 1999, 42, 11, 1863.
【2】 Rossowski, W.J.; Cheng, B.-L.; Jiang, N.-Y.; Coy, D.-H.; Examination of somatostatin involvement in the inhibitory action of GIP, GLP-1, amylin and adrenomedullin on gastric acid release using a new SRIF antagonist analogue. Br J Pharmacol 1998, 125, 1081.
【3】 Murphy, W.; Coy, D.H.; Morgan, B. (Biomeasure Inc.; Tulane Educational Fund); Somatostatin antagonists. WO 9824807 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	34945			C₉₀H₁₀₂ClFN₁₂O₁₆S₂	详情	详情
(XVII)	34946			C₅₉H₇₃FN₁₂O₈S₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)