DE1695385A1 - Substituted aminophenyl acetic acids and processes for their preparation - Google Patents

Description

Substituted amine phenylacetic acids as well as process too. their manufacture.

It has been found that substituted aminophenylacetic acids of the formula 1 where R1 and R2 are identical or different and H or alkyl with 1 - 4 carbon atoms, R3 H, halogen, CF3, OH, NO2, CN, R7, R4 is a tetramethylene optionally containing 1-2 double bonds, R5 and R, are identical or different and are linear or branched alkyl with 1-7 C atoms or together a linear or branched alkylene chain with 1-14 C which is optionally interrupted by an oxygen or sulfur atom Atoms, R7 alkyl with 1 - 4 atoms, A COOA1, CONA2A3, CCNA4, C (= NOH) OH or C (OR7) 3, A1 H, optionally 1 to 2 CC multiple bonds and / or an OH and / or an NH2 group containing and / or interrupted by 0 one to three times and / or and / or branched alkyl or cycloalkyl with up to 12 0 atoms each, A5-NA4, phenyl or aralkyl with a total of 6-14 carbon atoms , A2 and A3 are identical or different and A A4 is an optionally interrupted by 0 or Y alkylene with up to 6 carbon atoms, A5 is alkylene with 1 - 6 carbon atoms and YS, NH, optionally substituted by OH N-alkyl with 1 - 6 0 atoms, N-phenyl or N-phenylalkyl with 7-10 C atoms mean, as well as you e salts with acids or optionally bases and their quertary ammonium salts and optionally their arhydrides have an excellent anti-inflammatory effect. which is accompanied by a good analgesic and antipyrotetic effect. For example, 4-piperidino-α-methyl-naphthyl-1-acetic acid was about 300 to 500 times more effective on UV erythema in guinea pigs than the known commercial preparation (p-isobutylphenyl acetic acid) with almost the same acute toxicity of the two substances mentioned at the mouse. Even against constitutionally not comparable, very effective and commercially available anti-inflammatory drugs, such as phenylbutazone (1,2-diphenyl-4-n-butyl-3,5-pyrazolidinedione) and indomethacin, (1-p-chlorobenzoyl-5-methoxy-indolyl -3-acetic acid). 4-piperidino-α-methyl-naphthyl-1-acetic acid has decisive advantages. The new compound according to the invention is about ten times as effective against phenylbutazone on UV erythema in guinea pigs with about the same acute toxicity on mice and against indomethacin three times as effective on UV erythema in guinea pigs with only about 1/25 of the acute toxicity the mouse.

4-Dipemndino-a-methyl-naphthyl-1-acetic acid methyl ester was found on UV erythema in guinea pigs about 100 to 200 times and in the analgesic grinding test in the mouse about three times as effective as Ibufenac with almost the same acute toxicity of the substances mentioned on the mouse. Also towards phenylbutazone and Indomethacin is the 4-piperidino-amethyl-naphthyl-l-acetic acid methyl ester considerably think. So is this new compound of the invention versus phenylbutazone in the analgesic grinding test on the mouse five times and on the W erythema of guinea pigs about three times as effective with slightly lower acute toxicity in the mouse and against it Indomethacin is equally effective on UV erythema in guinea pigs at only-about 1/25 acute toxicity in mice.

The invention thus relates to substituted aminophenylacetic acids of the formula I, in which R1 to R6 and A have the meaning given at the beginning, as well as ibre salts with acids or optionally bases and quaternary ammonium salts and optionally their anhydrides.

Selected groups of the compounds according to the invention are particularly the following: compounds of the formula I, in which R1, R3, R5, R6 and h are the one meaning given, R3 is in the o-position to the NR5R6 group and R4 is butadiene- (1,3) -ylene mean.

Compounds of the formula I in which R1 is preferably. Methyl, methyl or n-propyl, R2 H, R3 is in the o-position to the -NR5R6 group and halogen, preferably C1 or Br, NO2, SCH3, SC2H5 or alkyl with 1 - 4 carbon atoms or H, R4 butadiene- (1,3) -ylene, A mean COOA1 and R5 and R6 have the meaning given at the beginning.

Compounds of the formula in which R1 to R4 and A are those given at the outset Have meaningiin0T and R5 and R6 together, optionally one or two times mean pentamethylene chain substituted by alkyl having 1 to 4 carbon atoms.

Compounds of the formula 1 in which R1 to R3 and A are those given at the outset Have meaning, R4 butadiene- (1,3) -ylene and R5 and R6 together one optionally Pentamethylene chain monosubstituted or disubstituted by alkyl having 1 to 4 carbon atoms mean.

Compounds of the formula I in which R4 is preferably methyl, ethyl or n-propyl, R2 H, R3 is in the o-position to the NR5R6 group and halogen, preferably Cl or Br, NO2, SCH3, SC2H5 or alkyl with 1 - 4 carbon atoms or H, R4 butadiene- (1,3) -ylene, R5 and R6 together optionally once or twice by alkyl having 1 to 4 carbon atoms substituted pentamethylene chain and A is COOA1.

Compounds of the formula 1 in which R1 to R4 and A are those given at the beginning Have meaning and R5 and R6 together, optionally once or twice Alkyl with 1 to 4 carbon atoms denotes hexamethylene chain substituted.

Compounds of the formula I in which R1 to R3 and A are those given at the outset Have meaning, R4 butadiene- (1,3) -ylene and R5 and R6 together one optionally Hexamethylene chain substituted once or twice by alkyl with 1 to 4 carbon atoms mean.

Compounds of the formula I in which R1 is preferably methyl, ethyl or n-propyl, R2 H, R3 is in the o-position to the NR5R6 group and Halegen, preferably Cl or Br, NO2, SCH3, SO2H5 or alkyl with 1 - 4 carbon atoms or H, R4 butadiene- (1,3) -ylene, R5 and R6 together, optionally one or two times hexamethylene chain substituted by alkyl having 1 to 4 carbon atoms and A is COOA1.

Compounds of the formula I in which R1 to R4 and A are those given at the outset Have meaning and 5 and R6 together ennE optionally once or twice Alkyl with 1 to 4 carbon atoms mean tetramethylene chain.

Compounds of the formula 1 in which R1 to R3 and A are those given at the outset Have meaning, R4 3utadien- (1'3) -ylen and R5 and R6 together one optionally Tetramethylene chain mono- or disubstituted by alkyl having 1 to 4 carbon atoms mean.

Y compounds of the formula I in which R1 is preferably methyl, ethyl or n-Propyl, R2 H, R3 is in the o-position to the NR5R6 group and Halogen, preferably Cl or Br, NO2, SCH3, SC2H5 or alkyl with 1 - 4 carbon atoms or H, R4 butadiene- (1,3) -ylene, R5 and R6 together, optionally one or two times tetramethylene chain substituted by alk with 1 to 4 carbon atoms and A denotes COOA1.

Compounds of the formula I in which R1 to R4 and A are those given at the outset Have meaning and R5 and R6 together, optionally once or twice Mean alkyl having 1 to 4 carbon atoms substituted 3-oxapentamethylene chain.

Compounds of the formula I in which R1 to R3 and A are those given at the outset Have meaning, R4 butadiene- (1, 3) -ylene and R5 and R6 together one optionally 3-oxapentamethylene-1-chain substituted one or two times by alkyl having 1 to 4 carbon atoms mean.

Compounds of the formula I in which R1 is preferably methyl, ethyl or n-Propyl, R2 H, R3 is in the o-position to the NR5R6 group and Halogen, preferably Cl or Br, NO2, SCH3, SO3H5 or alkyl with 4 carbon atoms or H, R4 Butadiene- (1,3) -ylene, R5 and R6 together, optionally once or twice Alkyl having 1 to 4 carbon atoms is a 3-oxapentamethylene chain and A is COOA1.

Compounds of the formula I in which R1 to R4 and A are those given at the outset Have meaning and, R5 and R6 together, optionally once or twice Mean alkyl with 1 to 4 carbon atoms substituted 3-thia-pentamethylene chain.

Compounds of the formula I in which R1 to R3 and A are those given at the outset Have meaning, R4 butadiene- (1,3) -ylene and R5 urrd R6 together an optionally 3-thia-penta-methylene chain mono- or disubstituted by alkyl having 1 to 4 carbon atoms mean.

Compounds of the formula I in which R1 is preferably methyl, ethyl or n-Propyl, R2 H, R3 is in the o-position to the NR5R6 group and Halogen, preferably Cl or Br, @@@, sCH3, SO2H5 or alkyl with 14 carbon atoms or H, R4 Butadiene- (1,3) -ylene, R and R together one optionally one-5 6 or two times substituted by alkyl having 1 to 4 carbon atoms 3-thia-penta-methylene chain and A COOA1 mean.

Compounds of the formula I in which R1 to R4 and A are those given at the outset Have meaning and R5 and R6 together, optionally once or twice Mean alkyl with 1 to 4 carbon atoms substituted 3-oxa-hexamethylene chain.

Compounds of the formula I in which R1 to R5 and h are those given at the outset Have meaning, R4 butadiene- (1,3) -ylene and R5 and R6 together one optionally 3-oxa-hexamethylene chain mono- or disubstituted by alkyl having 1 to 4 carbon atoms mean.

Compounds of the formula I in which R1 is preferably methyl, ethyl or n-propyl, R2 H, R3 is in the o-position to the NR5R6 group and halogen, preferably Cl or Br, NO2, SCH3, SC3H5, or alkyl with 1 - 4 carbon atoms or H, R4 Butadiene- (1,3) -ylene, R5 and R6 together, optionally once or twice Alkyl having 1 to 4 carbon atoms is a 3-oxa-hexamethylene chain and A is COOA1.

Compounds of the formula I in which R1 to R4 and A are those given at the outset Have meaning and R and R6 together are optionally single or double Alkyl is 3-thiahexamethylene chain substituted with 1 to 4 carbon atoms.

Compounds of the formula I in which R1 to R3 and A are those given at the outset Have meaning, R4 butadiene- (1,3) -ylene and R and R together one optionally 3-thiahexamethylene chain mono- or disubstituted by alkyl having 1 to 4 carbon atoms mean.

Compounds of the formula I in which R1 is preferably methyl, ethyl or n-Propyl, R2 H, R3 is in the o-position to the NR5R6 group and Halogen, preferably C1 or Br, NO2, SCH3, SC2H3 or alkyl iiif t. 1 - 4 carbon atoms or H, R4 butadiene- (1,3) -ylene, R5 and R6 together, optionally one or two times 3-thiahexamethylene chain substituted by alkyl having 1 to 4 carbon atoms and A COOA1 mean.

Compounds of the formula I in which R1 to R4 and A are those given at the outset Have meaning and R5 and R6 are identical or different and are alkyl with 1 to 6 carbon atoms mean.

Compounds of the formula I, in which R1 to R3 and A are as stated at the outset 3deanung port, R4 1,3-butadiene- (1,3) -ylene and R5 and R6 are identical or different are and are alkyl with 1 - 6 carbon atoms.

Compounds of the formula I in which R1 is preferably methyl, ethyl or n-Propyl, R2 H, R3 is in the o-position to the NR5R6 group and Halogen, preferably Cl or Br, NO2, SCH3, SC2H5 or alkyl with 1 - 4 carbon atoms or H, R4 butadiene- (1,3) -ylene, R5 and R6 are identical or different and are alkyl with 1-6 C atoms and A denote COOA1 and their salts with acids or, if appropriate, bases and quaternary ammonium salts. and optionally their anhydrides.

The following individual compounds are intended to characterize the invention in more detail: 4-di-n-butylamino-3-chloro-naphthyl-1-acetic acid 4-piperidino-naphthyl-1-acetic acid 4-piperidino-3-fluoro-naphthyl-i-acetic acid. 4-piperidino-3-chloro-naphthyl-1-acetic acid 4-piperidino-3-methyl-naphthyl-1-acetic acid 4-piperidino-3-amino-naphthyl-1-acetic acid 4-piperidino-2-chloro-naphthyl-1-acetic acid 4-piperidino-2-methyl-naphthyl-1-acetic acid 4-piperidino-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-fluoro-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-bromo-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-iodo-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-hydroxy-a-methyl-naphthyl-1-acetic acid 4-piperidino-3-trifluoromethyl-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-nitro-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-amino-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-cyano-a-methyl-1laphthlyl-1-acetic acid 4-piperidino-3-sulfamoyl-a-methyl-napIltllyl-1-acetic acid 4-piperidino-3-methyl-a-methyl-naphthyl-1-acetic acid 4-piperidino-3-metlloxy-a-methyl-naphthlyl-1-acetic acid 4-piperidino-3-methylmercapto-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-methylamino-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-dimethylamino-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-methylsulfamoyl-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-diethylsulfamoyl-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-acetylamino-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-methylsulfonyl-α-methyl-naphthyl-1-acetic acid 4-piperidino-3-methylsulfonyl-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-bromo-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-chloro-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-nitro-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-amino-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-methyl-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-methoxy-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-methylmercapto-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-methylamino-α-methyl-naphthyl-1-acetic acid 4-piperidino-2-diethylamino-α-methyl-naphthyl-1-acetic acid 4-piperidino-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-bromo-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-chloro-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-nitro-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-amino-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-methyl-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-ethoxy-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-methylmercapto-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-ethylamino-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-dimethylamino-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-bromo-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-chloro-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-nitro-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-amino-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-methyl-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-methoxy-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-methylmercapto-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-dimethylamino-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-chloro-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-3-bromo-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-3-nitro-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-3-amino-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-3-methyl-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-3-methoxy-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-3-methylmercapto-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-3-diethylamino-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-2-chloro-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-2-bromo-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-2-nitro-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-2-amino-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-2-methyl-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-2-methoxy-α-n-propyl-naphthyl-1-acetic acid 4-piperidino-α, α-dimethyl-naphthyl-1-acetic acid 4-piperidino-3-chloro-α, α-dimethyl-naphthyl-1-acetic acid 4-piperidino-3-bromo-α, α-dimethyl-naphthyl-1-acetic acid 4-piperidino-2-chloro-α, α-dimethyl-naphthyl-1-acetic acid 4-piperidino-α-methyl-α-ethyl-naphthyl-1-acetic acid 4-piperidino-3-chloro-α-methyl-α-ethyl-naphthyl-1-acetic acid 4-piperidino-2-chloro-α-methyl-α-ethyl-naphthyl-1-acetic acid 4-pyrrolidino-3-chloro-naphthyl-1-acetic acid 4-pyrrolidino-3-nitro-naphthyl-1-acetic acid 4-pyrrolidino-3-methyl-naphthyl-1-acetic acid 4-pyrrolidino-2-chloro-naphthyl-1-acetic acid 4-pyrrolidino-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-3-chloro-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-3-bromo-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-3-nitro-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-3-methyl-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-3-methylmercapto-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-2-chloro-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-2-bromo-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-2-nitro-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-2-methyl-α-methyl-naphthyl-1-acetic acid 4-pyrrolidino-2-methoxy-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-naphthyl-1-acetic acid 4-homopiperidino-3-chloro-naphthyl-1-acetic acid 4-homopiperidino-3-bromo-naphthyl-1-acetic acid 4-homopiperidino-3-nitro-naphthyl-1-acetic acid 4-homopiperidino-3-methyl-naphthyl-1-acetic acid 4-homopiperidino-2-chloro-naphthyl-1-acetic acid 4-homopiperidino-2-bromo-naphthyl-1-acetic acid 4-homopiperidino-2-nitro-naphthyl-1-acetic acid 4-homopiperidino-2-methyl-naphthyl-1-acetic acid 4-homopiperidino-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-3-chloro-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-3-bromo-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-3-nitro-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-3-methyl-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-2-chloro-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-2-bromo-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-2-nitro-α-methyl-naphthyl-1-acetic acid 4-homopiperidino-2-methyl-α-methyl-naphthyl-1-acetic acid 4-morpholino-naphthyl-1-acetic acid 4-morpholino-3-chloro-naphthyl-1-acetic acid 4-morpholino-α-methyl-naphthyl-1-acetic acid 4-morpholino-3-chloro-α-methyl-naphthyl-1-acetic acid 4-morpholino-2-chloro-α-methyl-naphthyl-1-acetic acid 4-morpholino-2-nitro-α-methyl-naphthyl-1-acetic acid 4-morpholino-2-methyl-α-methyl-naphthyl-1-acetic acid 4-thiomorpholino-naphthyl-1-acetic acid 4-thiomorpholino-3-chloro-naphthyl-1-acetic acid 4-Thiomorpholino-α-methyl-naphthyl-1-acetic acid 4-Thiomorpholino-3-chloro-α-methyl-naphthyl-1-acetic acid 4-thiomorpholino-3-bromo-α-methyl-naphthyl-1-acetic acid 4-thiomorpholino-3-nitro-α-methyl-naphthyl-1-acetic acid 4-thiomorpholino-3-methyl-α-methyl-naphthyl-1-acetic acid 4-thiomorpholino-2-chloro-α-methyl-naphthyl-1-acetic acid 4-thiomorpholino-2-methyl-α-methyl-naphthyl-1-acetic acid, 4-piperidino-3-chloro-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-bromo-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-nitro-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-ethylmercapto-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-chloro-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-bromo-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-nitro-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-nitro-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-3-amino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-3-methoxy-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-2-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-nitro-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-2-amino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-α-ethyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-chloro-α-ethyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-bromo-α-ethyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-3-nitro-α-ethyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-3-amino-α-ethyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-chloro-α-ethyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-bromo-α-ethyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-2-nitro-α-ethyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-piperidino-2-amino-α-ethyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-2-methyl-α-ethyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-pyrrolidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-pyrrolidino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-pyrrolidino-3-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-pyrrolidino-3-nitro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-pyrrolidino-3-amino-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-pyrrolidino-3-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-pyrrolidino-2-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-pyrrolidino-2-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-pyrrolidino-2-nitro-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-pyrrolidino-2-amino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-pyrrolidino-2-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-homopiperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-homopiperidino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-homopiperidino-3-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-homopiperidino-2-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-homopiperidino-2-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-morpholino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-morpholino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-morpholino-3-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-morpholino-2-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-morpholino-2-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-morpholino-2-amino-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-thiomorpholino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-thiomorpholino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-thiomorpholino-3-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-thiomorpholino-3-nitro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-thiomorpholino-3-amino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid 4-thiomorpholino-3-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (+) - 4-Piperidino-3-chloro-α-methyl-naphthyl-1-acetic acid (-) - 4-Piperidino-3-chloro-α-methyl-naphthyl-1-acetic acid (+) - 4-Piperidino-3-bromo-α-methyl-naphthyl-1-acetic acid (-) - 4-Piperidino-3-bromo-α-methyl-naphthyl-1-acetic acid (+) - 4-Piperidino-3-methyl-α-methyl-naphthyl-1-acetic acid (-) - 4-Piperidino-3-methyl-α-methyl-naphthyl-1-acetic acid (+) - 4-Piperidino-3-nitro-α-methyl-naphthyl-1-acetic acid (-) - 4-Piperidino-3-nitro-α-methyl-naphthyl-1-acetic acid (+) - 4-Homopiperidino-3-chloro-α-methyl-naphthyl-1-acetic acid (-) - 4-Homopiperidino-3-chloro-α-methyl-naphthyl-1-acetic acid (+) - 4-homopiperidino-3-bromo-α-methyl-naphthyl-1-acetic acid (-) - 4-Homopiperidino-3-bromo-α-methyl-naphthyl-1-acetic acid (+) - 4-homopiperidino-3-methoxy-α-methyl-naphthyl-1-acetic acid (-) - 4-Homopiperidino-3-methoxy-α-methyl-naphthyl-1-acetic acid (+) - 4-pyrrolidino-3-chloro-α-methyl-naphthyl-1-acetic acid (-) - 4-Pyrrolidino-3-chloro-α-methyl-naphthyl-1-acetic acid (+) - 4-pyrrolidino-3-methyl-α-methyl-naphthyl-1-acetic acid (-) - 4-Pyrrolidino-3-methyl-α-methyl-naphthyl-1-acetic acid (+) - 4-morpholino-3-chloro-α-methyl-naphthyl-1-acetic acid (-) - 4-Morpholino-3-chloro-α-methyl-naphthyl-1-acetic acid (+) - 4-piperidino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1 -acetic acid (-) - 4-Piperidino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (+) - 4-Piperidino-3-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-Piperidino-3-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (+) - 4-Piperidino-3-amino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-Piperidino-3-amino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (+) - 4-Pyrrolidino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-Pyrrolidino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (+) - 4-Homopiperidino-3-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-Homopiperidino-3-bromo-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (+) - 4-Homopiperidino-3-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-Homopiperidino-3-methyl-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (+) - 4-Morpholino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-Morpholino-3-chloro-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (+) - 4-Piperidino-α-methyl-naphthyl-1-acetic acid (-) - 4-Piperidino-α-methyl-naphthyl-1-acetic acid (+) - 4-Homopiperidino-α-methyl-naphthyl-1-acetic acid (-) - 4-Homopiperidino-α-methyl-naphthyl-1-acetic acid (+) - 4-Pyrrolidino-α-methyl-naphthyl-1-acetic acid (-) - 4-Pyrrolidino-α-methyl-naphthyl-1-acetic acid (+) - 4-Morpholino-α-methyl-naphthyl-1-acetic acid (-) - 4-Morpholino-α-methyl-naphthyl-1-acetic acid (+) - 4-Piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid (+) - 4-Morpholino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-morpholino-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid (+) - 4-Homopiperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-homopiperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid (+) - 4-Pyrrolidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid (-) - 4-pyrrolidino-α-methyl-5,6,7,8-tetrahydro-naphthyl -1-acetic acid 4-piperidino-α-methyl-5,6-dihydro-naphthyl-1-acetic acid 4-piperidino-α-methyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-α-ethyl-5,6-dihydro-naphthyl-1-acetic acid 4-piperidino-α-ethyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-α-ethyl-7,8-dihydro-naphthyl-1-acetic acid 4-piperidino-3-chloro-α-methyl-5,6-dihydro-naphthyl-1-acetic acid 4-piperidino-3-bromo-α-methyl-5,6-dihydro-naphthyl-1-acetic acid 4-piperidino-3-methyl-α-methyl-5,6-dihydro-naphthyl-1-acetic acid 4-piperidino-3-chloro-α-methyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-3-bromo-α-methyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-3-methyl-α-methyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-3-chloro-α-methyl-7,8-dihydro-naphthyl-1-acetic acid 4-piperidino-3-bromo-α-methyl-7,8-dihydro-naphthyl-1-acetic acid 4-piperidino-3-methyl-α-methyl-7,8-dihydro-naphthyl-1-acetic acid 4-piperidino-3-amino-α-methyl-7,8-dihydro-naphthyl-1-acetic acid 4-piperidino-2-chloro-α-methyl-5,6-dihydro-naphthyl-1-acetic acid 4-piperidino-2-bromo-α-methyl-5,6-dihydro-naphthyl-1-acetic acid 4-piperidino-2-methyl-α-methyl-5,6-dihydro-naphthyl-1-acetic acid 4-piperidino-2-chloro-α-methyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-2-amino-α-methyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-2-methyl-α-methyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-2-bromo-α-methyl-5,8-dihydro-naphthyl-1-acetic acid 4-piperidino-2-methyl-α-methyl-7,8-dihydro-naphthyl-1-acetic acid 4-Piperidino-2-methoxy-α-methyl-7,8-dihydro-naphthyl-1-acetic acid, 4-piperidino-α-methyl-naphthyl-1-acetic acid, methyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid ethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid n-propyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid n-butyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid n-pentyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid-n-hexyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid-n-dodecyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid-iso-butyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid-iso-amyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid ethyl ester hydrochloride 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid methyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid ethyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid n-propyl ester 3-Chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-n-hexyl ester 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid-ethyl ester 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid ethyl ester, 4-piperidino-α-ethyl-naphthyl-1-acetic acid ethyl ester 4-homopiperidino-α-ethyl-naphthyl-1-acetic acid-ethyl ester (+) - 4-piperidino-α-methyl-naphthyl-1-acetic acid-ethyl ester (-) - 4-Piperidino-α-methyl-naphthyl-1-acetic acid ethyl ester, 4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid ethyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid crotyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid propargyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-hydroxyethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-methoxyethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid 5'-hydroxyethyl ester, 4-piperidino-α-methyl-naphthyl-1-acetic acid 5'-methoxyethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-5'-butoxy-pentyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-3 ', 6'-dioxa-8'-hydroxyoctyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid crotyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid propargyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-hydroxyethyl ester 3-Chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 5'-methoxypentyl ester 3-Bromo-4-piperidino-α-methyl-naphthyl-acetic acid crotyl ester 3-Methyl-4-piperidino-α-methylnaphthyl-1-acetic acid propargyl ester 3-Bromo-4-peridino-α-methyl-naphthyl-1-acetic acid-2'-hydroxyethyl ester, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-methoxyethyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 3 ', 6'-dioxa-3'-hydroxy-octyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-amino-ethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-3'-amino-propyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-dimethylaminoethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-diethylaminoethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-di-n-propylaminoethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid 3'-dimethylaminopropyl ester, 4-piperidino-α-methyl-naphthyl-1-acetic acid 3-diethylaminopropyl ester 4-Piperidino-α-methylonaphthyl-1-acetic acid 2'-methyl-3'-diethylamino-propyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-aminoethyl ester 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-aminoethyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-dimethylamino-ethyl ester 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-dimethylamino-ethyl ester 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-dimethylamino-ethyl ester 4-piperidino-α-ethyl-naphthyl-1-acetic acid 2'-dimethylaminoethyl ester, 4-homopiperidino-α-methyl-naphthyl-1-acetic acid 2'-dimethylamino-ethyl ester 4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid-2'-dimethylamino-ethyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-diethylamino-ethyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 3'-diethylamino-propyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-methyl-3'-diethylamino-propyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid cyclohexyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid cyclopentyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-cyclohexylethyl ester, 4-piperidino-α-methyl-naphthyl-1-acetic acid 3'-cyclohexylpropyl ester 3-Chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid cyclohexyl ester 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid cyclopentyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-cyclohexyl-ethyl ester 3-Chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 3'-cyclohexyl-propyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid (1'-methyl-piperidyl-4 ') ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid (1'-methyl-piperidhyl-3 ') methyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid 2 '- (1 "-methyl-piperidyl-2") -ethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-piperidino-ethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-pyrrolidino-ethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-homopiperazinoethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-morpholinoethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-thiomorpholinoethyl ester 4-piperidino-α-methyl-naphhyl-1-acetic acid-2 '- (N'-methylpiperazi @) - ethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2 '- (N'-phenylpiperazino) -ethyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid-2 '(N'-2 "-hydroxyethyl-piperazino) -ethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-piperidinopropyl ester, 4-piperidino-α-methyl-naphthyl-1-acetic acid 3'-pyrrolidinopropyl ester 4-Piperidino-α-methyl-naphthyl-1-acetic acid 3 '- (N'-methylpiperazino) propyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-piperidino-ethyl ester 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-piperidinoethyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-pyrrolidino-ethyl ester 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-pyrrolidino-ethyl ester 4-piperidino-α-ethyl-naphthyl-1-acetic acid 2'-piperidino-ethyl ester, 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-morpholinoethyl ester 3-Chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2 '- (N'-methylpiperazino) ethyl ester 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid 2 '- (N'-phenylpiperazino) ethyl ester 3-Methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-piperidino-propyl ester 3-Chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 3'-pyrrolidino-propyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid phenyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-o-methyl-phenyl ester, 4-piperidino-α-methyl-naphthyl-1-acetic acid-benzyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid-2-phenylethyl ester, 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid phenyl ester 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid-o-methylphenyl ester, 3-chloro-4-piperidine-α-methyl-naphthyl-1-acetic acid benzyl ester 4-piperidino-α-ethyl-naphthyl-1-acetic acid benzyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-phenylethyl ester 4-homopiperidino-α-methyl-naphthyl-1-acetic acid-2'-phenylethyl ester 4-piperidino-α-methyl-naphthyl-1-acetic acid amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-dimethylaminoethyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-diethylamino-ethyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-methylthioethyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-dimethylamino-propyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-diethylamino-propyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-hydroxyethyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N, N-bis- (2'-hydroxyethyl) -amid 4-piperidino-α-methyl-naphthyl-1-acetic acid-N-methyl-N- (2'-dimethylamino-ethyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N-methyl-piperazide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N-phenyl-piperazide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-hydroxyethyl) piperazide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-piperidinoethyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-pyrrolidinoethyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-morpholinoethyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- [2 '- (N'-methylpiperazine ethyl] amide 4-piperidino-α-methyl-naphthyl-1-acetic acid N- [2 '- (N'-phenylpiperazino) ethyl] amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-piperidinopropyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-pyrrolidinopropyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-morpholinopropyl) -amide 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- [3 '- (N'-phenylpiperazino) propyl] amide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid amide 4-homopieridino-α-ethyl-naphthyl-1-acetic acid amide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-dimethylamino-ethyl) -amide 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-dimethylamino-ethyl) -amide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-diethylamino-ethyl) -amide 3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid-N- (2'-diethylamino-ethyl) -amide 4-piperidino-α-ethyl-naphthyl-1-acetic acid-N- (2'-diethylaminoethyl) -amide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-methylthio- ethyl) amide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-dimethylamino-propyl) -amide 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-diethylamino-propyl) -amide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-hydroxyethyl) -amide 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-hydroxy - @@@@@) - amide 3-chloro-4-homopiperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-hydroxyethyl) -amide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N, N-bis- (2'-hydroxyethyl) -amide 4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid-N, N-bis (2'-hydroxyethyl) -amide 3-chloro - @ - piperidino-α-methyl-naphthyl-1-acetic acid-N-methyl-N- (2'-dimethylamino-ethyl) -amide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N-methylpiperazide 3-bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid-N-ethylpiperazide 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid-N-phenylpiperazide 4-piperidino-α-ethyl-naphthyl-1-acetic acid-N-phenylpiperazide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-hydroxyethyl) piperazide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-piperidino-ethyl) -amide 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-pyrrolidino-ethyl) -amide 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2'-morpholino-ethyl) -amide 3-Chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-piperidino-propyl) -amide 3-Bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (3'-N'-phenylpiperazino-propyl) -amide 4-piperidino-α-methyl-naphthyl-1-acethydroxamic acid 3-chloro-4-piperidino-α-methyl-naphthyl-acethydroxamic acid 4-piperidino-α-methyl-naphthyl-orthoacetic acid triethyl ester 3-chloro-4-piperidino-α-methyl-naphthyl-orthoacetic acid triethyl ester, and their salts with acids or optionally bases and quaternary ammonium salts and optionally their anhydrides.

The invention is further characterized by: -Pharmaceutical preparations, containing an effective dose of a compound of the formula I in addition to customary carrier and additives; pharmaceutical preparations containing 1 to 2000 mg of one Compound of formula 1 in addition to the usual carriers and additives; Drug, characterized by a content of a compound of the formula I.

The procedure was to achieve an analgesic and / or antipyretic and / or anti-inflammatory effect in bebevesen, characterized in that an effective dose of a compound of formula I is administered.

