【结 构 式】 |
【药物名称】L-377202 【化学名称】N-[N-(4-Carboxybutyryl)-4(R)-hydroxy-L-prolyl-L-alanyl-L-seryl-L-cyclohexylglycyl-L-glutaminyl-L-seryl-L-leucyl]doxorubicin 【CA登记号】207395-85-5, 337359-45-2 (Na salt) 【 分 子 式 】C65H89N9O25 【 分 子 量 】1396.47938 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antibiotics and Alkaloids, Antineoplastic Antibiotics, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Oncolytic Drugs, Prostate Cancer Therapy, Anthracyclines |
合成路线1
The peptide moiety (XVII) was prepared by solid-phase synthesis in a peptide synthesizer starting from Boc-Leu-PAM resin (I). Removal of the Boc protecting group of (I) was effected by treatment with trifluoroacetic acid in CH2Cl2. To the deprotected Leu-resin (II) were sequentially incorporated the following amino acids: N-Fmoc-L-serine(O-t-Bu) (III), N-Fmoc-L-glutamine(Trt) (V), N-Fmoc-L-cyclohexylglycine (VII), again Fmoc-L-serine(O-t-Bu) (III), and N-Fmoc-L-alanine (X) using DCC and HOBt activation in N-methyl-2-pyrrolidinone, each followed by an Fmoc deprotection cycle with piperidine in DMF. The peptide resins (IV), (VI), (VIII), (IX) and (XI) were in turn obtained.
【2】 Garsky, V.M.; Feng, D.-M.; DeFeo-Jones, D. (Merck & Co., Inc.); Conjugates useful in the treatment of prostate cancer. JP 2000509407; WO 9818493 . |
【3】 Oliff, A.I.; Jones, R.E.; Defeo-Jones, D. (Merck & Co., Inc.); A method of treating cancer. WO 0059930 . |
【1】 Feng, D.-M.; Wai, J.; Ramjit, H.G.; Sardana, M.K.; Lumma, P.K.; DeFeo-Jones, D.; Jones, R.E.; Freidinger, R.M.; Oliff, A.; Garsky, V.M.; The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy. J Med Chem 2001, 44, 24, 4216. |
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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
(II) | 26057 | L-Leucine | 61-90-5 | C6H13NO2 | 详情 | 详情 |
(III) | 33118 | (2S)-3-(tert-butoxy)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | 71989-33-8 | C22H25NO5 | 详情 | 详情 |
(IV) | 53663 | (2S)-2-{[(2S)-2-amino-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C13H26N2O4 | 详情 | 详情 |
(V) | 53664 | (2S)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}-5-oxo-5-(tritylamino)pentanoic acid | n/a | C39H34N2O5 | 详情 | 详情 |
(VI) | 53665 | (2S)-2-{[(2S)-2-{[(2S)-2-amino-5-oxo-5-(tritylamino)pentanoyl]amino}-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C37H48N4O6 | 详情 | 详情 |
(VII) | 53666 | (2S)-2-cyclohexyl-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoic acid | n/a | C23H25NO4 | 详情 | 详情 |
(VIII) | 53667 | (2S)-2-{[(2S)-2-{[(2S)-2-{[(2S)-2-amino-2-cyclohexylethanoyl]amino}-5-oxo-5-(tritylamino)pentanoyl]amino}-3-(tert-butoxy)propanoyl]amino}-4-methylpentanoic acid | n/a | C45H61N5O7 | 详情 | 详情 |
(IX) | 53668 | (2S,5S,8S,11S,14S)-14-amino-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C52H74N6O9 | 详情 | 详情 |
(X) | 19926 | (2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]propionic acid | C18H17NO4 | 详情 | 详情 | |
(XI) | 53669 | (2S,5S,8S,11S,14S)-14-{[(2S)-2-aminopropanoyl]amino}-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C55H79N7O10 | 详情 | 详情 |
合成路线2
To the peptide resin (XI) was coupled N-Boc-trans-4-hydroxy-L-proline (XII) to produce resin (XIII). Simultaneous removal of the N-terminal and side-chain protecting groups of (XIII) with trifluoroacetic acid in CH2Cl2 furnished the deprotected peptide resin (XIV). Acylation of (XIV) with the mono-fluorenylmethyl ester of glutaric acid (XV) produced amide (XVI). The desired peptide (XVII) was then liberated from the resin (XVI) employing HF in the presence of anisole.
