Patent GB-1428480-A (GB)
Title: Heterocyclic spiro compounds and processes for their production
IPC: C07D209/96
Filed: 1973-04-30
Abstract: 1428480 Spiro-norbornane (or bicyclo-[2.2.2]- octane)-2,3<SP>1</SP>-piperidines (or pyrrolidines) CIBAGEIGY AG 30 April 1973 [4 May 1972] 20454/73 Heading C2C The invention comprises spiro compounds having the general Formula I wherein R 1  represents hydrogen; C 1 -C 6  alkyl; C 3 -C 6  alkenyl; 2-propynyl; an optionally chlorine substituted hydroxyalkyl group in which the bonds to the ring nitrogen, to the hydroxy group and to the chlorine atom when present proceed from different carbon atoms and which contains up to six carbon atoms; a phenyl-C 1 -C 4  alkyl group optionally substituted in the ring by up to three substituents selected from halogen, C 1 -C 4  alkyl or C 1 -C 4  alkoxy; or a basic radical of Formula Ia in which alk represents a nongeminal, bivalent, saturated aliphatic C 2 -C 5  hydrocarbon radical or a 2-hydroxytrimethylene radical; R 2  and R 3  represent groups as defined for R 1  except for the radical of Formula Ia and can also represent a C 4 -C 6  polymethylene radical, optionally substituted by methyl groups, the ethylene oxyethylene radical, or a tetra or pentamethylene radical substituted in the 2-position by a tetramethylene, pentamethylene, 1,4-methanopentamethylene or 1,4-ethanopentamethylene group; m is 0 or 1 and n is 1 or 2 and their acid addition salts with inorganic and organic acids. The compounds of Formula I may be prepared by (a) reduction of a dicarboxylic acid imide of Formula II using a complex hydride or diborane; (b) reaction of a compound of Formula I in which R 1  is hydrogen with a reactive ester of a compound of formula wherein R<SP>1</SP> 1  is as defined above for R 1 , other than hydrogen; (c) reduction of a compound of Formula IV wherein R<SP>11</SP> 1  is a radical corresponding to the radicals defined for R 1  but having absent that -CH 2 - group which in R 1  is bonded to the ring nitrogen atom or a compound of formula V in which m<SP>1</SP> and n<SP>1</SP> each represent 0 or 1 and always are in total 1, alk<SP>11</SP> represents a bivalent saturated aliphatic hydrocarbon radical having (2-m<SP>1</SP>) to (5-m<SP>1</SP>) carbon atoms which is non- geminal when m<SP>1</SP> = 0 and R<SP>11</SP> 2  represents a radical lessened by the group -(CH 2 ) n - but otherwise corresponding to the definition of R 2  given above, or if n<SP>1</SP> = 1, is an alkoxy group, using a complex hydride; (d) reaction of a reactive ester of a compound of Formula VI with a compound of Formula VII or an alkali metal compound of a secondary amine of Formula VII; (e) reduction of a nitrile of Formula VIII wherein alk<SP>1</SP> represents a bivalent, saturated, aliphatic C 1 -C 4  hydrocarbon radical; (f) reaction of a compound of Formula Id with a reactive ester of a compound of Formula IX where R 3  is as defined above other than hydrogen or with formaldehyde in formic acid; (g) reaction of a compound of Formula I wherein R<SP>1</SP> = H with a compound of general Formula X wherein, R 4  represents H, an optionally chlorine substituted alkyl group having at most 4 carbon atoms or a methyl group substituted by NR 2 R 3 , R 5  represents H or, when R 4  is an alkyl group optionally substituted by chlorine, can be an alkyl group provided that R 4  plus R 5  contain at most 4 carbon atoms. 