Patent GB-1373239-A (GB)
Title: N-substituted-2-carboxy-1-azacyclic compounds
IPC: A61K31/445
Filed: 1971-11-16
Abstract: 1373239 N - (1 - Adamantyl) - 2 - carboxy -1- azacyclic compounds SCHERICO Ltd 16 Nov 1971 [17 Nov 1970] 53177/71 Heading C2C Novel N - (1 - adamantyl) - 2 - carboxy - 1- azacyclic compounds of the general formula wherein Ad is a 1-adamantyl group, n is 0 or 1-5, R<SP>1</SP> is a hydrogen atom or a C 1-6  alkyl, C 1-6  hydroxyalkyl or C 3-6  cycloalkyl group or one equivalent of a pharmaceutically acceptable cation, R<SP>2</SP> is a hydrogen atom or a C 1-6  alkyl, C 1-6  hydroxyalkyl or C 3-6  cycloalkyl group, each R<SP>3</SP> is as R<SP>2</SP> or an OR<SP>4</SP> group and R<SP>4</SP> is as R<SP>2</SP> or a C 1-7  alkanoyl group, provided that, when n is 2-5, vicinal R<SP>3</SP>s are not both an OR<SP>4</SP> group, and the dehydro derivatives thereof having at least one cis-double bond in the azacyclic ring in the (CHR<SP>3</SP>) n  moiety thereof when n is greater than 1, provided that carbon atoms carrying an OR<SP>4</SP> group are not doubly bonded to another carbon atom, and pharmaceutically acceptable acid addition salts of those compounds in which R<SP>1</SP> is a hydrogen atom or an alkyl, hydroxyalkyl or cycloalkyl group are prepared (i) by condensing a compound of the general formula wherein each R<SP>5</SP> is a hydrogen atom, a C 1-6  alkyl, hydroxyalkyl, alkoxy or hydroxyalkoxy group, a C 3-6  cycloalkyl or cycloalkyloxy group, or a hydroxy or acyloxy group, except that, when n is 2-5, vicinal R<SP>5</SP> groups are not both selected from hydroxy, alkoxy, hydroxyalkoxy, cycloalkyloxy and acyloxy groups, or a salt or ester thereof at the carboxyl group, or a dehydro derivative thereof, or of said salt or ester thereof, having at least one cis-double bond in the (CHR<SP>5</SP>) n  moiety when n is greater than 1, except that a carbon atom carrying an R<SP>5</SP> substituent selected from hydroxy, alkoxy, hydroxyalkoxy, cycloalkoxy and acyloxy groups cannot be doubly bonded to another carbon atom, with a compound of the general formula Ad-Y<SP>2</SP>, wherein either the two moieties Y<SP>1</SP> together represent an imino group and Y<SP>2</SP> is a reactive ester residue or each Y<SP>1</SP> is a reactive ester residue and Y<SP>2</SP> is an amino group; (ii) by cyclizing a compound of the general formula wherein one of Y<SP>3</SP> and Y<SP>4</SP> is -NH-Ad and the other is a reactive ester residue, or a salt or ester thereof at the carboxyl group, or a dehydro derivative thereof, or of said salt or ester thereof, having at least one cis-double bond in the (CHR<SP>5</SP>) n  moiety when n is greater than 1, except that a carbon atom carrying an R<SP>5</SP> substituent selected from hydroxy, alkoxy, hydroxyalkoxy, cycloalkoxy and acyloxy groups cannot be double bonded to another carbon atom; and (iii) when at least one R<SP>3</SP> is a hydroxy or C 1-7  alkanoyloxy group, by reducing a compound of the general formula or a salt or ester thereof at the carboxyl group, wherein Z is (CRR<SP>5</SP>) m (C=O)(CHR<SP>5</SP>) n-m-1 , where m is 0 or 1-4 and n is 1-5 and is greater than m; followed, if necessary, by one or more of the following finishing steps in any appropriate order: (a) deesterification at the carboxyl group, (b) deesterification at an acyloxy group R<SP>5</SP>, (c) esterification at the carboxyl group to introduce a C 1-6  alkyl or hydroxyalkyl or C 3-6  cycloalkyl group, (d) esterification of a hydroxy group R<SP>6</SP> to introduce a C 1-7  alkanoyl group, (e) separation of a mixture of isomers into its constituents, (f) hydrogenation of a compound having at least one double bond to the corresponding saturated compound (not applicable to (iii)) and (g) conversion of the product into a salt having a pharmaceutically acceptable cation or anion.  Cis - 5 - (N - 1 - Adamantylbenzamido)- 1- bromopent - 3 - ene - 1 - carboxylic acid is prepared by reacting 1-aminoadamantane and 1,4- dichlorobut - 2 - yne, reacting the resulting 1 - (1 - adamantylamino) - 4 - chlorobut - 2 - yne with benzoyl chloride, reacting the resulting 1- (N - 1 - adamantylbenzamido)- 4 - chlorobut - 2- yne with diethyl formamidomalonate in the presence of sodium hydride, hydrogenating the resulting diethyl 5 - (N - 1 - adamantylbenzamido) 1 - formamidopent - 3 - yne - 1,1- dicarboxylate in the presence of palladium-oncharcoal, refluxing the resulting diethyl cis-5- (N - 1 - adamantylbenzamido)- 1 - formamidopent - 3 - ene - 1,1 - dicarboxylate with sulphuric acid and treating the resulting cis-5-(N-1- adamantylbenzamido)- 1 - aminopent - 3 - ene - 1- carboxylic acid (in a sulphuric acid solution containing KBr at 0 C.) with sodium nitrite. (+) and (-)-1-(1-Adamantyl)-2-benzyloxy-carbonyl-azetidine are prepared by reacting d,l-1-(1- adamantyl) - 2 - methoxycarbonyl - azetidine with benzyl alcohol in the presence of sodium, reacting the obtained d,l-1-(1-adamantyl)-2- benzyloxycarbonyl-azetidine with d-camphor-10- sulphonic acid, fractionally crystallizing the resulting (+) and (-) salts and treating the separated salts with sodium bicarbonate. Pharmaceutical compositions having anti- Parkinsonism activity comprise, as active ingredient, at least one N-(1-adamantyl)-2-carboxy-1-azacyclic compound of the first general formula above or dehydro derivative or salt thereof (as defined above), together with a pharmaceutical carrier or excipient.