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【结 构 式】

【药物名称】PRL-2915

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

【CA登记号】209006-18-8

【 分 子 式 】C59H71ClN12O8S2

【 分 子 量 】1175.88032

【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4

合成路线1

The compound was prepared by solid-phase peptide synthesis on a 4-methylbenzhydrylamine-functionalized resin. Coupling of N-Boc-L-(2-naphthyl)alanine (I) with the amino resin (II) was effected by means of diisopropylcarbodiimide (DIC) to yield the protected amino acid-linked resin (III). Deprotection of the Boc group with trifluoroacetic acid provided resin (IV). This was subsequently submitted to further coupling and deprotection cycles with the protected amino acids N-Boc-S-(4-methylbenzyloxycarbonyl)-L-cysteine (V), N-Boc-L-tert-leucine (VII) and N(alpha)-Boc-N(omega)-(2-chlorobenzyloxycarbonyl)-L-lysine (IX) to afford the peptide-resins (VI), (VIII) and (X), 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】 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
(III) 31369 tert-butyl (1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethylcarbamate C18H22N2O3 详情 详情
(IV) 31370 (2S)-2-amino-3-(2-naphthyl)propanamide C13H14N2O 详情 详情
(V) 31371 (2R)-2-[(tert-butoxycarbonyl)amino]-3-([[(4-methylbenzyl)oxy]carbonyl]sulfanyl)propionic acid C17H23NO6S 详情 详情
(VI) 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
(VII) 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
(VIII) 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
(IX) 31374 (2S)-2-[(tert-butoxycarbonyl)amino]-6-([[(2-chlorobenzyl)oxy]carbonyl]amino)hexanoic acid C19H27ClN2O6 详情 详情
(X) 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

合成路线2

Compound (X) was subsequently submitted to further coupling and deprotection cycles with the protected amino acids N-Boc-D-tryptophan (XI) and N-Boc-L-(3-pyridyl)alanine (XIII) to afford the peptide-resins (XII) and (XIV), 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】 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
(X) 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
(XI) 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
(XII) 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
(XIII) 31378 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3-pyridinyl)propionic acid C13H18N2O4 详情 详情
(XIV) 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

合成路线3

Compound (XIV) was subsequently submitted to further coupling and deprotection cycles with the protected amino acids N-Boc-S-(4-methylbenzyloxycarbonyl)-D-cysteine (XV) and N-Boc-L-(4-chlorophenyl)- alanine (XVII) to afford the peptide-resins (XVI) and (XVIII), 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】 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
(XIV) 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
(XV) 31382 (2S)-2-[(tert-butoxycarbonyl)amino]-3-([[(4-methylbenzyl)oxy]carbonyl]sulfanyl)propionic acid C17H23NO6S 详情 详情
(XVI) 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
(XVII) 31381 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-chlorophenyl)propionic acid 68090-88-0 C14H18ClNO4 详情 详情
(XVIII) 31380 S-[(2S,5S,8R,11S,14S,17R)-17-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-chlorophenyl)propanoyl]amino]-14-(tert-butyl)-11-[4-([[(2-chlorobenzyl)oxy]carbonyl]amino)butyl]-8-(1H-indol-3- C90H102Cl2N12O16S2 详情 详情

合成路线4

Cleavage of the peptide (XVIII) from the resin support with simultaneous side-chain deprotection using anhydrous HF containing the scavengers anisole and dithiothreitol produced the peptide amide (XIX). This was finally cyclized to the title disulfide employing 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】 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
(XVIII) 31380 S-[(2S,5S,8R,11S,14S,17R)-17-([[(1S)-2-amino-1-(2-naphthylmethyl)-2-oxoethyl]amino]carbonyl)-2-[[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-chlorophenyl)propanoyl]amino]-14-(tert-butyl)-11-[4-([[(2-chlorobenzyl)oxy]carbonyl]amino)butyl]-8-(1H-indol-3- C90H102Cl2N12O16S2 详情 详情
(XIX) 31383 (2S,5R,8S,11S,14R,17S,20S,23S)-23-amino-11-(4-aminobutyl)-8-(tert-butyl)-24-(4-chlorophenyl)-14-(1H-indol-3-ylmethyl)-2-(2-naphthylmethyl)-4,7,10,13,16,19,22-heptaoxo-17-(3-pyridinylmethyl)-5,20-bis(sulfanylmethyl)-3,6,9,12,15,18,21-heptaazatetracos C59H73ClN12O8S2 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)