【结 构 式】 |
【药物名称】NMI-377 【化学名称】2-[2-(2,6-Dichlorophenylamino)phenyl]acetic acid 3-[N-methyl-N-[1-(nitrososulfanyl)cyclohexylmethyl]amino]propyl ester 【CA登记号】 【 分 子 式 】C25H31Cl2N3O3S 【 分 子 量 】524.51412 |
【开发单位】NitroMed (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Antiarthritic Drugs, Chemical Delivery Systems, DRUG DELIVERY, Drug Delivery Systems, Non-Opioid Analgesics, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Nitric Oxide Donors, Non-Steroidal Antiinflammatory Drugs |
合成路线1
Treatment of cyclohexanecarboxaldehyde (I) with sulfur monochloride produced the dimeric disulfide (II). After condensation of (II) with 3-amino-1-propanol (III), reduction with NaBH4 afforded diamine (IV). Subsequent N-methylation of (IV) to give (VI) was achieved by condensation with formaldehyde, followed by NaBH4 reduction of the resulting oxazine (V). Reductive cleavage of the disulfide group of (VI) using LiAlH4 provided thiol (VII). Optionally, nitrosation of the sulfhydryl group of (VII) by means of tert-butyl nitrite gave rise to the nitrosothio derivative (VIII). Further coupling of this compound with diclofenac (IX) in the presence of DCC and DMAP furnished the title ester. Alternatively, the title compound was prepared by esterification of mercapto alcohol (VII) with diclofenac, followed by S-nitrosation of the resulting ester (X).
【1】 Bandarage, U.K.; et al.; Nitrosothiol esters of diclofonecac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs. J Med Chem 2000, 43, 21, 4005. |
【2】 Bandarage, U.K.; et al.; NMI-377, a nitric oxide-donating diclofenac derivative with gastroprotective properties. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 81. |
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) | 33694 | cyclohexanecarbaldehyde | 2043-61-0 | C7H12O | 详情 | 详情 |
(II) | 33695 | 1-[(1-formylcyclohexyl)disulfanyl]cyclohexanecarbaldehyde | C14H22O2S2 | 详情 | 详情 | |
(III) | 18522 | 3-amino-1-propanol | 156-87-6 | C3H9NO | 详情 | 详情 |
(IV) | 33696 | 3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol | C20H40N2O2S2 | 详情 | 详情 | |
(V) | 33697 | bis[1-(1,3-oxazinan-3-ylmethyl)cyclohexyl] disulfide; 3-[(1-[[1-(1,3-oxazinan-3-ylmethyl)cyclohexyl]disulfanyl]cyclohexyl)methyl]-1,3-oxazinane | C22H40N2O2S2 | 详情 | 详情 | |
(VI) | 33698 | 3-[([1-[(1-[[(3-hydroxypropyl)(methyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)(methyl)amino]-1-propanol | C22H44N2O2S2 | 详情 | 详情 | |
(VII) | 33699 | 3-[methyl[(1-sulfanylcyclohexyl)methyl]amino]-1-propanol | C11H23NOS | 详情 | 详情 | |
(VIII) | 33700 | 1-[[(3-hydroxypropyl)(methyl)amino]methyl]-N-oxocyclohexanesulfenamide | C11H22N2O2S | 详情 | 详情 | |
(IX) | 33701 | Diclofenac; 2-[2-(2,6-Dichloroanilino)phenyl]acetic acid | C14H11Cl2NO2 | 详情 | 详情 | |
(X) | 33702 | 3-[methyl[(1-sulfanylcyclohexyl)methyl]amino]propyl 2-[2-(2,6-dichloroanilino)phenyl]acetate | C25H32Cl2N2O2S | 详情 | 详情 |