The invention also relates to processes for the preparation of substituted aminophenylacetic acids of the formula I wherein Itil the rest of R4 1 R3 and R1 to R6 and A have the meaning given at the beginning, as well as their salts with acids or optionally bases and quaternary ammonium salts and optionally their anhydrides, which consist in the fact that carboxylic acids of the formula I are to be obtained in which A 00H means functional acid derivatives of such carboxylic acids, such as, in particular, amides, thioamides, thioesters, esters, IIydrazides, acid halides, azides, anhydrides, iminoesters, amidines, hydroxamic acids, nitriles, trihalomethanes, acid iminohalides, saponified in a neutral, acidic or alkaline medium or, in particular, tert .Alkyl esters, such as tert. Butyl ester, thermolytically decomposed or b) compounds of the formula II where Z, R1 and R2 have the meaning given above and L is a group which can be oxidized to a carboxyl group, such as in particular -CHo, CH2OH, CH3, 1-alkenyl, ti ny L, 12-1) hydroxyalkyl or 1-oxo-alkyl , oxidized or c) a diazoketone of the formula III where Z and R1 have the meaning given at the beginning, under the usual conditions of a Wolff rearrangement in the presence of water, A1OH, A2A3NH, A4NH or NH2OH, where A1 to A4 have the meaning given above, rearranges or d) an organometallic compound of the formula IV where hl is metal, in particular alkali metal, Cd-R7, Zn-R7 or Mg-halogen and Z, R1, R2 and R7 have the meaning given at the beginning, reacts with carbon dioxide or @) a haloketone of the formula V It, 1 Z-CO-CI: n lied I. R2 in which Z, R1 and R2 have the meaning given above and halogen means chlorine, bromine or iodine rearranges under the usual conditions of a Faworskij rearrangement or i ') a compound of the formula VI or VII where Z, R1 and R2 have the meaning given at the beginning and M has the meaning given in section d) and B1 is OH, esterified OH, OM, Cl, Br or J and RA are alkyl with 1-4 carbon atoms substituted by B1, with carbon monoxide or g) a malonic acid derivative of the formula VIII in which Z, R1 and A have the meaning given at the beginning, decarboxylated or h) a β-kotosäurederivat of the formula IX in which A, Z and R have the meaning given at the beginning and R8 is acyl or a hydrocarbon radical, subject to acid cleavage or i) a compound of the formula I in which one or more groups and / or CC multiple bonds which can be replaced or reducible by hydrogen are also present such as in particular those compounds of the formula I in which up to R7 and A have the meaning given at the beginning and one or more halogen atoms and / or one or more OH, SII, NH2 and / or OH, SH substituted by hydrocarbon radicals or NH2 groups and / or one or more C =O and / or C =S groups and / or one or more C =N and / or C =C double bonds and / or C @C triple bonds and / or in which R1 and R2 together denote 0 or S or an alkylidene group with 1-4 carbon atoms or in which R1 denotes halogen, OH, SH, NH2 or OH, SH or NH @ substituted by hydrocarbon radicals and / or in which the Benzene nucleus additionally in 2- or 3- Position and / or in which R4 - if R4 is butadien-1,3-ylene - carry halogen atoms and / or diazonium salt groups in the 1-, 2-, 3- or 4-position and / or in which A is a benzyl ester or - amide or benzyl equivalent ester or amide grouping which can be converted hydrogenolytically into the carboxyl group or the -CONHA1 group, where A has the meaning given at the beginning, or a compound of the formula X Z1 - R9 X a cin anion, R10 alkylidene with 1 -? C atoms and R11 denote alkyl with 1-7 C atoms, R1 to R6 and A have the meaning given at the beginning and R10 and R1 contain one or more C = C double or C # C triple bonds and also directly with one another can be pre-bonded via an oxygen or sulfur atom, treated with hydrogen-donating agents or catalytically activated hydrogen or j) a compound of the formula XI with a compound of the formula XII or a compound of the formula XIII with a compound of the formula XIV wherein Z, R2 and R7 have the meaning given at the beginning and M has the meaning given in section d) and X is a radical which can be split off with M as MX, in particular halogen, a sulfuric acid or sulfonic acid radical, or k) a compound of the formula XV with a Compound of the formula XVI or a compound of the formula XVII with a compound of the formula XVIII in which R1, R2, Z and A are as defined at the outset and M and X are as defined in sections d) and;) and Q is II or M, optionally reacts or in the presence of a Friedel-Crafts catalyst R5-NH-Z1 XXII R5-X1 XXIV R6NH-Z1 XXIII R6-X1 XXV and where R5 and R6 have the meaning given at the beginning, Z1 has the meaning given in section i), in connection XIX preferably denotes an electron-attracting group, such as NO2, or CF3 (where @ e @ R1, R2 and R7 have the meaning given at the beginning) and Xi denotes a radical which can be replaced by an amino group, such as in particular halogen, OH, acyloxy, a secondary or tertiary amino group, a sulfuric acid, alkylsulfuric acid or sulfonic acid radical and both radicals X1 of the compounds XXIV and XXV in the reaction with the amine XXI can also together represent an oxygen or sulfur atom or 1) a compound of the formula XIX with an amine of the formula XX or an amine of the formula XXI, XXII or XXIII with a compound of the formula XXIV or XXV under N-alkyl @ erungsbedingungen, where the compounds XXIV and XXV in the reaction with a compound of the formula XXI together with the meaning given for R5 and R6 can also represent a single compound m) a Amino compound of the formula I with one or two different straight-chain or branched olefins with 2-7 carbon atoms or with one straight-chain or branched one en alkadiene with 4-14 carbon atoms, whose chain can also be interrupted by an oxygen or sulfur atom, or amino compounds of the formula XXII or XXIII with a straight-chain or branched olefin with 2-7 carbon atoms, which also with the Radicals R5 or R6 can be connected directly or via eLn ileteroatom, such as 0, S, reacts or n) a compound of the formula XXVI, ZIH XXVI in which Z1 has the meaning given in section i), with an amine of the formula XXVII, IL 5) N-IIalogue XXSrII G in which R5 and R6 have the meaning given at the beginning and halogen @ is Cl, Br or I, especially in the presence of Friedel-Crafts catalysts, or o) in a compound of the formula I which contains hydrogen instead of R3, the substituent R3 introduces; namely, if R3 is chlorine, bromine or iodine, by halogenation, in particular by reaction with elemental halogen, preferably with the addition of catalysts, such as Exsen-III, aluminum, antimony-III-ahlogeniden, tin-IV halides, with Hypohalous acids, tert-butyl hypohalites, compounds of different halogens with one another, such as Cl @, chlorine, BrI, SO2 halogens, preferably with the addition of peracids, and N-halocarboxylic acid amides and imides or, if R3 is iodine, by iodination, in particular also by reacting the 2- or 3-Hg acetate compound with iodine or, if so.

R3 means NO2, by nitration, in particular by reaction with nitrogen oxides, nìtronium salts, preferably with the addition of Friedel-Crafts catalysts, HNO3, optionally mixed with acetic acid, acetic anhydride, H2SO4, pyrosulfuric acid, fuming sulfuric acid, H2SeO4, HClO4, such as acyl nitrates Acetyl or benzoyl nitrate, with nitric acid esters such as ethyl nitrate, with nitrosulfonic acid, nitrosylsulfuric acid, nitroguanidine, with metal (such as Cu, Fe, Mn; Co, Ni) nitrates in a mixture with acetic anhydride or glacial acetic acid or, if R3 R7, SR7, SOR7, SO2R7 or denotes in which Ri, R2 and R7 have the meaning given at the beginning, in particular by reaction with R7X2 or olefins having 1-4 carbon atoms or by reaction with R7SX2, R7SOX2, R7SO2X2 or R X2 in the presence of Levric acids, in particular of FriedeL-Crafts-Catalyst. gates, if necessary run under SX2 & l- end. Conditions in which.

X2 preferably Cl, Br, I, OH, acyloxy, alkylo, xy, a sulfuric acid or sulfonic acid radical. or p) in a compound of the formula I in which R3 is NH2, the NH2 group is exchanged after conversion into a diazonium salt for halogen, NO2, CN, R7S, R7O or OH (in which R7 has the meaning given at the beginning), or in which R3 CONH2 means that the CONE2 group is converted into the CN group by dehydrating agents, such as in particular P2O5, POCl3, PCl5 or SOC12, or in which R3 means N02 or instead of R3 JO or JO2, the N02 group to NH2 or . the JO or JO2 group is reduced to iodine, or where R3 is NH-NH2 or NHNH2 substituted by hydrocarbon radicals, this hydrazine grouping is replaced by bromine or iodine, or where R3 is halogen, ualogenic versus Nu (where Have meaning) exchanges R1, R2 are those specified at the outset or in which, instead of R3, one of the radicals OM1, SM1, or SO stands N111 and M1 denotes H or metal, in particular alkali metal or alkaline earth metal, iiicse instead of R3 substituents with olefins with 2-4 carbon atoms, diazoalkanes with 1-4 carbon atoms or with compounds R7X1, in which R7 is the at the beginning and X1 is the in Section 1) have given meaning, if necessary reacts under conditions which split off M1X1, or in which R3 denotes NH-R1, the N1 group by treatment with ketenes with 1 - 4 carbon atoms or with carboxylic acid derivatives suitable for acylation reactions, such as carboxylic acid esters, carboxylic acid anhydrides, -halides which derive sic from carboxylic acids with t - 4 carbon atoms, for NziC0R7 group it1 acylated (where R1 and R7 have the meaning given at the beginning) or sets this carbonamide group hydrolytically free from one of its non-functional derivatives, or where R3 is 5R7 or is NO instead of R3 and R7 has the meaning given at the beginning SR7 group to the SOR7 or S02-R7 group or the Nltroso oxidizes to the nitro group, or in which instead of R3 there is a sulfonic acid residue, in particular a sulfonic acid halide, a sulfonic acid ester or a sulfonic acid anhydride, this sulfonic acid derivative with an amine of the formula XXVIII in which R1 and R2 have the meaning given at the beginning, or q) compounds of the formula I in which R5 and R6 are identical or different and are alkyl having 1-7 carbon atoms substituted by OM1 or SM1, one of the substituents OM1 or SM1 can also be replaced by X1, and M1 and X1 have the meaning given in section p) or 1), converts to O-ring or S-ring-containing compounds under H2O, H2S or M1X1-releasing conditions, or r ) Compounds of the formula XXIX in which R1, R2 and Z have the meaning given at the beginning, decarbonylated or 5) compounds of the formula XXX treated with hydrogen-donating agents or catalytically activated hydrogen or with a compound of the formula XII (R7M), in which R2 to R7 and A have the meaning given at the beginning and Bs and M have the meaning given in sections i) and d), or t) a compound of the formula I, in which instead of A COOM1, COOR12, COOAcyl, COHal is, optionally with a compound of the formula XXXI or with an olefin derived from XXXI by formal H2O cleavage or with an epoxide derived from XXXI by formal dehydrogenation or with Compounds of the formulas XXXII to XXXVI or with one obtained by formal dehydrogenation from XXXIIY. and XXXIV derived ethylene imine or with diazomethane, diazoethane, phenyldiazomethane or hydroxyl amine A1OH XXXI A1OAcyl XXXII A2A3NH XXXIII A4NH XXXIV A2-N = C = O XXXV A1-X XXXVI in which A1 to A4 the above and M1 and X the in sections p) and j) have the meaning given and R12 denotes an optionally substituted hydrocarbon radical or converts u) compounds of the formula I in which instead of stands and R13 and R14 are identical or different and denote hydrogen or an optionally substituted hydrocarbon radical and A1 to Au have the meaning given at the beginning, hydrolyzed to carboxylic acids, esters or amides of the formula I or v) to compounds of the formula I in which instead of A ON stands, H2O attaches to form amides of the formula I or w) compounds of the formula XXXVII in the presence of the amines XXXIII or XXXIV, in particular with the addition of polysulfides, a Willgerodt reaction or compounds of the formula XXXVIII, in particular with the addition of acidic catalysts, a Beckmann's rearrangement or compounds of the formula XXXIX are subjected to Schmidt degradation by reaction with HN3 where Z, A1, R1 and R2 have the meaning given at the beginning, or s) an aldelium of the formula XL is reacted with nitrohydroxylamic acid or benzenesulfonylhydroxylamine, in particular in alkaline solution, or an aldoxime of an aldehyde of the formula XL in which Z, R1 and R2 have the meaning given at the beginning, in particular with H2O2 or peracids, oxidized to a hydroxamic acid of the formula I or y) compounds of the formula I in which, instead of A, the group C (= NR13) is OR12, which is preferably present as a salt , with alcohols of the formula XLI or compounds of the formula X @ II with orthocarbonic acid esters of the formula XLIII, * R7OH XLI C (OR7) 4 XLIII * in which A, Rl, R2, R7 and Z have the meanings given at the beginning and M, R12 and R13 have the meaning given in sections d), t) and u) to give orthoesters of the formula I or z) compounds of the formula XLIII with compounds of the formula XLIV or compounds of the formula XLV with compounds of the formula XLVI or compounds of the formula XLVII with compounds of the formula XLVIII under conditions which split off M1X3 or split off from compounds of the formulas XLIX to XIII M1X3 Z2-D-A6-X3 XLIII M1-Y- A7 XLIV Z2-D-A6-YM1 XLV X3A7 XLVI Z2-D-A5-X3 XLVII HNA4 XLVIII D COO, CONA2 or X3 OH, SH, OAcyl, SAcyl or X mean, A6-Y-A7 and A8Y mean the meanings of A1 and A9-Y-A10 mean the meanings of A4 and A1, A4, A5, Y and Z mean the at the outset and M1 and X have the meanings given in sections p) and respectively, or za) a compound of the formula I in which the grouping is partially or fully hydrogenated by the addition of hydrogen. and R3 and R4 have the meaning given at the beginning, treated with dehydrating agents such as, in particular, dehydrogenating or metal oxide catalysts, chloranil, sulfur, selenium or alkyl disulfides or, for example, in a compound of the formula I in which the radicals and -R15 are in place of -R4- and where R15 is a 3-formyltrimethylene of the formula LIV, optionally containing a double bond and / or functionally modified, or a tetramethylene derivative of the formula LV optionally containing 1 - 2 double bonds or n-butyl with 1 - 2 double bonds and / or optionally a triple bond, where X4 and X5 are the same or different and in particular OR13, Sr13, NR13 R14 or together are also O or E and R14, R13, E and X2 have the meaning given in section u) or o), in particular in counter-type of acids and / or Lewis acids, such as Friedel-Crafts catalysts, or optionally with dehydrating agents, such as P2O5, POCl3, PCl5 or SOCl2, or optionally under other HX4X5- or HX2-eliminating conditions introducing the divalent substituent R4 or zc) from compounds of general formula I, in which R4 is a tetramethylene which is monosubstituted by X6 and optionally contains a double bond and in which X6 is a test which can be split off with H as HX6, in particular halogen or OH, XH or N112 which is optionally preferably substituted by alkyl, acyl, alkylsulfonyl or alkoxysulfonyl , the substituent X6 eliminated as iDE6 with the formation of a double bond or zd) from compounds of the general formula I, wherein for R4 is a tetramethylene which is doubly substituted in the 1,2- or 1,4- or 3,4-position by X7 and X8 and optionally contains a double bond; and in which X7 and X8 are identical or different and Cl, Br, I or optionally preferably OH substituted by alkyl, acyl, alkylsulphonyl or alkoxysulphonyl, each of the two substituents X7 and X8 with formation of a double bond, in particular with metals such as In, Zn-Cu, Na or Li, or with organometallic compounds, such as Grignard or organolithium compounds, eliminated or ze) the compounds of the rormei I prepared in section a - d, optionally in their physiologically compatible salts with acids or bases or quaternary ammonium salts and / or converts anhydrides and optionally separates racemate mixtures of the formula I into the individual racemates and optionally separates any racemates of the formula I present into their optical antipodes in a manner known per se and / or sets the compounds of the formula I free from their salts with acids or bases.

Possible alkyl groups in the radicals R1, R2, R3 and R7 are: methyl, methyl, n-propyl, isopropyl, n-butyl, isobutyl, and also sec-butyl and tert-butyl. R4 means - (CH2) 4-, -CH = CH- (CH2) 2-, -CH2-CH = CH = CH2- and -CH = CH-CH = CH-. The radicals R5 and R6 individually preferably mean: and together in the form of alkylene derivatives, optionally alkylene derivatives interrupted by O or S, preferably - (CH2) 3-, - (CH2) 4-, - (CH2) 5-, - (CH2) 6-, - (CH2) 7- , - (CH2) 8-, -CH2-O- (CH2) 2-, - (CH) 22-O- (CH2) 2-, - (CH2) 2-O- (CH2) 3-, - (CH2 ) 3-O- (CH2) 3-, - (CH2) 3-O- (CH2) 4-, -CH2-S- (CH2) 2-, - (CH2) 2-S- (CH2) 2-, - (CH2) 2-S- (CH2) 3-, - (CH2) 3-S- (CH2) 3-, - (CH2) 3-S- (CH2) 4-, - (CH2) -O- ( CH2) 4-, - (CH2) 2-P- (CH2) 4-, - (CH2) 2-O- (CH2) 5-, - (CH2) -S- (CH2) 3-, - (CH2) -S- (CH2) 4-, - (CH2) 2-S- (CH2) 4-, The radicals A1, A2 and A3 are preferably: hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-amyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-dodecyl, allyl, grotyl, hydroxymethyl, propargyl, ß-hydroxyethyl, ß-hydroxyn-propyl, γ-hydroxy-n-propyl, ß-methoxyethyl , ß-ethoxyethyl, 3-oxa-5-hydroxy-pentyl, 3-oxa-5-methoxy-penthyl, 3-oxa-5-butoxy-pentyl, 3,6-dioxa-8-hydroxy-octyl, 3.6 -Dioxa-8-methoxy-octyl, 3-oxa-ethoxy-penthyl, ß-aminoethyl, γ-aminopropyl, ß-dimethylaminoethyl, ß-diethylaminoethyl, ß-di-npropylaminoethyl, γ-dimethylaminopropyl, γ-diethylaminopropyl, ß-methylaminopropyl -γ-diethylaminopropyl, cyclohexyl, cyclopentyl, ß-cyclohexylethyl, ß-cyclohexylpropyl, N-methylpiperidyl- (4), (N-methylpiperidyl-3) -methyl, ß- (N-methylpiperidyl-2) -ethyl, ß-piperidino -ethyl, ß-pyrrolidinoethyl, ß-homopiperidinoethyl, ß-morpholinoethyl, ß-thiomorpholinoethyl, ß- (N'-methylpiperazino) -ethyl, ß- (N'-ethylpiperazino) -ethyl, ß- (N'-phenylpiperazino) - Ä thyl, ß- (N'-2-Hydroxyäthylpiperazino) -äthyl, ß- (N'-Methylhomopiperazino) -äthyl, γ-Piperidinopropyl, γ-Pyrrolidinopropyl, γ- (N'-Methylpiperazino) -propyl, γ- (N ' -Aethylpiperazino) -propyl, γ- (N'-phenylpiperazino) -propyl, γ-morpholino-propyl, γ-thiomorpholino-propyl, ß-morpholino-propyl, ß-piperidinopropyl, ß-pyrrohdino-propyl, ß- (N ' -Methylpiperazino) propyl, ß-methyl-γ-morpholinopropyl, ß-methyl-y-piperidino-propyl, ß-methyl-y-pyrrolidinopropyl, a-dimethylaminobutyl, a-diethylaminobutyl, ß-mercaptoethyl, phenyl, benzyl, o- Methylphenyl, p-methylphenyl, p-ethylphenyl, p-niethylbenzyl, ß-phenylethyl, a-naphthyl, ß-naphthyl, α-phenylethyl.

A2 and / or A3 can preferably also be hydrogen.

In CONA4 -NA4 is preferably piperidino, pyrrolidino, Morpholino, Thiomorpholino, N'-methylpiperazino, N'-ethylpiperazino, N'-propylpiperazino, N'-phenylpiperazino, N '- (β-hydroxyethyl) piperazino, piperazino, N'-methyl homopiperazino, N'-phenylhomopiperazino.

In O (OR7) 3, R7 is preferably methyl, ethyl, n-propyl and n-butyl.

The individual procedures are explained in more detail below: (a) The saponification of suitable functional acid derivatives of compounds of the formula I can, as in Houben-Weyl, Methods of Organic Chemistry, 4th Edition, Georg Thieme Verlag, Stuttgart, Volume 8 (1952), pages 418 - 432 described in more detail, in the neutral, acidic or alkaline medium at temperatures between -20 ° and 300 °. Acids suitable for hydrolysis are, for example, especially salt, sulfur, phosphorus and hydrobromic acid; Sodium, potassium or sodium are expediently used as bases Calcium hydroxide, sodium or potassium carbonate. The preferred solvent is chosen Water, ethanol, methanol, dioxane, tetrahydrofuran, dimethyformamide or their mixtures, especially the water-containing mixtures. But you can use the acid derivatives z. B. also in ether or benzene with the addition of strong bases such as potassium carbonate or without solvents by fusing with alkalis such as potassium and / or sodium hydroxide or saponify alkaline earths to amino-phenylacetic acids of the formula I.

A particularly preferred embodiment of the invention is saponification corresponding thioamides, e.g. B. the appropriately substituted phenylthioaceto-morpholide, piperidides, pyrrolidides, dimethylamides or diethylamides. Such thioamides are by reacting the appropriately substituted acetophenones with sulfur and to the amine in question available. Also the amides, obtainable by reacting the acetophenones with ammonium polysulphide according to the Willgerodt method, are used as the starting material well usable. The hydrolysis of the thioamides or

Amides are preferably made by heating with aqueous hydrochloric acid. The thioamides or amides do not necessarily need to be isolated, but you can directly the reaction mixture in which they were formed Subject to hydrolysis. By dry heating suitable acid esters of compounds of formula 1, such as, in particular, tertiary alkyl esters, to temperatures between 50 and 350 the amino-phenylacetic acids of orel I are obtained. Thermolysis can be used also in inert solvents such as benzene, water, dimethylformamide, ethylene glycol, Glycerine, dimethyl sulfoxide, cyclohexanol, preferably with the addition of catalytic compounds from acids such as p-toluenesulfonic acid.

(b) The oxidation of suitable reduced precursors of formula II to the amino-phenylacetic acids of the formula I according to the invention, as in Houben-Weyl, l.c., Volume 8, pages 364-416, with a wide variety of oxidizing agents be carried out, in particular with atmospheric oxygen, preferably with the addition of Catalysts, such as Mn, Co, Fe, og, V2O5; with silver oxide, preferably together with Copper oxide; with H 2 O 2, preferably in the presence of alkalis; with organic peracids, such as peracetic acid, perbenzoic acid or perphthalic acid; with potassium permanganate in aqueous odor acetone solution and / or acidic, neutral or alkaline medium, optionally with the addition of MgSO4; with chromic acid or CrO3, preferably in glacial acetic acid, optionally with the addition of benzene or sulfuric acid; with nitrous acid; with preferably 2-69% nitric acid, optionally under pressure (up to 100 atü); with nitrogen oxides or with caustic alkalis / O2 in the melt; or with hypohalites. These oxidations are preferably carried out in inert solvents, such as water, Glacial acetic acid, Dioxane, benzene, acetone, tetrahydrofuran, dimethylformamide, Ethanol, methanol or mixtures of these solvents, and at temperatures between - 30 ° and 300 °, expediently at room temperature.

@ # -Diazoacetonones of the formula III, which can be obtained from the corresponding Benzoic acids obtained via the acid chlorides with diazoalkanes, can according to the method von Wolff, as in Organic Reactions, Volume I, (1942), Seile 38 ff, John Wiley @ Sons, Inc., New York, and described in more detail in Houben-Weyl, Volume 8, l.c., pages 456 - 458, for example by heating and / or exposure and / or in the presence of catalysts, such as copper, silver or silver oxide, as well as in the presence of an alcohol Ä1ÖH, a Amine A2A3NH or A4NH or hydroxylamine, where A1 to @ 4 are those specified at the beginning Have meaning between 0 ° and 120 ° in the substituted amino-phenylacetic acids of formula I are rearranged. It is advantageous to set the reaction mixture to be inert organic solvents such as dioxane or tetrahydrofuran are added.

(@) Organometallic compounds of the formula IV are obtainable through Metalation of appropriately substituted benzyl halides, especially with Alkali or alkaline earth metals, preferably with lithium or magnesium, or with C. dium or zinc dialkyl compounds. These supply with solid C02 according to known Methods such as those described, for example, in Houben-Weyl, l.c., Volume 8, pages 369-372 are described, the aminophenylacetic acids of the formula I.

The metalation, such as, for example, the Grignardation, takes place in solvents such as ether, tetrahydrofuran, dioxane or their mixtures with aromatic substances Hydrocarbons such as benzene at temperatures between -10 ° and the boiling point the solvents used. It is preferable to sit in a large excess of one GeF, isches of magnesium shavings and magnesium powder and already conducts during the Grignarding a powerful stream of carbon dioxide through the reaction mixture, To an organometallic synthesis he formed Grignard compounds with not yet to push back converted halide. Instead of the trrignard connections you can use also other, in particular the organometallic compounds described in more detail above, are used that are accessible analogously.

.) # -Halo-acetophenones of the formula V, producible by halogenation the corresponding acetophenones or from den'J-diazoacetophenones of the formula III with hydrogen halide in ether, according to the method of Faworskij, as in Houben-Weyl, l.c., Volume 8 (1952), described in more detail on page 458, for example in boiling Xylene in the presence of a strong base such as sodium hydroxide or by heating be rearranged into the acids I in aqueous-ethanolic silver nitrate solution.

(f) Benzyl alcohols of the formula VI, producible by hedging the corresponding benzaldehydes or benzoic acids, one can, as in Houben-Weyl, l.c., Volume 8, described on pages 367-368, at high pressures up to 400 at and high Temperatures up to 300 °, preferably with the addition of heavy metal catalysts, such as nickel or cobalt carbonyls or halides, to the aminophenylacetic acids the orel I carbonylate. One can also use the corresponding solate, such as in particular Use alkali (e.g. sodium) or alkaline earth (e.g. calcium) alcoholates and work at low pressures without the addition of heavy metal catalysts.

Finally, alcohols, esterified alcohols or halides succeed of formula VI or VII according to the method of och-Haaf, described in Chemical Reports, Volume 92 II, Selten 1629 to 1635 (1959), and in Angewandte Ghemie, volume 70, page 311 (1953) to carbonylate to the compounds of the formula I according to the invention, being used as a source of carbon oxide preferably a mixture of formic acid and mineral acids, especially if it concentrates sulfuric acid. The sulfuric acid dehydrates the formic acid and also catalyzes the incorporation of the carbon oxide. The process is carried out at 200 to 1200, advantageously at 0 ° to 30 ° C. with cooling. In connections of the formula VII, the respective substituent is replaced by hydrogen, from -RÄ Ri is formed and the compounds of formula 1 are formed via carbonylation.

(G) alonic acid derivatives of the formula VIII, preparable by thermal Decomposition of appropriately substituted phenyl oxalacetic acid diethyl esters and Subsequent partial or complete alkaline saponification can, as in Eouben-1ifeyl, l.c., Volume 8, on page 436, for example by dry heating or by heating in solvents such as water, ethanol, dioxane or xylene Temperatures between 500 and 2500 easily decarboxylated to the compounds of formula I. will.

It is expedient to heat until the evolution of carbon dioxide has ended.

(h) Substituted aminophenylacetic acids of the formula I are also included by acid cleavage of any appropriately substituted α-acyl-phenylacetic acid derivative of the formula IX, as in Houben-Weyl, Volume 8, l. c., page 433, described in more detail, available.

Ketoesters of the formula IX can, for. B. be produced by condensation of esters of acetic or benzoic acid with appropriately substituted benzyl cyanides to acetyl or. α-Benzoylbenzyl cyanides, subsequent conversion of the same with alcohols of the formula A1OH, in which A1 (apart from hydrogen) has the meaning given at the beginning has, in the corresponding imido ether salts (e.g. hydrochloride) and partial Hydrolysis.

The acid cleavage of the keto derivatives of the formula IX takes place by treatment with a strong base such as sodium, potassium or calcium hydroxide in solvents like water, methanol, Ethanol, tetrahydrofuran, dioxane, benzene, Ethers or mixtures thereof. The temperature range of the reaction is between 100 and 2000 If you want to get the free aminophenylacetic acids of formula 1, wherein A COOH then stands for heating - preferably a few hours to the boiling point of the solvent.

(i-) It is also possible to obtain a compound of the formula I by starting from a preliminary product that additionally or instead of hydrogen atoms one or more hydrogen-replaceable groups and / or -C = N and / or C = C double bonds and / or contains C = C triple bonds, and this with hydrogen donating agents treated.

Groups that can be replaced by hydrogen are, in particular, halogen and oxygen in an N-oxy, sulfinyl or carbonyl group, sulfur in a thiocarbonyl group, Hydroxyl, mercaptyl, amino or substituted by a hydrocarbon radical Hydroxyl, mercaptyl, amino or diazonium salt groupings. So you can, for example α-hydroxy, a-chlorine, a-bromine, α-iodine, α-mercapto, a-junino, α-Benzyloxy, α-benzylamino, α-oxo or α-thio-3-methyl-4- (piperidino-1) -naphthylacetic acid to 3-methyl-4-piperidino-1-naphthylacetic acid or 3-butyryl, 3-thiobutyryl, 3- (i-Hydroxy-n-butyl-1) -, 3- (1-Amino-n-butyl-1) -, 3- (1-chloro-n-butyl-1) -, 3- (1- Bromo-n-butyl-1) -, 3- (1-iodo-n-butyl-1) -, 3- (1-benzyloxy-n-butyl-1) -, 3- (1-benzylamino-n-butyl-1) -, 3- (1-Mercapto-n-butyl-1) -, or 3-) 1-Benzylmercapto-n-butyl-1) -4-pyrrolidino-a-methyl-naphthyl-acetic acid-2 ' diethylaminoethyl ester to 3-n-butyl-4-pyrrolidino-a-methylnaphthyl-acetic acid-2 diethylaminoethyl ester or 3-vinylz-ethyl-, 3-ethynyl-a-ethyl-, 3-ethyl-a-vinyl- or 3-ethyl-α-ethinyl-4-homopiperidino-naphthyl-acetic acid-2'-piperidinoethyl ester smoothly to 3, a-diethyl-4-homopiperidinonaphthyl-acetic acid 2'-piperidinoethyl ester to reduce. 4- (n-butyl-amino-) - 2-sulfamoyl-naphthyl-acetic acid isopropyl ester, for example, is also successful with propionaldehyde, butyraldehyde, acetone, butanone- (2) to 4- (n-butyl-npropyl-amino) -, 4- (n-dibutylamino) -, 4- (n-butyl-isopropylamino ) - or 4- (n-butyl sec. butyl-atino) -2-sulfannylnaphthyl-acetic acid isopropyl ester under hydrogenating conditions to alkylate. Sulfinyl compounds can also be reduced to thioethers, such as for example 3-methylsulfinyl-, 3-ethylsulfinyl- or 3-isopropylsulfinyl-4-homopiperidino-naphthyl-acetic acid-N- (2'-diethylaminoethyl) -amide to the corresponding thioethers. senzyl-F, for example, is still successful Diphenyl, triphenyl or α-picolyl esters of 3-trifluoromethyl, 3-tert. Butyl, 3-Ethyl mercapto, 3-sulfamoyl, 3-isopropoxy or) -hydroxy-4-morpholino-a-ethyl-naphthyl-acetic acid to split smoothly to the free carboxylic acids hydrogenolytically 'or z. B. the benzyl group remove in 4-piperidinonaphthylacetic acid benzylamide under hydrogenating conditions see below. The hydrogenation of unsaturated quaternary ammonium salts and li-oside of formula l. For example, n-ethylsulfonyl, 2-ethoxy, 3-diethylsulfamoyl or 3-trifluoromethyl-4-pyridinium-α-n-propylnaphthyl-acetic acid ethyl ester bromide reduce to the 4-piperidino derivatives. 3-Itro-4-pyridinium-α-methyl-naphthyl-acetic acid-n-butyl-ester-chloride can also be used hydrogenate to the 3-amino-4-piperidino compound. The reduction of, for example, is also successful 3-Methyl-4-piperidino-α-methyl-naphthyl-acetic acid-dodecyl ester-N-oxide for N-oxide-free derivative without difficulty.

The hydrogenations of naphthalene or setralone derivatives are also important to 5,6-, 6,7-, 7,8-dihydro- and 5,6,7,8-letranydro-naphthalenes. So you can, for example α-methyl-4-piperidino-naphthyl-acetic acid and 2-ethyoxy-4-pyrrolidino-5-oxo-5,6,7,8-tetrahydro-naphthyl-acetic acid ethyl ester to the corresponding 5,6,7,8-Tetrahydronr lthalin derivatives and 4-Homopiperiaino-naphthylacetic acid to the corresponding 5, 6 or 6,7 or 7,8-dihydro or 5,6,7,8-tetrahydronaphthalene compound hydrogenate.

