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【结 构 式】 
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【药物名称】Nepadutant, MEN-11420 【化学名称】Cyclo[N-[2-(acetylamino)-2-deoxy-beta-D-glucopyranosyl]-L-asparaginyl-L-aspartyl-L-tryptophyl-L-phenylalanyl-[2(S),3-diaminopropionyl]-L-leucine]-C-4.2-N-3.5-lactam 【CA登记号】183747-35-5 【 分 子 式 】C45H58N10O13 【 分 子 量 】947.02321 |
【开发单位】Menarini (Originator) 【药理作用】Asthma Therapy, GASTROINTESTINAL DRUGS, Irritable Bowel Syndrome, Agents for, RESPIRATORY DRUGS, Tachykinin NK2 Antagonists |
合成路线1
The protected diaminopropionic acid building block (III) was prepared as follows. Rearrangement of N-Fmoc-L-asparragine (I) upon treatment with bis(trifluoroacetoxy)phenyliodine afforded the Fmoc-diaminopropionic acid (II), which was subsequently protected at the 3-amino group with di-tert-butyl dicarbonate.
| 【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
| 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) | 56119 | 9-Fluorenylmethoxycarbonyl-L-asparagine; N-(9-Fluorenylmethoxycarbonyl)-L-asparagine; N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-L-asparagine | 71989-16-7 | C19H18N2O5 | 详情 | 详情 |
| (II) | 56120 | Fmoc-L-diaminopropionic acid | C18H18N2O4 | 详情 | 详情 | |
| (III) | 56121 | (2S)-3-[(tert-butoxycarbonyl)amino]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid | C23H26N2O6 | 详情 | 详情 |
合成路线2
The monocyclic peptide precursor (XVIII) was prepared by solid-phase peptide synthesis by two different sequences. In the first one, N-Fmoc-L-leucine (IV) was linked to chlorotrityl resin, and the resultant resin-bound Fmoc-leucine (V) was subsequently deprotected by treatment with piperidine in DMF. To the deprotected leucine-resin (VI) was attached the diaminopropionic acid derivative (III), using either dicyclohexylcarbodiimide or diisopropylcarbodiimide as the coupling reagents, to yield the dipeptide resin (VII), which was further deprotected to (VIII) by means of piperidine in DMF.
| 【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
| 【2】 Arcamone, F.; Maggi, C.A.; Quartara, L.; Giannotti, D. (Menarini Industrie Farma Riunite Srl); Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical compsn.. JP 1999501643; WO 9628467 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV),(V) | 19934 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-methylpentanoic acid | C21H23NO4 | 详情 | 详情 | |
| (III) | 56121 | (2S)-3-[(tert-butoxycarbonyl)amino]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid | C23H26N2O6 | 详情 | 详情 | |
| (VI) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
| (VII) | 56122 | (2S)-2-[((2S)-3-[(tert-butoxycarbonyl)amino]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoyl)amino]-4-methylpentanoic acid | C29H37N3O7 | 详情 | 详情 | |
| (VIII) | 56123 | (2S)-2-({(2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoyl}amino)-4-methylpentanoic acid | C14H27N3O5 | 详情 | 详情 |
合成路线3
To the resin (VIII) were in turn incorporated the following aminoacids: N-Fmoc-L-phenylalanine (IX), N-Fmoc-tryptophan (XI), N-Fmoc-L-aspartic acid beta-t-butyl ester (XIII) and the glycosylated asparragine derivative (XV), each followed by an Fmoc deprotection step to furnish the peptide resins (X), (XII), (XIV) and (XVI), respectively.