【2】 Garsky, V.M.; Feng, D.-M.; DeFeo-Jones, D. (Merck & Co., Inc.); Conjugates useful in the treatment of prostate cancer. JP 2000509407; WO 9818493 . |
【3】 Oliff, A.I.; Jones, R.E.; Defeo-Jones, D. (Merck & Co., Inc.); A method of treating cancer. WO 0059930 . |
【1】 Feng, D.-M.; Wai, J.; Ramjit, H.G.; Sardana, M.K.; Lumma, P.K.; DeFeo-Jones, D.; Jones, R.E.; Freidinger, R.M.; Oliff, A.; Garsky, V.M.; The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy. J Med Chem 2001, 44, 24, 4216. |
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) | 53673 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-1-{(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}-6,15-bis(hydroxymethyl)-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C52H72N8O15 | 详情 | 详情 |
(XI) | 53669 | (2S,5S,8S,11S,14S)-14-{[(2S)-2-aminopropanoyl]amino}-5-(tert-butoxymethyl)-11-cyclohexyl-2-isobutyl-17,17-dimethyl-4,7,10,13-tetraoxo-8-[3-oxo-3-(tritylamino)propyl]-16-oxa-3,6,9,12-tetraazaoctadecan-1-oic acid | n/a | C55H79N7O10 | 详情 | 详情 |
(XII) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
(XIII) | 53670 | (3S,6S,9S,12S,15S,18S)-1-[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]-6,15-bis(tert-butoxymethyl)-9-cyclohexyl-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-12-[3-oxo-3-(tritylamino)propyl]-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C65H94N8O14 | 详情 | 详情 |
(XIV) | 53671 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-6,15-bis(hydroxymethyl)-1-[(2S,4R)-4-hydroxypyrrolidinyl]-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C33H56N8O12 | 详情 | 详情 |
(XV) | 53680 | 5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoic acid | n/a | C19H18O4 | 详情 | 详情 |
合成路线3
Coupling of peptide (XVII) to the amino group of doxorubicin (XVIII) using DPPA yielded amide (XIX). Alternatively, EDC in the presence of HOAt can be used as the coupling reagent. The fluorenylmethyl ester of (XIX) was finally removed by treatment with piperidine in DMF to produce the title compound.
【2】 Garsky, V.M.; Feng, D.-M.; DeFeo-Jones, D. (Merck & Co., Inc.); Conjugates useful in the treatment of prostate cancer. JP 2000509407; WO 9818493 . |
【3】 Oliff, A.I.; Jones, R.E.; Defeo-Jones, D. (Merck & Co., Inc.); A method of treating cancer. WO 0059930 . |
【4】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
【1】 Feng, D.-M.; Wai, J.; Ramjit, H.G.; Sardana, M.K.; Lumma, P.K.; DeFeo-Jones, D.; Jones, R.E.; Freidinger, R.M.; Oliff, A.; Garsky, V.M.; The synthesis of a prodrug of doxorubicin designed to provide reduced systemic toxicity and greater target efficacy. J Med Chem 2001, 44, 24, 4216. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVII) | 53673 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-1-{(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}-6,15-bis(hydroxymethyl)-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C52H72N8O15 | 详情 | 详情 |
(XVIII) | 11675 | (8S,10S)-10-[[(2R,4S,5S,6S)-4-Amino-5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl]oxy]-8-glycoloyl-6,8,11-trihydroxy-1-methoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione | C27H29NO11 | 详情 | 详情 | |
(XIX) | 53674 | 9H-fluoren-9-ylmethyl 5-{(2S,4R)-2-[(3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-18-{[((2S,3S,4S,6R)-6-{[(1S,3S)-3-glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl]oxy}-3-hydroxy-2-methyltetrahydro-2H-pyran-4-yl)amino]carbonyl}-6,15-bis(hydroxymethyl)-3,20-dimethyl-4,7,10,13,16-pentaoxo-2,5,8,11,14,17-hexaazahenicos-1-anoyl]-4-hydroxypyrrolidinyl}-5-oxopentanoate | n/a | C79H99N9O25 | 详情 | 详情 |
合成路线4
The synthesis of the precursor peptide (XVII) was also reported in solution phase. trans-4-Hydroxy-L-proline (XX) was protected as the N-Boc derivative (XII), which was subsequently activated as the pentafluorophenyl ester (XXI). This was condensed with the dipeptide alanyl-serine (XXII) to furnish the protected tripeptide (XXIII). Acidic cleavage of the Boc protecting group of (XXIII) yielded tripeptide (XXIV).
【1】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XII) | 16094 | (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid;1-(tert-butoxycarbonyl)-4®-hydroxy-L-proline;(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid | 16094 | C10H17NO5 | 详情 | 详情 |
(XX) | 14489 | (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline | 51-35-4 | C5H9NO3 | 详情 | 详情 |
(XXI) | 53675 | 1-(tert-butyl) 2-(2,3,4,5,6-pentafluorophenyl) (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate | n/a | C16H16F5NO5 | 详情 | 详情 |
(XXII) | 53676 | (2S)-2-{[(2S)-2-aminopropanoyl]amino}-3-hydroxypropanoic acid | n/a | C6H12N2O4 | 详情 | 详情 |
(XXIII) | 53677 | (2S)-2-{[(2S)-2-({[(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}-3-hydroxypropanoic acid | n/a | C16H27N3O8 | 详情 | 详情 |
(XXIV) | 53678 | (2S)-3-hydroxy-2-{[(2S)-2-({[(2S,4R)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}propanoic acid | n/a | C11H19N3O6 | 详情 | 详情 |
合成路线5
Acylation of 9-fluorenylmethanol (XXV) with glutaric anhydride (XXVI) yielded the glutarate mono-ester (XV). This was further activated as the pentafluorophenyl ester (XXVII) upon treatment with pentafluorophenol and DCC. Coupling of active ester (XXVII) with tripeptide (XXIV) gave rise to the glutaryl tripeptide (XXVIII).