For catalytic hydrogenation and / or hydrogenolysis are used as catalysts for example noble metal, nickel and cobalt catalysts are suitable. The EdeJmetallkatalysatoren can be on carriers (e.g. palladium on carbon, calcium carbonate or strontium carbonate), as oxide catalysts (e.g. platinum oxide) or as finely divided metal catalysts are present. Nickel and cobalt catalysts are useful as aney metals, nickel also used on kieselguhr or pumice stone as a carrier. The hydrogenation can take place at Room temperature and normal pressure or also at elevated temperature and / or elevated Printing can be carried out.

It is preferable to work at pressures between 1 and 100 at and at Temperatures between -80 ° and 200 ° C, especially between room temperature and + 100 ° C. The reaction is expediently carried out in the presence of a solvent such as water, methanol, Ethanol, isopropanol, n-butanol, ethyl acetate, dioxane, acetic acid or tetrahydrofuran carried out; one can also use some of these solvents with one another. For the hydrogenation, the free compounds or the corresponding salts, for example the hydrochloride or sodium salts are used.

In the hydrogenation of multiple bonds and in hydrogenolysis of benzyl groups is preferably carried out at normal pressure in such a way that the hydrogenation stops after the calculated amount of hydrogen has been taken up. One can basically work in acidic, neutral or basic areas. For such connections, which contain a C = N double bond, one sees a reaction in neutral or basic medium.

Implementation is also generally applicable as a reduction method with nascent hydrogen. This can be done, for example, by treating Generate metals with acids or bases. So you can z. B. a mixture of zinc with acidic or alkaline lye, of bases with hydrochloric acid or 3-acid acid or use tin with hydrochloric acid. The use of sodium is also suitable or another alkali metal in ethanol, isopropanol or butanol. One can furthermore an aluminum-nickel alloy in an aqueous alkaline solution, if necessary with the addition of alcohol. Also sodium or aluminum amalgam in aqueous alcoholic or aqueous solution are suitable for generating the nascent hydrogen. The implementation can also be carried out in a heterogeneous phase, whereby one expedient an aqueous and a benzene or toluene phase are used. The reaction temperatures used lie between room temperature and the boiling point of the solvent used. The reaction is advantageously terminated by boiling the reaction mixture.

Complex metal hydrides, as above, can also be used as reducing agents all lithium aluminum hydride, also sodium borohydride in the presence of aluminum chloride or lithium bromide, are used. The 'reaction conditions must be chosen in such a way that group A (with the meaning given at the beginning) remains intact.

It is expedient to work in the presence of an inert solvent, z. B. ether, tetrahydrofuran, ethylene glycol dimethyl ether. The implementation will be beneficial brought to completion by boiling the reaction mixture. The decomposition of the educated Metal complexes can be made in the usual way, e.g. with an aqueous ammonium chloride solution, take place.

Further suitable reducing agents are, for example, sodium dithionite in alkaline or ammoniacal solution; Esen (II) hydroxide; Stannous chloride; Hydrogen sulfide, hydrogen sulfides, sulfides and polysulfides; Hydriodic acid or sodium sulfite. It is also possible to post one or more carbonyl groups to reduce the isolation methods of Olemmensen or Wolff-Kishner to CH2 groups.

The reduction of Clemmensen can, for example, be carried out by treatment of carbonyl compounds amalgamated with a mixture of zinc and hydrochloric acid Zinc and hydrochloric acid or Z @ nn and hydrochloric acid. One works either in aqueous-alcoholic Solution or in heterogeneous phase with a mixture of water and benzene or toluene. The reaction is achieved by sweating the reaction mixture to the boiling point of the used Solvent led to the end. In the rest of the day you can either present the metal and add the acid dropwise or, conversely, introduce the acid and the metal in portions assigned.

The Wolff-Kishner reduction is achieved by treating the carbonyl compound with anhydrous hydrazine in absolute alcohol as well as in an autoclave or in a bomb tube carried out, the reaction temperatures can be increased to 250 ° C. Sodium alcoholate is advantageously used as the catalyst in this reaction. The Wolff-Kishner reduction can also be varied according to the Huang-Minlon method by using hydrazine hydrate as a reducing agent and the implementation in a high-boiling, water-miscible solvent such as Diethylene glycol or triethylene glycol, and in the presence of alkali, such as Sodium hydroxide. The reaction mixture will last for a while, usually about 3 - 4 hours, refluxed.

The water is then distilled off and the residue a few Time heated to higher temperatures up to about 200 ° C.

The hydrazone formed and originally decomposed Any carbonyl group present is converted into a CH2 group.

Basically, as reduction methods come, depending on which of the mentioned starting materials is chosen, all customary in question, such as, for example are described in Houben-Weyl, 1. c., Volume 11/1, nitrogen compounds II, pages 341 to 731.

(J) Organometallic compounds of the formula XI, in particular the alkali, Alkaline earth, Zn-Cd or the alkaline earth, Zn or Cd-hafogen compounds that one by direct metalation, such as with butyllithium. Phenyllithium, Sodium hydride, sodium amide or metallic sodium or magnesium, the corresponding Hydrogen or hafogen compounds can be converted into compounds according to the invention of formula I, in particular with alkyl halides, preferably iodides, bromides or chlorides, or with alkylsulfur or alkylsulfonic acid esters of the formula XII, in inert solvents such as benzene, xylene, dioxane or tetrahydrofuran, implement. Preference is given to using Friedel-Crafts catalysts, such as AlCl3, FeCl3, ZnCl2 etc. to. on the other hand you can compounds of the formula XIII, in particular the correspondingly substituted a-chlorine, o'-3ro: n or α-iodine or the α-hydroxy-naphthyl-acetic acid derivatives esterified with sulfuric acid or sulfonic acid derivatives, with metal compounds of the formula XIV, in particular alkali derivatives such as lithium butyl or sodium methyl, or Grignard compounds such as n-propyl magnesium chloride, under to implement analogous conditions.

(k) Compounds of the formula I can also be prepared by reacting the halogen compounds of the formula XV with preferably Grignard or Grganolithium compounds from orel XVI, which are derived from appropriately substituted haloacetic acid derivatives, can be obtained. The bromo- or iodoacetic acid derivatives are preferably used. The reaction is carried out in internal solvents such as ether, tetrahydrofuran or dioxane, carried out at temperatures between 0 ° and 180 °.

Conversely, under the same conditions, phenyllithium- or corresponding Grigne d compounds of the formula XVII with appropriately substituted ones Haloacetic acid derivatives of the formula XVTII, preferably with the bromine or iodoacetic acid derivatives, realize. The compounds X are also obtained.

It is also possible to use compounds of the formula XVïI in which Q is the same Means hydrogen, with compounds of the formula XVIII, preferably with correspondingly substituted α-iodine, α-bromine, α-chlorine, α-hydroxy or α-Acyloxy-acetic acid derivatives under the conditions of a Friedel-Craftsian To implement alkylation of chromates to the compounds of formula I. As catalysts For example, in addition to the Lewis acid AlCl3, SbCl5, FeCl3, BF3, ZnCl2 or Protonic acids, e.g. B. HF, H2S04, H3P04 or P2O5 are used. One prefers to lead the reaction in inert solvents such as carbon disulfide, hexane or nitrobenzene, and at temperatures between 0 ° and 2000 through. In general, one works afterwards the methods described in the book by G. A. Olah "Friedel-Crafts and Related Reactions", Interscience Publishers, New York, 1964, Volume II, Alkylation and Redated Reactions, Pages 417 to 767 are given.

(1) The reaction of amines of the formula XX with compounds of the formula XIX or of amines of the formula XXI, XXII or XXIII with alkyl compounds of the formula XXIV or XXV, takes place in principle according to the in Houben-Weyl, l.c. Volume 11/1, (1957), Nitrogen compounds II, on pages 24 to 267 described or cited usual exchange reactions. If you choose a halide as the reaction component Formula XIX, XXIV or XXV, the reaction in the presence or absence of a Solvent are carried out. Lower solvents can be used, for example aliphatic alcohols or benzene or toluene etc. in wearing like after which. Halide is used as the starting material, one works at low temperatures, e.g. B. at room temperature or at the boiling point the solvent used. In individual cases it may be necessary to use the Implementation under pressure or at elevated temperature, The use a catalyst is generally not required in these reactions. Advantageous if the amines are used in excess.

If the starting material used is a phenol of the formula XIX or an alcohol of the formula XXIV or XXV or a preferably lower aliphatic one Carboxylic acid ester of such a phenol or alcohol, the reaction with the amines advantageously carried out in the presence of a catalyst. As a catalyst either a dehydrating agent or a dehydrating agent or a Mixture of these catalysts in question. An example of a dehydration catalyst is Called aluminum oxide, which is optionally activated with other suitable oxides can be. As a dehydrating agent, for. B. Raney nickel or the usual noble metal catalysts, such as palladium oxide or palladium carbon can be used.

A compound can also be used as the starting material for this reaction of the formula XIX or XXV or XXV, where X1 is a secondary or tertiary Means amino group.

Under the reaction conditions of a so-called transamination, such a secondary or tertiary amino group is formed in compounds of the formula XIX by treatment with amines of the formula XX by the group exchanged.

Completely analogously, a secondary or tertiary amino group in compounds of the formula XXIV or XXV can be converted into compounds of the formula XXIV or XXV by reaction with mines of the formula XXI or XXII or XXIII against the group Z1-Nij or exchange, in which Z1, R5 and R6 have the meaning given at the beginning.

The reaction conditions for such a transamination are customary. It is advantageous to use amines of the formula XIX or XXIV or XXV in a large excess. and works in the presence of catalysts such as acids, metal salts, iodine, Dehydration contacts, hydrogenation-dehydrogenation catalysts or sodium hydrogen sulfide. In individual cases, however, such transaminations also take place in the absence of one Catalyst. It is advantageous to carry out the reactions in the presence of an inert solvent carry out, furthermore, it is advantageous to carry out the implementation under increased pressure as well to be carried out at higher temperatures.

It is still possible to use the amines XXII or XXIII with aldehydes or Ketones with 1 - 7 carbon atoms, these aldehydes or ketones also directly or via a heteroatom, such as 0 or S, with the R5 or R6 radicals of the amines XXII or

XXIII can be linked to alkylate reductively. As intermediate products Aldehyde ammonia, i.e. compounds that are in a position relative to nitrogen, are formed in each case carry a hydroxyl group according to the reduction methods explained in section (i) is removed by hydrogenolysis.

Such reductive alkylations are preferably in the presence of a suitable catalyst carried out, the usual catalysts such as, for example Noble metal catalysts, but also Raney nickel or Raney cobalt come into question. These catalysts can, for. B. as oxide catalysts, as supported catalysts or as finely divided metal catalysts. One works expediently under increased hydrogen pressure as well as at higher temperatures (up to about 2500 o).

Such reductive alkylation can also be done with chemical reducing agents, such as with formic acid, formamide or ammonium formate according to the known Leuckart-Wallach method, as described in detail in Houben-Weyl, l.c., Volume 11/1, nitrogen compounds II, (1957) on pages 645-664 is.

As compounds XIX, n1ii preferably uses appropriately substituted ones p-iodine, p-bromine or p-chloro-phenylacetic acid derivatives, whereby the halogen-loosening Effect of strongly electron-attracting groups, such as NO2, CN, SO2NH2, Acylamino or CF3, in the 2 and especially in the 3 position, the reaction with the secondary Amines of the formula XX is made much easier.

The reaction is carried out depending on the reactivity of the p-halophenylacetic acid derivatives preferably between room temperature and 320 °, optionally in an autoclave under pressure (up to 200 at). You can use the respective amines to be converted of the formula XX, such as piperidine, morpholine or pyrrolidine, in a large excess at the same time as Use solvent. Otherwise it is preferred to work in inert solvents wle Ohloroforn, benzene, dioxane, tetrahydrofuran, dimethylformamide, dichlorobenzene or ethylene glycol with acid-binding additives, such as potash or soda.

For example, it is easy to make from 3-itro-, 3-cyano-, 3-methylsulfonyl- or 3-sulfamoyl-4-bromo-α-methyl-naphthylacetic acid by reaction with homopiperidine, Thiomorpholine or pyrrole @ in the 4-homopiperidino, 4-thiomorpholino or. 4-pyrrolidino-naphthyl-acetic acid derivatives to manufacture.

When reacting primary imines of the formula XXI with compounds of the formula XXIV and XXV, the two can the latter, due to the definition of the radicals R5 and R6 in formula I, together aucti a compound represent such. B. #, # - Dihalogenalkylenes, such as 1,4-dibromobutane, 1,5-bichloropentane, 1 1,6-diiodohexane or 2,21-dichloroethyl ether, 3,3'-dibromo-di-n-propylthioether, but also in particular sulfur or oxygen ring compounds, such as tetrahydrofuran, -pyran -thiophene or -thiopyran.

The implementation of such sulfur or oxygen ring compounds with Amines of the formula XXI is generally carried out under drastic conditions, such as preferably at temperatures above 1500 C in the autoclave.

(m) Alkaylation of the primary hmine of ormel XXI or the secondary Amines of the formula XXII or XXIII to the compounds of the formula according to the invention I can also be done with olefins with 2-7 carbon atoms. Is it the alkylation? of compounds of the formula XXI, then two can be the same or two different Olefins as alkenyls also to alkadienes, such as 1,4-pentadiene, or via an oxygen or sulfur atom to form doubly unsaturated ethers or thioethers, such as divinyl thioethers or divinyl tar. In the alkylation of secondary amines the Formula XXII or XXIII with an olefin can also use this alkenyl with one of the radicals R5 or R6 can be linked directly or via an oxygen or sulfur atom.

Such addition reactions of clefins to primary or secondary Amines are, for example, in Houben-Weyl, l.c., Volume 11/1, (1957), nitrogen compounds II, described on pages 267-270. It is expedient to work at elevated pressure (up to about 700 at) and at elevated temperature (up to about 3500). It is useful to add a catalyst in this reaction, such as a cobalt or molybdenum catalyst, or an alkali metal such as B. Sodium. In these reactions it is advantageous to use the amines of the formula XXI, XXII or

XXIII to be used in excess.

(n) The reaction of a compound of the formula XXVI with a haloamine of the formula XXVII takes place under the conditions of a Friedel-Crafts alkylation of aromatics, as they are in Section (k) or in the Journal of American Chemical Society, Volume 86, page 1650 (1964), are described in more detail. For example, 3, α-dimethyl-naphthylacetic acid diethylamide with N-chloropiperidine in nitrobenzene or carbon disulfide in the presence of AlCl3, BF3 or ZnCl2 to 3, α-dimethyl-4-piperidino-naphthyl-acetic acid diethylamide realize.

(o) In compounds of the formula I in which, instead of the radical R3, hydrogen the following substituents can be introduced directly in the 2- or 3-position: (a) Chlorine, for example by direct reaction with elemental chlorine in one inert solvents such as water, carbon tetrachloride, glacial acetic acid, with or without additives specific catalysts, such as. B. FeCl3, AlCl3, SbCl3 or SnCl4, preferably between -10 and 100 ° C (cf.

Houben-Weyl, l.c., Volume 5/3; Pages 653 and 705 ff), or for example by reaction in a strongly hydrochloric acid solution with H202 or with NaClO3, with the chlorination is caused by the chlorine arising in statu nascendi (cf.Houben-Weyl, l.c., Volume 5/3, page 706) or, for example, by implementing SO 2012 in an inert Solvents such as chlorobenzene in the presence of radical-forming catalysts, z. B. peroxides, preferably at 80 ° - 180 ° (see Houben-Weyl, l.c., tape 5/3, page 892), or, for example, by reaction with NO2Cl or NOCl in carbon disulfide or hexane; (ß) bromine, for example particularly easily by direct replacement elemental bromine in an inert solvent such as e.g. B carbon disulfide, glacial acetic acid or carbon tetrachloride, but especially with the addition of specific nuclear bromination catalysts, which act as bromine carriers, such as. B. iron filings, AlCl3, AlBr3, FeCl3, iodine or Pyridine, preferably between -30 ° and 90 ° (cf. Houben-Weyl, l.c., Volume @ / 4 (1960), Pages 233 ff and 274-278), or, for example, by reaction with sub-bromine Acid, acyl hypobromites, N-bromo-imides, such as N-bromosuccinimide, N-bromophthalimide or other bromine-releasing fillers, such as 1,3-dibromo-5,5-dimethylhydantoin, in inert ones Solvents such as nitrobenzene or carbon disulfide, preferably up to 1500 (see. Houben-Weyl, l.c., Volume 5/4, page 248 ff. or 274 ff), or for example by reaction with NOBr or NO2Br in carbon disulfide or cyclohexane; (y) Iodine, for example through direct reaction with elemental iodine, especially in Presence of HgO in an inert solvent such as alcohol. Glacial acetic acid or benzene, preferably at temperatures between 0 ° and 1200 (cf.

Houben-Weyl, l. c., Volume 5/4, page 565), or for example by Reaction with iodine-iodine alkali solutions in the presence of carbonates, acetates, alkali lye, Ammonia or amines (cf.Houben-Weyl, l.c., Volume 5/4. Page 567), or, for example, by reacting mixtures of alkali iodides and oxidizing agents, such as alkali iodates, alkali nitrate or H @ O @, in inert solvents such as water, B @@ vinegar or alcohol, whereby claus released iodine reacts in statu nascondi, or for example by reaction with chloro iodide in dilute @@@ ig acid, preferably at 50 ° to 100 ° (cf. Houben-Heyl, Eand 5/4, pages 582 ff), or after mercurying for example in an aqueous or acetic acid medium with mercury-II-acetate for 2 or. 3-Hg-O-COCH3 compound and exchange of the organometallic radical against Iodine, e.g. by reacting with iodine or iodine-alkali solutions (cf.Houben-Weyl, l.c., Volume 5/4, pages 539 ff); Nitro, for example by nitration methods such as see them in Houben-Weyl, l.c., Volume 4 (1041), pages 167 to 250, and in Olah, Friedel-Crafts and Related Reactions, l.c., Volume III, (1964), pages 1939-1491 are.

The crucial nitrating agent is the vitronium ion and all Nitronium salts or reaction mixtures in which this nitronium ion potentially can be used to nitrate the aromatic nucleus, for example: a mixture of anhydrous nitric acid with EF3; Rental nitrates, such as Cu, Fe, Mn, Co, Ni nitrate, mixed with acetic acid or acetic anhydride; Metal nitrates, such as Ag, Ba, Na, K, NH4 or Pb nitrate, mixed with Friedel-Crafts catalysts, such as AlCl3, FeCl3, BF3 or SiCl4; Alkyl nitrates, such as ethyl nitrate, in a mixture with concentrated sulfuric acid, HBF4 or Lewis acid chlorides, such as BCl3, SnCl4, PCl4, PCl3, AlCl3, SiCl4, SbCl5 or FeCl3; Nitryl fluoride, chloride, bromide, perchlorate or tetrafluoroborate, preferably in the presence of Friedel-Crafts catalysts, such as AlCl3, FeCl3, ZrCl4 or AlBr3, in solvents such as carbon disulfide, n-pentane or CX; ; Nitrogen oxides, such as, NSOJ N2O4 or N203, in the presence of concentrated H2SO4, HF or Friedel-Crafts catalysts, such as BF3, AlCl3 or FeCl3, if appropriate in solvents such as tetramethyl sulfone or glacial acetic acid. As a solvent for this There are also nitration reactions nitromethane, nitroethane, nitropropane or acetonitrile in question. It is preferred to work between -20.degree. And + 120.degree.

Generally applicable to the introduction of the nitro group into the aromatic The following agents are also at the core: Concentrated nitric acid; Nitrating acid, a mixture of concentrated sulfuric acid with concentrated or anhydrous Nitric acid; Alkali nitrates, such as sodium or potassium nitrate, mixed with concentrated Sulfuric acid; Mixtures of concentrated nitric acid with pyrosulfuric acid, fuming sulfuric acid, glacial acetic acid or acetic anhydride; Mixtures of nitric acid, Sulfuric acid and glacial acetic acid; Acetyl or benzene nitrate; Nitrosulfonic acid, producible by introducing SO2 into smoking HNO3; Nitrosyl sulfuric acid; Nitroguanidine; highly concentrated nitric acid in the presence of dehydrating agents such as P2O5 or anhydrous hydrofluoric acid, if appropriate. in solvents such as nitrobenzene or polychlorethanes; a special nitration reaction consists in that one the substance to be nitrated in a solvent such as CHCl3, CHCl2 or. CCl4 solves, underlayed with concentrated sulfuric acid and then 4 anhydrous nitric acid in CHCl3, CH2Cl2 or CCl4 added. One generally works between -20 ° and 150 °; @) Alkyl, alkylmercapto, alkylsulfinyl, alkylsulfonyl, amino, alkyl- or dialkylamino, for example by reaction with the corresponding chlorine-bromine, iodine, hydroxyl or acyloxy compounds such as ethyl iodide, n-propyl bromide, n-butanol, ethyl acetate, Isopropyl sulfur chloride, isobutyl sulfinyl bromide, sec. Butyl sulfochloride, hydroxylamine, Chloramine or diethylchloramine, according to the conditions of a Friedel-Crafts reaction, as they are in G.A.

Olah, Friedel-Crafts and Related Reactions, 1964, l.c., volume en II, Chapters 17 to 20, and nd Volume III, Chapters 40 and 44, are described in more detail are. Lewis acids such as AlCl3, AlBr3, @, SnCl4, ZnCl2, FeC13, SbCl5 or HF, and as solvent n-hexane, carbon disulfide, Nitrobenzene, tetramethylene sulfone or nitroethane. The reaction preferably leads to between 70 ° and 180 ° C.

Instead of alkyl derivatives, it is also possible to use the corresponding olefins implement according to Friedel-Crafts, as in G.A. Olah, l.c., Volume II, Chapter 14 is.

For example, 4-piperidino-a-methyl-naphthyl acetic acid di- n-butylamide with isobutylene, methyl iodide, n-propanol, isopropyl acetic ester according to Friedel-Crafts to the 2- and 3-alkyl-4-piperidino-a-methylnaphthyl-acetic acid-di-n-butylamides to alkylate. Similarly, from 4-pyrrolidinonaphthyl0essigsäure-piperidid and Isopropyl sulfur bromide, ethylsulfinyl chloride, n-butyl sulfochloride, i, hydroxylamine respectively.

N-dimethyl-hydroxylamine 2- and 3-isopropylmercapto-, 2- and ethylsulfinyl-, 2- and 3-n-butylsulfonyl-, 2- and 3-amino- or. 2- and 3-dimethylamino-4-pyrrolidino-naphthyl-acetic acid: win piperidide.

1695385 (p) After diazotization of compounds of the formula I in which the radical R3 means NH2, the diazonium group can be replaced by F, Cl, Br, J, Replace NO2, CN, alkylmercapto, alkyloxy or CH.

The exchange for fluorine is in Houben-Weyl, i.c., Volume 5/3 (1-9625 on pages 213-231. One diazotizes, for example, in anhydrous Hydrofluoric acid and then heated or decomposed poorly soluble diazonium tetrafluoroborate thermally, whereby the 2- or 3-fluorine compounds develop.

Chlorine is preferred to the diazonium chloride group in aqueous Solution exchanged in the presence of copper-I-chloride according to the method of Sandmeyer (cf. Houben-Acyl, l.c., Eand 5/3 (1962), pages 846 to 852).

The exchange of bromine can be carried out, for example, according to the methods as described in Houben-Weyl, l.c., Volume 5/4, on pages 438 to 457 are. You can either use the diazonium bromide in aqueous solution in the presence of Copper-I-bromide according to Sandmeyer or after the reaction with bromine into the diazonium perbromide by boiling in solvents such as water or alcohol, to the bromine compounds decompose. But it is also possible to use the diazonium bromide after the reaction with HgBr2 to the diazonium mercury bromides thermally to the desired bromine compounds to decompose.

The exchange of the diazonium iodide group for iodine already succeeds gentle heating. But you can use catalysts, such as OuJ, CuBr or CuCl, for acceleration add to the reaction (cf. Houben-Weyl, l.c., Volume 5/4 (1960), pages 639 to 647).

The replacement of the diazonium group with oyan succeeds, for example after Sandmeyer in the presence of CuN and alkali metal cyanides, such as NaCN or KON, already in the Cold, preferably at 0 ° to 50 ° C, or, according to Gattermann's variation, with Alkali cyanide with the addition of Eupfer powder. The Korzykski variant is used a double salt of KCN and nickel cyanide as a catalyst. The preferred pH ranges for the cyan exchange are between 4 and 9 (cf.

Houben-Weyl, l.c., Volume 8 (1952), pages 311 ff. And Chemical Reviews, Bsnd 42 (1948), pages 213 ff).

The exchange of the diazonium group, preferably the Diazoniumtetrafäuorborats or Diazonium-cobalt-III-nitrits, against the Niirogruppe is in Qusrterly Reviews, Volume 5 (1952), pages 361 ff, and Chemical Reviews, Volume 40 (1947), page 269 ff, described and succeeded, for example, by reaction with alkali nitrites, such as NaN02 or KNO2, in the presence of catalysts such as copper oxide or copper hydroxide, already in the cold.

Furthermore, the diazonium salt group succeeds without difficulty to be exchanged for alkoxy or alkyl mercapto groups, as in Houben-Weyl, l.c., Volume 9 (1955), on pages 124 ff and 116 ff is described. For example the diazonium group by heating in aqueous alcoholic solution against the corresponding alkoxy groups replaced. The exchange against alkyl mercapto groups takes place by reaction with alkyl mercaptans, preferably in an alkaline solution by heating or already in the cold with the addition of catalysts such as copper powder. The intermediate diazosulfides do not need to be isolated.

The aqueous solutions can be prepared by heating, if necessary by boiling hydrolyze the diazonium salts to the corresponding phenols (cf. Quarterly Reviews, Volume 6, pages 360 ff (1952).

Compounds of the formula I which have a carbonamide group instead of R3 in 2--. or 3-position can be converted into the corresponding nitriles by elimination of water convert; for example thermally, preferably between 170 ° and 300 ° C, in particular with the addition of catalysts such as A1203, pumice stone, glass powder, sand or graphite, or chemically with dehydrating agents such as P2O5; P2S5; PCl5; POCl3; PCl3 together with chlorine; SO2Cl2; AlC @ 3 as a double compound with NaCl; BF3, usually with the addition of an organic acid; COCl2 with the addition of tertiary amines, such as pyridine, or acylated secondary amines; Trichloromethyl chloroformate; Benzotrichloride with the addition of catalysts such as ZnCl2, FeCl3, AlCl3, more concentrated Sulfuric acid or phosphoric acid; Acid anhydrides, e.g., acetyl benzoic acid; aromatic Sulfonic acids or sulfonic acid halides, such as p-toluenesulfochloride. hall works without or with the addition of inert solvents such as benzene, dichlorobenzene, tetrahydrofuran, Xylene, or nitrotenzene, preferably between 100 and 250 ° C.

The nitro group in the 2- or 3-position of the compounds according to the invention of the formula I can be carried out according to the reduction process given under section (i) convert to the NH2 group.

It is also possible to produce 2- or 3-iodo or 2- or 3-iodoso derivatives To reduce 2- or 3-iodine compounds of the formula I, in particular with hydrogen iodide, optionally with the addition of red phosphorus. You can also use the 2- or 3-iodoso compounds disproportionate to the 2- or 3-iodine and 2- or 3-iodo compounds. The iodoso group can be directly in the 2- or 3-position, for example by reaction with (JO) 2SO4 introduce (see Houben-Weyl, l.c., Volume 5/4, pages 670 - 672).

Furthermore, compounds of the formula I which, instead of R3, have a Hydrazino or a hydrazione group substituted by hydrocarbon radicals wear, diazo aert. After conversion into the biazonium perbromide or iodide : iit bromine or iodine, preferably in solvents such as alcohol or glacial acetic acid the thermolysis at preferably 500 to 130 ° to the 2- or 3-bromine or 2- or 3-iodine compounds of formula 1.

Compounds of the formula I which have an OH-, SH-, Wear NH2 or SO2NH2 groups, optionally as salts, in particular as Alkali or alkaline earth salts, may be present, for example, by reaction with olefins such as isobutylene, alkyl halides such as ethyl iodide, n-propyl bromide, Isopropyl chloride, or with equivalent alkyl derivatives, such as alkyl sulfuric acid or alkyl sulfonic acid esters, e.g. dimethyl sulfate or isopropyl-p-toluene sulfonic acid ester, but also with aliphatic diazo compounds, such as diazomethane, with cleavage of nitrogen, optionally also with amines or alcohols, smoothly mono- or optionally also dialkylated. The solvents used are, for example, water, ethanol, Benzene, tetrahydrofuran, xylene or their mixtures. Often one uses alkalis, like NaO or ICOII, in an equivalent amount or in excess.

As far as possible, the alkylation conditions are used as they are are described in sections (1) and (m).

So you can choose from 3-hydroxy, 3-mercapto, 3-amino or

3-sulfamoyl-4-homomorpholino-naphthylacetic acid diethylamide through Reaction with methyl iodide, the 3-methoxy, 3-methylmercapto, 3-methylam @ no and 3-dimethylamino or. 3-methylsulfamoyl- and 3-dimethylsulfamoyl-4-homomorpholino-naphthylacetic acid diethylamides or from 2-mercapto or 2-hydroxy-4-d @ -n-butylamino-α-methylnaphthylacetic acid heptyl ester by reaction with Diazorriethar. or dimethyl sulfate the corresponding 2-methyl mercapto or 2-methoxy derivatives obtained.

2- or 3-amino derivatives of the compounds according to the invention of the formal I can be with carboxylic acids or carbic acid derivatives, as in Houben-Weyl, l.c., Volume 8, pages 655 to 572 described, acylate. Come as carboxylic acid derivatives for example carboxylic acid esters, anhydrides or halides, such as chlorides, bromides or iodides, but also amides in question. The carboxylic acid derivatives themselves are used as a solvent or works, for example, in benzene, toluene, dioxane, tetrahydrofuran or chloroform. In the case of acylation with carboxylic acid halides, preference is given to using Acid scavengers, such as sodium or potassium carbonate, pyridine, dimethylamine or trimethylamine. But you can also acylate with ketenes in inert solvents. You can too Thioamides, imino ethers, amidoximes, amidines or hydrazidines, for example by heating convert into the amides with water or aqueous solvents (cf.

Houben-steyl, l.c., volume 8, pages 695, 700, 703).

The oxidation of 2- or 3-alkyl mercapto derivatives of compounds of formula 1 to the corresponding sulfinyl or

Sulphonyl compounds succeed through the most varied of oxidation processes, as described in section (and in Nouben-Weyl, l.c., Volume 9. (1955), pages 217 bis 232. In particular, H22 is used as the oxidizing agent; Peracids, w @ e benzoic acid; Chromic acid; Nitric acid; nitrous gases; Chlorine or bromine, elemental or in the form of hypohalites; iodosobenzene or potassium permanganate. Electrolytically too can be oxidized.

For the oxidation of the 3-nitroso compounds to the 3-nitro compounds of formula I, strong nitric acid or mixtures of HNO3 are used predominantly and H2O2 in glacial acetic acid (cf. Eouben-Weyl, I.C., Volume 4 (1941), pages 253 ff).

Finally, the 2- or 3-sulfamoyl compounds succeed Formula I from appropriately substituted reactive 2- or 3-sulfonic acid derivatives, such as sulfonic acid chlorides, bromides, iodides, anhydrides or esters Reaction with ammonia to obtain primary or secondary amines, as in Houben-Weyl, l.c., Volume 9, (1955), pages 599-627. One works first in inert solvents such as benzene, toluene, tetrahy; rofuran, chloroform or Dioxane, at temperatures between -20 ° and 140 °. During the conversion of the sulfonic acid halides it is advantageous to add acid scavengers, such as K2CO3, pyridine or dimethylaniline. Even one can get the sulfonamides from the corresponding sulfonic acid ammonium salts at high Temperatures between 180 ° - 400 ° or by reducing sulfonic acid azides, e.g. 3. with zinc dust in glacial acetic acid. Finally it succeeds in using sulfinic acids Hydroxylamine or with amines with the addition of halogens, such as () chlorine or bromine, or to convert ulfenamide into sulfonamides by KMnO4 oxidation. (See Houben-Weyl, l.c., Volume 9, Pages 607-609).

