Patent GB-1154506-A (GB)
Title: 0-Substituted-3-Indenyl Aliphatic Amines and their preparation
IPC: C07D295/02
Filed: 1966-12-28
Abstract: 1,154,506. 1 - Substituted - 3 - indenyl aliphatic amines. MERCK & CO. Inc. 28 Dec., 1966 [30 Dec., 1965], No. 57942/66. Heading C2C. Novel 1 - substituted - 3 - indenyl aliphatic amines of the general formula wherein R 1  and R 2  are each a hydrogen atom or an alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or aralkyl radical that is substituted or unsubstituted and in which any aryl residue is carbocyclic or heteroeyclic, or R 1  and R 2  are joined to form, together with the carbon atom to which they are attached, a carbocyclic or heterocyclic radical; R 3  is a hydrogen or halogen atom or a hydroxy, alkyl, aryl, aralkyl, alkoxy, haloalkyl, alkylthio, arylthio, C 2-5  alkenyl, thienyl or (C 1-5  alkoxy)-phenyl radical; R 4  and R 5  are each a hydrogen atom or a C 1-5  alkyl, C 1-5  haloalkyl, (C 1-5  alkoxy)-C 1-5  alkyl, C 1-5  hydroxyalkyl, C 2-5  alkenyl, C 2-5  alkynyl, cyclopropyl-C 1-5  alkyl, cyclobutyl-C 1-5  alkyl, tetrahydrofurfuryl or C 3-6  cycloalkyl radical, or R 4  and R 5 , together with the nitrogen atom to which they are attached, form a morpholino, piperidino, piperazino, substituted piperazino, pyrrolidino or 1,2,5,6-tetrahydropyridino radical; each R 6  is a hydrogen or halogen atom or a C 1-5  alkyl, C 1-5  alkoxy, alkylthio, aryl, aryloxy or trifluoromethyl radical; and R 7  is a hydrogen or halogen atom or a hydroxy, C 1-5  alkyl, C 1-5  alkoxy, nitro, amino, C 1-5  alkylamino, di-(C 1-5  alkyl)-amino, C 1-6  alkanoylamino, C 1-6  alkanoyl, bis-(C 1-5  hydroxyalkyl)-amino, pyrrolidino, 4- methyl-1-piperazinyl, 4-morpholinyl, alkylsulphonyl, cyano, trifluoromethyl, di - (C 1-5  - alkyl)-sulphamoyl, benzylthio, benzyloxy, (C 1-5  alkyl)-benzyloxy, (C 1-5  alkoxy)-benzyloxy, halobenzyloxy, C 2-5  alkenyl, C 2-5  alkenyloxy, 1-azacyclopropyl, cyclopropyl-(C 1-5  alkoxy) or cyclobutyl-(C 1-5  alkoxy) radical, or R 6  and R 7  together form a C 1-5  alkylenedioxy or a benzo radical, provided that R 6  and R 7  are ortho to each other; and R 8  is a group of the formula -CHR 9 -, -CHR 9 -CHR 10 - or -CHR 9 - CHR 10 -CH 2 -, in which R 9  and R 10  are each a hydrogen atom or a C 1-5  alkyl, C 1-5  haloalkyl, benzyloxy-(C 1-5  alkyl), C 1-5  hydroxyalkyl, C 2-5  alkenyl, phenyl or C 2-5  alkynyl radical; and acid addition salts thereof are prepared (i) when R 8  is a -CHR 9 - group, by (a) condensing a #-aryl-propionic acid of the general formula to its corresponding indanone; (b) reacting said indanone with an α-halo-alkanoic ester of the general formula R 9 -CHX-COOE, wherein X is a halogen atom and E is an esterifying radical, to form a #-hydroxy-#-(3-indanyl)-alkanoic ester; (c) treating said indanyl ester with a dehydrating agent to form a 3-indenyl ester; (d) reacting said indenyl ester with a carbonyl compound of the general formula R 1 -CO-R 2  to produce a 1-substituted-3-indenyl ester; (e) hydrolysing said ester to an acid; (f) treating said acid with ammonia or an amine of the general formula NHR 4 R 5  to form an amide; and (g) subjecting said amide to a Hoffmann degradation: (ii) when R 8  is a -CHR 9 -CHR 10  group, by (a) condensing a #-aryl-propionic acid of the second general formula above to its corresponding indanone; (b) reducing said indanone to an indene; (c) reacting said indene with a 1-nitroalk-1-ene of the general formula R 9 CH= CR 10 NO 2  to form a #-(3-indenyl)-α-nitroalkane; (d) reducing said indenyl nitroalkane to an indenyl alkylamine; (e) condensing said amine with a carbonyl compound of the general formula R 1 -O-R 2  to produce a 1-substituted-3- indenyl imine; and (f) hydrolysing said imine to an amine; followed optionally by conversion of the terminal NH 2  group to a -NR 4 R 5  group by alkylation or an analogous procedure: or (iii) when R 8  is a -CHR 9 -CHR 10 -CH 2  group, by (a) condensing a #-aryl-propionic acid of the second general formula above to its corresponding indanone; (b) reducing said indanone to an indene; (c) reacting said indene with a 1-nitroalk-1-ene of the general formula R 9 CH=CR 10 - NO 2  to produce a #-(3-indenyl)-α-nitroalkane; (d) reducing said indenyl nitroalkane to its corresponding alcohol; (e) converting said alcohol to a nitrile; (f) reducing said nitrile to an amine; (g) condensing said amine with a carbonyl compound to produce a 1-substituted- 3-indenyl imine; and (h) hydrolysing said imine to an amine; followed optionally by conversion of the terminal NH 2  group to a -NR 4 R 5  group by alkylation or an analogous procedure; followed in either method by optional salification. Pharmaceutical compositions having antiinflammatory and anti-pyretic activity comprise, as active ingredient, a 1-substituted-3- indenyl aliphatic amine of the first general formula above or an acid addition salt thereof, together with an inert diluent, carrier or coating, and may be administered orally or parenterally.