【1】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XV) | 53680 | 5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoic acid | n/a | C19H18O4 | 详情 | 详情 |
(XXIV) | 53678 | (2S)-3-hydroxy-2-{[(2S)-2-({[(2S,4R)-4-hydroxypyrrolidinyl]carbonyl}amino)propanoyl]amino}propanoic acid | n/a | C11H19N3O6 | 详情 | 详情 |
(XXV) | 53679 | 9H-fluoren-9-ylmethanol | 24324-17-2 | C14H12O | 详情 | 详情 |
(XXVI) | 15512 | Glutaric Anhydride; dihydro-2H-pyran-2,6(3H)-dione | 108-55-4 | C5H6O3 | 详情 | 详情 |
(XXVII) | 53681 | 1-(9H-fluoren-9-ylmethyl) 5-(2,3,4,5,6-pentafluorophenyl) pentanedioate | n/a | C25H17F5O4 | 详情 | 详情 |
(XXVIII) | 53682 | (2S)-2-({(2S)-2-[({(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}carbonyl)amino]propanoyl}amino)-3-hydroxypropanoic acid | n/a | C30H35N3O9 | 详情 | 详情 |
合成路线6
Coupling between N-Boc-L-serine (XXIX) and L-leucine benzyl ester (XXX) furnished the Boc-dipeptide (XXXI), which was deprotected by means of a solution of HCl in isopropyl acetate. The resultant seryl-leucine benzyl ester (XXXII) was condensed with N-Boc-L-glutamine (XXXIII) to afford (XXXIV), which after N-Boc deprotection yielded tripeptide ester (XXXV). Further coupling of (XXXV) with N-Boc-L-cyclohexylglycine (XXXVI), followed by acidic deprotection, gave tetrapeptide (XXXVII). This was finally acylated with the glutaryl tripeptide (XXVIII) to provide the desired peptide intermediate (XVII).
【1】 Kaufman, M.J.; Almarsson, O.; Nerurkar, M.J.; Lynch, J.E.; Karki, S.B.; Cameron, M.; Lieberman, D.R.; Robbins, M.A.; Shi, Y.-J. (Merck & Co., Inc.); Salt form of a conjugate useful in the treatment of prostate cancer. US 6355611; WO 0130804 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XVII) | 53673 | (3S,6S,9S,12S,15S,18S)-12-(3-amino-3-oxopropyl)-9-cyclohexyl-1-{(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}-6,15-bis(hydroxymethyl)-18-isobutyl-3-methyl-1,4,7,10,13,16-hexaoxo-2,5,8,11,14,17-hexaazanonadecan-19-oic acid | n/a | C52H72N8O15 | 详情 | 详情 |
(XXVIII) | 53682 | (2S)-2-({(2S)-2-[({(2S,4R)-1-[5-(9H-fluoren-9-ylmethoxy)-5-oxopentanoyl]-4-hydroxypyrrolidinyl}carbonyl)amino]propanoyl}amino)-3-hydroxypropanoic acid | n/a | C30H35N3O9 | 详情 | 详情 |
(XXIX) | 20126 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropionic acid | C8H15NO5 | 详情 | 详情 | |
(XXX) | 22252 | Benzyl (2S)-2-amino-4-methylpentanoate; Benzyl (S)-leucinate | C13H19NO2 | 详情 | 详情 | |
(XXXI) | 53672 | benzyl (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl}amino)-4-methylpentanoate | n/a | C21H32N2O6 | 详情 | 详情 |
(XXXII) | 53683 | benzyl (2S)-2-{[(2S)-2-amino-3-hydroxypropanoyl]amino}-4-methylpentanoate | n/a | C16H24N2O4 | 详情 | 详情 |
(XXXIII) | 31820 | (2S)-5-amino-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid | 13726-85-7 | C10H18N2O5 | 详情 | 详情 |
(XXXIV) | 53684 | benzyl (6S,9S,12S)-6-(3-amino-3-oxopropyl)-9-(hydroxymethyl)-12-isobutyl-2,2-dimethyl-4,7,10-trioxo-3-oxa-5,8,11-triazatridecan-13-oate | n/a | C26H40N4O8 | 详情 | 详情 |
(XXXV) | 53685 | benzyl (2S)-2-[((2S)-2-{[(2S)-2,5-diamino-5-oxopentanoyl]amino}-3-hydroxypropanoyl)amino]-4-methylpentanoate | n/a | C21H32N4O6 | 详情 | 详情 |
(XXXVI) | 35619 | (2S)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoic acid | C13H23NO4 | 详情 | 详情 | |
(XXXVII) | 53686 | benzyl (2S)-2-({(2S)-2-[((2S)-5-amino-2-{[(2S)-2-amino-2-cyclohexylethanoyl]amino}-5-oxopentanoyl)amino]-3-hydroxypropanoyl}amino)-4-methylpentanoate | n/a | C29H45N5O7 | 详情 | 详情 |