(q) The cyclization of substituted aminophenylacetic acids of formula I, in which the radicals R5 and R6 are alkyl with 1-7 carbon atoms substituted by OH or SH mean for O-ring or S-ring-containing compounds takes place analogously to the methods, as used for the production of cyclic ethers of the morpholine or cyclic type Thioethers of the thiomorpholine type are known. Diols or dithiols can preferably by heating with acidic catalysts into the desired cyclic ethers or Thioethers are transferred. The main catalysts that may be mentioned are: hydrogen chloride (e.g. concentrated aqueous hydrochloric acid), hydrogen bromide, phosphoric acid, sulfuric acid (Concentration between about 50 and 98%), sulfonic acids such as p-toluenesulfonic acid, acidic ion exchangers, Lewis acids such as zinc chloride and acid anhydrides such as acetic anhydride. The acids mentioned can be used in the anhydrous or water-containing state will. If necessary, you can use an additional inert solvent such as Benzene, toluene or xylene. The reaction temperatures of the diol or

Dii: hiol cyclizations range from about 50 to 2000, each according to the cyclizing agent used; The reaction times range between about 8 and 120 hours. Ring closure with 48% hydrobromic acid is particularly preferred at about 130 °. The oxygen-containing or sulfur-containing blade can also be closed are made by heating a salt, e.g. B. the hydrochloride, a diol or dithiol to around 200 to 2100 or by H2O resp.

H2S cleavage of the free diol or dithiol on SiO2 / Al2O3 about 375 ° - 400 °. instead of the diols or dithiols, for example, the corresponding dihalides, such as dichlorides, dibromides or diiodides with metal oxides, like Na20, K20, HgO or CaO, or with metal sulfides like Na2S, K2S or BaS, in higher solvents such as dichlorobensol, ethylene glycol, diniethylformamide, xylene, at 600 to 250 ° C to form the desired compounds containing 0 or S rings.

Starting compounds of the formula I, wherein-one, the. Residues R5 and R6 through OH or SH the other radical R or R6 in each case through XJ, preferably chlorine, Bromine or iodine, which is substituted, are made according to the methods of Williamson's synthesis eyclisiert, whereby one expediently the OH or the SH group in the corresponding Alkali alcoholate or

Alkalimerkaptid transferred; this easily cleaves alkali halide and thus forms the desired O or S ring.

So you can use 3-chloro-4- (bis [ß-hydroxyethyl] -amino) - or 3-chloro-4- (bis Cycloheptyl [-β-chloroethyl] amino) naphthylacetic acid smoothly gives cycloheptyl 3-chloro-4-morpholino-naphthylacetate realize. 5. It is also possible to obtain 2-ethylmercapto-4- (thiomorpholino-1) -methyl-naphthylacetic acid-2'-thoxyethyl ester from 2-ethylmercapto-4- (bis- [ß-mercaptoethyl] -amino) - or from 2-ethylmercapto-4- (bis- [ß-bromoethyl] -amino) - # 053-methyl-napthylacetic acid-2'-ethoxy ethyl ester to win. Correspondingly substituted compounds containing sulfur rings, wherein the sulfur is present as a sulfinyl or sulfonyl group, according to the in Section (i) given methods to the desired S-ring-containing substituted Aminophenylacetic acids of the formula I reduce.

(r) Finally, it is possible to use substituted aminophenylacetic acids Formula I from appropriately substituted naphthylpyruvic acids by decarbonylation to obtain; namely thermally analogous to the I? eoarboxylation of malonic acids, such as in section (g) described-n, or chemically, for example by heating in concentrated Sulfuric acid or by oxidative decarbonylation in sulfuric acid or salic acid Solution in the presence of oxidizing agents such as H2O2.

For example, methyl 3-nitro-4-pyrrolidino-5,6- (butadien-1 ', 3'-ylene) cinnamate can be used Brominate in OS2 to the dibromocinnamic acid derivative, react with piperidine in alcohol and with dilute sulfuric acid to form 3-nitro-4-pyrrolidino-naphthylpyruvic acid hydrolyze, which then in hydrochloric acid solution with H202 to 3-nitro-4-pyrrolidinonaphthyl-acetic acid is decarbonylated smoothly by oxidation.

(s) Can be prepared by hydrogenation of quinone methides of the formula XXX by splitting off H 2 O or hydrogen halide from compounds of the formula 1, in which R1 denotes OH or halogen, with the aid of, for example, polyphosphoric acid, conc. H2SO4, Al2O3 or NaOH or KOH, according to the hydrogenation methods described in section (i) compounds of formula 1 are obtained smoothly.

For example, that from 4-homopiperidino-3, a-dimethyl-a-hydroxy-naphthylacetic acid n-butyl ester Quinone methide of the formula XXX obtained by splitting off H20 to give 4-Hompiperidino-3, Hydrogenate α-dimethyl-naphthylacetic acid n-butyl ester.

But you can also use organometallic compounds of the formula XIV, such as n-butyllithium or methylmagnesium iodide, to quinone methides Add formula XXX to the compounds of the formula I according to the invention. One works preferably in inert solvents such as ether, tetrahydrofuran, benzene, toluene, Dichloroethane, and at reaction temperatures between -? 0 and the boiling temperatures the solvent. You work with sensitive metal, organic compounds under a protective gas such as nitrogen.

So you can z. B. methyl, ethyl or isopropyl magnesium iodide that from 4-morpholino-2-trifluoro-methyl-α-chloronaphthylacetic acid diethylamide quinone methide of the formula XXX obtained by HCl stripping to the corresponding a-methyl-. a.-Ethyl-taw. Add α-isopropyl-naphthylacetic acid derivatives. t) In addition, aminophenylacetic acid esters or

-amides of the formula I by adding carboxylic acids of the formula I, in which for A COOH stands under dehydrating conditions with alcohols of the formula XXXI or amines of the formulas XXXIII or XXXIV.

In this way, the esters are obtained using the known methods as described in Houben-Weyl, l.c., Volume 8 (1952), pages 516-526. For example you can use the respective carboxylic acids with alcohols of the formula XXXI with or below Addition of catalysts such as sulfuric acid, hydrogen chloride, phosphorous acid, aromatic Sulphonic acids, such as p-toluenesulphonic acid, or of ion exchangers, preferably between 10 ° and the boiling point of the alcohols in question, which are usually in the Excess are used, esterify. The esterification equilibrium is favorable to influence, nan can also work in the presence of water-binding agents, such as B. with the addition of molecular sieves or anhydrous heavy metal sulfates, such as copper, isene, nickel, cobalt or zinc sulfate.

1 "on can also the reaction water according to the methods of azeotropic Remove distillation.

Esterification and amidation reactions take place under very mild conditions, if the water of reaction is chemically by adding preferably molar Kengen on carbodiimides, such as N, N'-dicyclohexylcarbodiimide, in inert solvents, such as Ether, dioxane, benzene or ethylene glycol dimethyl ether, especially in the presence of bases such as pyridine binds. For example, from 4-piperidino-3-chloro-α-ethyl-naphthyleseetic acid by reaction with 3-oxa-5-methoxy-pentanol-1, ß-aminoethyl alcohol, cyclohexanol or with ß-Pkhenyläthylamin, Homopiporidin, or # - (N'-ethyl-piperazino) -propylamine the corresponding esters or amides of the formula I are obtained.

Furthermore, one can use the carboxylic acids of the formula I, in which A 000H stands, also with any esters of the formula XXXII, which are preferably in excess are used, especially in the presence of basic or acidic catalysts, such as, for example, sodium alcoholate or sulfuric acid according to that in Houben-Weyl, I.C., volume 8, page 530, describe uresterification method for esters according to the invention Esterify Formula I. It is thus possible, for example, by reacting 4-homomorpholino-2-nitro-α-methyl-naphthylacetic acid with cyclopentyl acetate, α-hydroxy-ß-cyclohexylethane propionate or 1-hydroxy-4-thia-n-octane benzoate the corresponding cyclopentyl, cyclohexylethyl or 4-thiane-octyl-naphthyl acetic acid ester derivatives to manufacture. m.n also arrives at esters of the formula I if the respective Carboxylic acids with diazoalkanes, such as diazomethane, diazoethane or phenyldiazomethane, in inert solvents such as ether, benzene or methanol, with elimination of nitrogen according to Houben-sfeyl, l.c., Volume 8, page 533, or the carboxylic acids to olefins, which are derived from alcohols of the formula XXvI by formal elimination of H2O, such as Isobutylene or cyclohexene, or to acetylenes, is added. As in Houben-Weyl, l.c., beite 534 carried out, the addition succeeds preferably in the presence of catalysts, such as ZnCl2, BF3, concentrated sulfuric acid, arylsulfonic acids, pyrophosphoric acid, Boric acid or oxalic acid, at 0 ° - 200 ° and in inert solvents such as dioxane, Tetrahydrofuran, ether, benzene or xylene.

Pressures between 1 - 300 at are used. So you can z. B. 4- (2 ', 6'-Dimethyl-piperidino) -3-bromo-naphthylacetic acid with diazomethane, diazoethane or phenyldiazomethane smoothly to the corresponding methyl naphthylacetate, convert ethyl ester or benzyl ester derivatives and at 4-diethylamino-3, α-dimethyl-naphthylacetic acid 5,8-dixoa-n-decene-1, 4-ethyl-4-aze-n-hexene-1, 5-isopropyl-4-oxa-n-hepten-1 to the corresponding 5, ß-dioxane-decyl-, 4-ethyl-4-aza-n-hexyl- or 5-isopropyl-4-oxane-heptyl-esters of these naphylacetic acids.

One arrives at ß-hydroxyethyl or ß-aminoethyl ester derivatives, if you add the respective carboxylic acids to epoxides or to ethyleneimines, which can be formally obtained by dehydration from the alcohols XXXI or the amines XXXIII or XXXIV can think of originated. while the reaction with epoxides is preferred in the presence of basic catalysts, such as sodium acetate, and at temperatures up to 1200 succeeds, the ethyleneimines react at temperatures between 0 ° - 30 ° in inert solvents smoothly with the carboxylic acids to form amides of the formula I. So you can z. B. 4-Di-n-propylamino-2-bromo-α-isobutyl-naphthylacetic acid with ethyleneimine, propyleneimine, ethylene oxide or propylene oxide smoothly to the corresponding ß-Hydroxy-ethyl or ß-Hydroxy-propylnaphthylacetic acid amide or. ester derivatives realize.

Aminonaphthylacetic acid amides of the formula I can also be obtained when carboxylic acids of the formula I in which A is COOH, with isocyanates of the Formula XXXV boils in an inert solvent such as benzene, toluene or xylene, until the CO2 development has ended. So it succeeds z. B., from 4-thiomorpholino-3-chloro-a, a-dimethylnaphthylacetic acid by reaction with methyl, ethyl, n-octyl or n-Dodecyl isocyanate to produce the corresponding naphthylacetic acid ester derivatives.

According to Houben-Weyl, lc, Volume 8, page 660, instead of the isocyanates, the easily accessible in which A2 has the meaning given above can also be used . Azides AC <0 has, an N3, set, since these azides convert under the reaction conditions in the isocyanates XXXV.

In addition, esters of the formula I according to the invention are obtained by Metal salts of the formula 1, in which A is COOMetall, according to the Houben-Weyl, 1.c., Volume 8, page 541, described processes with compounds of the formula XXXVI implements. Men preferably uses the mostly poorly soluble silver or lead salts, but one can also use the alkali or alkaline earth salts Ei @. The salts are preferred in an inert solvent such as ether, benzene or petroleum ether with the compounds of the formula XXXVI, such as, for example, n-butyl bromide or n-dodecyl iodide, which one especially used in excess, implemented. So you get z. B. from 4-homothiomorpholino-2-nitro-5,6,7,8-teirahydronaphthyl-acetic acid Silver by reaction with n-butyl bromide, 2-ethyl-3-oxa-n-hexyl iodide or 2-isopropyl-2- @ za-n-pentyl bromide the associated tetrahydronaphthyl acetic acid ester derivatives.

Furthermore, aminophenylacetic acid derivatives of the formula 1 are obtained, by converting esters of the formula I in which A is COOR12 and R12 is an optionally means any substituted hydrocarbon radical, preferably in the presence basic catalysts, with alcohols of the formula XXXI, esters of the formula XXXII, Amines of the formulas XXXIII or

XXXIV or reacts with hydroxylamine.

The reaction of the esters of the formula I in which h is COOR12 with Alcohols of the formula XXXI or esters of the formula XXXII proceeds according to the in Houben-Weyl, + 1.c., Pages 526-529, described transesterification methods and is preferably used in the presence basic catalysts, such as sodium alcohol, in particular carried out in such a way that # after equilibrium has been established, a reactant equilibrates by distillation is withdrawn. So it succeeds z. B., 4-piperidino-3-ethylmercapto-α-ethyl-5,8-dihydro-naphthylacetic acid methyl ester with n-hexyl alcohol or n-hexyl acetate to form the dihydronaphthalene acetic acid n-hexyl ester derivative to transesterify.

+ Volume 8, Amides or hydroxamic acids of the formula I wins one can also react by reacting the esters of the formula I, in which A is COOR12, with amines of the formulas XXXIII or XXXIV or with hydroxylamine. You bet easily saponifiable windows, such as methyl or phenyl esters, and works if necessary # he addition of a basic catalyst, such as sodium alcoholate, in suitable solvents, such as siaseer, methanol, benzene, or chloroform, the temperature being preferred between 200 and the boiling point of the solvents used. This is how it works it z. X ,, 4-piperidino-3-methylmercapto-naphthylacetic acid ethereal ester with hydroxylamine tum corresponding naphthalenacethydroxamic acid derivative or with N -β-aminoethyl-N-methylpiperazine or with N- (ß-amino-n-propyl) piperidine. or morpholine to the corresponding naphthalene acetic acid amide derivatives to implement.

Furthermore, compounds of formula 1 are obtained - if acid halides are used or acid anhydrides of the formula I in which A is the radicals CO halo or COO acyl, with alcohols of the formula XXXI, with amines of the formula XXXIII or XXXIV or with hydroxylamine implements.

So you can analogously to the in Houben-Weyl, l.c., Volume 8, pages 543 - 547, methods described the acid halides or their salts, if it is are amino acid halides, or acid anhydrides with or without the addition of acid-binding agents, such as. Be caustic soda, potash or pyridine, with the alcohols of the formula XXXI, preferably using an excess of the alcohols as Solvent used.

The reaction with amines of the formula XXXIII or XXXIV or

Hydroxylamine proceeds as in Houben-Weyl, l.c., Volume 8, pages 655.- 658, in the same way. It is used here as an acid-binding agent preferably one Excess of the amine and sets as an inert solvent especially ether, benzene, tetrahydrofuran, dioxane, methanol or toluene.

So mah z. B. 4-homopiperidino-2-methyl-α. α-di-n-butyl-nap thylessigsäurech brid or acetane hydride with isopropanel or N-methyl-P @ perazine or with hydroxylamine to the corresponding isopropyl naphthylacetate derivative or -N-methyl-piperazide derivative or naphthyl acethydroxamic acid derivative implement.

In all of these reactions in section (t), preference is given to using the following alcohols A1OH of the formula XXXI or

Amines A2A3NH of formula XXXIII or isocyanates A2N = C = O of formula XXXV or compounds type of formula XXXVI: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-amyl, n-hexyl, n-heptyl, n-octyl, n-decyl, n-dodecyl, allyl, crotyl, hydroxymethyl, propargyl, ß-hydroxyethyl, ß-hydroxy-n-propyl, # -hydroxy-n-propyl, ß-methoxyethyl, ß-ethoxyethyl, 3-oxa-5-hydroxy-pentyl-, 3-oxa-5-methoxypentyl-, 3-oxa-5-butoxy-pentyl-, 3, 3,6-dioxa-8-hydroxy-octyl-, 3,6-Dioxa-8-hydroxy-octyl, 3,6-Dioxa-8-methoxy-octyl, 3-oxa-5-ethoxy-pentyl, ß-aminoethyl, # -Aminopropyl, ß-dimethylaminoethyl, ß-diethylaminoethyl, ß-di-n-propylaminoethyl, # -Dimethylaminopropyl-, # -Diethylaminopropyl-, ß-methyl - # - diethylamino-propyl-, Cyclohexyl-, cyclopentyl-, ß-cyclohexylethyl-, # -cyclohexylpropyl-, N-methylpiperidyl- (4) -, (N-methyl-piperidyl-3) -methyl-, ß- (N-methyl-piperidyl-2) -ethyl-, ß-piperidinoethyl-, ß-Pyrrolidino-ethyl-, ß-Homopiperidinoäthyl-, ß-Morpholinoäthyl-, ß-Thiomorpholinoäthyl-, ß- (N'Methylpiperazino) -äthyl-, ß- (N'-Aethylpiperazino) -äthyl-, ß- (N'-Phenylpiperazino) -äthyl-, ß- (N'-2-Hydroxyäthyl-piperazino) -äthyl-, ß- (N'-Methylhomopiperazino) -äthyl-, # -Piperidino-propyl-, # -Pyrrolidinopropyl-, # - (N'- Methylpiperazino) propyl, # - (N'-ethylpiperazino) propyl, # - (N'-Phenylpiperazino) -propyl-, -Morpholino-propyl-, # -Thiomorpholino-propyl-, ß-morpholino-propyl-, ß-piperidinopropyl-, ß-pyrrolidino-propyl-, ß- (N'-methylpiperazino) -propyl-, ß-methyl - # - morpho tno-propyl-, ß-methyl - # - piperidin -propyl-, ß-methy - # - pyrrolidino-propyl-, # -Dimethylaminobutyl-, # -Diethylaminobutyl-, # -Mercaptoäthyl-, i'henyl-, benzyl-, o-methyl-phenyl-, p-methylphe, nyl- 'p-ethylphenyl-, p-methylbenzyl-, ß-pnenylethyl-, α-naphthyl, ß-naphthyl, α-phenylethyl alcohol or amine or isocyanate or chloride, bromide, iodide, p-toluene sulfonate.

Esterification products are preferably used as esters of the formula XXXII of the above alcohols of the formula XXXI with formic acid, acetic acid, propionic acid, n-butyric acid, isobutyric acid or benzoic acid in question. -As amines A4NH of the formula XXXIV is preferably used piperidine, pyrrolidine, morpholine, thiomorpholine, N-methylpiperazine, N-ethylpiperazine, N-n-propylpiperazine, N-phenylpiperazine, N- (ß-hydroxyethyl) piperazine, Piperazine, N-methyl-homopiperazine, N-phenyl-homopiperazine.

(u) Furthermore, compounds of the formula I can be obtained by Derivatives of the formula I which, instead of A, contain corresponding thioester, imino ether, Oximinoether, hydrazone ether, thioamide, imidine, amidoxime or amidhydrazone groupings wear with dilute aqueous bases or acids, such as. B. ammonia, NaOH, K2C03, HCl, H2SO4, optionally with the addition of a solubilizer such as ethanol or Methanol, with elimination of hydrogen sulfide, ammonia or amines, hydrazine or hydrazine derivatives or hydroxylamine to the corresponding esters or amides hydrolyzed. While z. B. most Iminoatherhydrochloride in aqueous solution immediately decompose into the esters and ammonium chlorides at room temperature other Derivatives such as B. some amidoximes or thioamides, too hydrolysis temperatures up to 100 °.

For example, 4-piperidino-2-brc-a-ethyl-5,6,7,8-tetrahydronaphthy -essigsäureiminoäthylester # HCl or -ox minoäthylester # HCl or -hydrazone minoäthylester # HCl smooth to the ietrahydronaphthylacetic acid ethyl ester derivatives and 4-piperidino-3-nitro-naphthylacetic acid thioamide, - -amdoxime or -amidhydrazone to the corresponding naphthylacetic acid amide derivatives hydrolyze.

(v) In addition, amides of the formula I are obtained by using nitriles of the formula I, in which A is CN, according to Houben-Weyl, l.c., Volume 8, page 661, in alkaline or acidic medium, such as aqueous sodium hydroxide solution or concentrated sulfuric acid, preferably partially saponified between 200 and 200 °.

But you can also use the nitriles by hydrogen peroxide or organic Peracids, preferably in aqueous-alcoholic NaOH between 200-1000, to the hydrolyze amides of the formula I according to the invention.

This gives 4-piperidino-3-chloro- or 4-homopiperidino-3-n-butyl-5,6- (butadien-1 ', 3'-ylene) benzyl cyanide the corresponding naphthyl acetamide derivatives of formula 1.

(w) The hydrolysis of thioamides ultimately also leads to di.

Willgerodt reaction, with the help of which ketones of the formula XXXVII comes to amides of the formula I. According to Houben-Weyl, l.c., Volume 8, page 665, sets the ketones XXXVII with sulfur and amines of the formula XXXIII or XXXIV, if appropriate in inert solvents, such as. B. dioxane or tetrahydrofuran, by longer Boil under reflux to give the thioatnides. The hydrolysis of not necessarily to insulating th @ oamide is carried out so mildly that the saponification is at the amide level stop.

For example, from 4-dimethylam @ no-3-fluoro-1-acetyl naphthalene by reaction with NH3 / S 4-dimethylamino-3- @ luoro-naphthalene acetic acid amide.

Amides of the formula I are also obtained by oximes of the Formula XXXVIII, as described in more detail in Houben-Weyl, l.c., Volume 8p page 669, with acidic agents such as 3. concentrated sulfuric acid, phosphorus pentachloride or Benzols': Jfachlorid, preferably at temperatures between 80 ° -180 ° Beckmann rearrangement subjects. So you can z. B. [4- (2 ', 6'-Diethylpiperidino) -3-isopropoxy-α-methyl-5,6, - (butadien-1', 3'-ylene) -benzyl-] n-propyl ketone oxime to the corresponding naphthalene acetic acid-N-n-propylamide derivative rearrange.

Finally, ketones of the formula XXXIX according to Houben-Acyl, l.c., Volume 8, page 671, with HN3, preferably in inert solvents such as benzene or Chloroform, and in the presence of acidic Xatalysts, such as. B. concentrated sulfuric acid, at temperatures between 400 and + 100 ° due to Schmidt degradation in amides of the formula I convert.

For example, it is possible to produce [4-piperidino-2-methyl-5,6- (butadien-1 ', 3'-ylene) benzyl] ethyl ketone with HN3 to convert to 4-piperidino-2-methyl-naphthylacetic acid-N-ethylamide.

(x) Hydroxamic acids of the formula 1 can also be obtained by Aldehydes of the formula XL according to Angeli either with a Sslz, preferably alkali or alkaline earth metal salt, nitrohydroxylamic acid, for example in aqueous or alcoholic solution, cder with benzenesulfonylhydroxylamine, f nebesondera in alkaline-aqueous or alcoholic solution. In both cases the salts are obtained the end which amn can win the free hydroxamic acids by acidification.

So you can use the 4-piperidino or 4-homomorpholino or

4-Diethylamino-3-chloro-α-mathyl-naphthyl-acetaldehyde with nitro-hyd @@ xylamic acid or benzenesulfonylhydroxylamine to the corresponding naphthyl-acethydroxamic acid derivatives realize.

But one can also use the oximes of the aldehydes XL, as in Houben-Weyl, l.c., Volume 8, page 689, preferably with Carosher acid, with hydrogen peroxide or organic peracids, such as benzoic acid, between -20 ° and 100 ° to the corresponding Hydroxamic acids of the formula I oxydisren. thus obtained, for example, by oxidation of 4-morpholino-, 4-homomorpholino- and 4-thiomorpholino-α, α-dimethylnaphthyl-acetaldehyde oxime the corresponding N @ phthyl-acethyldroxamic acids.

Orthoesters of Formula 1 are obtained by adding salts of the iminoesters of the formula I, in which A is C (= NR13) OR12 and R12 and R13 are those given at the outset Have meaning with alcohols of the formula XLI, preferably between -20 ° and + 60 °, implements. In particular, the respective alcohols in excess are used as solvents. or dioxane, ether, benzene or uretrahydrofuran. The iminoesters are each off the corresponding nitriles by addition of any alcohols, preferably in the acid medium available.

For example, 4-piperidino-3-acetamino-α-ethyl-5,6-dihydronaphthalene-acetic acid iminoethyl ester is obtained # HCl by reaction with methanol, ethanol, isopropanol, n-buta # el, # ec.-butanol or isobutanol, the corresponding dinhydronaphthyl-acetic acid orthoester derivatives.

But one can use organometallic compounds of the formula XLII, in particular Grignard or lithium compounds, with orthocarbonic acid esters of Convert formula XLIII * to orthoesters of formula 1 according to the invention. This reaction takes place under the conditions customary for Grignard reactions, in that the components in an inert solvent such as ether tetrahydrofuran or dioxane, initially combined with cooling and the reaction at room temperature or by briefly Refluxing leads to results.

For example, from 4-piperidione-2-methyl-5,6- (butadiene-1 ' 3'-ylene) benzylmagnesium iodide and methyl, ethyl or isopropyl orthocarbonate the orthoesters of formula 1 according to the invention.

Z) Finally, compounds of the formula I can be obtained by one compounds of the formula XLIII with compounds of the formula XLIV or compounds the formula XLV with compounds of the formula XLVI or compounds of the formula XLVII with compounds of the formula XLVIII under conditions which split off M1X3 or split off from compounds of the formulas XLIX to LIII M1X3.

The same methods are used for inter- or intramolecular M1X3 cleavage Methods already described in detail in sections k) and / or 1) are.

The respective naphthalene-acetic acid derivatives of the formulas XLIII, XLV, XLVII, XLIX to LIII are obtained from the appropriately substituted naphthyl-acetic acids of the formula I, in which A is COOH, or suitable derivatives of these naphthyl acetic acids, such as acid chlorides, esters or anhydrides, by reacting with the appropriate, mostly known from the literature, correspondingly substituted alcohols or amines according to the in Section t) more detailed procedures.

For example, 4-piperidino-3-chloro-α-methylnaphthyl-estersic acid-3'-iodine-n-propylene @ er with sodium methanolate, sodium ethyl mercaptide, piperid @ n or N-methyl piperazine to the corresponding naphthyl-acetic acid-3'-methoxy or -3'-ethyl mercapt or -3'-piper ino- or -3 '- (N'-methyl-piperazino) -n-propyl ester derivatives @metzen.

It is also possible, for example, to use 4-homomorpholimo-2-trifluoromethyl-naphthyl-acetic acid 2'-aminoethyl ester smoothly on the 2'-amino group with methyl bromide, n-butyl iodide or isopropyl bromide to alkylate the corresponding 2'-dialkylaminoethyl esters.

Also 4-thiomorpholino-3-nit @ o-α-methyl-naphthyl-acetic acid-N- (2'-iodo-ethyl) -amide can be added to the with pyrrolidine, morpholine, N-phenyl-piperazine or homopiperidine corresponding naphthylacetic acid-N- (2'-pyrrolidino- or -N- (2'-morpholino- or. -N- (2'-phenylpiperazino- or -N- (2'-homopiperidino-ethyl) -amide derivatives.

The ring closures of, for example, 4-piperidino-3-chloro-naphthyl-acetic acid-bis-N- (2'-chloroethyl) -amide are also successful with aniline, n-butylamine or n-hexylamine to the corresponding naphthyl-acetic acid-piperazine derivatives, of 4-homomorpholino-3-methyl-α-ethyl-naphthyl-acetic acid-bis-N- (2'-hydroxyethyl) -amide to the corresponding naphthyl acetic acid morpholide and 4-xorpho-, lino-2-ethoxy-α-methyl-naphthyl-acetic acid-N- (2'-chloroethyl) -N- (2'-sodium mercapto-ethyl) -amide with elimination of NaCl to the corresponding naphthylacetic acid thiomorpholide. za) Compounds de @ general formula I, which by hydrogen planting in the naphthalene core Can be partially or completely hydrogenated under dehydrating reaction conditions be converted into naphthalene derivatives of the general formula I.

These dehydration reactions are treated with dehydrating agents such as e.g. sulfur, selenium, platinum, palladium, nickel or cobalt catalysts (as Metolle or on special carriers such as carbon, CaCO3 or SrCO3) or mi @ Selendi @ xide, dialkyl disulfidone such as diisoamyl disulfide, chloranil concentrated sulfuric acid or other mild oxidizing agents such as iron (III) chloride or nitrobenzene, executed. In favorable cases, even atmospheric oxygen can cause dehydration.

Silver @@ d copper catalysts, individually or as mixed catalysts, K @@ old-carbon catalysts, nickel-aluminum oxide catalysts as well as a variety of other mixed catalysts such as those used for dehydrogenation reactions in Houben-Weyl, I.C., Volume 4/2, pages 192-205, can be used.

The dehydrations with sulfur or selenium are calculated with the Amounts of sulfur or selenium carried out, with an excess because of the danger of side reactions is avoided.

The reaction is preferred at temperatures between 1400-3000 executed. Reaction times of 10-100 hours are usually required.

In the case of dehydrogenation with metal or metal oxide catalysts takes place dehydration in the case of solids, generally in the liquid phase; however, it can also take place in the gas phase when the substance to be hydrogenated is at normal pressure or reduced pressure and at the temperature necessary for dehydration in the vapor state passes over dehydration temperature and duration fluctuate in the case of catalytic substances. Dehydration naturally within wide limits, so that # reaction temperatures between 100 ° -350 ° C and reaction times between 5 - 100 hours may be required. Mesitylene, p-cymene, naphthalene, quinoline. Acetanilide and other highly aromatic compounds to be used.

The desired dehydrogenation reactions can be carried out with quinones such as chloranil achieve under much milder reaction conditions. Heating the to be dehydrated Compound in an inert solvent at temperatures between 700-1500C in a gentle way to the desired products.

So you can, for example, α-methyl-α- (4-piperidino-decalyl-1) acetic acid or 4-pyrrolidino-1,2,3,4-tetrahydro-α-ethyl naphthyl-1-acetic areamide smooth dehydrate to the corresponding naphthalene derivatives. zb) It continues to be possible, compounds of the general formula I in which instead of the divalent radical R4 is hydrogen and the radical R15 is as defined on page 46, to compounds of the formula I, in particular under acid-catalyzed reaction conditions, to cyclize. Such cyclization reactions are preferably carried out under the Conditions of a Friedel-Crafts reaction as described in section of) on page 73 and in detail in G.A. Olah, Friedel-Crafts and Related Reactions, 1964.1. c., Volume II, Chapters 14, 17 to 20 and 22, Volume III, Chapters 44 and 40 as well as in Chemical Reviews, Volume 38, 1946, pages 447-499. As catalysts one uses, for example, acids such as HC1, HBr, CF3COOh, HF, polyphosphoric acid or Lewis acids such as A1C13, AlBr3, SnCl, g, znCl2, BF3, ZrC14, FCC13, SbCl5 or TiC14 and as solvents n-hexane, carbon disulfide, carbon tetrachloride, Trichlorethylene, nitrobenzene, tetramethylene sulfone, nitroethane, polyphosphoric acid, Glacial acetic acid, trifluoroacetic acid and / or acetic anhydride. The cyclization reaction it is preferably carried out between 60 ° and 210 ° C. the aldehyde group in the remainder R15 can optionally be converted into thioaldehyde or Schiff's base or be protected as Acotal, Thioacetal or Aminal. It recommends s @ ch for the subsequent cyclization reaction to remove these protective groups. This can done by de-ketalization or re-ketalization according to known methods; in In some cases, however, the protected aldehyde component can also be involved in the reaction be used because the protective group among those used in the cyclization acidic reaction conditions are split up many times.

Compounds of the mel I in which, instead of the divalent radical R4, hydrogen and R15 is and where R15 is an optionally containing 1-2 double bonds Tetramethylene derivative of the formula LV or n-butyl with 1-2 double bonds and / or optionally denotes a triple bond, can also in general smoothly under Friedel-Crafts conditions intramolecularly to give compounds of the formula I alkylate. These cyclization reactions then run particularly rapidly and with good yields when X2 in the radical R15 of the formula LV is chlorine, bromine or iodine.

If X2 in LV has the meaning of a hydroxy, alkoxy, acyloxy, sulfuric acid or sulfonic acid residue assumes, there are also no difficulties in the intramolecular Friedel – Cafts alkylation. If R15 3-formyltrimethylene with possibly a double bond or X2 in the radical R15 of the formula LV OH, alkylated or acylated Mean OH, the cyclization can also be achieved excellently with dehydrating agents, how for example polyphosphoric acid, P2O5, POCl3, PCl5 or 30Cl2 with or without the addition of inert solvents such as benzene, xylene, nitrobenzene or dichlorobenzene, at temperatures between preferably 800 to 3000C.

