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【结 构 式】

【药物名称】JMV-1609

【化学名称】N-[2-[3(S)-[D-Arginyl-L-arginyl-L-prolyl-L-[4(R)-hydroxy]prolyl-glycyl-L-(2-thienyl)alanyl-L-serylamino]-8-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl]acetyl]-L-arginine

【CA登记号】

【 分 子 式 】C52H79N19O13S2

【 分 子 量 】1242.45693

【开发单位】Fournier (Originator)

【药理作用】Pharmacological Tools, Bradykinin B2 Agonists

合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

Alkylation of N-acetyl-D-cysteine (I) with 1-fluoro-5-methyl-2-nitrobenzene (II) gave adduct (III). After hydrolysis of the acetamido group of (III) with aqueous sulfuric acid, the resulting amine (IV) was protected as the benzyl carbamate (V). Reduction of the nitro group of (V) provided amino acid (VI), which was cyclized to the benzothiazepinone (VII) using EDC. Subsequent alkylation of (VII) with ethyl bromoacetate under phase-transfer conditions yielded (VIII) (1). Cleavage of both N-Cbz group and ethyl ester by HBr in AcOH, followed by introduction of the N-Boc group afforded intermediate (X) (2). Optionally, hydrogenolysis of the N-Cbz group of (VIII) provided amino lactam (XI). This was coupled with N-Boc-O-benzylserine (XII) to give amide (XIII). Then, basic hydrolysis of the ethyl ester produced carboxylic acid (XIV).

参考文献 中间体
【1】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
16640 Ethyl 2-bromoacetate; Ethyl bromoacetate 105-36-2 C4H7BrO2 详情 详情
(I) 39365 (2S)-2-(acetamido)-3-sulfanylpropionic acid 616-91-1 C5H9NO3S 详情 详情
(II) 39366 2-fluoro-4-methyl-1-nitrobenzene 446-34-4 C7H6FNO2 详情 详情
(III) 39367 (2S)-2-(acetamido)-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C12H14N2O5S 详情 详情
(IV) 39368 (2S)-2-amino-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C10H12N2O4S 详情 详情
(V) 39369 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-[(5-methyl-2-nitrophenyl)sulfanyl]propionic acid C18H18N2O6S 详情 详情
(VI) 39370 (2S)-3-[(2-amino-5-methylphenyl)sulfanyl]-2-[[(benzyloxy)carbonyl]amino]propionic acid C18H20N2O4S 详情 详情
(VII) 39371 benzyl (3S)-8-methyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-ylcarbamate C18H18N2O3S 详情 详情
(VIII) 39372 ethyl 2-[(3S)-3-[[(benzyloxy)carbonyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C22H24N2O5S 详情 详情
(IX) 39376 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C12H14N2O3S 详情 详情
(X) 39377 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C17H22N2O5S 详情 详情
(XI) 39373 ethyl 2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C14H18N2O3S 详情 详情
(XII) 16886 (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine 23680-31-1 C15H21NO5 详情 详情
(XIII) 39374 ethyl 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetate C29H37N3O7S 详情 详情
(XIV) 39375 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C27H33N3O7S 详情 详情

合成路线2

Construction of the peptide chain was carried out by solid phase synthesis on a Merrifield resin. The protected arginine bound to the resin (XV) was treated with trifluoroacetic to cleave the N-Boc group. The resulting NG-arginine-resin (XVI) was coupled with benzothiazepineacetic acid (X) by means of BOP reagent to produce (XVII). After deprotection of the Boc group of (XVII) with trifluoroacetic acid, further coupling with protected serine (XII) gave peptide resin (XIX). The Boc group of (XIX) was then deprotected with trifluoroacetic acid as above to furnish intermediate (XX).

参考文献 中间体
【1】 Daffix, I.; Bergé, G.; Amblard, M.; et al.; Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics. J Med Chem 1999, 42, 20, 4193.
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) 39377 2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C17H22N2O5S 详情 详情
(XII) 16886 (2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propionic acid; N-alpha-t-BOC-o-benzyl-L-serine 23680-31-1 C15H21NO5 详情 详情
(XV) 39378 (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid C18H28N4O6S 详情 详情
(XVI) 39379 (2S)-2-amino-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid C13H20N4O4S 详情 详情
(XVII) 39380 (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-([2-[(3S)-3-[(tert-butoxycarbonyl)amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)pentanoic acid C30H40N6O8S2 详情 详情
(XVIII) 39381 (2S)-2-([2-[(3S)-3-amino-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid C25H32N6O6S2 详情 详情
(XIX) 39382 (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-([2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)pentanoic acid C40H51N7O10S2 详情 详情
(XX) 39383 (2S)-2-([2-[(3S)-3-[[(2S)-2-amino-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid C35H43N7O8S2 详情 详情

合成路线3

An alternative access to intermediate (XX) consisted in coupling of arginine-resin (XVI) with building block (XIV) by means of BOP reagent, followed by trifluoroacetic acid deprotection of the Boc group.