| 【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
| 【2】 Arcamone, F.; Maggi, C.A.; Quartara, L.; Giannotti, D. (Menarini Industrie Farma Riunite Srl); Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical compsn.. JP 1999501643; WO 9628467 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 56123 | (2S)-2-({(2S)-2-amino-3-[(tert-butoxycarbonyl)amino]propanoyl}amino)-4-methylpentanoic acid | C14H27N3O5 | 详情 | 详情 | |
| (IX) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (X) | 56124 | (2S)-2-({(2S)-2-{[(2S)-2-amino-3-phenylpropanoyl]amino}-3-[(tert-butoxycarbonyl)amino]propanoyl}amino)-4-methylpentanoic acid | C23H36N4O6 | 详情 | 详情 | |
| (XI) | 56129 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(1H-indol-3-yl)propanoic acid | C26H22N2O4 | 详情 | 详情 | |
| (XII) | 56125 | (2S)-2-({(2S)-2-[((2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoyl)amino]-3-[(tert-butoxycarbonyl)amino]propanoyl}amino)-4-methylpentanoic acid | C34H46N6O7 | 详情 | 详情 | |
| (XIII) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XIV) | 56126 | (2S,5S,8S,11S,14S)-14-amino-8-benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-11-(1H-indol-3-ylmethyl)-2-isobutyl-18,18-dimethyl-4,7,10,13,16-pentaoxo-17-oxa-3,6,9,12-tetraazanonadecan-1-oic acid | C42H59N7O10 | 详情 | 详情 | |
| (XV) | 56127 | 2,3,4,5,6-pentafluorophenyl (2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxobutanoate | C39H36F5N3O13 | 详情 | 详情 | |
| (XVI) | 56128 | (2S,5S,8S,11S,14S)-14-{[(2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-amino-4-oxobutanoyl]amino}-8-benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-11-(1H-indol-3-ylmethyl)-2-isobutyl-18,18-dimethyl-4,7,10,13,16-pentaoxo-17-oxa-3,6,9,12-tetraazanonadecan-1-oic acid | C60H84N10O20 | 详情 | 详情 |
合成路线4
The linear precursor resin (XVI) was cleaved by means of trifluoroacetic acid yielding the side-chain protected peptide (XVII). Cyclization of (XVII) to furnish the monocyclic peptide (XVIII) was effected by treatment either with PyBOP or with 2-chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate (CIP) in the presence of HOAt. The side-chain-protecting groups were then cleaved by treatment with trifluoroacetic acid to give (XIX).
| 【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
| 【2】 Arcamone, F.; Maggi, C.A.; Quartara, L.; Giannotti, D. (Menarini Industrie Farma Riunite Srl); Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical compsn.. JP 1999501643; WO 9628467 . |
| 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),(XVII) | 56128 | (2S,5S,8S,11S,14S)-14-{[(2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-amino-4-oxobutanoyl]amino}-8-benzyl-5-{[(tert-butoxycarbonyl)amino]methyl}-11-(1H-indol-3-ylmethyl)-2-isobutyl-18,18-dimethyl-4,7,10,13,16-pentaoxo-17-oxa-3,6,9,12-tetraazanonadecan-1-oic acid | C60H84N10O20 | 详情 | 详情 | |
| (XVIII) | 56130 | tert-butyl 2-[(2S,5S,8S,11S,14S,17S)-17-[2-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-oxoethyl]-8-benzyl-11-{[(tert-butoxycarbonyl)amino]methyl}-5-(1H-indol-3-ylmethyl)-14-isobutyl-3,6,9,12,15,18-hexaoxo-1,4,7,10,13,16-hexaazacyclooctadecan-2-yl]acetate | C60H82N10O19 | 详情 | 详情 | |
| (XIX) | 56131 | 2-[(2S,5S,8S,11S,14S,17S)-17-[2-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-oxoethyl]-11-(aminomethyl)-8-benzyl-5-(1H-indol-3-ylmethyl)-14-isobutyl-3,6,9,12,15,18-hexaoxo-1,4,7,10,13,16-hexaazacyclooctadecan-2-yl]acetic acid | C51H66N10O17 | 详情 | 详情 |
合成路线5
Condensation between the side-chain amino and carboxy groups of (XIX) to produce the bicyclic peptide (XX) was accomplished by treatment with either PyBOP or CIP reagents. The acetate ester groups of (XX) were finally removed by alcoholysis with methanolic NaOMe yielding the title compound.
| 【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
| 【2】 Arcamone, F.; Maggi, C.A.; Quartara, L.; Giannotti, D. (Menarini Industrie Farma Riunite Srl); Bicyclic tachykinins antagonists, preparation thereof and their use in pharmaceutical compsn.. JP 1999501643; WO 9628467 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIX) | 56131 | 2-[(2S,5S,8S,11S,14S,17S)-17-[2-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-oxoethyl]-11-(aminomethyl)-8-benzyl-5-(1H-indol-3-ylmethyl)-14-isobutyl-3,6,9,12,15,18-hexaoxo-1,4,7,10,13,16-hexaazacyclooctadecan-2-yl]acetic acid | C51H66N10O17 | 详情 | 详情 | |
| (XX) | 56132 | (2R,3R,4R,5R,6R)-3-(acetylamino)-5-(acetyloxy)-6-[(acetyloxy)methyl]-2-({2-[(1S,4S,7S,10S,13S,16S)-4-benzyl-7-(1H-indol-3-ylmethyl)-16-isobutyl-3,6,9,12,15,18,21-heptaoxo-2,5,8,11,14,17,20-heptaazabicyclo[8.8.4]docos-13-yl]acetyl}amino)tetrahydro-2H-pyran-4-yl acetate | C51H64N10O16 | 详情 | 详情 |
合成路线6
In an alternative procedure, initial anchoring of N-Fmoc-L-phenylalanine (IX) to the chlorotrityl resin afforded resin (XXI), which was deprotected with piperidine in DMF to provide the phenylalanine-resin (XXII). Sequential coupling and deprotection cycles with N-Fmoc-L-tryptophan (XI), N-Fmoc-L-aspartic acid beta-t-butyl ester (XIII), and N-Fmoc-N’-(tetraacetyl-beta-D-glycosyl)asparragine (XXV) yielded the peptide resins (XXIII), (XXIV) and (XXVI), respectively.