2 - Cyano - bicyclo - [2.2.2] - oct - 5 - en - 2- propionitrile and 2 - exo - cyano - 5 - norbornene- 2 - endopropionitrile are prepared by reacting 2-methyleneglutaronitrile with, respectively, 1,3-cyclo-hexadiene and cyclopentadiene, the dinitriles are reduced with hydrogen to obtain 2 - cyanobicyclo - [2.2.2] - octane - 2 - propionitrile and 2 - exocyanonorbornane - 2 - endopropionitrile, and these compounds are cyclized by heating with concentrated HCl to obtain spiro - [bicyclo - [2.2.2] - octan - 2,3<SP>1</SP> - piperidine]- 2<SP>1</SP>6<SP>1</SP> - dione and spiro - [norbornane - 2,3<SP>1</SP>- piperidine] - 2<SP>1</SP>,6<SP>1</SP> - dione respectively. 2 - Carboxy - 5 - norbornen - 2 - acetic acid is prepared as an epimer mixture by reaction of cyclopentadiene with methylene succinic acid and is esterified with ethanol to obtain 2- carboxy - 5 - norbornen - 2 - acetic acid ethyl ester as an epimeric mixture. Reaction of this mixture with KI/I 2  in alkaline solution yields 2 - endocarboxy - 5 - exo - iodo - 6 - endo - hydroxy- 2 - exo - norbornanacetic acid ethyl ester and 2 - exo - carboxy - 5 - norbornene - 2 - endo - acetic acid ethyl ester. The latter compound is hydrolysed to obtain 2-exo-carboxy-5-norbornen-2- endo-acetic acid, which is hydrogenated to obtain 2 - exo - carboxy - 2 - endo - norbornanacetic acid. Cyclization of this compound with ammonia yields (1RS, 2RS, 4RS) - spiro - [norbornane-2,3<SP>1</SP>-pyrrolidine-2<SP>1</SP>,5<SP>1</SP>-dione]. 2 - Endo - carboxy - 5 - norbornen - 2 - exoacetic acid ethyl ester is prepared by reaction of 2 - endo - carboxy - 5 - exo - iodo - 6 - endohydroxy - 2 - exo - norbornanacetic acid (see above) with zinc powder in acetic acid and is reacted by the same sequence of reactions as described immediately above to obtain (1RS, 2SR,4SR) - spiro - [norbornane - 2,3<SP>1</SP> - pyrrolidine- 2<SP>1</SP>,5<SP>1</SP>-dione]. I<SP>1</SP> - Chloroacetyl - spiro - [bicyclo - [2.2.2]- octan - 2,3<SP>1</SP>- piperidine] is prepared by reacting spiro - [bicyclo - [2.2.2] - octan - 2,3<SP>1 </SP>- piperidine] with chloroacetyl chloride and is then reacted with dimethylamine to obtain 1<SP>1</SP>-[2-(dimethylamino) - acetyl] - spiro - [bicyclo - [2.2.2] - octan- 2,3<SP>1</SP> - piperidine. In the same manner are prepared 1<SP>1</SP> - (2 - piperidino acetyl) - spiro- [bicyclo - [2.2.2] - octane - 2,3<SP>1</SP> - piperidine]; 1<SP>1</SP> - [2 - (1 - pyrrolidinyl) - acetyl] - spiro - [bicyclo - [2.2.2] - octan - 2,31 - piperidine]; 1<SP>1</SP>- [2 - (benzylmethylamino)- acetyl] - spiro - [bicyclo - [2.2.2] - octan - 2,3<SP>1</SP> - piperidine] and 1<SP>1</SP> - [2 - (2 - azaspiro - [5.5] - undec - 2 - yl)- acetyl] - spiro - [bicyclo - [2.2.2] - octan - 2,3<SP>1</SP>- piperidine]. I<SP>1</SP> - (3 - Chloropropionyl) - spiro - [bicyclo- [2.2.2] - octane - 2,3<SP>1</SP> - piperidine] is prepared by reaction of spiro[bicyclo[2.2.2]-octane-2,3<SP>1</SP>- piperidine] with 3 chloropropionyl chloride and is reacted with (1RS,2RS,4SR)-spiro[norbornane - 2,31 - piperidine] and N - methylbenzylamine to obtain, respectively, 1<SP>1</SP>-[3-(1RS,2RS,- 4SR) - spiro - [norbornane - 2,31 - piperidin) - 1<SP>1</SP>- yl) - propionyl] - spiro - [bicyclo - [2.2.2] - octan- 2,3<SP>1</SP> - piperidine] and l<SP>1</SP> - [3 - (benzylmethylamino) - propionyl] - spiro - [bicyclo - [2.2.2] - octan-2,3<SP>1</SP>-piperidine]. Spiro - [bicyclo - [2.2.2] - octan - 2,3<SP>1</SP> - piperidine] - 1<SP>1</SP> - aceto - nitrile is obtained by reacting spiro - [bicyclo - [2.2.2] - octan - 2,3<SP>1</SP> - piperidine] with chloroacetonitrile. Pharmaceutical compositions having antiviral activity for oral, rectal or parenteral application comprise a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier.