【结 构 式】 |
【药物名称】Batimastat, ISV-615, ISV-120, BB-94 【化学名称】3(S)-(N-Hydroxycarbamoyl)-2(R)-isobutyl-4-(2-thienylthio)butyryl-L-phenylalanine methylamide 【CA登记号】130370-60-4, 130464-84-5 (monoNa salt) 【 分 子 式 】C23H31N3O4S2 【 分 子 量 】477.64922 |
【开发单位】British Biotech (Originator), InSite Vision (Licensee), Biocompatibles (Codevelopment) 【药理作用】Antiarthritic Drugs, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Diabetic Retinopathy, Agents for, ENDOCRINE DRUGS, NEUROLOGIC DRUGS, OCULAR MEDICATIONS, ONCOLYTIC DRUGS, Ophthalmic Drugs, Restenosis Treatment of, Stroke, Treatment of, Treatment of Age-Related Macular Degeneration, Treatment of Diabetic Complications, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Angiogenesis Inhibitors, Matrix Metalloproteinase Inhibitors |
合成路线1
The treatment of D-leucine (I) with NaNO2, H2SO4 and NaBr gives 2(R)-bromo-5-methylpentanoic acid (II), which is esterified with isobutene and H2SO4 to the corresponding tert-butyl ester (III). The condensation of (III) with dibenzyl malonate (IV) by means of potassium tert-butoxide in DMF yields the malonyl derivative (V), which is treated with trifluoroacetic acid to hydrolyze the tert-butyl ester, and without isolation is condensed with L-phenylalanine methyl amide (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC), affording 4-benzyloxy-3-(benzyloxycarbonyl)-2(R)-isobutylsuccinyl-L-phenylalanine methylamide (VII). The elimination of the benzyl groups of (VII) by hydrogenolysis over Pd/C in ethanol gives the dicarboxylic acid (VIII), which by partial decarboxylation and reaction with aqueous formaldehyde and piperidine yields 4-hydroxy-2(R)-isobutyl-3-methylenesuccinyl-L-phenylalanine methylamide (IX). The addition of thiophene-2-thiol (X) to the double bond of (IX) affords 4-hydroxy-2(R)-isobutyl-3(S)-(2-thienylsulfanylmethyl)succinyl-L-phenylalanine methylamide (XI), which is finally treated with hydroxylamine and hydroxybenzotriazole in dichloromethane/DMF.
【1】 Ngo, J.; Graul, A.; Castaner, J.; Batimastat. Drugs Fut 1996, 21, 12, 1215. |
【2】 Campion, C.; Davidson, A.H.; Dickens, J.P.; Crimmin, M.J. (British Biotech plc); Hydroxamic acid based collagenase inhibitors. US 5240958; US 5310763; WO 9005719 . |
【3】 Beckett, R.P.; Crimmin, M.J.; Galloway, W.A.; Matrix metalloproteinase inhibitors in the treatment of rheumatoid arthritis and cancer. 205th ACS Natl Meet (March 28-April 2, Denver) 1993, Abst MEDI 147. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 | |
(I) | 16010 | D-leucine | 328-38-1 | C6H13NO2 | 详情 | 详情 |
(II) | 16011 | (2R)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
(III) | 16012 | tert-butyl (2R)-2-bromo-4-methylpentanoate | C10H19BrO2 | 详情 | 详情 | |
(IV) | 16013 | dibenzyl malonate | 15014-25-2 | C17H16O4 | 详情 | 详情 |
(V) | 16014 | 1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate | C27H34O6 | 详情 | 详情 | |
(VI) | 16015 | (2S)-2-amino-N-methyl-3-phenylpropanamide | C10H14N2O | 详情 | 详情 | |
(VII) | 16016 | dibenzyl 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonate | C33H38N2O6 | 详情 | 详情 | |
(VIII) | 16017 | 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonic acid | C19H26N2O6 | 详情 | 详情 | |
(IX) | 16018 | 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]acrylic acid | C19H26N2O4 | 详情 | 详情 | |
(X) | 16019 | 2-Thienylhydrosulfide; 2-Thiophenethiol | 7774-74-5 | C4H4S2 | 详情 | 详情 |
(XI) | 16020 | (2S,3R)-3-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-5-methyl-2-[(2-thienylsulfanyl)methyl]hexanoic acid | C23H30N2O4S2 | 详情 | 详情 |