| 【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX),(XXI) | 19030 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-3-phenylpropionic acid; N-((9H-fluoren-9-ylmethoxy)carbonyl)-phenylalanine | 35661-40-6 | C24H21NO4 | 详情 | 详情 |
| (XI) | 56129 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-3-(1H-indol-3-yl)propanoic acid | C26H22N2O4 | 详情 | 详情 | |
| (XIII) | 22260 | (2S)-4-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-oxobutyric acid | C23H25NO6 | 详情 | 详情 | |
| (XXII) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (XXIII) | 56133 | (2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid | C20H21N3O3 | 详情 | 详情 | |
| (XXIV) | 56134 | (2S)-2-{[(2S)-2-{[(2S)-2-amino-4-(tert-butoxy)-4-oxobutanoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid | C28H34N4O6 | 详情 | 详情 | |
| (XXV) | 56135 | (2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-4-oxobutanoic acid | C33H37N3O13 | 详情 | 详情 | |
| (XXVI) | 56136 | (2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-amino-4-oxobutanoyl]amino}-4-(tert-butoxy)-4-oxobutanoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid | C46H59N7O16 | 详情 | 详情 |
合成路线7
Another route for the synthesis of intermediate (XVIII) has also been described: To resin (XXVI) was coupled N-Fmoc-L-leucine (IV) to afford resin (XXVII), after Fmoc deprotection with piperidine. Subsequent coupling with the protected diaminopropionic acid (III), followed by a new deprotection with piperidine, gave the resin-bound linear peptide (XXVIII). After trifluoroacetic acid-promoted cleavage from the resin, the resultant side-chain-protected peptide was cyclized to (XVIII)
| 【1】 Aimoto, S.; Akaji, K.; Synthesis of MEN11420, a glycosylated bicyclic peptide, by intramolecular double cyclization using a chloroimidazolinium coupling reagent. Tetrahedron 2001, 57, 9, 1749. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56121 | (2S)-3-[(tert-butoxycarbonyl)amino]-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acid | C23H26N2O6 | 详情 | 详情 | |
| (XVIII) | 56130 | tert-butyl 2-[(2S,5S,8S,11S,14S,17S)-17-[2-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-oxoethyl]-8-benzyl-11-{[(tert-butoxycarbonyl)amino]methyl}-5-(1H-indol-3-ylmethyl)-14-isobutyl-3,6,9,12,15,18-hexaoxo-1,4,7,10,13,16-hexaazacyclooctadecan-2-yl]acetate | C60H82N10O19 | 详情 | 详情 | |
| (XXVI) | 56136 | (2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-4-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-amino-4-oxobutanoyl]amino}-4-(tert-butoxy)-4-oxobutanoyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-phenylpropanoic acid | C46H59N7O16 | 详情 | 详情 | |
| (XXVII) | 56137 | (2S,5S,8S,11S,14S)-11-[2-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-oxoethyl]-14-amino-2-benzyl-8-[2-(tert-butoxy)-2-oxoethyl]-5-(1H-indol-3-ylmethyl)-16-methyl-4,7,10,13-tetraoxo-3,6,9,12-tetraazaheptadecan-1-oic acid | C52H70N8O17 | 详情 | 详情 | |
| (XXVIII) | 56138 | (7S,10S,13S,16S,19S,22S)-13-[2-({(2R,3R,4R,5R,6R)-3-(acetylamino)-4,5-bis(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl}amino)-2-oxoethyl]-7-amino-22-benzyl-16-[2-(tert-butoxy)-2-oxoethyl]-19-(1H-indol-3-ylmethyl)-10-isobutyl-2,2-dimethyl-4,8,11,14,17,20-hexaoxo-3-oxa-5,9,12,15,18,21-hexaazatricosan-23-oic acid | C60H84N10O20 | 详情 | 详情 |