For example, 4-pyrrolidino-y-chloro-2 (3'-formylpropyl) phenylacetic acid can be used smoothly to 4-pyrrolidino-2-chloro-7,8-dihydro-naphthalene-1-acetic acid and 4-piperidino-3- (4'bromobutyl) -α-methyl-phenylacetic acid amide cyclize to 4-piperidino-5,6,7,8-tetrahydro-α = methyl-naphthalene-1-acetic acid amide.

) To compounds of the general formula I in which R4 is tetramethylene with one odez means two double bonds, one also arrives at the fact that uan from compounds of the formula I in which, instead of the radical R4, one is simply represented by X6 substituted tetramethylene, optionally containing a double bond, the substituent X6, which is in particular C1, Br, J or by alkyl, acyl, alkylsulfonyl or alkoxysulfonyl substituted OH, SH or NH2, as HX6 under Eliminates the formation of a double bond.

Such elimination reactions proceed without difficulty. If compounds of the formula I are used in which, instead of R4, an optionally is tetramethylene containing a double bond and substituted by X6, then, by splitting off HX6, the respective dihydronaphthalene- or naphthalene derivatives.

In those cases where X6 is a halogen substance, can this under basic reaction conditions easily as hydrogen halide Formation of a double bond can be eliminated. The following can be used as bases: Alkali hydroxides, alkali carbonates, alcoholates such as potassium tert-butoxide. Amines like e.g. #imethylaniline, pyridine, collidine or quinoline; used as a solvent one: benzene, toluene, cyclohexane, methanol, dioxane, tetrahydrofuran, Dinethylfor mamid or tert. Butanol. The amines used as bases can often also be used in excess be used as a solvent.

If Z6 is its hydroxyl radical, then it is the elimination a simple elimination of water, which can be carried out according to known methods can. The preferred dehydrating agent is POCl3, polyphosphoric acid, Formic acid, perchloric acid, acetic anhydride, thionyl chloride, P205, molecular sieves, sintered aluminum oxides and other dehydrating oxides such as Bio2 or EHSO4, the addition of a solvent can be advantageous.

The elimination of water can also be acid-catalyzed by azeotrbpe Remove the water formed.

The elimination of alkyl, acyl and alkylsulfonyl as well as alkoxysulfonyl-oxy-, mercapto or amino residues can be carried out under similar conditions. In particular, the elimination of sulfonic acid residues, such as those of the mesylates or Tosylate, done gently and in good yield by boiling in dimethylformamide or dimethyl sulfoxide with alkali carbonates, such as Li2CO3, or with potassium acetate. For example, from 4-homopiperidino-3-chloro-5-bromo-5,6-dihydro-naphthalene-1-acetic acid diethylamide 4-homopiperidino-3-chloro-naphthalene-1-acetic acid diethylamide smoothly by splitting off HBr to win. It is also possible to obtain from 4-piperidino-2-nitro-α-methyl-5-hydroxy-5,6,7,8-tetrahydro-naphthyl-1-acetic acid to obtain the corresponding 7,8-dihydronaphthalene derivative by splitting off H2O. z @) Compounds of the formula I are also obtained by zn-ln from compounds of the general formula I, wherein for R4 a through 'X7 and X8 in 1,2- or 1,4-' or 3,4-position doubly substituted, optionally containing a double bond Tetramethylene is, in each case the two substituents X7 and X8 with formation a double bond, especially with metals such as Zn, Zn-Cu, Na, Li or K, or with organometallic compounds, such as Grignard or organolithium compounds, eliminated. In particular, the elimination of vicinal dihalides, such as dichlorides, Dibromides or diiodides, but also of halohydrons, such as chlorohydrins or bromohydrins, or of vicinal hal esters, where X7 is for example Cl, Br, I and X8 is acyloxy interpret, succeed, smoothly and are often described in the literature. These vicinal Eliminations are preferred with zinc in glacial acetic acid with the addition of sodium acetate or else carried out in ethanol by boiling under reflux. The response times The reaction temperatures vary preferably between 10 minutes and several hours between 80 ° and 300 °.

As a solution, for example, benzene, toluene, dichlorobenzene, Use ethylene glycol, ethylene glycol dimethyl ether or dimethylformamide.

For example, it is possible to prepare 4-piperidino-5,6-dichloro-5,6,7,8-tetrahydro-naphthalene-1-acetic acid without difficulty to 4-piperidino-7,8-dihydro-naphthalene-1-acetic acid and 4-morpholino # 7-chloro-8-hydroxy-7,8-dihydro-α-ethyl-naphthalene-1-acetic acid, to convert to 4-morpholino-α-ethyl-naphthalene-1-acetic acid. ze) Pure substituted aminophenylacetic acid obtained by the process of the invention of the formula I Can be converted into the associated acid addition salt with an acid in the customary manner be transferred. For this implementation, those acids come into question that are physiologically deliver a safe roller. Organic and inorganic acids, such as aliphatic, licyclic, araliphatic, aromatic or heterocyclic single or polybasic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, Pivalic acid, diethyl acetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, Fumaric acid, maleic acid1 lactic acid, tartaric acid, malic acid, aminocarboxylic acids, Sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanedisulfonic acid, ß-Hydroethylene sulfonic acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, Sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acids, or phosphoric acids such as orthophosphoric acid, etc. are used will. On the other hand, the substituted aminophenylacetic acids of the formula 1, in which A is COOH, by reaction with a base in one of its physiological harmless metal or ammonium salts are transferred.

In particular, the sodium, potassium, magnesium, calcium and aaonium salt into consideration, also substituted ammonium salts, such as the dimethyl and the diethylammonium salt.

Conversely, the substituted aminophenylacetic acids of the formula 1 from their acid addition salts by treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate, or optionally from their Metal and ammonium salts by treatment with acids, especially mineral acids such as Hydrochloric or sulfuric acid, can be set free.

Finally, a substituted aminophenylacetic acid of the formula 1 converted into the associated quaternary salt by treatment with lower alkyl radicals will.

For the quaternization, for example, alkyl halides, such as methyl bromine or Aethylchlo @ id, or dialkyl sulfates, such as dieth @ or dimethyl sulfate, suitable. The quaternization conditions are the usual ones, for example in bubeo Weil, Methods of Organic Chemistry, l.c., Volume 11/2, (1958), nitrogen compounds II / III, on pages 591 to 615 are described or cited.

The carboxylic acid anhydrides of substituted aminophenylacetic acids of the formula I, in which A stands for COOH, is obtained, for example, according to the Houben-Weyl, l.c., Volume 8, pages 476-480. So you can, for example Salts of aminophenylacetic acids, such as sodium, potassium or salts of aminophenylacetic acids, such as sodium, potassium or magnesium salts, by reaction with aminophenylacetic acid halides, how to convert chlorides, brorides or iodides into symmetrical anhydrides, preferably at 60 ° to 160 ° and in inert solvents such as dioxane, benzene, Tetrahydrofuran or dichlorobenzene works. For the production of mixed anhydrides one sets the aminophenyl acetic acid salts or the aminophenyl acetic acid halides with other carboxylic acid halides, such as acetyl chloride, or carboxylic acid anhydrides, such as acetic anhydride, preferably with the addition of catalytic amounts of mineral acids such as concentrated sulfuric acid, or with other carboxylic acid salts, such as propionic acid Sodium to. The free aminophenylacetic acids of the Formula Z by treatment with acetic anhydride or acetyl chloride in the heat, if necessary with the addition of inert solvents such as dioxane, benzene, carbon tetrachloride or xylene, convert to the mixed anhydrides. the anhydride formation is also excellent, if you e.g. a cold-prepared aminophenylacetic acid chloride-pyrdin mixture, optionally with the addition of an inert Solvent, like Ether, tetrahydrofuran or dioxane, mixed with the fieien aminophenyl acetic acid. Trimethylamine can also be used instead of pyridine.

If the substituted amnophenyl acetic acids of the formula I have a center of asymmetry contain; then they are usually in racemic form. Praise them two or more asymmetry, then all these compounds are used in the synthesis i: 'a generally as mixtures of racemates, from which one is known per se Way the individual racemates, for example, by repeated recrystallization isolate from suitable solvents and obtain in pure form.

Such racemates can be made by a variety of known methods, such as they are given, for example, in Houben-Weyl, l.c., Volume 4/2, pages 513-519, in their optical antipodes are separated.

So you can get some racemic mixtures as eutectics instead of in form from mixed crystals and in this way separate quickly, iri these cases selective precipitation can also be possible however, chemical separation is far preferable. Be after this method from the racemic mixture by reaction with an optically active resolving agent Diastereomers formed. So you can optionally with an optically active base the carboxyl group or an optically active acid substituted with the amino group of a Implement aminophenylacetic acid of the formula I.

For example, one can use salt diastereomers of substituted aminophenylacetic acids of the formula I optionally with optically active amines, such as quinine, cinchonidine, Brucine, cinchonine, hydroxyhydrin amine, morphine, α-phenylethylamine, pherlyloxynaphthylmethylamine, Quinidine, 1-fenchylamine, strychnine, basic amino acids, such as Lysine, arginine, amino acid esters and the like. Or with optically active acids, such as D and L- tartaric acid, dibenzoyl- D- and -L-tartaric acid, diacetyl-D- and -L-tartaric acid, ß-camphor sulfonic acid, D- and L-mandelic acid, D- and L-apple acid or D- and L-lactic acid and the like. Form. In a similar way, ester diastereomers of aminophenylacetic acids can be used Formula I, in which A stands for COOiS, with optically active alcohols such as borneol, menthol Octanol-2 and the like. To produce. The difference in the solubility of the resulting Diastereomer allows the selective crystallization of one form and regeneration of the respective optically active substituted aminophenyl acetic acids a.'s dem Mixture. However, there is a third, promising separation method available, those in the application of one or the other form of Liochemical working methods Use of selective, enzymatic reactions exists. So you can get the racemic substituted aminophenylacetic acids of an asymmetric oxidase or optionally Expose to decarboxylase, which destroys a shape through oxidation or decarboxylation, while the other form remains unchanged. It's even more rewarding to use one Hydrolase on a derivative of the racemic mixture to preferentially form a Form of the substituted aminophenylacetic acids. So you can use esters or amides of the Aminophenylacetic acids of the formula I expose to the action of a hydrolase, which one enantiomorph is selectively saponified and the other leaves unchanged.

The new compounds and / or, if appropriate, their physiological Harmless metal and ammonium and acid addition salts can be mixed together with common drug carriers in human or veterinary medicine. used will. Such organic or inorganic substances are used as carrier substances in question, these are suitable for parenteral, enteral or topical application and which do not react with the new compounds, wi. for example Water, vegetable oils, polyethylene glycols, Gelatine, milk sugar, Starch, magnesium stearate, talc, petroleum jelly, cholesterol, etc. For parenteral application In particular, solutions, preferably oily or aqueous solutions, and suspensions are used or emulsions. For enteral application, tablets or coated tablets can also be used, for topical application ointments or creams that may or may not be sterilized or with auxiliaries such as preservatives, stabilizers, wetting agents or salts Influencing the osmotic pressure or mixed with buffer substances are applied will.

The substances according to the invention are preferably administered in a dosage of 1 to 500 mg per dosage unit. The starting compounds for the preparation of the substances of the formula I according to the invention by the processes described under (a) to (zd) are accessible by the following key reaction processes: 1) The anilines of the formula LIV, largely known from the literature or analogously prepared, are alkylated wherein R3. H, halogen, R7 ,, 0R7, Sir7, R or loading .N½G0R7 Deut.t, can be in the o- or m-position and R4 and R7 have the meaning given at the beginning, for example with the largely known alkyl bromides R5Br and / or R6Br to the tertiary amines of the formula LV where R5 and R6 have the meaning given at the outset, and are nao-h Friedel-Crafts with kAethoxalychlorid to the p-ethoxalylanilines of the formula LVI around.

The α-keto esters of the formula LVIf can be converted into the α-hydroxy esters reduce or with Grignard compounds, such as R7MgJ, where R7 is the one specified at the beginning Has meaning to convert to a-alkyl-a-hydroxyesters. The esters can be smooth saponify to the carboxylic acids and the α-hydroxyphenylacetic acid derivatives with Convert HCl, HBr or HJ to the corresponding α-halo-phenylacetic acids.

(2) The p-toluidines of the formula LVII, some of which are known from the literature or can be prepared analogously thereafter, are alkylated in which R3 UIld R4 have the meaning given at the beginning, to the tertiary amines of the formula LVIII wherein R5 and% 6 have the meaning given at the beginning.

The CH3 group in the substituted toluidimes of the formula LVIII can be converted either directly by halogenation or indirectly by oxidation to the carboxyl group, reduction with LiAlH4 for CH2OH grapping and treatment with HCl or HBr gas to form the corresponding benzyl chloride or benzyl bromide group. Then you replace with KCN for the nitrile group, mono- or dialkyltert optionally with R7Br / NaNH2, where R7 has the meaning given above, in α-position to the nitrile group to the α-alkyl or α-dialkylbenzyl cyanides and obtained through acidic or alkaline saponification of the nitrile group is the aminophenylacetic acids of the formula LIX in which R1 to R6 have the meaning given at the beginning.

If in compounds of the formula LIX R3 assumes the meaning of NO2, this NO2 group can be hydrogenated to the NH2 group, diazotized and, according to the methods in section (p), against R3 = F, Cl, Br, J, CN, OH, specified Marg 7 SR7, N (<I COR7 RR N <1, S02-Ns 2 2 Replace SOR @ or S02R7, where R1, R2 and R7 have the meaning given at the beginning.

(3) The p-bromoacetophenones of the formula LX, which are largely known from the literature or can be prepared analogously thereafter, are used wherein the has the meaning given at the beginning, with the nurses of the formula X, formula LXIX to connections of the wherein R4 to R6 have the meaning given at the beginning to. The nitro group in compounds of the formula LXI can be exchanged for the substituent R3 after reduction and diazotization by the methods described in reaction key process (2), where R3 (other than CF3 or R7) and R7 have the meaning given at the beginning.

The acetophenone derivatives obtained in this way are converted according to the conditions : n a Willgerodt reaction into the corresponding ..:, ihenylthioacetamide to, as starting materials for the saponification process described in section (a) to serve.

Furthermore, the acetophenones can be added to the # -chlorine or

Halogenate # -bromine compounds as described in section (e) Favorskij reaction can be used.

Finally, one can get the acetophenones with the Grignard compounds R7MgJ convert to appropriately substituted methylalkyl-ph-enyl-carbinols, the used as starting material in the Koch-Haaf synthesis described in section (f) will.

(4), The 4-bromo-benzoic acids of the formula LXII, which are widely known from the literature or can be prepared analogously thereafter, are used in which R3 (apart from OH and R1 and R4 have the meaning given at the beginning, with the amines wherein R5 and R6 have the meaning given at the beginning, to the correspondingly substituted 4-amino-benzoic acids of the formula LXIII um, which are reduced via the acid chlorides by Rosenmund hydrogenation to the benzaldehydes and further to the benzyl alcohols. The benzyl alcohols are reacted with hydrohalic acids to give the benzyl halides and further with KON to give the benzyl cyanides, which can optionally be mono- or dialkylated in the α-position, so that compounds of the formula LXIV are obtained where R1, R2, R3 (except OH and NHR1) and R4 to R6 <have the meaning given at the beginning.

If R3 means @ NO2, one can use the key reaction procedure (2) this nitro group after reduction and diazotization against Cl, Br. J, F, OR7 or Replace Sr, in which R7 builds the meaning given at the beginning.

The correspondingly substituted benzylcyanines are then the most diverse Phenylacetic acid derivatives accessible by known methods, such as esters, amides, thioamides, Amidines, iminochlorides, hydrazides a. like

Finally, the correspondingly substituted 4-aminobenzoic acids of the formula LXIII can be esterified and the ester groups, with the Grignard compounds R7MgJ, simply to form R7-CO- or twice R7-01 groups R7 Grignard and reduce the R7-CO group to the R7-CHOH group. The hydroxyl groups are exchanged for chlorine or bromine with HCl or Hi3r.

Further reaction with KCN leads to the correspondingly substituted Nitriles, the immediate precursors to the substituted aminophenylacetic acids of formula I.

(5) By reacting the l-nitro-4-bromobenzenes of the formula LXV, which are largely known from the literature or which can be prepared analogously thereafter wherein R3 and R4 have the meaning given at the beginning, with sodium malonic or sodium cyaneacetic esters of the formula XXVI 1695385 in which R1 has the meaning given at the beginning and X9 is CN or COOC2H5. means, nitro-phenylacetic ester derivatives of the formula LXVII are obtained from which, by saponification and decarboxylation according to the method described in section (g), nitrophenylacetic acids of the formula LXVIII receives. The nitro group in compounds of the formula LXVIII can be reduced to the amino group and alkylated to give compounds of the formula I by the methods listed in section (1).

(6) By Friedel-Crafts acylation of the 4-acylaminophenylacetic acids of the formula zIX, some of which are known from the literature or can be prepared analogously thereafter E acyl R3 R2-6-R1 AOOH DXIX in which R1, R2 and R3 (apart from OH and NHR1) have the meaning given at the beginning, with succinic anhydride compounds of the formula LXX are obtained. ISH-acyl R3 -00 (CH2) 2-000H R2- G R1 LXX dooX The keto group directly linked to the benzene nucleus is reduced to the C112 group according to Clemmensen or Wolf-Kishner. Subsequent treatment with polyphosphoric acid leads to tetralons of the formulas LXXI and LXXII NH-acyl NH-aoyl ½ 0 R3H½, t Ri- R2C - R1Ò C - IilO LXXI R2-9 -R1 COOH the reduction of which gives the corresponding tetralines or hydroxytetralines. H20 can be split off from the latter and dialine can be obtained. If the acyl group has remained intact during the ring closure reaction, it is now removed hydrolytically and the remaining amino group is alkylated to give compounds of the formula I.

EXAMPLES Example 1 To a solution of 35.5 g of 4-amino-naphthyl-1-acetic acid hydrochloride and 77.0 g of dibromopentane in 240 ml of water is stirred and boiled inside a solution of 78.0 g of NaOH in 320 ml of water was added dropwise over a period of ~ 8 hours. Thereafter is refluxed for another 3 hours. The aqueous phase is extracted with ether and adjusted to pH 4.0 with 15% Hcl solution. The separated oil is with Ethyl acetate extracted, the organic phase washed with water, dried over Na2S04, Filtered charcoal and evaporated in vacuo. The residue is made from isopropyl ether recrystallized.

Yield: 15.6 g of 4-piperidino-naphthyl-1-acetic acid with a melting point of 1420 - 1430.

Analogously, from 3-chloro-4-amino-naphthyllyi-1-acetic acid from F. 2040-2060 (produced by chlorination of 4-acetamino-naphthyl-1-acetic acid in glacial acetic acid at room temperature to give the corresponding 3-chloro compound of F. 2440 - 2460 and subsequent deacetylation with boiling concentrated hydrochloric acid) 3-chloro-4-piperidinonaphthyl-1-acetic acid with a melting point of 166 ° -167 °; from 2-methyl-4-amino-naphthyl-1-acetic acid vom F. 2080-2100 (produced by reducing 2-methyl-4-nitro-naphthyl-1-acetic acid from 2230-2250) 2-methyl-4-piperidinonaphthyl-1-acetic acid from 1670-169 °; and from 4-amino-α-methyl-naphthyl-1-acetic acid from 1900-1920 (manufactured by catalytic reduction and decarboxylative saponification of 4-nitro-α-methyl-naphthyl-1-malonic acid diethyl ester from F. 8S0-900) 4-piperidino-α-methyl-naphthyl-1-acetic acid from M. 181 ° - 183 °.

Analogously one obtains. from-3-bromo-4-amino-α-methyl-naphthyl-1-acetic acid, 3-chloro-4-amino-α-methyl-naphthyl-1-acetic acid, 3-methyl-4-amino-α-methyl-naphthyl-1-acetic acid, 2-chloro-4-amino-α-methyl-naphthyl-1-acetic acid, 2-Me-4-amino-α-methyl-naphthyl-1-acetic acid, 3-chloro-4-amino-α-methyl-naphthyl-1-acetic acid or

3-chloro-4-amino-α-n-butyl-naphthyl-1-acetic acid, by reaction with 1,5 dibromopentane 3-bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid, 3-chloro-4-piperiino-methyl-naphthyl-1 acetic acid, 3-methyl-4-piperidino-a-methyl-naphthyl-l-e setic acid, 2-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid, 2-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid, 3-chloro-4-piperidino-α-ethyl-naphthyl-1-acetic acid respectively.

3-chloro-4-piperidino-a-n-butyl-naphthyl-1-e-acetic acid and from 3-chloro-4-amino-α-methyl-naphthyl-acetic acid by reaction with 1,7-dibromohexane or with 2,6-dibromoheptane $ -Homopiperidino- or 4- (2 ', 6'-dimethyl-piperidino-) 4-chloro-metnyF-naphthylacetic acid.

Example 2 Analogously to Example 1, 4-amino-naphthyl-1-acetic acid is obtained by reaction with 1,4-dibromobutane 4-pyrrolidinonaphthyl-l-acetic acid of 1100 - 1140.

Analogously from 3-bromo-4-amino-α-methyl-naphthylacetic acid, 3-chloro-4-amino-α-ethyl-naphthylacetic acid, 3-bromo-4-amino-α-butyl-naphthylacetic acid, 2-chloro-4-amino-α-methyl-naphthylacetic acid, 3-methyl-4-amino-α-ethyl-naphthylacetic acid, 4-amino-5,6,7,8-tetrahydronaphthyl-1-acetic acid respectively.

4-Amino-α-methyl-5,6,7,8-tetrahydronaphthyl-1-acetic acid Reaction with 1,4-dibromobrtane 3-methyl-4-pyrrolidino-α-methyl-naphthylacetic acid, 3-chloro-4-pyrrolidino-α-ethyl-naphthylacetic acid, 3-bromo-4-pyrrolidino-α-n-buthyl-naphthylacetic acid, 3-C-chloro-4-pyrrolidino-α-methyl-naphthylacetic acid, 2-Ne thXrl-4-pyrrolidino-a-ethyl-na'phthyle s igic acid, A-pyrrolidir. o-5, 6, 7 8-tetrahydronaphthynyl-1-acetic acid or

4-pyrrolidino-α-methyl-7,6,7,8-tetrahydronaphthyl-1-acetic acid.

Example. 3 31.6 g of ethyl 4-piperidino-a-methylene-naphthyl-1-acetic acid are in 350 ml of methanol with 12.0 g of palladium-carbon catalyst (5%) at room temperature and 1 atmosphere of hydrogen pressure hydrogenated until hydrogen uptake ceases. The catalyst is filtered off and the methanol is stripped off in vacuo. The oily one The residue is distilled in vacuo. 22.0 g of 4-piperidino-α-methylonaphthyl-1-acetic acid ethyl ester are obtained from bp 177 ° - 180 ° C / 0.2 num. 12.0 g of this ester are in a mixture of 150 ml alcohol, 40 ml water and 12.0 g NaOH gel-ost and 15, hours-under reflux # boiled, the ethanol distilled off and the oily residue dissolved in water. the aqueous phase is extracted with ether. Then the solution is made up with hydrochloric acid. pH -4 - 6 adjusted. The solution is extracted with ethyl acetate and the extract is dried over sodium sulfate, filtered, evaporated and the residue crystallized from ethyl acetate around, 6.7 g of 4-piperidino-amethyl-naphthyl-1-acetic acid with a melting point of 181 ° -183 ° are obtained.

Instead of the ester, the free carboxylic acid can also be hydrogenated, after evaporation of the methanol directly to 4-piperidino-α-methyl-naphthyl-1-acetic acid got.

Analogously, 4-piperidino-ethylidene-naphthyl-1-e is obtained by hydrogenation and saponification ethyl acetate 4-piperidino-α-ethyl-naphthyl-1-acetic acid from F. 1450-14600.

To prepare the starting material, a-naphthylamine is added 1,5-dibromopentane in butanol in the presence of potash to l-piperidino-naphthalene around that one in tetrachloroethane in the presence of aluminum chloride with ethoxalyl chloride according to Friedel-Crafts for ethyl 4-piperidinonaphthyl-1-glyoxylate with a boiling point of 220 ° - 22800 / 0.05mm acylated. To a molar equivalent of this dissolved in absolute ether An ethereal solution of ethyl glyoxylate is added dropwise with vigorous stirring 1.2 molar equivalents methyl magnesium iodide. The magnesium separates out of the solution odide alcoholate of 4-piperidino-a-methyl-ahydroxy-naphthyl-acetic acid ethyl ester away. It is decomposed while cooling with dilute hydrochloric acid, and the ether phase is separated off and makes the aqueous phase alkaline with ammonia with the addition of ammonium chloride. The alkaline aqueous phase is extracted with chloroform and that after drying and evaporation of the chloroform obtained residue distilled '. 4-Piperidino-α-hydroxy-α-methyl-naphthyl-1-acetic acid ethyl ester is obtained from bp 181 ° - 182 ° C / 0.05 mm.

The 4-piperidino-a-hydroxy-amethyl-naphthyl-1-acetic acid ethyl ester is used to split off water dissolved in ten to twenty times the amount of polyphosphoric acid and 15 minutes on 1300 heated. The reaction mixture is cooled, decomposed with ice water, the aqueous phase extracted with ether and the organic phase neutral with water washed, dried and evaporated. The residue is distilled in a high vacuum. 4-Piperidino - methylene-naphthyl-1-acetic acid ethyls are obtained in good yield Ster from bp 168 ° - 170 ° C / 0.05 mm and from 63 ° - 65 ° c.

Analogously, from 3-methyl-4-piperidino-a-methylene-naphthyl-1-acetic acid ethyl ester, 3-methyl-4-morpholino-a-methylene-naphthyl-1-acetic acid ethyl ester, 2-methyl-4-homopiperidino-a-methylene-naphthyl-l-acetic acid ethyl ester, 2-methyl-4-pyrrolidino-a-methylen-naphthyl-1-acetic acid ethyl ester, 3-chloro-4-piperidino-a-methylen-naphthyl-1-acetic acid ethyl ester, 2-fluoro-'4-piperidino-a-metbylen-naphthyl-1-acetic acid ethyl ester, 3-methoxy-4-piperidino-a-ethylidene-naphthyi-1-acetic acid ethyl ester, 3-Amino-4-piperidino-a-ethylidene-naphthYl-1-acetic acid ethyl ester or

2-methyl-4-pyrrolidino-butylidene-naphthyl-1-acetic acid ethyl ester by catalytic hydrogenation and subsequent saponification 3-methyl-4-piperidino-a-methyl-naphthyl-l-acetic acid, 3-methyl-4-morpholino-a-methyl-naphthyl-1-acetic acid, 2-methyl-4-homopiperidino-a-ethyl-naphthyl-1-acetic acid, 2-methyl-4-pyrrolidino-a-methyl-naphthyl-1-acetic acid, 3-chloro-4-piperidino-a-methyl-naphthyl-1-e ssigsoure, 2-bluor-4-piperidino-a-methyl-naphthyl-1-6 ssetic acid, 3-methoxy-4-piperidino-α-ethyl-naphthyl-1-acetic acid, 3-Amino-4-piperidino-α-ethyl-naphthyl-1-acetic acid or

2-Methyl-4-pyrrolidino-a-n-butyl-naphthyl-1-e 3sig acid.

Example 4 29.7 g of 4-piperidino-naphthyl-l-acetic acid ethyl ester, the obtainable by esterification of the free acid from Example 1 become one Solution of 2.5 g of sodium in 100 ml of absolute ethanol below 25 ° C was added. 15.0 g of diethyl oxalate are rapidly added dropwise to this solution with stirring. The reaction mixture is stirred for 1 hour at 60 °, cooled, with dilute sulfuric acid adjusted to pH 5.0-6.0 and the aqueous solution extracted with ethyl acetate. Of the The oily residue is decarbonylated by heating for three hours at 190 ° -200 ° The distillation gives 4-piperidino-naphthyl-1-malonic acid diethyl ester with a boiling point of 1800 - 18500 / 0.05 mm. Yield: 18.0 g.

18.5 g of 4-piperidino-naphthyl-1-malonic acid diethyl ester become one Solution of 1.3 g of sodium in 150 ml of absolute ethanol was added. In this solution 7.5 g of methyl iodide are added dropwise at room temperature with stirring. The reaction solution is then stirred at 40 ° C for 5 hours. The alcohol is evaporated in a vacuum, the The residue is diluted with water and the aqueous phase is diluted with dilute hydrochloric acid pH adjusted to 5.5. The aqueous phase is extracted with ether, the ether extract washed with 10% thiosulfate solution and with water and dried over sodium sulfate. 12.0 g of 4-piperidinoa-methyl-naphthyl-1-malonic acid diethyl ester of Xp are obtained 1990 -203 ° C / 0.05 mm.

19.0 g of 4-piperidino-a-methyl-naphthyl-1-inalonic acid diethyl ester become more ethanolic by boiling at 250 1 25%} Potassium hydroxide solution saponified. The alcohol is removed in a vacuum, the Ritokstand-dissolved in water, Shaken off once with ether and the aqueous phase with 2N HOl to pH 5.0-6.0 acidified. The oily precipitate is taken up in ethyl acetate, the ethyl acetate washed with water, dried and distilled off. The oily residue is under heated under reduced pressure at 100 ° - 120 ° C / 20 mm until C02 is split off is finished. 4-Piperidino-α-methyl-naphthyl-1-acetic acid is obtained from the residue obtained from m.p. 181 ° - 183 ° C.

Analogously from 3-chloro-4-piperidino-naphthyl-1-e ssigsäureäthyle s ter, 3-chloro-4-morpholino-naphthyl-1-acetic acid ethyl ester, 3-chloro-4-homopiperidino-naphthyl-1-acetic acid ethyl ester, 3-chloro-1- ('2 t, 5'-dimethyi-piperidino) -naphthyl-1-es-ethyl acetate, 3-bromo-4-homopiperidino-naphthyl-1-acetic acid ethyl ester, 3-methyl-4-piperidino-naphthyl-1-acetic acid ethyl ester, 2-chloro-4-homopiperidino-naphthyl-1-acetic acid ethyl ester, 2-chloro-4-piperidino-naphthyl-1-acetic acid ethyl ester, 3-chloro-4-piperidino-5, 6, 7. 8-tetrahydro-naphthyl-1-acetic acid ethyl ester, 3-methyl-4-piperidino-5,6,7,8-tetrahydro-naphthyl-1-acetic acid ethyl acid ester, 2-methyl-4-homopiperidino-5, 6, 7, 8-tetrahydro-naphthyl-1-acetic acid ethyl ester, 3-chloro-4-piperidino-5, 6, 7, 8-tetrahydro-naphthyl-1-acetic acid ethyl ester or

3-Methoxyl-4-piperidino-5,6,7,8-tetrahydro-naphthyl-1-acetic acid ethyl ester huber corresponding naphthyl-1-malonic acid derivatives and by reaction with methyl iodide 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid, 3-chloro-4-morpholino-α-methyl-naphthyl-1-acetic acid, 3-chloro-4-homopiperidino-a-methyl-naphthyl-1-acetic acid, 3-ahlor-4- (2 ', 5'-dimethylpiperidino) -a-methyl-naphthyl-lessetic acid, 3-bromo-4-homopiperidino-a-methyl-naphthyl-1-acetic acid, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid s 2-chloro-4-homopiperidino-a-methyl-naphthyl-1-acetic acid, 2-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid, 3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-acetic acid, 3-methyl-4-piperidino-a-methyl-5, 6, 7, 8-tetrahydronaphthyl-acetic acid, 2-methyl-4-homopiperidino-α-methyl-5,6,7,8-tetrahydronaphthyl-1- acetic acid, 3-chloro-4-piperidino-a-methyl-5, 6, 7, 8-tetrahydro-naphthyl- = l-acetic acid or

3-methoxy-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid; and from 3-methoxy-4-piperidino-naphthyl-l-acetic acid, 3-chloro-4-piperidino-naphthyl-l-acetic acid, 3-bromo-4-piperidino-naphthyl-1-acetic acid, 2-methyl-4-piperidino-naphthyl-1-acetic acid, 2-methoxy-4-piperidino-naphthyl-1-acetic acid or

2-chloro-4-piperidino-naphthyl-l-acetic acid via corresponding naphthyl-l-malonic acid derivatives and by reaction with ethyl iodide, n-propyl iodide, isopropyl iodide, n-butyl iodide or sec. butyl iodide 3-methoxy-4-piperidino-a-ethyl-naphthyl-1-acetic acid, 3-chloro-4-piperidino-a-ethyl-naphthyl-1-acetic acid, 3-chloro-4-piperidino- a-n-propyl-naphthyl- 1-acetic acid, 3-chloro-4-piperidino-a-n-butyl-naphthyl- 1-acetic acid, 3-chloro-4-piperidino-α-sec.brtyl-naphthyl-1-acetic acid, 3-bromo-4-piperidino-a-ethyl-naphthyl-1-acetic acid, 3-bromo-4-piperidino-α-n-propyl-naphthyl-1-acetic acid, 2-methyl-4-piperidino-α-ethyl-naphthyl-1-acetic acid, 2-methoxy-4-piperidino-a-n-propyl-naphthyl-1-acetic acid, 2-chloro-4-piperidino-a-ethyl-naphthyl-l-acetic acid or

2-chloro-4-piperidino-a-n-butyl-naphthyl-1-acetic acid.

