发明授权
EP0833837B1 PROCESS FOR PREPARING DERIVATIVES OF AZABICYCLO NAPHTHYRIDINE CARBOXYLIC ACID COMPRISING A DIPEPTIDE
失效
PROCESS FOR肽衍生物的制备含AZABIZYLO萘甲酸
- 专利标题: PROCESS FOR PREPARING DERIVATIVES OF AZABICYCLO NAPHTHYRIDINE CARBOXYLIC ACID COMPRISING A DIPEPTIDE
- 专利标题(中): PROCESS FOR肽衍生物的制备含AZABIZYLO萘甲酸
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申请号: EP96904996.4申请日: 1996-03-27
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公开(公告)号: EP0833837B1公开(公告)日: 2002-07-31
- 发明人: BRAISH, Tamim, F. , CASTALDI, Michael, J. , WATSON, Harry, A., Jr.
- 申请人: PFIZER INC.
- 申请人地址: 235 East 42nd Street New York, N.Y. 10017 US
- 专利权人: PFIZER INC.
- 当前专利权人: PFIZER INC.
- 当前专利权人地址: 235 East 42nd Street New York, N.Y. 10017 US
- 代理机构: Atkinson, Jonathan David Mark
- 优先权: US490827 19950615
- 国际公布: WO9700268 19970103
- 主分类号: C07K1/06
- IPC分类号: C07K1/06 ; C07K5/06 ; C07D471/04 ; A61K31/47
摘要:
A novel process for preparing a prodrug acid, viz., 7-[(1 alpha , 6 alpha , 7 alpha )-6-(L-Ala-L-Ala-amino)-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, in the form of a pharmaceutically acceptable acid addition salt, is disclosed, which involves (1) treating an N-protected 7-[(1 alpha , 5 alpha , 6 alpha )-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid C1-C4 alkyl ester, wherein the nitrogen-protecting group is benzyloxycarbonyl, C1-C4 alkoxycarbonyl or C1-C4 alkanoyl, with a strongly-protic acid to selectively remove the N-protecting group; (2) then condensing the resulting free amino ester compound with an N-protected L-alanyl-L-alanine dipeptide compound, wherein the N-protecting group is as previously defined, in the presence of a standard dehydrating agent to form the corresponding N-protected prodrug ester compound as the desired condensation product; and (3) thereafter hydrolyzing the intermediate N-protected prodrug ester in the presence of a pharmaceutically-acceptable strong acid to convert said N-protected prodrug ester to the desired naphthyridinone L-Ala-L-Ala prodrug acid final product, in the form of the corresponding pharmaceutically acceptable acid addition salt, indicated above. The latter prodrug acid final product is especially useful in the form of the corresponding methanesulfonic acid addition salt, which serves as a water-soluble prodrug companion to a known antibacterial agent, viz., 7-[(1 alpha , 5 alpha , 6 alpha )-6-amino-3-azabicyclo[3.1.0]hex-3-yl]-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1-naphthyridine-3-carboxylic acid.
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