Patent EP-0170775-B2 (EP)
Inventor: URBACH HANSJOERG DR
IPC: A61K38/00
Filed: 1982-12-24
Granted: 1994-10-12
Abstract: 1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A compound of the formula I  see diagramm : EP0170775,P20,F2  in which the hydrogen atoms on the bridgehead carbon atoms 3a and (6+n)a have the cis or trans configuration relative to one another, wherein, in the case of the cis configuration, the carboxyl group or carbon atom 2 is oriented exo to the bicyclic ring system and wherein n denotes 0, 1 or 2, R1 denotes hydrogen, (C1 -C6 )-alkyl which can optionally be substituted by amino, (C1 -C4 )-acylamino or benzoylamino, (C2 -C6 )-alkenyl, (C5 -C9 )-cycloalkyl, (C5 -C9 )-cycloalkenyl, (C5 -C7 )-cycloalkyl-(C1 -C4 )-alkyl, aryl or partially hydrogenated aryl, which can, in each case, be substituted by (C1 -C4 )-alkyl, (C1 -C2 )-alkoxy or halogen, aryl-(C1 -C4 )-alkyl, which can be substituted as defined previously in the aryl radical, a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or of which 1 to 4 ring atoms are nitrogen atoms, or a side chain of a naturally occuring amino acid, R2 denotes hydrogen, (C1 -C6 )-alkyl, (C2 -C6 )-alkenyl or aryl-(C1 -C4 )-alkyl, R' denotes hydrogen, benzyl or tert. butyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen or Y and Z together denote oxygen, X denotes (C1 -C6 )-alkyl, (C2 -C6 )-alkenyl, (C5 -C9 )-cycloalkyl, aryl which can be mono-, di- or tri-substituted by (C1 -C4 )-alkyl, (C1 -C4 )-alkoxy, hydroxyl, halogen, nitro, amino, (C1 -C4 )-alkylamino, di-(C1 -C4 )-alkylamino or methylenedioxy, or indol-3-yl, and aryl denotes phenyl or naphthyl, and the physiologically acceptable salts thereof, excluding compounds of the formula I in which the hydrogen atoms on the bridgehead carbon atoms 3a and (6+n)a have the trans configuration relative to one another and wherein R1 denotes methyl, R2 denotes hydrogen, (C1 -C4 )-alkyl or benzyl, R' denotes hydrogen and X denotes phenyl and n, Y and Z are as defined above, as well as the salts thereof. 1. Claims for the Contracting State : AT A process for the preparation of a compound of the formula I  see diagramm : EP0170775,P23,F4  in which the hydrogen atoms on the bridgehead carbon atoms 3a and (6+n)a have the cis or trans configuration relative to one another, wherein, in the case of the cis configuration, the carboxyl group on carbon atom 2 is oriented exo to the bicyclic ring system and wherein n denotes 0, 1 or 2, R1 denotes hydrogen, (C1 -C6 )-alkyl, which can optionally be substituted by amino, (C1 -C4 )-acylamino or benzoylamino, (C2 -C6 )-alkenyl, (C5 -C9 )-cycloalkyl, (C5 -C9 )-cycloalkenyl, (C5 -C7 )-cycloalkyl-(C1 -C4 )-alkyl, aryl or partially hydrogenated aryl, which can, in each case, be substituted by (C1 -C4 )-alkyl, (C1 -C2 )-alkoxy or halogen, aryl-(C1 -C4 )-alkyl, which can be substituted as defined previously in the aryl radical, a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, of which 1 to 2 ring atoms are sulfur or oxygen atoms and/or of which 1 to 4 ring atoms are nitrogen atoms, or a side chain of a naturally occurring amino acid, R2 denotes hydrogen, (C1 -C6 )-alkyl, (C2 -C6 )-alkenyl or aryl-(C1 -C4 )-alkyl, R' denotes hydrogen, benzyl or tert. butyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen or Y and Z together denote oxygen, X denotes (C1 -C6 )-alkyl, (C2 -C6 )-alkenyl, (C5 -C9 )-cycloalkyl, aryl which can be mono-, di- or tri-substituted by (C1 -C4 )-alkyl, (C1 -C4 )-alkoxy, hydroxyl, halogen, nitro, amino, (C1 -C4 )-alkylamino, di-(C1 -C4 )-alkylamino or methylenedioxy, or indol-3-yl, and aryl denotes phenyl or naphthyl, and the physiologically acceptable salts thereof, excluding compounds of the formula I in which the hydrogen atoms on the bridgehead carbon atoms 3a and (6+n)a have the trans configuration relative to one another and wherein R1 denotes methyl, R1 denotes hydrogen, (C1 -C4 )-alkyl or benzyl, R' denotes hydrogen and X denotes phenyl and n, Y and Z are as defined above, as well as the salts thereof, which a) comprises reacting a compound of the formula II  see diagramm : EP0170775,P23,F2  wherein R1 , R2 , X, Y and Z have the meanings as in formula I, with a compound of the formula III  see diagramm : EP0170775,P23,F3  in which the hydrogen atoms on the carbon atoms 3a and (6+n)a have the cis or trans configuration relative to one another, wherein, in the case of the cis configuration, the group -CO2 W is oriented exo to the bicyclic ring system and wherein n denotes 0, 1 or 2 and W denotes a radical which can be cleaved off by hydrogenolysis or by acid, and subsequently cleaving off, if appropriate, the radical W and, if appropriate, the radical R2 to form the free carboxyl group(s), or b) for the preparation of compounds of the formula I in which Y and Z together denote oxygen, comprises b1 ) reacting a compound of the formula IV  see diagramm : EP0170775,P23,F5  in which the hydrogen atoms on the carbon atoms 3a and (6+n)a have the cis or trans configuration relative to one another, wherein, in the case of the cis configuration, the group -CO2 W is oriented exo to the bicyclic ring system, and wherein n and R1 have the meanings as in formula I and W has the meaning as in formula III, with a compound of the formula V, R2 O2 C-CH=CH-CO-X wherein R2 and X have the meanings as in formula I, and subsequently cleaving off, if appropriate, the radical W and, if appropriate, also the radical R2 to form the free carboxyl group(s), or b2 ) reacting a compound of the formula IV mentioned under b1 ) with a compound of the general formula VI wherein R2 has the meaning as in formula I, and with a compound of the general formula VII OHC-CO2 R2 X-CO-CH3 wherein X has the meaning as in formula I, and subsequently cleaving off, if appropriate, the radical W and, if appropriate, the radical R2 to form the free carboxyl group(s), or c) for the preparation of compounds of the formula I in which Y and Z each denote hydrogen, comprises c1 ) reacting a compound of the formula IV mentioned unter b1 ) with a compound of the formula VIII  see diagramm : EP0170775,P24,F1 wherein R2 and X have the meanings as in formula I, reducing the Schiff's bases obtained and subsequently cleaving off, if appropriate, the radical W and, if appropriate, the radical R2 to form the free carboxyl group(s), or c2 ) catalytically reducing with hydrogen a compound of the formula I in which Y and Z together denote oxygen, or d) for the preparation of compounds of the formula I in which Y denotes hydroxyl and Z denotes hydrogen, comprises reducing a compound of the formula I in which Y and Z together denote oxygen, catalytically with hydrogen or with a reducing agent, such as sodium borohydride, and converting the compounds obtained as in (a)-(d), if appropriate, into the physiologically tolerated salts thereof.