Example 5 5.4 g, 4-piperidino-naphthyl-1-acetic acid are used in 60 ml of absolute amyl alcohol dissolved and heated to boiling. -In the boiling reaction solution 4.5 g of sodium metal are introduced in small quantities within 90 minutes.

The mixture is then stirred for a further 15 minutes and the amyl alcohol in. vacuum removed, the residue is diluted with water and the aqueous phase once with Aether extracted.

The aqueous solution is adjusted to pH 5.0 with 2N HCl and with Aether Aether extracted. The ether phase is washed with water over sodium sulfate dried and evaporated.

The oily residue is taken up in hexane, from which on cooling 4-piperidino-5, 6,;? , 8-tetrahydro-naphthyl-acetic acid with a melting point of 1250-1270C crystallized out.

Yield: 2.2 g.

Analogously, from 4-piperidino-a-methyl-naphthyl-1-acetic acid, 3-methyl-4-piperidino-a-methyl-naphthyl-1-e 9 acetic acid, 3-methoxy-4-piperidino-a-methyl-naphthyl-1-acetic acid, 3-Amino-4-piperidino-α-methyl-naphthyl-1-acetic acid, 2-methyl-4-pyrrolidino-a-methyl-naphthyl-1-acetic acid, 2-Me thoxy-4-piperidino-a-methyl-naphthyl-1-acetic acid or

2-Amino-4-piperidino-α-methyl-naphthyl-1-acetic acid by reduction with sodium 4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid, 5-methyl-4-piperidino-a-metwl-5, 6, 7, 8-tetrahyto-naphthyl-acetic acid, D-methoxy-4-piperidino-a-methyl-5, 6, 7, 8-tetrahydro-naphthyl-acetic acid, 3-amino-4kpiperidino-a-methyl-5, 6, 7, 8-tetrahydro-naphthyl-1-acetic acid, 2-methyl-4-pyrrolidino-α-methyl-5,6,7,8-tetrahydro-naphthyl 1-acetic acid, 2-methyl-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid respectively.

2-Amino-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid.

Example 6 12.5 g of 4-piperidino-1-acetonaphthon are used together with 4,, 8 g of sulfur and 8.7 g of morpholine boiled for 10 hours at 140 ° -1500. This creates 4-piperidino-naphthyl-1-thioacetomorpholide, which is not isolated. You bet 100 ml conc. Hydrochloric acid and 50 ml of water are added and the reaction mixture is boiled again 24 hours. Charcoal is added to the still warm solution and then filtered. That The filtrate is made with conc. NaOH solution adjusted to pH 5.5 and the amino acid which as oil precipitates, taken up in ethyl acetate. The organic phase is mixed with water washed, dried over sodium sulfate and evaporated in vacuo. Of the The residue is dissolved in a little ethyl acetate and the organic phase is boiled with charcoal and filtered. After concentration of the solution and addition of petroleum ether crystallized 4-piperidino-naphthyl-1-acetic acid with a melting point of 142 ° - 143 ° C.

Yield: 6.0 g.

Analogously from 3-chloro-4-piperidino-1-acetonaphthon, 3-methyl-4-piperidino-1-acetonaphthone is obtained, 3-bromo-4-piperidino-1-acetonaphthon, 2-chloro-4-pyrrolidinoo-1-acetonaphthon or

2-methyl-4-pyrrolidino-1-acetonaphthon according to Willgerodt 3-chloro-4-piperidino-1-acetic acid, 3-methyl-4-piperidino-1-acetic acid, 3-bromo-4-piperidino-1-acetic acid, 2-chloro-4-pyrrolidino-1-acetic acid respectively.

2-Methyl-4-pyrrolidino-1-acetic acid Example 7 a) A solution of 4 g crude 3-chloro-4-piperidino-chloro-acetonaphthon (obtainable from 3-chloro-4-piperidinol-acetonaphthon and Sulfüryichlorid in dichloromethane in the presence of potassium carbonate and azo-bis-isobutyronitrile) in 50 ml of ether becomes 100 ml of a saturated solution of potassium hydroxide in ethanol given and heated on the water bath for 2 hours. The alcohol is distilled off, adds water and adjusts the pH to 4 - 5 with dilute hydrochloric acid. Man extracted with chloroform, dried over sodium sulfate and evaporated the solvent. 3-Chloro-4-piperidino-naphthyl-1-acetic acid with a melting point of 166 ° -168 ° (diisopropyl ether) is obtained. b) To a solution of 4 g of 3-chloro-4-piperidino-J-chloro-lacetonaphthon in 100 ml of absolute 10 g of finely powdered potassium hydroxide are converted into ether while cooling and vigorously tapping added in portions. The mixture is boiled for 10 hours; mixed with 100 ml of water. the aqueous phase is separated off and adjusted to pH 4-5 with dilute hydrochloric acid. The procedure is as in a) and 3-chloro-4-piperidino-naphthyl-1-acetic acid is obtained.

Analogously from 3-fluoro-4-piperidino - # - chloro-1-acetonaphthon, 3-methoxy-4-piperidino - # - chlor-1-acetonaphthon or

2-chloro-4-piperidino - # - chloro-1-acetonaphthon with potassium hydroxide 3-fluoro-4-piperidino - # - chloro-1-acetic acid, 3-methoxy-4-piperidino - # - chloroacetic acid or

2-chloro-4-piperidino - # - chloro-1-acetic acid.

Example 3 a) 21.5 g of 4-amino-naphthyl-1-acetic acid methyl ester become with 26 g of 90% formic acid and 18 g of 35% formaldehyde solution for 10 hours 90 - 95 ° heated. After cooling, the reaction solution is filled with sodium carbonate neutralized and the aqueous phase extracted with chloroform.

The chloroform solution is washed with water and dried over Na2SO4 and then evaporated. The residue is dissolved in methanol and by adding ethereal hydrochloric acid of 4-dimethylamino-naphthyl-1 acetic acid methyl ester as Hydrochloride precipitated from F. 186-1880.

5 g of 4-dimethylamino-naphthyl-1-acetic acid methyl ester hydrochloride are boiled in a solution of 10 g of KOH and 100 ml of 90% ethanol for one hour. The alcohol is distilled off and the residue is dissolved in water.

The aqueous phase is adjusted to pH 5 with 2N HCl and the deposited Oil taken up in ethyl acetate.

The extract is dried over sodium sulfate and evaporated, whereby 4-dimethylamino-naphthyl-1-acetic acid is obtained.

Analogously, from 3-chloro-4-amino-a-methyl-naphthyl-1-acetic acid, 3-methyl-4-amino-α-methyl-naphthyl-1-acetic acid, 2-chloro-4-amino-α-methyl-naphthyl-1-acetic acid, 2-methoxy-4-amino-a-methyl-naphthyl-1-acetic acid or

3-chloro-4-amino-a-methyl-5, 6, 7, 8-tetrahydro-naphthyl-1-acetic acid by reaction with formic acid and formaldehyde and subsequent saponification of 3-chloro-4-dimethylamino-α-methyl-naphthyl-1-acetic acid, 3-methyl-4-dimethylamino-a-methyl-naphthyl-1-acetic acid, 2-chloro-4-dimethylamino-α-methyl-naphthyl-1-acetic acid, 2-methoxy - dimethy1amino - methyI-naphthyl-l-acetic acid or

3-chloro-4-dimethylamino-oc-methyl-5, 6, 7, 8-tetrahydronaphthyl-1-acetic acid.

Example 9 28.3 g of 4-piperidino-a-methyl-naphthyl-1-acetic acid become dissolved in 200 ml of methanol, the solution saturated with HCl and left to stand overnight. The methanol is distilled off, the residue is dissolved in water, the solution with Soda solution made alkaline and extracted with ether. The essential solution will dried over Na2SO4 and that obtained after evaporation of the ether 4-piperidino-a-methyl-naphthyl-l-acetic acid methyl ester recrystallized from methanol. F. 810-830.

Analogously, 4-piperidino-a-methyl-naphthyl-lessetic acid is obtained by reaction with ethanol, sec-butanol, cyclohexanol, n-hexanol, n-octanol, n-decanol, n-dodecanol, 2-ethyl-1-butanol and 2-methyl-1-pentanol: 4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester of b.p. 1720-1740 / 0.1 mm, 4-piperidino-a-methyl-naphthyl-1-acetic acid-s e c.-butyl ester from bp 1920-1960 / 0.05 mm, 4-piperidino-a-methyl-naphthyl-1-es sig acid cyclohesyl ester from bp 227 ° - 229 ° / 0.01 mm, 4-piperidino-α-methyl-naphthyl-1-acetic acid n-hexyl ester from bp 2100-2110 / 0.1 mm, 4-piperidino-α-methyl-naphthyl-1-acetic acid n-octyl ester from bp 1940-1960 / 0.01 mm, 4-piperidino-a-methyl-naphthyl-l-acetic acid n-decyl ester. vom-Kp 208-2100 / 0.01 mm, 4-piperidino-a-methyl-naphthyl-1-acetic acid-n-dodecyl ester of bp 2290-2350 / 0.01 mm, 4-piperidino-a-methyl-naphthyl-1-acetic acid 2'-ethyl-1-butyl ester from Kp 205 ° - 206 ° / 0.05 mm or

4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-methyln-pentyl ester from bp 1830 - 1850 / 0.01 mm.

Analogously, 3-chloro-4-piperidino-a-methyl-naphthyl-1-ess is obtained igsäure, 3-bromo-4-piperidino-a-methyl-naphthyl-1-es sig acid, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid, 2-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid, 2-methoxy-4-piperidino-a-methyl-naphthyl-1-acetic acid respectively.

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-acetic acid a) by esterification with methanol 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid methyl ester from bp 1920-1960 / 0, 1 mm, 3-: Bromo-4-piperidino-a-methyl-naphthyl-1-acetic acid methyl ester from bp 2020-2050/0, 1 mm, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid methyl ester from bp 1800-1860 / 0.2 mm, 2-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid methyl ester from bp 1850-1870 / 0.1 mm, 2-methoxy-4-piperidino-a-methyl-naphthyl-1-acetic acid methyl ester with a bp 210-212 ° / 0.1 mm, 3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-acetic acid methyl ester from bp 1700-1780 / 0.01 mm; by esterification with ethanol 3 -Chlor-4-piperidino-a-methyl-naphthy'l-l- ethyl acetate of bp 1850-1870 / 0.01 mm, 3-bromo-4-piperidino-a-methyl-naphthyl-l-acetic acid ethyl ester of bp 1900 - 1950/0, 01 mm, 3-methyl-4-piperidino-a-methyl-1-naphthyl-1-acetic acid ethyl ester from Kp 2010-2030/0, 3 mm, 2-chloro-4-piperidino-a-methyl-naphthyl-l-acetic acid ethyl ester from bp 1800-1860 / 0.03 mm, 2-methoxy-4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester from bp 2050-2080 / 0.05 mm or a-chloro-4-piperidino-a-methyl-5, 6, 7, 8-tetrahydro-naphthyl-acetic acid ethyl ester from bp 1860-1900 / 0.01 mm; c) by pre-esterification with n-propanol 3-chloro-1-piperidino-a-methyl-naphthyl-1-acetic acid n-propyl ester with a boiling point of 210-212 ° / 0.1 mm, 3-Bromo-4-piperidino-a-methyl-naphthyl-1-acetic acid-n-propyl ester of bp 205 - 208 ° / 0.1 mm, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid-n-propyl ester from bp 196-198 ° / 0.1 mm, 2-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-n-propyl ester of bp 180-183 ° / 0.05 mm, 2-methoxy-4-piperidino-α-methyl-naphthyl-1-acetic acid n-propyl ester from Kp 220 - 223 ° / 0.1 mm resp.

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydronaphthyl-1-acetic acid n-propyl ester from bp 190 - 195 ° / 0.1 mm.

Example 10 2.97 g of 4-piperidino-α-methyl-naphthyl-1-acetic acid and 0.6 g of propyl alcohol are added to 50 ml of tetrahydrofuran with 2 g of N, N'-dicyclohexyl added carbodiimide and stirred overnight. The precipitated N, N'-didcyclohexylurea is suctioned off and washed with 5 ml of tetrahydrofuran. The combined filtrates are dawped and the residue is distilled. 4-Piperidino-α-methyl-naphthyl-1-acetic acid n-propyl ester is obtained from bp 190 - 1950 / 0.1 mm.

Analogously, one obtains from -piperidino-α-methyl-naphthyl-1-acetic acid or 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid by esterification with allyl alcohol, plsopalgyl alcohol, isopropanol, benzyl alcohol 2-phenylethanol, Geraniol, 2-methoxyethanol and 2- (2-methoxyethoxy) ethanol 4-piperidino-α-methyl-naphthyl-1-acetic acid allyl ester of bp 185 - 1870 / 0.1 mm, propargyl ester of bp 190 - 1950 / 0.05 mm, isopropyl ester with a bp 175 - 178 ° / 0.05 mm, benzyl ester with a bp 205 - 2070 / 0.1 mm -2'-phenylethyl ester from bp 2250-2270 / 0.01 mm, geranyl ester (not distillable), -2'-methoxyethyl ester (not distillable), -2'- (2-methoxyethoxy) ethyl ester (not distillable) as well as 3-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid - allyl ester with a boiling point of 190 ° - 193 ° / 0.1 mm, propargyl ester of bp 2200 - 2250 / 0.2 mm, isopropyl ester of bp 180 ° - 185 ° / 0.1 mm, benzyl ester of bp 2200-2240 / 0.01 mm, -2'-phenylethyl ester from bp 2300-2320 / 0.01 mm, geranyl ester, -2'-methoxyethyl ester and -2 '- (2-methoxyethoxy) ethyl ester.

Example il 2.97 g of 4-piperidino-α-methyl-naphthyl-1-acetic acid are boiled in 50 ml of chloroform with 1.1 ml of SOCl2 for 1 hour and then the Solvent distilled off. The residue is mixed with 30 ml of n-propanol and Heated on the steam bath for 2 hours. The excess Phopanol is evaporated, the residue is mixed with aqueous soda solution, extracted with ether and the ethereal Solution dried over Na2SO4. The residue obtained after evaporation of the ether is distilled. 4-piperidino-a-methylnaphthyl-1-acetic acid n-propyl ester is obtained from Kp 190 ° - 195 ° / 0.1 mm.

Analogously, from 3-chloro ~ 4 ~ piperidino-a-methyl-naphthyl-1-acetic acid, 3-methyl ~ 4-pip-eridino-a-methyl-naphthyl-1-acetic acid or

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid a) by. Esterification with n-butanol 3-chloro-4-piperidino-a-methyl- naphthyl- 1-acetic acid- n-butyl ester with bp 2040-2050 / 0.1 mm, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid n-butyl ester from Kp 211 ° - 214 ° / 0.1 mm or

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1 n-butyl acetate with a boiling point of 198 ° - 201 ° / 0.02 mm; b) by esterification with n-hexanol 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid n-hexyl ester with a boiling point of 222 ° - 224 ° / 0.1 mm, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid-n-hexyl ester with a Kp of 227 ° - 228 ° / 0.05 mm or

3-Chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydronaphthyl-1-acetic acid n-hexyl ester from Xp 2320 2350 / 0.1 mm.

Example 12 5 g of 4-piperidino-α-methyl-naphthyl-1-acetic acid are dissolved in 100 ml of chloroform, 3 ml of SOCl2 are added and the mixture is boiled for 1 hour.

The chloroform is then evaporated off, the acid chloride thus obtained dissolved in 20 ml of diethylene glycol dimethyl ether and treated with 3 g of potassium tert-butoxide over Stirred overnight at room temperature, the deposited precipitate is filtered off with suction, the filtrate is evaporated and dilute soda solution is added. The separating Oil is taken up in ether and the organic phase is dried over Na2SO. Of the The residue obtained after filtering off the sodium sulfate and evaporation is 4-piperidino-.

α-methyl-naphthyl-1-acetic acid tert-butyl ester.

Analogously, from 3-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid or

3-methyl-4-piperidino-α-methyl-5,6,7,8-tetrahydronaphthyl-1-vinegar acid through reactions with SOCl2 and tert-bubanol 3-ahlor-4-piperidino-a-methyl-naphthyl-1-acetic acid tert-butyl ester, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid-tert. butyl ester or

3-Methyl-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid tert-methyl ester.

Example 13 7.3 g of 4-piperidino-α-methyl-naphthyl-1-acetic acid are boiled in 150 ml of isopropanol with 7.0 g of 2-diethylamino-ethyl chloride for 15 hours. The reaction solution is evaporated, and dilute sodium bicarbonate solution is added and with ether extract. The organic phase is first washed with dilute NaOH and then washed once with water. After drying over Na2SO4 the solvent becomes evaporated and the residue distilled, 3.8 g of 4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-diethylamino-ethyl ester are obtained from bp 185 ° - 189 ° / 0.01 mm.

Analogously, 4-piperidino-α-methyl-napthyl-1-acetic acid is obtained and 2-dimethylamino-ethyl chloride 4-iperidino-α-methyl-naphthyl-1-acetic acid 2'-dimethylamino-ethyl ester from bp 1800 - 1820 / 0.05 mm.

Analogously, from 4-piperidino-α-methyl-naphthyl-1-acetic acid, 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid, 2-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid or

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-acetic acid by Esterification with 2-pyrrolidinoethyl chloride, 3-morpholinopropyl chloride, 3-morpholino-2-propyIchlorld, 2-piperidinoethyl chloride and 2-) 2-methylpiperidino) ethyl chloride the following esters: 4-piperidino-α-methyl-naphthyl-1-acetic acid - 2'-pyrrolidinoethyl ester from Bp 227-229 / 0.05 mm, -3'-morpholinopropyl ester of bp 230-236 / 0.02 mm, -1'-methyl-2'-morpholinoethyl ester from b.p. 228 ° - 230 ° / 0.02 mm, -2'-piperidinoethyl ester from b.p. 218 ° - 222 ° / 0.02 mm, -2 '-) 2-kmthylpiperidino) ethyl ester of bp 224 ° - 225 ° / 0.01 mm, 3-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid - 2'-pyrrolidinoethyl ester from bp 2070-2120 / 0.05 mm ,, -3'-morpholinopropyl ester from bp 220 ° - 225 ° / 0.01 mm, -1'-methyl-2'-morpholino-ethyl ester with a boiling point of 220 ° - 225 ° / 0.10 mm, 0.05 mm, -2'-piperidinoethyl ester of b.p. 2300 -? 320 / 0.02 mm, -2 '- (2-methyl-piperidino) ethyl ester of b.p. 2350 - 2370 / 0.01 mm, -3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid -2'-pyrrolidinoethyl ester of bp 2200-2220 / 0.1 mm, -3'-morpholinopropyl ester of bp 230-2320 / 0.1 mm, -1'-methyl-2'-morpholino-ethyl ester of b.p. 2250 - 2260 / 0.02 mm, -2'-piperidinoethyl ester of b.p. 2170 -, 2180 / 0.01 mm, -2 '- (2-methylpiperidino) ethyl ester of bp 2230-2260 / 0.05 mm, 2-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid -2'-pyrrolidinoethyl ester from bp 2100-2120 / 0.1 mm, -3'-morpholinopropyl ester from Bp 2220-2240 / 0.1 mm, -1'-methyl-2'-morpholino-ethyl ester of bp 2170.2180 / 0.1 mm, -2'-piperidinoethyl ester of bp 205 ° - 206 ° / 0.1 mm, -2 '- (2-methyl-piperidino) -ethyl ester of bp 2210-2240 / 0.2 mm, 3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-acetic acid - 2'-pyrrolidinoethyl ester from, bp 1900 - 1920 / 0.1 mm, -3'-morpholinopropyl ester 'from bp 2050 - 2060 / 0.1 mm, -l'-methyl-2'-morpholinoethyl ester of b.p. 2020-2050 / 0.1 mm, -21-piperidinoethyl ester from 1980 - 2000 / 0.1 mm resp.

-2 '- (2-methylpiperidino) ethyl ester with a boiling point of 208 ° -210 ° / 0.05 mm.

Example 14 14.2 g of 4-piperidino- # 025-methyl-naphthyl-1-acetic acid are dissolved in 200 ml of absolute benzene and 8j8 g of SOC12 are added. The reaction mixture is heated on the steam bath for 30 minutes and then evaporated. The residue will Once more benzene was added and the benzene was drawn off again. The now remaining one The residue is mixed with 150 ml of dioxane and with 50 ml of 25% strength aqueous ammonia solution offset. The reaction mixture is left to stand for 20 minutes, then with 200 ml Water was added and the mixture was extracted several times with ethyl acetate. The organic phase is dried and evaporated. You get 4-piperidino-α-methyl-naphthyl-1-acetamide from mp 133 ° - 138 ° (from ethyl acetate).

Analogously, from 4-piperidino-α-methyl-naphthyl-1-acetic acid, 3-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid respectively.

3-chloro-4-piperidino-a-methyl-5, 6, 7, 8-tetrahydro-naphthyl-acetic acid by Reaction with a) aniline: 4-piperidino-a-methyl-naphthyl-l-acetic acid anilide, 3-chloro-4-piperidino-a-methyl-naphthyl-l-acetic acid anilide, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic anilide or

3-chloro-4-piperidino-a-methyl-5, S, 7, 8-tetrahydro-naphthyl-acetic anilide; b) p-ethoxyaniline: 4-piperidino-a-methyl-naphthyl-1-acetic acid-p-ethylanilide, 3-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid-pethoxyanilide, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid päthoxyanilid or

3-chloro-4-piperidino-a-methyl-5, 6,7,8-tetrahydro-naphthyl-acetic acid-p-ethoxyanilide; c) o-methoxyaniline: 4-piperidino-a-methyl-naphthyl-l-acetic acid-o-methoxy'-anilide, 3-chloro-4-piperidinQ-a-methyl-naphthyl-1-es3igsäue-omethoxy-anilid, 3-methyl-4-piperidino-a-methyl-naphthyl-1-e ssigsäure-omethoxy-anilid or

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-acetic acid-o-methoxy-anilide; d) m-trifluoromethylaniline: 4-piperidino-a-methyl-naphthyl-l-essigaEure-m-trifluoroniethylanilide, 3-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid-mtrifluoromethylanilide, 3-methyl-4-piperidino-a-methyl-napht, ethyl-1-acetic acid mtrifluoromethylanilide or

3-chloro-4piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid-m-trifluoromethylanilide; e) Benzylamine: 4-Piperidillo-a-methyl-naphthyl-1-acetic acid-bellzylamide, 3-Cholor-4-piperidino-α-methyl-naphthyl-1-acetic acid benzylamide, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid benzylamide or

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid benzyl amide; f) 2,3-Dihydroxy-n-butylamine: 4-Piperidino'-a-methyl-naphthyl-1-esæigsäure - N- (, 2,3-dihydroxy-n-butyl) -amide, 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2,3-dihydroxy-n-butyl) -amide, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid-N- (2,3-dihydroxy-n-butyl) -amide respectively.

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid-N- (2,3-dihydroxy-n-butyl) -amide; g) 2-methylmercaptoethylamine: 4-piperidino-α-methyl-naphthyl-1-acetic acid-N- (2-methyl mercaptoethyl) amide, -3-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid-N- (2-methylmercaptoethyl) amide, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid-N- (2-methylmercaptoethyl) -amide respectively.

3-chloro-4-piperidino-a-methyl-5, 6, 7, 8-tetrahydro-naphthyl-1-acetic acid-N- (2-methylmercaptoethyl) -amide.

Example l5, To a. Solution of 28 g of hydroxylamine hydrochloride in 70 ml of absolute ethanol becomes a solution of 1.0 g of sodium in 20 ml of absolute ethanol dripped closed. The precipitated sodium chloride is filtered off with suction. Become the filtrate 12.5 g of 4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester were added. Afterward a solution of 1.0 g of sodium in 10 ml of absolute ethanol is added. To Standing overnight, the ethanol is distilled off in vacuo and the residue in water dissolved and adjusted to pH 5-6 with 2N HCl. The separating oil is in Ethyl acetate added. The organic phase is dried over Na2S04, the Na2S04 filtered off and the filtrate evaporated. The residue is made from ethyl acetate / petroleum ether (400,) recrystallized. 4-Piperidino-α-methyl-naphthyl-1-acethydroxamic acid is obtained from the mp 172 ° - 174 °; Yield: 7.5 g.

Analogously from 3-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid methyl ester, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid methyl ester, 3-bromo-4-piperidino-a-methyl-naphthyl-1-acetic acid methyl ester, 2-chloro-4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester, 2-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester, 3-Methoxy-4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester, 3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl l-acetic acid methyl ester by reaction with hydroxylamine 3-chloro-4-piperidino-a-methyl-naphthyl-1-ac e thydroxamic acid, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acethydroxamic acid, 3-: 3rom-4-piperidino-a-methyl-naphthyl-1-acethydroxamic acid, 2-chloro-4-piperidino-a-methyl-naphthyl-1-acethydroxamic acid, 2-methyl-4-piperidino-a-methyl-naphthyl-1-acet'hydroxamic acid '3-methoxy-4-piperidino-a-methyl-naphthyl-1-acethydroxamic acid respectively.

3-chloro-4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyll-acethydroxamic acid.

Example 16 To an ice-cooled solution of diazomethane in ether a solution of 5.5 g of 4-piperidino-naphthyll-acetic acid in 200 ml of ether and 50 ml of tetrahydrofuran were slowly added dropwise. The excess diazomethane is then used decomposed by adding glacial acetic acid. The solution is made with sodium bicarbonate solution and water and then dried over Na2S04. After filtration of the sodium sulfate the solvent is evaporated and the residue is distilled in vacuo. That The distillate is dissolved in chloroform and ethereal hydrochloric acid is added. That precipitated hydrochloride is filtered off with suction and recrystallized from methanol. Man receives 4-piperidinonaphthyl-1-acetic acid methyl ester hydrochloride from P. 2000 - 2020; Yield: 5.0 g.

Analogously, from 4-piperidino- # 35-methyl-naphthyl-1-acetic acid, 5-chloro-4-piperidino-a-methyl-naphthyl-1-e-sigature or

3-methyl-4-piperidino-a-methyl-naphthyl-l-acetic acid duroh implementation with diazomethane 4-piperidino-α-methyl-naphthyol-1-acetic acid methyl ester, 3-chloro-4-piperidino- # 35-methyl-naphthyl-1-acetic acid methyl ester or

3-Methyl-4-piperidino- # 35-methyl-naphthyl-1-acetic acid methyl ester.

Example 17 32.4 g of 4-bromo-3-nitro-α-methyl-naphthyl-1-acetic acid are then refluxed for 40 hours with 18 g of piperidine in 150 ml of benzene Iland is cooled and extracted with 2N hydrochloric acid. The hydrochloric acid extract is made with dilute sodium hydroxide solution to pH 3 - 6, extracted with ethyl acetate and the ethyl acetate extract, after drying over sodium sulfate, filtered and evaporated.

After crystallization from isopropanol / water, the residue is obtained 4-piperidino-3-nitro-α-methyl-naphthyl-acetic acid from B. 197 ° - 199 °.

Analogously, by reacting the corresponding 4-bromo-3-nitro-naphthyl-1-acetic acids with piperidine or

Pyrrolidine or homopiperidine or morpholine or thiomorpholine or 2,6-1) imethylpiperidine or di-n-propylamine or di-n-butylamine or di-n-hexylamine make the following compounds: 4-pyrrolidino-3-nitro-α-methyl-naphthyl-1-acetic acid, 4-homopiperidino-3-nitro-α-methyl-naphthyl-1-acetic acid, 4-morphino-3-nitro-α-methyl-naphthyl-1-acetic acid, 4-thiomorpholino-3-nitro-α-methyl-naphthyl-1-acetic acid, 4- (2 ', 6'-dimethylpiperidino) -3-nitro-α-methyl-naphthyl-1-acetic acid, 4-di-n-propylamino-3-nitro-α-methyl-naphthyl-1-acetic acid, 4-di-n-butylamino-3-nitro-a-methyl-naphthyl-1-acetic acid, 4-Di-n-hexylamino-3-nitro-a-methyl-naphthyl-1-acetic acid, 4-piperidino-D-nitro-a-ethyl-naphthyl-1-e S etic acid, 4-homopiperidino-3-nitro-a-ethyl-naphthyl-1-acetic acid, 4-morpholino-3-nitro-a-ethyl-naphthyl-1-e acetic acid, 4-pyrrolidino-3-nitro-a-ethyl-naphthyl-1-acetic acid, 4-piperidino-3-nitro-naphthyl-1-acetic acid, 4-pyrrolidino-3-nitro-naphthyl-1-acetic acid, 4-morpholino-3-nitro-naphthyl-1-acetic acid, 4-homopiperidino-3-nitro-naphthyl-1-acetic acid or

4-thiomorpholino-3-nitro-naphthyl-1-acetic acid.

The starting material can be obtained, for example, by 4-Bromo-α-methyl-naphthyl-1-acetic acid with anhydrous nitric acid at 200 nitrated and the nitration products separated by fractional crystallization or by adding 4-acetamino-α-methyl-naphthyl-1-acetic acid with the H2504 / HN03 nitration mixture nitrated, 'the 4-acetamino group acidified and the 4-amino-3-nitro-a : -methyl-naphthyl-1-e acetic acid analogous to the procedure given in Example 19 diazotized and reacted with copper bromide.

Example 18 32.8 g of 4-piperidino-3-nitro-a-methyl-naphthyl-1-acetic acid are dissolved in 350 ml of absolute alcohol and mixed with Pd / H2 until the absorption of 6.7 1 H2 shaken (duration ~ 45 minutes). The catalyst is suctioned off, the solvent evaporated and the residue recrystallized from isopropanol. 4-piperidino-5-amino-a-methylnaphthyl-1-acetic acid is obtained with a temperature of 205 ° - 208 ° (decomposition).

The corresponding compounds are obtained analogously by catalytic hydrogenation 3-nitronaphthyl-l-acetic acids: -4-pyrrolidino-3-amino-a-methyl-naphthyl'-l-acetic acid 4-homopiperidino-3-amino-a-methyl-naphthyl-1-acetic acid, 4-morpholino-3-amino-α-methyl-naphthyl-1-acetic acid, 4-thiomorpholino-3-amino-a-methyl-naphthyl-1-acetic acid, 4- (2 ', 6'-dimethylpiperidino) -3-amino-a-methyl-naphthyl-acetic acid, 4-di-n-propyla, mino-3-amino-a-methyl-naphthyl-1-acetic acid, 4-di-n-butylamino-3-amino-α-methyl-naphthyl-1-acetic acid, 4-Di-n-hexylamino-3-amino-α-methyl-naphthyl-1-acetic acid, 4-piperidino-3-amino-a-ethyl-naphthyl-1-acetic acid, 4-homopiperidino-3-amino-a-ethyl-naphthyl-l-acetic acid, 4-morpholino-3-amino-a-ethyl-naphthyl-l-acetic acid, 4-pyrrolidino-3-amino-α-ethyl-naphthyl-l-acetic acid 4-piperidino-3-amino-naphthyl-l-acetic acid, 4-pyrrolidino-3-amino-naphthyl-1-acetic acid, 4-pyrrolidino-3-amino-naphthyl-1-acetic acid, 4-homopiperidino-3-amino-naphthyl-1-acetic acid or

4-Thiomorpholino-3-amino-naphthyI-1-acetic acid.