参考文献 中间体
【1】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .
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) 39375 2-[(3S)-3-([(2S)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetic acid C27H33N3O7S 详情 详情
(XVI) 39379 (2S)-2-amino-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid C13H20N4O4S 详情 详情
(XX) 39383 (2S)-2-([2-[(3S)-3-[[(2S)-2-amino-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid C35H43N7O8S2 详情 详情

合成路线4

Peptide resin (XX) was subjected to sequential coupling-deprotection cycles with the following amino acids: N-Boc-(2-thienyl)alanine (XXI), N-Boc-glycine (XXIII), N-Boc-4-hydroxyproline (XXV), N-Boc-proline (XXVII), Nalpha-Boc-Ngamma-tosyl-arginine (XXIX) and Nalpha-Boc-Ngamma-nitro-D-arginine (XXXI) to produce peptide resins (XXII), (XXIV), (XXVI), (XXVIII), (XXX) and (XXXII), respectively. The title peptide was finally obtained by deprotection and cleavage from the resin by means of treatment with HF.

参考文献 中间体
【1】 Daffix, I.; Bergé, G.; Amblard, M.; et al.; Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics. J Med Chem 1999, 42, 20, 4193.
【2】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XX) 39383 (2S)-2-([2-[(3S)-3-[[(2S)-2-amino-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]pentanoic acid C35H43N7O8S2 详情 详情
(XXI) 16888 (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-thienyl)propionic acid；Boc-D-2-Thienylalanine 78452-55-8 C12H17NO4S 详情 详情
(XXII) 39385 (2S)-5-[(amino[[(4-methylphenyl)sulfonyl]imino]methyl)amino]-2-([2-[(3S)-3-[[(2S)-2-[[(2S)-2-amino-3-(2-thienyl)propanoyl]amino]-3-(benzyloxy)propanoyl]amino]-8-methyl-4-oxo-3,4-dihydro-1,5-benzothiazepin-5(2H)-yl]acetyl]amino)pentanoic acid C42H50N8O9S3 详情 详情
(XXIII) 18066 N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid 4530-20-5 C7H13NO4 详情 详情
(XXIV) 39386 　 C44H53N9O10S3 详情 详情
(XXV) 19043 (2R,4S)-1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid C10H17NO5 详情 详情
(XXVI) 39387 　 C49H60N10O12S3 详情 详情
(XXVII) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(XXVIII) 39388 　 C54H67N11O13S3 详情 详情

合成路线5

Peptide resin (XX) was subjected to sequential coupling-deprotection cycles with the following amino acids: N-Boc-(2-thienyl)alanine (XXI), N-Boc-glycine (XXIII), N-Boc-4-hydroxyproline (XXV), N-Boc-proline (XXVII), Nalpha-Boc-NG-tosyl-arginine (XXIX) and Nalpha-Boc-NG-nitro-D-arginine (XXXI) to produce peptide resins (XXII), (XXIV), (XXVI), (XXVIII), (XXX) and (XXXII), respectively. The title peptide was finally obtained by deprotection and cleavage from the resin by means of treatment with HF.

参考文献 中间体
【1】 Daffix, I.; Bergé, G.; Amblard, M.; et al.; Synthesis and characterization of bradykinin B2 receptor agonists containing constrained dipeptide mimics. J Med Chem 1999, 42, 20, 4193.
【2】 Dodey, P.; Luccarini, J.-M.; Martinez, J.; Amblard, M.; Daffix, I. (Fournier Industrie et Santé); Peptides agonists of bradykinine B2 receptor. FR 2756566; WO 9824809 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XXVIII) 39388 　 C54H67N11O13S3 详情 详情
(XXIX) 39391 (2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid C18H28N4O6S 详情 详情
(XXX) 39389 　 C67H85N15O16S4 详情 详情
(XXXI) 32085 N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine; Nalpha-(tert-butoxycarbonyl)-Nomega-nitro-L-arginine C11H21N5O6 详情 详情
(XXXII) 39390 　 C73H96N20O19S4 详情 详情
Extended Information
Drug NewChemical Entity Original Patent(1)