Example 19 14.8 g of 4-piperidinoo-3-amino-α-methyl-naphthyl-1-acetic acid, are concentrated in a mixture of 25 ml of water and 5 ml.

Dissolved H2S04 and at 3 - 60 with a solution of 3.5 g NaN02 in 7 ml of water diazotized. This solution is in a boiling solution of 6.3 g CuSO4 5H20, 2 g copper powder, 13 g potassium bromide, 1.6 ml conc. H2504 in 100 ml of water k (previously Boiled under reflux for 3 hours) and then added dropwise for 30 minutes with stirring continued to cook. After cooling to room temperature, the acidic solution is 16% Sodium hydroxide solution adjusted to pH 5 - 5.5 and extracted with ethyl acetate. The ethyl acetate solution is dried over Na2SO4, filtered and evaporated. Of the The residue gives 11.2 g of 4-piperidino-o-3-bromo-α-methyl-naphthyl-1-acetic acid from isopropyl ether from the F. 186 ° / 187 °.

Analog - is obtained from: 4-morpholino-3-amino-a-methyl-naphthyl-1-acetic acid.

4-Di-n-butylaminoo-3-amino-α-methyl-naphthyl-1-acetic acid, 4; Pyrroiidino-9-amino-a-methyl-naphthy2-4-homopiperidinoo-3-amino-α-methyl-naphthyl- 1-acetic acid, 4-Di-n-hexylamino-3-amino-ac-methyl-naphthyl-1-esacetic acid, 4-piperidinoo-3-amino-α-ethyl-naphthyl-1-acetic acid, 4-homopiperidino-3-amino-a-ethyl-naphthyl-1-acetic acid or

4-pyrrolidinoo-3-amino-α-methyl-naphthyl-1-acetic acid after diazotization and exchange of the diazonium group for bromine: 4-morpholino-3-bromo-a-methyl-naphthyl-1-acetic acid, 4-di-n-butylamino-3-bromo-α-methyl-naphthyl-1-acetic acid, 4-pyrrolidino-3-bromo-α-methyl-naphthyl-1-acetic acid, 4-homopiperidino-3-bromo-a-methyl-naphthyl-1-acetic acid, 4-di-n-hexylamino-3-bromo-a-methyl-naphthyl-l-acetic acid ' 4-piperidino-3-bromo-a-ethyl-naphthyl-1-acetic acid, 4-homopiperidino. 3-bromo-a-ethyl-naphthyl-1-acetic acid respectively.

4-pyrrolidino-3-bromo-naphthyl-1-acetic acid.

Example 20 29.6 g of 4-piperidino-3-amino-α-methyl-naphthyl-1-acetic acid, are dissolved in 100 ml of water and 45 g of concentrated HO1 and at 3 60 with a Solution of 7 g NaNO2 diazotized in 1.5 ml of water. This diazonium salt solution becomes a boiling solution of CuCl (made from 20 g copper sulfate, 20 g NaCl in 80 ml of water with SO2) was added dropwise. After the addition, the temperature is still Maintained at 90-950 for 30 minutes. After cooling to room temperature, the acidic solution adjusted to pH 5 - 5.5 with dilute sodium hydroxide solution, the deposited Oil taken up in ethyl acetate and dried over Na2S04. The one after the evaporation The residue obtained from the ethyl acetate gives 4-piperidino-3-chloro-α-methyl-naphthyl-1-acetic acid from isopropyl ether of mp 173 ° - 174 "; yield 18.6 g.

Analogously, from 4-pyrrolidino-3-amino-methyl-naphthyl-4-pyiperidino-3-chloro-α-methyl-naphthyl-1-acetic acid and from 4-morpholino-3-amino-a-methyl-naphthyl-1-acetic acid 4-morpholino-3-chloro-α-methyl-naphthyl-1-acetic acid produce.

Analogously, from 4-homopiperidino-3-amino-α-methyl-naphthyl-1-acetic acid, 4-thiomorpholino-3-amino-α-methyl-naphthyl-1-acetic acid, 4-di-n-butylamino-3-amino-a-methyl-naphthyl-1-e s sigric acid, 4-di-n-propylamino-3-amino-a-methyl-naphthyl-1-acetic acid, 4-piperidino-3-amino-a-ethyl naphthyl-1-acetic acid 4-pyrrolidino-3-amino-α-ethyl-naphthyl-1-acetic acid and 4-morpholino-3-amino-naphthyl-l-acetic acid after diazotization and replacement of the Diazonium group against chlorine 4-homopiperidino-3-chloro-methyl-naphthyl-l-acetic acid, 4-hiomorphoino-3-chloro-a-methyl-nahth 4-di-n-butylaminoo-3-chloro-α-methyl-naphthyl-1-acetic acid, 4-di-n-propylamino-5-chloro-a-methyl-naphthyl-1-acetic acid, . 4-piperidino-3-chloro-a-ethyl-naphthyl-1-es acetic acid, 4-pyrrolidino-3-chloro-α-ethyl-naphthyl-1-acetic acid or

4-morpholino-3-chloro-naphthyl-1-acetic acid.

Example 21 27.8 g of 4-piperidino-3-amino-α-methyl-naphthyl-1-acetic acid are in a mixture of 25 g of concentrated HCl and 75 ml of water at 3-6 ° diazotized with a solution of 8 g of NaNO2 in 15 ml of water. This diazonium salt solution becomes a copper 1-cyanide solution heated to 60 - 700 (produced by Heat. of 25 g copper sulfate in 100 ml water with 28 g potassium cyanide) in approx.

Added for 10-15 minutes. After the end of the entry, the reaction mixture is warmed up on the steam bath for another 20 minutes. After cooling to room temperature the acidic solution is adjusted to pH 5-5.3 with 16% NaOH and with ethyl acetate extracted. The ethyl acetate solution is dried over Na2SO4, evaporated and recrystallized from diisopropyl ether-hexane. 17.3 g of 4-piperidino-3-cyano-α-methyl-naphthyl-1-acetic acid are obtained acid from B. 176 ° - 198 °.

Analogously, 4-piperidino-3-aminonaphthyl-1-acetic acid is obtained from 4-piperidino- 3-cyano-naphthyl-l-acetic acid and from 4-morpholino-3-amino-a-ethyl-naphthyl-l-acetic acid 4-morpholino-3-cyano-a-ethyl-naphthyl-1-acetic acid.

Analogously, from 4-pyrrolidino-3-amino-α-methyl-naphthyl-1-acetic acid, 4-homopiperidino-3-amino-a-methyl-naphthyl-1-acetic acid, 4-morpholino-3-amino-a-methyl-naphthyl-1-e acetic acid, 4-di-n-propylamino-3-amino-α-methyl-naphthyl-1-acetic acid, 4-piperidino-3-amino-α-ethyl-naphthyl-1-acetic acid and 4-homopiperidino-3-aminonaphthyl-1-acetic acid after diazotization and exchange the diazonium group against cyano 4-pyrrolidino-3-cyano-a-methyl-naphthyl-1-acetic acid, 4-homopeperidino-3-cyano-α-methyl-naphthyl-1-acetic acid, 4-morpholino-3-cyano-a-methyl-naphthyl-1-e Acetic acid, 4-di-n-propylamino-3-cyano-α-methyl-naphthyl-1-acetic acid, 4-propylamino-3-cyano-α-methyl-naphthyl-1-acetic acid respectively.

4-homopiperidino-3-cyano-naphthyl-1-acetic acid.

Example 22 28.9 g of 4-piperidino-3-amino-α-methyl-naphthyl-1-acetic acid are dissolved in 120 ml of 18% sulfuric acid and 7.5 g of NaNO2 in 12 ml of water diazotized. This solution is poured into a mixture of 25 g of KJ and -50 ml H2S04 given. After stirring overnight until complete. the evolution of nitrogen on the water. heated bath (duration about 30 minutes). The solution is made with animal charcoal decolorized and adjusted to pH 6-6.4 with 16% sodium hydroxide solution. The reaction mixture is extracted with ethyl acetate and the solution is dried over Na2SO4. After evaporation of the solvent, 15.2 g of 4-piperidino-3-iodo-α-methyl-naphthyl-1-acetic acid are obtained vom Fa 2010, .2020 (toluene).,.

Analogously one obtains. from 4-morpholino-3-amino-a-methyl-naphthyl-1-e 8Big8§we, 4-homopiperidino-3-amino-a-methyl-naphthyl-l-acetic acid, 4-pyrrolidino-3-amino- «- methyl-naphthyl-l-acetic acid, 4-2hiomorpholino-3-amino-a-methyl-naphthyl-1-acetic acid, 4-piperidino-3-amino-α-ethyl-naphthyl-1-acetic acid, 4-morpholino-3-amino-a-ethyl-naphthyl-l-acetic acid, 4-pyrrolidino-3-amino-a-ethyl-naphthyl-l-acetic acid, 4-piperidino-3-amino-naphthyl-1-acetic acid, 4-morpholino-3-amino-naphthyl-1-acetic acid and 4-homopiperidino-3-aminonaphthyl-1-acetic acid after diazotization and exchange of the diazonium salt against iodine 4-morpholino-3-iodo-α-methyl-naphthyl-1-acetic acid, 4-hemopiperidino-3-; od-a-methyl-naphthyl-l-e's8igsäure, 4-pyrrolidino-5-iodine - methyl-naphthyl-l-acetic acid, 4-thiomorpholino-3-iodo-α-methyl-naphthyl-1-acetic acid, 4-piperidino-3-iodo-a-ethyl-naphthyl-1-acetic acid, 4-morpholino-3-iodo-a-ethyl-naphthyl-1-acetate, 4-pyrrolidino-3-iodo-α-ethyl-naphthyl-1-acetic acid, 4-piperidino-3-iodo-naphthyl-1-acetic acid, 4-morpholino-3-iodo-naphthyl-1-acetic acid respectively.

4-homopiperidino-3-iodo-naphthyl-1-acetic acid.

Example 23 14.5 g of 3-amino-4-piperidino-naphthyl-1-acetic acid (available nach..Example 18 through Example 17) are dissolved in 0.125 mol of 10% hydrochloric acid, the solution is cooled to 5-100 and the gradual addition of 3.5 g of sodium nitrite diazotized. This diazonium salt solution is allowed to slowly and with stirring under the Surface of a solution of 2.7 g of methyl mercaptan in 40 ml of 20% sodium hydroxide solution drop, the reaction temperature being kept at 70-70 °. Then is heated to 900 and the temperature is kept at this level until the The evolution of nitrogen has ended. Then it is cooled and with concentrated hydrochloric acid acidified to pH 4-6. The dark precipitate is filtered off with suction and recrystallized from isopropyl ether with clarification with activated charcoal. 8.5 is obtained g of 3-methylmercapto-4-piperidino-naphthyl-1-acetic acid with a melting point of 167-169 °.

Analogously, from 3-amino-4-piperidino-a-methyl-naphthyl-1-acetic acid, 2-Amino-4-piperidino- # k035-n-butyl-naphthyl-1-acetic acid, 3-amino-4-pyrrolidino- # k035-methyl-naphthyl-1-acetic acid, 2-amino-4-pyrrolidino-naphthyl-1-acetic acid, 3-amino-4-morpholino- # k035-methyl-naphthyl-1-acetic acid, 2-amino-4-homopiperidino-naphthyl-1-acetic acid and 3-amino-4-homopiperidino-a-methyl-naphthyl-1-acetic acid, after diazotization and exchange for methyl mercapto 3-methylmercapto-4-piperidino-a-methyl-naphthyl-l-acetic acid, 2-methylmercapto-4-piperidino-a-n-butyl-naphthyl-l-acetic acid, 3-methylmercapto-4-pyrrolidino-a-methyl-naphthyl-l-acetic acid, 2-methylmercapto-4-pyrrolidino-naphthyl-1-acetic acid, D-methylmercapto-4-morpholino-a-methyl ~ naphthyl ~ l ~ acetic acid, 2-methylmercapto-4-homopiperidin9-naphthyl-l-acetic acid or

3-methylmercapto-4-homopiperidino-a-methyl-naphthyl-1-acetic acid.

Example 24 14.9 g of 3-amino-4-piperidino-α-methyl-naphthyl-1-acetic acid (obtainable according to Example 18 via Example 17) are 10% sulfuric acid in 0.125 mol dissolved and diazotized at 0-5 ° by adding 3.5 g of sodium nitrite in 8 ml of water. The dia zonium salt solution is stirred vigorously and as quickly as the evolution of nitrogen, . enables in 250 ml of boiling water. Then cook for another 30 minutes. On cooling and buffering to pH 4-6, 3-hydroxy-4-piperidino-α-methyl-naphthyl-1-acetic acid separates away. 29.9 g of this are dissolved in 250 ml of 1N sodium hydroxide solution under nitrogen, in portions 26 g of dimethyl sulfate are added while stirring. In the course of the reaction-separates 3-methoxy-4-piperidino-α-methyl-naphthyl-1-acetic acid methyl ester (Kp'192 - 1960 / 0.01 mm) oily. After stirring for half an hour, 100 ml of 2N sodium hydroxide solution are added to-and cooks while stirring for half an hour. The clear solution is then cooled to 0-100 and acidified to pH 4-6 with hydrochloric acid. The unusual one 3-Methoxy-4-piperidino-α-methyl-naphthyl-1-acetic acid is filtered off with suction, with Washed water, dried and recrystallized from diisopropyl ether.

Analogously, from the corresponding 3-amino-naphthyl-1-acetic acids by diazotization, boiling and, if necessary, reaction with dimethyl sulfate and Saponification are obtained: 3-Hydroxy-4-pyrrolidino-α-methyl-naphthyl-1-acetic acid, 3-hydroxy-4-homopiperidino-α-methyl-naphthyl-1-acetic acid, 3-hydroxy-4-morpholino-α-methyl-naphthyl-1-acetic acid, 3-hydroxy-4-thiomorpholino-α-methyl-naphthyl-1-acetic acid, 3-hydroxy-4-di-n-propylamino-α-methyl-naphthyl-1-acetic acid, 3-Hydroxy-4-di-n-butylamino-α-methyl-naphthyl-1-acetic acid, 3-methoxy-4-pyrrolidino-at-methyl-naphthyl-1 methyl acetate, 3-methoxy-4-homopiperidino-α-methyl-naphthyl-1-acetic acid methyl ester, 3-Me thoxy-4-morpholino-a-methyl-naphthyl-l-acetic acid methyl ester, 3-methoxy-4-thiomorpholino-a-methyl-naphthyl-l-acetic acid methyl ester, 3 -Methoxy-4-di-n-propylamino-a-methyl-naphthyl-1-acetic acid methyl ester, 3-methoxy-4-di-n-butylamino-a-methyl-naphthyl-1-acetic acid methyl ester, 3-methoxy-4-pyrrolidino-a-methyl-naphthyl-1-acetic acid, 3-methoxy-4-homopiperidino-a-methyl-naphthyl-1-acetic acid, 3-methoxy-4-morpholino-a-methyl-naphthyl-1-acetic acid, 3-methoxy-4-thiomorpholino-a-ynethyl-naphthyl-1-acetic acid 3-methoxy-4-di-n-propylamino-a-methyl-naphthyl-1-acetic acid, 3-methoxy-4-di-n-butylamino-methyl-naphthyl-l-acetic acid, 3-hydroxy-4-piperidino-a-ethyl-naphthyl-l-acetic acid, 3-hydroxy-4-pyrrolidino-a-ethyl-naphthyl-l-acetic acid, -3-Hydro "y-4-homopiperidino-a-ethyl-naphthyl-1-acetic acid, 3-hydroxy-4-morpholino-a-ethyl-naphthyl-lessetic acid, 3-methoxy-4-piperidino-α-ethyl-naphthyl-1-acetic acid, 3-methoxy-4-pyrrolidino-α-ethyl-naphthyl-1-acetic acid, 3-14ethoY ~ y-4-hom. opiperidino-a-ethyl-naphthyl-1-essiesälire, 3-methoxy-4-morpholino-a-ethyl-naphthyl-1-acetic acid, -3-metiioxy-4-piperidino-a-ethyl-naphthyl-1 methyl acetate, 3-methoxy-4-piperidino-α-ethyl-naphthyl-1-acetic acid methyl ester, 3-methoxy-4-homopiperidino-a-ethyl-naphthyl-l-acetic acid methyl ester or

3-Methoxy-4-morpholino-a-ethyl-naphthyl-1-acetic acid methyl ester and 3-methoxy-4-piperidino-naphthyl-1-acetic acid, 3-hydroxy-4-pyrrolidino-naphthyl-l-acetic acid, 3-hydroxy-4-homopiperidino-naphthyl-1-acetic acid, 3-hydroxy-4-morpholino-naphthyl-1-acetic acid, 3-methoxy-4-piperidino-naphthyl-1-acetic acid, 3-methoxy-4-pyrrolidino-naphthyl-1-acetic acid, 3-methoxy-4-homopiperidino-naphthyl-1-acetic acid, 3-methoxy-4-morpkholino-naphthyl-1-acetic acid, 3-methoxy-4-piperidino-naphthyl-1-acetic acid methyl ester, 3-methoxy-4-pyrrolidino-naphthyl-1-acetic acid methyl ester, 3-methoxy-4-homopiperidino-naphthyl-1-vinegar. q methyl ester, 3-methoxy-4-morpholino-naphthyl-1-acetic acid methyl ester.

Example 25 13.5 g of 4-piperidino-, a-dimethyl-1-naphthyl-acetonitrile are heated for 2 1/2 hours in 100 ml of 85% sulfuric acid on a water bath, then diluted with 200 ml of water and boiled for 10 hours. The solution is cooled and adjusted to pH 4-6 with 16% sodium hydroxide solution.

Then it is extracted with chloroform, the extract over.

Sodium sulfate dried and then evaporated.

4-Piperidino-a, a-dimethyl-naphthyl-1-es% acid is obtained.

The saponification of 4-piperidino-naphthyll-acetonitrile is analogous 4-piperidino-naphthyl-1-acetic acid was obtained.

The starting material 'is obtained from l-nitro-4-bromonaphthalene, the is first converted into l-nitro-4-piperidino-naphthalene with piperidine, with SnC12 reduced in concentrated hydrochloric acid to the l-amino derivative, diazotized, according to Sandmeyer introduces the cyano group and boiling with concentrated hydrochloric acid to give 4-piperidino-1-naphthoic acid saponified. The reduction with LiAlH4 / BF3 leads to the corresponding 1-hydroxymethyl derivative, which is converted into 1-bromomethyl-4-piperidino-naphthalene by treatment with 48% strength KBr will. The reaction with KCN in alcohol-water leads to 4-piperidinonaphthyl -l-acetonitrile, the result of the successive action of NsNH2 and dimethyl sulfate in boiling Benzene is methylated in the a-position.

Analogously from: 4-homopiperidino-α, α-dimethyl-4-piperidino-, a-diethyl-4-diisopropylamino-α, α-butyl-4-piperidino-α, α-di-n-butyl-4-dimethylamino-α, α-dimethyl- respectively.

4-diethylamino-α, α-dimethyl-naphthyl-1-acetonitrile Hydrolysis with sulfuric acid 4-homopiperidino-α, α-dimethyl-4-piperidino-α, α-diethyl-4-diisopropylamino-α, α-dimethyl-4-piperidino-a, a-di-n-butyl-4-dimethylamino-α, α-dimethyl or

4-diethylamino-a, -dimethyl-naphthyl-1-acetic acid.

Example 26 2.2 g of 4-piperidino-naphthyl-1-glyoxylic acid (available by acylation of l-piperidino-naphthalene with ethoxalyl chloride in the presence of aluminum chloride and subsequent saponification) with 0.8 g of red phosphorus and 40 ml 50% HJ boiled for 30 minutes. The mixture is cooled with 100 ml of water diluted and buffered to pH 4 - 6 with 25% sodium hydroxide solution. The work-up analogously to Example 25 gives 4-piperidino-naphthyl-acetic acid with a melting point of 1420-1430 ..

The following is obtained analogously from: 4-Diisopropylamino-naphthyl-1-glyoxylic acid by reduction with HJ 4-diisopropylamino-naphthyl-1-acetic acid example 27 A solution of 29.4 g of potassium dichromate in 280 ml of water is concentrated with 200 ml Sulfuric acid was added and the mixture was cooled to 150. Then add slowly while stirring and cooling at 150-200 a solution of 18.2 g of 3-methylmercapto-4-piperidino-α-methyl-naphthyl-1 acetic acid (obtainable according to Example 23) in 60 ml of glacial acetic acid. The mixture remains Stand for 1 1/2 hours at room temperature and is then poured into 1 liter of water.

The pH is adjusted to 5-6 with sodium hydroxide solution. The aqueous phase is decanted from the precipitate. This is taken up in chloroform. The extract is dried and concentrated. 3-Methylsulfonyl-4-piperidino-α-methyl-naphthyl-1-acetic acid is obtained.

Analogously from: 3-Aeth3Telmercapto-4-piperidino-a-methyl-naphthyl-1-essi, gic acid, 3-isopropylmercapto-4-piperidino-α-methyl-naphthyl-1-acetic acid, 3-methylmercapto-4-morpholino-a-methyl-naphthyl-1-acetic acid, 3-ethylmercapto-4-morpholino-a-methyl-naphthyl-1-es9igsäure, 3-methylmercapto-4-pyrrolidino-a-methyl-naphthyl-1-acetic acid, 3-methylmercapto-4-homopiperidino-α-methyl-naphthyl-1-acetic acid, 3-methylmercapto-4-piperidino-naphthyl-1-acetic acid, 3-methylmercapto-4-morpholino-naphthyl-1-acetic acid, 3-methylmercapto-4-pyrrolidino-naphthyl-1-acetic acid and 3-methylmercapto-4-homopiperidino-naphthyl-1-acetic acid by oxidation with Potassium dichromate 3-ethylsulfonyl-4-piperidino-a-methyl-naphthyl-lessetic acid, 3- isopropylsulfonyl-4-piperidino-a-methyl-naphthyl-lessetic acid, 3-methylsulfonyl-4-morpholino-a-methyl-naphthyl-l-acetic acid, 3-ethylsulfonyl-4-morpholino-a-methyl-naphthyl-1-acetic acid, 3-methylsulfonyl-4-pyrrolidino-a-methyl-naphthyl-1-acetic acid, 3-methylsulfonyl-4-homopiperidino-a-methyl-naphthyl-1-acetic acid ,.

3-MethylsulSonyl-4-piperidino-naphthyl-1-acetic acid, 3-methylsulfonyl-4-morpholino-naphthyl-1-acetic acid, 3-methylsulfonyl-4-pyrrolidino-naphthyl-1-acetic acid or

3-methylsulfonyl-4-homopiperidino-naphthyl-1-acetic acid.

Example 28 30 g of 3-chloro-Z-piperidino-a-methyl-naphthyl-1-ac e t onitrile (can be prepared analogously to Example 25) and 4.2 g of absolute alcohol are in 300 ml of absolute ether dissolved and saturated with HCl gas at 0 °. That after 8 days of standing Imino ether hydrochloride precipitated at 0 ° is separated from the ether in 80 ml Dissolved water, neutralized with sodium carbonate solution and then 30 minutes warmed up on the steam bath. The separated oil is extracted with ether, over Na2SO. dried and the residue obtained after evaporation of the ether is distilled.

18.3 g of 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid ethyl ester are obtained from bp 1850 - 1870 / 0.01 mm.

Analogously from 3-bromo-4-piperidino-a-methyl-naphthyl-1-acetonitrile, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetonitrile and 3-fluorine-4-piperi dino-a-methyl-naphthyl-1-ac e tonitrile by reaction with ethyl alcohol: 3-bromo-4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester from bp 1900-1950 / 0.01 mm, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester from bp 202 ° - 203 ° / 0.3 mm and 3-fluoro-4-piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester to from Kp 1810 - 1830 / 0.01 mm.

Example 29 30 g of 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetonitrile (prepared analogously to Example 25) and 4.2 g of absolute alcohol are in 300 ml of absolute Dissolved ether and saturated with HCl gas at 00. That after 8 days of standing at 0 ° Separated imino ether hydrochloride is separated from the ether, 2 days in a vacuum desiccator Left to stand over NaOH, then dissolved in 40 ml of ethanol and stand at 200 for 8 days calmly. Then the precipitated NH4Cl is filtered off, the excess alcohol evaporated and the residue treated with aqueous sodium bicarbonate solution and ether.

The ethereal solution is separated, washed with water, over Na2S04 dried, evaporated and the residue distilled in vacuo. Yield: 16.3 g of 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid orthoethyl ester from KP 2100 - .2120 / 0.01 mm.

Analogously from 3-bromo-4-piperidino-a-methyl-naphthyl-1-acetonitrile, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetonitrile and 3-bluor-4-piperidino-a-me thyl-naphthyl-l-ac e tonitrile over the corresponding imino ether hydrochloride by reaction with ethyl alcohol: 3-bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid orthoethyl ester of b.p. 218-2210 / 0.01 mm, 3-methyl-4-piperidino-ez-methyl-naphthyl-1-acetic acid orthoethyl ester of bp 203-205 ° / 0.01 mm and 3-fluoro-4-piperidino-α-methyl-naphthyl-1-acetic acid orthoethyl ester with a bp 200 - 203 ° / 0.01 mm.

Example 30 17.25 g of 4-pipelidino-a-methyl-naphthyl-1-acetic acid 2'-chloroethyl ester (Bp 178 ~ 1820 / 0.01 mm), obtainable from the sodium salt of 4-piperidino-α-methyl-naphthyl-1-acetic acid by reaction with 1-bromo-2-chloro-ethane, with a solution of 7.5 g of diethylamine heated to 1000 in 60 ml of absolute benzene in a tube for 10 hours. After cooling down the reaction mixture is extracted with water, the benzene phase over Dried sodium sulfate and evaporated. The residue is fractionated. You get 13.6 g of 4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-diethylaminoethyl ester from bp 185-189 ° / 0.01 mm.

Analogously, from 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-chloroethyl ester, 3-methyl-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-chloroethyl ester and 4-pyrrolidino-α-methyl-naphthyl-1-acetic acid-2'-chloroethyl ester by reaction with diethylamine 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid-2'-diethylamino-methyl ester, 3-Mothyl-4-piperidino-α-methyl-naphthyl-1-acetic acid 2'-diethylamino-ethyl ester respectively.

4-pyrrolidino-α-methyl-naphthyl-1-acetic acid 2'-diethylaminoethyl ester example 31 A mixture of G, 2 g of 4-piperidino-α-methyl-naphthyl-1-acetic acid ethyl ester (available according to Example 9) and 50 g of 2-diethylamino-ethanol is boiled for 24 hours, whereby a column is used as a cooler, which is distilled off at the upper end of the released ethanol is permitted. Then the excess diethylaminoethanol distilled off. 4-Piperidino-α-methyl-naphthyl-1-acetic acid 2'-diethylaminoethyl ester is obtained from bp 185 - 1890 / 0.01 mm.

Analogously, from 4-morpholino-α-methyl-naphthyl-1-acetic acid thyl ester, 4-homopipelidino-a-methyl-naphthyl-1-acetic acid ethyl ester and 3-chloro-4-pyrrolidino-α-methyl-naphthyl-1-acetic acid ethyl ester by reaction with 2-diethylamino-ethanol 4-morpholino-α-methyl-naphthyl-1-acetic acid 2'-diethylaminoethyl ester from bp 191-1940 / 0.01 mm, 4-ilomopiperidino-a-methyl-naphthyl-1-acetic acid-2 -di äthylamino-ethyl ester of bp 192-195 ° / 0.01 mm and 3-chloro-4-pyrrolidino-α-methyl-naphthyl-1-acetic acid 2'-diethylaminoethyl ester from bp 203 - 206 ° / 0.01 mm.

Example 32 2.87 g of 4-piperidino-α-methyl-5,6,7,8-tetrahydronaphthyl-1-acetic acid from F. 163 - 1650 are boiled in 100 ml of toluene with 5 g of Ohloranil for 48 hours. The solution is then extracted with aqueous sodium bicarbonate solution.

Careful acidification of the aqueous extract gives 4-piperidino-α-methyl-naphthyl-1-acetic acid vom F. 181-1830 (ethanol).

Example 33 30 g of methyl 3- (4'-hydroxy-n-butyl) -4-piperidino-phenylacetate from bp 150 - 154 ° / 0.01 mm are mixed with 180 g of polyphosphoric acid and 2 1/2 Heated to 150 ° for hours.

The still warm reaction mixture becomes / 15% sodium hydroxide solution with cooling adjusted to pH 7-8.

One extracts; is ethyl acetate, dry the extract over Na2S'Q- ,, filtered and the ethyl acetate evaporated. The oily residue is distilled. 4-Piperidino-5,6,7,8-tetrahydro-naphthyl-1-acetic acid methyl ester is obtained Bp 155 - 1530 / 0.05 mm, which is obtained by alkaline saponification in 4-piperidino-5,6,7,8-tetrahydro-naphthyl-1-acetic acid from F. 125 - 1270 can be transferred.

Analogously, 4-pyrrolidino-5,6,7,8-tetrahydro-naphthyl-1-acetic acid methyl ester is obtained from the corresponding starting materials, Bp 144-148 ° / 0.01 mm, 4-piperidino-5,6,7,8-tetrahydro-α-methyl-naphthyl-1-acetic acid methyl ester of bp 153-156 ° / 0.01 mm and 4-piperidino-5,6,7,8-tetrahydro-α-methyl-naphthyl-1-acetic acid from the F. 163 - 165 °.

The starting material is obtained, for example, from 3- (4-acetoxy-n-butyl) toluene by nitration to 3- (4-acetoxy-n-butyl) -4-nitro-toluene, its catalytic hydrogenation to the 4-amino compound, acetylation to 3- (4-acetoxy-butyl) -4-acetamido-toluene, Chlorination with sulfuryl chloride to 3- (4-acetoxybutyl) -4-acetamido-benzyl chloride, Reaction with KCN in dimethyl sulfoxide to the corresponding benzyl cyanide, saponification to 3- (4-hydroxy-n-butyl) -4-aminophenylacetic acid and reaction with 1,5-dibromopentane.

Example 34 3.63 g of methyl 3- (4,4-dimethoxy-buty) -4-piperidino-phenylacetate are heated to 70-80 ° for 5 hours with 50 ml of anhydrous technical hydrofluoric acid. After cooling to below 150, it is carefully poured into ice water, and diluted with Sodium hydroxide solution to pH 6-8, extracted with ethyl acetate, dry the extract over Na2S04, the solvent evaporates and the oily residue is distilled off. Man receives 4-piperidino-7,8-dihydro-naphthyl-1-acetic acid methyl ester with a boiling point of 152 - 156 ° / 0.01 mm.

The following are obtained analogously from the corresponding starting materials: 4-pyrrolidino-7,8-dihydro-naphthyl-1-acetic acid methyl ester with a boiling point of 148-153 ° / 0.05 mm, 4-homopiperidino-7,8-dihydro-naphthyl-1-acetic acid methyl ester, b.p. 153-155 ° / 0.02 mm.

The starting material is made from methyl 3- (4-hydroxy-n-butyl) -4-piperidinophenylacetate by oxidation according to Oppenauer with aluminum isopropoxide in acetone to the corresponding Aldehyde and its acetalization with methanol / HC1- obtained.

Example 35 5 g of 4-piperidino-6,7-dibromo-a-methyl-5, 6,7, 8-tetrahydronaphthyl-1-acetic acid amide and 3 g of zinc dust are dissolved in 80 ml of 96% aqueous ethanol with intensive panning Cooked for 3 hours. It is filtered off hot, the residue is washed several times with hot After ethanol, the combined filtrates evaporated and crystallized from ethyl acetate around. 4-piperidino-α-methyl-5,8-dihydro-naphthyl-1-acetic acid amide is obtained from F. 126 - 12000.

Analogously, from 4-pyrrolidino-6,7-dibromo-α-methyl-5,6,7,8-tetrahydronaphthyl-1-acetic acid, 4-pyrrolidino-6,7-dibromo-α-ethyl-5,6,7,8-tetrahydronaphthyl-1 acetic acid, 4-pyrrolidino-6,7-dibromo-5,6,7,8-tetrahydronaphthyl-1-acetic acid, 4-piperidino-6,7-dibromo-α-ethyl-5,6,7,8-tetrahydronaphthyl-1- acetic acid and 4-piperidino-6,7-dibromo-5,6,7,8-tetrahydronaphthyl-1-acetic acid by reaction with Zn dust 4-pyrrolidino-α-methyl-5,8-dihydro-naphthyl-1-acetic acid, 4-pyrrolidino-3035-ethyl-5,8-dihydro-naphthyl-1-acetic acid, 4-pyrrolidino-5,8-dihydro-naphthyl-1-acetic acid, 4-pyrrolidino-α-ethyl-5,8-dihydro-naphthyl-1-acetic acid respectively.

4-Piperidino-5, 8-dihydro-naphthyl-1-acetic acid.

Example 36 5 g of 4-piperidino-6,7-dibromo-α-methyl-5,6,7,8-tetrahydronaphthyl-1-acetic acid (Obtained from the 4-piperidino-α-methyl-5,8-dihydro-naphthyl-1-acetic acid prepared according to Example 33 in glacial acetic acid with bromine) together with 15 g of quinoline are heated to 150-160 ° for 30 minutes heated.

Then the reaction mixture is made alkaline with 50 ml of 2N NaOH, which Aqueous phase is separated off and adjusted to 4-5 with 2N HCl. The secluded Oil is extracted with ethyl acetate, the extract is dried with Na2SO4 and evaporated. fan receives 4-piperidino-α-methyl-naphthyl-1-acetic acid with a temperature of 181-182 °.

The corresponding 6,7-dibromo-5,6,7,8-tetrahydro-naphthyl-1-acetic acids are obtained analogously by treatment with quinoline: 3-chloro-4-piperidine-α-ethyl-naphthyl-1-acetic acid, 2-chloro-4-piperidine-α-ethyl-naphthyl-1-acetic acid, 3-chloro-4-piperidine-α-ethyl-naphthyl-1-acetic acid, 2-chloro-4-piperidine-α-ethyl-naphthyl-1-acetic acid, 3-bromo-4-piperidino-α, α-dimethyl-naphthyl-1-acetic acid, 2-bromo-4-piperidino-α, α-dimethyl-naphthyl-1-acetic acid, 3-nitro-4-piperidino-α-methyl-naphthyl-1-acetic acid, 2-nitro-4-piperidino-α-methyl-naphthyl-1-acetic acid, 3-methoxy-4-piperidino-α-methyl-naphthyl-1-acetic acid, 2-methoxy-4-piperidino-α-methyl-naphthyl-1-acetic acid, 3- methylmercapto-4- piperidino-a-methyl-'naphthyl-1-acetic acid or

2-methylmercapto-4-piperidino-α-methyl-naphthyl-1-acetic acid.

Example 37 A solution of 2.7 g of 4-piperidinonaphthyl-1-acetic acid is added to 0.2 g of lithium and 1.6 g of diethylamine in absolute tetrahydrofuran. After stirring for two hours at room temperature the solvent is distilled off and the residue in dilute Sulfuric acid dissolved. It is buffered to pH 4-6 and extracted with methyl acetate. The organic extract is dried and concentrated. 4-Piperidino-5,8-dihydronaphthyl-1-acetic acid is obtained.

Analog receives; from 4-piperidino-α-methyl-naphthyl-1-acetic acid, 4-piperidino-α-ethyl-naphthyl-1-acetic acid, 4-piperidino-2, = -dimethyl-naphthlyl-1-acetic acid, 4-piperidino-3, α-dimothyl-naphthyl-1-acetic acid, 4-piperidino-3-methyoxy-naphthyl-1-acetic acid, 4-piperidino-2-methyoxy-naphthyl-1-acetic acid, 4-piperidino-3-ethyl-naphthyl- 1-acetic acid, 1 4-piperidino-2-ethyl-naphthyl-1-acetic acid, 4-piperidino-3-acetamino-naphthyl-1-acetic acid and 4-piperidino-2-acetamino-naphthyl-1-acetic acid through reduction with lithium 4-piperidino-α-methyl-5,8-dihydro-naphthyl-1-acetic acid, 4-piperidino-a ; -ethyl-5, 8-dihydro-naphthyl-1-acetic acid, 4-piperidino-2, a-dimethyl-5, 8-dihydro-naphthyl-1-acetic acid, 4-piperidino-3, a-dimethyl-5, 8-dihydro-naphthyl-1-acetic acid, 4-piperidino-3-methoxy-5,8-dihydro-naphthyl-1-acetic acid, 4-piperidino-2-methoxy-5,8-dihydro-napht 4-piperidino-3-ethyl-5,8-dihydro-naphthyl-1-acetic acid, 4-piperidino-2-ethyl-5,8-dihydro-naphthyl-1-acetic acid, 4-piperidino-3-acetamino-5,8-dihydro-naphthyl-1-acetic acid respectively.

4-piperidino-2-acetamino-5,8-dihydro-naphthyl-1-acetic acid.

Example 38 6.2 g of the sodium salt of 4-piperidino-8-oxo-5,6,7,8-tetrahydro-naphthyl-1-acetic acid are dissolved in 100 ml of ethanol and with stirring with a solution of 0.8 g of NaBH4 added in 25 ml of ethanol. After stirring for two hours at room temperature, the Alcohol distilled off.

The residue is dissolved in 100 ml of 2N HCl, heated briefly to 60 ° and neutralized after cooling with sodium carbonate. The crude acid excreted is heated to 1200 for 30 minutes with 50 ml of 85% phosphoric acid. After cooling down it is diluted with water and neutralized with sodium carbonate. 4-piperidino-5,6-dihydronaphthyl-1-acetic acid is obtained. F. 1340-1360 (ethanol).

To prepare the starting compound, Y- (2-acetamido-5-methoxy methyl-phenyl) -butyric acid (obtained from 6-methoxy methyl-1,4-naphthoquinone by Schmidt reaction with HN3, reduction of the resulting unsaturated seven-membered ring lactam to the lactam of # - (2-amino-5-methoxy methyl-phenyl) -butyric acid, saponification of this Compound and subsequent acetylation of the amino group) with polyphosphoric acid to 5-acetamido-8-methoxymethyl -1-tetralone condensed. This becomes after saponification of the acetamido group with 1,5-dibromopentane in the 5-piperidino-8-methoxy methyl-1-tetralone transferred.

From this one obtains after ether cleavage, chlorination, reaction with KCN and saponification with KOH the desired acid.

The corresponding 8-oxo-5,6,7,8-tetrahydro-naphthyl-1-acetic acids are obtained analogously from by reducing and splitting off water: 4-pyrrolidino-5, 6-dihydro-naphthyl-l-acetic acid, 4-morpholino-5,6-dihydro-naphthyl-1-acetic acid, 4-di-n-isobutylamino-5,6-dihydro-naphthyl-1-acetic acid, 4-Di-n-isopropylamino-5, 6-dihydro-naphthyl-1-e s 9 igsäure or

4-thiomorpholino-5,6-dihydro-naphthyl-1-acetic acid.

Example 39 9.6 g of 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetonitrile (obtainable analogously to Example 25) are dissolved in 50 ml of concentrated H2S04 and left to stand overnight at room temperature. The yellow-brown colored solution will Poured onto ice water and the pH of the solution adjusted to 8 with sodium hydroxide solution. The precipitated 3-chloro-4-piperidino-α-methyl-naphthyl-1-acetic acid amide is suctioned off and recrystallized from ethyl acetate.

P. 1530-1550.

Analogously from 3-bromo-4 piperidlno-a-methyl-naphthyl-l-acetonitrile is obtained, 3-methyl-4-piperidino-os methyl-naphthyl-1-acetonitrile 3-amino-4-piperidino-α-methyl-naphthyl-1-acetonitrile and 3-trifluoromethyl-4-piperidino-α-methyl-naphthyl-1-acetonitrile by Treatment with concentrated, H2S04: 3-bromo-4-piperidino-α-methyl-naphthyl-1-acetic acid amide, 3-methyl-4-piperidino-a-methyl-naphthyl-1-acetic acid amide, 3-amino-4-piperidino-a-methyl-naphthyl-1-acetic acid amide respectively.

3-Trifluoromethyl-4-piperidino-a-methyl-naphthyl-1-acetic acid amide.

Example 40 A solution of 6 g of 4-piperidino-1-naphthoyl-diazomethane (obtainable by converting 4-piperidinol naphthoic acid with thionyl chloride in benzene into the acid chloride and reaction with diazomethane in ether) in 100 ml Dioxane is stirred into a mixture of 0.66 g of freshly precipitated silver oxide, 1.67 g sodium carbonate and 1.56 g sodium thiosulphate in 200 ml water of 50- - 550 added dropwise. The mixture is stirred for 1 hour - at this temperature and 15 minutes at 90 - 1000. Then it is cooled, filtered, adjusted to pH 4 with dilute hydrochloric acid, extracted with ethyl acetate and obtained from the extract 4-piperidino-naphthyl-l-acetic acid from F. 1420-1430.

Example 41 280 mg of crude α- (4-piperidino-naphthyl-1) α-methyl acetic acid ethyl ester (obtainable by condensation of ethyl acetate with 4-piperidino-1-naphthyl-acetonitrile to α-acetyl-4-piperidino-1-naphthyl-acetonitrile, methylation with methyl iodide, Reaction with ethanolic hydrochloric acid to imido ether hydrochloride and hydrolysis with aqueous sulfuric acid) and 4 ml of 0.5 N ethanolic potassium hydroxide are 2 1/2 Refluxed for hours and evaporated to dryness. The residue is in 8 ml Dissolved water and acidified to pH 4 with 1N hydrochloric acid. The precipitated oil is extracted with ethyl acetate. From the extract one obtains 4-piperidino-amethyl-naphthyl-l-acetic acid from B. 1810-1830.

Example 42 1.85 g of magnesium turnings and 1.85 g of magnesium powder are heated with stirring in 100 ml of absolute ether under reflux, passes a moderate, dry A stream of carbon dioxide is added, a grain of iodine is added and 6 g of 4-piperidino-1-naphthylmethyl chloride are added dropwise (obtainable by hydrogenation of 4-piperidino-1-naphthaldehyde over Raney nickel at 500 and 6 at in ethanol to alcohol and reaction with hydrogen chloride in benzene in present. of calcium chloride) in 25 ml of absolute ether. You cook 20 more Minutes, cool, filter, evaporate, add water, make up with hydrochloric acid pH 4, extracted with ethyl acetate and obtained 4-piperidino-naphthyl-lessetic acid from F. 1420 - 1430.

Example 43 23.2 g of potassium iodoacetate are brought along with stirring 0.85 g of magnesium turnings with the addition of traces of iodine by boiling in for six hours 350 ml of absolute tetrahydrofuran for reaction, uses 8 g of 1-bromo-4-piperidinonaphthalene (available from l-bromo-4-amino-naphthalene and 1,5-dibromopentane) and cook more 24 hours.

It is then evaporated to dryness and made up with 1N hydrochloric acid pH 4, extracted with ethyl acetate and obtained 4-piperidino-naphthyl-1-acetic acid from pp. 1420-1430.

Example 44 8 g of 1-grom-4-piperidino-naphthalene are added at 0.84 g of magnesium turnings in 150 ml of absolute tetrahydrofuran additive a trace of iodine to react with heating, 23.3 g of iodoacetic acid are added in portions Potassium and cook for 20 hours while stirring. Then you steam to dryness and works on as above. 4-Piperidino-naphthyl-1-acetic acid is obtained from 142-143 ° F.

Example 45 Analogously to Example 9, one obtains from the underlying Acids by esterification with the corresponding alcohols: 4-piperidino-naphthyl-1-acetic acid ethyl ester, Bp. 173-175 ° / 0.1 mm 4-piperidino-α-methyl-naphthyl-1-acetic acid (8-methyl-1-nonyl) ester, Bp 220-224 / 0.01 mm 3-chloro-4-piperidino-naphthyl-1-acetic acid methyl ester, mp 88 °.

Example 46 Analogously to Example 14, 4-piperidino-naphthyl-1 is obtained acetic acid via the corresponding acid chloride: 4-piperidino-naphthyl-l-acetamide, F, 167-168 °.

Example 47 Analogously to Example 13, 4-piperidino-naphthyl-1-acetic acid is obtained and 2-diethylaminoethyl chloride: 4-piperidino-naphthyl-1-acetic acid-2'diäthylaminoäthylester, Kp. 205 - 2100 / 0.1 mm.

Example 48 Analogously to Example 1, 2, α-dimethyl-4-aminonaphthyl-1-acetic acid is obtained 4-Amino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid or

3-chloro-4-amino-5,6,7,8-tetrahydro-naphthyl-1-acetic acid by reaction with 1,5-dibromopentane 2, α-dimethyl-4-piperidino-naphthyl-1-acetic acid, mp 163-164 ° 4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid, mp 163-165 ° respectively.

3-chloro-4-piperidino-5,6,7,8-tetrahydro-naphthyl-1-acetic acid, F. 180-182 °

Claims (1)

Claims 1. Substituted aminophenylacetic acids of the formula I where R1 and R2 are identical or different and H or alkyl with 1 - 4 carbon atoms, R3 H, halogen, CF3, OH, NO2, CN, R7, R4 is a tetramethylene optionally containing 1 - 2 double bonds, R5 and R6 are identical or different and linear or branched alkyl with 1 - 7 carbon atoms together is a linear or branched alkylene chain with 2 - 14 0- optionally interrupted by an oxygen or sulfur atom. Atoms, R7 alkyl with 1 - 4 C atoms, A COOA1, CONA2A3, CONA4, C (= NOH) OH OR C (OR7) 3, A1 H, optionally 1 to 2 CC multiple bonds and / or one OH and / or alkyl or cycloalkyl containing an NH2 group and / or interrupted by O one to three times and / or by Y and / or branched, each with up to 12 t each with up to 12 carbon atoms, A5-NA4, phenyl or aralkyl a total of 6-14 carbon atoms, A2 and A3 are identical or different and A1, A4 are alkylene optionally interrupted by 0 or Y and have up to 6 carbon atoms, A5 alkylene with 1-6 carbon atoms and YS, NH, optionally N-alkyl with 1 - 6 carbon atoms substituted by OH, N-phenyl or N-phenylalkyl with 7 - 10 carbon atoms mean en, and their salts with acids or, if appropriate, bases, their quaternary ammonium salts and, if appropriate, their anhydrides. 2. 4-pyrrolidino-naphthyl-1-acetic acid. 3. 4-piperidino-naphthyl-1-acetic acid. 4. 4-piperidino-α-methyl-naphthyl-1-acetic acid. 5. 4-piperidino-α-ethyl-naphthyl-1-acetic acid. 6. 4-piperidino-5,6,7,8-tetrahydro-naphthyl-1-acetic acid. 7. 4-piperidino-α-methyl-5,6,7,8-tetrahydro-naphthyl-1-acetic acid. 8. 2-Methyl-4-piperidino-naphthyl-1-acetic acid. 9. 3-chloro-piperidino-napthyL-acetic acid 10. 2, α-dimethyl-4-piperidino-naphthyl-1-acetic acid. 11. 4-Piperidino-naphthyl-1-acetic acid methyl ester. 12. 4-Piperidino-naphthyl-1-acetic acid ethyl ester. 13. 4-Piperidino-naphthyl-1-acetic acid-2'-diethylaminoethyl ester. 14. 4-Piperidino-a-methyl-naphthyl-acetic acid methyl ester. 15. 4-Piperidino-a-methyl-naphthyl-1-acetic acid ethyl ester. 16. 4-Piperidino-a-methyl-naphthyl-1-acetic acid-2-diethylaminoethyl ester. 17. A pharmaceutical preparation containing an effective dose of a Compound of formula 1 in addition to customary carriers and additives. 18. Process for the preparation of substituted aminophenylacetic acids of the formula I. wherein the rest R R4 ö-Ö 3 and R1 to R6 and A have the meaning given in claim 1, characterized in that a) if carboxylic acids of the formula I are to be obtained in which A is COOH, functional acid derivatives of such carboxylic acids, such as, in particular, amides, thioamides, thioesters, esters, Hydrazides, acid halides, azides, anhydrides, imino esters, amidines, hydroxamic acids, nitriles, trihalomethanes, acid imino halides, saponified in a neutral, acidic or alkaline medium or, in particular, tertiary alkyl esters, such as tert. Butyl ester, thermolytically decomposed or b) compounds of the formula II wherein Z, R1 and R2 have the meaning given in the preamble of this claim and L is a group that can be oxidized to a carboxyl group, such as in particular -CHO, CH2OH, CH3, 1-alkenyl, 1-alkynyl, 1,2-dihydroxyalkyl or 1-oxo- alkyl, means, oxidizes or c) a diazoketone of the formula III wherein Z and R1 have the meaning given in the preamble of this claim, rearranged under the usual conditions of a Wolff rearrangement in the presence of water, A1OH, A2A3NH, A4NH or NH20H, where A1 to A4 have the meaning given in the preamble of this claim or d) an organometallic compound of the formula IV wherein M is metal, in particular alkali metal, Cd-R7, Zn-R7 or Mg-halogen and Z, R1, R2 and R7 have the meaning given in the generic term of this claim, reacts with carbon dioxide or e) a haloketone of the formula V R1 Z-CO-C halogen R2 V wherein Z, R1 and R2 have the meaning given in the preamble of this claim and halogen is chlorine, bromine or iodine, rearranged under the usual conditions of a Faworskij rearrangement or f) a compound of the formula VI or VII wherein Z, R1 and R2 have the meaning given in the preamble of this claim and M the iL 'section d) and B1 is OH, esterified OH, OM, C1, Br or J and RA is alkyl with 1-4 carbon atoms substituted by B1 , reacts with carbon monoxide or g) a malonic acid derivative of the formula VIII wherein Z, R1 and A have the meaning given in the preamble of this claim, decarboxylated or h) a β-keto acid derivative of the formula IX in which A, Z and R1 have the meaning given in the preamble of this claim and R8 is acyl or a hydrocarbon radical, is subject to acid cleavage or i) a compound of the formula I in which one or more groups which can be replaced or reduced by hydrogen and / or CC multiple bonds are present, such as in particular those compounds of the formula I in which ni to R7 and A have the meaning given in the preamble of this claim and one or more halogen atoms and / or one or more OH-, SH-, NH2- and / or OH, SH or NII2 groups substituted by hydrocarbon radicals and / or one or more C = O and / or C = S groups and / or one or more C = N and / or C = C double bonds and / or contain C # C triple bonds and / or in which R1 and R2 together signify 0 or S or an alkylidene group with 1-4 atoms or in which R1 signifies halogen, OH, SH, NH2 or OH, SH or NH2 substituted by hydrocarbon radicals and / od he in which the benzene nucleus is additionally in the 2- or 3-position and / or in which R4 is butadien-1,3-ylene - carry halogen atoms and / or diazonium salt groups in the 1-, 2-, 3- or 4-position and / or in which A is a benzyl ester or amide or benzyl equivalent ester or amide group which can be converted hydrogenolytically into the carboxyl group or the -GONHA1 group, in which A1 has the meaning given in the preamble of this claim, or a compound of Formula X Z1 - R9 X B # is an anion, R10 is alkylidene with 1-7 carbon atoms and R11 is alkyl with 1-7 carbon atoms, R @ to R @ and A are as defined in the preamble of this claim and R10 and R11 are one or more C =C Contain double or C # C triple bonds and can also be linked directly or via an oxygen or sulfur atom in a ring, treated with hydrogen-donating agents or catalytically activated hydrogen, or j) a compound of the formula XI with a compound of the formula XII or a Compound of the formula XIII with a compound of the formula XIV wherein Z, R2 and R7 have the meaning given in the preamble of this claim and M has the meaning given in section d) and X is a radical which can be split off with M as MX, in particular halogen, a sulfuric acid or sulfonic acid radical, or k) a compound of the formula XV with a compound of the formula XVI or a compound of the formula XVII with a compound of the formula XVIII where R1, R2, Z and A are as defined in the preamble of this claim and bl and X are as defined in sections d) and j) and Q is H or K, ge; also reacts in the presence of a Friedel-Crafts catalyst or 1) reacts a compound of the formula XIX with an amine of the formula XX or an amine of the formula XXI, XXII or XXIII with a compound of the formula XXIV or XXV under N-alkylation conditions, wherein the compounds XXIV and XXV in the reaction with a compound of the formula XXI according to the meaning given in the preamble of this claim for R5 and R6 together can also represent a single compound R5 Z1 - X1 XIX @ NH XX NH2 - Z1 XXI R6 R5-NH -Z1 XXII R5 - X1 XXIV R6NH-Z1 XXIII R6 - X1 XXV and where -R5 and R6 have the meaning given in the preamble of this claim, Z1 has the meaning given in section i), R3 in compound XIX preferably denotes an electron-withdrawing group, like NO2, or CF3 (where R1, R2 and the generic term of this claim have the meaning given) - and X1 is a radical that can be replaced by an amino group, such as in particular halogen, OH, acyloxy, a secondary or tertiary amino group, a sulfuric acid, alkylsulfuric acid or sulfonic acid radical, and both X1 radicals of the compounds XXIV and XXV in the reaction with the amine XXI can also together represent an oxygen or sulfur atom or m) an amino compound of the formula XXI with one or two different straight-chain or branched olefins with 2-7 carbon atoms or with one straight-chain or branched alkadiene with 4-14 carbon atoms, the chain of which can also be interrupted by an oxygen or sulfur atom, or amino compounds of the formula XXII or XXIII with the straight-chain or branched olefin with 2-7 carbon atoms, which also can be connected to the radicals R or R6 directly or via an IIeteroatom, such as 0, S, or n) a compound of the form el XXVI Z1H XXVI wherein Z1 has the meaning given in section i), with an amine of the formula XXVII n5 / N-Xalogen XXVI 1 ß6 vzorin R5 and R6 have the meaning given in the preamble of this claim and are halogen C1, Br or J, especially in the presence of Friedel-Cralts catalysts, or .o) into a compound of Foimel I which contains hydrogen instead of R3, introduces the substituent R3; namely, if R3 is chlorine, bromine or iodine by halogenation, in particular by reaction with halogen elements, preferably with the addition of catalysts, such as iron (III), aluminum, antimony (III) halides, tin (IV) -halides, with hypohalous acids, tert-butyl hypohalites, compounds of different halogens with one another. such as GlI, ClBr, BrI, SO2-halogenone, preferably with the addition of peracids, and N-halocarbon acid amides and imides or, if R3 is iodine, by iodination, in particular also by reaction of the 2- or @ -Hg acetate compound with iodine or, if R3 NO2 is at the bottom, by nitration, in particular by reaction with nitrogen oxides, nitronium salts, preferably with the addition of Friedel-Craf @@ catalysts, HNO3, optionally in a mixture with acetic acid, acetic anhydride, H3SO4, pyrosulfuric acid, smoky sulfuric acid, H2 @@ O4, HclO4, with acyl nitrates such as acetyl or benzoyl nitrate, with nitric acid esters such as ethyl nitrate, with nitrosulfonic acid, nitrosylsulfuric acid, nitroguanidine, with metal (such as Ca, Fe, Mn, Co, Ni -) - nitrates mixed with acetic anhydride or glacial acetic acid or, if R3 R7, SR7 SOR7, SO2R7 or means in which R1, R2 and R7 have the meaning given in the preamble of this claim, in particular by reaction with R7X2 or olefins having 1-4 carbon atoms or by reaction with R7SX2, R7SOX2, R7SO2X2 or in the presence of Lewis acids, in particular Friedel-Crafts catalysts, optionally under conditions which split off HX2, in which X2 is preferably Cl, Br, I, OII, acyloxy, alkyloxy, a sulfuric acid or sulfonic acid radical, or p) in a compound of the formula 1, in which R3 is NH2, the NH2 group is exchanged after conversion into a diazonium salt for halogen, NO2, CN, R7S, R7O or OH (where R7 has the meaning given in the preamble of this claim), or where R3 is CONH2, the CONH2 -Group is converted into the CN group by dehydrating agents, such as in particular P2O5, POCl3, PCl5 or SOCl5, or where R3 is NO2 or instead of R3 is JO or JO2, the NO2 group is converted to NH2 or the JO- or JO2 -Group reduced to iodine, or where R3 is NH-NH2 or NHNH2 substituted by hydrocarbon radicals, this hydrazine grouping is replaced by bromine or iodine, or where R3 is halogen, halogen versus (where R1, R2 have the meaning given in the preamble of this claim), or in which, instead of R3, one of the radicals OM1, SM1, or stands and M1 denotes H or metal, in particular alkali or alkaline earth metal, these substituents in place of R3 with olefins with 2-4 carbon atoms> diazoalkanes with 1-4 carbon atoms or with compounds R7X1, wherein R7 is the in the preamble of this' claim and X1 have the meaning given in section 1), optionally reacts under conditions which split off M1X1, or in which R3 denotes NH-R1, the NHR1 group by treatment with ketenes having 1-4 carbon atoms or with carboxylic acid derivatives suitable for acylation reactions, such as carboxylic acid esters , anhydrides,? halides, which are derived from carboxylic acids with 1 - 4 carbon atoms, for COR N 7 group R1 acylated (in which R1 and R7 have the meaning given in the preamble of this claim or this carbonamide group is liberated hydrolytically from one of its functional derivatives, or in which R3 is SR7 or is Nu instead of R3 and R7 has the meaning given in the preamble of this claim , oxidizes the SR7 group to the SOR7 or So2-R7 group or the nitroso to the nitro group, or in which instead of a sulfonic acid residue, in particular a sulfonic acid halide, a sulfonic acid ester or a sulfonic acid anhydride, this sulfonic acid derivative with an amine of the formula XXVIII have the meaning given in the preamble of this claim, or q) compounds of the formula I in which R5 and R6 are identical or different and are alkyl having 1-7 carbon atoms substituted by OM1 or 5M1, also one of the substituents OM1 or SM1 can be replaced by X1, and M1 and X1 have the meaning given in section p) or 1), converts to O-ring or S-ring-containing compounds under H2O, H2S or M1X1-releasing conditions or r) Compounds of Formula XXIX in which R1, R2 and Z have the meaning given in the preamble of this claim @, decarbonylated or s) .Compounds of the formula XXI treated with hydrogen-donating agents or catalytically activated hydrogen or with a compound of the formula XIV (R7M), in which R2 to R7 and A have the meaning given in the preamble of this expression and B # and M have the meaning given in sections i) and d) or t) a compound of the formula I in which, instead of A, there is COOM1, COOR12, COOAcyl, COHal, optionally with a compound of the formula XXXI or with an olefin derived from XXXI by formal H2O elimination or with an olefin obtained by formal dehydrogenation XXXI derived epoxy or with compounds of the formulas XXXII to XXXVI or with an ethyleneimine derived by formal dehydrogenation from XXXIII and XXXIV or with diazomethane, diazoethane, phenyldiazomethane or hydroxylamine A1OH XXXI A1OAcyl XXXII A2A3NH XXXIV 0-A4NH XXXII A2A3NH XXXIV 0-A4NH XXX -X XXXVI in which A1 to A4 have the settings specified in the preamble of this claim and M1 and X the solutions specified in sections p) and @ j) @au R12 a given all arbitrarily substituted konlen @ aosen @@ offrest b 'means, converts or u) compounds of the formula 1 in which instead of R13 and R14 are identical or different and are hydrogen or an optionally substituted hydrocarbon radical and A1 to A4 have the meaning given in the preamble of this claim, hydrolyzed to carboxylic acids, esters or amides of the formula I or v) to compounds of the formula I, in which instead vo A is CN, H2O attaches to form amides of the formula I or w) compounds of the formula XXXVII in the presence of the amines XXXIII or XXXIV, in particular with the addition of solysulfides, a Willgerodt reaction or compounds of the formula XXXVIII, in particular with the addition of acidic Catalysts, a Beckmann rearrangement or compounds of the formula XXXIX by reaction with HN3 are subjected to Schmidt degradation wherein Z, A1, R1 and R2 have the meaning given in the preamble of this claim, or x) an aldehyde of the formula XL with nitrohydroxylamic acid or benzenesulfonylhydroxylamine, especially in alkaline solution, or an aldoxime of an aldehyde of the formula XL in which Z, R1 and R2 have the meaning given in the preamble of this claim, in particular with H2O2 or peracids, oxidized to a hydroxamic acid of the formula I or y) compounds of the formula t in which, instead of A, the group C (= NR13 ) OR12, with alcohols of the formula XLI or compounds of the formula XLII with orthocarbonic acid esters of the formula aLIII * R7OH XLI C (OR7) 4 XLIII * in which A, R1, R2, R7 and Z are as defined in the preamble of this claim and M, R12 and R13 are as defined in sections d), t) and u), to form orthoesters of the formula I or z) compounds of the formula XLI II with compounds of the formula XLIV or compounds of the formula XLV with compounds of the formula XLVI or compounds of the formula XLVII with compounds of the formula XLVIII under conditions which split off M1X3 or split off from compounds of the formulas XLIX to LIII M1X3 Z2-D-A6-X3 XLIII M1-Y-A7 XLIV Z2-D-A6-YM1 XLV X3A7 XLVI Z2-D-A5-X3 XLVII HNA4 XLVI II D COO, CONA2 or CONA3, X3-OH, SH, OAcyl, SAcyl or X mean, A6-Y-A7 and Ä8Y mean the meanings of A1 and A9-Y-A10 the meanings of A4 and A1, A4, A5, Y and Z. as in the preamble of this claim and M1 and X have the meaning given in sections p) and j), or za) a compound of the formula I in which the grouping is partially or glossy hydrogenated by hydrogen addition and R3 and R4 have the meaning given in the preamble of this claim, treated with dehydrogenating agents, such as, in particular, dehydrogenation or metal oxide catalysts, chloranil, sulfur, selenium or alkyl disulfides, or, for example, into a compound of the formula I, in which instead of the radicals -H and -R15 and where R15 is an optionally containing a double bond and / or functionally modified 3-formyltrimethylene of the formula LIV or a tetramethylene derivative of the formula LV optionally containing 1 - 2 double bonds or n- @ utyl with 1 - 2 double bonds and / or optionally a triple bond (CH2) 3-CH2X2 LV in which X4 and X5 are identical or different and in particular OR13, SR13, NR13 R14 or together are also O or E and R14, R13, E and X2 are the same as in section u) bz'll. o) have the specified meaning, especially in the presence of acids and / or Lewis acids, such as Friedel-Crafts catalysts, or optionally with dehydrating agents such as P2O5, POCl3, PCl5 or SOCl2, or optionally under other HX4X5 or HX2-releasing conditions introduces the bivalent substituent R4 or zc) from compounds of the general formula I in which R4 is a tetramethylene monosubstituted by X6, optionally containing a double bond, and in which X6 is a radical which can be split off with H as HX6, in particular lialoge @. or OH, SH or NH2 substituted by alkyl, acyl, alkylsulphonyl or alkoxysulphonyl, the substituent X6 is eliminated as HX6 with formation of a double bond or 2- or 1,4- or 3,4- position doubly substituted, optionally containing a D @@@ elbonding is tetramethylene and in which X7 and X8 are identical or different and C1, Br, I or optionally preferably by alkyl, acyl, alkylsulfonyl or alkoxysulfonyl-substituted OH, each of the two substituents X7 and X8 with formation of a double bond, in particular with metals such as Zn, Zn-Cu, Na or Li, or with organometallic compounds such as Grignard or organolithium compounds, eliminated oer ze) die Compounds of the formula I prepared according to section a-zd, if appropriate into their physiologically compatible salts with acids or bases or quaternary ammonium converts ms @ lse and / or anhydrides, and optionally mixtures of racemates of the formula I in the individual ftacemates, separates nt and optionally present 1 "acemates of the formula I into their optical antipodes in a manner known per se and / or separates the compounds of the formula I sets their salts with acids or bases in freedom.